A kind of resolution method of (r)-1-((2-chlorophenyl)-(phenyl)-methyl)-piperazine

A chlorophenyl and phenyl technology, applied in the field of chiral drug impurity preparation, can solve the problems of unavailability and poor splitting effect, and achieve the effects of short reaction time, low environmental pollution and high yield

Active Publication Date: 2019-01-08
ZHEJIANG YONGNING PHARMA
View PDF2 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Since the impurity (R)-1-((2-chlorophenyl)-(phenyl)-methyl)-piperazine cannot be purchased in the market, (R)-1- ((2-Chlorophenyl)-(phenyl)-methyl)-piperazine is of great significance for the quality improvement of levocetirizine hydrochloride
At present, there is no report on the resolution of racemic 1-((2-chlorophenyl)-(phenyl)-methyl)-piperazine using (S)-(-)-alpha-methylbenzyl isocyanate , and we also found that the resolution is very poor when using common resolving agents (such as L-(+)-tartaric acid, L-aspartic acid, etc.)

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
  • A kind of resolution method of (r)-1-((2-chlorophenyl)-(phenyl)-methyl)-piperazine
  • A kind of resolution method of (r)-1-((2-chlorophenyl)-(phenyl)-methyl)-piperazine
  • A kind of resolution method of (r)-1-((2-chlorophenyl)-(phenyl)-methyl)-piperazine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Racemic 1-((2-chlorophenyl)-(phenyl)-methyl)-piperazine (0.1mol, 28.6g) and resolving agent (S)-(-)-alpha-methylbenzyl isocyanate (0.15mol, 22.0g) was dissolved in 558ml of acetone, and reacted for 2h at 25°C to produce (R)-1-((2-chlorophenyl)-(phenyl)-methyl)-piperazine-(S)-( Precipitation of -)-alpha-methylbenzyl isocyanate, filtered and washed with acetone, yielded (R)-1-((2-chlorophenyl)-(phenyl)-methyl)-piperazine-(S) -(-)-alpha-methylbenzyl isocyanate 19.9g, add water to dissolve, adjust pH=8.0 with saturated sodium carbonate solution, add ethyl acetate to extract, dry, filter, concentrate to obtain (R)-1-((2- Chlorophenyl)-(phenyl)-methyl)-piperazine 12.9 g. The total yield is 45%, melting point: 91-93°C, specific rotation [α] D It is -21.8° (methanol), the purity is 99.85%, and the ee value is 99.5%.

[0019] 1 H-NMR (CDCl 3 ):7.37-7.18(m,9H),4.18(s,1H),2.88(q,J=6Hz,4H),2.34(s,4H),2.19(s,1H).

[0020] 13 C-NMR (CDCl 3 ):142.1,141.2,132.4,129.1,129.0,128....

Embodiment 2

[0030] Racemic 1-((2-chlorophenyl)-(phenyl)-methyl)-piperazine (0.1mol, 28.6g) and resolving agent (S)-(-)-alpha-methylbenzyl isocyanate (0.1mol, 14.7g) was dissolved in 558ml of acetone, and reacted for 2h at 25°C to produce (R)-1-((2-chlorophenyl)-(phenyl)-methyl)-piperazine-(S)-( Precipitation of -)-alpha-methylbenzyl isocyanate, filtered and washed with acetone, yielded (R)-1-((2-chlorophenyl)-(phenyl)-methyl)-piperazine-(S) -(-)-alpha-methylbenzyl isocyanate 17.8g, add water to dissolve, adjust pH=8.0 with saturated sodium carbonate solution, add ethyl acetate to extract, dry, filter, concentrate to obtain (R)-1-((2- Chlorophenyl)-(phenyl)-methyl)-piperazine 11.5 g. The total yield is 40.2%, melting point: 91-93°C, specific rotation [α] D It is -21.5° (methanol), the purity is 99.53%, and the ee value is 99.1%.

Embodiment 3

[0032] Racemic 1-((2-chlorophenyl)-(phenyl)-methyl)-piperazine (0.1mol, 28.6g) and resolving agent (S)-(-)-alpha-methylbenzyl isocyanate (0.2mol, 29.4g) was dissolved in 558ml of acetone, and reacted for 2h at 25°C to produce (R)-1-((2-chlorophenyl)-(phenyl)-methyl)-piperazine-(S)-( Precipitation of -)-alpha-methylbenzyl isocyanate, filtered and washed with acetone, yielded (R)-1-((2-chlorophenyl)-(phenyl)-methyl)-piperazine-(S) -(-)-alpha-methylbenzyl isocyanate 20.8g, add water to dissolve, adjust pH=8.0 with saturated sodium carbonate solution, add ethyl acetate to extract, dry, filter, concentrate to obtain (R)-1-((2- Chlorophenyl)-(phenyl)-methyl)-piperazine 13.6 g. The total yield is 47.5%, melting point: 91-93°C, specific rotation [α] D It is -21.5° (methanol), the purity is 99.50%, and the ee value is 99.0%.

[0033] By comparing Example 1 with Example 2 and Example 3, we found that racemic 1-((2-chlorophenyl)-(phenyl)-methyl)-piperazine and (S)-(-)-alpha -The reso...

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

PropertyMeasurementUnit
melting pointaaaaaaaaaa
specific rotationaaaaaaaaaa
specific rotationaaaaaaaaaa
Login to view more

Abstract

The invention belongs to the technical field of chiral drug impurity preparation, and mainly relates to a resolution method of a chiral drug levocetirizine hydrochloride impurity (R)-1-((2-chlorphenyl)-(phenyl)-methyl)-piperazine. The resolution method comprises the steps that racemic 1-((2-chlorphenyl)-(phenyl)-methyl)-piperazine and a resolution agent (S)-(-)-alpha-methylbenzyl isocyanate are dissolved into an organic solvent and react to generate precipitate of (R)-1-((2-chlorphenyl)-(phenyl)-methyl)-piperazine-(S)-(-)-alpha-methylbenzyl isocyanate salt, the precipitate is filtered and washed with acetone to obtain the (R)-1-((2-chlorphenyl)-(phenyl)-methyl)-piperazine-(S)-(-)-alpha-methylbenzyl isocyanate salt, the (R)-1-((2-chlorphenyl)-(phenyl)-methyl)-piperazine-(S)-(-)-alpha-methylbenzyl isocyanate salt is dissolved by adding water, the pH is regulated with a saturated sodium carbonate solution to be 8.0, extraction is conducted by adding ethyl acetate, and drying, filtering and concentrating are conducted to obtain (R)-1-((2-chlorphenyl)-(phenyl)-methyl)-piperazine. The resolution method has the advantages that the product purity is high, the reaction time is short, the reaction temperature is low, and the yield is high; in addition, the solvents are acetone and ethyl acetate and are easy to obtain, free of toxicity, easy to recycle and little in environmental pollution.

Description

technical field [0001] The invention belongs to the technical field of preparation of chiral drug impurities, and mainly relates to the preparation of chiral drug levocetirizine hydrochloride impurity (R)-1-((2-chlorophenyl)-(phenyl)-methyl)-piperazine Split method. Background technique [0002] The chiral antihistamine levocetirizine hydrochloride is the (R)-configuration isomer of cetirizine, which has good curative effect in the treatment of histamine-induced allergic rhinitis, allergic erythema, etc., and No central nervous system side effects such as sedation and drowsiness. Therefore, improving the quality of levocetirizine hydrochloride through impurity research has far-reaching significance no matter from the aspect of market prospect or from improving the safety and effectiveness of clinical medication of patients. [0003] (R)-1-((2-Chlorophenyl)-(phenyl)-methyl)-piperazine is a positioning impurity for preparing levocetirizine hydrochloride liquid-phase importan...

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 Patents(China)
IPC IPC(8): C07D295/073
CPCC07B57/00C07B2200/07C07D295/073
Inventor 叶天健陈鑫陈识峰
Owner ZHEJIANG YONGNING PHARMA
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

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

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap