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Preparation method of antihypertensive drug felodipine

A felodipine and anti-hypertensive technology, which is applied in the field of organic chemical synthesis, can solve the problems of lengthy and cumbersome post-processing operations, and achieve the effects of ideal purity, short reaction time and high yield

Active Publication Date: 2009-12-30
HEFEI LIFEON PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since the residue contains a large amount of pyridine, in order to remove pyridine, it must go through a series of separation and purification processes, so the post-treatment operation becomes lengthy and cumbersome.

Method used

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  • Preparation method of antihypertensive drug felodipine

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0034] The preparation of example 1 Felodipine:

[0035] 1.1. Cyclosynthesis and addition:

[0036] Add 640ml of absolute ethanol, 77.5ml of absolute ethanol, and g (pure: 0.59 mol.) ethyl 3-aminocrotonate and 6.9 g D072 type resin. Nitrogen flow was introduced into the bottle under stirring, and then 138.2 g (0.5 mol of pure equivalent) of methyl 2,3-dichlorobenzylidene acetoacetate was added. After the addition was completed, the temperature of the water bath was raised to 65° C. to 70° C., and the reaction was continued for 6 hours. Then the temperature was raised to reflux state to continue the reaction for 2 hr (the end point of the reaction can be determined by TLC method). The reaction solution was cooled to 30°C, the catalyst was filtered off, and rinsed with the same solvent until clear. Combine the filtered and washing liquids, and add 400ml of cyclohexane when vacuum-concentrating on a water bath to about 1 / 3 of the original volume. After the addition is complet...

Embodiment 2

[0044] Embodiment 2. The preparation of felodipine:

[0045] 1. Cycloaddition

[0046] In this experiment, the specifications, consumption and reaction temperature, time, concentration, precipitation and drying conditions of each raw material and catalyzer are the same as example 1, only use isopropanol (640ml.) n-heptane to replace dehydrated alcohol and n-hexane in example 1 alkyl. According to the law, 177.9 g of off-white powdery felodipine crude product was obtained, with a purity of 98.9% and a yield of 91.6%.

[0047] 2. Felodipine crude product recrystallization

[0048] Method, condition and result are the same as example 1.

Embodiment 3

[0049] Embodiment 3. Felodipine crude product preparation (imitation US2004 / 0204604A method):

[0050] 124.4 g (pure: 0.45 mol) of methyl 2,3-dichlorobenzylidene acetoacetate was mixed with 590 ml of isopropanol, and then 70.6 g (pure: 0.54 mol) of ethyl 3-aminocrotonate was added. The reaction mixture was refluxed on a water bath for 12 hours. The reaction solution was placed on a water bath to evaporate isopropanol under reduced pressure, and 390 ml of n-heptane was added with stirring to precipitate felodipine. After standing at room temperature for 1 hour, it was filtered. The filter cake was washed three times with n-heptane, and vacuum-dried to dryness below 50° C. to obtain 147.9 g of yellow hard lump felodipine crude product. The purity is 96.3%, and the pure yield is 82.4%.

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Abstract

The invention discloses a preparation method of felodipine. The method is mainly characterized by adding strong acid cation exchange resin to alcoholic solution of methyl 2-(2,3-dichlorobenzylidine)acetoacetate and ethyl-3-aminocrotonate as a catalyst, which shortens reaction time by more than 1 / 4 and improve yield of cyclization reaction by 6-8%. A crude product felodipine prepared by the preparation method has increased refining yield and product purity. The method is also applicable to preparing other 4-sustituted-1,4-dihydropyridine antihypertensive drugs with chemical structure and pharmaceutical and clinical actions similar to felodipine.

Description

technical field [0001] The invention relates to the field of organic (drug) chemical synthesis, in particular to a preparation method of antihypertensive drug felodipine and other 4-substituted-1,4-dihydropyridine antihypertensive drugs. Background technique [0002] EP007293 discloses a method for preparing felodipine by cycloaddition reaction using methyl 2,3-dichlorobenzylidene acetoacetate and ethyl 3-aminocrotonate as raw materials. The reaction uses tert-butanol as a solvent without a catalyst, and the reaction mixture is left at room temperature for 4 days, then the alcohol solution is evaporated, and the residue is recrystallized from isopropyl ether to obtain felodipine. Yield 75%. [0003] US5310970 discloses 2,3-dichlorobenzylidene acetoacetate methyl ester and 3-aminocrotonate ethyl ester as raw materials, ethanol as alcohol solution, moderate cooling after reflux reaction for an appropriate time, then add 6-12mol. hydrochloric acid or Toluenesulfonic acid was ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/90B01J31/10A61K31/4422A61P9/12
Inventor 季俊虬高美华陈军李孝常
Owner HEFEI LIFEON PHARMA
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