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

Preparation method of (1S, 2R)-1-phenyl 2-(phthalimide) methyl-N, N-diethyl-cyclopropanecarboxamide

A technology of phthalimide potassium salt and diisopropylethylamine, applied in the field of pharmaceutical synthesis, can solve the problems of many impurities, poor large-scale production efficiency, difficult solvent recovery, etc., and achieves high yield, few impurities, and easy operation easy effect

Active Publication Date: 2014-04-02
SHANGHAI SHYNDEC PHARMA CO LTD
View PDF6 Cites 2 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In addition, the document J.Med.Chem.1995,38,2964-2968 reported that (1S,2R)-1-phenyl-3-oxa[3.1.0]hexane-2-one in dimethyl sulfoxide React with potassium phthalimide, then react with diethylamine to obtain compound (I), but the yield of this method is only 57%, and there are many impurities. After purification by crystallization, the yield is only 25%-30%, and the solvent is very poor. Difficult to recycle, and the efficiency of large-scale production is very poor

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 (1S, 2R)-1-phenyl 2-(phthalimide) methyl-N, N-diethyl-cyclopropanecarboxamide
  • Preparation method of (1S, 2R)-1-phenyl 2-(phthalimide) methyl-N, N-diethyl-cyclopropanecarboxamide
  • Preparation method of (1S, 2R)-1-phenyl 2-(phthalimide) methyl-N, N-diethyl-cyclopropanecarboxamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Embodiment 1 prepares chloromethylene dimethyl ammonium chloride

[0045] Add 18.8mL (242mmol) of N,N‐N,N‐dimethylformamide and 50mL of dichloromethane into a 250mL three-neck flask, stir well and cool to 0°C with brine. Slowly add 17.62mL (242mmol) of thionyl chloride dropwise to the reaction solution under the condition of nitrogen protection, so that the reaction temperature is not higher than 10°C. After the dropwise addition, the temperature is raised to 45°C and the reaction is continued for 2 hours with stirring to complete the reaction. The excess solvent was evaporated under reduced pressure (the temperature of the water bath was not higher than 50° C.), and dichloromethane (50×2 mL) was strip-evaporated twice to remove the generated acid gas. Distilled off to obtain chloromethylene dimethyl ammonium chloride.

Embodiment 2

[0046] Example 2 Preparation of (1S, 2R)-1-phenyl-2-chloromethylcyclopropane-N, N-diethylformamide (III)

[0047] Add the chloromethylene dimethyl ammonium chloride of Example 1 and 100 mL of dichloromethane into a 250 mL three-necked flask, stir until completely dissolved and cool to 0°C, then put (1S,2R)-1-phenyl- 2‐Hydroxymethylcyclopropane‐N,N‐Diethylformamide (II) 30g (121mmol) was dissolved in 50mL of dichloromethane and slowly added dropwise to the reaction solution, the reaction temperature during the dropwise addition process was not higher than 5°C, continue the reaction for 1 hour after the dropwise addition (the reaction temperature is not higher than 25°C). After the reaction, the solvent was evaporated to obtain (1S,2R)-1-phenyl-2-chloromethylcyclopropane-N,N-diethylformamide 31.5g, yield 98%; 1 H NMR(CDCl3):δ0.55(3H,t,J=7.1Hz),1.12(3H,t,J=7.4Hz),1.18(1H,dd,J=9.2Hz,J=5.2Hz),1.61 –1.66(1H,m),2.16–2.21(1H,m),3.04–3.10(1H,m),3.12–3.19(1H,m),3.50–3.70(4H,m),7.20–...

Embodiment 3

[0048] Example 3 Preparation of (1S, 2R)-1-phenyl-2-(phthalimide) methylcyclopropane-N, N-diethylformamide (I)

[0049] In a 500mL round bottom flask, add 31.5g (119mmol) of compound (III) of Example 2, 12.0g (119mmol) of triethylamine and 200mL of toluene, stir at room temperature and dissolve it completely, then add phthalimide Potassium salt 23.2g (125mmol), heat the reaction to 90°C and react for 3 hours to complete the reaction. Cool to room temperature, wash once with 5% aqueous sodium hydroxide solution (126g), set aside the aqueous phase, wash the organic phase once with 1N dilute hydrochloric acid (150mL), wash twice with saturated brine (150mL x2), and set aside the organic phase. Use 100 mL of toluene to extract the obtained four water phases once respectively, combine the toluene layers and dry, filter, and evaporate the solvent to obtain (1S,2R)-1-phenyl-2-(phthalimide)methylcyclopropane- N, N-diethylformamide 40.4g, yield 90.3%. The spectrogram data is 1 H N...

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 provides a preparation method of (1S, 2R)-1-phenyl 2-(phthalimide) methyl-N, N-diethyl-cyclopropanecarboxamide. The preparation method comprises the following steps: step 1, reacting a compound (II) and an activating reagent so as to generate a compound (IX); and step 2, carrying out substitution reaction on the compound (IX) and tetrahydrophthalimide sylvite so as to obtain a compound (I). The equation is shown in the specification, wherein the LG group in the compound (IX) is selected from -Cl, -OSO2Me, -OCOCF3, -OSO2C6H4Me, and -OSO2C6H4NO2; correspondingly, the activating agent is selected from (Chloromethylene) dimethyliminium chloride, methylsufonyl chloride, trifluoroacetic anhydride, paratoluensulfonyl chloride, and nitrobenzenesulfonyl chloride. In the method provided by the invention, raw materials are available and are low in price; the reaction condition is moderate; the operation is simple; impurities are few; the yield is high; the preparation method of (1S, 2R)-1-phenyl 2-(phthalimide) methyl-N, N-diethyl-cyclopropanecarboxamide is a novel environmental-friendly synthesizing approach which is suitable for industrially producing levomilnacipran.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to the key intermediate (1S,2R)-1-phenyl-2-(phthalimide)methyl-N,N-diethyl-cyclo Preparation of propanamide. Background technique [0002] Levomilnacipran (X), known as levomilnacipran in English, is a new type of SNR class I drug, a serotonin‐norepinephrine reuptake inhibitor, used to treat patients with severe depression, (1S,2R)‐1‐ Phenyl‐2‐(phthalimide)methyl‐N,N‐diethyl‐cyclopropylcarboxamide (I) is a key intermediate for the preparation of L-milnacipran. [0003] [0004] Patent WO2010086394 reports (1S,2R)‐1‐phenyl‐2‐hydroxymethylcyclopropane‐N,N‐diethylformamide (II) reacts with thionyl chloride to obtain (III), and then reacts with phthaloyl The compound (I) is obtained by the substitution reaction of the amine potassium salt. Because the acidity of the reaction system is strong in this method, under high-temperature reaction conditions, the substrate (II) is prone to tak...

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): C07D209/49
CPCC07D209/49
Inventor 侯建郑少军戈耘郭林华
Owner SHANGHAI SHYNDEC PHARMA CO LTD
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