(S)-(+)-2-氨基-1-丙醇

反应条件: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-Fluoro-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-4-(trifluoromethyl)benzamide (250 mg), N-methylpiperidone (0.5 mL) and (2S)-2-aminopropan-1-ol (800 mg) were mixed, followed by stirring at 180° C. for 40 minutes under microwave irradiation. After spontaneous cooling and subsequent purification by silica gel column chromatography (chloroform:methanol, 99:1 to 95:5), 2-{[(1S)-2-hydroxy-1-methylethyl]amino}-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-4-(trifluoromethyl)benzamide (188 mg) was obtained as a solid. After spontaneous cooling subsequent purification by silica gel column chromatography (chloroform:methanol, 99:1 to 95:5)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Into a 10000 mL 4-necked, round bottomed flask purged and maintained with an inert atmosphere of nitrogen was placed 4-methoxybenzaldehyde (500 g, 3.67 mol), (S)-2-aminopropan-1-ol (276 g, 3.68 mol), 4-methylbenzenesulfonic acid (31.7 g, 184.09 mmol) and toluene (5000 mL). The resulting solution was maintained at reflux overnight. The reaction mixture was cooled and concentrated under vacuum. The residue was washed with 3000 mL of hexane and filtered to afford the title compound as a yellow solid. Into a 10000 mL 4-necked, round bottomed flask purged maintained with an inert atmosphere of nitrogen The resulting solution was maintained at reflux overnight The reaction mixture was cooled concentrated under vacuum The residue was washed with 3000 mL of hexane filtered

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared using a procedure similar to that used in Step 2 of the synthesis of 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[(1S)-2-hydroxy-1-methylethyl]-4-methylbenzamide by substituting D-alanine amide HCl for (S)-(+)-2-amino-1-propanol. 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.96 (m, 1H), 7.82 (m, 1H), 7.62 (q, 1H, J=8.0 Hz), 7.53 (d, 1H, J=8.0 Hz), 7.01 (m, 2H), 5.5.9 (m, 2H), 4.54 (q, 1H, J=6.0 Hz), 2.20 (s, 3H), 1.45 (d, 3H, J=6.0 Hz). ESHRMS m/z 521.0593 (M+H calculated for C22H20BrF2N4O4 requires 521.0630).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared using a procedure similar to that used in Step 2 of the synthesis of 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[(1S)-2-hydroxy-1-methylethyl]-4-methylbenzamide by substituting glycineamide HCl for (S)-(+)-2-amino-1-propanol. 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.95 (m, 1H), 7.80 (s, 1H), 7.61 (q, 1H, J=8.4 Hz), 7.53 (d, 1H, J=8.0 Hz), 7.01 (m, 2H), 5.58 (m, 2H), 4.01 (s, 2H), 2.20 (s, 3H). ESHRMS m/z 507.0474 (M+H calculated for C21H18BrF2N4O4 requires 507.0474).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared using a procedure similar to that used in Step 2 of the synthesis of 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[(1S)-2-hydroxy-1-methylethyl]-4-methylbenzamide by substituting methylamine for (S)-(+)-2-amino-1-propanol. 1H NMR (CD3OD/400 MHz) δ8.31 (s, 1H), 7.88 (m, 1H), 7.72 (s, 1H), 7.61 (q, 1H, J=8.0 Hz), 7.51 (d, 1H, J=8.0 Hz), 7.01 (m, 2H), 5.58 (m, 2H), 2.89 (s, 3H), 2.18 (s, 3H). ESHRMS m/z 481.0684 (M+H calculated for C20H16BrF2N3O3 NH4 requires 481.0681).

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a cooled (0° C.) solution of 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (from Step 1) (0.80 g, 1.77 mmol) in DMA (3.2 mL) was added isobutyl chloroformate (0.28 mL, 2.13 mmol) and 4-methylmorpholine (0.25 mL, 2.30 mmol). Stirred at 0° C. for 5 min, ambient temperature for 30 min. Added (S)-(+)-2-amino-1-propanol (0.21 mL, 2.66 mmol) and DMAP (0.02 g, 0.18 mmol). Stirred at ambient temperature overnight. Purified crude product by preparatory HPLC using a 10–90% CH3CN/H2O (30 min) gradient containing 0.5% TFA at a flow rate of 80 mL/min. Appropriate fractions (M+H m/z=509) were combined and concentrated to approximately 20 mL under reduced pressure. Added 5% NaHCO3 (20 mL) and extracted with DCM (3×15 mL). The organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure, and dried in vacuo to give the desired product as a pale yellow foam (0.61 g, 67%). Stirred at ambient temperature overnight Purified crude product by preparatory HPLC a 10–90% CH3CN/H2O (30 min) gradient containing 0.5% TFA at a flow rate of 80 mL/min concentrated to approximately 20 mL under reduced pressure Added 5% NaHCO3 (20 mL) extracted with DCM (3×15 mL) The organic extracts were dried over Na2SO4 filtered concentrated under reduced pressure dried in vacuo

反应条件: temp:61.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 1-[2,2-bis(methyloxy)ethyl]-5-(methyloxy)-6-[(methyloxy)carbonyl]-4-oxo-1,4-dihydro-3-pyridinecarboxylic acid (22.54 g) was dissolved in 220 mL of CH3CN. HOAc (20 mL) and CH3SO3H (1.4 mL) were added at room temperature and the mixture was heated to 58-65° C. for 19.5 h. Alaninol (7.511 g) in CH3CN (15 mL) was added slowly and the resultant mixture was stirred at 64° C. for 18.5 h. The mixture was concentrated, and the residue was redissolved in CH2Cl2 (170 mL). HCl (1 N, 170 mL) was added and the layers were separated. The aqueous layer was extracted with CH2Cl2 (170 mL×2) and the organic layers were combined and concentrated. MeOH (50 mL) was added and the resultant mixture was again concentrated. MeOH (80 mL) was added and the resultant mixture was heated at reflux for 4 h, gradually cooled to 20° C. and held at 20° C. for 15 h. The product was collected by filtration and dried under vacuum. The mixture was concentrated the residue was redissolved in CH2Cl2 (170 mL) HCl (1 N, 170 mL) was added the layers were separated The aqueous layer was extracted with CH2Cl2 (170 mL×2) concentrated MeOH (50 mL) was added the resultant mixture was again concentrated MeOH (80 mL) was added the resultant mixture was heated at reflux for 4 h gradually cooled to 20° C. The product was collected by filtration dried under vacuum

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: As described for example 325, 6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (60 mg, 0.18 mmol) was converted, using S-(+)-2-amino-1-propanol instead of rac-2-amino-1-propanol, to the title compound (28 mg, 59%) which was obtained as a white solid MS: m/e=370.3 [M−H]−.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: As described for example 325, 6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (60 mg, 0.18 mmol) was converted, using S-(+)-2-amino-1-propanol instead of rac-2-amino-1-propanol, to the title compound (28 mg, 59%) which was obtained as a white solid MS: m/e=370.3 [M−H]−.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: As described for example 254, 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.29 mmol) was converted, using L-alaninol instead of 2-amino-2-methyl-1-propanol, to the title compound (110 mg, 94%) which was obtained as a white solid. MS: m/e=402.3 [M+H]+.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of J-COOH (e.g., naphthylacetic acid) and HOAt (1 equiv) in dry N,N-dimethylformamide was added 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (1 equiv). After the mixture was stirred at room temperature for one-half hour, a chiral amino alcohol (e.g., (R)- or (S)-1-amino-2-propanol or (R)- or (S)-2-amino-1-propanol, affording a methyl group at R5 or R4, respectively) (1 equiv) was added. The reaction was continued for 16 hours. The reaction mixture was poured into water and extracted by EtOAc twice. The organic layer was washed by 1 N hydrochloric acid twice, 1 N sodium hydroxide twice, brine and dried over sodium sulfate. After evaporation, the product was purified on silica gel column with 10% methanol in methylene chloride.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of J-COOH (e.g., naphthylacetic acid) and HOAt (1 equiv) in dry N,N-dimethylformamide was added 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (1 equiv). After the mixture was stirred at room temperature for one-half hour, a chiral amino alcohol (e.g., (R)- or (S)-1-amino-2-propanol or (R)- or (S)-2-amino-1-propanol, affording a methyl group at R5 or R4, respectively) (1 equiv) was added. The reaction was continued for 16 hours. The reaction mixture was poured into water and extracted by EtOAc twice. The organic layer was washed by 1 N hydrochloric acid twice, 1 N sodium hydroxide twice, brine and dried over sodium sulfate. After evaporation, the product was purified on silica gel column with 10% methanol in methylene chloride.