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

Method for preparing Blonanserin intermediate

A technology of blonanserin and intermediates, applied in the field of medicinal chemistry, can solve problems such as difficulty in separation, decreased yield, bumping, etc., and achieve the effects of stable yield, shortened reaction time, and reduced usage

Inactive Publication Date: 2011-04-27
SHENZHEN WANHE PHARMA
View PDF4 Cites 13 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In the process of realizing the present invention, the inventor finds that the prior art has at least the following problems: we use HPLC to follow up when we study by the method of JP4099758A, and find that the reaction process goes through 3-(4-fluorophenyl)-3 oxopropionamide intermediate, which is then converted to the product 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctanopyridin-2(1H)-one, but the product is complex when the reaction is terminated , is difficult to separate, the yield is extremely low, and the product quality is also difficult to control
According to the synthesis of blonanserin [1] [Wang Junfang et al., Chinese Journal of Pharmaceutical Industry, 2009, 40(4), 247] and CN101747273, it was found that polyphosphoric acid was used to hydrolyze 3-(4-fluorophenyl)- In the process of converting 3-oxopropionitrile into 3-(4-fluorophenyl)-3-oxopropionamide, the polyphosphoric acid is very viscous, the dosage is large, the stirring is difficult, the yield decreases during amplification and the environmental protection treatment is difficult
In addition, in the condensation process of 3-(4-fluorophenyl)-3-oxopropanamide and cyclooctyl ketone, a small amount of feeding effect is good, but when it is enlarged, bumping is easy to occur, and the yield decreases

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 Blonanserin intermediate
  • Method for preparing Blonanserin intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] (1) Synthesis of BNSL-A【3-(4-fluorophenyl)-3-oxopropionitrile】

[0028] Add 480 ml of toluene to a 1000 ml four-necked flask equipped with a mechanical stirrer, a thermometer, a reflux condenser, a drying tube, and a dropping funnel. Add 40.8 g (1.02 mol) of sodium hydride (60% content) and 39.6 g (0.97 mol) of acetonitrile into the reaction flask under stirring. A toluene solution of methyl p-fluorobenzoate [75.0 g (0.49 mol) methyl p-fluorobenzoate dissolved in 72 ml of toluene] was added dropwise. After the dropwise addition was completed, 39.6 g (0.97 mol) of acetonitrile was added after heating to 90° C. for 2 hours, and then reacted at 90° C. for another 5 hours. TLC (Thin Layer Chromatography, Thin Layer Chromatography) monitored the completion of the reaction, cooled, and suction filtered to obtain a yellow sodium salt. Sodium salt was dissolved in 840 ml of water, and a small amount of toluene in the upper layer was removed. The solution was orange-red and tr...

Embodiment 2

[0044] (1) Synthesis of BNSL-A【3-(4-fluorophenyl)-3-oxopropionitrile】

[0045] Add 900 milliliters of toluene to a 2000 milliliter four-necked flask equipped with a mechanical stirrer, a thermometer, a reflux condenser, a drying tube, and a dropping funnel. Add 87.7 g (2.19 mol) of sodium hydride (60% content) and 82.9 g (2.02 mol) of acetonitrile into the reaction flask under stirring. A toluene solution of methyl p-fluorobenzoate [155.6 g (1.01 mol) methyl p-fluorobenzoate dissolved in 150 ml of toluene] was added dropwise. After the dropwise addition was completed, 82.9 g (2.02 mol) of acetonitrile was added after heating to 90° C. for 2 hours, and then reacted at 90° C. for another 5 hours. The completion of the reaction was monitored by TLC, cooled, and suction filtered to obtain a yellow sodium salt. Sodium salt was dissolved in 1680 ml of water, a small amount of toluene in the upper layer was removed, 695 ml of 3M hydrochloric acid was added dropwise with stirring, a...

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 method for preparing a Blonanserin intermediate. The method comprises the following two steps in sequence: (a) carrying out catalytic hydrolysis on 3-(4-fluorophenyl)-3-oxopropanenitrile by utilizing sulfuric acids so as to generate 3-(4-fluorophenyl)-3-oxopropionamide; and (b) carrying out catalytic reaction on the 3-(4-fluorophenyl)-3-oxopropionamide and cyclooctanone by utilizing anhydrous p-toluenesulfonic acids so as to generate 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b] pyridine-2(1H)-ketone. According to the method provided by the invention, the yield coefficient of the prepared 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b] pyridine-2 (1H)-ketone is increased from 63.5 percent to 75 percent.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to blonanserin intermediate 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctanopyridine-2(1H)- Method for the preparation of ketones. Background technique [0002] The blonanserin intermediate refers to 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctanopyridin-2(1H)-one, which is a new SARS It is an important intermediate in the synthetic process of type antipsychotic drug blonanserin (blonanserin), and its structure is shown in the following formula: [0003] [0004] JP4099758A and EP0385237 have reported the synthetic method of formula BNSL-C compound, and this method is raw material with 3-(4-fluorophenyl)-3 oxopropionitrile and cyclooctyl ketone, reacts in polyphosphoric acid to obtain 4-(4 -Fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctanopyridin-2(1H)-one, the reaction is carried out at 120°C, as shown in the following reaction formula: [0005] [0006] A...

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): C07D221/04
Inventor 王仲荪
Owner SHENZHEN WANHE PHARMA
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