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Preparation method of ticagrelor intermediate

A technology for ticagrelor and intermediates, which is applied in the field of preparation of small molecule anticoagulant ticagrelor intermediates, can solve problems such as danger, environmental unfriendliness, and environmental hazards, so as to improve operational safety and improve Generating efficient, environmentally friendly results

Active Publication Date: 2015-07-01
SHANGYU JINGXIN PHARMA +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] However, this method has insurmountable defects in the key step of controlling chirality. In one step of chiral reduction, a combination of relatively expensive trimethoxyborane and borane dimethyl sulfide is used as a reducing agent to reduce the carbonyl group to a hydroxyl group. Trimethoxyborane is a highly flammable and explosive liquid with a flash point of -7.5°C. It is an extremely dangerous organic reagent, and it is easily hydrolyzed when it meets water, so it has high requirements for experimental operations; borane dimethyl sulfide It is also a flammable, explosive, toxic chemical reagent, especially dimethyl sulfide has a bad smell, which is not friendly to the environment and will cause harm to personnel
[0008] Because of the above defects, this method and its improved method are still harmful to the environment, and are not suitable for the synthesis of industrialized formula II compounds.

Method used

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  • Preparation method of ticagrelor intermediate

Examples

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Embodiment 1

[0053] Embodiment 1: The specific preparation method of formula IV compound (S)-2-chloro-1-(3,4-difluorophenyl)ethanol:

[0054] A solution consisting of N,N-diethylaniline hydrochloride (18.0 g, 97 mmol) and 60 ml of dichloromethane was added dropwise at 0°C to sodium borohydride (7.2 g, 190 mmol) and In the suspension composed of 160 ml of ethylene glycol dimethyl ether, keep the reaction temperature at 20-30 degrees, and keep the temperature for 4 hours after dropping. A solution consisting of S-diphenylprolinol (2.7 g, 10.7 mmol) and 10 mL of dichloromethane was added. 2-Chloro-1-(3,4-difluorophenyl)ethanone (20.4 g, 107 mmol) was dissolved in 60 ml of dichloromethane and dropped into the above reaction system. After dripping, keep warm for 2 hours. 360 ml of 1N HCl was slowly added dropwise, the layers were separated, the water phase was removed, and the oil phase was spin-dried. Add 100 ml of ethyl acetate and wash three times with 1N HCl (100 ml each time). The oily...

Embodiment 2

[0060] Embodiment 2: The specific preparation method of formula IV compound (S)-2-chloro-1-(3,4-difluorophenyl)ethanol:

[0061] A solution consisting of N,N-diethylaniline hydrochloride (29.8 g, 160.5 mmol) and 150 ml of chloroform was added dropwise at 0°C to sodium borohydride (2.1 g, 54 mmol) and ethylene di In the suspension composed of 80 ml of alcohol dimethyl ether, keep the reaction temperature at 20-30 degrees, and keep the temperature for 24 hours after dropping. A solution consisting of S-diphenylprolinol (1.35 g, 5.3 mmol) and 10 mL of dichloromethane was added. 2-Chloro-1-(3,4-difluorophenyl)ethanone (20.4 g, 107 mmol) was dissolved in 60 ml of chloroform and dropped into the above reaction system. After dripping, keep warm for 2 hours. 90 ml of 1N HCl was slowly added dropwise, the layers were separated, and the aqueous phase was removed. The oil phase was washed three times with 1N HCl (100 ml each time), dried with anhydrous sodium sulfate, and spin-dried t...

Embodiment 3

[0063] Embodiment 3: the concrete preparation method of formula IV compound:

[0064] A solution consisting of N,N-diethylaniline hydrochloride (19.8 g, 107 mmol) and 198 ml of dichloromethane was added dropwise at 0°C to sodium borohydride (4.05 g, 107 mmol) and In the suspension composed of 150 ml of ethylene glycol dimethyl ether, keep the reaction temperature at 20-30 degrees, and keep the temperature for 10 hours after dropping. A solution of S-diphenylprolinol (1.35 g, 5.3 mmol) in 6 ml of dichloromethane was added and stirred for an additional hour. 2-Chloro-1-(3,4-difluorophenyl)ethanone (20.4 g, 107 mmol) was dissolved in 60 ml of dichloromethane and dropped into the above reaction system. After dripping, keep warm for 2 hours. 180 ml of 1N HCl was slowly added dropwise, and the aqueous phase was separated and removed. Add 100 ml of ethyl acetate and wash three times with 1N HCl (100 ml each time). The separated oily phase was dried with anhydrous sodium sulfate a...

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Abstract

The inventiondiscloses a preparation method of ticagrelor. The method comprises the following steps: (1) reducing a compound shown in a formula III in the presence of a proton source provided by sodium borohydride or potassium borohydride and diethyl aniline hydrochloride to obtain a compound shown in a formula IV; (2) reacting the compound IV in the presence of alkali to generate a compound VI; (3) hydrolyzing the compound VI without purification to generate a compound VII; (4) reacting the compound VII to generate acyl chloride, reacting the acyl chloride to generate formamide, thus obtaining a compound shown in a formula IX; and (5) carrying out Hofmann rearrangement on the compound IX to obtain a compound shown in a formula II. Regents used in the method are nontoxic, harmless, environmentally friendly and low in price; the used key reagents can be recycled. Therefore, the method is applicable to industrial production.

Description

technical field [0001] The invention relates to a preparation method of a small molecule anticoagulant ticagrelor intermediate, which belongs to the technical field of pharmacy. Background technique [0002] (1R,2S)-2-(3,4-Difluorophenyl)cyclopropylmethylamine, CAS No. 220352-38-5, is an important intermediate of the selective small molecule anticoagulant drug ticagrelor , shown in the following structural formula (compound of formula II): [0003] [0004] Ticagrelor (compound of formula I) is a new type of selective small molecule anticoagulant drug developed by AstraZeneca. The drug can reversibly act on the purine 2 receptor subtype P2Y12 on vascular smooth muscle cells (VSMC). Ticagrelor is not a prodrug, so it does not require metabolic activation. Obvious inhibitory effect, and rapid onset after oral administration, can effectively improve the symptoms of patients with acute coronary heart disease. Unlike thienopyridine drugs (clopidogrel, prasugrel, etc.), tica...

Claims

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Application Information

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IPC IPC(8): C07C211/40C07C209/56C07C233/58C07C231/02C07C61/04C07C27/02C07C33/46C07C29/143
Inventor 黄悦徐苗焕
Owner SHANGYU JINGXIN PHARMA
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