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

Preparation method of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzo[b]azepine

A technology of -1H-2 and benzonitrogen, applied in the direction of organic chemistry, can solve the problems of limited application, high cost, low total yield, etc.

Active Publication Date: 2016-02-03
CHANGCHUN DISCOVERY SCI
View PDF2 Cites 1 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But this method has following shortcoming: must use the xanthate (smell, poisonous) that price is expensive and bigger to environmental pollution, also will use flammable, highly toxic borane, make raw material cost higher, and total Yield is too low
But this method also has the following disadvantages: the reaction route is long, the total yield is low and expensive Grubbs catalyst needs to be used in the reaction, which limits the application of this method

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 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzo[b]azepine
  • Preparation method of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzo[b]azepine
  • Preparation method of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzo[b]azepine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Synthesis of A, 5-chloro-2-(diallylamino)-benzaldehyde: 2-fluoro-5-chloro-benzaldehyde (0.948g, 6mmol) was dissolved in acetonitrile / water (V:V=1:1 ) mixed solvent (6mL), potassium carbonate powder (1.24g, 9mmol) and diallylamine (3.7mL, 30mmol) were added. The reaction mixture was heated to reflux for 60 h. Cool the reaction solution to room temperature, add water (30 mL) to the reaction solution, extract with ethyl acetate (3×30 mL), combine the organic phases, wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter and evaporate to dryness to obtain 5-Chloro-2-(diallylamino)-benzaldehyde (1.34 g, 95%) as pale yellow oil.

[0031] 1 HNMR (300MHz, CDCl 3 )δ10.29(s,1H),7.75(d,J=2.7Hz,1H),7.40(dd,J=8.7,2.7Hz,1H),7.05(d,J=8.7Hz,1H),5.93– 5.69 (m, 2H), 5.27–5.16 (m, 4H), 3.76 (dt, J=6.0, 1.2Hz, 4H).

[0032] Synthesis of B, 1-allyl-7-chloro-2,3,4,5-tetrahydro-1H-2,5-epoxybenzene [b] azepine: 5-chloro-2-(two Allylamino)-benzaldehyde (1.3g, 5.5mmol...

Embodiment 2

[0039] Synthesis of A, 5-chloro-2-(diallylamino)-benzaldehyde: compound 1,2-fluoro-5-chloro-benzaldehyde (0.948g, 6mmol) was dissolved in acetonitrile / water (V:V= 1:1) mixed solvent (6mL), add potassium carbonate powder (1.24g, 9mmol), diallylamine (3.7mL, 30mmol). The reaction mixture was heated to reflux for 60 h. Cool the reaction solution to room temperature, add water (30 mL) to the reaction solution, extract with ethyl acetate (3×30 mL), combine the organic phases, wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter and evaporate to dryness to obtain 5-Chloro-2-(diallylamino)-benzaldehyde (1.36 g, 96%) as pale yellow oil.

[0040] Synthesis of B, 1-allyl-7-chloro-2,3,4,5-tetrahydro-1H-2,5-epoxybenzene [b] azepine: 5-chloro-2-(two Allylamino)-benzaldehyde (1.3g, 5.5mmol) was added to a steel reactor, and xylene (30mL) was added to dissolve it. After tightening the reactor, the oil bath was heated to 175°C and reacted for 18h. After the reaction...

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 belongs to the field of organic synthesis, and particularly relates to a synthetic method of a key intermediate, namely, 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzo[b]azepine, of Tolvaptan. The synthetic method comprises four steps of A, the synthesis of 5-chloro-2-(di-allyl amino)-benzaldehyde, B, the synthesis of 1-allyl-7-chloro-2,3,4,5-tetrahydro-1H-2,5-epoxy benzo[b]azepine, C, the synthesis of 1-allyl-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzo[b]azepine, and D, the synthesis of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzo[b]azepine. According to the process route, the key intermediate of Tolvaptan is synthesized through four reactions of substitution, cyclization, ring-opening and deprotection, the synthetic steps are less, the operation is easy and convenient, the equipment requirement is low, the yield in each step is relatively high, column chromatography separation is not needed in the four reactions, and the synthetic method has the advantages that the technology is simple, the industrial scale production is facilitated, and the cost is low.

Description

technical field [0001] The invention belongs to the field of organic synthesis, in particular to a method for synthesizing the key intermediate of tolvaptan, 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine . Background technique [0002] 7-Chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine is a key intermediate for the preparation of tolvaptan. Tolvaptan is a high-efficiency and low-toxicity arginine vasopressin (AVP) antagonist developed by Japan Otsuka Pharmaceutical Company. Vaptan is the only oral selective vasopressin antagonist approved for the treatment of hyponatremia. Its English trade name is Samsa (Tolvaptan), and its chemical name is N-[4-[(7-chloro-2,3,4,5-tetrahydro-1-benzoazepine-1-yl)carbonyl]- 3-methylphenyl]-2-methylbenzamide, English chemical name is N-(4-(7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-benzo[b] azepine-1-carbonyl)-3-methylphenyl)-2-methylbenzamide. The molecular structural formula is as follows: [0003] [0004] Tolvaptan can reduce t...

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
Inventor 柏旭张跃伟朱岳
Owner CHANGCHUN DISCOVERY SCI
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