Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Method for preparing tolvaptan intermediate

A technology of inorganic alkali and oxo substitution, applied in the direction of organic chemistry, can solve the problems of unreacted raw materials, difficult recrystallization and removal, affecting purification and yield, etc., to achieve increased yield, suitable for large-scale industrial production, and products The effect of high purity

Active Publication Date: 2012-03-21
ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD +1
View PDF5 Cites 4 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] This method prepares intermediate (1) document and only has 32% yield, and raw material is not reacted completely, influences purification and yield
Prolonging the reaction time will increase the yield, but will produce a large enol impurity (4), which is difficult to remove by recrystallization

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
  • Method for preparing tolvaptan intermediate
  • Method for preparing tolvaptan intermediate
  • Method for preparing tolvaptan intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] Add 12.04g (0.0664mol) of 4-nitro-2-methylbenzoic acid into a 100ml single-necked flask, add 9.49g (1.2eq) of thionyl chloride and 12ml of toluene, then add 3 drops of DMF, and reflux for 4 After 1 hour, the solvent and excess thionyl chloride were distilled off under reduced pressure to obtain 13.3 g of a brownish-yellow oil, which was condensed to a solid; dissolved in 5 ml of acetonitrile for later use.

[0016] Add 10g (0.051mol) of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine into a 100ml three-necked flask, dissolve it with 50ml of acetonitrile, and then Add 2.04g (1eq) NaOH, stir, add dropwise 13.3g of 4-nitro-2-methylbenzoyl chloride in 5ml acetonitrile solution, react at room temperature, as the reaction progresses, the reaction solution gradually changes from dark green to light green At the same time, a large amount of white solids were precipitated. After 60 minutes, the dropwise addition was completed, and the reaction was stopped. The reaction soluti...

Embodiment 2

[0018] Add 24.08g (0.133mol) of 4-nitro-2-methylbenzoic acid into a 250ml single-necked flask, add 63.26g (4eq) of thionyl chloride, reflux for 5 hours, and distill off excess dichloride under reduced pressure. Sulfoxide, to obtain 26.6g of a brownish-yellow oil, which was solidified after condensation; dissolved in 10ml of acetonitrile for later use.

[0019] Add 20g (0.102mol) of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine into a 250ml three-necked flask, dissolve it with 100ml of acetonitrile, and then Add 4.08g (1eq) NaOH, stir, add dropwise 10ml of acetonitrile solution of 26.6g 4-nitro-2-methylbenzoyl chloride, react at room temperature, as the reaction progresses, the reaction solution gradually changes from dark green to light green At the same time, a large amount of white solids were precipitated. After 60 minutes, the dropwise addition was completed, and the reaction was stopped. The reaction solution was concentrated to dryness, and 200ml of dichloromethane ...

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 relates to a method for preparing a tolvaptan intermediate, namely 7-chlorine-5-oxo-1-(2-methyl-4-nitrobenzene formyl)-1,2,3,4-tetrahydro-benzo-azepine. The tolvaptan intermediate which is a compound as shown in the formula (1) is obtained by 7-chlorine-5-oxo-2,3,4,5-tetrahydro-1H-1-benzo-azepine (2) reacting with 4-nitryl-2-methylbenzene formyl chloride (3). The tolvaptan intermediate prepared by the method has the advantages of high purity, high yield and short reaction time, thereby being suitable for large-scale industrialized production.

Description

technical field [0001] The present invention relates to the preparation of tolvaptan intermediate 7-chloro-5-oxo-1-(2-methyl-4-nitrobenzoyl)-1,2,3,4-tetrahydrobenzazepine Excellent method. Background technique [0002] Tolvaptan (trade name: Samsca) is a non-peptide AVP2 receptor antagonist developed by Otsuka, which can be used to treat hyponatremia caused by congestive heart failure, liver cirrhosis, and antidiuretic hormone deficiency syndrome . So far, among the reported synthetic methods of tolvaptan, only the basic patent route has expired. [0003] Bioorganic & Medicinal Chemistry, 1999, 7 (8), reported in 1743-1757 by 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine and 4 -Nitro-2-methylbenzoyl chloride synthesizes intermediate (1) in the presence of acid-binding agent triethylamine, and its synthetic route is as follows: [0004] [0005] The method for preparing the intermediate (1) has a yield of only 32%, and the raw materials are not completely reacted,...

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
Patent Type & Authority Applications(China)
IPC IPC(8): C07D223/16
Inventor 杜小秋潘领庆
Owner ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

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

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com