Preparation method of tolvaptan

A technology of tolvaptan and intermediates, applied in the field of preparation of tolvaptan, can solve the problems of high labor protection requirements for workers, unfavorable workshop safety operation, and large amount of solvent, so as to reduce labor protection requirements for workers and reduce purification Difficulty, improve the effect of quality control

Inactive Publication Date: 2017-06-23
天津泰普制药有限公司
View PDF3 Cites 8 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantages of this preparation method: (1) The preparation and purification of intermediates in each step need to be separated by column chromatography, the yield is low, the operation is cumbersome, the amount of solvent is large and it is not easy to recycle, which makes the production cost high and is not suitable for industrial production.
(2) The process of preparing intermediate II produces impurity compound V, which is not easy to purify and remove and directly affects the yield and quality
(3) The preparation of intermediate III uses tin dichloride to reduce the nitro group, the process is complicated and difficult to handle, and a large amount of waste water is produced, which seriously p

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation method of tolvaptan
  • Preparation method of tolvaptan
  • Preparation method of tolvaptan

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Synthesis of intermediate II compound

[0028] 10.0g 7-chloro-1,2,3,4-tetrahydrobenzo[b]azepin-5-one, 11.7g 4-nitro-2-methylbromobenzene, 14.3g potassium carbonate, 3.0g Add a solution of triphenylphosphine and 0.02g palladium acetate, N,N-dimethylformamide (150ml)-water (10.0ml) into a 500ml autoclave, replace with nitrogen three times under stirring, and introduce CO gas at a pressure of 3MPa Heat at 120°C and reflux for 8 hours. Cooling, filtration to remove palladium acetate, the reaction solution to 300ml of water, stirred for 30 minutes and filtered, the solid was recrystallized with methanol and cyclohexane, and the solid was dried in vacuo at 60°C for 8 hours to obtain 17.0 g of a light yellow solid with a yield of 92.7%. HPLC purity 99.0%.

Embodiment 2

[0030] Synthesis of intermediate II compound

[0031] 10.0g 7-chloro-1,2,3,4-tetrahydrobenzo[b]azepin-5-one, 13.3g 4-nitro-2-methylbromobenzene, 14.3g potassium carbonate, 3.0g Add the solution of triphenylphosphine and 0.03g palladium acetate, N,N-dimethylformamide (150ml)-water (10.0ml) into a 500ml autoclave, replace with nitrogen three times under stirring, and introduce CO gas at a pressure of 5MPa Heat at 110°C and reflux for 8 hours. Cooling, filtering to remove palladium acetate, the reaction solution to 300ml of water, stirring for 30 minutes and filtering, the solid was recrystallized with methanol, and the solid was dried under vacuum at 60°C for 6 hours to obtain 14.0g of a light yellow solid, the yield was 76.3%, and the HPLC purity was 99.3% .

Embodiment 3

[0033] Synthesis of intermediate II compound

[0034] 10.0g 7-chloro-1,2,3,4-tetrahydrobenzo[b]azepine-5-one, 10.6g 4-nitro-2-methylchlorobenzene, 14.3g potassium carbonate, 3.0g Add a solution of triphenylphosphine and 0.04g palladium acetate, N,N-dimethylformamide (150ml)-water (10.0ml) into a 500ml autoclave, replace it with nitrogen three times under stirring, and introduce CO gas at a pressure of 3MPa Heat at 125°C and reflux for 8 hours. Cooling, filtration to remove palladium acetate, the reaction solution to such as 300ml of water, stirred for 30 minutes and filtered, the solid was recrystallized with methanol and cyclohexane, and the solid was dried in vacuo at 60°C for 8 hours to obtain 15.0 g of a light yellow solid with a yield of 81.8%. HPLC purity 98.5%.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

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.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy, and relates to a preparation method of tolvaptan for treating indications such as hyponatremia, heart failure and polycystic kidney disease. Background technique [0002] Tolvaptan (Tolvaptan) trade name (Samsca) is a non-peptide AVP developed by Otsuka, Japan 2 receptor antagonists. The marketed drugs for the treatment of hyponatremia were approved in the United States, the European Union and Japan in 2009~2010. Until 2015, tolvaptan for the treatment of hepatic edema and cardiac edema had submitted new drug applications in relevant Asian countries; from 2014 to 2015, Japan and EMA successively approved tolvaptan for the treatment of adults with autosomal polycystic kidney disease. In 2014, Otsuka carried out phase III clinical trials of autosomal polycystic kidney disease in the United States; in addition, indications for cancerous edema, hemodialysis with volume overload, and perit...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
IPC IPC(8): C07D223/16
CPCC07D223/16
Inventor 郭心富王强刘兆国王志鹏
Owner 天津泰普制药有限公司
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap