Synthesis process of barnidipine hydrochloride

Abstract

The invention relates to a synthesis process of barnidipine hydrochloride. The synthesis process comprises the following steps: (1) reacting 3-hydroxypropionitrile (I) with ketene dimer (II) to obtaina compound (VI); (2) reacting the compound (VI) with m-nitrobenzaldehyde (III) to obtain a compound (VII); (3)reacting the compound (VII) with beta-amion ethyl crotonate (IV) to obtain a compound (VIII); (4) hydrolyzing the compound (VIII) by an alkali to obtain a compound (IX); (5) resolving the compound (IX) with a chiral organic base to obtain a compound (X); (6) carrying out a reaction between the compound (X) and benzyl pyrrole alcohol to obtain a compound (XI); and (7) adding the compound (XI) in a chlorine hydride solution to obtain barnidipine hydrochloride (XII). The synthesis process has the following advantages: (1) mild reaction conditions, easily separated and purified products obtained in every step, which has controllable quality, (2) higher yield in each step, easily obtainable raw and auxiliary materials, low total cost, (3) no column chromatography and industrialized production suitability.

Description

Technical field: [0001] The invention belongs to the field of production of fine chemical or pharmaceutical chemical products, and in particular relates to a synthesis process of a novel antihypertensive drug barnidipine hydrochloride. Background technique: [0002] The chemical name of Barnidipine Hydrochloride (CAS: 104757-53-1) is (S)-3-((S)-1-benzylpyrrolidinyl)-2,6-dimethyl-4- (3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride, the structural formula is: [0003] [0004] Barnidipine hydrochloride is a new type of long-acting dihydropyridine calcium ion antagonist for the treatment of essential hypertension and renal hypertension. This product is the first single optical isomer in this class of drugs. It has a high degree of vascular selectivity, can relax blood vessels, increase coronary blood flow, and lower blood pressure. ; This product has less toxic and side effects, and can reduce myocardial inhibition compared with similar drugs, so it is w...

AI Technical Summary

Problems solved by technology

[0008] (1) The first step reaction actually includes multi-step reactions at the same time, the reaction process is not easy to control, the obtained product is more complicated, there are more impurities, and it is not easy to separate and purify

(2) in the resolution step, the mixture of barnidipine and its diastereoisomers is resolved, and its other half of the diastereomers are discarded as impurities, which will greatly increase the total cost; use L- (-)-Malic acid is used as a resolving agent to obtain a product with low optical purity, which is not easy to purify and affects the quality of the final product

[0011] (1) in the resolution step, the mixture of barnidipine and its diastereomers is resolved, and its diastereomers are discarded as impurities, which will greatly increase the total cost; use L-(- )-malic acid is not high optical purity of the product obtained by the resolving agent, it is not easy to purify, and affects the quality of the final product

(2) The overall reaction yield is low, and each step needs column chromatography to separate, and this method has no practical production significance

[0014] (1) The intermediate and the final product generated from the first step reaction all need to pass through the column with a silica gel column, which is only suitable for a small amount of preparation in the laboratory and is difficult to industrialize; (2) the yield of the main intermediate monocarboxylic acid synthesis Not high, the quality is poor, affecting the purity of the final product, it must be purified through the column, which will lead to high product cost

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