137977-97-0

Usage

Uses

Used in Pharmaceutical Industry:
1-(4-Amino-2-methylbenzoyl)-7-chloro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one is used as a synthetic intermediate for the preparation of Tolvaptan (T536650), a selective nonpeptide arginine vasopressin V2 receptor antagonist. 1-(4-Amino-2-methylbenzoyl)-7-chloro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one plays a vital role in the development of medications targeting conditions related to the regulation of water balance in the body, such as hyponatremia and certain types of kidney diseases.

Synthetic route

1-(4-nitro-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (137982-91-3) → 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (137977-97-0)

Conditions	Yield
With indium(III) chloride; palladium on activated carbon; hydrogen In methanol at 30℃; under 2250.23 Torr; for 6h; Autoclave; Industrial scale; Green chemistry;	97.5%
With ammonium sulfate; sulfuric acid; iron In ethanol at 60℃; for 5h; Reagent/catalyst; Solvent; Time;	95.6%
With iron; ammonium chloride In methanol; water at 35 - 40℃; for 6h;	90.9%

4-chlorobenzenesulfonyl chloride (5202-89-1) → 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (137977-97-0)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: 85 percent / pyridine / 20 °C 2.1: 94 percent / K2CO3 / dimethylformamide / 4 h / 120 °C 3.1: t-BuOK / toluene / 0.5 h / Heating 3.2: 60 percent / conc. HCl / acetic acid / 5 h / Heating 4.1: 81 percent / polyphosphoric acid / 1.5 h / 80 - 100 °C 5.1: 32 percent / Et3N / CH2Cl2 / 2 h / 20 °C 6.1: 39 percent / SnCl2*2H2O; conc. HCl / ethanol / 20 °C View Scheme
Multi-step reaction with 5 steps 1: sodium carbonate / acetonitrile / 5 h / 80 °C 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 4 h / 20 °C 3: potassium tert-butylate / toluene / 1 h / 120 °C 4: acetic acid; hydrogenchloride / water / 6 h / 100 °C 5: hydrogenchloride; tin(II) chloride dihdyrate / ethanol / 4 h / 20 °C View Scheme

5-chloro-2-nitrobenzoic acid (2516-95-2) → 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (137977-97-0)

Conditions

Yield

Multi-step reaction with 8 steps 1.1: 100 percent / K2CO3 / acetone / 0.5 h / Heating 2.1: SnCl2*2H2O; conc. HCl / ethanol / 20 °C 3.1: 85 percent / pyridine / 20 °C 4.1: 94 percent / K2CO3 / dimethylformamide / 4 h / 120 °C 5.1: t-BuOK / toluene / 0.5 h / Heating 5.2: 60 percent / conc. HCl / acetic acid / 5 h / Heating 6.1: 81 percent / polyphosphoric acid / 1.5 h / 80 - 100 °C 7.1: 32 percent / Et3N / CH2Cl2 / 2 h / 20 °C 8.1: 39 percent / SnCl2*2H2O; conc. HCl / ethanol / 20 °C View Scheme

2-methyl-4-nitrobenzoyl chloride (30459-70-2) → 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (137977-97-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 32 percent / Et3N / CH2Cl2 / 2 h / 20 °C 2: 39 percent / SnCl2*2H2O; conc. HCl / ethanol / 20 °C View Scheme
Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / dichloromethane; water / pH 7 - 8 2: tin(ll) chloride / methanol / 16 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / water; dichloromethane / 0 - 5 °C / pH 7.0 - 8.0 2: tin(IV) chloride / methanol / 16 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: magnesium hydroxide / acetonitrile / 0.5 h / 10 °C 1.2: 5 h 2.1: methanol; tin(II) chloride dihdyrate / 23 h / 10 °C View Scheme

2-methyl-4-nitrobenzoic acid (1975-51-5) → 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (137977-97-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: SOCl2 2: 32 percent / Et3N / CH2Cl2 / 2 h / 20 °C 3: 39 percent / SnCl2*2H2O; conc. HCl / ethanol / 20 °C View Scheme

methyl 5-chloro-2-nitrobenzoate (51282-49-6) → 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (137977-97-0)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: SnCl2*2H2O; conc. HCl / ethanol / 20 °C 2.1: 85 percent / pyridine / 20 °C 3.1: 94 percent / K2CO3 / dimethylformamide / 4 h / 120 °C 4.1: t-BuOK / toluene / 0.5 h / Heating 4.2: 60 percent / conc. HCl / acetic acid / 5 h / Heating 5.1: 81 percent / polyphosphoric acid / 1.5 h / 80 - 100 °C 6.1: 32 percent / Et3N / CH2Cl2 / 2 h / 20 °C 7.1: 39 percent / SnCl2*2H2O; conc. HCl / ethanol / 20 °C View Scheme

7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azepin-5-one (160129-45-3) → 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (137977-97-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 32 percent / Et3N / CH2Cl2 / 2 h / 20 °C 2: 39 percent / SnCl2*2H2O; conc. HCl / ethanol / 20 °C View Scheme
Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / dichloromethane; water / pH 7 - 8 2: tin(ll) chloride / methanol / 16 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / water; dichloromethane / 0 - 5 °C / pH 7.0 - 8.0 2: tin(IV) chloride / methanol / 16 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: potassium carbonate; triphenylphosphine; palladium diacetate / N,N-dimethyl-formamide; water / 8 h / 120 °C / 22502.3 Torr / Autoclave 2: iron; ammonium chloride / water; methanol / 6 h / 35 - 40 °C View Scheme
Multi-step reaction with 2 steps 1.1: magnesium hydroxide / acetonitrile / 0.5 h / 10 °C 1.2: 5 h 2.1: methanol; tin(II) chloride dihdyrate / 23 h / 10 °C View Scheme

N-p-toluenesulfonyl-5-chloro-anthranilic acid methyl ester (247237-38-3) → 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (137977-97-0)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: 94 percent / K2CO3 / dimethylformamide / 4 h / 120 °C 2.1: t-BuOK / toluene / 0.5 h / Heating 2.2: 60 percent / conc. HCl / acetic acid / 5 h / Heating 3.1: 81 percent / polyphosphoric acid / 1.5 h / 80 - 100 °C 4.1: 32 percent / Et3N / CH2Cl2 / 2 h / 20 °C 5.1: 39 percent / SnCl2*2H2O; conc. HCl / ethanol / 20 °C View Scheme

7-chloro-1-(4-methylbenzenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one (193686-76-9) → 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (137977-97-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: 81 percent / polyphosphoric acid / 1.5 h / 80 - 100 °C 2: 32 percent / Et3N / CH2Cl2 / 2 h / 20 °C 3: 39 percent / SnCl2*2H2O; conc. HCl / ethanol / 20 °C View Scheme

methyl 5-chloro-2-[N-(3-ethoxycarbonyl)propyl-N-p-toluenesulfonyl]aminobenzoate (247237-43-0) → 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (137977-97-0)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: t-BuOK / toluene / 0.5 h / Heating 1.2: 60 percent / conc. HCl / acetic acid / 5 h / Heating 2.1: 81 percent / polyphosphoric acid / 1.5 h / 80 - 100 °C 3.1: 32 percent / Et3N / CH2Cl2 / 2 h / 20 °C 4.1: 39 percent / SnCl2*2H2O; conc. HCl / ethanol / 20 °C View Scheme

C13H16ClNO4 → 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (137977-97-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 4 h / 20 °C 2: potassium tert-butylate / toluene / 1 h / 120 °C 3: acetic acid; hydrogenchloride / water / 6 h / 100 °C 4: hydrogenchloride; tin(II) chloride dihdyrate / ethanol / 4 h / 20 °C View Scheme

C21H21ClN2O7 → 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (137977-97-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium tert-butylate / toluene / 1 h / 120 °C 2: acetic acid; hydrogenchloride / water / 6 h / 100 °C 3: hydrogenchloride; tin(II) chloride dihdyrate / ethanol / 4 h / 20 °C View Scheme

C20H17ClN2O6 → 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (137977-97-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: acetic acid; hydrogenchloride / water / 6 h / 100 °C 2: hydrogenchloride; tin(II) chloride dihdyrate / ethanol / 4 h / 20 °C View Scheme

C18H16Cl2N2O4 → 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (137977-97-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: dichloromethane / 4.5 h / 20 °C / Reflux 2: hydrogenchloride; tin(II) chloride dihdyrate / water; ethanol / 3 h / 20 °C View Scheme

4-chloro-aniline (106-47-8) → 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (137977-97-0)

Conditions	Yield
Multi-step reaction with 6 steps 1: sodium carbonate / acetonitrile / 4 h / 80 °C 2: triethylamine / dichloromethane / 3 h / 20 °C 3: sodium hydroxide / 1.5 h / 50 °C 4: thionyl chloride / dichloromethane / 2 h / 20 °C / Reflux 5: dichloromethane / 4.5 h / 20 °C / Reflux 6: hydrogenchloride; tin(II) chloride dihdyrate / water; ethanol / 3 h / 20 °C View Scheme

ethyl 4-(4-chlorophenylamino)butanoate → 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (137977-97-0)

Conditions	Yield
Multi-step reaction with 5 steps 1: triethylamine / dichloromethane / 3 h / 20 °C 2: sodium hydroxide / 1.5 h / 50 °C 3: thionyl chloride / dichloromethane / 2 h / 20 °C / Reflux 4: dichloromethane / 4.5 h / 20 °C / Reflux 5: hydrogenchloride; tin(II) chloride dihdyrate / water; ethanol / 3 h / 20 °C View Scheme

C20H21ClN2O5 → 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (137977-97-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium hydroxide / 1.5 h / 50 °C 2: thionyl chloride / dichloromethane / 2 h / 20 °C / Reflux 3: dichloromethane / 4.5 h / 20 °C / Reflux 4: hydrogenchloride; tin(II) chloride dihdyrate / water; ethanol / 3 h / 20 °C View Scheme

C18H17ClN2O5 → 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (137977-97-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: thionyl chloride / dichloromethane / 2 h / 20 °C / Reflux 2: dichloromethane / 4.5 h / 20 °C / Reflux 3: hydrogenchloride; tin(II) chloride dihdyrate / water; ethanol / 3 h / 20 °C View Scheme

2-bromo-5-nitrotoluene (7149-70-4) → 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (137977-97-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate; triphenylphosphine; palladium diacetate / N,N-dimethyl-formamide; water / 8 h / 120 °C / 22502.3 Torr / Autoclave 2: iron; ammonium chloride / water; methanol / 6 h / 35 - 40 °C View Scheme

ortho-toluoyl chloride (933-88-0) + 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (137977-97-0) → MOP-21826 (137973-76-3)

Conditions	Yield
Stage #1: 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine With magnesium hydroxide In dichloromethane; water at 10℃; for 0.5h; Stage #2: ortho-toluoyl chloride In dichloromethane; water for 3h;	96%
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 2h; Reagent/catalyst;	90.6%
With triethylamine In dichloromethane at 20℃; for 2.25h; Reagent/catalyst;	88%

2,3,4,5-tetradeuterio-6-(trideuteriomethyl)benzoic acid (207742-73-2) + 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (137977-97-0) → N-{4-(7-chloro-5-oxo-2,3,4-trihydro-1H-benzo[b]azepine-1-carbonyl)-3-methylphenyl}-3,4,5,6-tetradeutero-2-trideutero methylbenzamide (1296212-29-7)

Conditions	Yield
With triethylamine; HATU In N,N-dimethyl-formamide at 65℃; for 4h; Inert atmosphere;	94%

toluene-4-sulfonic acid (104-15-4) + 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (137977-97-0) → 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine p-toluenesulfonate

Conditions	Yield
In acetonitrile at 20℃; for 1h;	94%

1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (137977-97-0) → 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine hydrochloride

Conditions	Yield
With hydrogenchloride In diethyl ether; water; acetone Cooling with ice;	92%

oxalic acid (144-62-7) + 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (137977-97-0) → 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine oxalate

Conditions	Yield
In ethanol; di-isopropyl ether Cooling with ice;	89.7%

acetic acid (64-19-7) + 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (137977-97-0) → 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine acetate

Conditions	Yield
In ethanol; di-isopropyl ether Cooling with ice;	87.3%

1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (137977-97-0) → 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine sulfate

Conditions	Yield
With sulfuric acid In ethanol; di-isopropyl ether Cooling with ice;	85.7%

ethanesulfonic acid (594-45-6) + 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (137977-97-0) → 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine ethanesulfonic acid

Conditions	Yield
In acetonitrile at 20℃; for 1h;	84%

benzenesulfonic acid (98-11-3) + 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (137977-97-0) → 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine benzenesulfonic acid

Conditions	Yield
In acetonitrile at 20℃; for 1h;	84%

methanesulfonic acid (75-75-2) + 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (137977-97-0) → 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine methanesulfonic acid

Conditions	Yield
In acetonitrile at 20℃; for 1h;	81%

1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (137977-97-0) → tolvaptan (150683-30-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 53 percent / Et3N / CH2Cl2 / 1.5 h / 20 °C 2: 30 percent / NaBH4 / methanol / 1 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: sodium hydrogencarbonate / water; dichloromethane / 0 - 5 °C / pH 7.0 - 8.0 2.1: sodium tetrahydroborate / methanol / 1 h / 20 °C 2.2: pH 6.0 - 7.0 View Scheme

Upstream product

• 106-47-8 4-chloro-aniline 
• 7149-70-4 2-bromo-5-nitrotoluene 
• 247237-43-0 methyl 5-chloro-2-[N-(3-ethoxycarbonyl)propyl-N-p-toluenesulfonyl]aminobenzoate 
• 193686-76-9 7-chloro-1-(4-methylbenzenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one 
• 247237-38-3 N-p-toluenesulfonyl-5-chloro-anthranilic acid methyl ester 
• 160129-45-3 7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azepin-5-one 
• 51282-49-6 methyl 5-chloro-2-nitrobenzoate 
• 1975-51-5 2-methyl-4-nitrobenzoic acid 
• 30459-70-2 2-methyl-4-nitrobenzoyl chloride 
• 2516-95-2 5-chloro-2-nitrobenzoic acid 
• 5202-89-1 4-chlorobenzenesulfonyl chloride 
• 137982-91-3 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine 

Downstream Products

• 1296212-29-7 N-{4-(7-chloro-5-oxo-2,3,4-trihydro-1H-benzo[b]azepine-1-carbonyl)-3-methylphenyl}-3,4,5,6-tetradeutero-2-trideutero methylbenzamide 
• 150683-30-0 tolvaptan 
• 137973-76-3 MOP-21826 

Relevant academic research and scientific papers

Preparation method for tolvaptan intermediate

The invention discloses a preparation method for a tolvaptan intermediate. The tolvaptan intermediate is obtained by performing catalytic hydrogenation on 1-(4-nitro-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine in an organic solvent to obtain 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine; a catalytic system adopted by the catalytic hydrogenation is a metal chloride + a palladium carbon catalyst; and the metal chloride is lithium chloride or indium trichloride. The method provided by the invention adopts LiCl/InCl3 + the palladium carbon catalyst as the catalytic hydrogenation system, and the catalytic hydrogenation system can not only obtain a higher reaction yield, but also can effectively avoid an occurrence of a dechlorination reaction, thereby obtaining higher product purity; and the method provided by the invention has less pollution to the environment and lower production costs, and is suitable for industrialized production.

IMPROVED METHODS OF PRODUCING SYNTHETIC INTERMEDIATES OF TOLVAPTAN

PROBLEM TO BE SOLVED: To provide improved methods of producing 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine. SOLUTION: The present invention provides methods of producing 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine and 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine, which are synthetic intermediates of tolvaptan, by condensing an amino group and a carboxyl group in the presence of magnesium hydroxide. SELECTED DRAWING: None COPYRIGHT: (C)2018,JPOandINPIT

METHOD FOR PURIFYING 1-(4-AMINO-2-METHYLBENZOYL)-7-CHLORO-5-OXO-2,3,4,5-TETRAHYDRO-1H-1-BENZAZEPINE

PROBLEM TO BE SOLVED: To provide a method for purifying 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine, which is one of the producing intermediates of tolvaptan. SOLUTION: This invention relates to a purification method, comprising the steps of: (a) making a rough 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine react with sulfonic acid, to conduct isolation as a sulfonate; (b) recrystallizing the sulfonate obtained at the step (a) from an organic solvent; and (c) making the sulfonate obtained at the step (b) react with a base to conduct desalination, thereby conducting isolation as a free object. SELECTED DRAWING: None COPYRIGHT: (C)2018,JPOandINPIT

Method for preparing high-purity tolvaptan intermediate

The invention provides a method for preparing a high-purity tolvaptan intermediate, and concretely provides a method for purifying a tolvaptan intermediate N-[4-[(7-chloro-2,3,4,5-tetrahydro-5-oxo-1H-1-benzazepine-1-yl)carbonyl]-3-methylphenyl]-2-methylbenzamide (formula II). A crude product containing the compound of formula II is recrystallized by an organic solvent composed of ester, haloalkaneand ether to preferably obtain the compound of formula II, having a purity of above 99.00%.

A the request cuts down the Pu Tanzania intermediate and its preparation method

The invention relates to the field of pharmaceutical chemistry and particularly discloses preparation methods for a tolvaptan intermediate 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzoazepine (I) (shown in the description) and salts thereof. The tolvaptan intermediate prepared by utilizing the method disclosed by the invention has the characteristics of low cost, high yield, environmental friendliness, strong operability and suitability for industrial production.

Preparation method of tolvaptan

The invention discloses a preparation method of tolvaptan. According to the preparation method, 7-chloro-1,2,3,4-tetrahydrobenzo[b]azepine-5-one and 4-nitro-2-methyl bromobenzene are taken as the primary raw materials; high purity tolvaptan is obtained after steps of carbonyl inserting reactions, reduction reactions, and acylation reactions, and the yield is high. The preparation method has the advantages that no bromine or tin dichloride is used; the preparation method does not generate a large amount of industrial waste water, and the environment is protected. At the same time, the generation of impurities namely a compound V and a compound VIII is avoided, and the purification becomes easier. No explosive, flammable, and toxic solvent such as chloroform, ether, and the like, is used, the requirements on the protection of workers are lowered, and the safe production is guaranteed. Moreover, the route design is novel, the raw materials are easily available, the operation of the technology is simple and feasible, and a simple and feasible method is provided for the massive industrial production of tolvaptan.

Preparation method for cardiovascular disease treatment drug

The invention provides a preparation method for a cardiovascular disease treatment drug. Specifically, the invention provides a compound represented by a formula (IV) shown in the description and a method for preparing Tolvaptan from the compound represented by the formula (IV). The method provided by the invention has the advantages of being environment-friendly, being easy in raw material obtaining and high in total yield, and the like, thereby being applicable to the industrialized preparation of Tolvaptan.

Preparation method of high-efficiency low-toxicity pitressin antagonist

The invention provides a preparation method of a high-efficiency low-toxicity pitressin antagonist. Specifically, the invention provides a compound having the formula A shown in the description, and a method for preparing tolvaptan through the compound having the formula A. All groups in the formula are defined in the description. The method has advantages of environmental protection, available raw materials, and high overall yield, and is suitable for industrial preparation of tolvaptan.

PROCESS FOR PREPARING TOLVAPTAN INTERMEDIATES

The present invention provides a novel process for the preparation of 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one. The present invention also provides an improved process for the preparation of 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine. The present invention further provides an improved process for the preparation of 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine.

PROCESS FOR PREPARING TOLVAPTAN INTERMEDIATES

The present invention provides a novel process for the preparation of 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one. The present invention also provides an improved process for the preparation of 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine. The present invention further provides an improved process for the preparation of 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine.