Preparation method of chiral aryl cyclopropylamine derivative

A technology for arylcyclopropylamine and derivatives, which is applied in the field of preparation of chiral arylcyclopropylamine derivatives, can solve the problems of cumbersome operation and low conversion rate of raw materials, and achieve high reaction yield, high yield, and shortened reaction route effect

Inactive Publication Date: 2018-05-29
NANTONG CHANGYOO PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For the preparation of chiral arylcyclopropylamine derivatives, the existing technical route has disadvantages such as relatively cumbersome operation and low conversion rate of raw materials

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] a. Preparation of intermediate IN-1: add 1000mL dichloromethane and 200g (1.5mol, 1.5eq) aluminum trichloride to the reaction flask, stir, then add dropwise 136g (1.2mol, 1.2 eq) Chloroacetyl chloride; after dropping, stir, heat up to reflux, add dropwise 114g (1.0mol, 1eq) 1,2-difluorobenzene; after dropping, reflux reaction; then cool down to 25°C, pump in 500g of ice water, Stir, stand still for liquid separation, extract the aqueous layer with dichloromethane (500mL×2), combine the organic phases, wash with water (800mL×2), saturated sodium bicarbonate solution (800mL) and saturated sodium chloride solution (800mL), Dry over anhydrous sodium sulfate and concentrate under reduced pressure to obtain 175.3 g of the product. Molar yield: 92%;

[0033] b. Preparation of intermediate IN-2: put 200mL toluene and 12.7g S-CBS-4 (0.05mol, 0.05eq) into the reaction bottle, stir; under nitrogen protection, put 9.5g trimethyl borate (0.09mol, 0.1eq), heat up to about 50°C, kee...

Embodiment 2

[0041] a. Preparation of intermediate IN-1: Add 500mL of dichloromethane, 90.1g (0.9mol, 1.8eq) of zinc chloride, 2g of cuprous iodide into the reaction flask, stir, and then add dropwise at 0-5°C 84.8g (0.75mol, 1.5eq) chloroacetyl chloride; after dropping, stir, heat up to reflux, add dropwise 65g (0.5mol, 1eq) o-chlorofluorobenzene; 300g of ice water, stirred, left to stand for liquid separation, the aqueous layer was extracted with dichloromethane (300mL×2), the organic phase was combined, water (300mL×2), saturated sodium bicarbonate solution (200mL) and saturated sodium chloride solution ( 200mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 93.2g of the product. Molar yield: 90%;

[0042] b. Preparation of intermediate IN-2: put 200mL tetrahydrofuran and 5.1g S-CBS-4 (0.02mol, 0.05eq) into the reaction bottle, stir; under nitrogen protection, put 5.2g trimethyl borate (0.05mol, 0.1eq), heat up to about 50°C, keep warm for reac...

Embodiment 3

[0050] a. Preparation of intermediate IN-1: Add 1000mL dichloromethane and 240g (1.8mol, 1.8eq) aluminum trichloride to the reaction flask, stir, then add 170g (1.5mol, 1.5 eq) Chloroacetyl chloride; after dropping, stir, heat up to reflux, add 96g (1.0mol, 1eq) of fluorobenzene dropwise; solution, the aqueous layer was extracted with dichloromethane (500mL×2), the organic phases were combined, washed with water (800mL×2), saturated sodium bicarbonate solution (800mL) and saturated sodium chloride solution (800mL), dried over anhydrous sodium sulfate , and concentrated under reduced pressure to obtain 160.5 g of product. Molar yield: 93%;

[0051] b. Preparation of intermediate IN-2: put 300mL toluene and 12.7g S-CBS-4 (0.05mol, 0.05eq) into the reaction bottle, stir; under nitrogen protection, put 9.6g trimethyl borate (0.09mol, 0.1 eq), heat up to about 50°C, keep warm for reaction, then add 186mL 10mol / L borane dimethyl sulfide (1.86mol, 2.0eq) dropwise; after dropping, r...

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Abstract

The invention provides a preparation method of a chiral aryl cyclopropylamine derivative. The chiral aryl cyclopropylamine derivative is prepared by using benzene halide or benzene polyhalide as the initial raw material and subjecting the benzene halide or benzene polyhalide to Friedel-Crafts reaction, asymmetric reduction reaction, cyclization reaction, acylation reaction, hydrolysis reaction andCurtius rearrangement reaction, wherein the benzene halide or benzene polyhalide is preferably o-difluorobenzene, 2-chlorofluorobenzene or fluorobenzene. The preparation method has the advantages that carbonyl asymmetric reduction and a acylation reagent are used to build a cyclopropyl ester structure, and the use of chiral auxiliaries is avoided; the reaction route of the method is shortened ascompared with a reaction route in the prior art, and reaction yield is increased; acyl azide rearrangement is used to prepare primary amine, and the method is simple to operate, high in yield and suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to the field of pharmaceutical production, in particular to a preparation method of chiral arylcyclopropylamine derivatives. Background technique [0002] The chiral arylcyclopropylamine compound is an important intermediate in the process of synthesizing ticagrelor, and its molecular structure contains two chiral centers. Ticagrelor (Ticagrelor) is a new type of selective small molecule anticoagulant drug developed by AstraZeneca, which was approved by the US FDA in July 2011. Ticagrelor can reversibly act on the purinergic 2 receptor subtype P2Y12 on vascular smooth muscle cells, does not require metabolic activation, and has a significant inhibitory effect on platelet aggregation induced by adenosine diphosphate (ADP), and can play a role after oral administration. The effect is rapid, and it can effectively improve the symptoms of patients with acute coronary heart disease. Unlike thienopyridines, ticagrelor is a reversible ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C45/46C07C49/80C07C29/143C07C33/46C07C67/00C07C67/30C07C69/753C07C51/09C07C61/40C07C247/22C07C209/56C07C211/40C07D301/26C07D303/08
CPCC07C29/143C07C45/46C07C51/09C07C67/00C07C67/30C07C209/56C07C247/22C07D301/26C07D303/08C07C49/80C07C33/46C07C69/753C07C61/40C07C211/40
Inventor 李泽标肖建喜林燕峰王莹吴洪当陈丹
Owner NANTONG CHANGYOO PHARMATECH CO LTD
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