Method for preparing (1R,2S)-2-(3,4-difluorophenyl) -cyclopropylamine

A technology of difluorophenyl and cyclopropylamine, which is applied in the field of compound preparation, can solve the problems of low reduction stereoselectivity, low cyclopropanation yield, and high environmental protection pressure, and achieves low price, simple steps, and low environmental protection pressure Effect

Inactive Publication Date: 2015-02-11
SHANGHAI SUN SAIL PHARMA SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this method, the products of reduction, cyclization and cyclopropanation are all oily substances, and the stereoselectivity of reduction is relatively low, the ee (enantiomeric excess) value is 87.5%, and the yield of cyclopropanation is relatively high. Low, sodium hypochlorite is used as the reaction reagent in the last step, the pollution is serious, the pressure of environmental protection is relatively high and the measurement is difficult

Method used

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  • Method for preparing (1R,2S)-2-(3,4-difluorophenyl) -cyclopropylamine
  • Method for preparing (1R,2S)-2-(3,4-difluorophenyl) -cyclopropylamine
  • Method for preparing (1R,2S)-2-(3,4-difluorophenyl) -cyclopropylamine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Preparation of 2-chloro-1-(2-bromo-4,5-difluorophenyl)ethanone (compound 3)

[0065]

[0066]Add 3,4-difluorobromobenzene (300g, 1.554mol, compound 2) into a 1L three-necked flask, protect it with argon, add aluminum trichloride (414.5g, 3.109mol), stir mechanically, and heat the oil bath to At 40°C, add chloroacetyl chloride (263.3g, 2.331mol) dropwise. After the drop is complete, stir mechanically at 40°C for 72h. HPLC (reverse-phase high-performance liquid chromatography) monitors the completion of the reaction. Slowly pour the reaction solution into ice water (2L ), stirred, added dichloromethane (1.8L) for extraction, and the organic phase was washed with saturated sodium bicarbonate (1.8L), water (1.8L*2), saturated brine (1.8L), and anhydrous sulfuric acid Sodium-dried and concentrated to obtain 418.6g of oil, which was distilled under reduced pressure (200Pa, external temperature 150°C) to obtain 339.3g of colorless oil (compound 3), yield: 81.0%, HPLC: Purit...

Embodiment 2

[0070] Preparation of 2-chloro-1-S-(2-bromo-4,5-difluorophenyl)ethanol (compound 4)

[0071]

[0072] Dissolve S-diphenylprolinol (4.18g, 0.0165mol) in toluene (180mL), add trimethyl borate (2.63mL, 0.023mol), stir at 20-30°C for 90min, add boron dropwise at 40°C Alkane dimethyl sulfide (20.1g, 0.264mol), temperature control 35 ~ 45 ℃, dropwise, stirred at 40 ℃ for 60min, then dropwise added 2-chloro-1-(2-bromo-4,5-difluorobenzene Base) ethyl ketone (89g, 0.33mol, compound 3 obtained in Example 1) in toluene (225mL) solution, temperature control 35 ~ 45 ° C, dropwise, stirred at 40 ° C for 60 min. TCL (thin-layer chromatography) monitoring (ethyl acetate:petroleum ether=1:20), after the reaction is complete, cool in an ice bath to 0-5°C, add methanol (100mL) dropwise, gas is released, stir for 30min, and spin down at 40°C Remove methanol, then spin off toluene with an oil pump to obtain 99g of oil, add dichloromethane (300mL) to dissolve, wash with 10% acetic acid aqueous ...

Embodiment 3

[0078] Preparation of (2S)-2-(2-bromo-4,5-difluorophenyl)oxirane (compound 5)

[0079]

[0080] Dissolve 2-chloro-1-S-(2-bromo-4,5-difluorophenyl)ethanol (96g, 0.354mol, compound 4 obtained in Example 2) in toluene (300mL), add hydrogen Sodium (21.2g, 0.53mol) in water (200mL) solution, stirred at 40°C for 1h, monitored by TCL (ethyl acetate:petroleum ether=1:10), after the reaction was completed, separated, leaving the toluene layer, water (200mL* 3) Wash and spin off toluene to obtain 74.4g of crude product, add n-heptane to dissolve it, quickly flush the column (1 times the amount of silica gel), dry over anhydrous sodium sulfate, and spin off n-heptane to get 67.2g of white solid (ie Compound 5), yield: 86.6% (calculated based on compound 3), HPLC: Purity=94.1%.

[0081] Compound 5 1 H NMR (CDCl 3 ,400MHz) δ(ppm): 7.38(m,1H);7.07(m,1H);4.06(t,1H);3.18(m,1H);2.60(m,1H).

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Abstract

The invention discloses a method for preparing (1R,2S)-2-(3,4-difluorophenyl)-cyclopropylamine. The method comprises the following steps: carrying out a Fuke acyl reaction on 3,4-difluorobromobenzene (compound 2) which serves as a raw material and chloroacetyl chloride under conditions of lewis acid and certain temperature to obtain a compound 3; carrying out stereoselective reduction to obtain a compound 4; carrying out cyclization, olefination, hydrolyzation and debromination to obtain a compound 8; and preparing amide, and carrying out Hoffmann elimination to obtain a target compound 1. According to the method, the traditional preparation process is improved, the (1R,2S)-2-(3,4-difluorophenyl)-cyclopropylamine can be effectively, simply and conveniently prepared, the total yield is relatively high, the stereoselection is relatively high, and the intermediate in each step is easily purified and stored. The reaction formula in the method is as shown in the specification.

Description

technical field [0001] The present invention relates to a preparation method of compounds, more specifically to a preparation method of (1R,2S)-2-(3,4-difluorophenyl)-cyclopropylamine. Background technique [0002] Ticagrelor (Brilinta) is a new type of small molecule anticoagulant drug developed by AstraZeneca. It was approved by the European Union in December 2010 and approved by the US FDA in July 2011. Clinical trials have confirmed that this drug, unlike thienopyridine anticoagulant drugs clopidogrel and prasugrel, can reversibly act on the adenosine diphosphate (ADP) receptor subtype P2Y12, and has a significant effect on ADP-induced platelet aggregation. Inhibitory effect, and rapid onset of oral administration, can effectively improve the symptoms of patients with acute coronary syndrome (ACS), especially for patients who need coronary artery bypass grafting (CABG). [0003] (1R,2S)-2-(3,4-difluorophenyl)-cyclopropylamine is the key intermediate for the preparation ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C211/40C07C209/58
Inventor 王伟陈义朗王彬彬
Owner SHANGHAI SUN SAIL PHARMA SCI & TECH CO LTD
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