137977-97-0

Basic information

• Product Name: 1-(4-Amino-2-methylbenzoyl)-7-chloro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one
• Synonyms: 1-(4-Amino-2-methylbenzoyl)-7-chloro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one;5H-1-Benzazepin-5-one, 1-(4-aMino-2-Methylbenzoyl)-7-chloro-1,2,3,4-tetrahydro-;1,2,3,4-Tetrahydro-1-(4-amino-2-methylbenzoyl)-7-chloro-5H-1-benzazepin-5-one;1-(4-aMino-2-Methylbenzoyl)-7-chloro-3,4-dihydro-1H-benzo[b]azepin-5(2H)-one;1-(4-Amino-2-Methylbenzoyl)-7-Chloro-1,2,3,4-Tetrahydro-5H-1-benzazepine-5-One;1-(4-amino-2-methylbenzoyl)-7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azepin-5-one;1-(4-amino-2-methylbenzoyl)-7-chloro-3,4-dihydro-2H-1-benzazepin-5-one
• CAS NO: 137977-97-0
• Molecular Formula: C₁₈H₁₇ClN₂O₂
• Molecular Weight: 328.79
• EINECS: 1592732-453-0
• Product Categories: Pharmaceutical Intermediates
• Mol File: 137977-97-0.mol
• Article Data: 12

Chemical Properties

• Boiling Point: 565.435 °C at 760 mmHg
• Flash Point: 295.765 °C
• Appearance: /
• Density: 1.320
• Storage Temp.: -20°C Freezer
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 2.28±0.10(Predicted)
• CAS DataBase Reference: 1-(4-Amino-2-methylbenzoyl)-7-chloro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one(CAS DataBase Reference)
• NIST Chemistry Reference: 1-(4-Amino-2-methylbenzoyl)-7-chloro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one(137977-97-0)
• EPA Substance Registry System: 1-(4-Amino-2-methylbenzoyl)-7-chloro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one(137977-97-0)

Safety Data

• Hazardous Substances Data: 137977-97-0(Hazardous Substances Data)

Usage

Uses

Different sources of media describe the Uses of 137977-97-0 differently. You can refer to the following data:
1. 1-(4-Amino-2-methylbenzoyl)-7-chloro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one is an intermediate used in the synthetic preparation of Tolvaptan (T536650), a selective nonpeptide arginine vasopressin V 2 receptor antagonist.
2. 1,2,3,4-Tetrahydro-1-(4-amino-2-methylbenzoyl)-7-chloro-5H-1-benzazepin-5-one is an intermediate used in the synthetic preparation of Tolvaptan (T536650), a selective nonpeptide arginine vasopressin V2 receptor antagonist.

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

• 7149-70-4 2-bromo-5-nitrotoluene 
• 106-47-8 4-chloro-aniline 
• 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 articles and documents

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

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.