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Chemical Structure| 84358-13-4
Chemical Structure| 84358-13-4
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Product Details of [ 84358-13-4 ]

CAS No. :84358-13-4 MDL No. :MFCD00076999
Formula : C11H19NO4 Boiling Point : -
Linear Structure Formula :- InChI Key :JWOHBPPVVDQMKB-UHFFFAOYSA-N
M.W :229.27 Pubchem ID :392871
Synonyms :

Calculated chemistry of [ 84358-13-4 ]

Physicochemical Properties

Num. heavy atoms : 16
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.82
Num. rotatable bonds : 4
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 63.17
TPSA : 66.84 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.9 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.18
Log Po/w (XLOGP3) : 1.13
Log Po/w (WLOGP) : 1.34
Log Po/w (MLOGP) : 1.03
Log Po/w (SILICOS-IT) : 0.5
Consensus Log Po/w : 1.24

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -1.71
Solubility : 4.48 mg/ml ; 0.0195 mol/l
Class : Very soluble
Log S (Ali) : -2.13
Solubility : 1.71 mg/ml ; 0.00746 mol/l
Class : Soluble
Log S (SILICOS-IT) : -0.66
Solubility : 50.7 mg/ml ; 0.221 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.09

Safety of [ 84358-13-4 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 84358-13-4 ]

* 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.

  • Upstream synthesis route of [ 84358-13-4 ]
  • Downstream synthetic route of [ 84358-13-4 ]

[ 84358-13-4 ] Synthesis Path-Upstream   1~61

  • 1
  • [ 84358-13-4 ]
  • [ 39546-32-2 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 5, p. 757 - 761
  • 2
  • [ 67-56-1 ]
  • [ 84358-13-4 ]
  • [ 2971-79-1 ]
Reference: [1] Tetrahedron Letters, 2004, vol. 45, # 12, p. 2663 - 2665
  • 3
  • [ 67-56-1 ]
  • [ 84358-13-4 ]
  • [ 124443-68-1 ]
YieldReaction ConditionsOperation in experiment
90% 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: WO2006/86609, 2006, A2, . Location in patent: Page/Page column 160
[2] Tetrahedron Letters, 2004, vol. 45, # 12, p. 2663 - 2665
[3] Tetrahedron Letters, 2011, vol. 52, # 8, p. 849 - 852
  • 4
  • [ 84358-13-4 ]
  • [ 74-88-4 ]
  • [ 124443-68-1 ]
Reference: [1] Tetrahedron Letters, 2001, vol. 42, # 28, p. 4605 - 4607
[2] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 17, p. 4453 - 4459
[3] Patent: WO2010/57121, 2010, A1, . Location in patent: Page/Page column 179-180
[4] Patent: WO2013/19621, 2013, A1, . Location in patent: Page/Page column 57
  • 5
  • [ 84358-13-4 ]
  • [ 18107-18-1 ]
  • [ 124443-68-1 ]
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 ]
YieldReaction ConditionsOperation 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.

Reference: [1] Patent: WO2012/34526, 2012, A1, . Location in patent: Page/Page column 56
[2] Patent: US2013/190307, 2013, A1, . Location in patent: Paragraph 0205; 0206
[3] Patent: US2016/102095, 2016, A1, . Location in patent: Paragraph 0131
[4] Patent: CN104292233, 2016, B, . Location in patent: Paragraph 0047
[5] Patent: WO2016/34134, 2016, A1, . Location in patent: Paragraph 00538
[6] Patent: CN105461693, 2016, A, . Location in patent: Paragraph 0389; 0390; 0391; 0392; 0393
[7] Patent: CN105399698, 2016, A, . Location in patent: Paragraph 1618-1620
[8] Patent: WO2017/106607, 2017, A1, . Location in patent: Paragraph 00446
[9] Patent: WO2007/71035, 2007, A1, . Location in patent: Page/Page column 37
[10] Patent: WO2009/61676, 2009, A2, . Location in patent: Page/Page column 71
[11] Patent: US2006/63775, 2006, A1, . Location in patent: Page/Page column 18
  • 9
  • [ 142851-03-4 ]
  • [ 84358-13-4 ]
YieldReaction ConditionsOperation in experiment
65% 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 ]
YieldReaction ConditionsOperation 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)5 1H 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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YieldReaction ConditionsOperation 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.
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YieldReaction ConditionsOperation in experiment
94% With triethylamine In dichloromethane 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).
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YieldReaction ConditionsOperation 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]+.
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YieldReaction ConditionsOperation 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).

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  • 33
  • [ 84358-13-4 ]
  • [ 139290-70-3 ]
YieldReaction ConditionsOperation in experiment
79%
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
  • [ 84358-13-4 ]
  • [ 1117-97-1 ]
  • [ 139290-70-3 ]
YieldReaction ConditionsOperation 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 ]
YieldReaction ConditionsOperation 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.
Reference: [1] Patent: US2002/151717, 2002, A1,
[2] Patent: US2002/151717, 2002, A1,
[3] Patent: US2002/151717, 2002, A1,
  • 36
  • [ 6638-79-5 ]
  • [ 84358-13-4 ]
  • [ 530-62-1 ]
  • [ 139290-70-3 ]
Reference: [1] Patent: US2005/261341, 2005, A1,
[2] Patent: US5371093, 1994, A,
  • 37
  • [ 478408-77-4 ]
  • [ 6638-79-5 ]
  • [ 84358-13-4 ]
  • [ 139290-70-3 ]
Reference: [1] Patent: US2002/151717, 2002, A1,
  • 38
  • [ 84358-13-4 ]
  • [ 158407-04-6 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 17, p. 2615 - 2620
  • 39
  • [ 84358-13-4 ]
  • [ 18107-18-1 ]
  • [ 189321-63-9 ]
Reference: [1] Patent: WO2006/73361, 2006, A1, . Location in patent: Page/Page column 161-162
  • 40
  • [ 84358-13-4 ]
  • [ 189321-63-9 ]
Reference: [1] Patent: WO2013/19621, 2013, A1,
[2] Journal of Medicinal Chemistry, 2017, vol. 60, # 11, p. 4680 - 4692
[3] Patent: EP2009006, 2008, A1,
  • 41
  • [ 84358-13-4 ]
  • [ 301673-14-3 ]
YieldReaction ConditionsOperation in experiment
96% 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
  • 43
  • [ 84358-13-4 ]
  • [ 206989-61-9 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 13, p. 3419 - 3424
[2] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 4, p. 935 - 939
[3] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 5, p. 1299 - 1305
[4] Patent: WO2013/96744, 2013, A1,
[5] Tetrahedron, 2015, vol. 71, # 42, p. 8208 - 8212
[6] Patent: WO2016/40498, 2016, A1,
[7] Patent: KR2017/45749, 2017, A,
[8] Patent: EP3255042, 2017, A2,
[9] Patent: WO2018/33135, 2018, A1,
[10] Patent: TW2018/11794, 2018, A,
[11] Patent: WO2018/137681, 2018, A1,
[12] Patent: WO2009/150144, 2009, A1,
[13] Patent: WO2008/42925, 2008, A1,
  • 44
  • [ 6148-64-7 ]
  • [ 84358-13-4 ]
  • [ 479630-08-5 ]
YieldReaction ConditionsOperation in experiment
95%
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]+
Reference: [1] Patent: US2016/102095, 2016, A1, . Location in patent: Paragraph 0032
[2] Journal of Medicinal Chemistry, 2017, vol. 60, # 11, p. 4680 - 4692
[3] Patent: US2015/126449, 2015, A1, . Location in patent: Paragraph 0334; 0335; 0336
[4] Patent: WO2015/67549, 2015, A1, . Location in patent: Page/Page column 60
[5] Patent: WO2016/71216, 2016, A1, . Location in patent: Page/Page column 153
  • 45
  • [ 38330-80-2 ]
  • [ 84358-13-4 ]
  • [ 479630-08-5 ]
YieldReaction ConditionsOperation in experiment
81%
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).
Reference: [1] Patent: EP2719696, 2014, A1, . Location in patent: Paragraph 0221; 0222
  • 46
  • [ 2033-24-1 ]
  • [ 64-17-5 ]
  • [ 84358-13-4 ]
  • [ 479630-08-5 ]
Reference: [1] Tetrahedron Letters, 2003, vol. 44, # 8, p. 1627 - 1629
  • 47
  • [ 84358-13-4 ]
  • [ 479630-08-5 ]
Reference: [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 20, p. 7193 - 7205
[2] ChemMedChem, 2013, vol. 8, # 12, p. 1963 - 1977
[3] Patent: WO2013/25939, 2013, A2,
[4] Patent: WO2014/173289, 2014, A1,
[5] Tetrahedron, 2015, vol. 71, # 42, p. 8208 - 8212
[6] Patent: US9745288, 2017, B2,
[7] Patent: TWI602818, 2017, B,
  • 48
  • [ 84358-13-4 ]
  • [ 345627-80-7 ]
Reference: [1] Journal of Medicinal Chemistry, 2004, vol. 47, # 7, p. 1719 - 1728
  • 49
  • [ 64269-79-0 ]
  • [ 84358-13-4 ]
  • [ 187834-88-4 ]
Reference: [1] Patent: WO2006/36395, 2006, A2, . Location in patent: Page/Page column 51-52
  • 50
  • [ 84358-13-4 ]
  • [ 187834-88-4 ]
YieldReaction ConditionsOperation in experiment
95 g With hydrazine hydrate In methanolReflux 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).
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 11, p. 3178 - 3182
[2] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 14, p. 4191 - 4194
[3] Patent: WO2005/100344, 2005, A1, . Location in patent: Page/Page column 46
[4] Patent: US2013/150341, 2013, A1, . Location in patent: Paragraph 0272; 0273; 0274
[5] Patent: WO2013/83741, 2013, A1, . Location in patent: Page/Page column 75-76
[6] Patent: WO2006/135627, 2006, A2, . Location in patent: Page/Page column 100
[7] Patent: WO2006/135627, 2006, A2, . Location in patent: Page/Page column 91
  • 51
  • [ 84358-13-4 ]
  • [ 301221-79-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 8, p. 2129 - 2134
[2] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 13, p. 3419 - 3424
[3] Patent: WO2009/150144, 2009, A1,
[4] Patent: WO2008/42925, 2008, A1,
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  • [ 189442-87-3 ]
Reference: [1] Journal of Medicinal Chemistry, 2017, vol. 60, # 11, p. 4680 - 4692
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Reference: [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 24, p. 7520 - 7534
[2] Patent: WO2016/30443, 2016, A1,
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  • [ 252882-60-3 ]
Reference: [1] Patent: WO2015/144290, 2015, A1,
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  • [ 180307-56-6 ]
Reference: [1] Angewandte Chemie - International Edition, 2018, vol. 57, # 40, p. 13096 - 13100[2] Angew. Chem., 2018, vol. 130, # 40, p. 13280 - 13284,5
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  • [ 84358-13-4 ]
  • [ 280110-69-2 ]
Reference: [1] Patent: WO2015/8230, 2015, A1,
  • 57
  • [ 84358-13-4 ]
  • [ 769944-78-7 ]
Reference: [1] Angewandte Chemie - International Edition, 2016, vol. 55, # 33, p. 9676 - 9679[2] Angew. Chem., 2016, vol. 128, # 33, p. 9828 - 9831,4
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  • [ 84358-13-4 ]
  • [ 370864-73-6 ]
Reference: [1] Angewandte Chemie - International Edition, 2016, vol. 55, # 33, p. 9676 - 9679[2] Angew. Chem., 2016, vol. 128, # 33, p. 9828 - 9831,4
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  • [ 84358-13-4 ]
  • [ 873551-20-3 ]
Reference: [1] Journal of the American Chemical Society, 2015, vol. 137, # 18, p. 5875 - 5878
  • 60
  • [ 84358-13-4 ]
  • [ 887354-02-1 ]
Reference: [1] Journal of Medicinal Chemistry, 2017, vol. 60, # 13, p. 5507 - 5520
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  • [ 1048970-17-7 ]
Reference: [1] Science, 2017, vol. 357, # 6348, p. 283 - 286
[2] Science, 2017, vol. 357, # 6348, p. 283 - 286
[3] Science, 2017, vol. 357, # 6348, p. 283 - 286
[4] ACS Catalysis, 2018, vol. 8, # 10, p. 9537 - 9542
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