* 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.
7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-1- benzazepine (19.0g, 42.51mmol) was dissolved in methanol (200ml) in a solvent, at 0 for Conditional batch of sodium borohydride (2.42g, 63.77mmol), after the addition was complete stirring was continued for 2h, TLC the reaction was complete. The reaction mixture was poured into water, extracted with methylene chloride, dried over anhydrous sodium sulfate, filtration and vacuum distillation of crude with methanol: petroleum ether (2: 1) and recrystallized to give a white solid tolvaptan (18.33g , 96.0percent).
94%
at 20℃; for 5 h;
The compound (X) (20.0 g, 44.75 mmol) was dissolved in methanol (200 mL), sodium borohydride (3.39 g, 89.50 mmol) was added at room temperature and stirred for 5 h at room temperature. The reaction solution was poured into an ice-water bath (100 mL), quenched, the methanol was removed, the residue was extracted with dichloromethane (3 x 100 mL), the organic phases were combined and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulphate , Filtered and evaporated under reduced pressure to give a crude product which was recrystallized from methanol: petroleum ether (2: 1) to give tolvaptan as a white solid (18.89 g, 94percent).
94.2%
With sodium bis(2-methoxyethoxy)aluminium dihydride In tetrahydrofuran at -5 - 20℃;
5 g of the compound of Formula II is added to a 100 mL three-necked bottle,Then add 25mL of tetrahydrofuran,Stir and dissolveCool down to -5 ~ 0 °C,Temperature control -5 ~ 0 °C,1.73g of a 70wtpercent solution of sodium dihydrobis(2-methoxyethoxy)aluminate in toluene was added dropwise.After the completion of heating up to 10 ~ 20 °C,The reaction was stirred for 2 h.When the HPLC reaction is complete,Temperature control 10 ~ 20 °C,Add 50mL of water,There is a solid precipitated,Continue stirring for 1-2 hours, suction filtration, filter cake recrystallized with aqueous methanol,Drying under reduced pressureA white crystal of tolvaptan 4.73 g was obtained with a yield of 94.2percent.HPLC purity was 99.97percent, dechlorination impurity IV was not detected.
92%
for 1 h;
To a 1 L reactor was added 7-chloro-1- [2-methyl-4 - [(2-methylbenzoyl) amino] benzoyl] -5-oxo-2,3,4,5-tetrahydro- 1 H- 1 -benzazepine .0 g, 179.00 mmol) and methanol (675 ml), and the mixture was stirred for 30 minutes. Sodium borohydride (2.37 g, 62.65 mmol) was added to the reaction mixture and stirred for 1 hour. Thereafter, 0.5percent dilute hydrochloric acid (232 ml) was gradually added to the reaction mixture, and the mixture was gradually cooled at room temperature. When crystals were precipitated, the reaction mixture was filtered, and the resulting filtrate was dried under reduced pressure to obtain 7-chloro-5-hydroxy-1- [2-methyl-4- (2- methylbenzoylamino) benzoyl ] -2,3,4,5-tetrahydro-1 H-1-benzazepine (73.9 g, 92percent).
91.2%
With sodium tetrahydroborate In methanol; water at 25℃; for 1 h;
7-chloro-1-[2-methyl-4-(2-methyl benzoyl amino) benzoyl]-5 oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (25 gm.) was suspended in methanol (600 ml) & water (180 ml) and then added sodium borohydride (2.95 gm.) at 25° C. and the reaction mixture was stirred for 1hr. To the reaction mixture was added hydrochloric acid (150 ml). Then the reaction mixture was stirred for 2 hours. The solid obtained was collected by filtration and dried to give 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methyl benzoyl amino) benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (22.8 gm). Yield—91.2percent; Purity (HPLC)—98.92percent; Dehalogenated Impurity—0.01percent
79.6%
at 15 - 30℃; for 1 h;
10.0 g of intermediate compound IV,110ml of methanol into 250ml reaction flask, stirring, less than 15 under the conditions of adding 0.56g NaBH4, heated to 30 reaction,The solid gradually precipitated. After 1h, the sample TLC showed no raw material. After 2h, 0.75percent hydrochloric acid was added dropwise to terminate the reaction. After stirring for 0.5h, the mixture was cooled to 0 ° C and stirred for 2h. The mixture was filtered to obtain 9.0g of a white solid. The resulting solid methanol and water were recrystallized, filtered,Drying in vacuo at 60 ° C for 8 hours afforded 8.0 g of a white solid with a yield of 79.6percent HPLC purity of 99.9percent.
57 g
Stage #1: With sodium tetrahydroborate In methanol at 20℃; for 1 h; Stage #2: With hydrogenchloride In water
Example 5 Preparation of Tolvaptan 7-Chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (63 gm) as obtained in example 4 was dissolved in methanol (570 ml) and then added sodium borohydride (2.07 gm) at room temperature. The reaction mass was stirred for 1 hour and pH of the reaction mass was adjusted to 6.0 to 7.0 with hydrochloric acid solution (1percent, 630 ml). The separated solid was filtered and dried to obtain 57 gm of tolvaptan.
Reference：
[1] Patent: CN105315169, 2016, A, . Location in patent: Paragraph 0170; 0211; 0212
[2] Patent: CN105753735, 2016, A, . Location in patent: Paragraph 0181; 0221; 0222
[3] Patent: CN107663171, 2018, A, . Location in patent: Paragraph 0023; 0024; 0025; 0026; 0027; 0028
[4] Patent: JP2018/12690, 2018, A, . Location in patent: Paragraph 0031; 0032
[5] Patent: US2015/112059, 2015, A1, . Location in patent: Paragraph 0027
[6] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 23, p. 6455 - 6458
[7] Patent: CN106883175, 2017, A, . Location in patent: Paragraph 0019; 0020
[8] Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 8, p. 1743 - 1754
[9] Patent: WO2012/46244, 2012, A1, . Location in patent: Page/Page column 9
[10] Patent: US2013/190490, 2013, A1, . Location in patent: Paragraph 0066
2
[ 137973-76-3 ]
[ 150683-30-0 ]
Yield
Reaction Conditions
Operation in experiment
90%
Stage #1: With sodium tetrahydroborate In methanol for 1 h; Stage #2: With hydrogenchloride In methanol; water at 20℃;
Example 2; Preparation of 7-chloro-5-hydroxy- l-[2-methyl-4-(2-methyl- benzoylamino)benzoyl]-2,3,4,5-tetrahydro- IH- 1-benzazepine; 7-Chloro-l-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2, 3,4,5- tetrahydro-lH-l-benzazepin-5-one (3.2 g, 7.1 mM) is suspended in methanol (27 mL), and thereto is added at one time crystalline sodium borohydride (96 mg = 2.5 mM), and the mixture is reacted for about one hours. To the reaction mixture is added dropwise 0.5percent diluted hydrochloric acid (9.3 mL), and the mixture is stirred at room temperature and then cooled. The precipitated crystals are separated by filtration, and dried at room temperature to give the desired 7- chloro-5-hydroxy- 1 - [2 -methyl-4- (2 -methylbenzoylamino) benzoyl] - 2,3,4,5-tetrahydro- IH- 1-benzazepine (2.97 g) as white powder (Yield 92 percent, Mp 224.5-225.5°C). The pure 7-chloro-5-hydroxy-l-[2-methyl-4~(2-methylbenzoyl- amino)benzoyl]-2,3,4,5-tetrahydro- IH- 1-benzazepine is obtained by recrystallizing the above product from methanol/ water (4 : 1). The product thus obtained is while crystalline powder (yield of recrystallization, 90 percent, purity more than 99.5 percent, Mp 226-227.5°C). The 7-chloro-5-hydroxy-l-[2-methyl-4-(2-methylbenzoylamino)- benzoyl]-2,3,4,5-tetrahydro- IH- 1-benzazepine thus obtained has the following physical data; (1) NMR spectrum data, (2) IR spectrum data, (3) MS spectrum data and (4) powder X-ray diffraction spectrum data. (1) NMR spectrum: 1H NMR (300MHz, DMSO-d6): major conformational isomer δ= 1.49 (br EPO <DP n="35"/>ddd, J= I 1.3Hz, J= I 1.3Hz, J= I 1.3Hz, IH), 1.74 (br d, J= I 1.3Hz, IH), 1.95 (br ddd, J= I 1.3Hz, J= I 1.3Hz, J=I 1.3Hz, IH), 2.11 (br d, J= I 1.3Hz, IH), 2.34 (s, 6H), 2.68 (br dd, J= I 1.3Hz, J= I 1.3Hz, IH), 4.64 (br d, J=I 1.3Hz, IH), 4.90 (br d, J= 11.3Hz, IH), 5.70 (br d, J=4.6Hz, IH), 6.74 (d, J=8.2Hz, IH), 6.76 (d, J= 10. IHz, IH), 7.05 (dd, J=8.2Hz, J=2.3Hz, IH), 7.25-7.29 (m, 3H), 7.37 (dd, J=7.3Hz, J=7.3Hz, IH), 7.41 (d, J=7.3Hz, IH), 7.50 (d, J=2.3Hz, IH), 7.60 (s, IH), 10.2 (s, IH)(2) IR spectrumIR (KBr): 3397, 3221, 2926, 1657, 1622, 1609, 1395, 1304, 1094, 866, 827, 745 cm-1(3) MS spectrumMS (FAB): m/z = 449 (MH+); (4) Powder X-ray diffraction spectrum 2Ψ = 4.7, 15.4, 18.7, 21.7, 23.5°. The purity is measured by high performance liquid chromatography (HPLC) under the following conditions:Detector: Ultraviolet absorptiometer (UV 254 nm), column: YMC- Pack ODS-A A-312, column temperature: around 25°C, mobile phase: acetonitrile/ water/ phosphoric acid solution (500 : 500 : 1) or acetonitrile/water/phosphoric acid solution (700 : 300 : 1).
Stage #1: With magnesium hydroxide In dichloromethane; water at 10℃; for 0.5 h; Stage #2: for 3 h;
To a 3 L reactor was added 1- (4-amino-2-methylbenzoyl) -7-chloro-5-oxo-2,3,4,5-tetrahydro- 1 H- 1 -benzazepine (70. 0 g, 212.90 mmol), dichloromethane (560 ml) and distilled water (140 ml), and the mixture was stirred for 1 hour. Magnesium hydroxide (14.90 g, 14.90 mmol) was added to the reaction mixture at 10 ° C. or lower, and the mixture was stirred for 30 minutes. 2-Methylbenzoyl chloride (30.42 ml) was gradually added to the reaction mixture, followed by stirring for 3 hours. The reaction mixture was filtered to remove magnesium hydroxide and the pH of the reaction mixture was adjusted to pH 8 to 9 using aqueous sodium hydroxide solution and then the organic layer was separated. The obtained organic layer was dried with sodium sulfate (Na 2 SO 4), filtered and concentrated under reduced pressure to give 7-chloro-1- [2-methyl-4 - [(2-methylbenzoyl) amino] benzoyl] -5 - oxo-2,3,4,5-tetrahydro-1 H-1-benzazepine 91.35 g was obtained (yield: 96percent).
90.6%
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 2 h;
Compound (IX) (14.0g, 42.58mmol) was dissolved in dichloromethane (350 mL of) was added diisopropylethylamine (11.0g, 85.16mmol), stirred for 15min, then was added portionwise o-methylbenzoic chloride (7.90g, 51.10mmol), at RT for 2h, TLC detection, the reaction was complete. The reaction mixture was poured into water (200 mL), the organic phase washed with water twice (200mlx2), dried over anhydrous sodium sulfate, and methylene chloride to give a spin product 2-methyl-4- (2-methyl-benzoylamino) benzene acid (17.24g, 90.6percent).
88%
With triethylamine In dichloromethane at 20℃; for 2.25 h;
The compound (IX) (18.0 g, 54.75 mmol) was dissolved in dichloromethane (150 mL)Triethylamine (15.22 mL, 109.49 mmol) was added, stirred for 15 min,Then, 2-methylbenzoyl chloride (10.16 g, 65.70 mmol) was slowly added dropwise and reacted for 2 h at room temperature. The reaction was complete by TLC. The reaction solution was poured into water (100 mL), and the organic phase water was washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, removal of the dichloromethane gave the product compound (X) (21.53 g, 88percent).
88.2%
With pyridine In dichloromethane at 0 - 10℃; for 2 h;
The intermediate 10.0g,Pyridine 3.5g, 150ml dichloromethane into 500ml reaction flask,Stirring, dropping 4.9 g of 2-methylbenzoyl chloride in dichloromethane under the condition of 0 DEG C,The reaction was heated to 10 ° C for 2h, followed by TLC sampling, showing no starting material and the reaction was completed.The pH was adjusted to 2 with 6N aqueous hydrochloric acid, the layers were separated and the organic layer was concentrated under reduced pressure to give a light yellow solid,Recrystallization by addition of methanol and cyclohexane afforded 12g as an off-white solid in 88.2percent yield with an HPLC purity of 99.5percent.
86.1%
With pyridine In dichloromethane at 20 - 30℃;
To a 250 ml reaction flask was added 50 ml of dichloromethane, 5.6 ml of pyridine, and the compound of the formula III was added with stirring, then 3.5 g of o-methylbenzoyl chloride was added, and the reaction was completed at 20 to 30 ° C with stirring. Filtered 6.95g crude tolvaptan, purity95.39percent, impurity M 0.56percent.The solid obtained in the above step was added to a solvent of 32 g of ethyl acetate/dichloromethane/isopropyl ether (volume ratio 1:4:1), heated to 50 ° C to 60 ° C, stirred and dissolved, cooled and crystallized, and filtered to obtain a white solid 6.1 g. , yield: 86.1percent, purity: 99.51percent, impurity M content 0.04percent.
185 g
With sodium hydrogencarbonate In dichloromethane; water at 0 - 5℃;
Example 4 Preparation of 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine 1-(4-Amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (185 gm) as obtained in example 3 was dissolved in methylene chloride (4000 ml) and then added sodium bicarbonate solution (10percent, 47.3 gm). The reaction mass was cooled to 0 to 5° C. and then added 2-methyl benzoyl chloride (95.7 gm) slowly. The pH of the reaction mass was adjusted to 7.0 to 8.0 with aqueous sodium bicarbonate solution (120 ml). The separated aqueous layer was extracted with methylene chloride and then concentrated to obtain a residual solid of 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (185 gm).
Reference：
[1] Patent: JP2018/12690, 2018, A, . Location in patent: Paragraph 0029; 0030
[2] Patent: CN105315169, 2016, A, . Location in patent: Paragraph 0170; 0224; 0225
[3] Patent: CN105753735, 2016, A, . Location in patent: Paragraph 0181; 0217; 0218
[4] Patent: CN106883175, 2017, A, . Location in patent: Paragraph 0017; 0018
[5] Patent: CN108503586, 2018, A, . Location in patent: Paragraph 0044; 0045; 0054; 0055; 0056
[6] Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 8, p. 1743 - 1754
[7] Tetrahedron Asymmetry, 2010, vol. 21, # 19, p. 2390 - 2393
[8] Patent: WO2012/46244, 2012, A1, . Location in patent: Page/Page column 9
[9] Patent: US2013/190490, 2013, A1, . Location in patent: Paragraph 0064; 0065
4
[ 201230-82-2 ]
[ 160129-45-3 ]
[ 317374-07-5 ]
[ 137973-76-3 ]
Yield
Reaction Conditions
Operation in experiment
85%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 20 - 125℃; for 3 h;
Example 1; Preparation of 7-chloro-l-[2-methyl-4-(2-methylbenzoylamino)- benzoyl]-2,3,4,5-tetrahydro-lH-l-benzazepin-5-one; Well-dried 2-bromo-5-(2-methylbenzoylamino)toluene (3.2 g, 10.5 mM) and 7-chloro-2,3,4,5-tetrahydro-lH-l-benzazepin-5-one (1.8 g, 9.2 mM) are entered into a reaction vessel, and thereto are added 1,8- diazabicyclo[5.4.0]undecene-7 (DBU) (2.5 mL) and N3N- dimethylformamide (DMF) (6 mL), and the mixture is stirred at room temperature. To the solution thus obtained are added triphenyl- phosphine (221 mg) and Pd(OAc)2 (23.5 mg, 0.105 mM), and the mixture is heated under carbon monoxide at 125°C for 3 hours. The reaction mixture is cooled till room temperature, and thereto is blown argon gas to discharge excess carbon monoxide. Thereafter, to the mixture are added ethyl acetate (150 mL) and 0.5M aqueous NaOH solution (50 mL) to divide into two phases. The organic layer is washed with diluted hydrochloric acid and then with saturated saline and dried over magnesium sulfate. After filtering off magnesium sulfate, the filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: ethyl acetate/ n- hexane) to give the desired 7-chloro-l-[2-methyl-4-(2-methylbenzoyl- amino)benzoyl]-2,3,4,5-tetrahydro-lH-l-benzazepin-5-one (3.5 g) as pale yellowish white crystalline powder (Yield 85 percent, purity 99.1 percent, Mp 134-142°C).The 7-chloro- l-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro- lH-l-benzazepin-5-one thus obtained has the following physical data; (1) NMR spectrum data, (2) IR spectrum data, (3) MS spectrum data. (1) NMR spectrum:1H NMR (300MHz, DMSO-de, 1000C): δ= 1.98 (tt, J=6.6Hz, J=6.6Hz, 2H), 2.29 (s, 3H), 2.36 (s, 3H), 2.78 (t, J=6.4Hz, 2H), 3.87 (t, J=6.4Hz, 2H), 6.96 (d, J=8.5Hz, IH), 7.09 (d, J=8.5Hz, IH), 7.24 (m, 2H), 7.32 -7.46 (m, 4H), 7.59 (m, 2H), 9.96 (brs, IH) (2) IR spectrum EPO <DP n="34"/>IR (KBr): 3296, 2964, 2926, 1683, 1638, 1610, 1401, 1297, 836, 739 cm-1(3) MS spectrum MS (EI): m/z = 446 (M+). The purity is measured by high performance liquid chromatography (HPLC) under the following conditions:Detector: Ultraviolet absorptiometer (UV 254 nm), column: YMC- Pack ODS-AA-312, column temperature: around 25°C, mobile phase: acetonitrile/ water/ phosphoric acid solution (700 : 300 : 1).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 23, p. 6455 - 6458
[2] Patent: WO2007/26971, 2007, A2, . Location in patent: Page/Page column 32-33
To a 3 L reactor was added 1- (4-amino-2-methylbenzoyl) -7-chloro-5-oxo-2,3,4,5-tetrahydro- 1 H- 1 -benzazepine (70. 0 g, 212.90 mmol), dichloromethane (560 ml) and distilled water (140 ml), and the mixture was stirred for 1 hour. Magnesium hydroxide (14.90 g, 14.90 mmol) was added to the reaction mixture at 10 C. or lower, and the mixture was stirred for 30 minutes. 2-Methylbenzoyl chloride (30.42 ml) was gradually added to the reaction mixture, followed by stirring for 3 hours. The reaction mixture was filtered to remove magnesium hydroxide and the pH of the reaction mixture was adjusted to pH 8 to 9 using aqueous sodium hydroxide solution and then the organic layer was separated. The obtained organic layer was dried with sodium sulfate (Na 2 SO 4), filtered and concentrated under reduced pressure to give 7-chloro-1- [2-methyl-4 - [(2-methylbenzoyl) amino] benzoyl] -5 - oxo-2,3,4,5-tetrahydro-1 H-1-benzazepine 91.35 g was obtained (yield: 96%).
90.6%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h;
Compound (IX) (14.0g, 42.58mmol) was dissolved in dichloromethane (350 mL of) was added diisopropylethylamine (11.0g, 85.16mmol), stirred for 15min, then was added portionwise o-methylbenzoic chloride (7.90g, 51.10mmol), at RT for 2h, TLC detection, the reaction was complete. The reaction mixture was poured into water (200 mL), the organic phase washed with water twice (200mlx2), dried over anhydrous sodium sulfate, and methylene chloride to give a spin product 2-methyl-4- (2-methyl-benzoylamino) benzene acid (17.24g, 90.6%).
88%
With triethylamine; In dichloromethane; at 20℃; for 2.25h;
The compound (IX) (18.0 g, 54.75 mmol) was dissolved in dichloromethane (150 mL)Triethylamine (15.22 mL, 109.49 mmol) was added, stirred for 15 min,Then, 2-methylbenzoyl chloride (10.16 g, 65.70 mmol) was slowly added dropwise and reacted for 2 h at room temperature. The reaction was complete by TLC. The reaction solution was poured into water (100 mL), and the organic phase water was washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, removal of the dichloromethane gave the product compound (X) (21.53 g, 88%).
88.2%
With pyridine; In dichloromethane; at 0 - 10℃; for 2h;
The intermediate 10.0g,Pyridine 3.5g, 150ml dichloromethane into 500ml reaction flask,Stirring, dropping 4.9 g of 2-methylbenzoyl chloride in dichloromethane under the condition of 0 DEG C,The reaction was heated to 10 C for 2h, followed by TLC sampling, showing no starting material and the reaction was completed.The pH was adjusted to 2 with 6N aqueous hydrochloric acid, the layers were separated and the organic layer was concentrated under reduced pressure to give a light yellow solid,Recrystallization by addition of methanol and cyclohexane afforded 12g as an off-white solid in 88.2% yield with an HPLC purity of 99.5%.
86.1%
With pyridine; In dichloromethane; at 20 - 30℃;
To a 250 ml reaction flask was added 50 ml of dichloromethane, 5.6 ml of pyridine, and the compound of the formula III was added with stirring, then 3.5 g of o-methylbenzoyl chloride was added, and the reaction was completed at 20 to 30 C with stirring. Filtered 6.95g crude tolvaptan, purity95.39%, impurity M 0.56%.The solid obtained in the above step was added to a solvent of 32 g of ethyl acetate/dichloromethane/isopropyl ether (volume ratio 1:4:1), heated to 50 C to 60 C, stirred and dissolved, cooled and crystallized, and filtered to obtain a white solid 6.1 g. , yield: 86.1%, purity: 99.51%, impurity M content 0.04%.
With sodium hydrogencarbonate; In dichloromethane; at 0 - 5℃;pH 7 - 8;
Preparation of 7-chloro-l-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-dxo- 2,3,4,5-tetrahydro-lH-l-benzazepine1 -(4-Amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 - benzazepine (185 gm) as obtained in example 3 was dissolved in methylene chloride (4000 ml) and then added sodium bicarbonate solution (10%, 47.3 gm). The reaction mass was cooled to 0 to 5C and then added 2-methyl benzoyl chloride (95.7 gm) slowly. -The pH of the reaction mass was adjusted to 7.0 to 8.0 with aqueous sodium bicarbonate solution (120 ml). The separated aqueous layer was extracted with methylene chloride and then concentrated to obtain a residual solid of 7-chloro-l-[2- methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro- 1 H- 1 - benzazepine (185 gm).
185 g
With sodium hydrogencarbonate; In dichloromethane; water; at 0 - 5℃;pH 7.0 - 8.0;
Example 4 Preparation of 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine 1-(4-Amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (185 gm) as obtained in example 3 was dissolved in methylene chloride (4000 ml) and then added sodium bicarbonate solution (10%, 47.3 gm). The reaction mass was cooled to 0 to 5 C. and then added 2-methyl benzoyl chloride (95.7 gm) slowly. The pH of the reaction mass was adjusted to 7.0 to 8.0 with aqueous sodium bicarbonate solution (120 ml). The separated aqueous layer was extracted with methylene chloride and then concentrated to obtain a residual solid of 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (185 gm).
With methanol; sodium tetrahydroborate; at 0℃; for 2h;
7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-1- benzazepine (19.0g, 42.51mmol) was dissolved in methanol (200ml) in a solvent, at 0 for Conditional batch of sodium borohydride (2.42g, 63.77mmol), after the addition was complete stirring was continued for 2h, TLC the reaction was complete. The reaction mixture was poured into water, extracted with methylene chloride, dried over anhydrous sodium sulfate, filtration and vacuum distillation of crude with methanol: petroleum ether (2: 1) and recrystallized to give a white solid tolvaptan (18.33g , 96.0%).
94%
With methanol; sodium tetrahydroborate; at 20℃; for 5h;
The compound (X) (20.0 g, 44.75 mmol) was dissolved in methanol (200 mL), sodium borohydride (3.39 g, 89.50 mmol) was added at room temperature and stirred for 5 h at room temperature. The reaction solution was poured into an ice-water bath (100 mL), quenched, the methanol was removed, the residue was extracted with dichloromethane (3 x 100 mL), the organic phases were combined and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulphate , Filtered and evaporated under reduced pressure to give a crude product which was recrystallized from methanol: petroleum ether (2: 1) to give tolvaptan as a white solid (18.89 g, 94%).
94.2%
With sodium bis(2-methoxyethoxy)aluminium dihydride; In tetrahydrofuran; at -5 - 20℃;
5 g of the compound of Formula II is added to a 100 mL three-necked bottle,Then add 25mL of tetrahydrofuran,Stir and dissolveCool down to -5 ~ 0 C,Temperature control -5 ~ 0 C,1.73g of a 70wt% solution of sodium dihydrobis(2-methoxyethoxy)aluminate in toluene was added dropwise.After the completion of heating up to 10 ~ 20 C,The reaction was stirred for 2 h.When the HPLC reaction is complete,Temperature control 10 ~ 20 C,Add 50mL of water,There is a solid precipitated,Continue stirring for 1-2 hours, suction filtration, filter cake recrystallized with aqueous methanol,Drying under reduced pressureA white crystal of tolvaptan 4.73 g was obtained with a yield of 94.2%.HPLC purity was 99.97%, dechlorination impurity IV was not detected.
92%
With methanol; sodium tetrahydroborate; for 1h;
To a 1 L reactor was added 7-chloro-1- [2-methyl-4 - [(2-methylbenzoyl) amino] benzoyl] -5-oxo-2,3,4,5-tetrahydro- 1 H- 1 -benzazepine .0 g, 179.00 mmol) and methanol (675 ml), and the mixture was stirred for 30 minutes. Sodium borohydride (2.37 g, 62.65 mmol) was added to the reaction mixture and stirred for 1 hour. Thereafter, 0.5% dilute hydrochloric acid (232 ml) was gradually added to the reaction mixture, and the mixture was gradually cooled at room temperature. When crystals were precipitated, the reaction mixture was filtered, and the resulting filtrate was dried under reduced pressure to obtain 7-chloro-5-hydroxy-1- [2-methyl-4- (2- methylbenzoylamino) benzoyl ] -2,3,4,5-tetrahydro-1 H-1-benzazepine (73.9 g, 92%).
91.2%
With sodium tetrahydroborate; In methanol; water; at 25℃; for 1h;
7-chloro-1-[2-methyl-4-(2-methyl benzoyl amino) benzoyl]-5 oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (25 gm.) was suspended in methanol (600 ml) & water (180 ml) and then added sodium borohydride (2.95 gm.) at 25 C. and the reaction mixture was stirred for 1hr. To the reaction mixture was added hydrochloric acid (150 ml). Then the reaction mixture was stirred for 2 hours. The solid obtained was collected by filtration and dried to give 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methyl benzoyl amino) benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (22.8 gm). Yield-91.2%; Purity (HPLC)-98.92%; Dehalogenated Impurity-0.01%
79.6%
With methanol; sodium tetrahydroborate; at 15 - 30℃; for 1h;
10.0 g of intermediate compound IV,110ml of methanol into 250ml reaction flask, stirring, less than 15 under the conditions of adding 0.56g NaBH4, heated to 30 reaction,The solid gradually precipitated. After 1h, the sample TLC showed no raw material. After 2h, 0.75% hydrochloric acid was added dropwise to terminate the reaction. After stirring for 0.5h, the mixture was cooled to 0 C and stirred for 2h. The mixture was filtered to obtain 9.0g of a white solid. The resulting solid methanol and water were recrystallized, filtered,Drying in vacuo at 60 C for 8 hours afforded 8.0 g of a white solid with a yield of 79.6% HPLC purity of 99.9%.
Example 5:Preparation of tolvaptan7-Chloro- 1 -[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5- tetrahydro-lH-1 -benzazepine (63 gm) as obtained in example 4 was dissolved in methanol (570 ml) and then added sodium borohydride (2.07 gm) at room temperature. The reaction mass was stirred for 1 hour and pH of the reaction mass was adjusted to 6.0 to 7.0 with hydrochloric acid solution (1%, 630 ml). The separated solid was filtered and dried to obtain 57 gm of tolvaptan.
57 g
Example 5 Preparation of Tolvaptan 7-Chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (63 gm) as obtained in example 4 was dissolved in methanol (570 ml) and then added sodium borohydride (2.07 gm) at room temperature. The reaction mass was stirred for 1 hour and pH of the reaction mass was adjusted to 6.0 to 7.0 with hydrochloric acid solution (1%, 630 ml). The separated solid was filtered and dried to obtain 57 gm of tolvaptan.
With 1,8-diazabicyclo[5.4.0]undec-7-ene;palladium diacetate; triphenylphosphine; In N,N-dimethyl-formamide; at 20 - 125℃; for 3h;
Example 1; Preparation of 7-chloro-l-[2-methyl-4-(2-methylbenzoylamino)- benzoyl]-2,3,4,5-tetrahydro-lH-l-benzazepin-5-one; Well-dried 2-bromo-5-(2-methylbenzoylamino)toluene (3.2 g, 10.5 mM) and 7-chloro-2,3,4,5-tetrahydro-lH-l-benzazepin-5-one (1.8 g, 9.2 mM) are entered into a reaction vessel, and thereto are added 1,8- diazabicyclo[5.4.0]undecene-7 (DBU) (2.5 mL) and N3N- dimethylformamide (DMF) (6 mL), and the mixture is stirred at room temperature. To the solution thus obtained are added triphenyl- phosphine (221 mg) and Pd(OAc)2 (23.5 mg, 0.105 mM), and the mixture is heated under carbon monoxide at 125C for 3 hours. The reaction mixture is cooled till room temperature, and thereto is blown argon gas to discharge excess carbon monoxide. Thereafter, to the mixture are added ethyl acetate (150 mL) and 0.5M aqueous NaOH solution (50 mL) to divide into two phases. The organic layer is washed with diluted hydrochloric acid and then with saturated saline and dried over magnesium sulfate. After filtering off magnesium sulfate, the filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: ethyl acetate/ n- hexane) to give the desired 7-chloro-l-[2-methyl-4-(2-methylbenzoyl- amino)benzoyl]-2,3,4,5-tetrahydro-lH-l-benzazepin-5-one (3.5 g) as pale yellowish white crystalline powder (Yield 85 %, purity 99.1 %, Mp 134-142C).The 7-chloro- l-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro- lH-l-benzazepin-5-one thus obtained has the following physical data; (1) NMR spectrum data, (2) IR spectrum data, (3) MS spectrum data. (1) NMR spectrum:1H NMR (300MHz, DMSO-de, 1000C): delta= 1.98 (tt, J=6.6Hz, J=6.6Hz, 2H), 2.29 (s, 3H), 2.36 (s, 3H), 2.78 (t, J=6.4Hz, 2H), 3.87 (t, J=6.4Hz, 2H), 6.96 (d, J=8.5Hz, IH), 7.09 (d, J=8.5Hz, IH), 7.24 (m, 2H), 7.32 -7.46 (m, 4H), 7.59 (m, 2H), 9.96 (brs, IH) (2) IR spectrum EPO <DP n="34"/>IR (KBr): 3296, 2964, 2926, 1683, 1638, 1610, 1401, 1297, 836, 739 cm-1(3) MS spectrum MS (EI): m/z = 446 (M+). The purity is measured by high performance liquid chromatography (HPLC) under the following conditions:Detector: Ultraviolet absorptiometer (UV 254 nm), column: YMC- Pack ODS-AA-312, column temperature: around 25C, mobile phase: acetonitrile/ water/ phosphoric acid solution (700 : 300 : 1).
In tetrahydrofuran; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; ethyl acetate;
Example 86 0.85 g of 60% sodium hydride was added to 200 ml of tetrahydrofuran. Thereto was dropwise added 4.68 ml of ethyl diethylphosphonoacetate with ice-cooling and stirring. The mixture was stirred for 10 minutes with ice-cooling. To the reaction mixture was added 2.10 g of 5-oxo-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetra-hydro-1H-benzoazepine. The mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into 200 ml of ice water. The resulting mixture was subjected to extraction with 300 ml of ethyl acetate. The extract was washed with 300 ml of an aqueous sodium chloride solution, then dried over magnesium sulfate, and subjected to distillation to remove the solvent. The residue was purified by silica gel column chromatography (elutant: ethyl acetate/n-hexane=1/2) to obtain 2.22 g of 5-ethoxy-carbonylmethylidene-7-chloro-1-[2-methyl-4-(2-methylbenzoyl-amino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine as a mixture of the E form and the Z form. Colorless and amorphous 1 H-NMR (CDCl3) delta: 1.04-5.10 (17H, m), 5.96-6.17 (1H, m), 6.52-7.86 (11H, m)
Example 2; Preparation of 7-chloro-5-hydroxy- l-[2-methyl-4-(2-methyl- benzoylamino)benzoyl]-2,3,4,5-tetrahydro- IH- 1-benzazepine; 7-Chloro-l-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2, 3,4,5- tetrahydro-lH-l-benzazepin-5-one (3.2 g, 7.1 mM) is suspended in methanol (27 mL), and thereto is added at one time crystalline sodium borohydride (96 mg = 2.5 mM), and the mixture is reacted for about one hours. To the reaction mixture is added dropwise 0.5% diluted hydrochloric acid (9.3 mL), and the mixture is stirred at room temperature and then cooled. The precipitated crystals are separated by filtration, and dried at room temperature to give the desired 7- chloro-5-hydroxy- 1 - [2 -methyl-4- (2 -methylbenzoylamino) benzoyl] - 2,3,4,5-tetrahydro- IH- 1-benzazepine (2.97 g) as white powder (Yield 92 %, Mp 224.5-225.5C). The pure 7-chloro-5-hydroxy-l-[2-methyl-4~(2-methylbenzoyl- amino)benzoyl]-2,3,4,5-tetrahydro- IH- 1-benzazepine is obtained by recrystallizing the above product from methanol/ water (4 : 1). The product thus obtained is while crystalline powder (yield of recrystallization, 90 %, purity more than 99.5 %, Mp 226-227.5C). The 7-chloro-5-hydroxy-l-[2-methyl-4-(2-methylbenzoylamino)- benzoyl]-2,3,4,5-tetrahydro- IH- 1-benzazepine thus obtained has the following physical data; (1) NMR spectrum data, (2) IR spectrum data, (3) MS spectrum data and (4) powder X-ray diffraction spectrum data. (1) NMR spectrum: 1H NMR (300MHz, DMSO-d6): major conformational isomer delta= 1.49 (br EPO <DP n="35"/>ddd, J= I 1.3Hz, J= I 1.3Hz, J= I 1.3Hz, IH), 1.74 (br d, J= I 1.3Hz, IH), 1.95 (br ddd, J= I 1.3Hz, J= I 1.3Hz, J=I 1.3Hz, IH), 2.11 (br d, J= I 1.3Hz, IH), 2.34 (s, 6H), 2.68 (br dd, J= I 1.3Hz, J= I 1.3Hz, IH), 4.64 (br d, J=I 1.3Hz, IH), 4.90 (br d, J= 11.3Hz, IH), 5.70 (br d, J=4.6Hz, IH), 6.74 (d, J=8.2Hz, IH), 6.76 (d, J= 10. IHz, IH), 7.05 (dd, J=8.2Hz, J=2.3Hz, IH), 7.25-7.29 (m, 3H), 7.37 (dd, J=7.3Hz, J=7.3Hz, IH), 7.41 (d, J=7.3Hz, IH), 7.50 (d, J=2.3Hz, IH), 7.60 (s, IH), 10.2 (s, IH)(2) IR spectrumIR (KBr): 3397, 3221, 2926, 1657, 1622, 1609, 1395, 1304, 1094, 866, 827, 745 cm-1(3) MS spectrumMS (FAB): m/z = 449 (MH+); (4) Powder X-ray diffraction spectrum 2Theta = 4.7, 15.4, 18.7, 21.7, 23.5. The purity is measured by high performance liquid chromatography (HPLC) under the following conditions:Detector: Ultraviolet absorptiometer (UV 254 nm), column: YMC- Pack ODS-A A-312, column temperature: around 25C, mobile phase: acetonitrile/ water/ phosphoric acid solution (500 : 500 : 1) or acetonitrile/water/phosphoric acid solution (700 : 300 : 1).
With sodium tetrahydroborate; ethanol; at 0 - 30℃;
90 ml of ethanol was added to the reaction flask, and 9.6 g (21.5 mmol) of the intermediate obtained in 4 was added under stirring, and the mixture was cooled to 0 to 5 C, and 1.3 g (32.9 mmol) of sodium borohydride was added thereto, and the temperature was raised to 15 to 30 C. (TLC detection), the reaction solution was transferred to a 500 ml reaction flask, and the reaction was quenched by slowly adding 360 g of purified water under stirring, and filtered, and washed with 25 g of water to obtain a wet product. After drying, 7.2 g of a white solid was obtained, yield 75.0%. , purity (HPLC): 99.78%, impurity M content 0.03%,Its impurities are less than 0.05%.
With manganese(IV) oxide; In dichloromethane; for 7h;Reflux;
Manganese dioxide (2 g) was added to a suspension of N-(4-(7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-carbonyl)-3-methylphenyl)-2-methylbenzamide (2 g) in dichloromethane (40 mL), and the mixture was refluxed for 7 hours. After being cooled, the reaction mixture was filtered through Celite, washed with dichloromethane, and then purified by silica gel column chromatography (n-hexane:ethyl acetate = 10:1?3:1) to obtain 0.94 g of N-(4-(7-chloro-5-oxo-2,3,4-trihydro-1H-benzo[b]azepine-1-carbonyl)-3-methylphenyl)-2-methylbenzamide. Properties: Colorless amorphous powder 1H-NMR (CDCl3) deltappm 1.91-1.31 (2H, m), 2.43 (3H, s), 2.49 (3H, s), 2.89 (2H, t, J=6.3 Hz), 3.30-4.60 (2H, m), 6.48-7.00 (2H, m), 7.01-7.70 (8H, m), 7.78 (1H, s).
With sodium borodeuteride; d(4)-methanol; at 0℃; for 2h;
Sodium borodeuteride (0.045 g) was added to a solution of N-(4-(7-chloro-5-oxo-2,3,4-trihydro-1H-benzo[b]azepine-1-carbonyl)-3-methylphenyl)-2-methylbenzamide (0.4 g) in deuterated methanol (10 mL) at 0C, and the mixture was stirred at the same temperature for 2 hours. Deuterium oxide (2 mL) was added to the resulting reaction mixture, and the mixture was stirred for 10 minutes. Water was added thereto, followed by extraction with ethyl acetate. The resulting water layer was subjected to extraction with ethyl acetate again. The ethyl acetate layers thus obtained were combined and dried over anhydrous magnesium sulfate. Subsequently, the solvent was distilled off and the residue was recrystallized from acetone-diethyl ether to obtain 0.35 g of N-(4-(7-chloro-5-hydroxy-2,3,4-trihydro-5-deutero-1H-benzo[b]azepine-1-carbonyl)-3-methylphenyl)-2-methylbenzamide. Yield: 87% Properties: White powder 1H-NMR (DMSO-d6, 80C) deltappm 1.40-2.19 (4H, m), 2.36 (3H, s), 2.38 (3H, s), 3.35-4.94 (2H, br), 5.35 (1H, s), 6.56-7.70 (10H, m), 9.93 (1H, brs) MS: (M+, 449) Melting point: 227.8C.
A 0.05 M sodium hydroxide deuterated methanol solution (13 mul) was added to a solution of <strong>[137973-76-3]N-(4-(7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-carbonyl)-3-methylphenyl)-2-methylbenzamide</strong> (300 mg) in deuterated methanol (10 mL). The mixture was stirred under an argon atmosphere at room temperature. After stirring for 16 hours, elimination of the proton at the 4-position was confirmed by 1H-NMR. Sodium borodeuteride (0.037 g) was added to the reaction mixture at 0C and the mixture was stirred at the same temperature for 2 hours. Deuterium oxide (2 mL) was added to the resulting reaction mixture and stirred for 10 minutes. Water was added thereto, followed by extraction with ethyl acetate. The resulting water layer was subjected to extraction with ethyl acetate again. The ethyl acetate layers thus obtained were combined and dried over anhydrous magnesium sulfate. Subsequently, the solvent was distilled off, and the residue was recrystallized from acetone-diethyl ether to obtain 0.22 g of N-(4-(7-chloro-2,3-dihydro-5-hydroxy-4,4,5-trideutero-1H-benzo[b]azepine-1-carbonyl)-3-methylphenyl)-2-methylbenzamide. Yield: 73% Properties: White powder 1H-NMR (DMSO-d6, 80C) deltappm 1.51-2.06 (2H, m), 2.36 (3H, s), 2.38 (3H, s), 3.36-5.02 (2H, br), 5.34 (1H, s), 6.58-7.70 (10H, m), 9.94 (1H, brs) MS: (M+, 451) Melting point: 225.1C.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
