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Preparation method of felodipine synthetic intermediate methyl 2-(2,3-dichlorobenzylidine)acetoacetate

A technology of methyl dichlorobenzylidene acetoacetate and methyl acetoacetate, which is applied in the field of organic chemical synthesis to achieve the effects of clean production, good crystal form, and bright color

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

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Problems solved by technology

According to the method and conditions disclosed by the applicant, the condensation yield is 70%-75%, and the purity of the intermediate is 94%-97% (high performance liquid chromatography). There is a certain gap with the level reported in this patent.

Method used

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  • Preparation method of felodipine synthetic intermediate methyl 2-(2,3-dichlorobenzylidine)acetoacetate
  • Preparation method of felodipine synthetic intermediate methyl 2-(2,3-dichlorobenzylidine)acetoacetate
  • Preparation method of felodipine synthetic intermediate methyl 2-(2,3-dichlorobenzylidine)acetoacetate

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example 1

[0029] Example 1: Preparation of felodipine synthetic intermediate-2,3-dichlorobenzylidene acetoacetate methyl ester

[0030] Put 600ml of absolute ethanol, 119.2g (pure: 1.02mol.) methyl acetoacetate, 3.53g (pure: 41mmol.) piperidine, 7.68g (pure: 44mmol.) into a 1000ml. 2-quinolinecarboxylic acid and 141.4 g (reduced purity: 0.8 mol) of 2,3-dichlorobenzaldehyde. After the addition was completed, the temperature of the water bath was raised to 41° C. to 45° C., and the stirring was continued for 6 hours (the end point of the reaction was determined by TLC). Place the reaction solution in a cold water bath at 15°C±2°C and stir for crystallization for 2 hours, filter the mother liquor, wash the filter cake with an appropriate amount of cold solvent, and dry it in vacuum below 50°C to obtain a white shiny intermediate crystal (one time precipitates). Yield 138.6 g., purity 98.7%.

[0031] Combine the mother liquor and washing liquid of the primary precipitate, concentrate in ...

example 2

[0032] Example 2. Felodipine synthetic intermediate-2, the preparation of 3-dichlorobenzylidene acetoacetate methyl ester

[0033] In this embodiment, isopropanol (640ml.) is used instead of absolute ethanol as the condensation reaction and recrystallization solvent, and all other raw materials, catalyst specifications, dosages and ratios are the same as in Example 1, and are obtained according to the preparation method of Example 1 once Precipitate 140.1g., purity 98.5%; secondary precipitate crude product 50.3g., purity 95.6%. The crude product was purified once with isopropanol to obtain 44.3 g of the secondary product with a purity of 99.1%. Condensation and refining total yield: 83.06%.

example 3

[0034] Example 3. Felodipine synthetic intermediate-2, the preparation method of 3-dichlorobenzylidene acetoacetate methyl ester (the comparative patent method of example 1)

[0035] Dissolve 141.4g (purity 0.8moL) of 2,3-dichlorobenzaldehyde in 660ml.isopropanol, then add 4.97g (purity 0.04mol) of picolinic acid, 3.44g (purity 0.04mol) ) piperidine and 119.6 g (1.02 mol of pure) of methyl acetoacetate. After the addition is complete, the temperature of the water bath is raised to 40-45° C., and the reaction is stirred for 6 hours. The reaction solution was stirred and crystallized on a water bath at 15°C±2°C for 2 hours. The mother liquor was filtered off in vacuo, and the filter cake was washed with a small amount of cold isopropanol and then vacuum-dried to dryness below 50° C. to obtain 131.4 g of off-white powder crystals with a purity of 97.6% (HPLC normalization method).

[0036] The mother liquor of the primary precipitate was combined with the washing liquid, concen...

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Abstract

The invention discloses a preparation method of methyl 2-(2,3-dichlorobenzylidine)acetoacetate which is a synthetic intermediate of antihypertensive drug felodipine. The method is characterized by allowing a condensation reaction between 2, 3-dichlorobenzaldehyde and methyl acetoacetate in alcohol solution under the catalytic action of a novel combined catalyst consisting of secondary amine and quinoline carboxylic acid. Reaction liquid is cooled at room temperature for crystallization, filtered, washed and dried after the condensation reaction to obtain primary eluent of the intermediate methyl 2-(2,3-dichlorobenzylidine)acetoacetate with purity not less than 98%. Mother liquor is subject to vacuum condensation, cooling crystallization, filtering and recrystallization to obtain secondary eluent product of the intermediate methyl 2-(2,3-dichlorobenzylidine)acetoacetate with purity not less than 98%. Compared with the prior art, the new method helps enhance synthetic yield of the felodipine intermediate, and provide ideal intermediate purity. The method is also applicable to preparing other 4-sustituted-1,4-dihydropyridine antihypertensive drug intermediates with chemical structure and pharmaceutical and clinical actions similar to those of felodipine.

Description

technical field [0001] The invention relates to the field of organic (drug) chemical synthesis, in particular to a method for preparing an antihypertensive drug felodipine synthetic intermediate 2,3-dichlorobenzylidene acetoacetate methyl ester. The method is also applicable to the preparation of other synthetic intermediates of 4-substituted-1,4-dihydropyridine antihypertensive drugs similar in chemical structure, pharmacology and clinical action to felodipine. Background technique [0002] Felodipine [4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate methylethyl ester] is a well known 1,4 - Representative drugs in dihydropyridine antihypertensive drugs. The chemical structure is as follows: [0003] [0004] The chemical synthesis of felodipine is generally completed through a two-step synthesis method shown in the following formula: [0005] [0006] In the first step of condensation reaction, due to the chemical activity of the olefinic b...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C69/738C07C67/343C07C67/307B01J31/02B01J31/04
Inventor 季俊虬高美华陈军李孝常
Owner HEFEI LIFEON PHARMA
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