拉科酰胺EP杂质J 盐酸盐

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Glutaraldehyde (25% solution in water) (910 mL, 2.4 mol) and benzylamine hydrochloride (344.1 g, 2.4 mol) in water (1050 mL) was cooled to 0° C. 3-Oxopentanedioic acid (350.0 g, 2.4 mol) was added followed by addition of sodium acetate (aq.) (79.7 g in 797 mL water) resulting in formation of a thick orange precipitate. The reaction mixture was heated to 50° C. and stirred at this temperature for 4 h. It was then cooled to ambient temperature and allowed to stand for 24 h. The reaction mixture was acidified to pH2 with 5N aqueous hydrochloric acid (˜150 mL) and the resulting aqueous mixture was washed with diethyl ether (2×500 mL). The aqueous extracts were basified to pH12 with 4N aqueous sodium hydroxide (˜650 mL) and extracted with dichloromethane (6×500 mL). The organic phase was dried (MgSO4) and concentrated under reduced pressure to afford the crude product as a red oil. Purification by chromatography on silica gel with dichloromethane:methanol (49:1, v/v) as eluent afforded 9-benzyl-9-azabicyclo[3.3.1]nonan-3-one (300.0 g, 1.3 mol, 54%) as a pale orange solid. resulting in formation of a thick orange precipitate It was then cooled to ambient temperature to stand for 24 h the resulting aqueous mixture was washed with diethyl ether (2×500 mL) extracted with dichloromethane (6×500 mL) The organic phase was dried (MgSO4) concentrated under reduced pressure to afford the crude product as a red oil Purification by chromatography on silica gel with dichloromethane:methanol (49:1

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Glutaraldehyde (25% solution in water) (910 mL, 2.4 mol) and benzylamine hydrochloride (344.1 g, 2.4 mol) in water (1050 mL) was cooled to 0° C. 3-Oxopentanedioic acid (350.0 g, 2.4 mol) was added followed by addition of sodium acetate (aq.) (79.7 g in 797 mL water) resulting in formation of a thick orange precipitate. The reaction mixture was heated to 50° C. and stirred at this temperature for 4 h. It was then cooled to ambient temperature and allowed to stand for 24 h. The reaction mixture was acidified to pH2 with 5N aqueous hydrochloric acid (˜150 mL) and the resulting aqueous mixture was washed with diethyl ether (2×500 mL). The aqueous extracts were basified to pH12 with 4N aqueous sodium hydroxide (˜650 mL) and extracted with dichloromethane (6×500 mL). The organic phase was dried (MgSO4) and concentrated under reduced pressure to afford the crude product as a red oil. Purification by chromatography on silica gel with dichloromethane:methanol (49:1, v/v) as eluent afforded 9-benzyl-9-azabicyclo[3.3.1]nonan-3-one (300.0 g, 1.3 mol, 54%) as a pale orange solid. resulting in formation of a thick orange precipitate It was then cooled to ambient temperature to stand for 24 h the resulting aqueous mixture was washed with diethyl ether (2×500 mL) extracted with dichloromethane (6×500 mL) The organic phase was dried (MgSO4) concentrated under reduced pressure to afford the crude product as a red oil Purification by chromatography on silica gel with dichloromethane:methanol (49:1

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

实验步骤: A solution of 2,5-dimethoxytetrahydrofuran (50 g, 378 mmol) in hydrochloric acid (0.025 N, 160 ml) was cooled to 0° C. for 16 hours. Benzylamine hydrochloride (65 g, 453 mmol), ketomalonic acid (55 g, 377 mmol) and an aqueous solution of sodium acetate (300 ml, 0.69 M) were added and the reaction stirred at room temperature for one hour. The mixture was heated to 50° C. for further 90 minutes, then cooled in an ice bath and basified to pH12 with 2N sodium hydroxide solution. The layers were separated and the aqueous phase extracted with ethyl acetate (3×300 ml). The combined organic extracts were washed with water, dried (MgSO4), filtered and evaporated under reduced pressure. The residual brown oil was distilled under reduced pressure (126°/3 mmHg) to afford the title compound as an off-white solid (37.81 g). The mixture was heated to 50° C. for further 90 minutes cooled in an ice bath The layers were separated the aqueous phase extracted with ethyl acetate (3×300 ml) The combined organic extracts were washed with water dried (MgSO4) filtered evaporated under reduced pressure The residual brown oil was distilled under reduced pressure (126°/3 mmHg)

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

实验步骤: A mixture of 5-methoxy-2-[(1-phenyl-1H-pyrazol-5-yl)amino]benzoic acid (made by Ullmann reaction as described in Example 1, 42.0 mg, 0.14 mmol), benzylamine hydrochloride (23.4 mg, 0.16 mmol), EDCI (31.2 mg, 0.16 mmol), HOBT (22.0 mg, 0.16 mmol), and triethylamine (0.066 mL, 0.48 mmol) in DMF (3 mL) was stirred at rt for 16 h. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Flash chromatography of the residue over silica gel, using 20% ethyl acetate/hexane, gave the title compound (16.1 mg, 30%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.72 (s, 1H), 9.14 (t, 1H), 7.57 (d, 1H), 7.38-7.51 (m, 4H), 7.16-7.36 (m, 7H), 6.96-7.06 (m, 2H), 6.15 (s, 1H), 4.37 (d, 2H), 3.70 (s, 3H); ES-MS m/z 399.1 (MH+), HPLC RT (min) 3.72. The reaction was quenched with water (20 mL) extracted with ethyl acetate (10 mL) The organic layer was washed with brine dried over Na2SO4 filtered concentrated under reduced pressure

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

实验步骤: To 2-isopropyl-pyrazolo[1,5-a]pyridine (6.80 g, 42.50 mmol) in n-propionic anhydride (15 mL, 97%) at 140° C. was added concentrated H2SO4 (0.5 ml). The mixture was maintained at 140° C. overnight, cooled to room temperature basified with NaOH (aqueous 50%) until pH>11. The aqueous layer was extracted with chloroform (3×100 mL), dried (Na2SO4), filtered and concentrated. The crude product was purified by flash column chromatography (100% hexane, 9:1 hexane:ethyl acetate) to afford 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one (4.81 g, 22.27 mmol, 53%) as a yellow oil. 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one (0.500 g, 2.3 mmol), paraformaldehyde (0.069 g, 2.3 mmol), and benzylamine hydrochloride (0.329 g, 2.3 mmol) were added to a 5-mL round bottom flask. To this ethanolic hydrochloride (1 mL, 1.25% concentrated HCl in ethanol) was added and the mixture was heated to reflux for 16 hours. The mixture was then cooled and diluted with Et2O (5 mL) and 1M NaOH (aq) (10 mL). The aqueous layer was then extracted with Et2O (4×5 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to afford a dark brown oil. This oil was subjected to flash column chromatography (10% gradient of EtOAc/hexane ranging from 0 to 90%) which afforded 0.073 g (9.5% yield) of 3-(benzylamino)-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one as a pale yellow oil. the mixture was heated to reflux for 16 hours The mixture was then cooled The aqueous layer was then extracted with Et2O (4×5 mL) The combined organic layers were washed with brine dried (Na2SO4) filtered concentrated to afford a dark brown oil

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

实验步骤: N-benzyl-S-(naphthoquinon-2-yl)-dithiocarbamate) (32). To a suspension of benzylamine hydrochloride (300 mg, 1.87 mmoles) in CH2Cl2 (5 mL) at 0° C. was added NEt3 (208.4 mg, 2.05 mmoles) and the reaction mixture was stirred for 15 minutes followed by the addition of CS2 (142.5 mg, 1.87 mmoles). After 30 minutes, 1,4-naphthoquinone (296.1 mg, 1.87 mmoles) was added and the reaction was allowed to slowly warm to rt overnight. The reaction was poured into 1 M H2SO4 and extracted with EtOAc (3×50 mL). The organic layer was washed with brine, dried with Na2SO4, and filtered. Concentration afforded a crude product that was chromatographed (CHCl3/EtOAc/Hexanes, 1:1:2) to afford a brick red solid (125 mg, 20% yield). After 30 minutes extracted with EtOAc (3×50 mL) The organic layer was washed with brine dried with Na2SO4 filtered Concentration afforded a crude product that was chromatographed (CHCl3/EtOAc/Hexanes, 1:1:2)

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

实验步骤: N-benzyl-S-(naphthoquinon-2-yl)-dithiocarbamate) (32). To a suspension of benzylamine hydrochloride (300 mg, 1.87 mmoles) in CH2Cl2 (5 mL) at 0° C. was added NEt3 (208.4 mg, 2.05 mmoles) and the reaction mixture was stirred for 15 minutes followed by the addition of CS2 (142.5 mg, 1.87 mmoles). After 30 minutes, 1,4-naphthoquinone (296.1 mg, 1.87 mmoles) was added and the reaction was allowed to slowly warm to rt overnight. The reaction was poured into 1 M H2SO4 and extracted with EtOAc (3×50 mL). The organic layer was washed with brine, dried with Na2SO4, and filtered. Concentration afforded a crude product that was chromatographed (CHCl3/EtOAc/Hexanes, 1:1:2) to afford a brick red solid (125 mg, 20% yield). After 30 minutes extracted with EtOAc (3×50 mL) The organic layer was washed with brine dried with Na2SO4 filtered Concentration afforded a crude product that was chromatographed (CHCl3/EtOAc/Hexanes, 1:1:2)

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

实验步骤: To a solution of 2-(dibenzylamino)-3-(difluoromethoxy)propanoic acid (335.4 mg, 1 mmol) and triethylamine (404.8 mg, 4 mmol) in THF (5 mL) at −5° C., isobutyl chloroformate (143.5 mg, 1.05 mmol) was added dropwise. After 20 minutes, benzylamine hydrochloride (215.4 mg, 1.5 mmol) was added and the reaction mixture allowed to warm up to room temperature. The mixture was then diluted with ethyl acetate and washed with water, 0.5N HCl and Brine. The organic layer was dried over magnesium sulphate, concentrated with silica gel and purified by column chromatography, eluting with 10-20% ethyl acetate in hexanes to give 2-(dibenzylamino)-3-(difluoromethoxy)-N-benzylpropanamide (367 mg, 86.5%) as a white solid. 1H NMR (300 MHz, CDCl3): δ(ppm) 7.56 (t, 1H), 7.17-7.34 (m, 15H), 6.35 (wt, 1H), 4.60 (dd, 1H), 4.43 (m, 3H), 3.95 (d, 2H), 3.68 (d, 2H) and 3.67 (m, 1H). washed with water, 0.5N HCl and Brine The organic layer was dried over magnesium sulphate concentrated with silica gel purified by column chromatography eluting with 10-20% ethyl acetate in hexanes

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A warm solution of benzylamine hydrochloride in water (1 mL) was added to a mixture of 6-acetamido-4-methoxy-2-methyl-quinoline (1.0 g, 4.3 mmol) in n-butanol (10 mL) after which complete solution occurred. The solution was stirred for 3 days at 100° C. under a nitrogen atmosphere, cooled, and the precipitated solid filtered, washed with ether, and dried to afford 1.0 g (75%) of 6-acetamido-4-benzylamino2-methyl-quinoline hydrochloride. A solution of this material (0.76 gm, 2.49 mmol) in 25% hydrochloric acid (12 mL) was heated for 5 hr at 90° C. and subsequently cooled. The precipitated solid was filtered, washed with water, dried at 50° C. under high vacuum for several hours to give 0.38 gm (58%) of 6-amino-4-benzylamino-2-methyl-quinoline. This material was dissolved in glacial acetic acid (3 mL) to which was added dropwise a solution of 2-chlorocinnamoyl chloride in glacial acetic acid over a 5 min period. The reaction mixture was stirred for 1 hr at room temperature and diluted with diethyl ether (25 mL). The solid was filtered, washed with ether, and dried by suction. It was then dissolved in a hot mixture of methanol (50 mL) and water (25 mL), cooled, and 5N sodium hydroxide added to give a yellow precipitate that was filtered, washed with water, and dried under high vacuum. Recrystallization from isopropanol afforded the title compound as pale yellow crystals; yield 0.32 g (52%), m.p. 253-4°, MS (FAB): m/z 428 (M+1). cooled the precipitated solid filtered washed with ether dried

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A warm solution of benzylamine hydrochloride in water (1 mL) was added to a mixture of 6-acetamido-4-methoxy-2-methyl-quinoline (1.0 g, 4.3 mmol) in n-butanol (10 mL) after which complete solution occurred. The solution was stirred for 3 days at 100° C. under a nitrogen atmosphere, cooled, and the precipitated solid filtered, washed with ether, and dried to afford 1.0 g (75%) of 6-acetamido-4-benzylamino2-methyl-quinoline hydrochloride. A solution of this material (0.76 gm, 2.49 mmol) in 25% hydrochloric acid (12 mL) was heated for 5 hr at 90° C. and subsequently cooled. The precipitated solid was filtered, washed with water, dried at 50° C. under high vacuum for several hours to give 0.38 gm (58%) of 6-amino-4-benzylamino-2-methyl-quinoline. This material was dissolved in glacial acetic acid (3 mL) to which was added dropwise a solution of 2-chlorocinnamoyl chloride in glacial acetic acid over a 5 min period. The reaction mixture was stirred for 1 hr at room temperature and diluted with diethyl ether (25 mL). The solid was filtered, washed with ether, and dried by suction. It was then dissolved in a hot mixture of methanol (50 mL) and water (25 mL), cooled, and 5N sodium hydroxide added to give a yellow precipitate that was filtered, washed with water, and dried under high vacuum. Recrystallization from isopropanol afforded the title compound as pale yellow crystals; yield 0.32 g (52%), m.p. 253-4°, MS (FAB): m/z 428 (M+1). cooled the precipitated solid filtered washed with ether dried

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A warm solution of benzylamine hydrochloride (1.5 g, 10.4 mmol) in water (2 mL) was added to a mixture of 6-acetamido-4methoxy-2-methylquinoline (2.0 g, 8.7 mmol) in n-butanol (20 mL). The mixture was stirred for 4 days at 100° C., cooled in an ice bath, and the resulting precipitated solid was filtered, washed with ether, and dried by suction to afford 2.1 g (71%) of 6-acetamido-4-benzylamino-2-methyl-quinoline hydrochloride. This material was heated in 25% hydrochloric acid (33 mL) for 5 h at 90° C. After cooling, the separated solid was filtered, washed with ether, and dried by suction. The solid was dissolved in water, made basic (pH >10) with 5N sodium hydroxide to afford a yellow solid that was filtered, washed with water, and dried. 6Amino-4-benzylamino-2-methyl-quinoline was obtained in 43% yield (0.98 g). 0.5 Grams (1.9 mmol) of this material was dissolved in glacial acetic acid, and the solution was treated with oxalyl chloride (0.17 mL) for 1 h at room temperature with stirring. Ether was then added (25 mL) and the mixture stirred for 30 min. The solid was filtered, washed with ether, and dried by suction. It was dissolved in water (25 mL) and warm ethanol (200 mL) with additional water added to achieve complete solution. After cooling to room temperature, 5N sodium hydroxide was added to give a yellow precipitate that was filtered, and dried under high vacuum to yield 0.46 g (41%) of the title compound; m.p. 292-294° (dec.); MS (FAB): m/z 581 (M+1). cooled in an ice bath the resulting precipitated solid was filtered washed with ether dried by suction

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

实验步骤: A suspension of N-(4-chloromethylphenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.1g), benzylamine hydrochloride (0.5g) and potassium carbonate (0.6g) in dimethylformamide (10ml) was stirred at room temperature over night. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give N-(4-((benzylamino)methyl)-phenyl)-7-(4-methylphenyl)-2,3-dihydro-l-benzoxepine-4-carboxamide (Compound 117) (0.08g) as colorless crystals. The solvent was evaporated to the residue was added water The mixture was extracted with ethyl acetate The organic layer was washed with water and saturated sodium chloride solution dried with anhydrous magnesium sulfate Under reduced pressure, the solvent was evaporated the residue was purified with silica gel column (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane