Preparation and purification method of diltiazem chiral isomer impurity

A technology of chiral isomer and diltiazem, applied in the field of medicine, can solve the problems of long time consumption, complicated operation and the like

Inactive Publication Date: 2019-11-05
SHANDONG XINHUA PHARMA CO LTD
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  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although this ancient method can also obtain diastereoisomers, the operation is cumbersome and time-consuming, so there is an urgent need for a simple, short-cycle method for preparing and purifying the three chiral impurities of diltiazem

Method used

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  • Preparation and purification method of diltiazem chiral isomer impurity
  • Preparation and purification method of diltiazem chiral isomer impurity

Examples

Experimental program
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Embodiment 1

[0018] Add 500mL of methanol into a 1L four-neck flask, under nitrogen protection, add 6g of sodium in batches under stirring at 0°C, then slowly add 27.2g of p-methoxybenzaldehyde and 28.5g of methyl chloroacetate dropwise at a controlled temperature of 0-10°C, After the dropwise addition, it was raised to 25°C for reaction. After the reaction was completed, it was poured into 1L of ice water, and a large amount of white solid was precipitated, which was filtered, washed, and dried to obtain 28 g of white solid VI.

[0019] Add 20 g of the obtained white solid VI into a 1L reaction flask, add 500 mL of toluene, add 14.4 g of o-aminothiophenol and 1.5 g of calcium chloride, heat up to 50 ° C for 24 hours, cool down to room temperature after the reaction, and filter to remove the solid For the insoluble matter, the toluene layer was extracted twice with 100 mL of concentrated hydrochloric acid, and the concentrated hydrochloric acid layer was added to 1 L of water under ice coo...

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Abstract

The invention provides a method for preparing and purifying a diltiazem chiral isomer. The method comprises the steps of taking p-methoxybenzaldehyde as a starting raw material, carrying out Darzens condensation, a reaction with o-aminobenzenethiol and a cyclization reaction to prepare an intermediate, carrying out chiral column separation on the intermediate, then carrying out an alkylation and acetylation reaction separately to obtain a diltiazem chiral isomer impurity I. The method is simple to operate and short in period, and the purity of the obtained diltiazem chiral isomer impurity is high, so that a reference substance is provided for quality research and drug synthesis process research of diltiazem drugs, and the method has important significance in control and checking of the chiral purity in the pharmaceutical research of diltiazem.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a method for preparing and purifying chiral isomer impurities of diltiazem. Background technique [0002] Diltiazem hydrochloride, diltiazem is widely used in the treatment of cardiovascular diseases in my country. It is one of the most important calcium ion antagonists in clinical practice. It can selectively act on vascular smooth muscle and directly expand coronary blood vessels and peripheral blood vessels. Mainly used for the treatment of angina pectoris and high blood pressure. The chemical name of the active ingredient of diltiazem is cis-(2S,3S)-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy -2,3-dihydro-1,5-benzothiazepine-4(5 hydrogen)-one (general formula I), its structure is as follows: [0003] [0004] Drug impurities are the most important factor affecting the quality of drugs, and the research on chiral isomer impurities is one of the most difficu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D281/10
CPCC07B2200/07C07D281/10
Inventor 徐启乐吴辉张红贞雷天莉沈红于磊
Owner SHANDONG XINHUA PHARMA CO LTD
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