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Preparation method of tolvaptan

A technology of tolvaptan and methyl, which is applied in the field of preparation of tolvaptan, a selective non-peptidin arginine vasopressin V2 receptor antagonist, can solve the problem of low yield, difficulty in obtaining starting materials, Reduce the total yield and other problems, achieve high yield and purity, improve work efficiency, and protect the environment

Inactive Publication Date: 2015-03-18
SHANGHAI TIANCI BIOLOGICAL VALLEY BIOLOGICAL ENG
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  • Abstract
  • Description
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  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The method has the following disadvantages: 1) the single-line synthesis of the reaction greatly reduces the overall total yield; 2) the reduction in the reaction uses high price and heavy metal platinum oxide as a catalyst, which is not suitable for economical production and environmental protection; 3 ) Each step of the reaction has been purified by column chromatography, which is not conducive to industrial production; 4) in the process, a large number of organic solvents that are not conducive to safe production have been used, such as chloroform as extraction reagents, etc.
[0012] This route has starting material to be difficult to obtain, and the first step reaction adopts a class of solvent 1,2-ethylene dichloride, is unfavorable for environmental protection, rearrangement reaction and the shortcoming such as the yield of rear two-step reduction is low, so this route is not suitable Conducive to industrialized operation and economical industrialized production

Method used

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  • Preparation method of tolvaptan
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  • Preparation method of tolvaptan

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] (1) 7-Chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepine Synthesis:

[0070] Add 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine into the reaction flask (5.0g, 25.56mmol) and methanol (50ml), stirred until clear, placed in an ice-water bath to cool to 0 ~ 5 ° C, slowly added sodium borohydride (1.45g, 38.34mmol), stirred for 1h, TLC detection, the reaction complete. Pour the reaction solution into ice water to quench, spin off the methanol under reduced pressure, extract with dichloromethane (30mlx3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate by rotary evaporation under reduced pressure to obtain a white solid 7-chloro -5-Hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepine (4.71 g, 93%), MS calculated 197.06, found 197.10.

[0071] (2) Synthesis of 4-amino-2-methylbenzoic acid

[0072] To the suspension of 4-nitro-2-methylbenzoic acid (20.0 g, 110.4 mmol) in concentrated hydrochloric acid (100 ml) and ethano...

Embodiment 2

[0080] (1) 7-Chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepine Synthesis:

[0081] Add 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine into the reaction flask (5.0g, 25.56mmol) and methanol (50ml), stirred until clear, placed in an ice-water bath to cool to 0 ~ 5 ° C, slowly added sodium borohydride (1.16g, 30.67mmol), stirred for 1h, TLC detection, the reaction complete. Pour the reaction solution into ice water to quench, spin off the methanol under reduced pressure, extract with dichloromethane (30mlx3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate by rotary evaporation under reduced pressure to obtain a white solid 7-chloro -5-Hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepine (4.60 g, 91.1%), MS calcd. 197.06, found 197.10.

[0082] (2) Synthesis of 4-amino-2-methylbenzoic acid

[0083] To the suspension of 4-nitro-2-methylbenzoic acid (10.0 g, 55.2 mmol) in concentrated hydrochloric acid (50 ml) and ethanol (10...

Embodiment 3

[0091] The steps of embodiment 3 and embodiment 1 are basically the same, the only difference is:

[0092] Step (1) 7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepine Lithium aluminum hydride is used to replace sodium borohydride in the synthesis of

[0093] Use palladium / carbon to replace SnCl in the synthesis of step (2) 4-amino-2-methylbenzoic acid 2 2H 2 O;

[0094] Sodium carbonate is used to replace triethylamine in the synthesis of step (3) 2-methyl-4-(2-methylbenzamido)benzoic acid;

[0095] Phosphorus trichloride is used to replace oxalyl chloride in the synthesis of step (4) 2-methyl-4-(2-methylbenzamido)benzoyl chloride;

[0096] In the synthesis of step (5) tolvaptan, triethylamine is used to replace sodium hydroxide.

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Abstract

The invention discloses a preparation method of tolvaptan. The method is characterized in that tolvaptan is obtained through an amidation reaction of 7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzoaza and 2-methyl-4-(2-methylphenylamido)benzoyl chloride. The method has the advantages of novel design, work time efficiency increase, reduction of waste liquid discharge, simple operation, easily available raw materials, simple post-treatment and high yield, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy and relates to a selective non-peptidin arginine vasopressin (AVP) V 2 A preparation method of receptor antagonist tolvaptan. Background technique [0002] The English name of tolvaptan is Tolvaptan, and the trade name is Samsca. In 2009, tolvaptan was approved by the US FDA as an oral selective vasopressin antagonist for the treatment of hyponatremia. In 2011, tolvaptan was officially approved by the State Food and Drug Administration and began to be produced and sold in China. This drug is a selective vasopressin V 2 Receptor antagonists can prevent AVP from binding to the V2 receptor at the distal end of the nephron, increase urine excretion of water, but do not change urine sodium and potassium secretion and blood potassium value, reduce urine osmotic pressure, and increase blood sodium Therefore, it is clinically used to treat hypervolemic and isometric hyponatremia caused by li...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D223/16
CPCC07D223/16
Inventor 李新涓子李健之汪迅李勇刚池王胄刘海沈小良高艳吕兴红
Owner SHANGHAI TIANCI BIOLOGICAL VALLEY BIOLOGICAL ENG
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