Preparation method of levamlodipine besylate

Abstract

The invention belongs to the technical field of medicine synthesis, and provides a production method of levamlodipine besylate, which comprises the following steps: using (R, S)-amlodipine besylate asa raw material to react with a resolving agent, and directly reacting with benzenesulfonic acid salt conversion to obtain the levamlodipine besylate, wherein the yield and purity are very good, the used reaction solvent is economic and environment-friendly, and the resolving agent can be further recycled. The method is simple and convenient to operate and does not need special equipment, so thatthe method has a better industrial application prospect.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a preparation method of levamlodipine besylate. Background technique [0002] Amlodipine Besylate, chemical name: 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3, 5-Pyridinedicarboxylic acid-3-ethyl-5-methyl ester benzenesulfonate is the third generation 1,4-dihydropyridine calcium ion antagonist developed by Pfizer in 1990. Launched first in the UK and Ireland under the trade name It is mainly used for the treatment of hypertension, coronary heart disease and angina pectoris. Amlodipine besylate has a longer plasma half-life and a longer duration of action; compared with similar antihypertensive drugs, it has fewer adverse reactions and has good bioavailability, neither affecting myocardial contraction rate nor causing reflexes It has obvious antihypertensive effect and good tolerance for patients with essential hypertension. Its c...

AI Technical Summary

Problems solved by technology

[0014] In 1994, the WO9525722A1 patent of Pfizer Company provided a resolving agent with D-(-)-tartaric acid or L-(+)-tartaric acid, dimethyl Sulfoxide (DMSO) is a solvent, and the method for directly splitting amlodipine to obtain amlodipine enantiomers has an optical purity of 99% and a high yield, but the limitation of this method is to utilize DMSO as a solvent, and Only levorotatory amlodipine can be obtained, and the boiling point of DMSO (189°C) is relatively high, which may easily cause the problem that the solvent is not easy to recover during the production process, and because DMSO will produce a violent disproportionation reaction during the heating recovery process, resulting in an explosion. Industrial production is very dangerous; at the same time, its melting point is also high, and it will solidify when it is lower than 18°C, which will bring great inconvenience to production.

[0015] U.S. Patent US6646131B2 and Chinese Patent CN00102701.8, CN201410370738.7 use tartaric acid as a resolution reagent, deuterated dimethyl sulfoxide (DMSO-d 6) as a solvent resolution method, this method can simultaneously obtain two isomers of amlodipine, but the price of DMSO-d6 is very expensive, and the deuterated reagent has Very toxic, banned in the pharmaceutical industry, so it does not have industrial application prospects

[0016]Patents WO03035623A1, CN02825939.4, CN200910136780.1 and CN201110418986.0 etc. disclose a kind of D-(-)-tartaric acid or L-(+)-tartaric acid As a resolving agent, use N,N-dimethylacetamide (DMAc) or N,N-dimethylformamide (DMF) as a method for solvent resolution of amlodipine, but DMAc (166°C) or DMF ( 153°C) has a high boiling point and is not easy to recover, and it is a second-class solvent with high toxicity and easy to cause serious pollution in the production process

[0017] Chinese patent CN200310119335.7 adopts L-(+)-tartaric acid as a resolution reagent and 2-butanone as a solvent for resolution, but the method used The amount of 2-butanone is relatively large, reaching 20 times (volume / mass) of racemic amlodipine, and 2-butanone is also highly irritating to eyes, nose, throat and mucous membranes

However, methyl ethyl sulfoxide is not a common solvent in industry, and there is no industrial source. In this patent, methyl ethyl sulfide is separated and prepared by hydrogen peroxide oxidation, but in the process of obtaining the target product through distillation and separation of the reaction mixture, it is easy explosion occurs

[0019] Chinese patents CN200810094428.1 and CN1915674A utilize N-methylpyrrolidone (NMP) as a resolution solvent, but NMP has a stimulating effect on the skin, and its chronic effect can be Cause central nervous system dysfunction, cause respiratory organ, kidney, vascular system lesions

[0025] (1). Using DMSO, DMSO-d6, DMF, DMAc or NMP, these high-boiling solvents are highly toxic, not only The price is more expensive and difficult to recycle. At the same time, due to the high boiling point, it is easy to remain in the product, and it is difficult to meet the pharmaceutical standard

[0026] (2). The resolving agent used cannot be effectively recovered from the mother liquor, resulting in high production costs, and the mother liquor is difficult to green treatment, resulting in high environmental pressure

[0027] (3). The resolution conditions in the prior art are prone to produce amlodipine 1,4-dihydropyridine ring reduction impurity (impurity D), and it is difficult to It is effectively removed by conventional refining, and it is difficult to obtain qualified products

[0028]Therefore, research is looking for a suitable industrial benzene production method with mild reaction conditions, simple operation process, high product yield, high purity, easy recovery of resolving agent and low production cost. The preparation method of levamlodipine sulfonate is still a problem to be solved at present

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