Synthesis of high-purity amlodipine besylate

A kind of technology of amlodipine besylate and synthesis method, applied in the field of amlodipine besylate, and can solve the problems such as that the purity of amlodipine besylate product cannot meet requirements and the like

Active Publication Date: 2009-02-18
CHINA RESOURCES SAIKE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The purity of the amlodipine besylate product pre

Method used

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  • Synthesis of high-purity amlodipine besylate
  • Synthesis of high-purity amlodipine besylate
  • Synthesis of high-purity amlodipine besylate

Examples

Experimental program
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Embodiment 1

[0025] Embodiment 1: the synthesis of impurity E

[0026] (4RS)-4-(2-chlorophenyl)-2-[(2-aminoethoxy)methyl]-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid ethyl ester

[0027]

[0028] resolve resolution

[0029] 1, Preparation of ethyl 3-aminobutyrylate

[0030] In a 500ml three-neck flask, add 300ml of ethyl acetoacetate and 150ml of ethanol, cool below 10°C, pass ammonia gas for 5 hours, precipitate crystals, filter to obtain 100g of the product.

[0031] 2. (4RS)-4-(2-chlorophenyl)-2-[[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy ]Methyl]-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate ethyl ester (impurity E3)

[0032] In a 250ml reaction flask, add 15g of ethyl 3-aminocrotonate, 18g of ethyl 4-(2-phthalimidoethoxy)acetoacetate, 7g of o-chlorobenzaldehyde, 100ml of methanol, Stir and reflux for 20 hours. After completion, recover the solvent under reduced pressure, add 30 ml of glacial acetic acid, stir until crystals are precipitated, and filter to obtain...

Embodiment 2

[0038] Embodiment 2: the preparation of impurity F

[0039] (4RS)-4-(2-chlorophenyl)-2-[(2-aminoethoxy)methyl]-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid methyl ester

[0040]

[0041] resolve resolution

[0042] 1, Synthesis of ethyl 4-bromoacetoacetate (B)

[0043] Add 80g of liquid bromine dropwise to a 500ml chloroform solution containing 58g of methyl acetoacetate at -5°C to 0°C, drop it within 2 hours, react at room temperature for 15 hours, add water 500ml×2 for extraction, separate the organic layer, and dry Chloroform was distilled under reduced pressure (recyclable and used mechanically) to obtain 100 g of the product with a yield of 82%.

[0044] 2, Preparation of 4-[2-(phthalimido) ethoxy] ethyl acetoacetate (C)

[0045] Add 350ml of tetrahydrofuran and 43g of NaH to the three-necked flask, add 97g of phthalimide ethanol in batches, cool to -10°C, add 100g of methyl 4-bromoacetoacetate dropwise, react at -5°C to 0°C for 1 hour, and rise to React at ...

Embodiment 3

[0054] Embodiment 3: the preparation of high-purity amlodipine besylate

[0055] 1, the preparation of phthaloyl amlodipine

[0056] Inhale 50Kg of 4-(2-phthalimidoethoxy)ethyl acetoacetate (content 90%), 200kg of anhydrous methanol, 22Kg of o-chlorobenzaldehyde, and add 3-aminobutyl Acrylic acid methyl ester 54Kgkg, insulation reflux reaction after 20 hours, decompression recovery methanol, recovery is complete. Add 100kg of glacial acetic acid, stir at 12-18°C for about 12 hours, discharge the material in stages and perform rejection filtration in a centrifuge to obtain about 50kg of crude wet product of phthaloyl amlodipine. (Feeding molar ratio 4—(2-phthalimidoethoxy)ethyl acetoacetate: 3-aminobutyrylic acid methyl ester=1:1.12:3.35)

[0057] Use 70 kg of mixed solvent of toluene: glacial acetic acid = 1:1 system to dissolve the above-mentioned crude product by heating, then naturally cool to 20-30 ° C for 1 hour, shake off the filter, rinse with cold toluene, and obtain...

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Abstract

The present invention relates to a synthesis method of high-purity amlodipine besylate. In particular, o-chlorobenzaldehyde, 4-(2-phthalyl imino radical ethoxy) acetoacetic ester and 3-amino methyl cro-tonate are used as raw materials for ring closure in an alcohol solvent, and when the amount of the 3-amino methyl cro-tonate is three times, the intermediate for ring closure can be prepared; the intermediate is refined by toluene/glacial acetic acid, dissolved in methylamine to form a salt in the aqueous solution, and the high-purity amlodipine besylate can be acquired after recrystallization with ethyl alcohol.

Description

Technical field: [0001] The invention relates to a preparation method of antihypertensive drug amlodipine besylate, which can obtain high-purity amlodipine besylate. Background technique: [0002] Amlodipine besylate is developed by Pfizer, and its domestic product name is Norvasc. It is a first-line drug for the treatment of hypertension. This product has the following structure: [0003] [0004] Document US4572909 has reported a kind of preparation method of amlodipine besylate, with o-chlorobenzaldehyde, 4-(2-phthalimidoethoxy) ethyl acetoacetate, 3-aminobutyrylic acid methyl The invention discloses a method for synthesizing an intermediate phthaloyl amlodipine in an organic solvent using an ester as a raw material. The purity of the amlodipine besylate product obtained by the method cannot meet the requirements. [0005] The present invention has been improved on the basis of above synthetic method, and we have carried out HPLC-MS analysis to impurity, find two tra...

Claims

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Application Information

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IPC IPC(8): C07D211/90A61P9/12
Inventor 杨琰吕会超
Owner CHINA RESOURCES SAIKE PHARMA
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