* 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.
Reference:
[1] Journal of the American Chemical Society, 1995, vol. 117, # 36, p. 9369 - 9370
[2] Journal of Organic Chemistry, 1997, vol. 62, # 15, p. 5023 - 5033
[3] Journal of the American Chemical Society, 1999, vol. 121, # 4, p. 700 - 709
[4] Tetrahedron, 2013, vol. 69, # 48, p. 10311 - 10315
2
[ 50-00-0 ]
[ 1723-00-8 ]
[ 41447-17-0 ]
Yield
Reaction Conditions
Operation in experiment
100%
With 5%-palladium/activated carbon; hydrogen In methanol; water for 20 h;
37percent Aqueous solution of formaldehyde (1.26 mL, 16.9 mmol) was added to a mixture of (2R)-piperidine-2-carboxylic acid (2.00 g, 15.5 mmol) and 5percent Pd/C (500 mg) in MeOH (20 mL). After the reaction mixture was purged with H2 gas, additional formaldehyde (0.60 mL, 8.06 mmol) was added, and stirred under H2 atmosphere for 20 h. The reaction mixture was filtered through a pad of Celite, and washed with MeOH (200 mL). The filtrate was concentrated by rotary evaporation to afford analytically pure amino acid 8 (2.23 g, quantitative yield) as a white solid, which was used in the next step without further purification. TLC: Rf 0.25 (1:1 CH2Cl2/MeOH). Mp: 208-210 °C. [α]D27.1 = + 67.6 (c 1.27, MeOH). IR (KBr, film): 3407, 2950, 1615, 1399 cm-1. 1H NMR (400 MHz, CDCl3): d8.22 (br s, 1H), 3.64 (d, 1H, J = 12.0 Hz), 3.28 (m, 1H), 2.86 (s,3H), 2.70 (m, 1H), 2.34 (d, 1H, J = 14.4 Hz), 2.00–1.74 (m, 4H),1.46 (m, 1H). 13C NMR (100 MHz, DMSO-d6): d 170.4, 68.3, 53.3,42.3, 28.0, 23.1, 21.8. HRMS (ESI) m/z calculated for C7H13NO2143.0946, found 143.0947.
90%
With palladium 10% on activated carbon; hydrogen In methanol; water
To a solution of D-pipecolinic acid (10.0 g, 77.4 mmol, 1.0 eq.) in methanol (100 mL) was added formaldehyde (37percent aqueous solution, 30.8 mL, 154.8 mmol, 2.0 eq.), followed by Pd/C (10 wtpercent, 1.0 g). The reaction mixture was stirred under H2 (1 atm) overnight, and then filtered through Celite, with washing of the filter pad with methanol. The filtrate was concentrated under reduced pressure to afford compound 126 (10.0 g, 90percent yield) as a white solid.
Reference:
[1] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 21, p. 6827 - 6843
[2] Angewandte Chemie - International Edition, 2006, vol. 45, # 43, p. 7235 - 7239
[3] Patent: WO2016/59622, 2016, A2, . Location in patent: Page/Page column 95-96
[4] Journal of Organic Chemistry, 2016, vol. 81, # 21, p. 10302 - 10320
[5] Patent: WO2018/86139, 2018, A1, . Location in patent: Page/Page column 143
[6] Journal of the American Chemical Society, 2006, vol. 128, # 50, p. 16018 - 16019
3
[ 24424-99-5 ]
[ 1723-00-8 ]
[ 28697-17-8 ]
Yield
Reaction Conditions
Operation in experiment
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. [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
With thionyl chloride; In methanol; at 0 - 50℃; for 18.0h;
First Step (R)-Piperidine-2-carboxylic acid methyl ester hydrochloride (R)-Piperidine-2-carboxylic acid (300 mg, 2.32 mmol) was dissolved in methanol (4.64 mL), thionyl chloride (0.508 mL, 6.97 mmol) was added dropwise at 0 C., and the mixture was stirred at 50 C. for 18 hours. The reaction mixture was concentrated at reduced pressure, and toluene was added for azeotropic removal to obtain the title compound as a crude product.
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).
In water; at 24.84℃; for 2h;Inert atmosphere; UV-irradiation;Kinetics;
2.6. Photocatalytic reaction
With Cp*Ir(biot-p-L)Cl; D-amino acidoxidase from porcine kidney; L-amino acid oxidase from Crotalus atrox; streptavidin S112A mutant; oxygen; sodium formate; catalase from bovine liver; In aq. buffer; at 37℃;pH 7.8;Enzymatic reaction;
General procedure: The following stock solutions were prepared. Catalase from bovine liver (50 kU ml-1) was dissolved in MOPS/sodium formate buffer (0.6 M in MOPS, 3.0 M in sodium formate, pH adjusted with aq. KOH to pH 7.8). Sav S112T (16.4 mg ml-1, 0.75 mM free binding sites, assuming three free binding sites per tetramer) was dissolved in the catalase containing buffer. [IrCp*(biot-p-L)Cl] was dissolved in DMF (37.5 mM). Affinity purified MAO-N-9 (buffer exchange with MOPS, 0.6 M, pH adjusted with KOH to 7.8) was diluted in MOPS buffer (0.6 M, pH adjusted with KOH to 7.8) to a concentration of 0.38 mg ml-1. Substrate stock was prepared by dissolving the hydrochloride of 1-ox in H2O (1 M). The ATHase was prepared by adding [IrCp*(biot-p-L)Cl]-stock (10 mul ml-1) to the Sav-stock solution. MAO-N-stock was placed in 1.5 ml PP-tubes (100 mul) and ATHase was added (100 mul). The reactions were initiated by addition of substrate stock solution (7.5 mul) and incubated at 37 C and 250 r.p.m. in a lying position. For work-up aq. NaOH solution was added (50 mul of a 10 M solution) and the mixture extracted with CH2Cl2 (1 × 1 ml). The organic phase was dried over Na2SO4 and analysed by HPLC (Supplementary Sections S2.3.1 and S2.4.1).
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃;Reflux;
LiAlH4 (3.42 g, 30.00 mmol) was added to a stirred solution ofD-pipecolic acid (3.87 g, 30.00 mmol) in THF (40 mL) at 0 C, and the resulting suspension was refluxed for 2 h. After cooling, the reactionwasquenched with 10% NaOH (aq), and the aqueous mixturewas extracted with hot ethyl acetate (10 mL5). The organic extractswere combined, dried over Na2SO4, and evaporated to givea colorless oil, which was used directly in the next step. SaturatedNaHCO3 (aq) (40 mL) and ClCO2Me (2.5 mL, 33.00 mmol) wereadded to a stirred solution of the above alcohol in THF (40 mL) atroom temperature, and the resulting mixturewas stirred overnight.The reaction mixture was diluted with CH2Cl2, the organic layerwas separated, and the aqueous layer was extracted with CH2Cl2(20 mL3). The organic layer and extracts were combined, driedover Na2SO4, and evaporated to give a pale yellow oil, which waschromatographed on silica gel (30 g, hexane/acetone8:1) to afford2 (5.1 g, 98%) as a colorless oil.IR (neat) 3414, 2939, 1695, 1450, 1271, 770 cm1; 1H NMR(400 MHz) d 1.25e1.53 (2H, m), 1.56e1.71 (4H, m), 2.92 (1H, t-like,J10.9 Hz), 3.61e3.67 (1H, m), 3.70 (3H, s), 3.83 (1H, td-like, J10.9,4.0 Hz), 3.96 (1H, br), 4.30e4.33 (1H, m); 13C NMR (125 MHz)d 19.40, 25.07, 25.26, 40.00, 52.65 (two carbons), 60.81, 157.14; MS(EI):m/z 173 [M]; HRMS: Calcd for C8H15NO3 [M] 173.1052; found173.1051; a26D40.2 (c 2.90, CHCl3).
With thionyl chloride; In 0 - 20C;Inert atmosphere;
(R)-Methyl piperidine-2-carboxylate (238)237 238 [282] To (R)-Piperidine-2-carboxylic acid (5.00 g, 38.73) in 150 ml of dry methanol at O0C was added thionyl chloride (5.2 ml, 71.28 mmol) under Ar. The mixture was stirred at O0C for 30 min, then at RT overnight, evaporated and crystal]ized with EtOH/hexane to afford 4.96 g (92%) of the title product. 1R NMR (CD3OD) 3.67 (s, 3H), 3.57 (m, IH), 2.79 (m, IH), 2.69 (m, IH), 2.01 (m, IH), 1.98 (m, IH), 1.73 (m, IH), 1.55 - 1.45 (m, 4H); 13C NMR 171.22, 62.50, 51.35, 45.35, 29.52, 28.41, 23.82; MS m/z + 144.0 (M + H).
With thionyl chloride; at -10 - 20℃; for 18h;Inert atmosphere;
(R)-Methyl piperidine-2-carboxylate (R)-(D)-Pipecolic acid (15 g, 116 mmol) was dissolved in methanol (120 mL) under an N2 atmosphere. To this solution thionyl chloride (17 mL, 232 mmol) was slowly added at -10 C. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was concentrated and co-evaporated with toluene. The crude (R)-methyl piperidine-2-carboxylate was dried under vacuum and was then used in the next step without further characterization or purification.
With 5%-palladium/activated carbon; hydrogen; In methanol; water; for 20h;
37% Aqueous solution of formaldehyde (1.26 mL, 16.9 mmol) was added to a mixture of (2R)-piperidine-2-carboxylic acid (2.00 g, 15.5 mmol) and 5% Pd/C (500 mg) in MeOH (20 mL). After the reaction mixture was purged with H2 gas, additional formaldehyde (0.60 mL, 8.06 mmol) was added, and stirred under H2 atmosphere for 20 h. The reaction mixture was filtered through a pad of Celite, and washed with MeOH (200 mL). The filtrate was concentrated by rotary evaporation to afford analytically pure amino acid 8 (2.23 g, quantitative yield) as a white solid, which was used in the next step without further purification. TLC: Rf 0.25 (1:1 CH2Cl2/MeOH). Mp: 208-210 C. [alpha]D27.1 = + 67.6 (c 1.27, MeOH). IR (KBr, film): 3407, 2950, 1615, 1399 cm-1. 1H NMR (400 MHz, CDCl3): d8.22 (br s, 1H), 3.64 (d, 1H, J = 12.0 Hz), 3.28 (m, 1H), 2.86 (s,3H), 2.70 (m, 1H), 2.34 (d, 1H, J = 14.4 Hz), 2.00-1.74 (m, 4H),1.46 (m, 1H). 13C NMR (100 MHz, DMSO-d6): d 170.4, 68.3, 53.3,42.3, 28.0, 23.1, 21.8. HRMS (ESI) m/z calculated for C7H13NO2143.0946, found 143.0947.
90%
With palladium 10% on activated carbon; hydrogen; In methanol; water; under 760.051 Torr;
To a solution of D-pipecolinic acid (10.0 g, 77.4 mmol, 1.0 eq.) in methanol (100 mL) was added formaldehyde (37% aqueous solution, 30.8 mL, 154.8 mmol, 2.0 eq.), followed by Pd/C (10 wt%, 1.0 g). The reaction mixture was stirred under H2 (1 atm) overnight, and then filtered through Celite, with washing of the filter pad with methanol. The filtrate was concentrated under reduced pressure to afford compound 126 (10.0 g, 90% yield) as a white solid.
90%
With palladium 10% on activated carbon; hydrogen; In methanol; water; under 760.051 Torr;
To a solution of D-pipecolinic acid (10.0 g, 77.4 mmol, 1.0 eq. ) in methanol (100 mL) was added formaldehyde (37%aqueous solution, 30.8 mL, 154.8 mmol, 2.0 eq. ) , followed by Pd/C (10 wt%, 1.0 g) . The reaction mixture was stirred under H 2 (1 atm) overnight, and then filtered through Celite, with washing of the filter pad with methanol. The filtrate was concentrated under reduced pressure to afford compound 22 (10.0 g, 90%yield) as a white solid.
90%
With palladium 10% on activated carbon; hydrogen; In methanol; under 760.051 Torr;
To a solution of D-pimidic acid (10.0 g, 77.4 mmol) in methanol (100 mL) was added formaldehyde (37% aqueous solution, 30.8 mL, 154.8 mmol) and Pd / C (10 wt%, 1.0 g). The reaction solution was stirred under H2 (1 atm) environment overnight, and then filtered through celite and washed with methanol. The filtrate was concentrated to give the title compound (10.0 g, 90% yield) as a white solid.
2-[(1R,3R)-1-Hydroxy-4-methyl-3-((3-methyl-butyryloxymethyl)-{(2S,3S)-3-methyl-2-[((R)-1-methyl-piperidine-2-carbonyl)-amino]-pentanoyl}-amino)-pentyl]-thiazole-4-carboxylic acid pentafluorophenyl ester[ No CAS ]
(2S,3S)-3-carboxy-2,3-dihydroxypropanoic acid (R)-2-carboxypiperidinium salt[ No CAS ]
[ 1723-00-8 ]
Yield
Reaction Conditions
Operation in experiment
With ammonia; In methanol; water; at 20℃; for 0.5h;
[0185] To a slurry of (+/-)-pipecolinic acid (395 g, 3.06 moles) in MeOH (1.8 L) at 60 C. was added L-tartaric acid (459 g, 3.06 moles). The slurry was warmed to reflux and aged 1 h (hour). The slurry was cooled to 23 C., filtered, and the desired (R)-pipecolinic acid/L-tartaric acid filtercake was washed with MeOH (200 mL). The filtercake was air dried a white solid was isolated. The pipecolinic acid tartrate salt typically assayed at 85-89% ee. [0186] A slurry of salt (383 g) in 2:1H2O/acetone (380 mL/190 mL) was warmed to reflux (60-65 C.) until all solids had dissolved. Acetone (1330 mL) was added over 2 h while maintaining a reflux. The slurry was allowed to cool to 15-20 C. over 1 h and then filtered, washed with 4:1 acetone/H2O (380 mL) and then air dried under vacuum. Isolated 313 g of pipecolinic acid tartrate salt (>99% ee). [0187] To a slurry of (R)-pipecolinic acid tartrate salt (312 g) in MeOH (3.0 L) was added 28% NH4OH (83 mL, 1.1 eq) over 0.5 h. The white slurry was aged 0.5 h at ambient temperature and then the ammonium tartrate precipitate was filtered off. The filtercake was rinsed with MeOH (300 mL). The combined filtrate and rinse was concentrated to a white solid of (1).
To a slurry of (R)-pipecolinic acid tartrate salt (312 g) in MeOH (3.0 L) was added 28% NH4OH (83 mL, 1.1 eq) over 0.5 h. The white slurry was aged 0.5 h at ambient temperature and then the ammonium tartrate precipitate was filtered off. The filtercake was rinsed with MeOH (300 mL). The combined filtrate and rinse was concentrated to a white solid of (1).
With sodium hydroxide; sulfuric acid; In 1,4-dioxane; diethyl ether;
Preparation 87 tert-Butyl (2R)-1-[(1,4-dichloro-7-isoquinolyl)sulphonyl]-2-piperidinecarboxylate Concentrated H2SO4 (2.0 ml) was added to an ice-cold solution of <strong>[1723-00-8]2-(R)-piperidine carboxylic acid</strong> (415 mg, 3.21 mmol) in dioxan (10 ml). Condensed isobutylene (40 ml) was carefully added, and the reaction stirred at room temperature in a sealed vessel for 21 h. The reaction mixture was poured into an ice-cooled solution of Et2O (100 ml) and 5N NaOH (20 ml), the mixture allowed to warm to room temperature with stirring, and then diluted with water. The phases were separated, the organic layer washed with 1N NaOH, then concentrated in vacuo, to half the volume, and extracted with 2N HCl. The combined acidic extracts were basified using 1N NaOH, and extracted with CH2Cl2, the combined organic solutions dried (MgSO4) and evaporated in vacuo to afford tert-butyl 2(R)-piperidine carboxylate (210 mg, 1.14 mmol) as an oil. 1H (CDCl3, 300 MHz) delta1.4-1.6 (11H, m), 1.75 (3H, m), 1.9 (1H, m), 2.65 (1H, m), 3.1 (1H, m), 3.2 (1H, m) ppm. LRMS 186 (MH+).
{4-[4-(3-Chloro-4-fluorophenylamino)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3,6-dihydro-2H-pyridin-1-yl}-(R)-piperidin-2-yl-methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
28.2%
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h;
General procedure C: A small vial was charged with an amine (0.117 mmol), an acid (0.128 mmol), TBTU (40.0 mg, 0.125 mmol), DIPEA (0.102 mL, 0.583 mmol), DMF (0.5 mL) and a stirring bar. The reaction mixture was allowed to stir at room temperature for 2 h. LC-MS indicated complete conversion of the starting materials. Water (30 mL) was added to the reaction mixture and the precipitate was collected in a sintered glass frit by filtration. The crude product was washed with 3×5 mL H2O and then dissolved in MeOH/dichloromethane and purified by silica gel chromatography to afford the desired product. Yield: 28.2%. 1H-NMR (CDCl3/MeOD, 400 MHz): delta=7.83 (d, J=5.81 Hz, 1H), 7.33 (dd, J=6.06, 2.28 Hz, 1H), 7.16 (s, 1 H), 7.09 (d, J=8.59 Hz, 1 H), 6.56 (d, J=5.31 Hz, 1 H), 6.46 (d, J=5.31 Hz, 1 H), 6.20-6.12 (m, 1 H), 4.29 (m, 2 H), 4.03 (m, 2 H), 3.80 (m, 2 H), 3.54-3.36 (m, 2 H), 2.97 (m, 2 H), 1.88 (m, 2 H), 1.62 (m, 2 H), 1.75 (m, 1 H). MS (ES+): m/z 454.41 (MH+). HPLC: tR=2.03 min (OpenLynx, polar-5 min).
With sodium hydroxide; In tetrahydrofuran; at 20℃; for 1.5h;
(iii) Hexahydro-2-pyridinecarboxylic acid To the compound obtained in the step (ii), tetrahydrofuran (5 mL) and a 1N sodium hydroxide aqueous solution (5 mL) were added. The mixture was stirred at room temperature for 1.5 hours. After it was confirmed that the compound obtained in the step (ii) was completely used, dichloromethane was added and the water layer was separated. The existence of hexahydro-2-pyridinecarboxylic acid (146 mg, 1.1 mmol, yield: 88%,
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.
(2R)-Piperidine-2-carboxylic acid (37 mg, 0.29 mmol) and Intermediate 47 (1000.24 mmol) were stirred in NMP (2 mL) for 3.5 h at 80C. Triethylamine (0.03 g,mmol) was added and the reaction mixture was heated at 80C for 2 h, then at 100Ch, and then at 120C for 4 h. Further <strong>[1723-00-8](2R)-piperidine-2-carboxylic acid</strong> (37 mg,mmol) and triethylamine (0.03 g, 0.29 mmol) were added and the mixture wasat 150C for 4 h. The solvent was removed and the residue was purified by preparative HPLC (Method D), to afford the title compound (15.5 mg, 13%) as a yellowOH (250 MHz, CDC13) 8.18 (s, 2H), 7.59 (s, 1H), 7.48 (s, 1H), 7.20 (d, J7.6 Hz,7.11-6.99 (m, 2H), 6.89-6.27(m, 2H), 5.56(s, 1H), 4.69 (d,J11.9 Hz, 1H), 4.20 (s,3.27 (t, J 11.2 Hz, 1H), 2.44 (s, 4H), 2.24 (s, 3H), 1.77 (s, 3H), 1.55 (s, 2H). MethodHPLC-MS: MH+ m/z 508, RT 2.32 minutes (96%).
2-piperazino-N-(2,4-dichlorobenzyl)-6-methylpyrimidin-4-amine[ No CAS ]
[ 1723-00-8 ]
(R)-2-[4-(piperidin-2-yl)carbonylpiperazino]-N-(2,4-dichlorobenzyl)-6-methylpyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71.4%
General procedure: A mixture of compound 5b (0.51 g, 1.5 mmol), EDCI (0.35 g, 1.8 mmol), HOBt (0.24 g, 1.8 mmol), (R)-N-piperidine-2-carboxylic acid (0.35 g, 1.5 mmol), TEA (1.5 mL) and dichloromethane (30 mL) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. Water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue (0.74 g) was dissolved in dichloromethane (10) and 4 M HCl in dioxane (0.5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 h. Then the pH of reaction mixture was adjusted to 10 with a 10% NaOH aqueous solution. The resulting mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Ethyl acetate was added to the crude residue, stirred and filtered. The solid was washed with additional ethyl acetate and dried to obtain compound 6d (0.47 g, 70.6%) as a white solid.
6-chloro-2-piperazino-N-(4-chlorobenzyl)pyrimidin-4-amine[ No CAS ]
[ 1723-00-8 ]
(R)-6-chloro-2-[4-(piperidin-2-yl)carbonylpiperazino]-N-(4-chlorobenzyl)pyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70.6%
A mixture of compound 5b (0.51 g, 1.5 mmol), EDCI (0.35 g, 1.8 mmol), HOBt (0.24 g, 1.8 mmol), (R)-N-piperidine-2-carboxylic acid (0.35 g, 1.5 mmol), TEA (1.5 mL) and dichloromethane (30 mL) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. Water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue (0.74 g) was dissolved in dichloromethane (10) and 4 M HCl in dioxane (0.5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 h. Then the pH of reaction mixture was adjusted to 10 with a 10% NaOH aqueous solution. The resulting mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Ethyl acetate was added to the crude residue, stirred and filtered. The solid was washed with additional ethyl acetate and dried to obtain compound 6d (0.47 g, 70.6%) as a white solid.
6-chloro-2-piperazino-N-(2,4-difluorobenzyl)pyrimidin-4-amine[ No CAS ]
[ 1723-00-8 ]
(R)-6-chloro-2-[4-(piperidin-2-yl)carbonylpiperazino]-N-(2,4-difluorobenzyl)pyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65.4%
General procedure: A mixture of compound 5b (0.51 g, 1.5 mmol), EDCI (0.35 g, 1.8 mmol), HOBt (0.24 g, 1.8 mmol), (R)-N-piperidine-2-carboxylic acid (0.35 g, 1.5 mmol), TEA (1.5 mL) and dichloromethane (30 mL) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. Water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue (0.74 g) was dissolved in dichloromethane (10) and 4 M HCl in dioxane (0.5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 h. Then the pH of reaction mixture was adjusted to 10 with a 10% NaOH aqueous solution. The resulting mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Ethyl acetate was added to the crude residue, stirred and filtered. The solid was washed with additional ethyl acetate and dried to obtain compound 6d (0.47 g, 70.6%) as a white solid.
(R)-1-(benzyloxycarbonyl)-1,2,3,6-tetrahydropyridine-2-carboxylic acid[ No CAS ]
[ 1723-00-8 ]
Yield
Reaction Conditions
Operation in experiment
87%
With hydrogen; palladium(II) hydroxide; In tetrahydrofuran; methanol; at 20℃; for 3h;
General procedure: To a stirred solution of 15 (65 mg, 0.26 mmol) in anhyd THF-MeOH (1:1, 7 mL), Pd(OH)2 (21 mg) was added at r.t.; stirring was continued for 3 h under H2. The resulting solution was then filtered over Celite and the filtrate was further concentrated to give the free amino acid 16 (25 mg, 83%) as a yellowish solid
87%
With hydrogen; palladium(II) hydroxide; In tetrahydrofuran; methanol; at 20℃; for 3h;
With triethylamine; In tetrahydrofuran; water; at 90℃; for 18h;
General procedure: General procedure B A solution of amino nucleophile (3 equiv.), triethylamine (10 equiv.), and Intermediate 1 (1 equiv.) was stirred in dioxane and water (2:1 ratio) at 90 C until complete consumption of starting material was observed by LC/MS. The solution was diluted withiN hydrochloric acid and dichloromethane. The layers were then separated and thelayer was extracted with dichloromethane. The organics were combined, dried over magnesium sulfate, filtered, and the solvent was removed in vacuo. Purification yielded theproductThe title compound was prepared following general procedure B, except <strong>[1723-00-8](R)-piperidine-2-carboxylic acid</strong> (4 equiv.) was the amine reactant, 5 equivalents of triethylamine was used, and the contents were heated to 90 C for 18 h as a solution in THF/water (9:1). Solvent was removed under a stream of nitrogen, and the crude material was purified via reverse phase HPLC using a 20-51% acetonitrile/water (in 0.1% TFA) gradient to deliver the desired compound, Compound 1-87 (12 mg, 48% yield).1H NMR (500 MHz, METHANOL-d4) oe 8.79-8.83 (m, 1H), 8.34-8.39 (m, 1H), 7.60 (s, 1H),7.27-7.35 (m, 1H), 7.03-7.15 (m, 2H), 6.90-6.98 (m, 2H), 6.02 (s, 2H), 4.61-4.83 (m, 1H),3.43-3.58 (m, 1H), 2.43-2.5 1 (m, 1H), 1.69-2.02 (m, 5H), 1.55-1.69 (m, 1H).
(R)-1-(6-((tert-butoxycarbonyl)amino)hexyl)piperidine-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; for 1h;
Tert-butyl (6-oxohexyl)carbamate (276, 210 mg, 975 mumol) and <strong>[1723-00-8](R)-piperidine-2-carboxylic acid</strong> (216 mg, 1.67 mmol) in 1,2-dichloroethane (4 ml) was stirred for 10 min. Sodium triacetoxyborohydride (317, 1.50 mmol) was added. After stirring for 1 h, the heterogeneous mixture was filtered and the filtrate was directly flash chromatographed on silica gel (12 g) with methylene chloride:methanol as the eluent 100:0 to 80:20 over 10 min to afford 168 mg (52% yield) of (R)-1-(6-((tert-butoxycarbonyl)amino)hexyl)piperidine-2-carboxylic acid, 278, as a white solid after lyophilization.
methyl (2R,1R)-1-(1-(tert-butylcarbamoyl)-3-phenyl-1-ethyl)piperidine-2-carboxylate[ No CAS ]
methyl (2R,1S)-1-(1-(tert-butylcarbamoyl)-3-phenyl-1-ethyl)piperidine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36%; 19%
With iron(III) chloride; In methanol; at 20℃; for 24h;
General procedure: FeCl3 (for 1a-c) or TiCl4 (for 1d-g) (5 mol%) and isocyanide (1.0 eq.) were added to a stirred solution of appropriate alpha-amino acid (1.2 eq.) and carbonyl component (1.0 eq.) in MeOH (100 mL).The mixture was stirred at rt for 24 h (72 h for 1d-g) and the volatiles were removed under reduced pressure. The resulting crude products were purified by FC.
6-(2,5-dioxo-2,5-dihydro-1 H-pyrrol-1-yl)hexanal[ No CAS ]
[ 1723-00-8 ]
(R)-1-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexyl)piperidine-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
21%
With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane;
Example 18 6-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanal (270, 0.3 g, 1.54 mmol) and <strong>[1723-00-8](R)-piperidine-2-carboxylic acid</strong> (271, 0.5 g, 3.87 mmol) in 1,2-dichloroethane (10 ml) was stirred for 20 min. Sodium triacetoxyborohydride (1.6 g, 7.55 mmol) was added. After stirring for 1 h, the heterogeneous mixture was filtered and the filtrate was directly flash chromatographed on silica gel (12 g) with methylene chloride:methanol as the eluent 100:0 to 80:20 over 10 min to afford 0.1 g (21% yield) of (R)-1-(6-((tert-butoxycarbonyeamino)hexyl)piperidine-2-carboxylic acid, 272, as a white solid after lyophilization.
With palladium 10% on activated carbon; hydrogen; acetic acid; at 20℃; under 2585.81 Torr; for 3h;
4.6 (R)-Piperidine-2-carboxylic acid ent-1 A solution of compound N-Cbz-(R)-pipecolic acid 16 (0.1 g, 0.49 mmol) in dry EtOH (5 mL) was mixed with Pd/C (10%) (20 mg) and AcOH (0.1 mL) in a hydrogenation flask pressured with hydrogen gas (50 psi) and then the mixture was shaken vigorously at ambient temperature for 3 h. The mixture was then filtered through a pad of Celite. After evaporation of the solvent under vacuum, the precipitate was collected by filtration, washed with Et2O and dried under high vacuum to afford pure (R)-pipecolic acid ent-1 (0.06 g). Rf: 0.4 (CH2Cl2-MeOH-NH4OH, 9:1:1%); Yield: 95%; mp: 271-273 C; lit. 20 271-274 C; [alpha]D25 = +24.9 (c 1.15, H2O), {Lit. 19 [alpha]D25 = +25.8 (c 1, H2O)}; 1H NMR (400 MHz, D2O): delta 1.46-1.64 (m, 3H), 1.73-1.80 (m, 2H), 2.14-2.18 (m, 1H), 2.87-2.94 (m, 1H), 3.31-3.54 (m, 1H), 3.78 (dd, J = 8.0 Hz and 10.0 Hz, 1H); 13C NMR (100 MHz, D2O): delta 21.5, 21.6, 26.0, 44.0, 57.2, 172.2. MS (ESI): m/z: 152.28 (M+Na)+.
(R)-1‘-(tert-butoxycarbonyl)-[1,4-bipiperidine]-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With palladium 10% on activated carbon; hydrogen; In methanol; at 20 - 27℃; under 760.051 Torr; for 48h;
To a solution of R-pipecolinic acid (1 g, 7.75 mmol) and tert-butyl4-oxopiperidine-1-carboxylate (2.31 g, 11.6 mmol) in MeOH (40 mL), 1 0% Pd on charcoal (1 g, 50% wet) was added and the reaction mixture was stirred at room temperature under H2 (1 atm) for 48 h. The reactionmixture was filtered through a celite bed and the filtrate was evaporated in vacuo. This crude residue was triturated in DCM (50 mL) to give (R)-1 ?-(tert-butoxycarbonyl)-[l ,4-bipiperidine]-2- carboxylic acid (1.2 g, 50%) as a white solid. This crude residue was used for the next step without further purification.1H-NMR (400 MHz; CDCI3) 6: 1.46 (s, 9H), 1.50- 1.59 (m, IH), 1.75- 1.91 (m, 4H), 1.93-2.05(m, 2H), 2.10 - 2.19 (m, 2H), 2.35 - 2.41 (m, 1 H), 2.51 - 2.69 (m, 3H), 3.41 - 3.49 (m, 1 H), 3.55 -3.61 (m, 1H), 3.70- 3.79 (m, 1H), 4.25-4.36 (m, 2H).
With hydrogen; palladium(II) hydroxide; In methanol; under 3102.97 Torr; for 24h;
A stirred suspension of D-pipecolic acid (100.0 g, 0.77 mol, 1eq.) and Pd(OH)2 (20% wt. Pd, 10 g) in a mixture MeOH/acetone (2:1 v/v, 1.5 L) was submitted to hydrogenation (H2 60 psi) for 24 h. Reaction was monitored by TLC (ethanol) and deemed complete when no D-pipecolic acid was observed. The mixture was filtered through a Celite (~50 g) bed. The clear filtrate was concentrated to ca. 100 mL and TBME (50 mL) was added. ER-808998 was filtered as a white crystalline solid in 88% yield.
With hydrogen; palladium(II) hydroxide; In methanol;
To a suspension of D-pipecolic acid 1Z (750 mg, 5.81 mmol) in MeOH (23.2 mL) and 2-butanone (11.6 mL) was added Pd(OH)2 (175 mg). Gaseous H2 (balloon pressure) was charged in and the reaction mixture was allowed to stir under an H2 atmosphere overnight. The reaction solution was then filtered through a bed of celite, and concentrated to give a crude white solid. The crude product was subjected to flash chromatography (SiO2) eluting with 100% EtOH. This provided compound 2Z (721 mg, white solid) as a mixture of diastereomers in 67% yield.
With hydrogen; palladium(II) hydroxide; triethylamine; In methanol;
To a suspension of D-pipecolic acid 1Z (1.00 g, 7.74 mmol) in MeOH (31 mL) and 3-methyl-2-butanone (15.5 mL) was added Et3N (1.1 mL) and Pd(OH)2 (250 mg). Gaseous H2 (balloon pressure) was charged in and the reaction mixture was allowed to stir under an H2 atmosphere overnight. The reaction solution was then filtered through a bed of celite, and concentrated to give a crude white solid. The crude product was subjected to flash chromatography (SiO2) eluting with 100% EtOH. This provided compound 5Z (377.9 mg, white solid) as a single diastereomer in 24.5% yield. Rf= (SiO2, 0.280, 100% EtOH).
2-bromo-5-cyclopropyl-6-methyl [1,3]thiazolo[5,4-d]pyrimidin-7(6H)-one[ No CAS ]
[ 1723-00-8 ]
C15H18N4O3S[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 5h;
In DMF solution (4 mL) of the compound obtained in Reference Example 617 (250mg), (R) -piperidine-2-carboxylic acid (339 mg) and potassium carbonate (326 mg) was added, 5 hours stirring the reaction mixture at 120. C. did.The reaction mixture was cooled to room temperature, acidified with 1.0 mol / L hydrochloric acid, sodium chloride was added and the mixture was extracted three times with chloroform.The organic layer was dried over sodium sulfate, filtered, and concentrated.The resulting residue N, N-diisopropylethylamine (228muL), benzylamine (143muL), added EDC hydrochloride (251 mg) and HOBt monohydrate (201 mg), and the reaction mixture was stirred at room temperature overnight.Ethyl acetate was added to the reaction mixture, the mixture was washed with water and saturated brine.The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated.The residue was purified by silica gel column chromatography, and purified by (solvent: hexane / ethyl acetate = 70 / 30-0 / 100), reverse phase and the resulting crude product was HPLC (Capcelpak C18; 0.05% trifluoroacetic acid - water / and purified with acetonitrile = 55 / 45-45 / 55).The resulting ethyl acetate / diethyl Yale added to the product, the solid was collected by filtration to give the title compound (213mg).MS (ESI) M / Z; 424 [M Tasu H]Tas
(2R)-1-butylpiperidine-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With palladium 10% on activated carbon; hydrogen; In methanol; at 25℃; for 20h;
(7?)-l-Butylpiperidine-2-carboxylic acid (78): To a stirred solution of D-Pipecolinic acid 78a (200 mg, 1.5 mmol) in anhydrous methanol (3 mL), under argon condition were added 10% Pd/C (50mg) followed by cyclopropanecarboxaldehyde (0.12 mL, 1.7 mmol) at 25 C. The argon balloon was replaced with hydrogen, additionally aldehyde (0.06 ml, 0.08 mmol) was added and the reaction mixture was stirred for 20 h at 25 C. The reaction mixture was filtered through celite, wash with methanol and evaporated under reduced pressure. The obtained residue was purified by flash column chromatography (silica gel, 5?20% MeOH in CH2CI2) to afford acid 78 (11.4 mg, 86%) as a white solid. 78: Rt = 0.5 (silica gel, 15% MeOH in CH2C12); NMR: (CDCI3, 600 MHz) delta = 4.07 (s, 1H), 3.58 (d, J = 12.7 Hz, 1H), 3.37 - 3.25 (m, 1H), 3.25 - 3.13 (m, 1H), 2.81 (td, J = 12.7, 12.1, 5.5 Hz, 1H), 2.61 (t, J = 11.8 Hz, 1H), 2.16 (d, J = 14.2 Hz, 1H), 1.90 - 1.71 (m, 3H), 1.68 - 1.58 (m, 3H), 1.39 (t, J = 12.4 Hz, 1H), 1.31 - 1.17 (m, 2H), 0.84 (t, J = 7.3 Hz, 3H); 13C NMR: (CDCI3, 150 MHz) delta = 171.0, 68.0, 55.7, 51.3, 28.0, 25.4, 22.4, 21.6, 19.8, 13.2; HRMS calcd for C10H19NO2 [ +H+] 186.1494 found 186.1489.
70%
With palladium 10% on activated carbon; hydrogen; In methanol; at 23℃; for 20h;
To a stirred solution of D-pipecolinic acid (200 mg, 1.54 mmol, 1.0 equiv) in anhydrous methanol (3 mL), under argon atmosphere were added palladium on carbon (10% w.w, 50.0 mg) followed by cyclopropane carboxaldehyde (120 pL, 1.70 mmol, 1.1 equiv) at 23 C. The argon atmosphere was replaced with hydrogen, additional aldehyde (60.0 pL, 85.0 pmol, 0.55 equiv) was added and the reaction mixture was stirred for 20 h at 23 C. The reaction mixture was then filtered through a pad of Celite, washed with methanol and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography (silica gel, 5 20% MeOH in CH2CI2) to afford acid 19 (201 mg, 1.08 mmol, 70% yield) as a white solid. 19: Rf=0.50 (silica gel, 15% MeOH in CH2CI2); NMR: (CDC13, 600 MHz) d 4.07 (s, 1H), 3.58 (d, 7= 12.7 Hz, 1H), 3.37-3.25 (m, 1H), 3.25-3.13 (m, 1H), 2.81 (td,7= 12.7, 12.1, 5.5 Hz, 1H), 2.61 (t,.7= 11.8 Hz, 1H), 2.16 (d,.7= 14.2 Hz, 1H), 1.90-1.71 (m, 3 H), 1.68-1.58 (m, 3 H), 1.39 (t, J= 12.4 Hz, 1H), 1.31-1.17 (m, 2H), 0.84 (t,.7= 7.3 Hz, 3 H) ppm; 13C NMR: (CDC13, 150 MHz) d 171.0, 68.0, 55.7, 51.3, 28.0, 25.4, 22.4, 21.6, 19.8, 13.2 ppm; HRMS calcd for C10H20M [M+H]+ 186.1494 found 186.1489.
To a round bottom flask equipped with reflux condenser, <strong>[842133-18-0]Canagliflozin</strong> (5 gm), ethanol (10ml) and ethyl acetate (50 ml) were added and stined the contents for 10 mm at 25-30C.acid (1.74 gm) was added, heated the contents to reflux temperature and stined for30 mm. Then, the reaction mass was cooled to 25-30C and the solid was filtered. Theresulting wet solid was charged into the mixture of ethanol (10 ml) and ethyl acetate (50 ml), heated to reflux, cooled to 25-30C and the solids were filtered to get <strong>[842133-18-0]Canagliflozin</strong> Dpipecolic acid co-crystal (3.5 gms).
(R)-Pipecolic acid (6.46g; 50.0mmol) was dissolved in 10 cm3 of 5mol/L aqueous NaOH solution and 8.20g (50.0mmol) of 2-chrolomethylpyridine hydrochloride was added to the resulting solution. After careful addition of 20cm3 of 5mol/L aqueous NaOH solution the reaction mixture was stirred for 3h. The resulting solution was evaporated to ca. 30cm3, and 200cm3 of methanol was added to the residue. The deposited salt was filtered off, and the filtrate was evaporated to dryness. The residue was washed with 100cm3 of ethanol to give crude sodium (R)-N-(2-pyridylmethyl)pipecolate. A hundred milliliters of water was added to the obtained sodium salt and adjusted to ca. pH 7 by 6mol/L aqueous HCl solution. The resulting solution was evaporated to dryness, and 100 cm3 of methanol was added to the residue. The deposited salt was filtered off, and the filtrate was evaporated to dryness, washed with water and acetone to give Hpmpi. Yield: 6.97g (63.3%). [alpha]D20 +26.8 (c 1.0, H2O); mp. 150-152C (decomp.). 1H NMR (400MHz, D2O, DSS) deltaH: 8.61 (1H, d, 6?-CH), 7.95 (1H, dd, 4?-CH), 7.58 (1H, d, 3?-CH), 7.52 (1H, dd, 5?-CH), 4.60 (1H, d, >NCHHAr), 4.30 (1H, d, >NCHHAr), 3.60 (1H, dd, 2-CH), 3.52-3.40 (1H, m, 6-CHH), 3.10-2.97 (1H, m, 6-CHH), 2.29-2.15 (1H, m, 3-CHH), 1.92-1.76 (3H, m, 3-CHH, 4-CHH and 5-CHH), 1.76-1.60 (1H, m, 5-CHH), 1.60-1.46 (1H, m, 4-CHH)
With ammonium hexafluorophosphate; Selectfluor; In toluene; at 130℃; for 24h;
General procedure: A mixture of aldehyde (1.0 mmol), amino acid (0.75 mmol), Selectfluor (1.0 mmol), and NH4PF6 (1.0 mmol) in toluene (5 mL), the reaction mixture was stirred at 130 C for 24 h After cooling, the iminium salt formed was converted to corresponding amine by NaBH4. The mixture was extracted with dichloromethane (3 x 10 mL). The organic solvent was removed under vacuum. The crude product was purified by column chromatography on silica gel (n-hexane/ethyl acetate 10/1) to afford the corresponding product.
With hydrogenchloride; In chloroform; at 50℃; for 1h;
To a solution of solid-supported methoxypiperidine 5(0.80 g, 0.80 mmol/g, 0.640 mmol) in THF-CH2Cl2 (1:1, 10mL) at -78C, TMSCN (0.150 mL, 1.184 mmol) was addedfollowed by the addition of TMSOTf (0.495 mL, 2.74mmol). The mixture was stirred at -78C by 5 min. Then, themixture was filtered and washed with CH2Cl2 (3 x 10 mL),transferred to a flask, followed by the addition of 10 mL ofCHCl3 and a solution of HCl in CHCl3 (10.0 mL, 1.0 M).The mixture was stirred at 50C by 1 h. Then, the organic layer was filtered, extracted with H2O (3 x 5.0 mL),basified with NH4OH, and extracted with CH2Cl2 (3 x 5.0mL mL). The organic layer was dried with MgSO4 and thesolvent was removed in vacuum to give a white solid in 50%overall yield. White solid; mp 270-271 oC; [alpha]D +27.0 (c =0.15, H2O); 1H NMR (300 MHz, D2O), delta: 1.40-1.58 (3H,m), 1.69-1.75 (2H, m), 2.06 (1H, d, J 12.8), 2.85 (1H, t, J12.5), 3.26 (1H, d, J 12.5), 3.43 (1H, d, J 7.7). 13C NMR (75MHz, D2O), delta: 21.4, 21.7, 26.3, 43.4, 58.8, 174.1. HRMS(MALDI): m/z Calcd. for [C6H11NO2 + H]+ 130.0868, found130.0864.
With sodium carbonate; In 1,4-dioxane; water; at 20℃;
To a stirred solution of D-pipecolic acid (500 mg, 3.87 mmol) in 10% aqueous sodium carbonate (5 mL) was added N-(9-fluorenylmethoxycarbonyloxy)succinimide (1.3 g, 3.87 mmol) in dioxane (5 mL) and the resulting milky -white suspension was stirred at room temperature overnight. The crude reaction mixture was poured onto water, the pH was adjusted to pH = 9 with saturated sodium bicarbonate, and the resulting mixture was washed into EtOAc (3X). The combined EtOAc washes were discarded. The aqueous phase was acidified to pH = 4 with 10% aqueous HC1 and the resultant mixture was extracted with EtOAc (3X). The combined EtOAc extracts were dried over sodium sulfate and concentrated in vacuo to afford (R)-l-(((9H-fluoren-9-yl)methoxy)carbonyl)piperidine-2-carboxylic acid (1.21 g, 90% yield) as a white powder. MS (ESI) m/z 374.1 [M + Na]+.
2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylidenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)acetaldehyde[ No CAS ]
[ 1723-00-8 ]
(2R)-1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)piperidine-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
12.54%
Step 1 (2R)-1-(2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-m ethylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)piperidine-2-carb oxylic acid 2-((3R,4aR,6aS,7R,10bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)acetaldehyde (500.00 mg, 1.44 mmol) was dissolved in tetrahydrofuran (20 mL), and piperidine-2-carboxylic acid (280.00 mg, 2.17 mmol) and acetic acid (1.05 g, 17.48 mmol, 1.00 mL) were added successively and stirred at 45 C. for 1 hour. Sodium borohydride-acetic acid (915.58 mg, 4.32 mmol) was added followed by stirring at 45 C. for 8 hours. The reaction solution was diluted with 150 mL water and extracted with ethyl acetate (50 mL*3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by column chromatography (silica, dichloromethane/methanol 20/1) to give (2R)-1-(2-((3R,4aR,6aS,7R,10 bR)-3-cyclopentyl-6a,10b-dimethyl-8-methylene-decahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethyl)piperidine-2-carboxylic acid 451 (83 mg, yield: 12.54%). MS m/z (ESI):460.4 [M+1] 1H NMR (400 MHz, CDCl3) 4.84 (s, 1H), 4.59 (d, J=5.5 Hz, 1H), 4.53 (br. s., 1H), 3.98 (d, J=11.5 Hz, 1H), 3.63 (d, J=9.5 Hz, 1H), 3.49-3.32 (m, 4H), 2.94-2.68 (m, 2H), 2.42-2.17 (m, 3H), 2.14-1.39 (m, 21H), 1.34 (s, 3H), 1.27-1.11 (m, 3H), 0.74 (s, 3H).
2-bromo-15-propyl-7,7a,8,9,10,11-hexahydro-6a,12a-(methanooxymethano)indolizino[2,3-c]quinoline-6,13(5H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With copper(l) iodide; In N,N-dimethyl-formamide; at 80℃; for 0.166667h;Sealed tube; Microwave irradiation;
General procedure: All microwave irradiation experiments were carried out in an Anton Paar Monowave 200 apparatus. Isatin 1 (1.0 equiv.) L-proline, 2 (1.0 equiv.), Baylis-Hillman adduct 3 (1.0 equiv.) and CuI (20 mol%) were suspended in DMF (2 mL) and placed in a 10 mL reaction vial, which was sealed with a septum and irradiated with microwave 200 for 10 min at 80 C. The reaction mixture was allowed to cool to r.t. and then diluted with CH2Cl2 (10 mL) and filtered. The organic layer was separated and the solvent was evaporated under reduced pressure and the resulting residue was purified by column chromatography to afford the pure polycyclic pyrrolidine- and piperidinoquinolinone derivatives.
alkyl [(4‐chlorophenyl)(hydroxy)methyl]prop‐2‐enoate[ No CAS ]
15-(4-chlorophenyl)-2-methoxy-7,7a,8,9,10,11-hexahydro-6a,12a-(methanooxymethano)indolizino[2,3-c]quinoline-6,13(5H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With copper(l) iodide; In N,N-dimethyl-formamide; at 80℃; for 0.166667h;Sealed tube; Microwave irradiation;
All microwave irradiation experiments were carried out in an Anton Paar Monowave 200 apparatus. Isatin 1 (1.0 equiv.) L-proline, 2 (1.0 equiv.), Baylis-Hillman adduct 3 (1.0 equiv.) and CuI (20 mol%) were suspended in DMF (2 mL) and placed in a 10 mL reaction vial, which was sealed with a septum and irradiated with microwave 200 for 10 min at 80 C. The reaction mixture was allowed to cool to r.t. and then diluted with CH2Cl2 (10 mL) and filtered. The organic layer was separated and the solvent was evaporated under reduced pressure and the resulting residue was purified by column chromatography to afford the pure polycyclic pyrrolidine- and piperidinoquinolinone derivatives.