* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With sodium hydrogencarbonate In methanol at 20℃; for 24 h;
To a 1000 mL round bottom flask, 2R-piperidine carboxylic acid (8.0 g, 0.062 mol), di-tert-butyl dicarbonate (14.8 g, 0.068 mol), sodium bicarbonate (26.04 g, 0.310 mol) and methanol (400 mL) were added, and stirred at room temperature for 24 hours. Thereafter, the reaction product was subjected to vacuum distillation for removal of methanol, dissolved with water, washed 3 times with ethyl ether, adjusted to pH = 2 with saturated potassium hydrogen sulfate, and extracted 3 times with dichloromethane. The extracts were combined, washed 3 times with saturated brine, concentrated, and separated through a silica gel column (eluent: petroleum ether/ethyl acetate/acetic acid), to give 12.48 g of a white product, yield 87.8percent. [0075] 1H-NMR (400 MHz, DMSO) δ ppm: 12.71 (1H, s), 4.61 (1H, d, J = 28.8 Hz), 3.82 (1H, d, J = 12 Hz), 2.93 (1H, m), 2.06 (1H, s), 1.62 (3H, m), 1.39(11H, m); EI-MS (m/z): 229.1[M]+.
87.8%
With sodium hydrogencarbonate In methanol at 20℃; for 24 h;
To a 1000 mL round bottom flask, 2R-piperidine carboxylic acid (8.0 g, 0.062 mol), di-tert-butyl dicarbonate (14.8 g, 0.068 mol), sodium bicarbonate (26.04 g, 0.310 mol) and methanol (400 mL) were added, and stirred at room temperature for 24 hours. Thereafter, the reaction product was subjected to vacuum distillation for removal of methanol, dissolved with water, washed 3 times with ethyl ether, adjusted to pH=2 with saturated potassium hydrogen sulfate, and extracted 3 times with dichloromethane. The extracts were combined, washed 3 times with saturated brine, concentrated, and separated through a silica gel column (eluent: petroleum ether/ethyl acetate/acetic acid), to give 12.48 g of a white product, yield 87.8percent.1H-NMR (400 MHz, DMSO) δ ppm: 12.71 (1H, s), 4.61 (1H, d, J=28.8 Hz), 3.82 (1H, d, J=12 Hz), 2.93 (1H, m), 2.06 (1H, s), 1.62 (3H, m), 1.39(11H, m); EI-MS (m/z): 229.1[M]+.
83%
With triethylamine In 1,4-dioxane; water at 20℃; for 20 h;
To a suspension of (R)-piperidine-2-carboxylic acid (12.5 g, 96.8 mmol) in water (88mL) and 1,4-dioxane (133 mL), were added di-tert-butyl dicarbonate (23.2 g, 106 mmol) andtriethylamine (13.5 mL, 96.8 mmol). The solution was stirred at room temperature for 20hours. The mixture was concentrated in vacuo, diluted with ethyl acetate (200 mL) and25 washed with 5percent aqueous HCl. The organic phase was separated, dried over anhydrousNa2S04, filtered, and concentrated to afford the compound as a white solid (18.5 g, 83percent).MS 130 (MH+- boc).
Reference：
[1] Journal of Medicinal Chemistry, 1998, vol. 41, # 4, p. 591 - 601
[2] Journal of Medicinal Chemistry, 1992, vol. 35, # 9, p. 1550 - 1557
[3] ChemMedChem, 2013, vol. 8, # 4, p. 577 - 581
[4] Patent: EP2805947, 2014, A1, . Location in patent: Paragraph 0074-0075
[5] Patent: US2015/126500, 2015, A1, . Location in patent: Paragraph 0127; 0128
[6] Patent: WO2014/25706, 2014, A1, . Location in patent: Page/Page column 73
[7] Journal of the American Chemical Society, 1995, vol. 117, # 32, p. 8488 - 8489
[8] Patent: US2004/198701, 2004, A1, . Location in patent: Page/Page column 10
[9] Patent: US2005/227969, 2005, A1, . Location in patent: Page/Page column 10
Reference：
[1] Chemistry - A European Journal, 2010, vol. 16, # 13, p. 4082 - 4090
[2] Journal of the American Chemical Society, 2010, vol. 132, # 21, p. 7260 - 7261
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[1] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 2, p. 184 - 187
18
[ 67-56-1 ]
[ 28697-17-8 ]
[ 18650-38-9 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 9, p. 2711 - 2714
19
[ 28697-17-8 ]
[ 250249-85-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 17, p. 2621 - 2624
20
[ 28697-17-8 ]
[ 74-88-4 ]
[ 164456-75-1 ]
Yield
Reaction Conditions
Operation in experiment
99%
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
Example 1.1; (R)-Piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester; To (R)-Piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (5.1 g, 22.2 mmol) in DMF (60 mL) were added K2CO3 (12.3 g, 88.8 mmol) and Mel (1.7 mL, 26.6 mmol). After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate. The organic layer was washed with water (6 times) and brine, dried over anhydrous Na2SO4, filtered and concentrated to give the title product (5.4 g, 99percent).1H NMR (300 MHz, CDCl3): δ 4.82 (m, 1H), 3.99 (m, 1H), 3.75 (s, 3H), 2.95 (m, 1H), 2.21 (m, 1H), 2.45 (m, 14H).
99%
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
Example 1.1(R)-Piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester To (R)-Piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (5.1 g, 22.2 mmol) in DMF (60 mL) were added K2CO3 (12.3 g, 88.8 mmol) and MeI (1.7 mL, 26.6 mmol). After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate. The organic layer washed with water (6 times) and brine, dried over anhydrous Na2SO4, filtered and concentrated to give the title product (5.4 g, 99percent).1H NMR (300 MHz, CDCl3): δ (ppm) 4.82 (m, 1H), 3.99 (m, 1H), 3.75 (s, 3H), 2.95 (m, 1H), 2.21 (m, 1H), 2.45 (m, 14H)
With ammonium chloride; N-ethyl-N,N-diisopropylamine; HATU In DMF (N,N-dimethyl-formamide) at 0 - 20℃; for 18 h;
Step B. tert-Butyl (2R)-2-(aminocarbonyl)piperidine-1-carboxylate; HATU (5.60 g, 14.7 mmol) was added to a mixture of the (2R)- 1 -(tert- butoxycarbonyl) piperidine-2-carboxylic acid (2.29 g, 10 mmol), ammonium chloride (3.21 g, 60 mmol) and DIPEA (3.88 g, 30 mmol) in DMF (70 mL) at 0 °C. The mixture was stirred for 18 h at room temperature, diluted with H20 (100 mL) and extracted with EtOAc (3x100 mL). The combined organic phases were washed with 10percent Na2C03 solution (2x30 mL), brine (2x30 mL) and dried with Na2S04. After filtration and concentration, the title compound was purified by MPLC on silica gel using hexane/EtOAc (1:1) g, 100 percent) as a white solid. (at)H NMR(400 MHz, CDCl3) No. 1.46 (s, 9 H), 1.63 (m, 2 H), 2.22 (m, 1 H), 2.91 (m, 1 H), 3.06 (m, 3 H), 4.01 (m, 1 H), 4.71 (m, 1 H), 6.46 (s broad, 2 H). MS (ESI) (M+H) (at)= 228.92
99%
Stage #1: With triethylamine; methyl chloroformate In tetrahydrofuran at 0℃; Stage #2: With ammonia In tetrahydrofuran; water at 0 - 20℃; for 4 h;
a) 1, 1-Dimethylethyl (2/tO-2-(aminocarbonyI)-1-piporidinecarboxylalc. To a cold (0°C) solution of fe/iS-1-iUl, 1-dimethylethy^oxy]carbonyl]-2-piperidinecarboxylic acid(1.0 g, 4.36 mmol) in THF (20 ml) was added triethylamine (0.60 mL, 4,36 rnmol)followed by slow addition of methyl chloroform ate (0.34 mL, 4,36 rnmol). After a fewminutes a suspension had formed, To this mixture was added concentrated NI-LiOH(1.5 mL) and the solution was allowed to warm to rt as the bath warmed and stirredfor a total of 4 h. The mixture was concentrated in vacuo and the residue was takenup in EtOAc, The organic layer was washed with citric acid, bicard and then brine,dried over NasSO-i. Filtration and concentration gave 1, 1-dimethylethyl(2R)-2-(aminocarbonyl)-1-piperidinecarboxylate (3 .0 g, 99percent). 1H NMR (CDCl3) δ 6,03(br, 1 H), 5.45 (br, 1 H), 4.77 (br, 1 H), 4.06 (br, 1 H), 2.82 (m, 1 H), 2.29 (m, 1 H),1.67- 1.43 (m, 13 H),
89%
With ammonium chloride; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 20℃; for 1.5 h;
Example 1; 1-{(R)-2-[4-(4-Chloro-phenyl)-thiazol-2-yl]-piperidin-1-yl}-2-phenoxy-ethanone; The title compound was prepared as illustrated in scheme 1, steps 1 to 5.; Step 1. A suspension of ammonium chloride (3.44 g, 64 mmol) in N,N-dimethylacetamide (150 mL) under argon was treated with diisopropylethylamine (13.44 g, 17.7 mL, 104 mmol). A solution of (R)-(+)-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (5.10 g, 22 mmol) was added, followed by TBTU (10.11 g, 31 mmol). The mixture was stirred at room temperature for 1.5 h, then diluted with ethyl acetate (850 mL) and washed several times with water (5*50 mL) and finally with saturated sodium chloride. The organic phase was dried over sodium sulphate and evaporated. The resulting oil was purified by flash chromatography (heptane/ethyl acetate gradient) to yield (R)-2-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (4.54 g, 89percent) as a white solid, MS (ISP): 229.0 (M+H)+..
Compound 2a (5.0 g, 21.8 mmol, 1.0 eq) was dissolved in THF (60 mL),The temperature of the reaction system was lowered to 0 C, BH3.THF (26.2 ml, 26.2 mmol, 1.2 eq) was added to the reaction system, and the temperature was raised to room temperature and stirred for 2 h.The reaction was quenched with saturated NaHCO3 and extracted with EtOAc (2 x 30 mL).It was washed with saturated brine, dried over Na2SO4, and spin-dried to obtain compound 2b (4.8 g, yield: 100%).TLC: DCM / MeOH = 10/1, I2, Rf (compound 2a) = 0.2, Rf (compound 2b) = 0.4.
99%
EXAMPLE 50(b); Starting Material for Examples 50 Et Seq; Step 1; (R)-2-Hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester; To a solution of (R)-Piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (5 g, 21.8 mmol) in anhydrous THF (32 mL) at 0-5 C. was added borane-tetrahydrofuran complex (1M solution in THF) (3.6 g, 41.84 mmol) over a period of 15 min. The mixture was stirred at 0-5 C. for 2 h and then at it for 2 h. The mixture was added over a period of 10 min to cold water (75 mL) and extracted with EtOAc (300 mL). The aqueous layer was re-extracted with EtOAc (2×150 mL). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated to obtain the title product as a colorless oil (4.65 g., 99%).
82%
With dimethylsulfide borane complex; In tetrahydrofuran; at 0 - 20℃; for 18.25h;
A solution of (R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (Example 15g,18.5 g, 80.7 mmol) in anhydrous THF (44.4 mL) was cooled to 0C. BH3"Me2S (44.4 mL,88.8 mmol) was added drop wise over 15 minutes. After complete addition, the mixture wasallowed to warm to room temperature, and stirring was continued for 18 hours. The mixturewas quenched with water, and extracted with ethyl acetate. The organic extract was dried15 over anhydrous Na2S04, filtered, and concentrated. The resulting residue was flashchromatographed on silica gel (35% ethyl acetate in hexanes) to provide (R)-tert-butyl-2-(hydroxymethyl)piperidine-1-carboxylate as a white solid (14.2 g, 82%). MS 116 (MH+boc)
With sodium hydrogencarbonate; In methanol; at 20℃; for 24h;
To a 1000 mL round bottom flask, 2R-piperidine carboxylic acid (8.0 g, 0.062 mol), di-tert-butyl dicarbonate (14.8 g, 0.068 mol), sodium bicarbonate (26.04 g, 0.310 mol) and methanol (400 mL) were added, and stirred at room temperature for 24 hours. Thereafter, the reaction product was subjected to vacuum distillation for removal of methanol, dissolved with water, washed 3 times with ethyl ether, adjusted to pH = 2 with saturated potassium hydrogen sulfate, and extracted 3 times with dichloromethane. The extracts were combined, washed 3 times with saturated brine, concentrated, and separated through a silica gel column (eluent: petroleum ether/ethyl acetate/acetic acid), to give 12.48 g of a white product, yield 87.8%. [0075] 1H-NMR (400 MHz, DMSO) delta ppm: 12.71 (1H, s), 4.61 (1H, d, J = 28.8 Hz), 3.82 (1H, d, J = 12 Hz), 2.93 (1H, m), 2.06 (1H, s), 1.62 (3H, m), 1.39(11H, m); EI-MS (m/z): 229.1[M]+.
87.8%
With sodium hydrogencarbonate; In methanol; at 20℃; for 24h;
To a 1000 mL round bottom flask, 2R-piperidine carboxylic acid (8.0 g, 0.062 mol), di-tert-butyl dicarbonate (14.8 g, 0.068 mol), sodium bicarbonate (26.04 g, 0.310 mol) and methanol (400 mL) were added, and stirred at room temperature for 24 hours. Thereafter, the reaction product was subjected to vacuum distillation for removal of methanol, dissolved with water, washed 3 times with ethyl ether, adjusted to pH=2 with saturated potassium hydrogen sulfate, and extracted 3 times with dichloromethane. The extracts were combined, washed 3 times with saturated brine, concentrated, and separated through a silica gel column (eluent: petroleum ether/ethyl acetate/acetic acid), to give 12.48 g of a white product, yield 87.8%.1H-NMR (400 MHz, DMSO) delta ppm: 12.71 (1H, s), 4.61 (1H, d, J=28.8 Hz), 3.82 (1H, d, J=12 Hz), 2.93 (1H, m), 2.06 (1H, s), 1.62 (3H, m), 1.39(11H, m); EI-MS (m/z): 229.1[M]+.
83%
With triethylamine; In 1,4-dioxane; water; at 20℃; for 20h;
To a suspension of <strong>[1723-00-8](R)-piperidine-2-carboxylic acid</strong> (12.5 g, 96.8 mmol) in water (88mL) and 1,4-dioxane (133 mL), were added di-tert-butyl dicarbonate (23.2 g, 106 mmol) andtriethylamine (13.5 mL, 96.8 mmol). The solution was stirred at room temperature for 20hours. The mixture was concentrated in vacuo, diluted with ethyl acetate (200 mL) and25 washed with 5% aqueous HCl. The organic phase was separated, dried over anhydrousNa2S04, filtered, and concentrated to afford the compound as a white solid (18.5 g, 83%).MS 130 (MH+- boc).
With sodium hydroxide; In tetrahydrofuran; water; for 5h;Heating / reflux;
[0189] To a slurry of pipecolinic acid (109.7 g) and BOC2O (222.4 g) in 1:1 tetrahydrofuran (THF)/H2O (550/550 mL) was added 50% NaOH (45 mL). The slurry was warmed to reflux and aged 5 h at reflux. The solution was cooled to 23 C. and then washed with heptane (550 mL) to remove unreacted BOC2O. The aqueous (aq.) layer was then acidified with 5N HCl (170 mL) to pH 4-5. The resulting slurry was extracted with 550 mL of tert-butyl methyl ether (MTBE). The organic layer was dried over Na2SO4 and then concentrated to a white solid of (2).
PREPARATIVE EXAMPLE 2; To a slurry of pipecolinic acid (109.7 g) and BOC2O (222.4 g) in 1:1 tetrahydrofuran (THF)/H2O (550/550 mL) was added 50% NaOH (45 mL). The slurry was warmed to reflux and aged 5h at reflux. The solution was cooled to 23 C. and then washed with heptane (550 mL) to remove unreacted BOC20. The aqueous (aq.) layer was then acidified with 5N HCl (170 mL) to pH 4-5. The resulting slurry was extracted with 550 mL of tert-butyl methyl ether (MTBE). The organic layer was dried over Na2SO4 and then concentrated to a white solid of (2).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
Example 1.1; (R)-Piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester; To (R)-Piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (5.1 g, 22.2 mmol) in DMF (60 mL) were added K2CO3 (12.3 g, 88.8 mmol) and Mel (1.7 mL, 26.6 mmol). After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate. The organic layer was washed with water (6 times) and brine, dried over anhydrous Na2SO4, filtered and concentrated to give the title product (5.4 g, 99%).1H NMR (300 MHz, CDCl3): delta 4.82 (m, 1H), 3.99 (m, 1H), 3.75 (s, 3H), 2.95 (m, 1H), 2.21 (m, 1H), 2.45 (m, 14H).
99%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
Example 1.1(R)-Piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester To (R)-Piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (5.1 g, 22.2 mmol) in DMF (60 mL) were added K2CO3 (12.3 g, 88.8 mmol) and MeI (1.7 mL, 26.6 mmol). After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate. The organic layer washed with water (6 times) and brine, dried over anhydrous Na2SO4, filtered and concentrated to give the title product (5.4 g, 99%).1H NMR (300 MHz, CDCl3): delta (ppm) 4.82 (m, 1H), 3.99 (m, 1H), 3.75 (s, 3H), 2.95 (m, 1H), 2.21 (m, 1H), 2.45 (m, 14H)
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 40℃; for 4.5h;
[0191] To a solution of N-BOC-pipecolinic acid (166.5 g, 726 mmoles) in 500 mL dimethylformamide (DMF) was added MeI (123.7 g, 871 mmoles) and K2CO3 (100.4 g, 726 moles). The reaction mixture slowly exothermed to 40 C. after 0.5 h during a 4 h age period at ambient temperature. Added MTBE (830 mL) and then washed with H2O (2×830 mL) and 20% brine (300 mL). The organic layer was dried over Na2SO4 and concentrated to an oil (3).
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20 - 40℃; for 4.5h;
PREPARATIVE EXAMPLE 3; To a solution of N-BOC-pipecolinic acid (166.5 g, 726 mmoles) in 500 mL dimethylformamide (DMF) was added MeI (123.7 g, 871 mmoles) and K2CO3 (100.4 g, 726 moles). The reaction mixture slowly exothermed to 40 C. after 0.5 h during a 4 h age period at ambient temperature. Added MTBE (830 mL) and then washed with H2O (2×830 mL) and 20% brine (300 mL). The organic layer was dried over Na2SO4 and concentrated to an oil (3).
With ammonium chloride; N-ethyl-N,N-diisopropylamine; HATU; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 18.0h;
Step B. tert-Butyl (2R)-2-(aminocarbonyl)piperidine-1-carboxylate; HATU (5.60 g, 14.7 mmol) was added to a mixture of the (2R)- 1 -(tert- butoxycarbonyl) piperidine-2-carboxylic acid (2.29 g, 10 mmol), ammonium chloride (3.21 g, 60 mmol) and DIPEA (3.88 g, 30 mmol) in DMF (70 mL) at 0 C. The mixture was stirred for 18 h at room temperature, diluted with H20 (100 mL) and extracted with EtOAc (3x100 mL). The combined organic phases were washed with 10% Na2C03 solution (2x30 mL), brine (2x30 mL) and dried with Na2S04. After filtration and concentration, the title compound was purified by MPLC on silica gel using hexane/EtOAc (1:1) g, 100 %) as a white solid. (at)H NMR(400 MHz, CDCl3) No. 1.46 (s, 9 H), 1.63 (m, 2 H), 2.22 (m, 1 H), 2.91 (m, 1 H), 3.06 (m, 3 H), 4.01 (m, 1 H), 4.71 (m, 1 H), 6.46 (s broad, 2 H). MS (ESI) (M+H) (at)= 228.92
99%
a) 1, 1-Dimethylethyl (2/tO-2-(aminocarbonyI)-1-piporidinecarboxylalc. To a cold (0C) solution of fe/iS-1-iUl, 1-dimethylethy^oxy]carbonyl]-2-piperidinecarboxylic acid(1.0 g, 4.36 mmol) in THF (20 ml) was added triethylamine (0.60 mL, 4,36 rnmol)followed by slow addition of methyl chloroform ate (0.34 mL, 4,36 rnmol). After a fewminutes a suspension had formed, To this mixture was added concentrated NI-LiOH(1.5 mL) and the solution was allowed to warm to rt as the bath warmed and stirredfor a total of 4 h. The mixture was concentrated in vacuo and the residue was takenup in EtOAc, The organic layer was washed with citric acid, bicard and then brine,dried over NasSO-i. Filtration and concentration gave 1, 1-dimethylethyl(2R)-2-(aminocarbonyl)-1-piperidinecarboxylate (3 .0 g, 99%). 1H NMR (CDCl3) δ 6,03(br, 1 H), 5.45 (br, 1 H), 4.77 (br, 1 H), 4.06 (br, 1 H), 2.82 (m, 1 H), 2.29 (m, 1 H),1.67- 1.43 (m, 13 H),
94%
With ammonium chloride; 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 - 20℃; for 15.0h;
(R)-1-(tert-Butoxycarbonyl)piperidine-2-carboxylic acid (0.500 g, 2.18 mmol) and ammonium chloride (0.700 g, 13.1 mmol) were suspended in DMF (10 mL), and HATU (1.24 g, 3.27 mmol) and diisopropylethylamine (1.14 mL, 6.54 mmol) were added at 0 C. After stirring the reaction mixture at room temperature for 15 hours, distilled water was added to the reaction mixture and the aqueous layer was extracted with diethyl ether. The organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=60/40 to 30/70) to obtain the title compound (hereinafter referred to as the compound of Reference Example 13) (0.467 g, 2.05 mmol, 94%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ: 1.42-1.68 (m, 5H), 1.48 (s, 9H), 2.28-2.30 (m, 1H), 2.79-2.85 (m, 1H), 4.05 (brs, 1H), 4.78 (brs, 1H), 5.44 (brs, 1H), 6.03 (brs, 1H). ESI-MS: m/z=251(M+Na)+.
89%
With ammonium chloride; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 20℃; for 1.5h;
Example 1; 1-{(R)-2-[4-(4-Chloro-phenyl)-thiazol-2-yl]-piperidin-1-yl}-2-phenoxy-ethanone; The title compound was prepared as illustrated in scheme 1, steps 1 to 5.; Step 1. A suspension of ammonium chloride (3.44 g, 64 mmol) in N,N-dimethylacetamide (150 mL) under argon was treated with diisopropylethylamine (13.44 g, 17.7 mL, 104 mmol). A solution of (R)-(+)-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (5.10 g, 22 mmol) was added, followed by TBTU (10.11 g, 31 mmol). The mixture was stirred at room temperature for 1.5 h, then diluted with ethyl acetate (850 mL) and washed several times with water (5*50 mL) and finally with saturated sodium chloride. The organic phase was dried over sodium sulphate and evaporated. The resulting oil was purified by flash chromatography (heptane/ethyl acetate gradient) to yield (R)-2-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (4.54 g, 89%) as a white solid, MS (ISP): 229.0 (M+H)+..
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide;
O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU, 4.96 g, 13.1 mmol) was added to a stirred solution of (R)-N-Boc-2-piperidinecarboxylic acid (3.00 g, 13.1 mmol) and DIPEA (9.0 mL, 51.2 mmol) in anhydrous DMF (50 mL). The mixture was stirred at room temperature for 5 min and then <strong>[5307-14-2]2-nitro-1,4-phenylenediamine</strong> (3.00 g, 13.1 mmol) was added. The mixture was stirred for a further 18 hr, then the DMF was removed by evaporation. The residue was partitioned between water (200 mL) and EA (100 mL) and the phases separated. The aqueous phase was extracted with two further portions of EA (100 mL each) and the combined organic extracts washed with water, 1M sodium carbonate solution, water, and brine (100 mL each). The solution was dried over magnesium sulfate and concentrated to give (R)-tert-butyl 2-[(4-amino-3-nitrophenyl)aminocarbonyl]-piperidine-1-carboxylate as a brown solid (4.80 g).(R)-tert-Butyl 2-[(4-amino-3-nitrophenyl)aminocarbonyl]piperidine-1-carboxylate (4.80 g, 13.2 mmol) was suspended in dioxane (100 mL) and hydrogen chloride (75 mL of a 4M solution in dioxane) was added. The resulting dark colored solution was stirred at room temperature for 3.5 hr resulting in a yellow/brown suspension. The solid was collected by filtration and briefly dried under high vacuum. The solid was suspended in water, the pH was adjusted to pH 8 with 1M sodium carbonate solution and the resulting suspension stirred for 15 minutes. The solid was collected and dried under high vacuum to give (R)-N-(4-amino-3-nitrophenyl)piperidine-2-carboxamide hydrochloride salt as an orange solid (2.08 g). This was treated with 1M sodium carbonate solution (200 mL) and extracted with EA (3×). The combined EA extracts were washed with brine, dried over magnesium sulfate, and concentrated to give (R)-N-(4-amino-3-nitrophenyl)piperidine-2-carboxamide as an orange foam (1.77 g).(R)-N-(4-Amino-3-nitrophenyl)piperidine-2-carboxamide (2.09 g, 7.9 mmol) was dissolved in MeOH (50 mL), and paraformaldehyde (0.95 g) and sodium cyanoborohydride (0.50 g, 8.0 mmol) were added. The mixture was stirred at room temperature for 70 min, and water added dropwise. The solvent was evaporated and the residue partitioned between water and EA (150 mL each). The phases were separated and the aqueous phase extracted with EA (2×100 mL). The combined EA layers were washed with brine, dried over magnesium sulfate, and concentrated to give (R)-N-(4-amino-3-nitrophenyl)-1-methylpiperidine-2-carboxamide as an orange foam (2.17 g), which was used without purification.A solution of (R)-N-(4-amino-3-nitrophenyl)-1-methylpiperidine-2-carboxamide (2.17 g, 7.8 mmol) in ethanol (75 mL) was degassed under vacuum and then backfilled with argon. 10% Palladium on carbon (0.44 g) was added and the mixture again degassed under vacuum. Hydrogen was introduced by a balloon and the reaction stirred at room temperature for 23 hr. The mixture was degassed by bubbling argon through it, and was then filtered through a pad of diatomaceous earth. The filtrate was concentrated to give (R)-N-(3,4-diaminophenyl)-1-methylpiperidine-2-carboxamide as a purple solid (1.78 g).
Step 1 : To an ice-cold mixture of D-pipecolic acid (2.0 g, 15.5 mmol) in THF (30 mL) was added dropwise a 1 M solution of borane in THF (46 mL). It was stirred over night at room temperature and the clear solution was carefully quenched with aq. 3 M NaOH (63 mL). The mixture was heated with reflux over night. It was cooled with ice and bis- tert-butyl dicarbonate (3.49 g, 16.0 mmol) was added. It was stirred again over night while another amount of the dicarbonate was added in order to drive the reaction to completion. The organic solvent was removed under reduced pressure and the remaining aqueous mixture was extracted with ether. The organic layer was washed with brine, dried over MgS04, and concentrated in vacuo.
Step 2: The residue from Step 1 , a mixture of the N-Boc and Nu,Omicron-bis-Boc protected aminoalcohol, was treated with a solution of KOH in MeOH (0.36 M). After stirring over night it was diluted with chloroform and neutralized with aq. 1 N HCI. The aqeous layer was extracted several times with chloroform, the combined organic layers dried over MgS04, and concentrated under reduced pressure. The residue was chromatographed (silica gel, cyclohexane/EtOAc 90: 10 to 80:20) to leave the intermediate (R)-N-Boc-2- hydroxypiperidine (0.97 g, 29 %).
Multi-step reaction with 5 steps
1.1: lithium hydroxide; silver nitrate / dichloromethane / 0.17 h / 25 °C
1.2: 10 h / 90 °C
2.1: magnesium / diethyl ether / 2 h / 20 °C
2.2: 7 h / 0 - 3 °C
3.1: palladium on activated charcoal; hydrogen / methanol / 3 h / 35 °C
4.1: triethylamine / chloroform / 9 h / 45 °C
5.1: N-ethyl-N,N-diisopropylamine; hydrogenchloride / tetrahydrofuran / 8 h / 50 °C
Stage #1: N-BOC-D-pipecolic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane for 0.666667h;
Stage #2: 4-(1-aminocyclopropyl)-benzoic acid methyl ester With triethylamine In dichloromethane at 20℃; for 15h;
2.2a - Example 2a: synthesis of intermediate (V) tert-butyl (R)-2-((1-(4- (methox vcarbon yl ) phen vDcycloprop vDcarbamo yl) piperidine- 1 -carbox ylate
(0173) Boc-D-pipecolic acid (500 mg, 2.181 mmol) was dissolved in DCM (13 ml). N- hydroxybenzotriazole hydrate (2.62 mmol) and EDCI (3.05 mmol) were added and the reaction mixture was left stirring for 40 min. SM2 (2.268 mmol) was added followed by TEA (2.94 mmol). The reaction mixture was left stirring at room temperature for 15h, then water (20ml) was added. Phases were separated and the aqueous layer was extracted with DCM (2 x 15ml_). The combined organic layers were evaporated and loaded on SNAP Ultra-HP Sphere-Si (10g) column eluting with cyclohexane/AcOEt 100% up to 70/30. Yield 810mg (92%), light yellow foam. 1H NMR (400MHz, CHLOROFORM-d) d = 8.00 - 7.93 (m, J= 8.3 Hz, 2H), 7.27 - 7.22 (m, J= 8.3 Hz, 2H), 6.76 (br s, 1 H), 4.85 - 4.67 (m, 1 H), 4.12 (br s, 1 H), 3.92 (s, 3H), 2.97 - 2.66 (m, 1 H), 2.29 (br s, 1 H), 1 .72 - 1 .59 (m, 3H), 1.54 - 1.22 (m, 15H). (0174) ESI + m/z 403 [M+H]+
tert-butyl-(R)-2-((6,7-dihydro-[1,4]dioxino[2′,3′:4,5]benzo[1,2-d]-thiazol-2-yl)carbamoyl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: N-BOC-D-pipecolic acid 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 for 0.333333h;
Stage #2: SKA-30 In N,N-dimethyl-formamide for 12h;
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