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

Method for preparing important Suvorexant intermediate

A formula and compound technology, which is applied in the preparation of important intermediates, {2-[--amino]ethyl}-carbamic acid tert-butyl ester, can solve the cumbersome post-processing, low yield and difficult quality assurance and other problems, to achieve the effect of simple post-treatment operation, high purity and yield, and less reaction by-products

Inactive Publication Date: 2017-05-10
TIANJIN INSTITUTE OF PHARMA RESEARCH
View PDF5 Cites 3 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The disadvantages of this route are: (1) methyl ketene, a highly toxic drug, is used in the route, which is highly irritating to the eyes, skin and upper respiratory tract, and is difficult to purchase and transport, so it is not suitable for industrial production; (2) three-step reaction one The pot method is used, the intermediate is not separated, it is not conducive to process control, and the quality is difficult to guarantee
[0009] The disadvantages of this route are: (1) the highly poisonous methyl ketene is used in the route, which is not suitable for industrial production; (2) the post-treatment is relatively cumbersome, requiring multiple extraction operations, and the yield is low, only 47.7%

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 important Suvorexant intermediate
  • Method for preparing important Suvorexant intermediate
  • Method for preparing important Suvorexant intermediate

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0030] Preparation of starting material compound (1)

[0031] A: Preparation of 2-mercapto-5-chlorobenzoxazole

[0032] Add 2-amino-4-chlorophenol (100g, 0.69mol), potassium ethyl xanthate (13.3g, 0.83mol) and 1500ml of absolute ethanol into a 3L four-necked reaction flask, and heat to reflux for 8 hours. Ethanol was distilled off under reduced pressure, and the residue was dissolved in 1300ml of water, acidified with 100ml of concentrated hydrochloric acid and filtered to obtain 122.6g of white solid with a yield of 94.9%. 1 H NMR (400MHz, d6-DMSO): δ13.998 (s, 1H, heavy water exchange disappears), 7.513 (d, 1H, J=8.8Hz), 7.302-7.277 (m, 2H).

[0033] B: Preparation of {2-[(5-chlorobenzoxazol-2 base)-amino]ethyl}-tert-butyl carbamate (compound of formula 1)

[0034] Add 2-mercapto-5-chlorobenzoxazole (100g, 0.54mol) and 1200ml of dichloromethane into a 3L four-neck reaction flask, stir, add oxalyl chloride (102.6g, 0.81mol), add dropwise 395ml of DMF, After reacting at roo...

Embodiment 1

[0036] Preparation of {2-[(5-chlorobenzoxazol-2yl)-(3-keto-butyl)-amino]ethyl}-carbamic acid tert-butyl ester (compound 3)

[0037] {2-[(5-Chlorobenzoxazol-2 base)-amino]ethyl}-carbamic acid tert-butyl ester (10g, 0.032mol), 4-chloro-2-butanone (6.8g, 0.064 mol), DBU (19.5g, 0.128mol) and 60ml of acetonitrile were added into a 250ml four-necked reaction flask, and reacted at 20-30°C for 9 hours. Add 120ml of water, stir for 1 hour, and filter to obtain 12g of white solid with a yield of 98%. 1 HNMR (400MHz, CDCl 3 ): δ7.272(d, 1H, J=2Hz), 7.114(d, 1H, J=8.4Hz), 6.947(dd, 1H, J=8.4, 2Hz), 4.864(s, 1H), 3.754(t ,2H,J=2.8Hz),3.653(t,2H,J=6.4Hz),3.398(t,2H,J=5.6Hz),2.908(t,2H,J=6.4Hz),2.165(s,3H ), 1.347(s,9H).

Embodiment 2

[0039] Preparation of {2-[(5-chlorobenzoxazol-2yl)-(3-keto-butyl)-amino]ethyl}-carbamic acid tert-butyl ester (compound 3)

[0040] {2-[(5-Chlorobenzoxazol-2 base)-amino]ethyl}-carbamic acid tert-butyl ester (10g, 0.032mol), 4-(p-toluenesulfonyloxy)-2- Butanone (15.5g, 0.064mol), DBU (19.5g, 0.128mol) and THF 60ml were added to a 250ml four-necked reaction flask, and reacted at 20-30°C for 9 hours. Add 120ml of water, stir for 1 hour, and filter to obtain 11.7g of white solid, yield 95.5%.

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 belongs to the technical field of medicines and relates to a method for preparing an important intermediate {2-[(5-chlorobenzoxazole-2-yl)-(3-one-butyl)-amino]ethyl}-tert-butyl carbamate. A highly toxic product methyl vinyl ketone is substituted by a compound with low toxicity, and due to catalytic reactions of DBU, LDA, NaHMDS, KHMDS and the like, a compound of a formula (3) can be obtained at high yield of 90% or higher. Moreover, the HPLC (high performance liquid chromatography) content of the crude product reaches 99.5% or higher, and the method disclosed by the invention is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine and relates to a preparation method of an important intermediate, in particular to {2-[(5-chlorobenzoxazol-2 base)-(3-keto-butyl)-amino]ethyl The preparation method of}-tert-butyl carbamate. Background technique [0002] Suvorexant is a dual orexin receptor antagonist newly developed by Merk, which can help patients improve sleep by blocking orexin that makes it difficult for people to fall asleep. At present, phase III clinical research has been completed, and the research found that it can reduce the sleep initiation time, improve the sleep quality of patients, have few side effects, and is suitable for long-term treatment. Suvorexant is expected to become the first marketed orexin receptor antagonist for the treatment of insomnia. Its structural formula is as follows: [0003] [0004] {2-[(5-Chlorobenzoxazol-2yl)-(3-keto-butyl)-amino]ethyl}-carbamic acid tert-butyl ester is an important ...

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): C07D263/58
CPCC07D263/58
Inventor 康江鹏潘毅陈蔚苏慕君房思萌陶勇
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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