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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
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  • 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 pollutes the environment
(4) Methanol and ether are used as solvents in the process of purifying the target compound I. Because ether is flammable and volatile, there are potential safety hazards and it is not suitable for industrial production.
The disadvantages of this preparation method: (1) The bromination process of preparing intermediate VII uses bromine as a raw material, which has serious environmental pollution and high labor protection requirements for workers, which is not conducive to safe operation in the workshop
(2) The process of preparing intermediate IV produces impurity compound VII, which is very difficult to purify and remove and directly affects the quality control of target compound I

Method used

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  • 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%.

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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

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Application Information

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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
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