Supercharge Your Innovation With Domain-Expert AI Agents!

Preparation method of cariprazine intermediate

An intermediate and reaction technology, applied in the field of preparation of cariprazine intermediates, can solve the problems of incomplete reaction, unstable temperature, process impurities and the like, and achieve the effects of few steps, easy availability of raw materials and high purity

Pending Publication Date: 2022-05-27
泰州精英化成医药科技有限公司
View PDF0 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, the classic synthesis process has the following problems: it uses p-toluenesulfonyl chloride to produce genotoxic impurities (p-toluenesulfonate); the intermediate SMO1 needs to be docked with piperazine at a temperature above 80 ° C, otherwise the reaction is incomplete, and SMO1 has a high impact on the temperature. It is unstable, and begins to degrade at 60°C, so that the yield of docking of SMO1 and piperazine is only about 75-80% all the time, and the reaction time needs about 10-12h; there are process impurities; therefore, there is an urgent need in this field for a solution to the above New preparation method of cariprazine of technical problem

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 cariprazine intermediate
  • Preparation method of cariprazine intermediate
  • Preparation method of cariprazine intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023]

[0024] Trans-(N-Boc-4-aminocyclohexyl)acetic acid (25.7g, 0.1mol) was added to the reaction flask, dissolved in 300mL of tetrahydrofuran, the temperature was lowered to 0°C, and 1.0M / L borane tetrahydrofuran solution was added dropwise 150 mL (0.15 mol), and reacted at this temperature for 3 hours. Water was added to quench, MTBE was added, washed twice with saturated aqueous sodium bicarbonate solution, and the organic phase was concentrated to no flow to obtain trans-(N-Boc-4-aminocyclohexyl)ethanol 22.5g, HPLC 96%, yield 92%.

Embodiment 2

[0026]

[0027] To the reaction flask was added 2,3-dichloroaniline 1 (10g, 61.72mmol, 1eq.) and bis(2-chloroethyl)ethylamine 1 (8.7g, 1eq, 61.72mmol) The stirring solution was added p-toluene A solution of sulfonic acid (1.17 g, 0.1 eq, 6.17 mmol) and tetrabutylammonium bromide (1.5 g, 0.1 eq, 6.17 mmol) in xylene (150 mL). The resulting reaction mixture was heated at 130-135°C for 48 hours. After the reaction is complete. The reaction mixture was cooled to room temperature and the pH of the solution was adjusted to pH 6-7 with aqueous ammonia. The organic compound was extracted with ethyl acetate, dried over sodium sulfate, and dried under reduced pressure. After concentration, 12.5 g of 1-(2,3-dichlorophenyl)piperazine was obtained, HPLC 91.6%, yield 88%. Go to the next step without purification.

Embodiment 3

[0029]

[0030] Under nitrogen protection, 24.3g (0.1mol) of trans-(N-Boc-4-aminocyclohexyl)ethanol (Int.1), 1-(2,3-dichlorophenyl)piperazine were added to the reaction flask. (Int.2) 25.4 g (0.11 mol), 31.5 (0.12 mol) of triphenylphosphine and 240 mL of dried dichloromethane, under nitrogen atmosphere, ice-bath temperature-controlled 0-5 ℃ diethyl azodicarboxylate was added dropwise 210 mL of 22.6 g (0.123 mol) of dichloromethane was dripped and kept the temperature stirring for 3 hours. HPLC monitored the reaction and added saturated aqueous sodium bicarbonate solution. The organic phase was concentrated, filtered under reduced pressure, and the filter cake was washed with 20 mL of dichloromethane. Once, a large amount of triphenylphosphine was added to the filter cake, zinc chloride was added to the filtrate, filtered, the filtrate was concentrated, and n-heptane was added to make a slurry to obtain trans-N-tert-butoxycarbonyl-4-{2-[4-(2,3 -Dichlorophenyl)-piperazin-1-yl...

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 a cariprazine intermediate, and belongs to the technical field of organic synthesis. The preparation method comprises the following steps: reducing a raw material trans-(N-Boc-4-aminocyclohexyl) acetic acid to obtain trans-(N-Boc-4-aminocyclohexyl) ethanol (Int.1), carrying out intramolecular cyclization on raw materials 2, 3-dichloroaniline and bis (2-chloroethyl) ethylamine under a phase transfer catalysis effect to obtain 1-(2, 3-dichlorophenyl) piperazine (Int.2), carrying out a Mitsunobu reaction on Int.1 and Int.2, and carrying out a reaction to obtain the 1-(2, 3-dichlorophenyl) piperazine (Int.2). And purifying to remove triphenylphosphine oxide to obtain the cariprazine intermediate (the chemical formula is Int.3). The method has the advantages of easily available raw materials, simple steps, mild and continuous reaction conditions, relatively low requirements on equipment, and product purity of more than 99.0%.

Description

technical field [0001] The invention relates to a preparation method of a cariprazine intermediate, and belongs to the technical field of organic synthesis. Background technique [0002] Cariprazine was jointly developed by Gedeon Richter Ltd and Forest Laboratories, and it was reported for the first time that it has a dopamine D3 / D2 partial agonist, and has the characteristics of preferentially binding to D3R and DA partial agonists for the treatment of schizophrenia, Mania, major depressive disorder, its hydrochloride was marketed in the United States as an anti-schizophrenic drug in 2015, the chemical name is trans-1-{4-[2-[4-(2,3-dichlorobenzene yl)-piperazin-1-yl]ethyl]cyclohexyl}-3,3-dimethylurea hydrochloride. [0003] while trans-N-tert-butoxycarbonyl-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}-cyclohexylamine (Int.3) is The important raw material of cariprazine in the previous step, the genotoxic impurities will be completely removed here, so as to further...

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): C07D295/135
CPCC07D295/135Y02P20/55
Inventor 李国伟孙桂淦徐清雨
Owner 泰州精英化成医药科技有限公司
Features
  • R&D
  • Intellectual Property
  • Life Sciences
  • Materials
  • Tech Scout
Why Patsnap Eureka
  • Unparalleled Data Quality
  • Higher Quality Content
  • 60% Fewer Hallucinations
Social media
Patsnap Eureka Blog
Learn More

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

© 2025 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com