* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With diazomethyl-trimethyl-silane In hexanes; acetonitrile at 0 - 20℃; for 3.5 h;
A solution of trimethylsilyl diazomethane in hexanes (2.00 M, 52.9 mL, 106 mmol) was added dropwise to a suspension of l-fert-butoxycarbonyl-piperidine-4-carboxylic acid (12.14 g, 52.95 mmol) in acetonitrile (100 mL) and methanol (10 mL) at 0 °C. The mixture let stand for 30 minutes and then was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and product was purified from the residue by column chromatography [n-hex/EtOAc (4.5:1 v/v)] to give l-tert-butyl 4-methyl piperidine-1,4- dicarboxylate as an oil (11.5 g, 90percent). 1H NMR (400 MHz, d6-DMSO) δ 4.02 (dt, 2H, J= 3.5, 13.7 Hz), 3.69 (s, 3H), 2.82 (ddd, 2H5 J= 3, 11.5, 14.5 Hz), 2.45 (tt, 1H, J= 3.9, 11.5 Hz), 1.90-1.84 (m, 2H), 1.67-1.57 (m, 2H), 1.45 (s, 9H). MS(ES) m/z 265.8 (MNa+); MS cald: 243.1 (M).
Reference：
[1] Patent: US5576313, 1996, A,
[2] Patent: WO2007/8140, 2007, A1, . Location in patent: Page/Page column 107
[3] Patent: US2005/70609, 2005, A1, . Location in patent: Page/Page column 51; 57-58
[4] Patent: WO2007/3965, 2007, A1, . Location in patent: Page/Page column 27
[5] Patent: US5891889, 1999, A,
6
[ 84358-13-4 ]
[ 39674-99-2 ]
Reference：
[1] Patent: CN105399698, 2016, A,
7
[ 84358-13-4 ]
[ 91419-52-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 2007, vol. 50, # 9, p. 2225 - 2239
[2] European Journal of Medicinal Chemistry, 1984, vol. 19, # 2, p. 181 - 186
[3] Journal of the American Chemical Society, 2015, vol. 137, # 18, p. 5875 - 5878
8
[ 124443-68-1 ]
[ 84358-13-4 ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: With water; lithium hydroxide In tetrahydrofuran; methanol at 20℃; Stage #2: With hydrogenchloride In water
A mixture of 1 -tert-butyl 4-methyl piperidine-1 ,4-dicarboxylate (4.84 g 20 mmol), and LiOH(2.52 g,60 mmol) in THF(90 mL) /MeOH (90 mL) /H2O(30 mL) was stirred at r.t overnight. Then the solvents were removed, and the pH of the residue was adjusted to 2 by using 2N HCI. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4, and concentrated to give 1 -(tert-butoxycarbonyl)piperidine -4-carboxylic acid (4.6 g, yield 100.0percent).
100%
With lithium hydroxide In tetrahydrofuran; methanol; water at 20℃;
A mixture of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (4.84 g 20 mmol), and LiOH (2.52 g, 60 mmol) in THF (90 mL)/MeOH (90 mL)/H2O (30 mL) was stirred at r.t overnight. Then the solvents were removed, and the pH of the residue was adjusted to 2 by using 2N HCl. The resulting mixture was extracted with EtOAc (3*20 mL). The combined organic layers were dried over Na2SO4, and concentrated to give 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (4.6 g, yield 100.0percent).
96%
at 50℃; for 24 h;
(0031) (1) To compound 2 (24.33 g, 0.1 mol) was added dropwise 5M NaOH (60 mL, 0.3 mol), then stirred at 50° C. for 24 hours. 3M HCl was then added dropwise to the solution to adjust pH 3. The mixture was extracted with ethyl acetate (3*200 mL), dried over anhydrous sodium sulfate, filtered, evaporated to dryness to give a yellow oily liquid 4 (19.72 g, 96percent)
96%
at 50℃; for 24 h;
To a solution of compound 2 (24.33 g, 0.1 mol) was added dropwise 5 M NaoH (60 mL, 0.3 mol) and stirred at 50 ° C for 24 hours. Then 3 μ HC1 to ρ H 3 were added dropwise to the solution, Ethyl acetate (3 * 200 mL), dried over anhydrous sodium sulphate, filtered, and dried to give a yellow oily liquid 4 (19.72 g, 96percent)
91%
With lithium hydroxide monohydrate; water In tetrahydrofuran at 45℃; for 1 h; Inert atmosphere
A solution of 1-tert-butyl 4-methyl piperidine-1, 4-dicarboxylate (1.0 g, 4.1 mmol) and lithium hydroxide monohydrate (860 mg, 21 mmol) in a mixed solvent of THF (10 mL) and water (5 mL) was stirred at 45 for 1 h, and then adjusted with hydrochloric acid (1 M) to pH 1. The resulting mixture was extracted with EtOAc (20 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid as a white solid (860 mg, 91) .1H NMR (400 MHz, CD3OD) : δ ppm 3.97-4.02 (m, 2H) , 2.88-2.95 (m, 2H) , 2.48-2.55 (m, 1H) , 1.88-1.92 (m, 2H) , 1.54-1.61 (m, 2H) , 1.47 (s, 9H) and MS-ESI: m/z 174.20 [M-55] +.
91%
With lithium hydroxide monohydrate; water In tetrahydrofuran at 45℃; for 1 h;
Compound 4-methoxy carbonyl piperidine-1-carboxylic acid T-butyl ester (1.0g, 4 . 1mmol) and LiOH·H 2 O (860 mg, 21mmol) dissolved in tetrahydrofuran (10 ml) and water (5 ml) in the mixed solvent, 45 °C reaction 1h, plus 1.0mol/L adjusting pH=1 hydrochloric acid, extraction with ethyl acetate (10 ml × 3), the organic phase is dried with sodium sulfate, to remove the solvent, get 860 mg white solid, yield 91percent.
91%
With lithium hydroxide monohydrate In tetrahydrofuran; water at 45℃; for 1 h;
The compound N- tert-butoxycarbonyl-4-piperidine carboxylic acid methyl ester (1.0g, 4.1mmol) and lithiumhydroxide monohydrate (860mg, 21mmol) It was dissolved in tetrahydrofuran (10mL) and water (5mL) mixedsolvent, 45 ° C the reaction 1h, add hydrochloric acid (1M) adjusting the pH to 1, plus B Acetate (20mL × 3)was extracted, combined organic layers were dried over Na 2 SO 4, the solvent was removed to give a white solid860mg: 1- (tert Carbonyl) piperidine-4-carboxylic acid. Yield: 91percent.
84%
With water; lithium hydroxide In tetrahydrofuran; methanol at 20℃; for 15 h;
To a solution of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (1.19 g, 4.87 minol) in methanol (24 mL) and tetrahydrofuran (24 mL) were added a solution of LiOH (599 mg, 24.99 minol) in water (8 mL) at room temperature. The resultingminxture was stirred for 15 h at room temperature. When the reaction was done, the pH value of the reactionminxture was adJusted to 2 with hydrogen chloride solution (1 M). The resultingminxture was extracted with ethyl acetate (200 mL x 3), and the organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield 1-[(tert-butoxy)carbonyljpiperidine-4-carboxylic acid as white solid (1.10 g, 84percent). MS: m/z = 128.0 [M-Hj.
With lithium hydroxide monohydrate In tetrahydrofuran; water at 0 - 25℃; for 15 h;
2. Synthesis of intermediate C-1: B-1 C-1 To a solution of B-1 (138 g, 0.54 mol) in 1 L of THF and 1 L of H20 was added LiOH.H20 (67.51 g, 1.61 mol) at 0 °C. After the addition, the mixture was stirred at 25 °C for 15 hrs. The organic solvent was removed under reduced pressure. The mixture was extracted with EtOAc (500 mL x 3), and the aqueous layer was separated and treated with 0.5 M aq. HC1 to adjust to pH = 3 and extracted with CH2C12 (1L x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated to give intermediate C-1 (80 g, 65percent) as a white solid.
65%
With lithium hydroxide monohydrate; water In tetrahydrofuran at 25℃; for 15 h;
To a solution of B-1 (138 g, 0.54 mol) in 1 L of THF and 1 L of H2O was added LiOH.H2O (67.51 g, 1.61 mol) at 0° C. After the addition, the mixture was stirred at 25° C. for 15 hrs. The organic solvent was removed under reduced pressure. The mixture was extracted with EtOAc (500 mL×3), and the aqueous layer was separated and treated with 0.5 M aq. HCl to adjust to pH=3 and extracted with CH2Cl2 (1 L×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give intermediate C-1 (80 g, 65percent) as a white solid.
65%
With lithium hydroxide monohydrate; water In tetrahydrofuran at 0 - 25℃; for 15 h;
To a solution of B-1 (138 g, 0.54 mol) in 1 L of THF and 1 L of H2O was added LiOH.H2O (67.51 g, 1.61 mol) at 0° C. After the addition, the mixture was stirred at 25° C. for 15 hrs. The organic solvent was removed under reduced pressure. The mixture was extracted with EtOAc (500 mL×3), and the aqueous layer was separated and treated with 0.5 M aq. HCl to adjust to pH=3 and extracted with CH2Cl2 (1 L×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give intermediate C-1 (80 g, 65percent) as a white solid.
62%
With lithium hydroxide monohydrate; water In methanol at 20℃; for 1 h;
Preparation of 1-[fei -butoxycarbonyl}piperidine-4-carboxyic aeid A solution of l-(ferf-butyl) 4-ethyl pfperidine-1,4-dicarbQxylate (5.0 g, 0,02 mol) and LiOH.H20 (4.3 g, 0.1 mol) in MeOH/H20 (10 mL/10 ml) was stirred at room temperature for 1 hour. When TLC indicated that the reaction was complete, the solution was acidified (pH 6) with 2 N HCI and filtered. The residue was washed with water and dried in vacuo to give a white solid {2.9 g, 62percent), 1H NMR (400 MHz, COC): δ 4.07-4.02 (m, 2H), 2,93-2.82 (m, 2H), 2.54-2.50 (m, 1H), 1.95-1.92 (m, 2H), 1.69-1.64.(m, 2H), 1.48 (s, 9H).
Reference：
[1] Patent: WO2006/21449, 2006, A1, . Location in patent: Page/Page column 8; 9
[2] Helvetica Chimica Acta, 1997, vol. 80, # 5, p. 1528 - 1551
[3] Journal of Medicinal Chemistry, 2013, vol. 56, # 22, p. 9222 - 9241
[4] Chemistry--A European Journal, 2014, vol. 20, # 35, p. 11101 - 11110,10
[5] Patent: WO2013/164337, 2013, A1, . Location in patent: Page/Page column 27
[6] Patent: US2015/87651, 2015, A1, . Location in patent: Paragraph 0102-0103
[7] Patent: US2017/334880, 2017, A1, . Location in patent: Paragraph 0100-0101
[8] Patent: WO2015/74123, 2015, A1, . Location in patent: Page/Page column 58
[9] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 5, p. 757 - 761
[10] Chemistry of Heterocyclic Compounds, 2009, vol. 45, # 8, p. 957 - 964
[11] Journal of Medicinal Chemistry, 2010, vol. 53, # 7, p. 2825 - 2835
[12] Patent: WO2013/160810, 2013, A2, . Location in patent: Paragraph 0319
10
[ 498-94-2 ]
[ 24424-99-5 ]
[ 84358-13-4 ]
Yield
Reaction Conditions
Operation in experiment
100%
With sodium hydroxide In tetrahydrofuran at 20℃; for 1 h; Cooling with ice
According to the above synthetic line of PT106,Compound 9 (1 g, 7.74 mmol) was dissolved in NaOH solution (2 M, 10 mL)A solution of BOC anhydride (2.53 g, 11.61 mmol) in THF (10 mL) was slowly added under ice-cooling,The reaction was stirred at room temperature for 1 hour,The THF was removed on a rotary evaporator and the aqueous phase was adjusted to pH 5-6 with dilute hydrochloric acid,Then extracted with ethyl acetate. The combined organic phases were dried over anhydrous Na2SO4 and filtered,The filtrate was concentrated on a rotary evaporator and dried in vacuoWhite solid compound 10 (1.78 g, 7.76 mmol, yield 100percent).
99%
With hydrogenchloride; sodium hydroxide In <i>tert</i>-butyl alcohol
EXAMPLE 58 Scheme G, step a: 1,4-Piperidinedicarboxylic acid, 1-(1,1-dimethylethyl)ester (14) A 3-L three-neck flask containing 1.0 L (1 mol) of 1N NaOH was cooled to 0° C. 4-Piperidinecarboxylic acid (13) (108 g, 0.84 mol) and 500 mL of t-butanol were then added to the aqueous solution which was maintained at 0° C. A solution of 200 g (0.92 mol) of di-t-butyldicarbonate in 500 mL of t-butanol was placed in a pressure equalizing addition funnel and added to the reaction mixture over a 45 minute period while maintaining the temperature below 5° C. After completion of the addition, the reaction was allowed to warm to room temperature and then stirred an additional 22 hours. The cloudy reaction mixture was reduced to one half of its original volume using a rotary evaporator at 40° C. The resulting solution was cooled to 5° C. in a 3 L flask, then 500 mL (1.5 mol) of 3N HCl was added to the cooled solution over a 30 minute period. The resulting thick slurry was extracted with tetrahydrofuran (3*500 mL) and the combined extracts were dried over sodium sulfate. The drying agent was removed by filtration and the solvent was then evaporated (20 mm Hg, 40° C.) to give the title compound (14) as a white solid (189.5 g, 99percent yield).
99%
With hydrogenchloride In sodium hydroxide; <i>tert</i>-butyl alcohol
EXAMPLE 57 Scheme G, step a: 1,4-Piperidinedicarboxylic acid, 1-(1,1-dimethylethyl)ester (14) To a solution of 4-piperidinecarboxylic acid (13) (16.2 g, 0.125 mol) in aqueous sodium hydroxide (IM, 150 mL), and t-butanol (100 mL) at 0° C. was added a solution of di-t-butyldicarbonate (30.0 g, 0.137 mol) in t-butanol (50 mL). The resulting mixture was stirred overnight at ambient temperature. The reaction was quenched by addition of hydrochloric acid (3M, 75 mL) at 0° C. and extracted with ether (3*200 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuum to afford the title compound (14) as a fluffy white solid (28.4 g, 99percent); mp 149-150° C.
99%
With hydrogenchloride; sodium hydroxide In <i>tert</i>-butyl alcohol
EXAMPLE 58 Scheme G, step a: 1,4-Piperidinedicarboxylic acid, 1-(1,1-dimethylethyl)ester (14) A 3-L three-neck flask containing 1.0 L (1 mol) of 1N NaOH was cooled to 0° C. 4-Piperidinecarboxylic acid (13) (108 g, 0.84 mol) and 500 mL of t-butanol were then added to the aqueous solution which was maintained at 0° C. A solution of 200 g (0.92 mol) of di-t-butyldicarbonate in 500 mL of t-butanol was placed in a pressure equalizing addition funnel and added to the reaction mixture over a 45 minute period while maintaining the temperature below 5° C. After completion of the addition, the reaction was allowed to warm to room temperature and then stirred an additional 22 hours. The cloudy reaction mixture was reduced to one half of its original volume using a rotary evaporator at 40° C. The resulting solution was cooled to 5° C. in a 3 L flask, then 500 mL (1.5 mol) of 3N HCl was added to the cooled solution over a 30 minute period. The resulting thick slurry was extracted with tetrahydrofuran (3*500 mL) and the combined extracts were dried over sodium sulfate. The drying agent was removed by filtration and the solvent was then evaporated (20 mm Hg, 40° C.) to give the title compound (14) as a white solid (189.5 g, 99percent yield).
99%
With hydrogenchloride In sodium hydroxide; <i>tert</i>-butyl alcohol
EXAMPLE 57 Scheme G, step a: 1,4-Piperidinedicarboxylic acid, 1-(1,1-dimethylethyl)ester (14) To a solution of 4-piperidinecarboxylic acid (13) (16.2 g, 0.125 mol) in aqueous sodium hydroxide (1M, 150 mL), and t-butanol (100 mL) at 0° C. was added a solution of di-t-butyldicarbonate (30.0 g, 0.137 mol) in t-butanol (50 mL). The resulting mixture was stirred overnight at ambient temperature. The reaction was quenched by addition of hydrochloric acid (3M, 75 mL) at 0° C. and extracted with ether (3*200 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford the title compound (14) as a fluffy white solid (28.4 g, 99percent); mp 149-150° C.
97%
Stage #1: for 0.25 h; Stage #2: With sodium hydroxide; water In 1,4-dioxane at 20℃; Stage #3: With hydrogenchloride In water
Example 11 : (2RS)-I- [2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl] -piperidine- 4-carboxylic acid (2,3-dihydro-benzo[l,4]dioxin-6-yl)-amide:11 i. Piperidine-1 ,4-dicarboxylic acid mono-tert-butyl ester.To a solution of isonipecotic acid (12.9 g, lOO mmol) in dioxane (10O mL) and water (100 mL) was slowly added a solution Of BoC2O (24 g, 1.1 eq.) in dioxane (100 mL). After15 min, \\M NaOH (10O mL) was added and the mixture stirred at rt overnight. The mixture was concentrated in vacuo and the residue partitioned between ether and \\M HCl(120 mL). The aq. phase was extracted with ether (2 x 200 mL) and the combined org. extracts were washed with brine, dried over MgSO4 and concentrated. The expected compound was isolated as a colourless solid (22.4 g, 97percent yield) and used as such in the next step.1H NMR (DMSO d6) δ: 12.5 (s, IH); 3.83 (m, 2H); 2.82 (m, 2H); 2.40 (m, IH); 1.78 (m,2H); 1.39 (s, 9H); 1.34 (m, 2H).
97%
Stage #1: for 0.25 h; Stage #2: With sodium hydroxide In 1,4-dioxane; water at 20℃;
To a solution of isonipecotic acid (12.9 g, 100 mmol) in dioxane (100 mL) and water (100 mL) was slowly added a solution of Boc2O (24 g, 1.1 eq.) in dioxane (100 mL). After 15 min, 1M NaOH (100 mL) was added and the mixture stirred at rt overnight. The mixture was concentrated in vacuo and the residue partitioned between ether and 1M HCl (120 mL). The aq. phase was extracted with ether (2*200 mL) and the combined org. extracts were washed with brine, dried over MgSO4 and concentrated. The expected compound was isolated as a colourless solid (22.4 g, 97percent yield) and used as such in the next step. 1H NMR (DMSO d6) δ: 12.5 (s, 1H); 3.83 (m, 2H); 2.82 (m, 2H); 2.40 (m, 1H); 1.78 (m, 2H); 1.39 (s, 9H); 1.34 (m, 2H).
97%
Stage #1: With sodium hydroxide In water; <i>tert</i>-butyl alcohol at 0 - 20℃; for 22.75 h; Stage #2: With hydrogenchloride In water; <i>tert</i>-butyl alcohol at 0 - 5℃; for 0.5 h;
To a solution of 4-piperidinecarboxylic acid (13) (16.2 g, 0.125 mol) in aqueous sodium hydroxide (1M, 150 mL), and t-butanol (100 mL) at 0°C was added a solution of di-t-butyldicarbonate (30.0 g, 0.137 mol) in t-butanol (50 mL). The resulting mixture was stirred overnight at ambient temperature. The reaction was quenched by addition of hydrochloric acid (3M, 75 mL) at 0°C and extracted with ether (3 x 200 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuum to afford the title compound (14) as a fluffy white solid (28.4 g, 99percent); mp 149-150°C.; Example 58 Scheme G, step a: 1,4-Piperidinedicarboxylic acid, 1-(1,1-dimethylethyl)ester (14) A 3-L three-neck flask containing 1.0 L (1 mol) of 1N NaOH was cooled to 0°C. 4-Piperidinecarboxylic acid (13) (108g, 0.84 mol) and 500 mL of t-butanol were then added to the aqueous solution which was maintained at 0°C. A solution of 200 g (0.92 mol) of di-t-butyldicarbonate in 500 mL of t-butanol was placed in a pressure equalizing addition funnel and added to the reaction mixture over a 45 minute period while maintaining the temperature below 5°C. After completion of the addition, the reaction was allowed to warm to room temperature and then stirred an additional 22 hours. The cloudy reaction mixture was reduced to one half of its original volume using a rotary evaporator at 40°C. The resulting solution was cooled to 5°C in a 3 L flask, then 500 mL (1.5 mol) of 3N HCl was added to the cooled solution over a 30 minute period. The resulting thick slurry was extracted with tetrahydrofuran (3 x 500 mL) and the combined extracts were dried over sodium sulfate. The drying agent was removed by filtration and the solvent was then evaporated (20 mm Hg, 40°C) to give the title compound (14) as a white solid (189.5 g, 99percent yield).; Example 59 Scheme G, step a: 1,4-Piperidinedicarboxylic acid, 1-(1,1-dimethylethyl)ester (14) Solid di-t-butyldicarbonate (300 g, 1.37 mol) was added to a solution of 4-piperidinecarboxylic acid (13) (162 g, 1.25 mol) in aqueous NaOH (1N, 1.5 L) and t-BuOH (1.5 L) at 4°C over 30 minutes. The reaction mixture was stirred at room temperature for 18 hours. The resulting solution was concentrated (40°C/20 torr) to half of its volume. Aqueous HCl (3N, 750 mL) was added to the concentrated solution at 4°C over 30 minutes. The resulting slurry was extracted with ethyl ether (3 x 2 L). The combined ethereal solutions were dried (MgSO4). The mixture was filtered and the filtrate was concentrated (30°C/20 torr) to give the title compound (14) after air drying (277 g, 97percent); m.p. 145-147°C. 1H NMR (CDCl3) δ 4.01 (d, 2H, J = 12.0 Hz, CHN's), 2.83 (dd, 2H, J = 12.0 Hz, CHN's), 2.5 (m, 1H, CH), 1.9 (m, 2H), 1.6 (m, 2H), 1.46 (s, 9H); 13C NMR (CDCl3) δ 180.2, 154.7, 79.8, 43.0, 40.8, 28.4, 27.7; MS (CI,CH4)m/z (rel. Intensity) 230 (MH+, 32percent), 174 (100), 156 (71), 130 (25); IR (KBr) 3451, 3208, 3002, 2974, 2932, 1734, 1661, 1452, 1431, 1393, 1369, 1283, 1170, 1159, 1035, 924, 862 cm-1; Anal. Calc'd for C11H19NO4 (229.3): C, 57.62; H, 8.35; N, 6.11. Found: C, 57.68; H, 8.62; N, 6.00.; Example 60 Scheme G, step a: 1,4-Piperidinedicarboxylic acid, 1-(1,1-dimethylethyl)ester (14) To a solution of 4-piperidinecarboxylic acid (13) (700 g, 5.42 mol) in aqueous NaOH (1N, 6.5 L) and t-butanol (6.5 L) at 0°C was added di-t-butyldicarbonate (1295.8 g, 5.94 mol) slowly over 30 minutes. The reaction mixture was stirred overnight at ambient temperature. The resulting solution was concentrated (48°C/20 torr) to half of its volume and quenched by the addition of HCl (10percent, 2.6 L). The white solid which precipitated was filtered off, washed with water (1L) and air-dried to give the title compound (14) (1178 g, 100percent yield); m.p. 144-146°C. 1H NMR (CDCl3) δ 4.1 (d, 2H, J=12.0 Hz), 2.91 (t, 2H, J=12.0 Hz), 2.5 (m, 1H), 2.0 (m, 2H), 1.7 (m, 2H), 1.52 (s, 9H).
96%
With sodium hydroxide In tetrahydrofuran; water at 20℃; for 19 h;
(c) l-(toer/-Butoxycarbonyl)piperidine-4-carboxylic acidDi-tert-butyl dicarbonate (7.2 g, 33 mmol) was added in portions to a solution of isonipecotic acid (3.9 g, 30 mmol) in THF/water/NaOH (60/30/30 1 M) at rt, the mixture was stirred for 19 h. The organic solvent was concentrated in vacuo and the alkaline water phase was washed with dimethylether (2 x 15 mL). The solution was then acidified with 1 M KHSO4 (70 mL) and the water phase was extracted with dimethylether (1 xlOO + 1 x 50 mL). The combined organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid as a white powder. Yield: 6.60 g (96percent).1H-NMR (400 MHz, CDCl3) δ 1.46 (9H, s), 1.60-1.71 (2H, m), 1.87-1.96 (2H, m), 2.44- 2.54 (IH, m), 2.81-2.92 (2H, m), 3.95-4.09 (2H, m).
95%
With potassium carbonate In dichloromethane at 20℃; for 18 h;
[0210] Isonipecotic acid (5.51 g, 0.022 mol) was dissolved in dichloromethane (110 ml). Di-t-butyl dicarbonate ((Boc)2O) (7.31 g, 0.033 mol) and potassium carbonate (K2CO3) (9.62 g, 0.67 mol) were added to the resulting solution and the solution was stirred at room temperature for 18 hrs. After completion of the reaction by addition of water, the solution was extracted with ethylacetate, washed with distilled water, and dried over magnesium sulfate (MgSO4) to concentrate. The resulting residue was isolated and purified by silica gel column chromatography (dichloromethane/methanol, 10/1) to give the white title compound (7.36 g, 95.0 percent). 1H NMR (400 MHz, CD3OD) δ 3.97 (m, 2H), 2.88 (br, 2H), 2.48 (m, 1H), 1.88 (m, 2H), 1.54 (m, 2H), 1.44 (s, 9H)
94%
Stage #1: With sodium hydroxide In tetrahydrofuran at 20℃; for 2.5 h; Stage #2: With hydrogenchloride In tetrahydrofuran; water
1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid. Isonipecotic acid (1.05 g, 8.1 mmol) was suspended in a mixture of tetrahydrofuran (20 mL) and 1N sodium hydroxide (20 mL). Di-tert-butyl dicarbonate was added to the mixture. Reaction stirred at room temperature for 2.5 hours. Mixture was made acidic with 1N hydrochloric acid. Mixture was extracted 2.x. ethyl acetate. Combined organics were washed with brine and then dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained as white solid in 94percent yield. MS m/e (M-H)-=228.0.
94%
With sodium hydroxide In tetrahydrofuran; water at 20℃; for 2.5 h;
1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid; Isonipecotic acid (1.05 g, 8.1 mmol) was suspended in a mixture of tetrahydrofuran (20 mL) and 1N sodium hydroxide (20 mL). Di-tert-butyl dicarbonate was added to the mixture. Reaction stirred at room temperature for 2.5 hours. Mixture was made acidic with 1N hydrochloric acid. Mixture was extracted 2.x. ethyl acetate. Combined organics were washed with brine and then dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained as white solid in 94percent yield. MS m/e (M-H)-=228.0.
94%
With sodium hydroxide In 1,4-dioxane; water at 20℃;
Reagents and conditions: (a) B0C2O, 1,4-dioxane, H2O, NaOH, overnight, rt, (yield 94percent); (b) HOBt, EDCl, TEA,DMF, NHMeOMe-HCl, overnight, rt, (yield 42percent); (c) BuLi, 2-bromobiphenyl, TMEDA, THF, 3h, -78°C, (yield 35percent) ; (d) TFA, DCM , lh, rt, (yield quant); (e) toluene, 2h, (yield 24percent), (f) NaBH4, THF, MeOH, overnight, rt, (yield 25percent). Compounds 8-9 were synthesized from isonipecotic acid. The amine function was first protected with tert-butyl carbamate group followed by the formation of the Weinreb amide using HOBt and EDCl. Then, the lithium anion of 2-bromobiphenyl reacted on the Weinreb amide and Boc deprotection to give compounds 8. Addition reaction on iso(thio)cyanate with the piperidine in toluene afforded (thio)urea 9a-9b, followed by a reduction of the ketone group give the alcohol derivatives lOa-lOb.
94%
With triethylamine In 1,4-dioxane at 4 - 20℃; for 21 h;
A solution of 24 (50 g, 387 mmol) and triethylamine (110 mL) in dioxane (400 mL) at 4°C was treated with BoC2O (93 g, 426 mmol). The cooling bath was removed and the solution allowed to warm to room temperature. After 2 Ih, the volume was reduced by two-thirds under vacuum. The residue was poured into ethyl acetate (250 mL) and water (250 mL). Saturated aqueous NaHCO3 (250 mL) was added and the organic phase was separated and discarded. <n="40"/>The aqueous phase was acidified with 10percent HCl and extracted with ethyl acetate. The combined organic phases were washed with water, brine, and dried (Na2SO4), and concentrated to provide 25 as a white powder (82 g, 94percent).
93%
With sodium carbonate In 1,4-dioxane; water at 20℃;
Piperidine-4-carboxylic acid (5G, 38.7 mmol, leq. ) was dissolved in SODIUM CARBONATE SOLUTION (4. 5G, 42.61MMOL, 2.2 EQ. ), 70ML, AND 1,4-DIOXANE (30ML). A solution of di-tert-butyldicarbonate (9. 3G, 42. 61mmol, L. LEQ.) in 1,4-dioxane (40ml) was added dropwise and the resulting mixture was stirred overnight at room temperature. The organic solvent was removed under reduced pressure and the resulting solution was acidified with HCI 37percent till pH 2. The obtained suspension was filtered, the white solid washed with diethyl ether (5ml). The mother liquor has been extracted with ethyl acetate (120ML) and the previous solid was added. The organic solution was dried over anhydrous sodium sulfate, evaporated under reduced pressure to give a white solid that was dried at 80°C under vacuum to give the title compound. Yield 93percent, 8.2g. Analytical data: m. p. 133°-135°C. H NMR (DMSO-D6) 12.3 (1H br s); 3.85 (2H, d); 2.8 (2H, br); 2.35 (1H, t); 1.8 (2H, d) ; 1.4 (1 1H, M).
91%
With hydrogenchloride; sodium hydroxide; nitrogen In ethanol; water
EXAMPLE 56 Scheme G, step a: 1,4-Piperidinedicarboxylic acid, 1-(1,1-dimethylethyl)ester (14) Into a 500-mL jacketed-bottom-drain resin pot fitted with a four-joint head equipped with a mechanical stirrer, reflux condenser topped with a nitrogen bubbler, a thermowell with a thermocouple, and a septum with a needle connected to a nitrogen source was placed 4-piperidinecarboxylic acid (13) (15.0 g, 0.12 mol), aqueous 50percent solution of sodium hydroxide (10.4 g, 0.13 mol), water (90 g), and ethanol 2B (79.5 g). The reaction mixture was warmed to 50° C. and di-tert-butyl dicarbonate (26.7 g, 0.122 mol) was added via syringe in one portion (6° C. exotherm) and the reaction stirred for 1.25 hours. The reaction was cooled to 5° C. and aqueous hydrochloric acid (15.0 g of 37percent) was added, causing the product to precipitate. To the thick slurry was added water (130 g) and the product was collected by suction filtration and dried under vacuum (28 Hg, 58° C.) for 72 hours to give the title compound (14) as a white crystalline material (23.9 g, 91percent); m.p. 150-151° C. 1H-NMR (CDCl3) 64.10 (m, 2H), 2.84 (t, 2H, J=11.7 Hz), 2.47 (m, 1H), 1.90 (m, 2H), 1.62 (m, 2H), 1.45 (s, 9H, (CH3)Si)); 13C NMR (CDCl3) δ 180.0, 154.8, 79.8, 43.1; 40.9; 28.5; 27.5.
91%
With sodium hydrogencarbonate; citric acid In 1,4-dioxane; water
a N-tert-butoxycarbonylisonipecotic acid Di-tert-butyl dicarbonate (6.55 g, 30 mmol) was added to the mixture of isonipecotic acid (3.90 g, 30 mmol) and NaHCO3 (5.05 g, 60 mmol) in 1:1 1,4-dioxane/water (100 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was evaporated in vacuo, acidified to pH 6 using 10percent citric acid and extracted with ethyl acetate (3*100 mL). The organic phase was washed with brine (2*50 mL) and dried over Na2 SO4. The solvent was evaporated to give the title compound as a white solid (6.25 g, 91percent). 1 H-NMR (300 MHz, CDCl3) δ 1.43 (s, 9H), 1.63 (m, 2H), 1.88 (dd, 2H, J=1.5, 6.6 Hz), 2.45 (m, 1H), 2.83 (t, 2H, J=11.4 Hz), and 4.00 (d, 2H, J=6.7 Hz).
91%
With sodium hydrogencarbonate; citric acid In 1,4-dioxane; water
e N-(tert-butoxycarbonyl)isonipecotic acid Isonipecotic acid (3.90 g, 30 mmol), NaHCO3 (5.05 g, 60 mmol) were dissolved in 1:1 1,4-dioxane:water (100 mL). Di-tert-butyl dicarbonate (6.55 g, 30 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo. The residue was acidified to pH=6 using 10percent citric acid and extracted into ethyl acetate (3*100 mL). The organic phase was then washed with brine (2*50 mL), dried over Na2 SO4, and concentrated in vacuo to give the title compound as a white solid (6.25 g, 91percent). 1 H-NMR (300 MHz, CDCl3) δ 1.43 (s, 9H), 1.63 (m, 2H), 1.88 (dd, 2H), 2.45 (m, 1H), 2.83 (t, 2H), 4.00 (d, 2H).
91%
With hydrogenchloride; sodium hydroxide; nitrogen In ethanol; water
EXAMPLE 56 Scheme G, step a: 1,4-Piperidinedicarboxylic acid, 1-(1,1-dimethylethyl)ester (14) Into a 500-mL jacketed-bottom-drain resin pot fitted with a four-joint head equipped with a mechanical stirrer, reflux condenser topped with a nitrogen bubbler, a thermowell with a thermocouple, and a septum with a needle connected to a nitrogen source was placed 4-piperidinecarboxylic acid (13) (15.0 g, 0.12 mol), aqueous 50percent solution of sodium hydroxide (10.4 g, 0.13 mol), water (90 g), and ethanol 2B (79.5 g). The reaction mixture was warmed to 50° C. and di-tert-butyl dicarbonate (26.7 g, 0.122 mol) was added via syringe in one portion (6° C. exotherm) and the reaction stirred for 1.25 hours. The reaction was cooled to 5° C. and aqueous hydrochloric acid (15.0 g of 37percent) was added, causing the product to precipitate. To the thick slurry was added water (130 g) and the product was collected by suction filtration and dried under vacuum (28 Hg, 58° C.) for 72 hours to give the title compound (14) as a white crystalline material (23.9 g, 91percent); m.p. 150-151° C. 1H NMR (CDCl3) δ 4.10 (m, 2H), 2.84 (t, 2H, J=11.7 Hz), 2.47 (m, 1H), 1.90 (m, 2H), 1.62 (m, 2H), 1.45 (s, 9H, (CH3)Si)); 13C NMR (CDCl3) δ 180.0, 154.8, 79.8, 43.1; 40.9; 28.5; 27.5.
91%
Stage #1: With sodium hydroxide In ethanol; water at 5 - 56℃; for 1.25 - 22.25 h; Stage #2: With hydrogenchloride In ethanol; water at 5℃; for 2 h;
Into a 500-mL jacketed-bottom-drain resin pot fitted with a four-joint head equipped with a mechanical stirrer, reflux condenser topped with a nitrogen bubbler, a thermowell with a thermocouple, and a septum with a needle connected to a nitrogen source was placed 4-piperidinecarboxylic acid (13) (15.0 g, 0.12 mol), aqueous 50percent solution of sodium hydroxide (10.4 g, 0.13 mol), water (90 g), and ethanol 2B (79.5 g). The reaction mixture was warmed to 50°C and di-tert-butyl dicarbonate (26.7 g, 0.122 mol) was added via syringe in one portion (6 °C exotherm) and the reaction stirred for 1.25 hours. The reaction was cooled to 5°C and aqueous hydrochloric acid (15.0 g of 37percent) was added, causing the product to precipitate. To the thick slurry was added water (130 g) and the product was collected by suction filtration and dried under vacuum (28 Hg, 58°C) for 72 hours to give the title compound (14) as a white crystalline material (23.9 g, 91percent); m.p. 150-151°C. 1H NMR (CDCl3) δ 4.10 (m, 2H), 2.84 (t, 2H, J=11.7 Hz), 2.47 (m, 1H), 1.90 (m, 2H), 1.62 (m, 2H), 1.45 (s, 9H, (CH3)Si)); 13C NMR (CDCl3) δ 180.0, 154.8, 79.8, 43.1; 40.9; 28.5; 27.5.; Example 61 Scheme G, step a: 1,4-Piperidinedicarboxylic acid, 1-(1,1-dimethylethyl)ester (14) 4-Piperidinecarboxylic acid (10 kg, 77.4 mol) and 50 L of water were charged to a suitable vessel maintained under nitrogen. The stirred mixture was cooled to 5°C. 20percent Sodium hydroxide (17 kg, 85 mol) and 70 L of ethanol were charged while maintaining a reaction temperature of 5°C. A solution of di-t-butyl dicarbonate (17.8 kg, 81.6 mol) in 65 L of ethanol was charged to the stirred reaction mixture over a period of 15 minutes. Cooling was discontinued and the reaction mixture was stirred for a total of 22 hours. A total of 150 L of solvent was distilled from the reaction mixture below 50°C at 150 torr. The residue was diluted with 110 L of water and the stirred mixture was cooled to 5°C. The stirred mixture was diluted with 22 L of water and 33percent hydrochloric acid (10 kg). After stirring at 5°C for 2 hours, product was filtered off, washed with 2 x 5 L, then dried below 40°C at 150 torr to give 16.5 kg, 93percent yield.
91%
Stage #1: With sodium hydrogencarbonate In 1,4-dioxane; water at 20℃; for 3 h; Stage #2: With hydrogenchloride In 1,4-dioxane; water
A solution of isonipecotic acid (18) (2.6 g, 20 mmol) in 1,4-dioxane/H2O (3:2, 100 mL) was treated with NaHCO3 (8.4 g, 100 mmol, 20 mL H2O), followed by t-Boc2O (4.8 g, 22 mmol) at room temperature. After stirring for 3 h, the solution was acidified with 1 N HCl (50 mL), extracted with EtOAc (3.x.100 mL). The combined organic extracts were washed with saturated solution of NaHCO3 (50 mL), brine (50 mL), dried over MgSO4 and concentrated to give a white solid (19) (4.16 g, 91percent). 1H NMR (500 MHz, CDCl3) δ4.02 (br s, 2H), 2.86 (t, J=12.0 Hz, 2H), 2.50 (tt, J=11.0, 4.0 Hz, 1H), 1.91 (dd, J=13.0, 2.5 Hz, 2H), 1.65 (m, 2H), 1.46 (s, 9H), MS (ESI-) m/z 228.65 (M-H-).
90%
With sodium carbonate In 1,4-dioxane; water
Part A: To a solution of isonipecotic acid (5.8 g, 44.9 mmol) in water (200 mL) was added sodium carbonate (4.62 g, 44.9 mmol) followed by the drop-wise addition of di-tert-butyl-dicarbonate (10.1 g, 46.3 mmol) in dioxane (40 mL). After 4 hr, the solvent was concentrated in vacuo and the solution was extracted with ethyl ether. The aqueous layer was acidified with 3N hydrochloric acid to pH=2. The solution was extracted with ethyl ether and the organic layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. Concentration in vacuo provided N-Boc-isonipecotic acid as a white solid (9.34 g, 90percent).
90%
With sodium carbonate In 1,4-dioxane; water
Part A: To a solution of isonipecotic acid (5.8 g, 44.9 mmol) in water (200 mL) was added sodium carbonate (4.62 g, 44.9 mmol) followed by the drop-wise addition of di-tert-butyl-dicarbonate (10.1 g, 46.3 mmol) in dioxane (40 mL). After four hours the solvent was concentrated in vacuo and the solution was extracted with ethyl ether. The aqueous layer was acidified with 3N hydrochloric acid to pH=2. The solution was extracted with ethyl ether and the organic layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. Concentration in vacuo provided N-Boc-isonipecotic acid as a white solid (9.34 g, 90percent).
90%
With potassium carbonate In tetrahydrofuran; water at 0 - 20℃;
Isonipecotic acid (5.00 g, 38.7 mmol) and K2CO3 (10.7 g, 77.4 mmol) were dissolved in 75 mL of H2O. At 0 °C, a solution of di-tert-butyl dicarbonate (8.89 mL, 38.7 mmol) in 10 mL of THF was added and the mixture was stirred at room temperature overnight. Then, THF was removed and the aqueous layer was washed with Et2O, brought to pH = 2 with HCl 1 M (80 mL) and extracted with EtOAc. The solvent was removed under vacuum to afford 24 as a white solid (8.00 g, 90percent). Spectral data were in accordance with the literature [37].
89%
Stage #1: With sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; for 1 h; Stage #2: With potassium hydrogensulfate In water; ethyl acetate
Isonipecotic acid (3 g, 23.2 mmol) was dissolved in dioxane/NaOH (1M) (1/1) (70 mL). Boc-anhydride (5.57 g, 25.5 mmol) was added to the solution at 0°C, which was then allowed to warm up to room temperature and stirred for lh. The solution was concentrated in vacuo and ethyl acetate (10 mL) was added. The mixture was acidified to pH 2 using saturated aqueous KHS04. The organic layer was dried over Na2S04 and evaporated to give 4.7 g (89percent) of N-Boc isonipecotic acid G as a colorless solid. G was used in the coupling step with the amine E (100mg, 0.22 mmol) following the general method. The intermediate H was purified by column chromatography eluting with ethyl acetate/cyclohexane (1/1). H was treated with dichloromethane/trifluoroacetic acid (8/2) (2 mL) for 2h at room temperature. Saturated aqueous NaHCO3 was then added carefully until pH 9 was reached and the dichloromethane layer was separated, dried over Na2S04, filtered and the solvent removed in vacuo to give the free amine 99mg (81 percent over two steps).
86%
With potassium carbonate In tetrahydrofuran; water at 20℃; for 12 h;
Compound 10 (10 g, 77.5 mmol) and potassium carbonate (21.4 g, 155 mmol) were dissolved in water (150 mL) and asolution of Boc anhydride (16.9 g, 77.5 mmol) in THF (50 mL)wasslowly added dropwiseunder ice-cooling.After the reaction was added dropwise at room temperature 12h, the reaction afterrotary evaporation to remove THF, 1N hydrochloric acid to adjust pH to 1, large amount of solid precipitated was filtered, the resulting solid was washed with water again, washed and driedto give compound. 11 (30.4 g of, 86percent).
85%
With sodium hydroxide In 1,4-dioxane
1.2 Synthesis of N-Boc-isonipecotic acid (1) To a solution of isonipecotic acid (15 g, 117.2 mmol) in 40 mL dioxane and 40 mL 1M NaOH was added di-tert-butyl dicarbonate (28.14 g, 129 mmol). The mixture was allowed to stir at room temperature. After 12 hours the mixture was then partitioned between diethyl ether and water. The aqueous phase was acidified to pH 3.0 with 1N HCl and extracted with ethyl acetate (4*100 mL). The organic phases were washed with brine, dried (MgSO4) and concentrated to give a white solid (22.96 g, 85percent); m/z (M+H)+ 230.2 (C11 H19 NO4).
85%
Stage #1: With sodium hydroxide In 1,4-dioxane; water for 18 h; Stage #2: With hydrogenchloride In water
Piperidine-4-carboxylic acid (12.9 g, 100 mmol) was dissolved in a rapidly stirred mixture of dioxane (100 mL) and IM sodium hydroxide (300 mmol). Di-t-butyldicarbonate (22 g, 100 mmol) was added. After 18 hours the volatiles were evaporated. The aqueous residue was acidified with IM hydrochloric acid and extracted with methylene chloride. The organic phase was evaporated to give the intermediate piperidine-l,4-dicarboxylic acid mono-tert- butyl ester as a white solid (19.6 g, 85percent). 1HNMR (300MHz, DMSO-d6): D (ppm) 12.20 (s, IH), 3.85-3.80 (m, 2H), 2.85-2.77 (m, 2H), 2.44-2.35 (m, 2H), 1.80-1.75 (m, 2H), 1.44-1.31 (m, 1 IH). A portion of this intermediate (2.29 g, 10 mmol) was mixed with potasium carbonate (1.7 g, 12 mmol) and benzyl bromide (1.2 mL, 10 mmol) in acetonitrile (20 mL). Heated the reaction to 60 0C for 18 hours. The reaction was partitioned between ethyl acetate and water. The organic phase was washed with water and brine, then dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel with 0-25percent ethyl acetate in methylene chloride. Obtained the title compound (2.3 g, 72percent) as a colorless oil. 1H NMR (300MHz, DMSO-d6): D (ppm): 7.41-7.30 (m, 5H), 5.10 (s, 2H), 3.86-3.81 (m, 2H), 2.87-2.78 (m, 2H), 2.64-2.55 (m, IH), 1.85-1.80 (m, 2H), 1.49-1.38 (m, HH).
75%
With potassium carbonate In tetrahydrofuran; water at 0 - 20℃;
1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (1) - To a stirred solution of isonipecotic acid (77.4 mmol, 10.0 g) and potassium carbonate (154.8 mmol, 21.4 g) in water (150 mL) at 0°C, was added dropwise a solution of di-tbutyldicarbonate (77.4 mmol, 16.9 g) in THF (150 mL). The reaction mixture wasgradually warmed to r.t. and stirred overnight. The solvents were evaporated and theresidue was dissolved in DCM. DCM layer was washed with iN HC1 (3 x 100 mL),water, dried over sodium sulfate, and concentrated in vacuo to give pure 1 (13.03 g,75percent) as a white powder. ‘H NMR (500 MHz, CDC13) ö 4.02 (br s, 2H), 2.85 (t, J =11.5 Hz, 2H), 2.49 (m, 1H), 1.90 (d, J= 11.5 Hz, 2 H), 1.65 (m, 2H), 1.45 (s, 9H); ‘3CNMR (125 MHz, CDC13) ö 180.1, 154.7, 79.7, 40.7, 28.3, 27.6. MS calc’d for C,,H,8N04 (M-H) 228.1241, found 228.1240.
75%
With potassium carbonate In tetrahydrofuran; water at 0 - 20℃;
To a stirred solution of isonipecotic acid (77.4 mmol, 10.0 g) and potassium carbonate (154.8 mmol, 21.4 g) in water (150 mL) at 0° C., was added dropwise a solution of di-t-butyldicarbonate (77.4 mmol, 16.9 g) in THF (150 mL). The reaction mixture was gradually warmed to r.t. and stirred overnight. The solvents were evaporated and the residue was dissolved in DCM. DCM layer was washed with 1N HCl (3*100 mL), water, dried over sodium sulfate, and concentrated in vacuo to give pure 1 (13.03 g, 75percent) as a white powder. 1H NMR (500 MHz, CDCl3) δ 4.02 (br s, 2H), 2.85 (t, J=11.5 Hz, 2H), 2.49 (m, 1H), 1.90 (d, J=11.5 Hz, 2H), 1.65 (m, 2H), 1.45 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 180.1, 154.7, 79.7, 40.7, 28.3, 27.6. MS calculated for C11H18NO4 (M-H)- 228.1241, found 228.1240.
73%
With sodium hydroxide In water; <i>tert</i>-butyl alcohol at 10 - 20℃; for 3 h;
To a stirred solution of isonipecotic acid (6.0 g, 46.6 mmol) in tert-BuOH (18 mL), NaOH solution (12 mL, 3.71 g, 92.8 mmol in 12 mL water) was added at 10-15 °C, followed by di-tert-butyl dicarbonate (10.1 g, 46.6 mmol) and the mixture was stirred at rt for 3 h. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water and washed with petroleum ether (3 x 25 mL). The pH of the aqueous layer was adjusted to 6-6.5 using citric acid and was extracted with DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the title compound. Yield: 73percent (10.0 g, white solid). 1H NMR (400 MHz, DMSO-d6): δ 12.25 (s, 1H), 3.83-3.80 (m, 2H), 2.80-2.49 (m, 2H), 2.39-2.36 (m, 1 H), 1.79-1.75 (m, 2H), 1.41-1 .34 (m, 11 H).
61%
Stage #1: With sodium hydroxide In 1,4-dioxane at 20℃; for 21 h; Stage #2: With hydrogenchloride; water In 1,4-dioxane; ethyl acetate
Piperidine-l,4-dicarboxylic acid mono-tert-butyl ester HVB01031 C11H19NO4 MW 229.28Di-t-butyl dicarbonate (3.4 g, 15.6 mmol) and sodium hydroxide (6.2 g, 154.5 mmol) were added to a solution of isonipecotic acid (2 g, 15.5 mmol) in 1,4-dioxane (50 ml) and water (50 ml). Stirred at room temperature for 21 h. Concentrated in-vaco to approximately 15 ml, diluted with ethyl acetate and acidified to pH 3-4 using hydrochloric acid (IM). Extracted with ethyl acetate and washed with water. Organic layers dried over anhydrous magnesium sulphate and evaporated to dryness, to afford a white solid, 2.16 g, 61 percent. m.p. 151-153 0C, Rf: 0.72 (10percent MeOH in DCM)51H NMR (270 MHz5 CDCl3)δ 1.4 (9H5 s, CH3), 1.64 (2H5 m, CH2), 1.89 (2H5 dd, J=3.0, 13.4 Hz, CH2), 2.5 (IH, m, CH), 2.83 (2H5 1, J=I 1.1 Hz5 N-CH2), 4.03 (2H5 d5 J=12.0 Hz, N-CH2).; Piperidine-l,4-dicarboxylic acid mono-tert-butyl ester HVB01031 C11H19NO4 MW229.28Di-/-butyl dicarbonate (3.4 g, 15.6 mmol) and sodium hydroxide (6.2 g, 154.5 mmol) were added to a solution of isonipecotic acid (2 g, 15.5 mmol) in 1,4-dioxane (50 ml) and water (50 ml). Stirred at room temperature for 21 h. Concentrated in-vaco to approximately 15 ml, diluted with ethyl acetate and acidified to pH 3-4 using hydrochloric acid (IM). Extracted with ethyl acetate and washed with water. Organic layers dried over anhydrous magnesium sulphate and evaporated to dryness, to afford a white solid, 2.16 g, 61 percent. m.p. 151-153 0C, Rf: 0.72 (10percent MeOH in CHCl3), 1H NMR (270 MHz, CDCl3)B 1.4 (9H, s, CH3), 1.64 (2H, m, CH2), 1.89 (2H, dd, J=3.0, 13.4 Hz, CH2), 2.5 (IH, m, CH), 2.83 (2H, t, J=ILl Hz, N-CH2), 4.03 (2H, d, J=12.0 Hz, N-CH2).
49%
at 80℃; for 2 h;
Step A 1-N-(tert-Butoxycarbonyl-4-piperidine carboxylic acid or 1-N-(tert -butoxycarbonyl)isonipecotic acid Isonipecotic acid (5g; 1 equivalent) is dissolved in water (50 ml) and a solution of di-tert -butyldicarbonate (8.62g; 1.02 equivalents) in THF (70 ml) is added with stirring. The mixture is stirred at 80°C for 2 h and then evaporated to dryness. The residue is partitioned between dichloromethane and brine and the dichloromethane layer is dried over magnesium sulfate, filtered and evaporated to dryness. The product is chromatographed on a silica gel column (30 X 5cm) using 15percent (10percent concentrated ammonium hydroxide in methanol)-dichloromethane as the eluant to give the title compound (4.3109g; 49percent yield), CIMS: m/z 230 (MH+).
7.63 mmol, 98%
With triethylamine In dichloromethane; ethyl acetate
Step A: N-(t-Butoxycarbonyl)piperidine-4-carboxylic acid To a suspension of 1.0 g (7.74 mmol) of piperidine-4-carboxylic acid in 20 mL of methylene chloride at room temperature was added 1.13 mL of triethylamine (0.82 g, 8.1 mmol, 1.05 eq) followed by 1.87 mL of di-t-butyl-dicarbonate (1.77 g, 8.1 mmol, 1.05 eq). The mixture was stirred at room temperature for 48 hours then concentrated under vacuum. The residue was redissolved in ethyl acetate and the solution washed with 5percent citric acid and brine, then dried over magnesium sulfate, filtered and evaporated under vacuum to afford 1.75 g (7.63 mmol, 98percent) of the product. 1 H NMR (200 MHz, CD3 OD): 1.42 (s,9H), 1.50 (m,2H), 1.84 (m,2H), 2.46 (m,1H), 2.86 (t,9 Hz,2H), 3.91 (t,3 Hz,1H), 3.98 (t,3 Hz,1H). FAB-MS: calculated for C11 H19 NO 4 229; found 230 (M+H,17percent).
90%
With sodium hydroxide In 1,4-dioxane; water
Step E N-BOC-Isonipecotic acid To a cold solution of 12.4 g (0.31 mmol, 1.0 eq) of sodium hydroxide in 300 ml of water and 600 ml of dioxane was added 40.0 g (0.31 mmol, 1.0 eq) of isonipecotic acid, followed by 84.0 g (38 mmol, 1.2 eq) of di-t-butyl dicarbonate. The mixture was stirred at ambient temperature for 5 h then partitioned between ethyl acetate and 0.5N citric acid. The organic phase was washed with water, brine, dried over sodium sulfate, and concentrated. The crystalline product was collected by filtration, washed with hexane, and dried under vacuum. Yield: 64.0 g (90percent), 1H NMR (300 MHz, CDCl3) δ10.78 (1H, exc), 4.0 (2H, d), 2.85 (2H, t), 2.48 (1H, m), 1.9 (2H, m), 1.65 (2H, m), 1.42 (9H, s). MS (FAB, M+H) 230.1.
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11
[ 498-94-2 ]
[ 24424-99-5 ]
[ 75-65-0 ]
[ 84358-13-4 ]
Yield
Reaction Conditions
Operation in experiment
96%
With sodium hydroxide In water
a) Piperidine-1,4-dicarboxylic acid, 1-tert-butyl ester Di-tert-butyl dicarbonate (101.1 g, 464 mM) was added dropwise to a solution of isonipecotic acid (60 g, 464 mM) and sodium hydroxide (37.6 g, 940 mM) in water (86 ml) and tert-butyl alcohol (176 ml) with stirring. After the end of the addition, the above mixture was added with tert-butyl alcohol (100 ml), and stirred at room temperature for three hours. The resulting solution was diluted with water (200 ml), and extracted twice with 150 ml of pentane. The aqueous layer was acidified with 70 g of potassium bisulfate with cooling, and extracted with ethyl acetate. Standard workup gave the title compound as a white powder (102.3 g. yield 96percent). Melting point: 144-146°C.
1-(1,1-Dimethylethoxycarbonyl)Piperidine-4-Carboxylic Acid Di-t-butyldicarbonate (23.42 g, 107.3 mmol) in dichloromethane (100 mL) was added slowly to a mixture of 4-piperidinecarboxylic acid (12.60 g, 97.6 mmol) and triethylamine (13.60 mL, 9.87 g, 97.6 mmol) in dichloromethane (50 mL) and the mixture was stirred at room temperature for 18 h. N,N-Dimethylethylenediamine (3.46 mL, 2.87 g, 32.5 mmol) was added and the mixture was stirred at room temperature for 30 min. Dichloromethane (100 mL) was added and the mixture was washed with aqueous citric acid (10percent, 2*200 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (21.05 g, 94percent). 1H NMR (250MHz, CDCl3) δ4.02 (2H, m), 2.86 (2H, m), 2.49 (1H, m), 1.91 (2H, m), 1.64 (2H, m), and 1.46 (9H, s).
Reference：
[1] Advanced Synthesis and Catalysis, 2007, vol. 349, # 8-9, p. 1475 - 1480
26
[ 24424-99-5 ]
[ 5984-56-5 ]
[ 84358-13-4 ]
Reference：
[1] Journal of Labelled Compounds and Radiopharmaceuticals, 1996, vol. 38, # 1, p. 53 - 60
27
[ 84358-13-4 ]
[ 91419-48-6 ]
Yield
Reaction Conditions
Operation in experiment
73%
With 1-hydroxy-7-aza-benzotriazole; ammonium chloride; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 10 h; Inert atmosphere
A mixture of 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (220 mg, 2.88 mmol) , ammonium chloride (154 mg, 2.88 mmol) , EDCI (367 mg, 1.92 mmol) and HOAT (195 mg, 1.44 mmol) in DCM (10 mL) was stirred at 0 , and then DIPEA (1.0 mL, 5.77 mmol) was added dropwise. After the addition, the mixture was stirred at rt for 10 h and washed with water (10 mL × 3) . The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with EtOAc to give tert-butyl 4-carbamoylpiperidine-1-carboxylate as a white solid (160 mg, 73) .1H NMR (400 MHz, CD3OD) : δ ppm 4.11 (d, J 13.4 Hz, 2H) , 2.76-2.86 (m, 2H) , 2.38-2.45 (m, 1H) , 1.79 (d, J 11.2 Hz, 2H) , 1.52-1.62 (m, 2H) , 1.47 (s, 9H) and MS-ESI: m/z 173.20 [M-55] +.
73%
With 1-hydroxy-7-aza-benzotriazole; ammonium chloride; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 10 h;
The compound 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (220mg, 0.96mmol), ammoniumchloride (154mg, 2.88mmol), 1- ethyl 3- (3-dimethylaminopropyl) carbodiimide hydrochloride (367mg,1.92mmol) and N- hydroxy-7-aza-benzotriazole (195mg, 1.44 mmol) were dissolved in dichloromethane (10mL), and the conditions under 0 ° C, to this solution was added dropwise N, N- diisopropylethylamine(1.0mL, 5.77 mmol), stirred for 10H at room temperature, add water (10mL × 3) washing the organic phase wasdried over anhydrous Na 2 SO 4, the solvent was removed, the concentrate was subjected to columnChromatography (eluent: EtOAc), to give a white solid 160mg: 4-carbamoyl-piperidine-1-carboxylate, yield:73percent.
56%
With ammonia; N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃;
To a mixture of l-(tert- butoxycarbonyl)piperidine-4-carboxylic acid 1 (2.29 g, 10 mmol), DIEA (3.87 g, 30 mmol) and HATU (4.18 g, 11 mmol) in DMF (50 mL) was added NH3 by bubbling for 20 min. The resulting mixture was stirred at rt overnight. The mixture was diluted with water (200 mL) and extracted with EA (2 x 50 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was applied onto silica gel column eluting with EA to get the title compound (1.3 g, 56percent) as white solid. MS (ESI): m/z = 173.2 [M + H - 56]+.
Reference：
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[4] Patent: WO2015/48662, 2015, A2, . Location in patent: Page/Page column 114
[5] European Journal of Medicinal Chemistry, 1984, vol. 19, # 2, p. 181 - 186
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[10] Patent: WO2016/30443, 2016, A1, . Location in patent: Page/Page column 102
[11] Chemical Biology and Drug Design, 2016, p. 54 - 65
Reference：
[1] Journal of Medicinal Chemistry, 2017, vol. 60, # 11, p. 4680 - 4692
31
[ 84358-13-4 ]
[ 157688-46-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 15, p. 4646 - 4661
32
[ 6638-79-5 ]
[ 84358-13-4 ]
[ 139290-70-3 ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: With triethylamine In DMF (N,N-dimethyl-formamide) at 20℃; for 0.166667 h; Stage #2: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In DMF (N,N-dimethyl-formamide) Stage #3: With hydrogenchloride In water
To a stirring suspension of t-Boc-isonipecotic acid (19) (2.34 g, 10.2 mmol) and the Weinreb amine (1.5 g, 15 mmol) in DMF (50 mL), was added triethylamine (2.8 mL, 20 mmol) at room temperature. After stirring for 10 min, HOBt (1.62 g, 12 mmol) was added, followed by EDCI (2.3 g, 12 mmol). The resulting solution was stirred overnight and concentrated. The residue was taken up in 1 N HCl (100 mL) and extracted with EtOAc (3.x.100 mL). The combined organic extracts were washed with sat NaHCO3 (50 mL), brine (50 mL), dried (MgSO4) and concentrated to obtain a colorless oil (20) (2.79 g, >100percent). 1H NMR (500 MHz, CDCL3) δ4.14 (m, 2H), 3.71 (s, 3H), 3.19 (s, 3H), 2.78 (m, 3H), 1.68 (m, 4H), 1.46 (s, 9H); MS (ESI+) m/z 217.72 (M+H+-isobutylene).
99%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 48 h;
PREPARATION 557erf-butyl 4-acetylpiperidine-1 -carboxylatea) Tert-butyl 4-[methoxy(methyl)amino]carbonyl}piperidine-1 -carboxylateTo a solution of N.O-dimethylhydroxylamine hydrochloride (894 mg, 9.17 mmol), 2- benzotriazol-1-yl-N,N,N',N'-tetramethyluronio hexafluorphosphate (HBTU) (3.48 g, 9.17 mmol) and diisopropylethylamine (DIPEξA) in N,N-dimethylformamide (40 mL) was carefully added 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (2 g, 8.73 mmol) and the reaction mixture was stirred at room temperature for 2 days. The mixture was diluted with water (200 mL), extracted with ethyl acetate, washed with aqueous citric acid 5percent, aqueous sodium bicarbonate 4percent, water, and brine and dried over sodium sulphate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica flash, using ethyl acetate as eluent (isocratic), to yield the title compound (2.63 g, 99percent) as yellowish oil. <n="63"/>1H-NMR δ (CDCI3): 1.46 (s, 9H), 1.63-1.74 (m, 4H), 2.70-2.84 (m, 3H), 3.19 (s, 3H), 3.72 (s, 3H), 4.11-4.18 (m, 2H).
99%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;
To a solution of compound 25 (40 g, 175 mmol) in DMF (250 mL) at 4°C was added N.O - dimethyl-OHamine, hydrochloride (34 g), EDCI (44 g, 0.228 mol), HOBT (2.4 g), and DIPEA (120 mL). The reaction was warmed to room temperature and stirred overnight. The reaction was then concentrated to half volume in vacuo and poured onto 1:1 ethyl acetate: water. The organic layer was separated and the aqueous layer extracted with additional ethyl acetate. The combined organic layers were washed with saturated aqueous NH4Cl, saturated aqueous NaHCO3, water, and brine, and dried. Concentration gave 26 as a light yellow oil (46.7 g, 99percent)
95%
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 72 h;
Intermediate 1; 1,1-dimethylethyl4-[methyl(methyloxy)amino]carbonyl}-1-piperidine-carboxylate; QN,O-Dimethylhydroxylamine hydrochloride (4.26 g, 43.7 mmols), di-isopropylethylamine (33.88 g, 45.66 ml, 262.2 mmols) and HATU (19.94 g, 52.4 mmols) were added to a solution of N-Boc-piperidine-4-carboxylic acid (11.03 g, 48.1 mmols) in dry DMF (250 ml_). The reaction mixture was stirred at room temperature for 72 hrs. The DMF was removed in vacuo and the residue was partitioned between ethyl acetate (200 mL) and saturated aqueous sodium bicarbonate (200 mL). The organic phase was separated, washed with saturated aqueous sodium bicarbonate (200 mL) and brine (200 mL), and dried over MgSO4. Evaporation of the solvent afforded a dark oil (21.0 g) that was purified by flash chromatography (Silica, gradient elution with pentane/ethyl acetate 9:1 v/v to 3:2 v/v) to give the title compound 12.5 g (95percent) as a gum. LC/MS-M+H 273
95%
Stage #1: With 1,1'-carbonyldiimidazole In dichloromethane at 0 - 25℃; for 1 h; Inert atmosphere Stage #2: With triethylamine In dichloromethane at 25℃; for 0.5 h; Stage #3: at 25℃; for 15 h;
3. Synthesis of intermediate D-1: C-1 D-1 To a stirred solution of C-1 (80 g, 0.35 mol) in 1 L of anhydrous CH2CI2 was added CDI (62.24 g, 0.38 mol) under N2 at 0°C. After the addition, the mixture was stirred at 25°C for 1 hour, gas formation was observed. Et3N (42.37 g, 42 mol) was added, the mixture was stirred at 25°C for 30 min, then Ο,Ν-dimethylhydroxylamine hydrochloride (42.54 g, 0.44 mol) was added. After the addition, the mixture was stirred at 25 °C for 15 hrs. The mixture was washed with water, aq. NaHC03 and aq. citric acid monohydrate. The organic layer was separated, dried over anhydrous Na2S04 and concentrated to get intermediate D-1 (80 g, 95percent) as a white solid.
95%
Stage #1: With 1,1'-carbonyldiimidazole In dichloromethane at 0 - 25℃; for 1 h; Inert atmosphere Stage #2: With triethylamine In dichloromethane at 25℃; for 0.5 h; Stage #3: at 25℃; for 15 h;
To a stirred solution of C-1 (80 g, 0.35 mol) in 1 L of anhydrous CH2Cl2 was added CDI (62.24 g, 0.38 mol) under N2 at 0° C. After the addition, the mixture was stirred at 25° C. for 1 hour, gas formation was observed. Et3N (42.37 g, 42 mol) was added, the mixture was stirred at 25° C. for 30 min, then O,N-dimethylhydroxylamine hydrochloride (42.54 g, 0.44 mol) was added. After the addition, the mixture was stirred at 25° C. for 15 hrs. The mixture was washed with water, aq. NaHCO3 and aq. citric acid monohydrate. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated to get intermediate D-1 (80 g, 95percent) as a white solid.
95%
With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide
Add N,O-dimethylhydroxylamine hydrochloride (2.52 g, 26 mmol), 1-hydroxybenzotriazole (HOBt) (2.8 g, 20.8 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI.HCl)(4 g, 20.8 mmol) and 4-methylmorpholine (5.28 g, 52 mmol) at 0° C. to the solution of N-Boc-piperidine-4-carboxylic acid (4 g, 17.4 mmol) in DMF (50 mL), stir the mixture overnight at room temperature. TLC (PE:EtOAc=1:1) shows the reaction is complete. Partition between ethyl acetate and water, collect the organic layer and wash with brine, dry over anhydrous sodium sulfate, filter and concentrate the filtrate under reduced pressure to give the crude product (4.5 g, 95percent) which is used in next step without further purification.
95%
Stage #1: With 1,1'-carbonyldiimidazole In dichloromethane at 0 - 25℃; Inert atmosphere Stage #2: With triethylamine In dichloromethane at 25℃; for 0.5 h; Stage #3: at 25℃; for 15 h;
To a stirred solution of C-1 (80 g, 0.35 mol) in 1 L of anhydrous CH2Cl2 was added CDI (62.24 g, 0.38 mol) under N2 at 0° C. After the addition, the mixture was stirred at 25° C. for 1 hour, gas formation was observed. Et3N (42.37 g, 42 mol) was added, the mixture was stirred at 25° C. for 30 min, then O,N-dimethylhydroxylamine hydrochloride (42.54 g, 0.44 mol) was added. After the addition, the mixture was stirred at 25° C. for 15 hrs. The mixture was washed with water, aq. NaHCO3 and aq. citric acid monohydrate. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated to get intermediate D-1 (80 g, 95percent) as a white solid.
95%
With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 18 h;
[0211] 1-(1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (6.51 g, 0.022 mol) was dissolved in dichloromethane (50 ml). To the resulting solution were added 1,1'-carbonyldiimidazole (CDI) (6.31 g, 0.033 mol) and N,O-dimethylhydroxylamine hydrochloride (9.62 g, 0.67 mol) and the solution was stirred at room temperature for 18 hrs. After completion of the reaction by addition of water, the solution was extracted with dichloromethane, washed with distilled water, and dried over magnesium sulfate (MgSO4) to concentrate. The resulting residue was isolated and purified by silica gel column chromatography (dichloromethane/methanol = 10/1) to give the white title compound (5.36 g, 95.0 percent). 1H NMR (400 MHz, CDCl3) δ 4.14 (m, 2H), 3.71 (s, 3H), 3.13 (s, 3H), 2.79 (m, 5H), 1.42 (s, 9H).
88%
Stage #1: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide for 0.333333 h; Stage #2: With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide
INTERMEDIATE B4 tert-Butyl 4-[methoxy(methyl)amino]carbonyl}piperidine-l-carboxylate A suspension of l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (5.0 g, 21.8 mmol), EDC (6.27 g, 32.7 mmol) and HOBT (2.95 g, 21.8 mmol) in DMF (10 mL) was stirred for20 min. To the mixture were then added 1 ,2-dimethylhydroxylamine hydrochloride (3.19 g, 32.7 mmol) and DIEA (13 mL, 76.3 mmol) and the stirring continued overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was concentrated and the residue was purified by flash chromatography on silica using EtOAc as eluent. Yield 5.22 g (88percent). Analytical HPLC: purity 100percent (System A and B);LRESIMS (ESI+) m/z = 217 (M+H-φu)+.
80%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 19 h;
Synthesis of 4-(Methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid t-butyl ester Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.0 eq, 21.8 mmol) was dissolved under inert conditions in 35 ml dry N,N-dimethylformamide. O,N-dimethyl-hydroxylamine hydrochloride (1.03 eq, 22.5 mmol), benzotriazol-1-ol monohydrate (1.03 eq, 22.5 mmol) and triethylanine (1.5 eq, 32.7 mmol) were added. The reaction mixture was cooled to 0° C., N-(3-Dimethylaminopropyl)-N-ethylcarbodiimid hydrochloride (1.0 eq, 21.8 mmol) was added over a period of 1.0 minutes and the mixture was stirred vigorously at 0° C. for 1 h and at r.t. for 18 h. The solvent was removed under vaccum and the residue was suspended in 400 ml ethylacetate. The organic layer was extracted 3 times with 100 ml of 1 M citric acid, aqueous sodium carbonate and twice with 100 ml brine, dried over MgSO4 and filtered. The solvent was removed and the residue as purified by distillation resulting in a yield of 80percent.
80%
at 0 - 20℃; for 19.8333 h;
Synthesis of 4-(Methoxy-methyl-carbamoyl)-piperidine-l-carboxylic acid t-butyl esterPiperidine-l,4-dicarboxylic acid mono-tert-butyl ester (1.0 eq, 21.8 mmol) was dissolved under inert conditions in 35 ml dry N, N- dimethylformamide. O,N-dimethyl- hydroxylarnine hydrochloride (1.03 eq, 22.5 mmol), benzotriazol-1-ol monohydrate (1.03 eq, 22.5 mmol) and triethylamine (1.5 eq, 32.7 mmol) were added. The reaction mixture was cooled to O0C, N-(3-Dimethylaminopropyl)-N-ethylcarbodiimid hydrochloride (1.0 eq,21.8 mmol) was added over a period of 10 minutes and the mixture was stirred vigorously at O0C for 1 h and at r.t. for 18 h.The solvent was removed under vaccum and the residue was suspended in 400 ml ethylacetate. The organic layer was extracted 3 times with 100 ml of 1 M citric acid, aqueous sodium carbonate and twice with 100 ml brine, dried over MgSO4 and filtered. The solvent was removed and the residue was purified by distillation resulting in a yield of 80percent.
80%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 19.1667 h;
Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.0 eq, 21.8 mmol) was dissolved under inert conditions in 35 ml dry N, N- dimethylformamide. O,N-dimethylhydroxylamine hydrochloride (1.03 eq, 22.5 mmol), benzotriazol-1-ol monohydrate (1.03 eq, 22.5 mmol) and triethylamine (1.5 eq, 32.7 mmol) were added. The reaction mixture was cooled to 0°C, N-(3-Dimethylaminopropyl)-N-ethylcarbodiimid hydrochloride (1.0 eq, 21.8 mmol) was added over a period of 10 minutes and the mixture was stirred vigorously at 0°C for 1 h and at r.t. for 18 h. The solvent was removed under vaccum and the residue was suspended in 400 ml ethylacetate. The organic layer was extracted 3 times with 100 ml of 1 M citric acid, aqueous sodium carbonate and twice with 100 ml brine, dried over MgSO4 and filtered. The solvent was removed and the residue was purified by distillation resulting in a yield of 80percent.
80%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 19.1667 h;
Piperidine-l,4-dicarboxylic acid rnono-tert-butyl ester (1.0 eq, 21.8 mmol) was dissolved under inert conditions in 35 ml dry N, N- dimethylformamide. O,N-dimethyl- hydroxylamine hydrochloride (1.03 eq, 22.5 mmol), benzotriazol-1-ol monohydrate (1.03 eq, 22.5 mmol) and triethylamine (1.5 eq, 32.7 mmol) were added. The reaction mixture was cooled to 00C, N-(3 -Dimethyl aminopropyl)-N-ethylcarbodiimid hydrochloride (1.0 eq, 21.8 mmol) was added over a period of 10 minutes and the mixture was stirred vigorously at 0°C for 1 h and at r.t. for 18 h.The solvent was removed under vaccum and the residue was suspended in 400 ml ethylacetate. The organic layer was extracted 3 times with 100 ml of 1 M citric acid, aqueous sodium carbonate and twice with 100 ml brine, dried over MgSO4 and filtered. The solvent was removed and the residue was purified by distillation resulting in a yield of 80percent.
80%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 19.1667 h;
Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.0 eq, 21.8 mmol) was dissolved under inert conditions in 35 ml dry N,N-dimethylformamide. O,N-dimethyl-hydroxylamine hydrochloride (1.03 eq, 22.5 mmol), benzotriazol-1-ol monohydrate (1.03 eq, 22.5 mmol) and triethylamine (1.5 eq, 32.7 mmol) were added. The reaction mixture was cooled to 0° C., N-(3-Dimethylaminopropyl)-N-ethylcarbodiimid hydrochloride (1.0 eq, 21.8 mmol) was added over a period of 10 minutes and the mixture was stirred vigorously at 0° C. for 1 h and at r.t. for 18 h.The solvent was removed under vacuum and the residue was suspended in 400 ml ethylacetate. The organic layer was extracted 3 times with 100 ml of 1 M citric acid, aqueous sodium carbonate and twice with 100 ml brine, dried over MgSO4 and filtered. The solvent was removed and the residue was purified by distillation resulting in a yield of 80percent.
80%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 19 h;
Synthesis of 4-(Methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid t-butyl ester Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.0 eq, 21.8 mmol) was dissolved under inert conditions in 35 ml dry N, N- dimethylformamide, O,N-dimethyl-hydroxylamine hydrochloride (1.03 eq, 22.5 mmol), benzotriazol-1-ol monohydrate (1.03 eq, 22.5 mmol) and triethylamine (1.5 eq, 32.7 mmol) were added. The reaction mixture was cooled to 0°C, N-(3-Dimethylaminopropyl)-N-ethylcarbodiimid hydrochloride (1.0 eq, 21.8 mmol) was added over a period of 10 minutes and the mixture was stirred vigorously at 0°C for 1h and at r.t. for 18h. The solvent was removed under vaccum and the residue was suspended in 400 ml ethylacetate. The organic layer was extracted 3 times with 100 ml of 1 M citric acid, aqueous sodium carbonate and twice with 100 ml brine, dried over MgSO4 and filtered. The solvent was removed and the residue was purified by distillation resulting in a yield of 80percent.
77%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 16 h;
To the mixture of 10 (47.0 g, 205 mmol) and N,O-dimethylhydroxylamine hydrochloride (20.8 g, 213 mmol) in CH2Cl2 (1 L) was added EDC (44.6 g, 232 mmol) in one portion followed by Et3N (32.4 mL, 232 mmol) dropwise at rt. The resulting solution was stirred at rt for 16 h. The solution was washed with brine (800 mL x 4) and a saturated NaHCO3 solution (500 mL), and then dried over Na2SO4. After evaporating the solvent, the residue was purified on silica gel using 60percentEtOAc/hexane to give 11 (43.2 g, 77percent) as an oil.
71%
Stage #1: With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 0℃; for 0.166667 h; Stage #2: at 20℃; for 2 h;
To a stirred solution of l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (5.0 g, 21.7 mmol) in DMF (20 mL) was added HATU (12.39 g, 32.60 mmol) and diisopropylethylamine (18.94 ml, 108.6 mmol). The solution was stirred for 10 min at 0 °C. After that Ν,Ο-dimethylhydroxylamine hydrochloride (2.12 g, 21.7 mmol) was added and stirred at RT for 2 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain a crude residue which was purified by column chromatography to afford tert-butyl 4- (methoxy(methyl)carbamoyl)piperidine-l-carboxylate (4.3 g, 71percent). LCMS: m/z = 173.05 (M-Boc)+.
61%
Stage #1: With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 2 h; Stage #2: at 20℃;
Example 5; Synthesis of 2-(4-(phenyl(4-(trifluoromethyl)phenyl)methyl)piperidin- 1 -yl)acetic acidStep lTo a solution of l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (11 g, 48 mmol) in DCM (120 mL) was added CDI (11 g). After stirring at rt for 2 h, N,O-dimethylhydroxyl- amine hydrochloride was added in portions. The mixture was stirred for 3 h at rt and was then left to stand overnight. The solvent was removed under vacuum, the residue was extracted with DCM, washed with brine and water, dried over anhydrous sodium sulfate and concentrated to give crude tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-l-carboxylate (8 g, 61percent yield) as a white solid which was used directly in the next step.
42%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃;
Reagents and conditions: (a) B0C2O, 1,4-dioxane, H2O, NaOH, overnight, rt, (yield 94percent); (b) HOBt, EDCl, TEA,DMF, NHMeOMe-HCl, overnight, rt, (yield 42percent); (c) BuLi, 2-bromobiphenyl, TMEDA, THF, 3h, -78°C, (yield 35percent) ; (d) TFA, DCM , lh, rt, (yield quant); (e) toluene, 2h, (yield 24percent), (f) NaBH4, THF, MeOH, overnight, rt, (yield 25percent). Compounds 8-9 were synthesized from isonipecotic acid. The amine function was first protected with tert-butyl carbamate group followed by the formation of the Weinreb amide using HOBt and EDCl. Then, the lithium anion of 2-bromobiphenyl reacted on the Weinreb amide and Boc deprotection to give compounds 8. Addition reaction on iso(thio)cyanate with the piperidine in toluene afforded (thio)urea 9a-9b, followed by a reduction of the ketone group give the alcohol derivatives lOa-lOb.
%
Stage #1: With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; Stage #2: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃;
N,Oτdimethylhydroxylamine hydrochloride (851 mg, 8.72 mmols) was, :,O suspended in dichloromethane (6 ml) and cooled to 0 C. N, N-diisopropylethylaminev (1.66 ml, 9.53 mmols) was added and the mixture was stirred at 0 C until a clear solution was obtained. The resulting solution was kept at 0 C for further use. Boc- isonipecotic acid (2 g, 8.72 mmol), 1-hydroxybenzotriazole (1.2 g, 8.88 mmols) and 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (1.83 g, 9.58 mmols) were dissolved in DMF (15 ml) and cooled to 0 C. The solution of N,O- dimethylhydroxylamine in dichloromethane was added with stirring, and the resulting reaction mixture was allowed to stir overnight at room temperature. DMF was removed under reduced pressure and residue was partitioned between ethyl acetate and 10percent citric acid. Organic layer was isolated, washed with water, saturated NaHCO3, water and brine and dried over MgSO4. Solvent was removed under reduced pressure and the residue was purified on silica gel eluting with ethyl acetate in hexanes (2:1 ) to provide the title compound (1.88 g, 79percent). LCMS m/e (295, M + Na).
Stage #1: With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; Stage #2: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃;
λ/,O-dimethylhydroxylamine hydrochloride (851 mg, 8.72 mmols) was suspended in dichloromethane (6 ml) and cooled to 0 C. N, /V-diisopropylethylamine (1.66 ml, 9.53 mmols) was added and the mixture was stirred at 0 C until a clear solution was obtained. The resulting solution was kept at 0 C for further use. Boc- isonipecotic acid (2 g, 8.72 mmol), 1 -hydroxybenzotrazole (1.2 g, 8.88 mmols) and 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (1.83 g, 9.58 mmols) were dissolved in DMF (15 ml) and cooled to 0 C. The solution of MO- dimethylhydroxylamine in dichloromethane was added with stirring, and the resulting reaction mixture was allowed to stir overnight at room temperature. DMF was <n="258"/>removed under reduced pressure and residue was partitioned between ethyl acetate and-10-percent-citric-acid.-OrganiG-layer-was-isolated,-washed-with-wateFj r saturated . JSIaHCCh- water and brine and dried over MgSO4. Solvent was removed under reduced pressure and the residue was purified on silica gel eluting with ethyl acetate in hexanes (2:1 ) to provide the title compound (1.88 g, 79percent). LCMS m/e (295, M + Na).
Reference：
[1] Patent: WO2007/70398, 2007, A1, . Location in patent: Page/Page column 255
[2] Organic Preparations and Procedures International, 2000, vol. 32, # 1, p. 96 - 99
[3] Patent: WO2008/42925, 2008, A1, . Location in patent: Page/Page column 95-96
[4] Chemical Communications, 2013, vol. 49, # 87, p. 10245 - 10247
[5] Patent: WO2008/42925, 2008, A1, . Location in patent: Page/Page column 95-96
34
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[ 1117-97-1 ]
[ 139290-70-3 ]
Yield
Reaction Conditions
Operation in experiment
88.5%
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 25℃; for 16 h;
To a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (20.0 g, 87.23 mmol) in DCM (200 mL) was added HATU (36.46 g, 95.95 mmol), TEA (17.62 g, 174.46 mmol) and N,O-dimethylhydroxylamine (8.93 g, 91.59 mmol). The mixture was stirred at 25 C for 16 h. The mixture was washed with H2O and the DCM layer was evaporated and the residue purified by silica column (PE/EA=1:1) to give the tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (21.0 g, yield: 88.5percent)
51%
With triethylamine; HATU In dichloromethane at 20℃;
N,0_Dimethylhydroxylamine (1.6 g, 26.2 mmol) in DCM (50 mL) was added HATU (9.9 g, 26.2 mmol) and Et3N (2.65 g, 26.2 mmol) at rt. The formed mixture was stirred at rt overnight. The mixture was washed with water, and purified by column chromatography to give the desired product (3 g, 51percent).
Reference：
[1] Patent: KR2017/45749, 2017, A, . Location in patent: Paragraph 0614; 0617-0619
[2] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 8, p. 1381 - 1385
[3] Patent: WO2013/96744, 2013, A1, . Location in patent: Page/Page column 191
[4] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 13, p. 3419 - 3424
[5] Journal of Labelled Compounds and Radiopharmaceuticals, 2010, vol. 53, # 5-6, p. 394 - 397
[6] Patent: WO2011/103715, 2011, A1, . Location in patent: Page/Page column 46
[7] Patent: WO2011/106276, 2011, A1, . Location in patent: Page/Page column 46
[8] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 4, p. 1062 - 1066
[9] Journal of Medicinal Chemistry, 2017, vol. 60, # 13, p. 5507 - 5520
35
[ 478408-77-4 ]
[ 6638-79-5 ]
[ 84358-13-4 ]
[ 530-62-1 ]
[ 139290-70-3 ]
Yield
Reaction Conditions
Operation in experiment
89%
With sodium hydrogencarbonate In n-heptane; dichloromethane; water; toluene
EXAMPLE 66 Scheme G, step b: 4-[(Methoxymethylamino)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15) Into a 250-mL four-neck flask equipped with a mechanical stirrer, a nitrogen bubbler, a 125-mL addition funnel with a stopper, and a thermowell with a thermocouple was placed 1,1 '-carbonyldiimidazole (7.2 g, 0.044 mol) and methylene chloride (20 g). The addition funnel was charged with a solution of 1,4-piperidinedicarboxylic acid, 1-(1,1-dimethylethyl)ester (14) (10.0 g, 0.043 mol) and methylene chloride (75 g). The solution was added to the reaction mixture over a 2 minute period, causing rapid CO2 evolution. The reaction mixture was allowed to stir at 28° C. for 2 hours. Into a 500-mL four-neck flask equipped with a mechanical stirrer, a nitrogen bubbler, a thermowell with a thermocouple, and a 125-mL addition funnel with a septum was placed N,O-dimethylhydroxylamine hydrochloride (4.9 g, 0.049 mol) and methylene chloride (38 g). The imidazole amide intermediate/methylene chloride solution was added to the slurry of N,O-dimethylhydroxylamine hydrochloride and methylene chloride over a 20 minute period. The resulting slurry was allowed to stir at 28° C. for 2 hours. To the reaction mixture was added sodium bicarbonate (4.3 g) and water (75 g). After stirring for 30 minutes at ambient temperature, the phases were allowed to stand and separate for 20 minutes. The phases were separated and to the organic phase was added toluene (100 g). The solution was concentrated and azeotropically dried by rotary evaporation (29 Hg, bath 60° C.) to afford the crude title compound as a thick oil. The oil and heptane (25 g) were placed into a 100-mL jacketed-bottom-drain resin pot fitted with a four-joint head equipped with a mechanical stirrer, a thermowell with a thermocouple, a nitrogen bubbler, and a stopper. The slurry was warmed to 60° C. before allowing it to slowly cool to 10° C. over a 2 hour period. The solution was maintained at 10C for 1 hour (nucleation temperature) before cooling to 3° C. and stirring overnight. The title compoundcompound was collected by suction filtration and washed with cold heptane (7 g, 0° C.). The wet cake was allowed to air dry for 24 hours to afford the title compound (15) as a white crystalline material (10.5 g, 89percent); m.p. 69-71° C. 1H NMR (CDCl3) δ 4.08 (m, 2H, CHN's), 3.66 (s, 3H, -OCH3), 3.13 (s, 3H, -NCH3), 2.76 (m, 3H), 1.51 (m, 4H, CH2's), 1.40 (s, 9H, t-Bu); 13C NMR (CDCl3) δ 175.5, 154.7, 121.6, 79.5, 61.6, 43.3, 36.1, 28.5, 28.0; IR (KBr) 2973, 2935, 1694, 1663, 1421, 1367, 1289, 1133, 998, 870, 770 cm-1.
With 1,3-Diiodo-5,5-dimethyl-2,4-imidazolidinedione In chlorobenzene for 1 h; Reflux; Fluorescent lighting
EXAMPLE 3; Radical iodo-de-caboxylation induced by TV-iodo amides/V-iodo amideR-COOH *- R-lGeneral procedure[00111] Procedure: A mixture of R-COOH (1 mmol), N-iodo amide (1-4 equiv), and solvent (3-6 mL) was refluxed (Δ) for 1-24 h in the dark (NL) or under irradiation with 500 W tungsten lamp (TL) or under fluorescent room lighting (FL).[00112] Treatment: The reaction mixture was cooled to rt, and washed with aq NaHS03 and NaHC03 to destroy excess of iodination agent and dissolve unreacted carboxylic acid. The organic solution was dried (Na2S04), filtered through short silica or alumina pad and concentrated in vacuo to give iodide R-I. 100113J Purification: Optionally, the iodide R-I was further purified by crystallization (if the iodide is crystalline compound), or rectification (if the iodide is liquid compound). Analytical sample of the product was purified by column chromatography./V-iodoamideAlk-COOH *- Alk-I[00114] A mixture of Alk-COOH (1 mmol), N-iodo amide (1-3 equiv), and solvent (4 mL) was refluxed (Δ) in the dark (NL) or under irradiation with 500 W tungsten lamp (TL), or under fluorescent room lighting (FL).
Reference：
[1] Patent: WO2011/154953, 2011, A1, . Location in patent: Page/Page column 28-30
[2] Advanced Synthesis and Catalysis, 2011, vol. 353, # 9, p. 1438 - 1442
42
[ 84358-13-4 ]
[ 162504-75-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 1998, vol. 41, # 14, p. 2492 - 2502
Stage #1: With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 4 h; Stage #2: With dmap; triethylamine; magnesium chloride In tetrahydrofuran; acetonitrile at 0 - 20℃;
(0032) (2) Compound 4 (14.56 g, 63.5 mmol), N,N′-carbonyldiimidazole (24.00 g, 86 mmol) were dissolved in tetrahydrofuran (100 mL), stirred at room temperature for 4 hours. Compounds potassium monoethyl malonate (28.10 g, 165 mmol), anhydrous magnesium chloride (18.15 g, 191 mmol) and 4-dimethylaminopyridine (800 mg, 6.35 mmol) were dissolved in acetonitrile (100 mL) and tetrahydrofuran (200 mL), stirred at room temperature for 6 hours. The two reaction mixtures were cooled to 0° C. after they sufficiently reacted separately. Then the above-mentioned first solution and triethylamine (52 mL, 254 mmol) were simultaneously added to the second solution, and then stirred overnight at room temperature. After completion of the reaction, the solvent is removed by evaporation. The residue is diluted with water (200 mL), extracted with ethyl acetate (3*200 mL), dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give a yellow oily liquid 5 (18.06 g, 95percent).
182 g
Stage #1: With dmap; 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 15 h; Stage #2: With magnesium chloride In tetrahydrofuran at 50℃; for 35 h;
To a solution of boc-isonipecotic acid (150 g, 654 mmol) in tetrahydrofuran (2100 mL) was added di-1H-imidazol-1-ylmethanone (159 g, 981 mmol) and N,N-dimethylpyridin-4-amine (40.0 g, 327 mmol) at RT. The mixture was stirred at RT for 15 h (CAUTION: moderate gas evolution). In a second flask, a suspension of potassium 3-ethoxy-3-oxopropanoate (200 g, 1.18 mol) and magnesium dichloride (112 g, 1.18 mol) in tetrahydrofuran (2100 mL) was heated to 50° C. for 15 h. The resulting warm suspension was slowly added to the first flask under extensive stirring. The resulting mixture was stirred at RT for 20 h. Tetrahydrofuran was evaporated in vacuo, water (1500 mL) and ethyl acetate (1500 mL) were added. The mixture was cooled to 10° C. and 3N aqueous HCl was added until pH 1 was achieved. The organic phase was separated, the aqueous phase was extracted with ethyl acetate (1500 mL) and the combined organic phases were washed with 10percent aq. NaHCO3 (750 mL) and 10percent aq. NaCl (750 mL), dried over magnesium sulfate, filtered and evaporated in vacuo to yield the title compound (182 g, 505 mmol) in a purity of 83percent. LC-MS (Method 1B): Rt=1.00 min, MS (ESIPos): m/z=300 [M+H]+
Stage #1: With 1,1'-carbonyldiimidazole In acetonitrile at 20℃; for 0.5 h; Stage #2: With magnesium chloride In acetonitrile for 2 h; Reflux
The intermediate 12h was obtained as describe below: piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (150 g, 0.655 mol) in anhydrous acetonitrile (800 ml), 1,1'-carbonyldiimidazole was added in small portions (132 g, 0.851 mol) under vigorous stirring. The resulting mixture was stirred for 30 min at ambient temperature. Then powder of mixture of anhydrous MgCl2 (62g, 0.655 mol) and methyl potassium malonate (102g, 0.655 mol) was added in portions. The resulted slurry was heated at reflux for 2 h. The reaction mixture was cooled down, diluted with mixture of ice-cold water and dichloromethane and neutralized by citric acid. The separated organic layer was washed with 5percent aqueous solution of potassium carbonate, dried over sodium sulfate and concentrated under reduced pressure. Further flash-chromatography using ethyl acetate/ hexane (1/1) gave 151 g (81percent) of intermediate 31. 4-(6-Hydroxy-2-methyl-pyrimidin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (32) [0223] Acetamidine hydrochloride (29 g, 0.3 mol) was added to the solution of sodium ethylate (0.3 mol) in anhydrous ethanol (400 ml). The mixture was stirred at ambient temperature for 10 min, and compound 31 (0.3 mol) in ethanol was added. The resulting mixture was heated at reflux for 5 h (TLC control). The reaction mixture was concentrated under reduced pressure, the remains was dissolved in water and acidified with 1N HCl to pH 5.0 and extracted with ethyl acetate (2x200 ml). The combined extracts were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash-chromatography on silica gel (eluent: n-hexane/ethyl acetate - 1/1). As a result, compound 32 (50 g, 33percent) was obtained. 4-(6-Chloro-2-methyl-pyrimidin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (12h) [0224] Intermediate 32 (50 g, 0.170 mol) and N,N-dimethylaniline (166 g, 1.365 mol) was dissolved in anhydrous toluene (1000 ml) and POCl3 (52 g, 0.34 mol) was added dropwise. The reaction mixture was heated at reflux for 3 h; then cooled down to ambient temperature and allowed to stay overnight. To this end, the mixture was poured into water; organic layer was separated, washed with 1N HCl and water. The crude product was concentrated under reduced pressure and purified with flash chromatography on silica gel (eluent: n-hexane/ethyl acetate 4/1) to provide 12h (34.3 g , 65percent).
6.0.1.23.01 4-Hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester 100 g piperidine-1,4-dicarboxylic acid 1-tert-butyl ester was dissolved in 100 mL methanol and 100 mL hydrazine monohydrate was added. The mixture was reflux overnight. The reaction was cooled to RT and then the solvent was removed under vacuum to give 95 g of the desired product. Rf: 0.2 (DCM/MeOH=20/1) 1H NMR: (400 MHz, MeOD): δ 4.08 (d, J=13.2 Hz, 2H, CH2), 2.27 (br, 2H, NH2), 2.38-2.29 (m, 1H, CH), 1.72-1.68 (m, 2H, CH2), 1.63-1.56 (m, 2H, CH2), 1.45 (s, 9H, 3CH3).
95 g
With hydrazine hydrate In methanolReflux
4-Hydrazinocarbonyl-piperidine- 1-carboxylic acid tert-butyl ester 100 g piperidine-1, 4-dicarboxylic acid 1 -tert-butyl ester was dissolved in 100 mL methanol and 100 mL hydrazine mono hydrate was added. The mixture was reflux overnight. The reaction was cooled to RT and then the solvent was removed under vacuum to give 95 g of the desired product. Rf: 0.2 (DCM/ MeOH= 20/1) 1H NMR: (400 MHz, MeOD): δ 4.08 (d, J = 13.2 Hz, 2H, CH2), 2.27 (br, 2H, NH2), 2.38-2.29 (m, 1H, CH), 1.72-1.68 (m, 2H, CH2), 1.63-1.56 (m, 2H, CH2), 1.45 (s, 9H, 3CH3).
5.50 l-tert-Butyl 4-(3-(5-((3-(3-chloro-4-methylphenvnureido)methvn-l- oxoisoindolin-2-yl)-2,6-dioxopiperidin-l-yl)methyl piperidine-l,4- dicarboxylate; Step 1: 1 -tert- Butyl 4-chloromethyl piperidine- 1 ,4-dicarboxylate; To a mixture of l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (3 g, 13.1 mmol) in dichloromethane (40 mL) and water (50 mL)was added NaHCO3 (4.4 g, 52.3 mmol) and tetrabutylammonium hydrogen sulfate (444 mg, 1.3 mmol). After stirring the mixture in an ice bath at 0 0C for -10 min, chloromethyl chlorosulfate (2.59 g, 15.7 mmol) in 10 mL of dichloromethane was added dropwise. The reaction mixture was allowed to warm up to rt and stirred vigorously overnight. The mixture was transferred to a separatory funnel with dichloromethane and water (200 mL, each). The organic layer was washed with additional water and brine, dried (Na2SO4), and concentrated in vacuo to give 1-tert-butyl 4-chloromethyl piperidine- 1,4-dicarboxy late as a clear oil (3.5 g, 96percent yield). This material was used without further purification. 1H NMR (DMSO-d6) delta 1.26 - 1.48 (m, 1 IH, CHH, CHH, tertBu), 1.83 (dd, J= 3.0, 13.2 Hz, 2H, CHH, CHH), 2.58 - 2.75 (m, IH, CH), 2.74 - 2.99 (m, 2H, CHH, CHH), 3.61 - 4.02 (m, 2H, CHH, CHH), 5.87 (s, 2H, CH2O); 13C NMR (DMSO- d6) delta 27.16, 27.98, 39.58, 42.35, 69.41, 78.67, 153.75, 172.25; LCMS: MH = 278.
86%
With tetra(n-butyl)ammonium hydrogensulfate; sodium hydrogencarbonate; In dichloromethane; water; at 20℃; for 5h;
To a solution of l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (5 g, 21.8 m mol) in a mixture of dichloromethane and water (60 mL : 80 mL) was added chloromethyl chlorosulfonate (4.3 g, 26 mmol) drop wise, subsequently solid NaHC03 (7 g, 84 mmol) was added portion wise, followed by n-tetrabutylammonium hydrogen sulphate (TBAHS) (0.7 g, 2.1 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 5 h. The organic layer was separated, washed with water and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide 5.2 g of a white solid, yield: 86percent. This was confirmed by LCMS and used as such for next step.
With sodium hydrogencarbonate;tetra(n-butyl)ammonium hydrogensulfate; In dichloromethane; water; at 20℃; for 0.5h;
Preparation 9; Chloromethyl N- tert-butoxycarbonyl-4-piperidylcarboxylate; To a solution of N-tert-butoxycarbonyl-4-piperidyl-carboxylic acid (6.4 g) in dichloromethane (30 ml) was added water (30 ml), sodium bicarbonate (8.91 g) and tetrabutylammonium hydrogensulfate (0.95 g). The mixture was stirred at room temperature while chloromethyl chlorosulfate (3.19 ml) was added slowly. After stirring for a further 30 minutes the organic phase was separated and evaporated in vacuo. The crude product was distributed between diethyl ether and water. The organic phase was separated, dried and evaporated to yield the title compound as an oil. 13C NMR (CDOs) 8 = 172.6, 154.6, 79.7, 68.7, 42.8, 40.8, 28.4, 27.5
With tetra(n-butyl)ammonium hydrogensulfate; sodium hydrogencarbonate; In dichloromethane; water; at 20℃; for 5h;
Step-1: To a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (5 g, 21.8 m mol) in a mixture of dichloromethane and water (60 mL:80 mL) was added chloromethyl chlorosulfonate (4.3 g, 26 mmol) drop wise, subsequently solid NaHCO3 (7 g, 84 mmol) was added portion wise, followed by n-tetrabutylammonium hydrogen sulphate (TBAHS) (0.7 g, 2.1 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 5 h. The organic layer was separated, washed with water and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide 5.2 g of a white solid, yield: 86percent. This was confirmed by LCMS and used as such for next step.
With 1-hydroxy-7-aza-benzotriazole; ammonium chloride; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 10h;Inert atmosphere;
A mixture of 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (220 mg, 2.88 mmol) , ammonium chloride (154 mg, 2.88 mmol) , EDCI (367 mg, 1.92 mmol) and HOAT (195 mg, 1.44 mmol) in DCM (10 mL) was stirred at 0 , and then DIPEA (1.0 mL, 5.77 mmol) was added dropwise. After the addition, the mixture was stirred at rt for 10 h and washed with water (10 mL × 3) . The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with EtOAc to give tert-butyl 4-carbamoylpiperidine-1-carboxylate as a white solid (160 mg, 73) .1H NMR (400 MHz, CD3OD) : delta ppm 4.11 (d, J 13.4 Hz, 2H) , 2.76-2.86 (m, 2H) , 2.38-2.45 (m, 1H) , 1.79 (d, J 11.2 Hz, 2H) , 1.52-1.62 (m, 2H) , 1.47 (s, 9H) and MS-ESI: m/z 173.20 [M-55] +.
73%
With 1-hydroxy-7-aza-benzotriazole; ammonium chloride; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 10h;
The compound 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (220mg, 0.96mmol), ammoniumchloride (154mg, 2.88mmol), 1- ethyl 3- (3-dimethylaminopropyl) carbodiimide hydrochloride (367mg,1.92mmol) and N- hydroxy-7-aza-benzotriazole (195mg, 1.44 mmol) were dissolved in dichloromethane (10mL), and the conditions under 0 C, to this solution was added dropwise N, N- diisopropylethylamine(1.0mL, 5.77 mmol), stirred for 10H at room temperature, add water (10mL × 3) washing the organic phase wasdried over anhydrous Na 2 SO 4, the solvent was removed, the concentrate was subjected to columnChromatography (eluent: EtOAc), to give a white solid 160mg: 4-carbamoyl-piperidine-1-carboxylate, yield:73%.
56%
With ammonia; N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;
To a mixture of l-(tert- butoxycarbonyl)piperidine-4-carboxylic acid 1 (2.29 g, 10 mmol), DIEA (3.87 g, 30 mmol) and HATU (4.18 g, 11 mmol) in DMF (50 mL) was added NH3 by bubbling for 20 min. The resulting mixture was stirred at rt overnight. The mixture was diluted with water (200 mL) and extracted with EA (2 x 50 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was applied onto silica gel column eluting with EA to get the title compound (1.3 g, 56%) as white solid. MS (ESI): m/z = 173.2 [M + H - 56]+.
To a stirred solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (10.0 g, 43.6 mmol) in dry THF (150 mL,), CDI (9.95 g, 65.6 mmol) was added at 0-5 C and the reaction mixture was stirred at rt for 16 h. Then the reaction mixture was cooled to 0-5 C and a continueous flow of ammonia was applied to the solution for 2 h. MeOH (30 ml.) was added and the flow of ammonia was applied for 2 additional hours at the same temperature. The reaction mixture was then stirred at rt for 16 h. It was concentrated under reduced pressure and the resulting crude mixture was dissolved in EtOAc and washed with 10% citric acid, 10% sodium bicarbonate, water, dried over anhydrous Na2SO4 and concentrated under vacuum to afford the title compound (white solid). 1H NMR (400 MHz, DMSO-d6): delta 6.77 (s, 2H), 3.91-3.88 (m, 2H), 2.71-2.49 (m, 2H), 2.25-2.17 (m, 1H), 1.66-1.62 (m, 2H), 1.39-1.35 (m, 13H). LCMS: (Method A) 130.2 (M+H), Rt. 2.62 min, 99.0% (Max).
To a stirring suspension of t-Boc-isonipecotic acid (19) (2.34 g, 10.2 mmol) and the Weinreb amine (1.5 g, 15 mmol) in DMF (50 mL), was added triethylamine (2.8 mL, 20 mmol) at room temperature. After stirring for 10 min, HOBt (1.62 g, 12 mmol) was added, followed by EDCI (2.3 g, 12 mmol). The resulting solution was stirred overnight and concentrated. The residue was taken up in 1 N HCl (100 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with sat NaHCO3 (50 mL), brine (50 mL), dried (MgSO4) and concentrated to obtain a colorless oil (20) (2.79 g, >100%). 1H NMR (500 MHz, CDCL3) delta4.14 (m, 2H), 3.71 (s, 3H), 3.19 (s, 3H), 2.78 (m, 3H), 1.68 (m, 4H), 1.46 (s, 9H); MS (ESI+) m/z 217.72 (M+H+-isobutylene).
99%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 48h;
PREPARATION 557erf-butyl 4-acetylpiperidine-1 -carboxylatea) Tert-butyl 4-[methoxy(methyl)amino]carbonyl}piperidine-1 -carboxylateTo a solution of N.O-dimethylhydroxylamine hydrochloride (894 mg, 9.17 mmol), 2- benzotriazol-1-yl-N,N,N',N'-tetramethyluronio hexafluorphosphate (HBTU) (3.48 g, 9.17 mmol) and diisopropylethylamine (DIPExiA) in N,N-dimethylformamide (40 mL) was carefully added 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (2 g, 8.73 mmol) and the reaction mixture was stirred at room temperature for 2 days. The mixture was diluted with water (200 mL), extracted with ethyl acetate, washed with aqueous citric acid 5%, aqueous sodium bicarbonate 4%, water, and brine and dried over sodium sulphate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica flash, using ethyl acetate as eluent (isocratic), to yield the title compound (2.63 g, 99%) as yellowish oil. <n="63"/>1H-NMR delta (CDCI3): 1.46 (s, 9H), 1.63-1.74 (m, 4H), 2.70-2.84 (m, 3H), 3.19 (s, 3H), 3.72 (s, 3H), 4.11-4.18 (m, 2H).
99%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
To a solution of compound 25 (40 g, 175 mmol) in DMF (250 mL) at 4C was added N.O - dimethyl-OHamine, hydrochloride (34 g), EDCI (44 g, 0.228 mol), HOBT (2.4 g), and DIPEA (120 mL). The reaction was warmed to room temperature and stirred overnight. The reaction was then concentrated to half volume in vacuo and poured onto 1:1 ethyl acetate: water. The organic layer was separated and the aqueous layer extracted with additional ethyl acetate. The combined organic layers were washed with saturated aqueous NH4Cl, saturated aqueous NaHCO3, water, and brine, and dried. Concentration gave 26 as a light yellow oil (46.7 g, 99%)
95%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 72h;
Intermediate 1; 1,1-dimethylethyl4-[methyl(methyloxy)amino]carbonyl}-1-piperidine-carboxylate; QN,O-Dimethylhydroxylamine hydrochloride (4.26 g, 43.7 mmols), di-isopropylethylamine (33.88 g, 45.66 ml, 262.2 mmols) and HATU (19.94 g, 52.4 mmols) were added to a solution of N-Boc-piperidine-4-carboxylic acid (11.03 g, 48.1 mmols) in dry DMF (250 ml_). The reaction mixture was stirred at room temperature for 72 hrs. The DMF was removed in vacuo and the residue was partitioned between ethyl acetate (200 mL) and saturated aqueous sodium bicarbonate (200 mL). The organic phase was separated, washed with saturated aqueous sodium bicarbonate (200 mL) and brine (200 mL), and dried over MgSO4. Evaporation of the solvent afforded a dark oil (21.0 g) that was purified by flash chromatography (Silica, gradient elution with pentane/ethyl acetate 9:1 v/v to 3:2 v/v) to give the title compound 12.5 g (95%) as a gum. LC/MS-M+H 273
95%
3. Synthesis of intermediate D-1: C-1 D-1 To a stirred solution of C-1 (80 g, 0.35 mol) in 1 L of anhydrous CH2CI2 was added CDI (62.24 g, 0.38 mol) under N2 at 0C. After the addition, the mixture was stirred at 25C for 1 hour, gas formation was observed. Et3N (42.37 g, 42 mol) was added, the mixture was stirred at 25C for 30 min, then Omicron,Nu-dimethylhydroxylamine hydrochloride (42.54 g, 0.44 mol) was added. After the addition, the mixture was stirred at 25 C for 15 hrs. The mixture was washed with water, aq. NaHC03 and aq. citric acid monohydrate. The organic layer was separated, dried over anhydrous Na2S04 and concentrated to get intermediate D-1 (80 g, 95%) as a white solid.
95%
To a stirred solution of C-1 (80 g, 0.35 mol) in 1 L of anhydrous CH2Cl2 was added CDI (62.24 g, 0.38 mol) under N2 at 0 C. After the addition, the mixture was stirred at 25 C. for 1 hour, gas formation was observed. Et3N (42.37 g, 42 mol) was added, the mixture was stirred at 25 C. for 30 min, then O,N-dimethylhydroxylamine hydrochloride (42.54 g, 0.44 mol) was added. After the addition, the mixture was stirred at 25 C. for 15 hrs. The mixture was washed with water, aq. NaHCO3 and aq. citric acid monohydrate. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated to get intermediate D-1 (80 g, 95%) as a white solid.
95%
With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide;
Add N,O-dimethylhydroxylamine hydrochloride (2.52 g, 26 mmol), 1-hydroxybenzotriazole (HOBt) (2.8 g, 20.8 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI.HCl)(4 g, 20.8 mmol) and 4-methylmorpholine (5.28 g, 52 mmol) at 0 C. to the solution of N-Boc-piperidine-4-carboxylic acid (4 g, 17.4 mmol) in DMF (50 mL), stir the mixture overnight at room temperature. TLC (PE:EtOAc=1:1) shows the reaction is complete. Partition between ethyl acetate and water, collect the organic layer and wash with brine, dry over anhydrous sodium sulfate, filter and concentrate the filtrate under reduced pressure to give the crude product (4.5 g, 95%) which is used in next step without further purification.
95%
To a stirred solution of C-1 (80 g, 0.35 mol) in 1 L of anhydrous CH2Cl2 was added CDI (62.24 g, 0.38 mol) under N2 at 0 C. After the addition, the mixture was stirred at 25 C. for 1 hour, gas formation was observed. Et3N (42.37 g, 42 mol) was added, the mixture was stirred at 25 C. for 30 min, then O,N-dimethylhydroxylamine hydrochloride (42.54 g, 0.44 mol) was added. After the addition, the mixture was stirred at 25 C. for 15 hrs. The mixture was washed with water, aq. NaHCO3 and aq. citric acid monohydrate. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated to get intermediate D-1 (80 g, 95%) as a white solid.
95.0%
With 1,1'-carbonyldiimidazole; In dichloromethane; at 20℃; for 18h;
[0211] 1-(1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (6.51 g, 0.022 mol) was dissolved in dichloromethane (50 ml). To the resulting solution were added 1,1'-carbonyldiimidazole (CDI) (6.31 g, 0.033 mol) and N,O-dimethylhydroxylamine hydrochloride (9.62 g, 0.67 mol) and the solution was stirred at room temperature for 18 hrs. After completion of the reaction by addition of water, the solution was extracted with dichloromethane, washed with distilled water, and dried over magnesium sulfate (MgSO4) to concentrate. The resulting residue was isolated and purified by silica gel column chromatography (dichloromethane/methanol = 10/1) to give the white title compound (5.36 g, 95.0 %). 1H NMR (400 MHz, CDCl3) delta 4.14 (m, 2H), 3.71 (s, 3H), 3.13 (s, 3H), 2.79 (m, 5H), 1.42 (s, 9H).
88%
INTERMEDIATE B4 tert-Butyl 4-[methoxy(methyl)amino]carbonyl}piperidine-l-carboxylate A suspension of l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (5.0 g, 21.8 mmol), EDC (6.27 g, 32.7 mmol) and HOBT (2.95 g, 21.8 mmol) in DMF (10 mL) was stirred for20 min. To the mixture were then added 1 ,2-dimethylhydroxylamine hydrochloride (3.19 g, 32.7 mmol) and DIEA (13 mL, 76.3 mmol) and the stirring continued overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was concentrated and the residue was purified by flash chromatography on silica using EtOAc as eluent. Yield 5.22 g (88%). Analytical HPLC: purity 100% (System A and B);LRESIMS (ESI+) m/z = 217 (M+H-phiu)+.
84%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 25℃; for 16h;Inert atmosphere;
A mixture of A-Boc-isonipecotic acid (10.0 g, 43.6 mmol), 0,N- dimethylhydroxylamine HC1 (6.38 g, 65.4 mmol), triethylamine (12.2 mL, 87.23 mmol) and l-hydroxybenzotriazole (7.07 g, 52.3 mmol) and EDC1 (10.0 g, 52.3 mmol) in DMF (50 mL) was stirred at 25 C for 16 h. The mixture was concentrated in vacuo to give a residue which was neutralized by HC1 (1M) to pH = 7 and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over Na^SCL, filtered and concentrated in vacuo to give a residue which was purified by flash column (petroleum ether: ethyl acetate 10:1) to give / /-butyl 4-(methoxy(methyl)carbamoyl)piperidine-l -carboxylate (10 g, 84%) as a light yellow solid; LC-MS: 295.1 [M+Na]+.
80%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 19h;
Synthesis of 4-(Methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid t-butyl ester Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.0 eq, 21.8 mmol) was dissolved under inert conditions in 35 ml dry N,N-dimethylformamide. O,N-dimethyl-hydroxylamine hydrochloride (1.03 eq, 22.5 mmol), benzotriazol-1-ol monohydrate (1.03 eq, 22.5 mmol) and triethylanine (1.5 eq, 32.7 mmol) were added. The reaction mixture was cooled to 0 C., N-(3-Dimethylaminopropyl)-N-ethylcarbodiimid hydrochloride (1.0 eq, 21.8 mmol) was added over a period of 1.0 minutes and the mixture was stirred vigorously at 0 C. for 1 h and at r.t. for 18 h. The solvent was removed under vaccum and the residue was suspended in 400 ml ethylacetate. The organic layer was extracted 3 times with 100 ml of 1 M citric acid, aqueous sodium carbonate and twice with 100 ml brine, dried over MgSO4 and filtered. The solvent was removed and the residue as purified by distillation resulting in a yield of 80%.
80%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; at 0 - 20℃; for 19.8333h;
Synthesis of 4-(Methoxy-methyl-carbamoyl)-piperidine-l-carboxylic acid t-butyl esterPiperidine-l,4-dicarboxylic acid mono-tert-butyl ester (1.0 eq, 21.8 mmol) was dissolved under inert conditions in 35 ml dry N, N- dimethylformamide. O,N-dimethyl- hydroxylarnine hydrochloride (1.03 eq, 22.5 mmol), benzotriazol-1-ol monohydrate (1.03 eq, 22.5 mmol) and triethylamine (1.5 eq, 32.7 mmol) were added. The reaction mixture was cooled to O0C, N-(3-Dimethylaminopropyl)-N-ethylcarbodiimid hydrochloride (1.0 eq,21.8 mmol) was added over a period of 10 minutes and the mixture was stirred vigorously at O0C for 1 h and at r.t. for 18 h.The solvent was removed under vaccum and the residue was suspended in 400 ml ethylacetate. The organic layer was extracted 3 times with 100 ml of 1 M citric acid, aqueous sodium carbonate and twice with 100 ml brine, dried over MgSO4 and filtered. The solvent was removed and the residue was purified by distillation resulting in a yield of 80%.
80%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 19.1667h;
Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.0 eq, 21.8 mmol) was dissolved under inert conditions in 35 ml dry N, N- dimethylformamide. O,N-dimethylhydroxylamine hydrochloride (1.03 eq, 22.5 mmol), benzotriazol-1-ol monohydrate (1.03 eq, 22.5 mmol) and triethylamine (1.5 eq, 32.7 mmol) were added. The reaction mixture was cooled to 0C, N-(3-Dimethylaminopropyl)-N-ethylcarbodiimid hydrochloride (1.0 eq, 21.8 mmol) was added over a period of 10 minutes and the mixture was stirred vigorously at 0C for 1 h and at r.t. for 18 h. The solvent was removed under vaccum and the residue was suspended in 400 ml ethylacetate. The organic layer was extracted 3 times with 100 ml of 1 M citric acid, aqueous sodium carbonate and twice with 100 ml brine, dried over MgSO4 and filtered. The solvent was removed and the residue was purified by distillation resulting in a yield of 80%.
80%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 19.1667h;
Piperidine-l,4-dicarboxylic acid rnono-tert-butyl ester (1.0 eq, 21.8 mmol) was dissolved under inert conditions in 35 ml dry N, N- dimethylformamide. O,N-dimethyl- hydroxylamine hydrochloride (1.03 eq, 22.5 mmol), benzotriazol-1-ol monohydrate (1.03 eq, 22.5 mmol) and triethylamine (1.5 eq, 32.7 mmol) were added. The reaction mixture was cooled to 00C, N-(3 -Dimethyl aminopropyl)-N-ethylcarbodiimid hydrochloride (1.0 eq, 21.8 mmol) was added over a period of 10 minutes and the mixture was stirred vigorously at 0C for 1 h and at r.t. for 18 h.The solvent was removed under vaccum and the residue was suspended in 400 ml ethylacetate. The organic layer was extracted 3 times with 100 ml of 1 M citric acid, aqueous sodium carbonate and twice with 100 ml brine, dried over MgSO4 and filtered. The solvent was removed and the residue was purified by distillation resulting in a yield of 80%.
80%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 19.1667h;
Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.0 eq, 21.8 mmol) was dissolved under inert conditions in 35 ml dry N,N-dimethylformamide. O,N-dimethyl-hydroxylamine hydrochloride (1.03 eq, 22.5 mmol), benzotriazol-1-ol monohydrate (1.03 eq, 22.5 mmol) and triethylamine (1.5 eq, 32.7 mmol) were added. The reaction mixture was cooled to 0 C., N-(3-Dimethylaminopropyl)-N-ethylcarbodiimid hydrochloride (1.0 eq, 21.8 mmol) was added over a period of 10 minutes and the mixture was stirred vigorously at 0 C. for 1 h and at r.t. for 18 h.The solvent was removed under vacuum and the residue was suspended in 400 ml ethylacetate. The organic layer was extracted 3 times with 100 ml of 1 M citric acid, aqueous sodium carbonate and twice with 100 ml brine, dried over MgSO4 and filtered. The solvent was removed and the residue was purified by distillation resulting in a yield of 80%.
80%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 19h;
Synthesis of 4-(Methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid t-butyl ester Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.0 eq, 21.8 mmol) was dissolved under inert conditions in 35 ml dry N, N- dimethylformamide, O,N-dimethyl-hydroxylamine hydrochloride (1.03 eq, 22.5 mmol), benzotriazol-1-ol monohydrate (1.03 eq, 22.5 mmol) and triethylamine (1.5 eq, 32.7 mmol) were added. The reaction mixture was cooled to 0C, N-(3-Dimethylaminopropyl)-N-ethylcarbodiimid hydrochloride (1.0 eq, 21.8 mmol) was added over a period of 10 minutes and the mixture was stirred vigorously at 0C for 1h and at r.t. for 18h. The solvent was removed under vaccum and the residue was suspended in 400 ml ethylacetate. The organic layer was extracted 3 times with 100 ml of 1 M citric acid, aqueous sodium carbonate and twice with 100 ml brine, dried over MgSO4 and filtered. The solvent was removed and the residue was purified by distillation resulting in a yield of 80%.
77%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 16h;
To the mixture of 10 (47.0 g, 205 mmol) and N,O-dimethylhydroxylamine hydrochloride (20.8 g, 213 mmol) in CH2Cl2 (1 L) was added EDC (44.6 g, 232 mmol) in one portion followed by Et3N (32.4 mL, 232 mmol) dropwise at rt. The resulting solution was stirred at rt for 16 h. The solution was washed with brine (800 mL x 4) and a saturated NaHCO3 solution (500 mL), and then dried over Na2SO4. After evaporating the solvent, the residue was purified on silica gel using 60%EtOAc/hexane to give 11 (43.2 g, 77%) as an oil.
71%
To a stirred solution of l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (5.0 g, 21.7 mmol) in DMF (20 mL) was added HATU (12.39 g, 32.60 mmol) and diisopropylethylamine (18.94 ml, 108.6 mmol). The solution was stirred for 10 min at 0 C. After that Nu,Omicron-dimethylhydroxylamine hydrochloride (2.12 g, 21.7 mmol) was added and stirred at RT for 2 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain a crude residue which was purified by column chromatography to afford tert-butyl 4- (methoxy(methyl)carbamoyl)piperidine-l-carboxylate (4.3 g, 71%). LCMS: m/z = 173.05 (M-Boc)+.
61%
Example 5; Synthesis of 2-(4-(phenyl(4-(trifluoromethyl)phenyl)methyl)piperidin- 1 -yl)acetic acidStep lTo a solution of l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (11 g, 48 mmol) in DCM (120 mL) was added CDI (11 g). After stirring at rt for 2 h, N,O-dimethylhydroxyl- amine hydrochloride was added in portions. The mixture was stirred for 3 h at rt and was then left to stand overnight. The solvent was removed under vacuum, the residue was extracted with DCM, washed with brine and water, dried over anhydrous sodium sulfate and concentrated to give crude tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-l-carboxylate (8 g, 61% yield) as a white solid which was used directly in the next step.
42%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃;
Reagents and conditions: (a) B0C2O, 1,4-dioxane, H2O, NaOH, overnight, rt, (yield 94%); (b) HOBt, EDCl, TEA,DMF, NHMeOMe-HCl, overnight, rt, (yield 42%); (c) BuLi, 2-bromobiphenyl, TMEDA, THF, 3h, -78C, (yield 35%) ; (d) TFA, DCM , lh, rt, (yield quant); (e) toluene, 2h, (yield 24%), (f) NaBH4, THF, MeOH, overnight, rt, (yield 25%). Compounds 8-9 were synthesized from isonipecotic acid. The amine function was first protected with tert-butyl carbamate group followed by the formation of the Weinreb amide using HOBt and EDCl. Then, the lithium anion of 2-bromobiphenyl reacted on the Weinreb amide and Boc deprotection to give compounds 8. Addition reaction on iso(thio)cyanate with the piperidine in toluene afforded (thio)urea 9a-9b, followed by a reduction of the ketone group give the alcohol derivatives lOa-lOb.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 18h;
To a solution of N-tert-butoxycarbonyl isonipecotic acid (7.20 g) and N,O-dimethylhydroxylamine hydrochloride (3.68 g) in dichloromethane (100 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.23 g), N-hydroxybenzotriazole (5.10 g) and triethylamine (10.52 ml). The resulting solution was stirred at ambient temperature for 18 hours. The solution was diluted with dichlioromethane and washed with water, 2M aqueous citric acid solution, saturated aqueous sodium bicarbonate solution, dried (Na2SO4) and evaporated to give 1-(tert-butoxycarbonyl)-4-(N,O-dimethylhydroxylamino carbonyl)piperidine (8.01 g) as an oil: NMR (CDCl3): 1.40 (s, 9H), 1.70 (m, 4H), 2.80 (m, 3H), 3.20 (s, 31) 3.70 (s, 31H), 4.20 (m, 21H); m/z 273 (M+1).
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h;
N-Boc-isonipecotic acid (8.04 g, 35.1 mmol) was combined with N, O-DIMETHYLHYDROXYLAMINE hydrochloride (5.13 g, 52.6 mmol), EDC (10.1 g, 52.6 mmol) and DIEA (9.2 mL, 53 mmol) in DCM (100 mL). Then N, N-DIMETHYLAMINOPYRIDINE (-200 mg) was added and the reaction mixture was permitted to stir at rt for 2h. The reaction mixture was diluted with more DCM and washed with 2 N HC1 solution, saturated NAHCO3 solution, and brine. The organic layer was dried over anhydous MGS04, filtered, and concentrated to give 8.43 g of crude product which was used without further purification. ESI-MS calc. for C13H24N204 : 272; Found: 273 (M+H).
In dichloromethane; 1,1'-carbonyldiimidazole;
B 4-(N-Methoxy-N-methylcarboxamido)-1-piperidinecarboxylic acid 1,1-dimethylethyl ester To a stirred solution of 1-(1,1-dimethylethyl)1,4-piperidinedicarboxylic acid (50.0 g, 218 mmol) in anhydrous CH2 Cl2 (500 mL) under N2 in a 2L flask was added 1,1'-carbonyldiimidazole (38.9 g, 240 mmol) portionwise. After stirring for 1 hour, N,O-dimethylhydroxylamine hydrochloride (23.4 g, 240 mmol) was added in one portion. After stirring overnight, the solution was washed twice with 1N HCl, twice with saturated NaHCO3, once with brine, dried (MgSO4), filtered, and evaporated to an oil. Distillation afforded 4-(N-methoxy-N-methylcarboxamido)-1-piperidinecarboxylic acid 1,1-dimethylethyl ester as a clear oil, b.p. 120-140 C., 0.8 mm.
A. N-Methoxy-N-methylpiperidine-4-carboxamide: A mixture of N-tert- butoxycarbonyl isonipecotic acid (1.50 g, 6.54 mmol, 1 eq), l-(3-dimethylaminopropyl)3- ethylcarbodiimide hydrochloride (1.88 g, 9.81mmol, 1.5 eq), 1-hydroxybenzotriazole (1.33 g, 9.81 mmol, 1.5 eq), and N,N-dimethylformamide (26 ml) was treated with N5N- diisopropylethylamine (4.60 ml, 26.2 mmol, 4 eq). The resultant yellow solution was stirred at room temperature for 5 minutes, and then N,O-dimethylhydroxylamine hydrochloride (766 mg, 7.85 mmol, 1.2 eq) was added, and stirring continued for 92 hours. The reaction mixture was diluted with 100 ml of ethyl acetate and washed sequentially with 1 N aq. NaOH, 1 N aq. HCl and brine. The organic phase was dried over Na2SO4 and concentrated to give an oil which was used with no further purification. This oil was dissolved in 1 :2 trifluoroacetic acid/dichloromethane (9 ml), and the reaction mixture was stirred at ambient temperature for 17 hours and then concentrated. Ether (30 ml) was added and the white solid which formed was collected by filtration, washed with ether and dried to afford 1.50 g (80% yield, 2 steps) of analytically pure product: 400 MHz 1H NMR (d6-DMSO): 8.55 (br s, 1 H), 8.25 (br s, 1 H), 3.69 (s, 3 H), 3.31 (m, 2 H), 3.10 (s, 3 H), 2.98 (m, 3 H), 1.65-1.84 (m, 4 H).
To a stirred solution of 1-(1,1-dimethylethy)-1,4-piperidinedicarboxylic acid (50.0 g, 218 mmol) in anhydrous CH2Cl2 (500 mL) under N2 in a 2 L flask was added 1,1'-carbonyldiimidazole (38.9 g, 240 mmol) portionwise. After stirring for 1 hour, N,O-dimethylhydroxylamine hydrochloride (23.4 g, 240 mmol) was added in one portion. After stirring overnight, the solution was washed twice with 1N HCl, twice with saturated NaHCO3, once with brine, dried (MgSO4), filtered, and evaporated to an oil. Distillation afforded 4-(N-methoxy-N-methylcarboxamido)-1-piperidinecarboxylic acid 1,1-dimethylethyl ester as a clear oil, b.p. 120-140 C., 0.8 mm.
A. N-Methoxy-N-methylpiperidine-4-carboxamide:; A mixture of N-tert- butoxycarbonyl isonipecotic acid (1.50 g, 6.54 mmol, 1 eq), l-(3-dimethylaminopropyl)3- ethylcarbodiimide hydrochloride (1.88 g, 9.81mmol, 1.5 eq), 1-hydroxybenzotriazole (1.33 g, 9.81 mmol, 1.5 eq), and N,N-dimethylformamide (26 ml) was treated with N5N- diisopropylethylamine (4.60 ml, 26.2 mmol, 4 eq). The resultant yellow solution was stirred at room temperature for 5 minutes, and then N,O-dimethylhydroxylamine hydrochloride (766 mg, 7.85 mmol, 1.2 eq) was added, and stirring continued for 92 hours. The reaction mixture was diluted with 100 ml of ethyl acetate and washed sequentially with 1 N aq. NaOH, 1 N aq. HCl and brine. The organic phase was dried over Na2SO4 and concentrated to give an oil which was used with no further purification. This oil was dissolved in 1 :2 trifluoroacetic acid/dichloromethane (9 ml), and the reaction mixture was stirred at ambient temperature for 17 hours and then concentrated. Ether (30 ml) was added and the white solid which formed was collected by filtration, washed with ether and dried to afford 1.50 g (80% yield, 2 steps) of analytically pure product: 400 MHz 1H NMR (d6-DMSO): 8.55 (br s, 1 H), 8.25 (br s, 1 H), 3.69 (s, 3 H), 3.31 (m, 2 H), 3.10 (s, 3 H), 2.98 (m, 3 H), 1.65-1.84 (m, 4 H).
6.6. Preparation of ( l-(Pyrimidin-2-vDpiperidin-4-vD(4-4- trifluoromethylphenvD-phenvDmethanoneThe title compound was prepared from (4-bromophenyl)(l-(pyrimidin-2- yl)piperidin-4-yl)methanone as described below.N-methoxy-N-methylpiperidine-4-carboxamide: A mixture of N-tert- butoxycarbonyl isonipecotic acid (1.50 g, 6.54 mmol, 1 eq), l-(3-dimethylaminopropyl)3- ethylcarbodiimide hydrochloride (1.88 g, 9.81mmol, 1.5 eq), 1-hydroxybenzotriazole <n="52"/>(1.33 g, 9.81 mmol, 1.5 eq), and N,N-dimethylformamide (26 ml) was treated with N5N- diisopropylethylamine (4.60 ml, 26.2 mmol, 4 eq). The resultant yellow solution was stirred at room temperature for 5 minutes, and then N,O-dimethylhydroxylamine hydrochloride (766 mg, 7.85 mmol, 1.2 eq) was added, and stirring continued for 92 hours. The reaction mixture was diluted with 100 ml of ethyl acetate and washed sequentially with 1 N aq. NaOH, 1 N aq. HCl and brine. The organic phase was dried over Na2SO4 and concentrated to give an oil which was used with no further purification. This oil was dissolved in 1 :2 trifluoroacetic acid/dichloromethane (9 ml), and the reaction mixture was stirred at ambient temperature for 17 hours and then concentrated. Ether (30 ml) was added and the white solid which formed was collected by filtration, washed with ether and dried to afford 1.50 g (80% yield, 2 steps) of analytically pure product: 400 MHz 1H NMR (d6-DMSO): 8.55 (br s, 1 H), 8.25 (br s, 1 H), 3.69 (s, 3 H), 3.31 (m, 2 H), 3.10 (s, 3 H), 2.98 (m, 3 H), 1.65-1.84 (m, 4 H).
EXAMPLE 1; l-benzoyI-4-(l-methyl-l-[3-(trifluoromethyI)phenyl]sulfonyI}ethyl)piperidineStep 1 : tert-butyl- 4- { [methoxy(methyl)amino] carbonyl } piperidine- 1 -carboxylate <n="34"/>To a 500 ml round bottom flask was added 150 ml tetrahydrofuran and 24.8 g -{tert- butoxycarbonyl)piperidine-4-carboxylic acid (108 mmol). Carbonyldiimidazole (CDI) (18.4 g, 114 mmol) was added in portions. The reaction mixture was stirred at room temperature for 1 hour. Methylmehoxy amine hydrochloride salt (14.8 g, 151 mmol) was added followed by 22.6 ml triethylamine. The reaction mixture was heated at 55 C for 1 hour. It was cooled with ice bath and diluted with 200 ml ether. The resulting mixture was washed sequentially twice with 150 ml of saturated ammonium chloride solution, 150 ml 5% KOH solution and 100 ml brine. The organic layers were dried over sodium sulfate, filtered and concentrated. The residue was dissolved in 50 ml toluene and then reconcentrated under vacuum to give 29 g colorless oil which was used for next step without further purification.1H-NMR (CDCl3): delta 4.17 (b, 2H), 3.74 (s, 3H), 3.21 (s, 3H)5 2.8 (b, 3H), 1.7 (b, 4H), 1.49 (s, 9H) Mass Spectra (m/e): 273 (M+ 1).
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine;dmap; In dichloromethane; at 20℃; for 2h;
N-BOC-ISONIPECOTIC acid (8.04 g, 35.1 mmol) was combined with N, O-dimethylhydroxylamine hydrochloride (5.13 g, 52.6 mmol), EDC (10.1 g, 52.6 mmol) and DIEA (9.2 mL, 53 mmol) in DCM (100 mL). Then N, N-dimethylaminopyridine (-200 mg) was added and the reaction mixture was permitted to stir at rt for 2h. The reaction mixture was diluted with more DCM and washed with 2 N HC1 solution, saturated NAHC03 solution, and brine. The organic layer was dried over anhydous MGS04, filtered, and concentrated to give 8.43 g of crude product which was used without further purification. ESI-MS calc. for C13H24N204 : 272; Found: 273 (M+H).
To a solution of l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (50 g, 218 mmol) in DCM (500 mL), 1,1-carbonyldiimidazole (46 g, 284 mmol) was added and the reaction mixture was stirred for 1 h at 25-30 0C. N,O-Dimethylamine hydrochloride (30 g, 306 mmol) was then added and the resulting mixture was stirred for 15 h at 25-30 0C. After completion of the reaction, the reaction mixture was diluted with DCM and washed with water, saturated NaHCtheta3 solution, and 10% NaOH solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to afford pure tert-butyl 4-(methoxy(methyl)carbamoyl)- piperidine- 1 -carboxylate product.
1.78 g of carbonyldiimidazole are added, in several stages, to 2.29 g of commercially available N-BOC isonipecotic acid in 40 ml of methylene chloride, and the whole mixture is stirred for 2.5 h at ambient temperature. 1.072 g of N,O-dimethoxyhydroxylamine hydrochloride are then added and the reaction is stirred at ambient temperature overnight. The medium is washed with water, then 0.01N HCl, then NaHCO3, then again with water. After drying and evaporation, the crude product is purified on a silica cartridge, elution being carried out with a 9/1 and then 8/2 mixture of methylene chloride/ethyl acetate.2.67 g of the expected product are obtained.
N-methoxy-N-methylpiperidine-4-carboxamide A mixture of N-tert-butoxycarbonyl isonipecotic acid (1.50 g, 6.54 mmol, 1 eq), 1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (1.88 g, 9.81mmol, 1.5 eq), 1-hydroxybenzotriazole (1.33 g, 9.81 mmol, 1.5 eq), and N,N-dimethylformamide (26 ml) was treated with N,N-diisopropylethylamine (4.60 ml, 26.2 mmol, 4 eq). The resultant yellow solution was stirred at room temperature for 5 minutes, and then N,O-dimethylhydroxylamine hydrochloride (766 mg, 7.85 mmol, 1.2 eq) was added, and stirring continued for 92 hours. The reaction mixture was diluted with 100 ml of ethyl acetate and washed sequentially with 1 N aq. NaOH, 1 N aq. HCl and brine. The organic phase was dried over Na2SO4 and concentrated to give an oil which was used with no further purification. This oil was dissolved in 1:2 trifluoroacetic acid/dichloromethane (9 ml), and the reaction mixture was stirred at ambient temperature for 17 hours and then concentrated.
With 1,1'-carbonyldiimidazole; In tetrahydrofuran; for 14h;
N,O-BOC-piperidine-4-carboxylic acid (3.00 g, 13.08 mmol) was dissolved in THF and CDI (4.00 g, 24.7 mmol) was added in portions. The mixture was stirred for 2 h and N1O- dimethylhydroxylamine hydrochloride (4.00 g, 41 mmol) was added and stirring continued for 12 hours. The mixture was diluted with EtOAc and extracted 3 times with brine, dried <n="207"/>over Na2SO4, filtered and concentrated in vacuo. The residue was purified Biotage to provide the title compound. 1H NMR (CD2CI2) delta 4.12 (d,2H), 3.71 (s, 3H), 3.15 ( s, 3H), 2.83 (m, 1H), 2.76 (t, 2H), 1.70 (dd, 2H), 1.59 (m, 2H), 1.45(s, 9H).
With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 22.1667h;
N-Boc isonipecotic acid (13.566 g, 59.2 mmol), N,O-dimethyl hydroxylamine hydrochloride (8.657 g, 88.7 mmol), and 1-hydroxybenzotriazole hydrate (15.99 g, 118.3 mmol) were dissolved in DMF (225 mL) in a 500 mL round-bottom flask and diisopropylethylamine (15.29 g, 20.6 mL, 118.3 mmol) was then added with stirring at RT. 1-Ethyl-3-(3-dimethylamino-propyl)carbodiimide (17.01 g, 88.74 mmol) was added in several portions over 10 min with stirring. After 22 h, the reaction mixture was poured into a water and ice mixture (600 mL) and was extracted with ethyl acetate (5*125 mL). The combined organic layers were washed with 1N HCl (2*200 mL), 5% sodium bicarbonate (2*200 mL), water and brine, dried over sodium sulfate and concentrated to give the title compound as a yellowish oil. 1H NMR (500 MHz, CDCl3): delta4.11-4.20 (m, 2 H), 3.72 (br s, 3 H), 3.20 (br s, 3 H), 2.75-2.86 (m, 3 H), 1.63-1.76 (m, 4 H), 1.47 (s, 9 H).
N,O-Dimethylhydroxylamine hydrochloride (98%, 2.55 g, 26.17 mmol), NMM (14.39 mL, 130. 8 mmol), HOBT (1.47 g, [10.] 90 mmol) and HBTU (9.83 g, 26.16 mmol) were added to a solution of Compound 3a [(5.] 00 g, 21. 80 mmol) in MeCN (75 mL). The mixture was stirred for 1 h at [0 C] and overnight at rt, quenched with saturated [NH4CL,] concentrated and extracted with EtOAc (3x75 mL). The organic layer was dried [(NA2S04)] and concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel, 30-60% ethyl [ACETATE/HEXANE] with a few drops of TEA) to give Compound [3B] as a liquid. MS (ES+) m/z 273 [ (M+H+).] n-BuLi (2.5M in hexane, 7.34 mL, 18.35 mmol) was added dropwise to a stirred solution of 3-bromoquinoline (3.81 g, 18.35 mmol) in anhydrous [ET2Q] (65 mL) at-78 [C] over a period of 30 min. The mixture was stirred at-78 [C] for 30 min and a solution of Compound 3b (1.0 g, 3.67 mmol) in Et2O (20 mL) was added dropwise over a period of 10 min. The resulting mixture was stirred for 30 [MIN-78 C] and allowed to warm to rt. After stirring for 2 h at rt, the mixture was quenched with a saturated NH4C1 solution and diluted with EtOAc. The organic layer was washed with brine, dried [(NA2S04)] and concentrated in vacuo. The residue was purified via chromatography (silica gel, 15-25% ethyl acetate/hexane) to give Compound 3c as a liquid. MS (ES+) m/z 341 (M+H+). A solution [OF NAHMDS (1M,] 3.17 mL, 3.17 mmol) in THF was added over a period of 15 min to a stirred solution of trimethyl phosphonoacetate (0.51 mL, 3.17 mmol) in THF (15 mL) at [0 C] under argon. After the resulting mixture was stirred for 20 min, a solution of Compound 3c (0.27 g, 0.79 mmol) in THF (3 mL) was added over a period of 15 min. The mixture was stirred at [0 C] for 30 min, refluxed for 2.5 h, cooled to rt, diluted with Et2O (30 mL) and washed with a saturated [NAHC03] solution (2x25 mL) and brine (2x25 mL). The aqueous layer was extracted with Et2O and'the combined. organic layers were dried [(NA2S04)] and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 10-30% ethyl acetate/hexane) to give Compound 3d as a mixture of E-and Z-isomers. MS (ES+) m/z 397 (M+H+). A mixture of the [E-AND] Z-isomers of Compound 3d (0.25 g, 0.63 mmol) and [10%] Pd/C [ 1}] (0. [12 G) IN MEOH] (15 mL) was shaken overnight under hydrogen pressure (5 psi) in a Parr apparatus. The mixture was filtered through celite and concentrated under vacuum. The crude product was purified by flash chromatography (70% ethyl acetate in hexane) to yield Compound 3e as an oil. MS (ES+) m/z 399 [(M+H+).'H NMR] [(DMSO-D6,] 300 MHz) 8 1.38 [(M,] 4H), 1.41 (s, 9H), 1.80 (m, 1H), 2.53 [(M,] 2H), 3.18 [(M,] 2H), 3.51 (s, 3H), 3.71 [(M,] [1H),] 4.13 [(M,] 2H), 7.54 [(T,] [J=] 8 Hz, [1H),] 7.69 (t, [J=] 8 Hz, 1H), 7.80 (d, J= 8 Hz, [1H),] 7.89 (s, 1H), 8.09 (d, J= 8 Hz, 1H), 8. 75 (s, 1H). Compound 3e (0.11 g) was dissolved in dioxane (3 mL), one drop of anisole was added and 4N [HC1] in dioxane (3 mL) was added dropwise. The mixture was stirred at rt for 2 h and concentrated using MeCN as an azeotrope. The resulting solid was triturated with Et2O and hexane and dried to give Compound 3f as a sticky solid. MS (ES+) [M/Z] 299 [(M+H).'HNMR (DMSO-D6,] 300 MHz) [81.] 34 [(M,] 4H), 1.94 [(M,] 1H), 2. 67 (m, 2H), 3.01 [(M,] [2H),] 3.24 [(M,] 2H), 3.43 (s, 3H), 3.68 [(M,] 1H), 7.79 (t, J= 8 Hz, 1H), 7.94 (t, [J=] 8 Hz, [1H),] 8.13 (d, [J=] 8 Hz, [1H), 8.] 23 (d, [J=] 8 Hz, [1H),] 8.48 [(M,] [1H),] 8.70 [(M,] [1H).] Anal. Calcd for [C18H22N202-2.] [2 TFA-0. 4H20] : C, 48.36 ; H, 4.53 ; N, 5.04 ; F, 22.54. Found: C, 48.24 ; H, 4.42 ; N, 4.99 ; F, 22.56. [1,] 3-Diamino-2-hydroxypropane Compound 3i (10.0 g, 111 mmol) was dissolved in ethanol (30 mL) and deionized water (30 mL). Carbon disulfide (6.67 mL, 110.95 mmol) was added dropwise via an addition funnel over a period of 35 min while the temperature was maintained at [25-33 C] to afford a milky white mixture. The resulting mixture was refluxed for 2 h to afford a yellow solution. After cooling the mixture in ice water, concentrated HC1 (7 [ML)] was added dropwise while maintaining the mixture's temperature at [25-26 C.] The temperature of the mixture was then raised to [79 C.] After stirring for 21 h, the mixture was cooled to [2 C] and filtered via vacuum filtration. A white solid was collected, washed three times with a 1: 1 mixture of cold ethanol and water and dried in vacuo at [40 C] to give Compound 3j. MS [(ES+)] m/z 174 [(M+MECN). LH NMR (DMSO-D6,] 300 MHz) 8 2.96 (d, J= 15 Hz, 2H), 3.15 (d, J [= 13] Hz, 2H), 3.33 [(M,] 1H), 3.89 [(M,] [ 1H).] [ ] Methyl iodide (2.9 mL, 46 mmol) was added to a stirred solution of Compound [3J] (6.1 g, 46 mmol) in absolute ethanol (35 mL) and the mixture was refluxed for 1 h and cooled to [RT.] After concentration, the residue was triturated with Et2O and dried in vacuo to give Compound 3k as a white solid. MS [(ES+)] m/z 188 [(M+MECN). LH] NM...
With dmap; triethylamine; In dichloromethane; at 20℃;
INTERMEDIATE 1 fert-Butyl 4-[3-(4-chlorophenyl)-l H-pyrazol-5-vi]piperidine~l -carboxylateStep 1 : fert-Butyl 4-[methoxy(methyl)carbamoyl]piperidine-l-carboxylate (1.2). A mixture of 1- (fe?-t-butoxycarbonyl)piperidine-4-carboxylic acid (Aldrich, 6.0 g, 26.2 mmol), N, 0- dimethylhydroxylamine hydrochloride (3.06 g, 31.4 mmol), DMAP (3.20 g, 26.2 mmol), and triethyl amine (4.74 mL, 34 mmol) in DCM (200 mL) was stilted at room temperature overnight. The mixture was washed with saturated aqueous KHSO4 and brine. The organic layer was dried (MgS04) and the solvent was removed. The crude material was directly used in the next step.
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0 - 20℃;
Add Nu,Omicron-dimethylhydroxylamine hydrochloride (2.52 g, 26 mmol), 1-hydroxybenzotriazole (HOBt) (2.8g, 20.8 mmol), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(EDCI HCl)(4 g, 20.8 mmol) and 4-methylmorpholine (5.28 g, 52 mmol) at 0C to the solution of N-Boc-piperidine-4-carboxylic acid (4 g, 17.4 mmol) in DMF (50 mL), stir the mixture overnight at room temperature. TLC (PE:EtOAc=l :l) shows the reaction is complete. Partition between ethyl acetate and water, collect the organic layer and wash with brine, dry over anhydrous sodium sulfate, filter and concentrate the filtrate under reduced pressure to give the crude product (4.5 g, 95%) which is used in next step without further purification.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 18h;Inert atmosphere;
To a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (25.00 g, 107.72 mmol) in DMF (250 mL) is added Nu,Nu-diisopropyl ethylamine (57.01 mL, 323.16 mmol), 1-hydroxybenzotriazole hydrate (1.67 g, 10.77 mmol), (3- dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (25.03 g, 129.27 mmol) followed by the addition of Omicron,Nu-dimethyl-hydroxylamine hydrochloride (1 .68 g, 118.49 mmol) in small portions at 0 C under nitrogen atmosphere. The reaction mixture is stirred at room temperature for 18 h. After completion of the reaction the solvent is evaporated under reduced pressure. The residue is dissolved in ethyl acetate (300 mL), washed with 10% sodium bicarbonate (2 x 200 mL), 0.5 N HCI (2 x 100 mL), water (200 mL) and brine (200 mL). The organic layer is dried over anhydrous Na2S04 and evaporated under vacuum to afford 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester as colourless liquid; 1H NMR (400 MHz, CDCI3): delta 4.15-4.09 (m, 2H), 3.70 (s, 3H), 3.17 (s, 3H), 2.79-2.72 (m, 3H), 1.72-1.60 (m, 4H), 1.44 (s, 9H); LC/MS (Method B): 173.2 (M+H; BOC-cleaved mass), Rt. 3.54 min.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 18h;Inert atmosphere;
To a solution of piperidine-1 ,4-dicarboxylic acid mono-tert-butyl ester (25.00 g, 107.72 mmol) in DMF (250 mL) were added Nu,Nu-diisopropyl ethylamine (57.01 mL, 323.16 mmol), 1 -hydroxybenzotriazole hydrate (1.67 g, 10.77 mmol), (3- dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (25.03 g, 129.27 mmol) followed by the addition of Omicron,Nu-dimethyl-hydroxylamine hydrochloride (11.68 g, 18.49 mmol) in small portions at 0 C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 18 h. After completion of the reaction the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL), washed with 0% sodium bicarbonate (2 x 200 mL), 0.5 N HCI (2 x 100 ml_), water (200 ml_) and brine (200 mL). The organic layer was dried over anhydrous a2S04 and evaporated under vaccum; yield: 24.0 g (81%), colorless liquid (crude product); 1H NMR (400 MHz, CDCI3): delta 4.15-4.09 (m, 2H), 3.70 (s, 3H), 3. 7 (s, 3H), 2.79-2.72 (m, 3H), 1.72-1.60 (m, 4H), 1.44 (s, 9H); LC/MS (Method A): 173.2 (M+H; BOC-cleaved mass), Rt. 3.54 min, purity 99%.
With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine; In dichloromethane; at 15 - 20℃;
To a mixture of DCM (8.0 v) , BG-5 (80.0 Kg, 1.0 eq. ) , N, O-dimethylhydroxylamine hydrochloride (1.2 eq. ) , HOBt (1.2 eq. ) and EDCI (1.2 eq. ) , TEA (2.6 eq. ) was charged dropwise below 15. the mixture was stirred at RT until the reaction was completed, centrifuged and the cake was washed with DCM (1.0 v) twice. The filtrate was washed with 20aqueous NH4Cl (3 × 4.0 v) . The filtrate was concentrated under vacuum to give the crude product BG-6, which was used in the next step without further purification. The residue was dissolved in toluene (5.0 v) and THF (1.0 v) , cooled to 10 , charged dropwise MeMgBr (1.4 eq. ) at 10 and then stirred at RT until the reaction was completed. The solution was cooled below 10. Saturated aqueous NH4Cl was charged dropwise below 10. The mixure was centrifuged, separated, filtrated, and the organic phase was washed with aqueous NaCl twice. The organic phase was concentrated to give the crude product, which was used in the next step without further purification. The residue in DMF (2.5 v) and DMF-DMA (2.5 v) was stirred at 110 until the reaction was completed. The reaction mixture was cooled, concentrated and then DCM was added. The final mixture was washed with saturated aqueous NH4Cl. The organic layer was cconcentrated and precipitated by charging hexane. The mixture was ccentrifuged and the cake was collected. The cake was dried under vacuum. This gave 82.2 Kg of the desired product. 1H NMR (DMSO-d6) delta 7.49 (d, J 12.6 Hz, 1H) , 5.01 (d, J 12.6 Hz, 1H) , 3.99-3.82 (m, 2H) , 3.14-2.94 (m, 2H) , 2.89-2.61 (m, 6H) , 2.49-2.37 (m, 1H) , 1.66-1.56 (m, 2H) , 1.39 (s, 9H) , 1.39-1.20 (m, 2H) .
With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine; In dichloromethane; at 15 - 20℃;Large scale;
To less than 15 C, to DCM (8.0 v), BG-5 (80.0 Kg, 1.0 equivalent), N,O-dimethylhydroxylamine hydrochloride (1.2 equivalents), HOBt (1.2 equivalents) and EDCI (1.2 TEA (2.6 equivalents) was added dropwise to the mixture of equivalents. The mixture was stirred at room temperature until the reaction was completed, centrifuged and the filter cake was washed twice with DCM (1.0 v). The filtrate was washed with 20% aqueous NH4Cl (3 x 4.0 v). The filtrate was concentrated in vacuo to give abr. The residue was dissolved in toluene (5.0 v) and THF (1.0 v), cooled to 10 C, MeMgBr (1.4 eq.) was added dropwise at 10 C and then stirred at room temperature until the reaction was completed. The solution was cooled to below 10 C. A saturated aqueous NH4Cl solution was added dropwise at less than 10 C. The mixture was centrifuged, separated, filtered, and the organic phase was washed twice with aqueous NaCI. The organic phase was concentrated to give a crude material which was used in the next step without further purification. The residue in DMF (2.5 v) and DMF-DMA (2.5 v) was stirred at 110 C until the reaction was completed. The reaction mixture was cooled, concentrated and then DCM was added. The final mixture was washed with a saturated aqueous solution of NH4Cl. The organic layer was concentrated and precipitated by the addition of hexane. The mixture was centrifuged and the filter cake was collected. The filter cake was dried under vacuum. This gave 82.2 Kg of the desired product.
%
N,Otaudimethylhydroxylamine hydrochloride (851 mg, 8.72 mmols) was, :,O suspended in dichloromethane (6 ml) and cooled to 0 C. N, N-diisopropylethylaminev (1.66 ml, 9.53 mmols) was added and the mixture was stirred at 0 C until a clear solution was obtained. The resulting solution was kept at 0 C for further use. Boc- isonipecotic acid (2 g, 8.72 mmol), 1-hydroxybenzotriazole (1.2 g, 8.88 mmols) and 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (1.83 g, 9.58 mmols) were dissolved in DMF (15 ml) and cooled to 0 C. The solution of N,O- dimethylhydroxylamine in dichloromethane was added with stirring, and the resulting reaction mixture was allowed to stir overnight at room temperature. DMF was removed under reduced pressure and residue was partitioned between ethyl acetate and 10% citric acid. Organic layer was isolated, washed with water, saturated NaHCO3, water and brine and dried over MgSO4. Solvent was removed under reduced pressure and the residue was purified on silica gel eluting with ethyl acetate in hexanes (2:1 ) to provide the title compound (1.88 g, 79%). LCMS m/e (295, M + Na).
With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine; In dichloromethane; at 15 - 20℃;Large scale;
[0109] To a mixture of DCM (8.0 v), BG-5 (80.0 Kg, 1.0 eq.), N,0-dimethylhydroxylamine hydrochloride (1.2 eq.), HOBt (1.2 eq.) and EDCI (1.2 eq.), TEA (2.6 eq.) was charged dropwise below 15C. the mixture was stirred at RT until the reaction was completed, centrifuged and the cake was washed with DCM (1.0 v) twice. The filtrate was washed with 20% aqueous NH4C1 (3 x 4.0 v). The filtrate was concentrated under vacuum to give the crude product BG-6, which was used in the next step without further purification. The residue was dissolved in toluene (5.0 v) and THF (1.0 v), cooled to 10 C, charged dropwise MeMgBr (1.4 eq.) at 10C and then stirred at RT until the reaction was completed. The solution was cooled below 10C. Saturated aqueous NH4CI was charged dropwise below 10C. The mixure was centrifuged, separated, filtrated, and the organic phase was washed with aqueous NaCl twice. The organic phase was concentrated to give the crude product, which was used in the next step without further purification. The residue in DMF (2.5 v) and DMF-DMA (2.5 v) was stirred at 110C until the reaction was completed. The reaction mixture was cooled, concentrated and then DCM was added. The final mixture was washed with saturated aqueous NH4CI. The organic layer was cconcentrated and precipitated by charging hexane. The mixture was ccentrifuged and the cake was collected. The cake was dried under vacuum. This gave 82.2 Kg of the desired product. 1H NMR (DMSO-de) delta 7.49 (d, J= 12.6 Hz, 1H), 5.01 (d, J = 12.6 Hz, lH), 3.99-3.82 (m, 2H), 3.14-2.94 (m, 2H), 2.89-2.61 (m, 6H), 2.49-2.37 (m, lH), 1.66-1.56 (m, 2H), 1.39 (s, 9H), 1.39-1.20 (m, 2H).
According to Scheme 5 a dry 500 mL round bottom flask (oven-heated/argon cooled), was charged with 25 g (109.2 mmol) of Boc-isonipecotic acid (21). The flask was purged with argon, and 150 mL of dry THF were injected by syringe into the air-free system. The mixture was then stirred while being cooled to 0 C., and an oil-bubbler was attached, then 131 mL of a 1 M solution of borane/THF (131 mmol) were injected into the solution slowly, and the solution was stirred for ½ hour. Methanol was dripped into the solution slowly until bubbles ceased to be evolved. The solution was washed with 200 mL of a saturated sodium bicarbonate solution, and extracted twice with ethyl acetate, and the organic layer was dried over magnesium sulfate. The yield of the reaction was 22.44 g (96%) of the 22 product as a white solid. 1H NMR in CDCl3:a 3H multiplet from 0.85-1.2 ppm, a 9H singlet at 1.45 ppm, a 4H multiplet 1.455-1.8 ppm, a 2H broad signal at 2.65 ppm, a 1H broad signal at 3.45 ppm, and a 1H broad signal at 3.6 ppm.
89%
With borane-THF; In tetrahydrofuran; at 0℃; for 0.666667h;Inert atmosphere;
Under argon, 24 (3.00?g, 13.1?mmol) was dissolved in 40?mL of dry THF. At 0?C, 15.7?mL of BH3·THF (1?M in THF) was added and the mixture was stirred 40?min at 0?C. Then, 40?mL of CH3OH was added and 18?mL of a saturated solution of NaHCO3. The aqueous layer was extracted with EtOAc (3*). The organic layers were combined and solvents were removed under vacuum. The crude product was purified by flash column chromatography using CH2Cl2/CH3OH (98:2) to afford 25 as a white solid (2.40?g, 89%). Spectral data were in accordance with the literature [38].
80%
With diborane; In tetrahydrofuran; at 0℃; for 2h;Inert atmosphere;
a) Tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate 1-(tert-butoxycarbonyl) piperidine-4-carboxylate (5.0 g, 22 mmol) was dissolved in anhydrous THF (80 mL). After the temperature was lowered to 0 C, a solution of borane in THF (1M, 33 mL, 33 mmol) was added under the protection of nitrogen. After the addition was completed, the reaction mixture was stirred at 0 C for 2 hours. A hydrochloric acid solution was added dropwise slowly (1M, 33 mL, 33 mmol). After the reaction mixture was stirred at 0 C for 30 min, DCM (100 mL) was added to separate out the organic phase, and the aqueous phase was extracted with DCM (50 mL*2). The organic phases were combined, washed with a saturated saline solution, dried with anhydrous sodium sulfate, filtered, and concentrated at reduced pressure to obtain the targeted compound (3.8 g, 80% yield, colorless oil). LC-MS (ESI): m/z (M+1) 216.16.
76%
With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 7h;
A 1M-borane/tetrahydrofuran solution (4.36 ml, 4.36 mmol) was added dropwise to a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (1.0 g, 4.36 mmol) in tetrahydrofuran (20 ml) at 0C. After 1 hour, the mixture thus obtained was warmed up to room temperature. After another 6 hours, a saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture and the resulting mixture was poured into water (100 ml) and extracted with ethyl acetate (50 ml x 2). The organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (715 mg, 76%).
75%
With borane-THF; In tetrahydrofuran; at 0℃; for 2h;Cooling with ice;
To an ice cold solution of 1 -(tert-butoxycarbonyl)piperidine-4-carboxylic acid (5.00 g, 21.8 mmol) in THF (50 mL) was slowly added 1 M BH3-THF in THF (32.7 ml_, 32.7 mmol) and the mixture was allowed to stir at 0 C for 2 hours after which time TLC (10% MeOH/DCM, KMn04 stain) indicated complete reaction. MeOH (5 mL) was added dropwise and the mixture was stirred at ambient temperature for 10 minutes. Saturated NaHC03 (50 mL) was added and the mixture was extracted with EtOAc. The extracts were washed with brine, dried over Na2S04, filtered and concentrated to afford the title compound as a viscous colorless oil (3.53 g, 75% yield). 1H NMR (400MHz, DMSO-c/6) delta 4.45 (t, J = 5.3 Hz, 1H), 4.00 - 3.85 (m, 2H), 3.23 (t, J = 5.8 Hz, 2H), 2.79 - 2.53 (m, 2H), 1.66 - 2H), 1.55 - 1.44 (m, 1H), 1.43 - 1.33 (m, 9H), 1.01 -0.90 (m, 2H).
With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 4h;
[1- { [ (L, 1-DIMETHYLETHYL)] oxy] [CARBONYL}-4-PIPERIDINECARBOXYLIC] acid (2. 0g, 8. [73MMOL)] was dissolved in dry tetrahydrofuran (20ml), cooled in an ice bath and treated with 1 M [BORANE-TETRAHYDROFURAN SOLUTION (17. 46ML,] 17. [46MMOL)] under argon. The mixture was allowed to warm to ambient temperature and stirred under argon for 4 hours. A solution of methanol (5ml) in tetrahydrofuran [(10MOI)] was added followed by methanol (4ml) and water [(2ML).] The solvent was removed in vacuo and the residue dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution (x2). The organic layer was separated, dried under magnesium sulphate and evaporated in vacuo to give the title compound (1. 83g). 1H NMR [(CDCI3)] 8 4.18-4. 10 (2H, m), 3.51-3. 50 (2H, m), 2.72- 2.68 (2H, m), 1.75-1. 69 (2H, m), 1.62 (1H, m), 1.46 [(9H,] s), 1.20-1. 10 (2H, m).
In tetrahydrofuran;
Step 1 1-(t-Butoxycarbonyl)-4-hydroxymethyl-piperidine A solution of 25.03 g (109.2 mmole) N-Boc isonipecotic acid was dissolved in 200 mL THF and treated with 200 mL 1 M borane-tetrahydrofuran complex in THF, and the mixture was stirred overnight. The mixture was concentrated under vacuum, diluted with 750 mL ethyl acetate, and washed with 150 mL 1 N HCl (6*) and then saturated brine. The organic layer was dried over sodium sulfate and concentrated to give crude product as a white solid. 1H NMR (500 MHz) delta4.15 (br d, J=13.7 Hz, 2H), 3.52 (d, J=6.2 Hz, 2H), 2.69~2.75 (m, 2H), 1.71~1.75 (m, 2H), 1.62~1.70 (m, 1H), 1.47 (s, 9H), 1.12~1.21 (m, 2H). This was used as is in the next step.
In tetrahydrofuran;
Step 1 1-(t-Butoxycarbonyl)-4-hydroxymethyl-piperidine A solution of 25.03 g (109.2 mmole) N-Boc isonipecotic acid was dissolved in 200 mL TBF and treated with 200 mL 1 M borane-tetrahydrofuran complex in THF, and the mixture was stirred overnight. The mixture was concentrated under vacuum, diluted with 750 mL ethyl acetate, and washed with 150 mL 1 N HCl (6*) and then saturated brine. The organic layer was dried over sodium sulfate and concentrated to give 24.327 g of crude product as a white solid. H NMR (500 MHz) delta 4.15 (br d, J=13.7 Hz, 2H), 3.52 (d, J=6.2 Hz, 2H), 2.69-2.75 (m, 2H), 1.71-1.75 (m, 2H), 1.62-1.70 (m, 1H), 1.47 (s, 9H), 1.12-1.21 (m, 2H). This was used as is in the next step.
With borane-THF; In tetrahydrofuran; at -40 - 0℃; for 3h;Cooling with acetone-dry ice;
To 5 g of N-BOC-isonipecotic acid (21.8 mmol, Bachem) dissolved in 100 ml THF, cooled in a dry ice/acetone bath, was slowly added 43.6 ml 1 M borane-THF complex in THF (43.6 mmol). The reaction was stirred to -40 C and then replaced with an ice/water bath. After 3 hours the reaction was neutralized by careful addition of water and then worked up by addition of ethyl acetate and 1 M HCl. The layers were separated and the aqueous layer was extracted one more time with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over sodium sulfate and evaporated to give 4.9 g 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (MS: M+H=238).
With borane; In tetrahydrofuran; methanol;
Step B: N-t-butoxycarbonyl-4-hydroxymethyl piperidine. To a solution of N-t-butoxycarbonyl isonipecotic acid (15.0 g, 65.4 mmol) from example 3 step A, in anhydrous THF (50 ml), was added borane (65.4 ml of a 1M solution in THF, 65.4 mmol) at room temperature. After 72 hours methanol (50 ml) was added and the solvent evaporated in vacuo. The residue was dissolved in methanol (100 ml) and the solvent evaporated in vacuo. The eesidue was partitioned between EtOAc and NaHCO3, the organic layer separated and washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by chromatography (Silica gel, eluding with 50% EtOAc in hexanes) to afford the title compound.
With sodium tetrahydroborate; In tetrahydrofuran; at -5 - 0℃; for 3.5h;
(6) using N-Boc-4-piperidinecarboxylic acid as a reaction raw material, using tetrahydrofuran as a solvent, under the reduction of sodium borohydride, at -5 to 0 C, adding organic iodine, reacting for 3.5 h, After the reaction is completed, deionized water is added dropwise at normal temperature, and the mixture is stirred while being added dropwise. After the dropwise addition is completed, the mixture is filtered, and the filtrate is allowed to stand for separation. The solid obtained by removing the solvent from the organic phase is added to the aqueous phase and stirred and mixed, and ethyl acetate is used. Extraction, the organic phase is dried with anhydrous copper sulfate, and ethyl acetate is evaporated to obtain the product N-Boc-4 piperidine methanol;
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 3h;
Example 5: Compound No.59 (S)-1 -(2-amino-3-(thiophen-2-yl)propanoyl)-N-cvclohexyl-4-(4- (dimethylcarbamoyl)benzyl)piperidine-4-carboxamide hydrochloride STEP A: Piperidine-1 ,4-dicarboxylic acid 4-benzyl ester 1 -tert-butyl ester: To a solution of piperidine-1 ,4-dicarboxylic acid mono-tert-butyl ester (35.94 mmol; 8.24 g) in dichloromethane (100 mL) was added benzyl alcohol (55.79 mmol; 4.73 mL), dimethylaminopyridine (0.72 mmol; 0.08 g) and dicyclohexylcarbodiimide (43.13 mmol; 8.27 g) and the resulting mixture was stirred for 3 hours at room temperature. The resulting solution was evaporated and the residue was dissolved in ethyl acetate (300 mL). The resulting solution was washed with a 1 N hydrochloric acid solution (2 x 50 mL) and brine (50 mL), and dried over magnesium sulfate. After filtration and evaporation, the residue was purified via flash column chromatography ((eluent gradient: 0 to 50% EtOAc in heptane) to yield piperidine-1 ,4-dicarboxylic acid 4-benzyl ester 1 -tert-butyl ester after evaporation. MS (ESI) m/z 320.19 [M+H]+.
With dicyclohexyl-carbodiimide;dmap; In dichloromethane; at 20℃; for 3h;
STEP A: Piperidine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester To a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (35.94 mmol; 8.24 g) in dichloromethane (100 mL) was added benzyl alcohol (55.79 mmol; 4.73 mL), dimethylaminopyridine (0.72 mmol; 0.08 g) and dicyclohexylcarbodiimide (43.13 mmol; 8.27 g) and the resulting mixture was stirred for 3 hours at room temperature. The resulting solution was evaporated and the residue was dissolved in ethyl acetate (300 mL). The resulting solution was washed with a 1N hydrochloric acid solution (2*50 mL) and brine (50 mL), and dried over magnesium sulfate. After filtration and evaporation, the residue was purified via flash column chromatography ((eluent gradient: 0 to 50% EtOAc in heptane) to yield piperidine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester after evaporation. MS (ESI) m/z 320.19 [M+H]+.
1-(tert-butoxycarbonyl) piperidine-4-carboxylic acid (229 mg,1 mmol) was dissolved in anhydrous THF (4 mL), 1,10-carbonyldiimidazole(190 mg, 1.10 mmol) and triethylamine (154 mL,1.10 mmol) were added to the solution. After 0.5 h at 50 C a solutionof dimethylamine 2 M in THF (802 mL) were added. The reactionwaskept at room temperature overnight. In order to removethe imidazole NaOH 2 M was added to the mixture and thenextracted with EtOAc, the organic extracts were pooled together,dried over MgSO4, and evaporated to give 21 (128 mg, 77%) as aclear oil. Spectroscopy data was in agreement with previous report[40]
(d) fer^Butyl 4-[(benzylsuIfonyl)carbamoyl]piperidine-l-carboxylate <n="136"/>TEA (66 g, 0.65 mol) was added drop wise to a solution of -{tert- butoxycarbonyl)piperidine~4-carboxylic acid (Example 33 (c)) (50 g, 0.22 mol) and TBTU (77 g, 0.24 mol) in THF (600 mL), the reaction mixture was stirred at rt for 1.5 h. N- Phenylsulfamide (41 g, 0.24 mol) was added and the reaction was stirred over night at rt. The organic solvent was concentrated in vacuo and the residue was dissolved in EtOAc (600 mL), washed with 2 M HCl, IM HCl, water and concentrated in vacuo. The residue was dissolved in EtOH (250 mL) and water was added (600 mL), the precipitate was filtered, washed with EtOH and dried to give tert-butyl 4- [(benzylsulfonyl)carbamoyl]piperidine-l-carboxylate. Yield: 69 g (83%). 1H-NMR (300 MHz, DMSO-Cf5) delta 1.30-1.47 (2H, m), 1.39 (9H, s), 1.61-1.71 (2H, m), 2.32-2.42 (IH, m), 2.60-2.76 (2H, m), 3.86-3.98 (2H, m), 4.68 (2H, s), 7.25-7.30 (2H, m), 7.34-7.43 (3H, m), 11.54 (IH, s).
78%
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; lithium chloride; In tetrahydrofuran; at 20℃;
Triethylamine (591 g, 5840 mmol) was added to a stirred suspension of l-(tert- butoxycarbonyi)piperidine-4-carboxylic acid (448 g, 1954 mmol), LiCl (23.1 g, 545 mmol) and TBTU (657 g, 2046 mmol) in THF (3000 mL) under an atmosphere of nitrogen at r.t.. A solution of 1-phenylmethanesulfonamide (352 g in 1300 mL THF, 2056 mmol) was added after 1.5 hours and the stirring was continued over night . The solvent was removed in vaccuo to give a thick grey-beige slurry (volume about 2500 mL). EtOAc (3500 mL) was added followed by an aqueous solution of HCl (1960 mL 3.6 M HCl and 1960 mL water). The water phase was removed and the organic phase was washed with 2 x 1500 mL 1 M HCl. The organic phase was cooled to O0C which gave a precipitate of HOBt that was filtered off. Most of the solvent was removed in vaccuo to give a thick grey- white slurry. EtOH (50 %, 4000 mL) was added and the slurry was stirred for 1.5 hours. The precipitated product was filtered off, washed with 50 % EtOH ( 500 mL + 2 x 1500 mL) and dried in a vaccum oven at 25 oC EPO <DP n="111"/>to give tert-butyl 4-[(benzylsulfonyl)carbamoyl]piperidine-l-carboxylate as a white solid. Yield 584 g (78 %).1HNMR (400 MHz, CDCl5): delta 1.46 (9H, s), 1.54-1.61 (2H, m), 1.70-1.74 (2H, m), 2.19-2.27 (IH, m), 2.68-2.75 (2H, m), 4.07-4.12 (2H, m), 4.66 (2H, s), 7.32-7.41 (5H, m), 7.54 (IH, br 5 s).
78%
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; lithium chloride; In tetrahydrofuran; at 20℃;
(d) tert-Butyl 4-[(benzyIsulfonyl)carbamoyl]piperidine-l-carboxylate10Triethylamine (591 g, 5840 mmol) was added to a stirred suspension of l-(tert- butoxycarbonyl)piperidine-4-carboxylic acid (448 g, 1954 mmol), LiCl (23.1 g, 545 mmol) and TBTU (657 g, 2046 mmol) in THF (3000 mL) under an atmosphere of nitrogen at r.t. A solution of 1-phenylmethanesulfonamide (352 g in 1300 mL THF, 2056 mmol) was is added after 1.5 hours and the stirring was continued over night . The solvent was removed in vaccuo to give a thick grey-beige slurry (volume about 2500 mL). EtOAc (3500 mL) was added followed by an aqueous solution of HCl (1960 mL 3.6 M HCl and 1960 mL water). The water phase was removed and the organic phase was washed with 2 x 1500 mL 1 M HCl. The organic phase was cooled to O0C which gave a precipitate of HOBT that was20 filtered off. Most of the solvent was removed in vaccuo to give a thick grey- white slurry. EtOH (50 %, 4000 mL) was added and the slurry was stirred for 1.5 hours. The precipitated product was filtered off , washed with 50 % EtOH ( 500 mL + 2 x 1500 mL) and dried in a vaccum oven at 25 0C to give tert-butyl 4- [(benzylsulfonyl)carbamoyl]piperidine-l-carboxylate as a white solid. Yield: 584 g (78 %).
78%
(a) tert-Butyl4-[(benzylsulfonyl)amino]carbonyl}piperidine-1-carboxylate TEA (591 g, 5840 mmol) was added to a stirred suspension of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (448 g, 1954 mmol), LiCl (23.1 g, 545 mmol) and TBTU (657 g, 2046 mmol) in THF (3000 mL) under an atmosphere of nitrogen at r.t. A solution of 1-phenylmethanesulfonamide (352 g in 1300 mL THF, 2056 mmol) was added after 1.5 hours and the stirring was continued over night. The solvent was removed in vacuo to give a thick grey-beige slurry (volume about 2500 mL). EtOAc (3500 mL) was added followed by an aqueous solution of HCl (1960 mL 3.6 M HCl and 1960 mL water). The water phase was removed and the organic phase was washed with 2*1500 mL 1 M HCl. The organic phase was cooled to 0 C. which gave a precipitate of HOBt that was filtered off. Most of the solvent was removed in vacuo to give a thick grey-white slurry. EtOH (50%, 4000 mL) was added and the slurry was stirred for 1.5 hours. The precipitated product was filtered off, washed with 50% EtOH (500 mL+2*1500 mL) and dried in a vaccum oven at 25 C. to give tert-butyl 4-[(benzylsulfonyl)carbamoyl]piperidine-1-carboxylate as a white solid. Yield 584 g (78%). 1H NMR (400 MHz, CDCl3): delta 1.46 (9H, s), 1.54-1.61 (2H, m), 1.70-1.74 (2H, m), 2.19-2.27 (1H, m), 2.68-2.75 (2H, m), 4.07-4.12 (2H, m), 4.66 (2H, s), 7.32-7.41 (5H, m), 7.54 (1H, br s).
78%
TEA (591 g, 5840 mmol) was added to a stirred suspension of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (448 g, 1954 mmol), LiCl (23.1 g, 545 mmol) and TBTU (657 g, 2046 mmol) in THF (3000 mL) under an atmosphere of nitrogen at r.t. A solution of 1-phenylmethanesulfonamide (352 g in 1300 mL THF, 2056 mmol) was added after 1.5 hours and the stirring was continued over night. The solvent was removed in vaccuo to give a thick grey-beige slurry (volume about 2500 mL). EtOAc (3500 mL) was added followed by an aqueous solution of HCl (1960 mL 3.6 M HCl and 1960 mL water). The water phase was removed and the organic phase was washed with 2×1500 mL 1 M HCl. The organic phase was cooled to 0 C. which gave a precipitate of HOBt that was filtered off. Most of the solvent was removed in vaccuo to give a thick grey-white slurry. EtOH (50%, 4000 mL) was added and the slurry was stirred for 1.5 hours. The precipitated product was filtered off, washed with 50% EtOH (500 mL+2×1500 mL) and dried in a vacuum oven at 25 oC to give tert-butyl 4-[(benzylsulfonyl)carbamoyl]piperidine-1-carboxylate as a white solid. Yield 584 g (78%).1H NMR (400 MHz, CDCl3): delta 1.46 (9H, s), 1.54-1.61 (2H, m), 1.70-1.74 (2H, m), 2.19-2.27 (1H, m), 2.68-2.75 (2H, m), 4.07-4.12 (2H, m), 4.66 (2H, s), 7.32-7.41 (5H, m), 7.54 (1H, br s).
78%
(d) tert-Butyl 4-[(benzylsulfonyl)amino] carbonyl}piperidine-l-carboxylatTriethylamine (591 g, 5840 mmol) was added to a stirred suspension of l-(tert- butoxycarbonyl)piperidine-4-carboxylic acid (448 g, 1954 mmol), LiCl (23.1 g, 545 mmol) and TBTU (657 g, 2046 mmol) in THF (3000 mL) under an atmosphere of nitrogen at r.t. A solution of 1-phenylmethanesulfonamide (352 g in 1300 mL THF, 2056 mmol) was added after 1.5 hours and the stirring was continued over night . The solvent was removed in vaccuo to give a thick grey-beige slurry (volume about 2500 mL). EtOAc (3500 mL) was added followed by an aqueous solution of HCl (1960 mL 3.6 M HCl and 1960 mL water). The water phase was removed and the organic phase was washed with 2 x 1500 mL <n="106"/>1 M HCl. The organic phase was cooled to O0C which gave a precipitate of HOBt that was filtered off. Most of the solvent was removed in vaccuo to give a thick grey- white slurry. EtOH (50 %, 4000 niL) was added and the slurry was stirred for 1.5 hours. The precipitated product was filtered off, washed with 50 % EtOH ( 500 mL + 2 x 1500 mL) 5 and dried in a vaccum oven at 25 oC to give tert-butyl 4-[(benzylsulfonyl)carbamoyl]piperidine-l-carboxylate as a white solid. Yield 584 g (78 %). 1HNMR (400 MHz, CDCl3): delta 1.46 (9H, s), 1.54-1.61 (2H, m), 1.70-1.74 (2H, m), 2.19- 2.27 (IH, m), 2.68-2.75 (2H, m), 4.07-4.12 (2H, m), 4.66 (2H, s), 7.32-7.41 (5H, m), 7.54 (IH, br s). 0_
78%
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; lithium chloride; In tetrahydrofuran; at 20℃;Inert atmosphere;
(d) tert-Buty 4-[(benzylsulfonyl)amino]carbonyl}piperidine-l-carboxylateTriethylamine (591 g, 5840 mmol) was added to a stirred suspension of l-(tert- butoxycarbonyl)piperidine-4-carboxylic acid (448 g, 1954 mmol), LiCl (23.1 g, 545 mmol) and TBTU (657 g, 2046 mmol) in THF (3000 mL) under an atmosphere of nitrogen at r.t.. A solution of 1-phenylmethanesulfonamide (352 g in 1300 mL THF, 2056 mmol) was added after 1.5 hours and the stirring was continued over night . The solvent was removed in vaccuo to give a thick grey-beige slurry (volume about 2500 mL). EtOAc (3500 mL) was added followed by an aqueous solution of HCl (1960 mL 3.6 M HCl and 1960 mL water). The water phase was removed and the organic phase was washed with 2 x 1500 mL I M HCl. The organic phase was cooled to O0C which gave a precipitate of HOBt that was filtered off. Most of the solvent was removed in vaccuo to give a thick grey- white slurry. EtOH (50 %, 4000 mL) was added and the slurry was stirred for 1.5 hours. The precipitated product was filtered off , washed with 50 % EtOH ( 500 mL + 2 x 1500 rnL) and dried in a vaccum oven at 25 oC to give tert-butyl 4-[(benzylsulfonyl)carbamoyl]piperidine-l-carboxylate as a white solid. Yield 584 g (78 %). 1H NMR (400 MHz, CDCl3): delta 1.46 (9H, s), 1.54-1.61 (2H, m), 1.70-1.74 (2H, m), 2.19- 2.27 (IH, m), 2.68-2.75 (2H, m), 4.07-4.12 (2H, m), 4.66 (2H, s), 7.32-7.41 (5H, m), 7.54 (IH, br s).
With sodium bicarbonate; sodium monohydrogen sulfate; dimethyl amine; In methanol; ethanol; dichloromethane; N,N-dimethyl-formamide;
1-(tert-Butoxycarbonyl)piperidine-4-carboxylic acid (8.0 g, 35 mmol) was dissolved in dichloromethane (70 ml) and N,N-dimethylformamide (35 ml). 1-Hydroxy-7-azabenzotriazole (4.75 g, 35 mmol) was added. The solution was cooled to 0 C. N-3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (6.69 g, 35 mmol) was added. The reaction mixture was stirred for 20 min at 0 C. A 5.6 M solution of dimethylamine in ethanol (37 ml, 209 mmol) was added. The reaction mixture was stirred for 3 days, while it was warming up to room temperature. It was diluted with ethyl acetate (400 ml) and washed with a 10% aqueous solution of sodium hydrogen sulfate (400 ml). The aqueous phase was extracted with ethyl acetate (2*200 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate (300 ml) and dried over magnesium sulfate. The solvent was removed in vacua. The crude product was purified by flash chromatography on silica (300 g), using dichloromethane/methanol 20:1 as eluent, to give 4.56 g of 4-(dimethylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester. 1H-NMR (CDCl3): delta 1.47 (s, 9H); 1.70 (m, 4H); 2.60-2.90 (m, 3H); 2.96 (s, 3H); 3.08 (s, 3H); 4.17(m, 2H).
With 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃;
A mixture of 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (198 mg), <strong>[123066-64-8]4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]aniline</strong> (206 mg), WSCD hydrochloride (172 mg) and THF (3 ml) was stirred overnight at room temperature. After adding ethyl acetate, the reaction solution was washed with water, saturated sodium bicarbonate aqueous solution, 1 N hydrochloric acid and saturated brine in that order. The organic layer was dried over anhydrous sodium sulfate and then concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromtaography (eluent; n-hexane:ethyl acetate=7:1-5:1) to give tert-butyl 4-[4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenylaminocarbonyl]piperidine-1-carboxylate (279 mg) as a colorless amorphous solid. 4 N hydrochloric acid ethyl acetate solution (2.60 ml) was added to a mixture of this solid (263 mg) and ethyl acetate (2.6 ml), followed by stirring at room temperature for 2 hours and 45 minutes. The reaction solution was concentrated under a reduced pressure, diethyl ether was added to the thus obtained residue, and the mixture was concentrated under a reduced pressure. By recrystallizing the resulting residue from a mixed solvent of ethyl acetate and n-hexane, [4'-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]piperidine]-4-carboxyanilide hydrochloride (201 mg) was obtained as colorless powder crystals.
tert-butyl 4[(1H-indazol-5-ylmethyl)amino]carbonyl}-1-piperidinecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of <strong>[267413-25-2]1-<strong>[267413-25-2](1H-indazol-5-yl)methanamine</strong></strong> (291 mg) in N,N-dimethylformamide (8 ml) were added 1-(tert-butoxycarbonyl)-4-piperidinecarboxylic acid (507 mg, 2.21 mmol), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide monohydrochloride (578 mg, 3.02 mmol) and hydroxybenzotriazole (229 mg, 2.21 mmol), and the resulting mixture was stirred at room temperature for 14 hours. Subsequently, a saturated aqueous sodium hydrogencarbonate solution and then water were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol = 40/1). To a solution of the resulting solid in a mixture of methanol (1 ml) and tetrahydrofuran (1 ml) was added a 2N-aqueous lithium hydroxide solution (0.68 ml), and the resulting mixture was stirred at room temperature for 30 minutes. Then, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol = 30/1) to obtain tert-butyl 4[(1H-indazol-5-ylmethyl)amino]carbonyl}-1-piperidinecarboxylate (179 mg).
With polystyrene-CH2NEt2; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;
1-(TEFF-BUTOXYCARBONYL)-PIPERIDINE-4-CARBOXYLIC acid (0.53g), (S)-1-BENZYLOXYCARBONYL-3- METHYLPIPERAZINE (D19) (0.5g), HOBt (0.29g) and diethylaminomethyl polystyrene (1.78g) were stirred in DCM (30MI), then EDC (0.53g) was added and the reaction was stirred at rt overnight. The mixture was filtered and washed with saturated sodium hydrogen carbonate solution (3 x 50ML) and brine (30ml). The organic layer was dried (MGS04) and evaporated to give a crude yellow oil which was purified by chromatography [silica gel ; 0-100% ethyl acetate/hexane) to give the title compound (D20) as a clear oil which crystallised on standing (0.88g).
1-cyclopentyl-4-[1-tert-butoxycarbonyl-piperidine-4-carbonyl]-piperazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;1-hydroxy-7-aza-benzotriazole; In DMF (N,N-dimethyl-formamide); at 20℃; for 18h;
1-TERT-BUTOXYCARBONYL-PIPERIDINE-4-CARBOXYLIC ACID (2.2g) in dry DMF (40ML) was treated with EDC (3. 71g) followed by HOAT (0.1g). After 5min, <strong>[21043-40-3]N-cyclopentylpiperazine</strong> (1.5g) in dry DMF (5ML) was added and the reaction mixture was stirred at rt for 18h. Excess DMF was removed by evaporation and the resulting residue was re-dissolved in DCM, adsorbed onto SILICA GEL (10G) and purified by chromatography [silica gel 0-10% MEOH (containing 10% 0. 88 ammonia solution/DCM)]. The pure fractions were combined and the solvent removed by evaporation to give the subtitled compound (2g). LCMS electrospray (+ve) 366 (MH+).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃;
1-Benzyl- [1, 4] -diazepane (3.78g) and 1-TERT-BUTOXYCARBONYL-PIPERIDINE-4-CARBOXYLIC ACID (5. 0g) were dissolved in DCM (150 mi) and TEA (3. 6ML) was added followed by HOBT (1.34g) and finally EDC (4.90g). The reaction was stirred at rt overnight. The reaction mixture was then evaporated to a minimum, re-dissolved in DCM (50 ML) and washed with saturated sodium hydrogen carbonate solution (3 x 50MI) and brine (50MI). The organic layer was dried (MGS04) and evaporated to a crude which was purified by column chromatography [silica gel, step gradient 0-10% MEOH (containing 10% 0.880 ammonia solution) in DCM]. Fractions containing pure desired product were combined and evaporated to give the subtitled compound as a pale brown solid (7.1 g).
With potassium carbonate; In acetone; for 2h;Heating / reflux;
To a solution of 1-tert-butoxycarbonyl-4-piperidinecarboxylic acid (647 mg, 2.82 mg) in acetone (30 ml) was added benzyl bromide (0.36 ml, 3.0 mmol) and potassium carbonate (480 mg, 3.47 mmol). The resultant was heated under reflux for 2 hours and then cooled to room temperature. The reaction solution was concentrated under a reduced pressure, and distilled water was added to the residue, followed by extraction with ethyl acetate. The organic layer was dried and then concentrated under a reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to give a title compound (750 mg, 2.35 mmol, 83%) as a colorless oil product. 1H-NMR (400 MHz, CDCl3) delta: 1.45 (9H, s), 1.60-1.70 (2H, m), 1.88-1.96 (2H, m), 2.46-2.54 (1H, m), 2.78-2.87 (2H, m), 3.93-4.12 (2H, m), 5.13 (2H, s), 7.30-7.39 (5H, m).
72%
With potassium carbonate; In acetonitrile; at 60℃; for 18h;
Piperidine-4-carboxylic acid (12.9 g, 100 mmol) was dissolved in a rapidly stirred mixture of dioxane (100 mL) and IM sodium hydroxide (300 mmol). Di-t-butyldicarbonate (22 g, 100 mmol) was added. After 18 hours the volatiles were evaporated. The aqueous residue was acidified with IM hydrochloric acid and extracted with methylene chloride. The organic phase was evaporated to give the intermediate piperidine-l,4-dicarboxylic acid mono-tert- butyl ester as a white solid (19.6 g, 85%). 1HNMR (300MHz, DMSO-d6): D (ppm) 12.20 (s, IH), 3.85-3.80 (m, 2H), 2.85-2.77 (m, 2H), 2.44-2.35 (m, 2H), 1.80-1.75 (m, 2H), 1.44-1.31 (m, 1 IH). A portion of this intermediate (2.29 g, 10 mmol) was mixed with potasium carbonate (1.7 g, 12 mmol) and benzyl bromide (1.2 mL, 10 mmol) in acetonitrile (20 mL). Heated the reaction to 60 0C for 18 hours. The reaction was partitioned between ethyl acetate and water. The organic phase was washed with water and brine, then dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel with 0-25% ethyl acetate in methylene chloride. Obtained the title compound (2.3 g, 72%) as a colorless oil. 1H NMR (300MHz, DMSO-d6): D (ppm): 7.41-7.30 (m, 5H), 5.10 (s, 2H), 3.86-3.81 (m, 2H), 2.87-2.78 (m, 2H), 2.64-2.55 (m, IH), 1.85-1.80 (m, 2H), 1.49-1.38 (m, HH).
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 72h;
(b) 4-Benzyloxycarbonyl-1-tert-butoxycarbonylpiperidine A solution of 1-tert-butoxycarbonyl-piperidine-4-carboxylic acid (20g) in DMF (100ml) was treated with anhydrous potassium carbonate (60g) and then benzyl bromide (16.43g) and the mixture was stirred at room temperature for 72 hours. It was filtered, evaporated to dryness, dissolved in ethyl acetate, washed with sodium carbonate solution and water and dried over sodium sulfate. The product was evaporated to give an oil (29g).
Carbonyl diimidazole (3.57 g, 22 mmol) was added to a solution of 1-(tert- butoxycarbonyl) -piperidine-4-carboxylic acid (4.59 g, 20 mmol) in methylene chloride (50 mL) and stirred for two hours until gas evolution ceased. Then hydrazine (0.8 mL, -26 mmol) was added to the reaction and the reaction was stirred at room temperature for another two hours. The reaction was diluted with more methylene chloride and washed with sat'd aqueous NaHC03. The organic layer was dried over anhydrous Na2S04, filtered and the solvent evaporated to give a viscous residue. Trituration with diethyl ether afforded tert-butyl 4-(hydrazinocarbonyl)-piperidine-l-carboxylate as an off-white solid.NMR(CDC13): 86.77 (1H, br s), 4.15 (2H, br s), 3.90 (2H, v br s), 2.75 (2H, b s), 2.22 (1H, m), 1.78 (2H, br d, J=11.9 Hz), 1.66 (2H, br q, J=12.2 Hz, J=27.5 Hz), 1.47 (9H, s).
95 g
With hydrazine hydrate; In methanol;Reflux;
6.0.1.23.01 4-Hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester 100 g piperidine-1,4-dicarboxylic acid 1-tert-butyl ester was dissolved in 100 mL methanol and 100 mL hydrazine monohydrate was added. The mixture was reflux overnight. The reaction was cooled to RT and then the solvent was removed under vacuum to give 95 g of the desired product. Rf: 0.2 (DCM/MeOH=20/1) 1H NMR: (400 MHz, MeOD): delta 4.08 (d, J=13.2 Hz, 2H, CH2), 2.27 (br, 2H, NH2), 2.38-2.29 (m, 1H, CH), 1.72-1.68 (m, 2H, CH2), 1.63-1.56 (m, 2H, CH2), 1.45 (s, 9H, 3CH3).
95 g
With hydrazine hydrate; In methanol;Reflux;
4-Hydrazinocarbonyl-piperidine- 1-carboxylic acid tert-butyl ester 100 g piperidine-1, 4-dicarboxylic acid 1 -tert-butyl ester was dissolved in 100 mL methanol and 100 mL hydrazine mono hydrate was added. The mixture was reflux overnight. The reaction was cooled to RT and then the solvent was removed under vacuum to give 95 g of the desired product. Rf: 0.2 (DCM/ MeOH= 20/1) 1H NMR: (400 MHz, MeOD): delta 4.08 (d, J = 13.2 Hz, 2H, CH2), 2.27 (br, 2H, NH2), 2.38-2.29 (m, 1H, CH), 1.72-1.68 (m, 2H, CH2), 1.63-1.56 (m, 2H, CH2), 1.45 (s, 9H, 3CH3).
To a solution of l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (12O g, 520 mmol) in DCM (250 mL) was added carbonyldiimidazole (96 g, 590 mmol) in portions at room temperature. After 30 minutes, the reaction mixture was added to a freshly prepared solution of hydrazine (27 g, 840 mmol) in DCM (100 mL). After 30 minutes, the reaction was washed with a saturated solution of sodium carbonate, brine, dried over sodium sulfate, filtered and concentrated. The resulting solid was suspended in ether and filtered to give tert-buyl 4-(hydrazinocarbonyl)piperidine-l-carboxylate as a white solid. 1H NMR (400 MHz, DMSO -d6): delta 9.00 (s, IH), 4.15-4.10 (s, 2H), 3.95-3.90 (m, 2H), 2.80- 2.60 (m, 2H), 2.25-2.20 (m, IH), 1.62-1.55 (m, 2H), 1.40 (s, 9H).A solution of pyrazinecarbonitrile (2.0 g, 19 mmol) in methanol (20 mL) was treated with sodium methoxide in methanol (25wt%, 1.3 mL, 5.7 mmol) at room temperature. After 30 minutes, a solution of tert-butyl 4-(hydrazinocarbonyl)piperidine-l-carboxylate (4.6 g, 19 mmol) in methanol (20 mL) was added and the reaction was heated to reflux for 19 hours. The reaction mixture was concentrated, dissolved in ethoxyethanol (50 mL) and heated to reflux for 22 hours. The reaction was cooled to room temperature, quenched with acetic acid (0.38 mL, 6.6 mmol) and concentrated. The residue was suspended in ether and filtered to give tert-butyl 4-(5~pyrazin-2-yl-lH-l,2,4-triazol-3- yl)piperidine-l-carboxylate as a solid. EtaRMS (M+Eta+): observed = 331.1876, calculated = 331.1877; 1H NMR (400 MHz, CD3OD): delta 9.29 (d, J = 1.6 Hz, IH), 8.70 (dd, J = 2.4, 1.6 Hz, IH), 8.64 (d, J = 2.4 Hz, 2H), 4.19-4.15 (m, 2H), 3.15-3.09 (m, IH), 2.97 (m, 2H), 2.07-2.03 (m, 2H), 1.84-1.75 (m, 2H), 1.48 (s, 9H). A solution of tert-butyl 4-(5-pyrazin-2-yl-lH-l,2,4-triazol-3-yl)piperidine-l-carboxylate(6.0 g, 18 mmol) in trifluoroacetic acid (25 mL) was stirred at room temperature. After 1 hour, the reaction was concentrated. The resulting solid was suspended in ethyl acetate and methanol and filtered to give 10-1 as the TFA salt. The salt was dissolved in 1:1 acetonitrile: water, loaded onto an SCX ion exchange resin, rinsed with acetonitrile, and eluted with 10% NEta3 in ethanol to give 10-1 as a solid. 1H NMR (400 MHz, CDCl3): delta 9.28-9.26 (m, IH), 8.70-8.68 (m, IH), 8.60-8.58 (m, IH), 3.35-3.22 (m, 2H), 3.15-3.05 (m, IH), 2.90-2.85 (m, 2H), 2.15-2.08 (m, 2H), 1.95-1.90 (m, 2H).
Carbonyl diimidazole (3.57 g, 22 mmol) was added to a solution of l-(tert- butoxycarbonyl)-piperidine-4-carboxylic acid (4.59 g, 20 mmol) in methylene chloride (50 mL) and stirred for two hours until gas evolution ceased. Then hydrazine (0.8 mL, -26 mmol) was added to the reaction and the reaction was stirred at room temperature for another two hours. The reaction was diluted with more methylene chloride and washed with sat'd aqueous NaHCtheta3. The organic layer was dried over anhydrous Na2SO4, filtered and the solvent evaporated to give a viscous residue. Trituration with diethyl ether afforded tert-butyl 4-(hydrazinocarbonyl)-piperidine-l-carboxylate as an off-white solid. IH NMR(500 MHz, CDCI3): beta 6.77 (IH, br s), 4.15 (2H, br s), 3.90 (2H, v br s),2.75 (2H, b s),2.22 (IH, m), 1.78 (2H, br d, J=I 1.9 Hz), 1.66 (2H, br q, J=12.2 Hz, J=27.5 Hz), 1.47 (9H, s).This material (2.43g, 10 mmol) was dissolved in anhydrous 2-ethoxyethanol (20 mL) and 2-cyanopyridine (1.14 g, 11 mmol) was added to the solution. After 25 wt. % sodium methoxide/methanol (1.1 mL, ~5 mmol) was added the mixture was heated to 1300C for 16 hours. The cooled reaction was neutralized with acetic acid and partitioned between ethyl acetate and aq. NaHCtheta3. The organic layer was dried over Na2SO4, the salts removed by filtration and the solvent evaporated under vacuum. This residue was triturated with diethyl ether to give tert-butyl 4-(5-pyridin-2-yl-lH- l,2,4-triazol-3-yl)piperidine-l-carboxylate as a white solid. IH NMR(500 MHz, CDCI3): delta 8.70 (IH, d, J= 3.9Hz), 8.19 (IH, d, J=7.9Hz), 7.87 (IH, d t, J=1.7Hz, J=8Hz), 7.40 (IH, m), 4.20 (2H, br s), 3.03 (IH, m), 2.95 (2H, br s), 2.09 (2H, br d, J=12 Hz), 1.86 (2H, br q, J= 4.2Hz), 1.49 (9H, s); m/e (m+1): 330.2This material (2.68 g, 8.14 mmol) was suspended in 4 N HCl/dioxane. The stoppered reaction mixture was stirred at room temperature for 16 hours and then diluted with diethyl ether. The solids were isolated by filtration and the hygroscopic solid was digested in acetonitrile. This solid was isolated by filtration and partially dissolved in hot methanol. Upon cooling and addition of some ethyl ether to the solution 2-(3-piperidin-4-yl-lH-l,2,4-triazol-5-yl)pyridine slowly precipitated as the EPO <DP n="92"/>dihydrochloride salt. IH NMR (500 MHz, DMSO-d6): delta 9.10 (IH, br s), 8.92 (IH, br s), 8.73 (IH, d, J=4.9Hz), 8.10-8.20 (2H, m), 7.64 (IH, t, J=5.7 Hz), 3.33 (2H, br d, J=12.7 Hz), 3.16 (IH, m), 3.05 (2H, br q, J=I 1.9 Hz, J=21.8 Hz),2.18 (2H, br d, J=I 1.5 Hz), 1.99 (2H, br q, j=11.0 Hz, J=22.2 Hz): m/e(m+l): 230.3.
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;dmap; In dichloromethane; at 20℃;
C. Synthesis of tert-butyl-4-(<strong>[108-49-6]3,5-dimethylpiperazine</strong>-l -carbon yl)piperidine-l-carboxylate; [00107] A solution of l-(tert-butoxycarbonyl)piperidin-4-carboxylic acid 2.3 g (10 mmol), <strong>[108-49-6]2,6-dimethylpiperazine</strong> 1.14 g (10 mmol), and EDC 3.82 g (20 mmol) and DMAP (trace) in 20 ml dichloromethane was stirred at room temperature overnight. The mixture was concentrated, and water was added before the reaction product was extracted with ethyl acetate 2x50ml. The combined organic solution was dried over sodium sulfate and concentrated. The residue was applied to flash column chromatography using methylene chloride and methanol (100:5) as eluents to give 1.9 g of the desired product.
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;dmap; In dichloromethane; at 20℃;
A solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (2.3 g, 10 mmol), <strong>[108-49-6]2,6-dimethylpiperazine</strong> (1.14 g, 10 mmol), and EDC (3.82 g, 20 mmol) and DMAP (catalytic) in 20 ml dichloromethane was stirred at room temperature overnight, concentrated, added water and extracted with ethyl acetate 2*50 ml. The combined organic solution was dried over sodium sulfate and concentrated. The residue was applied to flash column chromatography using methylene chloride and methanol (100:5) as eluents to give 1.9 g of desired product.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 3h;
To the solution of <strong>[270912-72-6]3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester</strong> (269 mg, 1.34 mmol) and piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (310 mg, 1.35 mmol) in dichloromethane (6.0 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (390 mg, 2.03 mmol) and 4-dimethylaminopyridine (10 mg, 0.08 mmol). After stirred at room temperature for three hours, the solution was partitioned between ethyl acetate and water. The separated organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to give a white solid (550 mg, 100%).
A mixture of 1 -tert-butyl 4-methyl piperidine-1 ,4-dicarboxylate (4.84 g 20 mmol), and LiOH(2.52 g,60 mmol) in THF(90 mL) /MeOH (90 mL) /H2O(30 mL) was stirred at r.t overnight. Then the solvents were removed, and the pH of the residue was adjusted to 2 by using 2N HCI. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4, and concentrated to give 1 -(tert-butoxycarbonyl)piperidine -4-carboxylic acid (4.6 g, yield 100.0percent).
100%
With lithium hydroxide; In tetrahydrofuran; methanol; water; at 20℃;
A mixture of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (4.84 g 20 mmol), and LiOH (2.52 g, 60 mmol) in THF (90 mL)/MeOH (90 mL)/H2O (30 mL) was stirred at r.t overnight. Then the solvents were removed, and the pH of the residue was adjusted to 2 by using 2N HCl. The resulting mixture was extracted with EtOAc (3*20 mL). The combined organic layers were dried over Na2SO4, and concentrated to give 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (4.6 g, yield 100.0percent).
96%
With sodium hydroxide; at 50℃; for 24h;
(0031) (1) To compound 2 (24.33 g, 0.1 mol) was added dropwise 5M NaOH (60 mL, 0.3 mol), then stirred at 50° C. for 24 hours. 3M HCl was then added dropwise to the solution to adjust pH 3. The mixture was extracted with ethyl acetate (3*200 mL), dried over anhydrous sodium sulfate, filtered, evaporated to dryness to give a yellow oily liquid 4 (19.72 g, 96percent)
96%
With sodium hydroxide; at 50℃; for 24h;
To a solution of compound 2 (24.33 g, 0.1 mol) was added dropwise 5 M NaoH (60 mL, 0.3 mol) and stirred at 50 ° C for 24 hours. Then 3 mu HC1 to rho H 3 were added dropwise to the solution, Ethyl acetate (3 * 200 mL), dried over anhydrous sodium sulphate, filtered, and dried to give a yellow oily liquid 4 (19.72 g, 96percent)
91%
With lithium hydroxide monohydrate; water; In tetrahydrofuran; at 45℃; for 1h;Inert atmosphere;
A solution of 1-tert-butyl 4-methyl piperidine-1, 4-dicarboxylate (1.0 g, 4.1 mmol) and lithium hydroxide monohydrate (860 mg, 21 mmol) in a mixed solvent of THF (10 mL) and water (5 mL) was stirred at 45 for 1 h, and then adjusted with hydrochloric acid (1 M) to pH 1. The resulting mixture was extracted with EtOAc (20 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid as a white solid (860 mg, 91) .1H NMR (400 MHz, CD3OD) : delta ppm 3.97-4.02 (m, 2H) , 2.88-2.95 (m, 2H) , 2.48-2.55 (m, 1H) , 1.88-1.92 (m, 2H) , 1.54-1.61 (m, 2H) , 1.47 (s, 9H) and MS-ESI: m/z 174.20 [M-55] +.
91%
With lithium hydroxide monohydrate; water; In tetrahydrofuran; at 45℃; for 1h;
Compound 4-methoxy carbonyl piperidine-1-carboxylic acid T-butyl ester (1.0g, 4 . 1mmol) and LiOH·H 2 O (860 mg, 21mmol) dissolved in tetrahydrofuran (10 ml) and water (5 ml) in the mixed solvent, 45 °C reaction 1h, plus 1.0mol/L adjusting pH=1 hydrochloric acid, extraction with ethyl acetate (10 ml × 3), the organic phase is dried with sodium sulfate, to remove the solvent, get 860 mg white solid, yield 91percent.
91%
With lithium hydroxide monohydrate; In tetrahydrofuran; water; at 45℃; for 1h;
The compound N- tert-butoxycarbonyl-4-piperidine carboxylic acid methyl ester (1.0g, 4.1mmol) and lithiumhydroxide monohydrate (860mg, 21mmol) It was dissolved in tetrahydrofuran (10mL) and water (5mL) mixedsolvent, 45 ° C the reaction 1h, add hydrochloric acid (1M) adjusting the pH to 1, plus B Acetate (20mL × 3)was extracted, combined organic layers were dried over Na 2 SO 4, the solvent was removed to give a white solid860mg: 1- (tert Carbonyl) piperidine-4-carboxylic acid. Yield: 91percent.
84%
With water; lithium hydroxide; In tetrahydrofuran; methanol; at 20℃; for 15h;
To a solution of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (1.19 g, 4.87 minol) in methanol (24 mL) and tetrahydrofuran (24 mL) were added a solution of LiOH (599 mg, 24.99 minol) in water (8 mL) at room temperature. The resultingminxture was stirred for 15 h at room temperature. When the reaction was done, the pH value of the reactionminxture was adJusted to 2 with hydrogen chloride solution (1 M). The resultingminxture was extracted with ethyl acetate (200 mL x 3), and the organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield 1-[(tert-butoxy)carbonyljpiperidine-4-carboxylic acid as white solid (1.10 g, 84percent). MS: m/z = 128.0 [M-Hj.
B. Synthesis of l-(tert-butoxycarbonyl)piperidin-4-carboxylic acid; [00106] A mixture of l-(tert-butoxycarbonyl)piperidin-4-carboxylic acid methyl ester 2.42g (10 mmol) and LiOH. 3H2O 1.26g (30 mmol) in THF (45ml) water (15ml) and methanol (15ml) was stirred at room temperature overnight. The mixture was then concentrated to remove the solvent. The residue was adjust to pH~2 with 2N HCl and extracted with ethyl acetate (2x40 ml). The combined organic solution was dried with sodium sulfate and concentrated to give 2.3g of desired acid.
Step 2: Piperidine-I,4-dicarboxylic acid mono-/-tau/-butyl ester[00383] To piperidine-lAdicarboxylic acid 1-tert-bxtiyl ester 4-methyl ester (1.34g, 5.51piiraol) in THF (7mL) was added lithium hydroxide (l.ldeltag, 27.57mmol) and H2O (7mL), and the reaction was stirred at room temperature overnight. The mixture was then acidified with aqueous 1N HCl to pH 3-4 and extracted with EtOAc three times. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the desired product as a white solid ( 1 28g).
A mixture of 1-(tert-butoxycarbonyl)piperidine-4-methylcarboxylate (2.42 g, 10 mmol) and LiOH. 3H2O in THF (45 ml) water (15 ml) and methanol (15 ml) was stirred at room temperature overnight. The mixture was then concentrated to remove the solvent. The residue was adjust to pH~2 with 2N HCl and extracted with ethyl acetate (2*40 ml). The combined organic solution was dried with sodium sulfate and concentrated to give 2.3 g of desired product.
(a) l-tert-Buty 4-methyI piperidine-l,4-dicarboxylate; EPO <DP n="163"/>1-(tert-Butoxycarbonyl)piperidine-4-carboxylic acid (3.00 g, 13 ramol) was dissolved in MeOH (50 mL) and TM5CHN2 (32.7 mL of a 2 M solution in hexanes, 65 mmol) was added drop- wise at r.t. TM5CHN2 was added until a persistent yellow color was produced indicating excess reagent. AcOH was added drop- wise to quench the excess TM5CHN2 and the the reaction mixture was concentrated under reduced pressure and azeotroped with Toluene (3 X 30 mL) to remove any trace MeOH or AcOH. The crude 1-tert-Butyl 4- methyl piperidine-1,4- dicarboxylate was used without further purification.
With dmap; 1,2-dichloro-ethane; benzyl alcohol;SiO2; In dichloromethane; ethyl acetate;
Step A: N-t-butoxycarbonyl isonipecotic acid benzyl ester. To a solution of N-t-butoxycarbonyl isonipecotic acid (12.0 g, 52.3 mmol) from example 3 step A, in anhydrous CH2 Cl2 (100 ml), was added benzyl alcohol (6.0 ml, 58 mmol), followed by EDC (11.04 g, 57.6 mmol), and DMAP (642 mg, 5.25 mmol). The resulting mixture was stirred for 6 hrs, then diluted with CH2 Cl2 (150 ml) and washed successively with water, 10% aqueous citric acid, saturated NaHCO3, and brine and dried (MgSO4). Concentration in vacuo afforded a colorless oil which was chromatographed (SiO2, 20% EtOAc in hexanes) to afford the product as a white solid.
4-(1-Carboxy-2-naphthalen-1-yl-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In 1,4-dioxane; water;
A. 4-(1-Carboxy-2-naphthalen-1-yl-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester To 200 mg (0.607 mmol) of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester in 5 mL of dioxane and 1.2 mL of water was added 0.186 mL (1.33 mmol) of triethylamine and 198 mg (0.607 mmol) of D-3-(1'-Napthyl)alanine and the mixture was stirred overnight at room temperature. Excess solvent was removed by concentration and the residue was diluted with water and acidified to pH 5 with acetic acid. The solution was extracted three times with methylene chloride, and the combined organics were washed twice with water and once with brine. The organic portion was dried over MgSO4 and the product was purified by silica gel chromatography (96:4:0.1 v/v/v methylene chloride:methanol:acetic acid) to give 132 mg of 78A.
With triethylamine; HATU; In dichloromethane; at 20℃;
To a mixture of piperidine- 1 ,4-dicarboxylic acid mono-tert-butyl ester (65) (229 mg, 1 mmol, AalenChem) in DCM (5 mL) was added TEA (202 mg, 2 mmol) and HATU (414 mg, 1.2 mmol). The reaction mixture was stirred for 5 min and dimethylamine hydrochloride (81 mg, 1 mmol) was added. The reaction mixture was stirred at RT overnight. The mixture was diluted with water (10 mL), and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried over Na2S04, and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography to give 4-dimethylcarbamoyl-piperidine-l-carboxylic acid tert-butyl ester (66) (220 mg, 0.85 mmol, 85% yield) as a light yellow oil.
With 1,1'-carbonyldiimidazole; In N,N-dimethyl-formamide; for 5h;
l-[2-(lH-Indazol-4-yl)-4-mophiholin-4-yl-thieno[3,2-dlpyrimidin-6-ylmethyl1- piperidine-4-carboxylic acid dimethylamide (100) .Prepared via 1 -(2-Chloro-4-mophiholin-4-yl-thieno[3,2-d]pyrimidin-6- ylmethyl)-piperidine-4-carboxylic acid dimethylamide, prepared from piperidine-4- carboxylic acid dimethylamide.Amine preparation: to a stirring solution of BOC-isonipecotic acid (400mg) in DMF (4mL) was added l,l'-carbonyldiimidazole (560mg). The reaction mixture was stirred overnight and then dimethylamine hydrochloride (280mg) and triethylamine (0.48mL) were added. After 5 h the reaction mixture was diluted with ethyl acetate, washed with water, dried (MgSO4) and the solvent was removed in vacuo to yield 4-dimethylcarbamoyl-piperidine-l-carboxylic acid tert-butyl ester.Removal of the BOC group with HCl yielded the desired compound, which was isolated as the hydrochloride salt. EPO <DP n="54"/>1H NMR (400MHz, CDCl3): 1.72 (2H, m), 1.98 (2H, m), 2.20 (2H, t), 2.55 (IH, m),2.97 (3H, s), 3.00-3.10 (5H, m), 3.86 (2H, s), 3.94 (4H, m), 4.10 (4H, m), 7.36 (IH, s), 7.50 (IH, t, J=7.7Hz), 7.60 (IH, d, J=8.2Hz), 8.28 (IH, d, J=7.3Hz); 9.02 (IH, s); 10.15 (IH, br s); MS (ESI+) 506 (MH+).
To a stirring solution of BOC-isonipecotic acid (400 mg) in N5N- dimethylformamide (4mL) was added l,r-carbonyldiimidazole (560 mg). The reaction <n="151"/>mixture was stirred overnight and then dimethylamine hydrochloride (280 mg) and triethylamine (0.48 niL) were added. After 5 hours the reaction mixture was diluted with ethyl acetate, washed with water, dried (MgSO4) and the solvent removed in vacuo to yield 4- dimethylcarbamoyl-piperidine-1-carboxylic acid tert-butyl ester. Removal of the BOC group with HCl yielded piperidine-4-carboxylic acid dimethylamide_, which was isolated as the hydrochloride salt.
With water; dimethyl dicarbonate;palladium diacetate; P(p-CH3OC6H4)3; In tetrahydrofuran; at 20℃;
PREPARATION 8; SYNTHESIS OF PIPERIDIN-4-YL-(2-TRIFLUOROMETHYLPHENYL)METHANONEA.; To a 50-mL flask was charged with Lambda/-Boc-isonipecotic acid (0.916 g, 4.000 mmol), <strong>[1423-27-4]2-(trifluoromethyl)phenylboronic acid</strong> (0.835 g, 4.400 mmol), palladium acetate (0.030 g, 0.12 mmol) and tris-(4-methoxyphenyl)phosphane (0.100 g, 0.280 mmol). THF (16 mL), dimethyl dicarbonate (DMDC) (1.600 g, 12 mmol) and water (190 muL, 10 mmol) were added by syringe. The reaction mixture was purged with nitrogen and stirred at ambient temperature overnight, then concentrated in vacuo. The product was isolated by column chromatography. Yield 0.812 g, 57%.
Carbonyl diimidazole (3.57 g, 22 mmol) was added to a solution of l-(tert- butoxycarbonyl)-piperidine-4-carboxylic acid (4.59 g, 20 mmol) in methylene chloride (50 mL) and stirred for two hours until gas evolution ceased. Then hydrazine (0.8 mL, ~26 mmol) was added to the reaction and the reaction was stirred at room temperature for another two hours. The reaction was diluted with more methylene chloride and washed with sat'd aqueous NaEtaCObeta. The organic layer was dried over anhydrous Na2SO_i, filtered and the solvent evaporated to give a viscous residue. Trituration with diethyl ether afforded tert-butyl 4-(hydrazinocarbonyl)-piperidine-l-carboxylate as an off-white solid. NMR(CDCl3): 56.77 (1Eta, br s), 4.15 (2Eta, br s), 3.90 (2H, v br s),2.75 (2H, b s), 2.22 (IH, m), 1.78 (2H, br d, J=I 1.9 Hz), 1.66 (2H, br q, J=12.2 Hz, J=27.5 Hz), 1.47 (9H, s).This material (2.43g, 10 rnmol) was dissolved in anhydrous 2-ethoxyethanol (20 mL) and 2-cyanopyridine (1.14 g, 11 mmol) was added to the solution. After 25 wt. % sodium methoxide/methanol (1.1 mL, ~5 mmol) was added the mixture was heated to 1300C for 16 hours. The EPO <DP n="53"/>cooled reaction was neutralized with acetic acid and partitioned between ethyl acetate and aq. NaHCO3.The organic layer was dried over Na2SO4, the salts removed by filtration and the solvent evaporated under vaccum. This residue was triturated with diethyl ether to give tert-butyl 4-(5-pyridin-2- yl-lH-l,2,4-triazol-3-yl)piperidine-l-carboxylate as a white solid. NMR(CDCl3): 58.70 (1Eta, d, J=3.9Etaz), 8.19 (IH, d, J=7.9Hz), 7.87 (IH, d t, J=1.7Hz, J=8Hz), 7.40 (IH, m), 4.20 (2H, br s), 3.03 (IH, m), 2.95 (2H, br s), 2.09 (2H, br d, J= 12 Hz), 1.86 (2H, br q, J= 4.2Hz), 1.49 (9H, s); m/e (m+1): 330.2This material (2.68 g, 8.14 mmol) was suspended in 4 N HCl/dioxane. The stoppered reaction mixture was stirred at room temoerature for 16 hours and then diluted with diethyl ether. The solids were isolated by filtration and the hydroscopic solid was digested in acetonitrile. This solid was isolated by filtration and partially dissolved in hot methanol. Upon cooling and addition of some ethyl ether to the mixture 2-(3-piperidin-4-yl-lH-l,2,4-triazol-5-yl)pyridine (A) was obtained as the dihydrochloride salt. NMR(DMSO-d): 89.10 (1Eta, br s), 8.92 (1Eta, br s), 8.73 (1Eta, d, J=4.9Etaz), 8.10- 8.20 (2H, m), 7.64 (IH, t, J=5.7 Hz), 3.33 (2H, br d, J=12.7 Hz), 3.16 (IH, m), 3.05 (2H, br q, J=I 1.9 Hz, J=21.8 Hz),2.18 (2H, br d, J=11.5 Hz), 1.99 (2H, br q, j=11.0 Hz, J=22.2 Hz): m/e(m+l): 230.3.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃;
General procedure: To a stirred solution of compound 7 (200 mg, 0.87 mmol) in DCM (10 mL) was added amines (1.0 mmol), EDC(186 mg, 1.2 mmol), and HOBt (153 mg, 1.2 mmol) at room temperature. The mixture was stirred for 3 hrs, quenchedby H2O (15 mL), and extracted by DCM (15 mL × 3). The organic layer was dried over anhydrous MgSO4, filtered,and concentrated. The residue was purified by chromatography on a silica gel column to afford compound 8a-l as acolorless oil.4.2.3.1. tert-butyl 4-(piperidine-1-carbonyl)piperidine-1-carboxylate 8aFollowing the general procedure, employing piperidine as the amine yielded compound 8a as a colorless oil in 85percentyield, 1H NMR (500 MHz, CDCl3) delta 4.14 (brs, 2H), 3.55 (brs,2H), 3.43 (brs, 2H), 2.76 (brs, 2H), 2.62 (m, 1H), 1.66 (m,6H), 1.55 (brs, 4H), 1.45 (s, 9H); MS-ESI (m/z): 297 (M + H)+.
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; In acetonitrile; at 85℃; for 6h;
To a suspension of N-Boc-isonipecotic acid (3.0 g, 13.1 mmol) and <n="22"/>TBTU (4.2 g, 13.1 mmol) in 60 mL of CH3CN, piperidine (1.67 g, 19.6 mmol) was added. The resulting solution was stirred at 85°C for 6 hours. The reaction mixture was concentrated under reduced pressure and then dissolved in DCM and washed twice with saturated aqueous Na2CO3 solution. Solvent removal gave 3.2 g of title compound that was used without further purification in the next step
To a stirred solution of 4-aminobenzylamine (285 mg, 2.33 mmol) and triethylamine (1200 mg, 11.7 mmol, 5eq) in CHCl3 (5 mL) at rt was added 7-methyl-2,4- dichloroquinazoline (500 mg, 2.33 mmol) as solid and the mixture was allowed to stir for a minimum of 3 hours. After TLC showed only minimal amounts of starting materials remaining, THF (10 mL), HOBT (629 mg, 4.66 mmol, 2 eq), N-BOC-isonipecotic acid (600 mg, 2.62 mmol, 1.1 eq) and EDCI (670 mg, 3.5 mmol, 1.5 eq) were added in the described order and the mixture was allowed to stir overnight. For work up CHCl3 (100 mL) and water (20 mL) were added and the organic layer was separated. The aqueous layer was washed twice with CHCI3 (20 mL) and the combined organic layers were dried over MgSO4. After <n="118"/>filtration Of MgSO4 and solvent removal, the 1.5 g crude product (which was a l : l-mixture of (4- {4-[(2-Chloro-7-methyl-quinazolin-4-ylamino)-methyl]-phenylcarbamoyl} -piperidine- 1 - carboxylic acid tert-butyl ester) and 4-(tert-Butoxycarbonyl-{4-[(2-chloro-7-methyl- quinazolin-4-ylamino)-methyl]-phenyl}-aminocarbonyl)-piperidine-l-carboxylic acid tert- butyl ester) was taken forward without further purification.
Step A: A mixture of 1-(tert-butoxycarbonyl)piperidin-4-carboxylic acid (2.47 g, 10.78 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.43 g, 17.96 mmol), 1-hydroxybenzotriazole (2.42 g, 17.96 mmol) and <strong>[17672-21-8]methyl 2-amino-3-hydroxybenzoate</strong> (1.50 g, 8.98 mmol) in dichloromethane (25 mL) was stirred under nitrogen at room temperature for 10 min, and then triethylamine (1.47 mL, 10.6 mmol) was added. The resulting reaction mixture was stirred at room temperature for 5 h, the reaction was quenched with a saturated aqueous solution of sodium bicarbonate (15 mL), and then extracted with dichloromethane (2*150 mL). The combined organic phase was washed with water (2*100 mL), brine (2*100 mL), and dried (Na2SO4), filtered and concentrated to afford a light yellow solid. The crude solid was dissolved in toluene (20 mL) and the solution was treated with p-toluenesulfonic acid monohydrate (2.08 g, 10.9 mmol). The reaction mixture was then heated to reflux under nitrogen for 4 h. The reaction was cooled to room temperature and concentrated. The crude product was purified by column chromatography (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford 2-(piperidin-4-yl)benzoxazole-4-carboxylate methyl ester (1.64 mg, 70%) as an off-white solid: 1H NMR (500 MHz, CDCl3) delta 7.99 (dd, J=7.8, 0.9 Hz, 1H), 7.78 (dd, J=7.8, 0.9 Hz, 1H), 7.39 (t, J=7.8 Hz, 1H), 4.00 (s, 3H), 3.52-3.45 (m, 2H), 3.36-3.30 (m, 1H), 3.10-3.03 (m, 2H), 2.33-2.20 (m, 4H); MS (ESI+) m/z 261 (M+H).
With O-<[cyano(ethoxycarbonyl)methylene]amino>-1,1,3,3-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 20h;
To a solution of the product derived from step 1 , example 92 (5.65 g, 24.6 mmol) in DMF (35 ml), were added TOTU (8.62 g, 26.3 mmol), and piperidine-1 ,4-dicarboxylic acid mono-tert-butyl ester (6.03 g, 28 mmol) and DIPEA (7.0 ml). The reaction mixture was stirred at ambient temperature for 20 h and afterwards evaporated. The residue was dissolved in ethyl acetate (200 ml) and washed with brine (50 ml), and sodium hydrogen carbonate (sat., 50 ml) and dried over sodium sulphate. Evaporation and purification of the crude product by silica gel chromatography using ethyl acetate/heptane gave the desired product (3.72 g , 36%).
Thionyl chloride (0.028 mol, 2.0 mL) was added to a solution of 1-(tert- butoxycarbonyl)piperidine-4-carboxylic acid (0.024 mol, 5.6 g; CASNo. 84358-13- 4), pyridine (0.060 mol, 4.9 mL), in DCM (32 mL) at 0 0C under an atmosphere of <n="209"/>argon. After 5 min., a solution of <strong>[50397-74-5]4-amino-3-bromo-benzonitrile</strong> (0.027 mol, 5.3 g; CASNo. 50397-74-5), DMAP (0.037 mol, 4.5 g) in DCM (44 mL) was added to the reaction mixture and allowed to slowly warm to room temperature over 16 hrs. Triethylamine (0.047 mol, 6.6 mL) was added and the reaction mixture was refluxed for 4 hours, stirred at room temperature for 16 hrs, and concentrated in vacuo. The residue was dissolved in Et2O and extracted with water (2x), 1 N aq. HCI (2x), saturated aq. NaHCO3, brine, dried over Na2SO4, filtered and concentrated in vacuo. The resulting material was purified on a silica gel column eluting with heptane/EtOAc (3:2) to afford 8a as a white solid (3.2 g, 32%).
Ethyl (2Z)-amino(hydroxyimino)ethanoate (1.1 eq.) was added to a solution of TBTU (1.2 eq.), l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (1 eq.) and DIPEA (2 eq.) in DCM(0.2 M) at RT. The reaction mixture was stirred at RT overnight. After dilution with EtOAc, the organic phase was washed with sat. sol. NaHCO3 and dried (Na2SO4). Evaporation of the solvent under reduced pressure afforded a white solid which was diluted with THF (0.2 M). The resulting solution was treated with TBAF (0.5 eq.) and the reaction mixture was heated to reflux overnight. Then, the reaction mixture was diluted with EtOAc and washed with sat. sol. NaHCO3 and dried (Na2SO4). Evaporation of the solvent under reduced pressure gave a crude which was purified by by flash chromatography on silica using EtO Ac/Petroleum ether (1 :1) as solvent to afford (49%) the title compound as a brown oil. MS (ES+) CiSH23N3Os required: 325, found: 326(M+H)+.
1-methyl-2-piperidin-4-yl-1H-imidazo[4,5-d]pyridine trifluoroacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
55.3 1-methyl-2-piperidin-4-yl-1H-imidazo[4,5-d]pyridine (V-17) 450 mg N4-methylpyridin-3,4-diamine and 838 mg mono-tert-butyl piperidine-1,4-dicarboxylate are heated for 4 h in 8.6 g polyphosphoric acid at 200 C. After cooling the mixture is made basic with 4 N NaOH and acidified with trifluoroacetic acid. The mixture is purified by preparative HPLC (method C). 3.37 g (50%) (V-17) are obtained as the trifluoroacetate. Analytical HPLC-MS (method B): RT=0.30 min.
Example 110: l-(l-isopropyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V-(thiazol-2- ylmethyl)piperidine-4-carboxamide(a) Preparation of the intermediate compound tert-butyl 4-(thiazol-2-ylmethylcarbamoyl)- piperidine- 1 -carboxylate :To a mixture of l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (500 mg, 2.18 mmol), triethylamine (220.7 mg, 2.18 mmol) and dichloromethane (10 mL) was carefully added thionyl chloride (311.3 mg, 2.62 mmol) and the reaction mixture was stirred at room temperature (reaction mixture 1). In a separate vial was mixed <strong>[3364-78-1]2-(chloromethyl)thiazole</strong>, triethylamine (882.7 mg, 8.723 mmol) and dichloromethane (10 mL) that was stirred and cooled on ice-batch and reaction micture 1 was added over 5 minutes while stirring. The reaction mixture was allowed to reach room temperature, washed with aqueous hydrochloric acid (2 x20 mL, 2 N), aqueous saturated sodium bicarbonate (2 x20 mL), dried over magnesium sulphate, filtered and concentrated in vacuo. The residue was collected and the acidic and basic washes were combined and extracted with dichloromethane (3 x30 mL), the organic phase dried over magnesium sulphate and concentrated. The two residues were combined to give 474 mg (67 % yield) of tert- butyl 4-(thiazol-2-ylmethylcarbamoyl)-piperidine-l -carboxylate. LC-MS (m/z) 326.2 (M+ 1).
With benzotriazol-1-ol; dicyclohexyl-carbodiimide; In acetonitrile; at 50℃;
Example 123: Preparation of l-[7-chloro-2-(2-chIoro-6-fluoro-phenyl)-lH- benzimidazole-5-carbonyl]-piperidine-4-carboxylic acid (1-naphthalen-l-yl-ethyl)- amide; The title compound was prepared as follows:; Step 1 : Preparation of 4-(l-naphthalen-2-yl-ethylcarbamoyl)-piperidine-l- carboxylic acid tert-butyl ester; To a solution piperidine-l,4-dicarboxylic acid mono-tert-butyl ester (0.30 g, 1.30 mmol) in acetonitrile was added DCC(0.26g, 1.30 mmol) and HOBT (0.19g, 1.43 mmol), 1-naphthalen-l-yl-ethylamine (0.25 ml, 1.57 mmol). This reaction mixture was stirred overnight at 50 C , then the solvent was evaporated, and the residue stirred with sat- NaHC03(aq) solution was added, and the mixture was then extracted with ethyl acetate. The organic phase was separated, dried over Na2S04 and concentrated in vacuo. Purification of the residue by silica gel chromatography (Hex/EA=2/1) to give the title compound: 0.45 g (92 %). NMR (DMSO-d6, 300 MHz) : 6(ppm) 8.05-7.43 (m, 7H), 5.87 (q, J=8.5 Hz, 1 H), 2.75-1.60 (m, 8H), 1.67 (d, J=7.5 Hz, 3H), 1.43 (s, 9H)
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 3h;
Example 3: Compound No.15 (S)-cvclohexylmethyl 1 -(2-amino-3-(thiophen-2-yl)propanoyl)-4-(4- cvanobenzyl)piperidine-4-carboxylate hydrochloride STEP A: Piperidine-1 ,4-dicarboxylic acid 1 -tert-butyl ester 4- cyclohexylmethyl ester: To a solution of piperidine-1 ,4-dicarboxylic acid mono- tert-butyl ester (66.94 mmol; 15.35 g) in dichloromethane (100 mL) was added cyclohexylmethanol (55.79 mmol; 6.37 g), dimethylaminopyridine (1 .12 mmol; 0.14 g) and dicyclohexylcarbodiimide (66.94 mmol; 12.83 g) and the resulting mixture was stirred for 3 hours at room temperature. The resulting solution was evaporated and the residue was dissolved in ethyl acetate (200 mL). The resulting solution was washed with a 1 N hydrochloric acid solution (2 x 50 mL) and brine (50 mL), and dried over magnesium sulfate. After filtration and evaporation, the residue was purified via flash column chromatography ((eluent gradient: 0 to 5% EtOAc in heptane) to yield piperidine-1 ,4-dicarboxylic acid 1 - tert-butyl ester 4-cyclohexylmethyl ester after evaporation. MS (ESI) m/z 326.29 [M+H]+.
With dicyclohexyl-carbodiimide;dmap; In dichloromethane; at 20℃; for 3h;
STEP A: Piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-cyclohexylmethyl ester To a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (66.94 mmol; 15.35 g) in dichloromethane (100 mL) was added cyclohexylmethanol (55.79 mmol; 6.37 g), dimethylaminopyridine (1.12 mmol; 0.14 g) and dicyclohexylcarbodiimide (66.94 mmol; 12.83 g) and the resulting mixture was stirred for 3 hours at room temperature. The resulting solution was evaporated and the residue was dissolved in ethyl acetate (200 mL). The resulting solution was washed with a 1N hydrochloric acid solution (2*50 mL) and brine (50 mL), and dried over magnesium sulfate. After filtration and evaporation, the residue was purified via flash column chromatography ((eluent gradient: 0 to 5% EtOAc in heptane) to yield piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-cyclohexylmethyl ester after evaporation. MS (ESI) m/z 326.29 [M+H]+.
Example 1Synthesis of compound Ia-1Step 1 Compound 1 (3.44 g, 15.0 mmol) in N,N'-dimethylformamide (20 mL) at room temperature was added with <strong>[22236-10-8]4-difluoromethoxyaniline</strong> (2.23 mL, 18.0 mmol), HOBt (2.63 g, 19.5 mmol) and EDC hydrochloride (3.45 g, 18.0 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was poured into 0.05 N hydrochloride and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, and dried over magnesium sulfate, and then, the solvent was removed in vacuo. The residue was added with ethyl acetate and hexanes, and the precipitated crystals were collected by filtration to give the desired amide compound 2 (3.88 g, yield 70%).
General procedure: A solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (9, 2.85 g, 12.45 mmol) and 1,1?-carbonyldiimidazole (2.29 g, 14.11 mmol) in DMF (3 mL) was stirred at room temperature for 45 min. This solution was added dropwise to a solution prepared by stirring for 20 min the suitable ketone 1a, 1b or 1c (7.64 mmol) with NaH (60% in oil, 0.93 g, 23.20 mmol) in DMF (20 mL). The resulting mixture was heated for the appropriate time. After cooling, H2O was added and the mixture was extracted with Et2O (3 × 30 mL). The organic phase was dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography.
30.3 1-methyl-2-piperidin-4-yl-1H-imidazo[4,5-c]pyridine (V-6) 450 mg N4-methylpyridin-3,4-diamine and 838 mg mono-tert-butyl piperidine-1,4-dicarboxylate are heated to 200 C. in 8.6 g polyphosphoric acid for 4 h. After cooling the mixture is made basic with 4 N NaOH and acidified with trifluoroacetic acid. The mixture is purified by preparative HPLC (method C). 3.37 g (50%) (V-6) are obtained as the trifluoroacetate. Analytical HPLC-MS (method B): RT=0.30 min.
tert-butyl 4-(ethyl(4-methylbenzyl)carbamoyl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20.0℃; for 18.0h;
General procedure: To a solution of 1-(tert-butoxycarbonyl) piperidine-4-carboxylic acid (0.23g, 1.00mmol) in DCM (10.00ml), EDC·HCl (1.00mmol), 13a-r (1.00mmol) and triethylamine (15.00muL, 0.10mmol) were added successively at room temperature, and the resulting reaction mixture was stirred for 18h at the same temperature. Then the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/PE 1/1) to furnish the title compound.
tert-butyl 4-((4-chlorobenzyl)(ethyl)carbamoyl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 18h;
General procedure: To a solution of 1-(tert-butoxycarbonyl) piperidine-4-carboxylic acid (0.23g, 1.00mmol) in DCM (10.00ml), EDC·HCl (1.00mmol), 13a-r (1.00mmol) and triethylamine (15.00muL, 0.10mmol) were added successively at room temperature, and the resulting reaction mixture was stirred for 18h at the same temperature. Then the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/PE 1/1) to furnish the title compound.
The intermediate 12h was obtained as describe below: piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (150 g, 0.655 mol) in anhydrous acetonitrile (800 ml), 1,1'-carbonyldiimidazole was added in small portions (132 g, 0.851 mol) under vigorous stirring. The resulting mixture was stirred for 30 min at ambient temperature. Then powder of mixture of anhydrous MgCl2 (62g, 0.655 mol) and <strong>[38330-80-2]methyl potassium malonate</strong> (102g, 0.655 mol) was added in portions. The resulted slurry was heated at reflux for 2 h. The reaction mixture was cooled down, diluted with mixture of ice-cold water and dichloromethane and neutralized by citric acid. The separated organic layer was washed with 5percent aqueous solution of potassium carbonate, dried over sodium sulfate and concentrated under reduced pressure. Further flash-chromatography using ethyl acetate/ hexane (1/1) gave 151 g (81percent) of intermediate 31. 4-(6-Hydroxy-2-methyl-pyrimidin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (32) [0223] Acetamidine hydrochloride (29 g, 0.3 mol) was added to the solution of sodium ethylate (0.3 mol) in anhydrous ethanol (400 ml). The mixture was stirred at ambient temperature for 10 min, and compound 31 (0.3 mol) in ethanol was added. The resulting mixture was heated at reflux for 5 h (TLC control). The reaction mixture was concentrated under reduced pressure, the remains was dissolved in water and acidified with 1N HCl to pH 5.0 and extracted with ethyl acetate (2x200 ml). The combined extracts were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash-chromatography on silica gel (eluent: n-hexane/ethyl acetate - 1/1). As a result, compound 32 (50 g, 33percent) was obtained. 4-(6-Chloro-2-methyl-pyrimidin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (12h) [0224] Intermediate 32 (50 g, 0.170 mol) and N,N-dimethylaniline (166 g, 1.365 mol) was dissolved in anhydrous toluene (1000 ml) and POCl3 (52 g, 0.34 mol) was added dropwise. The reaction mixture was heated at reflux for 3 h; then cooled down to ambient temperature and allowed to stay overnight. To this end, the mixture was poured into water; organic layer was separated, washed with 1N HCl and water. The crude product was concentrated under reduced pressure and purified with flash chromatography on silica gel (eluent: n-hexane/ethyl acetate 4/1) to provide 12h (34.3 g , 65percent).
(0032) (2) Compound 4 (14.56 g, 63.5 mmol), N,N?-carbonyldiimidazole (24.00 g, 86 mmol) were dissolved in tetrahydrofuran (100 mL), stirred at room temperature for 4 hours. Compounds potassium monoethyl malonate (28.10 g, 165 mmol), anhydrous magnesium chloride (18.15 g, 191 mmol) and 4-dimethylaminopyridine (800 mg, 6.35 mmol) were dissolved in acetonitrile (100 mL) and tetrahydrofuran (200 mL), stirred at room temperature for 6 hours. The two reaction mixtures were cooled to 0 C. after they sufficiently reacted separately. Then the above-mentioned first solution and triethylamine (52 mL, 254 mmol) were simultaneously added to the second solution, and then stirred overnight at room temperature. After completion of the reaction, the solvent is removed by evaporation. The residue is diluted with water (200 mL), extracted with ethyl acetate (3*200 mL), dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give a yellow oily liquid 5 (18.06 g, 95%).
182 g
To a solution of boc-isonipecotic acid (150 g, 654 mmol) in tetrahydrofuran (2100 mL) was added di-1H-imidazol-1-ylmethanone (159 g, 981 mmol) and N,N-dimethylpyridin-4-amine (40.0 g, 327 mmol) at RT. The mixture was stirred at RT for 15 h (CAUTION: moderate gas evolution). In a second flask, a suspension of potassium 3-ethoxy-3-oxopropanoate (200 g, 1.18 mol) and magnesium dichloride (112 g, 1.18 mol) in tetrahydrofuran (2100 mL) was heated to 50 C. for 15 h. The resulting warm suspension was slowly added to the first flask under extensive stirring. The resulting mixture was stirred at RT for 20 h. Tetrahydrofuran was evaporated in vacuo, water (1500 mL) and ethyl acetate (1500 mL) were added. The mixture was cooled to 10 C. and 3N aqueous HCl was added until pH 1 was achieved. The organic phase was separated, the aqueous phase was extracted with ethyl acetate (1500 mL) and the combined organic phases were washed with 10% aq. NaHCO3 (750 mL) and 10% aq. NaCl (750 mL), dried over magnesium sulfate, filtered and evaporated in vacuo to yield the title compound (182 g, 505 mmol) in a purity of 83%. LC-MS (Method 1B): Rt=1.00 min, MS (ESIPos): m/z=300 [M+H]+
To a solution of boc-isonipecotic acid (150 g, 654 mmol) in tetrahydrofuran (2100 mL) was added di- lH-imidazol-l-ylmethanone (159 g, 981 mmol) and N,N-dimethylpyridin-4-amine (40.0 g, 327 mmol) at RT. The mixture was stirred at RT for 15h (CAUTION: moderate gas evolution). In a second flask, a suspension of potassium 3-ethoxy-3-oxopropanoate (200 g, 1.18 mol) and magnesium dichloride (112 g, 1.18 mol) in tetrahydrofuran (2100 mL) was heated to 50C for 15 h. The resulting warm suspension was slowly added to the first flask under extensive stirring. The resulting mixture was stirred at RT for 20 h. Tetrahydrofuran was evaporated in vacuo, water (1500 mL) and ethyl acetate (1500 mL) were added. The mixture was cooled to 10 C and 3N aqueous HQ was added until pH 1 was achieved. The organic phase was separated, the aqueous phase was extracted with ethyl acetate (1500 mL) and the combined organic phases were washed with 10% aq. NaHCCh (750 mL) and 10% aq. NaCl (750 mL), dried over magnesium sulfate, filtered and evaporated in vacuo to yield the title compound (182 g, 505 mmol) in a purity of 83%. LC-MS (Method IB): Rt = 1.00 min, MS (ESIPos): m/z = 300 [M+H]+
To a solution of boc-isonipecotic acid (150 g, 654 mmol) in tetrahydrofuran (2100 niL) was added di- lH-iniidazol-l-ylmethanone (159 g, 981 mmol) and N,N-dimethylpyridin-4-amine (40.0 g, 327 mmol) at RT. The mixture was stirred at RT for 15h (CAUTION: moderate gas evolution). In a second flask, a suspension of potassium 3-ethoxy-3-oxopropanoate (200 g, 1.18 mol) and magnesium dichloride (112 g, 1.18 mol) in tetrahydrofuran (2100 mL) was heated to 50C for 15 h. The resulting warm suspension was slowly added to the first flask und extensive stirring. The resulting mixture was stirred at RT for 20 h. Tetrahydrofuran was evaporated in vacuo, water (1500 mL) and ethyl acetate (1500 mL) were added. The mixture was cooled to 10 C and 3N aqueous HQ was added until pH 1 was achieved. The organic phase was separated, the aqueous phase was extracted with ethyl acetate (1500 mL) and the combined organic phases were washed with 10% aq. NaHC03 (750 mL) and 10% aq. NaCl (750 mL), dried over magnesium sulfate, filtered and evaporated in vacuo to yield the title compound (182 g, 505 mmol) in a purity of 83% of theory. LC-MS (Method IB): Rt = 1.00 min, MS (ESIPos): m/z = 300 [M+H]+
1-tert-butyl 4-(1-methylpiperidin-4-yl)methyl piperidine-1,4-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.2 g
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;
To a solution of 1-[(tert-butoxy)carbonyl]piperidine-4-carboxylic acid (1.00 g, 4.36 mmol) in DCM (50 mL) was added (1-methylpiperidin-4-yl)methanol (1.13 g, 8.75 mmol), EDC.HCl (1.0 g, 5.22 mmol), 4-dimethylaminopyridine (54 mg, 0.44 mmol), The resulting solution was stirred at room temperature overnight. Water (50 mL) was added. Phases were separated. The aqueous phase was extracted with DCM (*2) and the organic layers combined. The organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with 6% MeOH in DCM. This resulted in 1.2 g of 1-tert-butyl 4-(1-methylpiperidin-4-yl)methyl piperidine-1,4-dicarboxylate as light yellow oil. LCMS (Method 28) [M+H]+=341.0, RT=0.58 min.
With hydrogenchloride; In ethyl acetate; at 20.0℃; for 2.0h;
A mixture of 1 -(ieri-butoxycarbonyl)piperidine-4-carboxylic acid (1.0 g, 4.4 mmol) in saturated EtOAc/HCI solution (10 mL) was stirred at room temperature for 2 hours. The mixture was concentrated to give the title compound (720 mg, 99%) as a white solid. LCMS- C: RT 0.72 min; m/z 130.1 [M+H]' for free base
tert-butyl 4-[[2-(4-fluorophenyl)-2-oxo-ethyl]carbamoyl]piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2220 g
Add N-methylmorpholine (3.8 L, 33 mol) to a solution of 1 -tertbutoxycarbonylpiperidine-4-carboxylic acid (1900 g, 8.3 mol) in tetrahydrofuran (THF; 24 L). Cool to -10C for 1 hour. Add isobutyl chloroformate (1.42 L, 1.26 equivalents)over 1 hour and stir the suspension for an additional 1 hour at -10C. Add 2-amino-i -(4- fluorophenyl)ethanone hydrochloride (1750 g, 9.13 mol) and stir the suspension for 1 hour at room temperature. Quench the reaction by the addition of water (1.2 L), pour the reaction mixture into methyl tert-butyl ether (MTBE; 10 L) and 0.1 M aqueous NaOH (10L). Separate the organic phase, wash with saturated aqueous sodium chloride (10 L), dryorganic phase over sodium sulfate, filter drying agent, concentrate until 2L of solvent anddry over sodium sulfate, filter, concentrate, and add petroleum ether (5 L). Collect the resulting solid by filtration and dry under vacuum to give the title compound as a white solid (2220 g, 73% yield); mass spectrum (mlz): 387(M+Na).
4-(quinolin-2-yl-carbamoyl)piperidin-1-carboxylic acid t-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 16h;
The N-Boc-4-piperidine carboxylic acid (200 mg, 0 . 87mmol), <strong>[580-22-3]2-amino-quinoline</strong> (151 mg, 1 . 05mmol), 1-ethyl-3 - (3-dimethylamino-propyl) carbodiimide hydrochloride (251 mg, 1 . 31mmol) and N-hydroxy-7-azabenzene and triazazole (297 mg, 2 . 18mmol) dissolved in dichloromethane (15 ml) in, 0 C to this solution under the conditions of adding dropwisely N, N-diisopropyl ethylamine (0.61 ml, 3 . 49mmol), stirring the mixture at room temperature for 16h, by adding water (10 ml × 2), the organic phase is dried with anhydrous sodium sulfate, removal of solvent, concentrate under column separation (V (petroleum ether)/ V =3/1 (ethyl acetate)), to obtain compound 4 - (quinolin-2-yl-carbamoyl) piperidin-1-carboxylic acid T-butyl ester: 290 mg yellow oily, yield: 93%.
4-((quinoline-2-methylene)carbamoyl)piperidin-1-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 10h;
The compound 1 - (tert-butoxy-carbonyl) piperidine-4-carboxylic acid (200 mg, 0 . 87mmol), compound <strong>[5760-20-3]quinoline-2-methylamine</strong> (165 mg, 1 . 05mmol), 1-ethyl-3 - (3-dimethylamino-propyl) carbodiimide hydrochloride (334 mg, 1 . 74mmol) and N-hydroxy-7-azabenzene and triazazole (180 mg, 1 . 31mmol) dissolved in dichloromethane (10 ml) in, 0 C to this solution under the conditions of adding dropwisely N, N-diisopropyl ethylamine (0.45 ml, 2 . 62mmol), stirring the mixture at room temperature for 10h, and washing with water (10 ml × 3), the organic phase is dried with anhydrous sodium sulfate, removal of solvent, concentrate under column separation (V (petroleum ether)/ V (ethyl acetate) =1/1) to obtain 285 mg white solid, yield: 88%.
General procedure: To a mixture of N-Boc-4-piperidinecarboxylic acid (3.65 g,16.0 mmol), pyridine (3.4 mL, 40.0 mmol) and CH2Cl2 (30.0 mL),SOCl2 (1.5 mL, 19.0 mmol) was added under N2 at room temperature.The mixture was stirred for half an hour, and a solution ofcorresponding amine (2a-i, 18.0 mmol), Et3N (8.0 mL, 56.0 mmol)and a catalytic amount of DMAP in CH2Cl2 (30.0 mL) was addeddropwise. The suspension was stirred overnight. The organic phasewas washed with 1 N HCl (2 x 30 mL) and aqueous NaHCO3(2 x 30 mL), dried over Na2SO4 (For compounds 6a, 6e and 6f, thesolvent was evaporated and washed with aqueous NaHCO3). Thesolvent was evaporated under reduced pressure and the crudeproduct was purified by flash column chromatography (ethyl acetate:petroleum ether = 1:2-3:1) to give compounds 6a-i. Thedetails of compounds 6a-c, 6e-f and 6h have been reported in our previous work.
tert-butyl 4-((6-bromoisoquinolin-3-yl)carbamoyl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Step 1 To a stirred solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (XXVIII) (1.542 g, 6.72 mmol) and HATU (2.56 g, 6.72 mmol) was added DIPEA (2.349 mL, 13.45 mmol). After 10 min, <strong>[891785-28-7]6-bromoisoquinolin-3-amine</strong> (XII) (1 g, 4.48 mmol) was added followed by the addition of DMAP (0.110 g, 0.897 mmol) and the mixture was heated to 70 C. overnight. The LC/MS of mixture showed complete conversion of the amine to the product. The solvents were concentrated in vacuo, the residue taken into EtOAc, washed with water, sat. aq. NaHCO3 and brine solution. The organic layer was dried over anhydrous Na2SO4, solvents removed in vacuo and the residue was dried under high vacuo to obtain crude tert-butyl 4-((6-bromoisoquinolin-3-yl)carbamoyl)piperidine-1-carboxylate (XXIX) as a brown gummy solid (2.29 g, 5.27 mmol, 11.8% yield). Used for next step without purification.
(S)-1-tert-butyl 4-(2-(4-(5-chloro-2-(isopropylamino)pyridin-4-yl)-1H-pyrrole-2-carboxamido)-2-(3-chlorophenyl)ethyl)piperidine-1,4-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With dmap; 1,2-dichloro-ethane; In dichloromethane; at 20℃;
To a mixture of (S)-.4.-(5.-chioro.-2(isopropyiainino)pyridiri.-4.-yi).-N-.( I .-(3 chl orophenyi)2-hydroxyethyl)- 1 El-pyrrol e-2-carboxamide (65 m, 0.15 mmol) and I -(tert.butoxycarbonyl)piperidine -4-carhoxylic acid (38 mg, 0.165 mmol) in dry CH2CI2 (4 mU) was added EDC (32 mg, 0.165 mmoi) and DMAP (20 mg, 0. 165 mmol), The reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM and washed with aqueous NHiCi solution. The organic layer was dried over Na2SO. and concentrated in vacuum. The crude residue was purified by ISCO using DCMIMeOH (0.-10%) as eluent to afford 95 mg (98%) of product. ESMS calculated (C32H39C12N505): 64459; found: 645 (M+H).
With 4-methyl-morpholine; 1,2-dichloro-ethane; In N,N-dimethyl-formamide; at 20℃;
To a solution of N-Boc--piperidine4carboxv1ic acid A (007 g, 0.3 rnmol) and FP-241(i5Orng, 0.3 mmoi) in DMF (3 mL) was added EDC (0.01 g, 0.5 mmoi) and NMM (001 g, 0.01 rnrnol). The mixture was stirred overnight at RT. The reaction mixture was diluted with F;tOAc, washed with water and saturated aq. NaC1, The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel DMCMeOH 99:1 to 9:1) to give compound 13 as white solid (007 g, 32.5% yield).
tert-butyl 4-(4-(trifluoromethyl)piperidine-1-carbonyl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃;
General procedure: To a stirred solution of compound 7 (200 mg, 0.87 mmol) in DCM (10 mL) was added amines (1.0 mmol), EDC(186 mg, 1.2 mmol), and HOBt (153 mg, 1.2 mmol) at room temperature. The mixture was stirred for 3 hrs, quenchedby H2O (15 mL), and extracted by DCM (15 mL × 3). The organic layer was dried over anhydrous MgSO4, filtered,and concentrated. The residue was purified by chromatography on a silica gel column to afford compound 8a-l as acolorless oil.
With copper(I) thiophene-2-carboxylate; (4,4'-di-tert-butyl-2,2'-dipyridyl)-bis-(5-methyl-2-(4-fluorophenyl)pyridine(-1H))-iridium(III) hexafluorophosphate; N,N,N?,N?-tetramethyl-N?-tert-butylguanidine; bathophenanthroline; iodomesitylene diacetate; In 1,4-dioxane; at 20℃; for 1h;Inert atmosphere; Irradiation;
General procedure: To a 20 ml or 40 ml viale quipped with a stir bar was added photocatalyst, nitrogen nucleophile, iodomesitylene dicarboxylate, copper salt, and ligand. Dioxane was added followed by addition of the base. The solution was sonicated for 1-3 min until it became homogeneous. Next, the solution was degassed by sparging with nitrogen for 5-10 min before sealing with Parafilm. The reaction was stirred and irradiated using two 34-W blue LED lamps (3 cm away, with cooling fan to keep the reaction at room temperature) for 1 h. The reaction mixture was removed from the light, cooled to ambient temperature, diluted with water (15 ml) and ethyl acetate (25 ml), and the aqueous layer was extracted with ethyl acetate (3 × 25 ml). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel to afford the desired decarboxylative C-N coupling product. For aniline substrates, a solution of these nitrogen nucleophiles in dioxane was used; additionally, if the iodomesitylene dicarboxylate is a liquid, its solution in dioxane was used.
tert-butyl 4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
6 g
Step a [00125] To a stirred solution of 1 -(ie f-butoxycarbonyl)piperidine-4-carboxylic acid (CAS Number 183673-71 -4, available from Combi blocks) (5 g, 21.80 mmol) in DMF (30 ml), were added HATU available from Reddy & Reddy chemicals) (12.43 g, 32.70 mmol) and diisopropylethylamine (1 1.27 g, 87.22 mmol) at 0C under nitrogen atmosphere and allowed to stir for 15 min. A solution of <strong>[280-07-9]3-oxa-8-azabicyclo[3.2.1]octane</strong> (CAS Number 904316-92-3, available from Synthonix) (2.95 g, 26.16 mmol) in DMF (10 ml) was added drop wise and the resulting reaction mixture was allowed to stir at room temperature for 2 h. The reaction mixture was diluted with ice-cold water (500 ml) and extracted with ethyl acetate (4 x 50 ml). The combined organic layer was brine washed, dried over Na2S04 and concentrated under reduced pressure. The crude material, thus obtained was purified by column chromatography (15% ethyl acetate in hexane) to afford tert-butyl 4-(<strong>[280-07-9]3-oxa-8-azabicyclo[3.2.1]octane</strong>-8- carbonyl)piperidine-1 -carboxylate (6.0 g, 18.507 mmol) as a white solid. LCMS: Method B, 1.942 min, MS: ES+ 269.1 (M-56).
tert-butyl 4-(quinolin-4-ylcarbamoyl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
20%
General procedure: Compound 2 (1g, 4.361mmol) was dissolved in DCM. To this mixture, 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimide hydrochloride (1.67g, 8.72mmol) and 1-hydroxybenzotriazole (1.17g, 8.72mmol) was added and stirred for 20min in nitrogen environment. Aniline (0.796mL, 8.72mmol) and triethylamine (1.8mL, 13.08mmol) was added to above mixture and stirred overnight. Reaction mixture was diluted with DCM and washed with saturated aqueous solution of sodium bicarbonate. DCM layer dried over sodium sulphate and evaporated. The crude solid was purified by column chromatography (EtOAc: Hexane; 2.5:7.5) to get 0.9g compound 3a as white solid (yield 75.35%).
[(2S,3S)-3-(4-{4-[4-(4-[(3R,5R)-5-(2,4-difluorophenyl)-5-[(1H-1,2,4-triazol-1-yl)methyl]oxolan-3-yl]methoxy}phenyl)piperazin-1-yl]phenyl}-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)pentan-2-yl] 1-tert-butoxycarbonyl-piperidine-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane;Reflux;
110 mg (0.16 mmol, 1.0 eq) of posaconazole, 91 mg (0.39 mmol, 2.5 eq) of 1-tert-butoxycarbonylpiperidine-4-carboxylic acid, 52.8 mg (0.48 mmol, 3.0 eq) of triethylamine was dissolved in 5 mL In dichloromethane. After adding 75 mg of EDCI (0.39 mmol, 2.5 eq), the reaction was refluxed overnight, and the reaction was monitored by TLC. The reaction solution was slowly poured into water, and the aqueous phase was extracted with dichloromethane. The combined organic phases, the organic phase washed with water and saturated sodium bicarbonate, the organic phase was dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure, the residue was purified by column chromatography to give the product (114 mg, yield = 80%).
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