methyl pyrrolidine-3-carboxylate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Pyrrolidine-3-carboxylic acid methyl ester (100 mg, 0.77 mmol) was dissolved in dry DMF (0.5 MI) in a shield tube. 6-Bromonicotinonitrile (140 mg, 077 mmol) was added to the reaction mixture, followed by 2,2,6,6-tetramethylpiperadine (110 mg, 0.77 mmol) and the mixture was heated to 130° C. for 3 h, cooled to room temperature, and diluted with EtOAc. The organic layer was washed with H2O and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 15-18% EtOAc in petroleum ether) to afford methyl 1-(5-cyanopyridin-2-yl)pyrrolidine-3-carboxylate (90 mg, yield 70%). 1H NMR (300 MHz, CDCl3) δ 8.42 (d, J=2.2 Hz, 1H), 7.62-7.59 (dd, J=8.9 Hz, J=2.3 Hz, 1H), 6.36 (d, J=9.0 Hz, 1H), 3.78-3.77 (m, 2H), 3.75 (s, 3H), 3.67 (m, 1H), 3.56-3.52 (m, 1H), 3.28-3.23 (t, J=7.1 Hz, 1H), 2.37-2.30 (q, J=7.1 Hz, 2H). MS (ESI) m/z: Calculated for C12H13N3O2: 231.10. found: 232.2 (M+H)+ cooled to room temperature The organic layer was washed with H2O and brine dried over anhydrous sodium sulfate concentrated under reduced pressure The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 15-18% EtOAc in petroleum ether)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-bromo-4-phenylthiazole (300 mg, 1.25 mmol) and pyrrolidine-3-carboxylic acid methyl ester (177 mg, 1.37 mmol) and potassium phosphate (290 mg, 1.37 mmol) in dry toluene (5 mL) were taken in a sealed tube and purged argon gas for 10 min. A catalytic amount of tri-tert-butylphosphine (12 mg, 0.06 mmol) was added, followed by palladium acetate (15 mg, 0.06 mmol), and the reaction mixture was heated to 80° C. for 10 h. The reaction mixture was then filtered through Celite and the clear filtrate was concentrated under reduced pressure to get the crude product which was purified by column chromatography (silica 60-120 mesh, eluant 15-18% EtOAc in petroleum ether) to get methyl 1-(4-phenylthiazol-2-yl)pyrrolidine-3-carboxylate (75 mg, yield 73%). 1H NMR (300 MHz, CDCl3) δ 7.87-7.83 (m, 2H), 7.44-7.31 (m, 4H), 3.88-3.78 (m, 2H), 3.75 (s, 3H), 3.70-3.67 (m, 1H), 3.61-3.55 (m, 1H), 3.32-3.23 (m, 1H), 2.41-2.32 (m, 2H). MS (ESI) m/z: Calculated for C16H16N2O2S: 288.09. found: 289.2 (M+H)+ were taken in a sealed tube purged argon gas for 10 min The reaction mixture was then filtered through Celite the clear filtrate was concentrated under reduced pressure to get the crude product which was purified by column chromatography (silica 60-120 mesh, eluant 15-18% EtOAc in petroleum ether)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: With a procedure similar to above, 1-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carbonyl)-pyrrolidine-3-carboxylic acid was prepared from 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carboxylic acid 4-nitro-phenyl ester and pyrrolidine-3-carboxylic acid methyl ester. LCMS calcd for C28H27F3N4O5 (m/e) 556, obsd 557 (M+H). The NMR spectrum obtained on the sample is compatible with its structure. The NMR spectrum obtained on the sample

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (500 mg, 1.34 mmol, prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1) and methylpyrrolidine-3-carboxylate (173 mg, 1.34 mmol) and N,N-diisopropylethylamine (346 mg, 2.68 mmol) was heated with stirring in a sealed 10 mL of microwave process vial for 1.5 hours at 140° C. under microwave irradiation. The resulting mixture was purified by preparative HPLC to afford 120 mg of the pure product (yield was 19.8%). was heated The resulting mixture was purified by preparative HPLC

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:85.01; pressure:0.00; stir:

Procedure: A suspension of methyl pyrrolidine-3-carboxylate (2.1 g, 16.26 mmol), 1,4-dibromobenzene (3.84 g, 16.26 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.372 g, 0.41 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.759 g, 1.22 mmol) and Sodium Tert-Butoxide (1.875 g, 19.51 mmol) in anhydrous toluene (60 mL) was stirred at 85 °C under nitrogen for 16 hours. The reaction was cooled to ambient temperature, diluted with Ether (100 mL) and filtered through celite. The filtrate was evaporated in vacuo to yield crude product. The crude product was purified by flash silica chromatography, elution gradient 5 to 20% EtOAc in heptane. Pure fractions were evaporated to dryness to afford methyl 1-(4-bromophenyl)pyrrolidine-3-carboxylate (1.460 g, 31.6 %) as a yellow solid.

Conditions: temp:85.01; pressure:0.00; stir:

Procedure: A suspension of methyl pyrrolidine-3-carboxylate (800 mg, 6.19 mmol), 1,4-dibromobenzene (1461 mg, 6.19 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (142 mg, 0.15 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (289 mg, 0.46 mmol) and Sodium Tert-Butoxide (714 mg, 7.43 mmol) in anhydrous toluene (30 mL) was stirred at 85 °C under nitrogen for 4 hours. The reaction was cooled to ambient temperature, diluted with Ether (100 mL) and filtered through celite. The filtrate was evaporated in vacuo to yield crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in heptane. Pure fractions were evaporated to dryness to afford methyl 1-(4-bromophenyl)pyrrolidine-3-carboxylate (513 mg, 29.1 %) as a yellow solid.

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-chloro-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)-pyrazolo-[1,5-a]pyrimidin-7-amine (55 mg, 0.10 mmoL), methylpyrrolidine-3-carboxylate (52 mg, 0.30 mmoL) and EtN(iPr)2 (86 uL, 0.50 mmoL) in DMF (1.0 mL) was heated at 180° C. under microwave condition for 45 min. The mixture was purified by prep-LC to afford the title compound. LC/MS RT=3.30 min. Mass calculated for, M+H 389.17, observed 389.17. The mixture was purified by prep-LC

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a sample of 150 mg (0.47 mmol) of 5-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]thien-2-ylcarboxylic acid in a three-necked round bottomed flask under an atmosphere of nitrogen were added 3.6 mL anhydrous dimethylformamide and 0.11 mL (0.99 mmol) of N-methylmorpholine. The reaction mixture was stirred and 90 mg (0.51 mmol) of 2-chloro-4,6-dimethoxy-1,3,5-triazine were added at once. The reaction mixture was stirred at room temperature for 0.5 hours and 162 mg (1.25 mmol) of 3-carbomethoxypyrrolidine were added in 1.0 mL of dimethylformamide. After stirring at room temperature for another 3.5 hours, the reaction was concentrated in vacuo and the residue was chromatographed on silica gel with 2-8% CH3OH/CHCl3 to give 78 mg (40%) of methyl 1-{5-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]thien-2-ylcarbonyl}pyrrolidine-3-carboxylate as a white solid. Mass Spectrum (FAB+): M+1=432; IR (KBr, cm-1): 643, 734, 768, 809, 1219, 1336, 1417, 1464, 1601, 1684, 1736, 2854, 2924, 3390; UV (C2H5 OH): λmax =222 (ε=21034), 279 (ε=19777). The reaction mixture was stirred at room temperature for 0.5 hours After stirring at room temperature for another 3.5 hours the reaction was concentrated in vacuo the residue was chromatographed on silica gel with 2-8% CH3OH/CHCl3

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4.6 g of benzyl 3-carbomethoxypyrrolidine-1-carboxylate in 150 mL of anhydrous methanol was added 0.92 g of 10% Pd/C. The reaction mixture was placed under an atmosphere of hydrogen and stirred overnight at room temperature. The reaction mixture was then filtered through a Celite® pad, and the filtrate concentrated in vacuo. The residue was chromatographed on silica gel with 2-16% CH3OH/CHCl3 to give 1.40 g (62% yield) of 3-carbomethoxypyrrolidine as a clear oil, 1H NMR (300 MHz, CDCl3) δ1.90-2.10 (m, 2 H); 2.97-3.11 (m, 4H); 3.18-3.29 (m, 2H); 3.44 (s, 3H). The reaction mixture was then filtered through a Celite® pad the filtrate concentrated in vacuo The residue was chromatographed on silica gel with 2-16% CH3OH/CHCl3

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Method 5—Step a 2-(5-Bromo-2-chloro-phenyl)-5-methyl-benzoimidazole-1-carboxylic acid tert-butyl ester (obtained as described in general method 4, step c) (1.80 g, 4.28 mmol), pyrrolidine-3-carboxylic acid methyl ester (0.92 g, 5.56 mmol) and cesium carbonate (6.95 g, 21.38 mmol) were to a dry flask under nitrogen containing palladium acetate (0.19 g, 0.86 mmol) and BINAP (0.80 g, 1.28 mmol) in dry toluene (11 mL) and previously stirred for 20 minutes under nitrogen. The reaction mixture was heated at 80° C. overnight, cooled to room temperature, diluted with AcOEt (40 mL), salts were filtered off, the organic layer washed with water (1×30 mL) and brine (1×20 mL), dried over Na2SO4 and then concentrated under reduced pressure. To the crude a mixture of solvents cyclohexane:AcOEt/4:1 (15 mL) was added and filtered through a column with Na2SO4 to remove all the salts, washed with the mixture of solvents and the organic layer purified by flash chromatography (eluent: cyclohexane:AcOEt/4:1) to afford 1.71 g of the title compound (86%). cooled to room temperature were filtered off the organic layer washed with water (1×30 mL) and brine (1×20 mL) dried over Na2SO4 concentrated under reduced pressure To the crude a mixture of solvents cyclohexane AcOEt/4:1 (15 mL) was added filtered through a column with Na2SO4 to remove all the salts washed with the mixture of solvents the organic layer purified by flash chromatography (eluent: cyclohexane:AcOEt/4:1)