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Method for selectively synthesizing diltiazemchiral intermediate

A technology for chiral intermediates and diltiazem, which is applied in the field of selective synthesis of diltiazem chiral intermediates, can solve the problems of low utilization rate of raw materials, low yield of Darzens condensation reaction and high cost

Inactive Publication Date: 2017-06-27
郭彦超
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Due to the lack of selectivity of the epoxy ester formed in this method, the optically pure intermediate cannot be directly obtained, and subsequent resolution is required, and the resolution yield can only be about 48%, the raw material utilization rate is low, and the cost is high
[0004] CN105566248 uses anisaldehyde as a raw material, first carries out Darzens condensation reaction with the ester formed by chloroacetyl chloride and L-menthol, utilizes the asymmetric synthesis of the chiral environment of L-menthol, does not require lipase catalysis and complicated resolution process, However, the Darzens condensation reaction yield is not high, resulting in only 37% yield of the whole process

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0013] The preparation of embodiment 1 intermediate product 1

[0014] Add p-methoxycinnamaldehyde (48.6g, 0.3mol) into 1L reactor and dissolve in 300ml tetrahydrofuran, control the ice bath between 0°C and 5°C, add BF3·Et2O (8.52g, 0.06mol), then Methyl tartrate (64.1g, 0.36mol) was added dropwise, the reaction was stirred for 1 hour after the addition was completed, and the reaction was detected by TLC. After the reaction was completed, water was added to separate the layers. After the water layer was removed, the remaining organic layer was dried and then concentrated to dryness to obtain 91.8g of an intermediate product 1.

Embodiment 2

[0015] The preparation of embodiment 2 intermediate product 2

[0016] Add intermediate product 1 (91.8g, 0.28mol) and 200ml methanol in a 1L reactor, control the temperature between -5°C and 0°C under an ice-salt bath, add dropwise mass concentration of 30% hydrogen peroxide (51ml, 0.45mol), After the dropwise addition was completed, the mixture was incubated and stirred for 0.5 h. The reaction was detected by TLC. After the reaction was completed, most of the solvent was removed, and the reaction solution was slowly poured into ice water, stirred and filtered to obtain 89.9 g of solid intermediate product 2 after filtration.

Embodiment 3

[0017] The preparation of embodiment 3 intermediate product 3

[0018] Add intermediate product 2 (89.9g, 0.26mol) and 200ml methanol to a 1L reactor, control the ice bath between 0°C and 5°C, and dropwise add an acidic potassium permanganate solution (81ml, 0.41 mol), the dropwise addition was completed and the reaction was stirred for 0.5h, and the reaction was detected by TLC. If the reaction was incomplete, 5ml of acidic potassium permanganate solution was added. After the reaction was completed, most of the solvent was removed, and the reaction solution was slowly poured into ice water. Afterwards, 47.9 g of intermediate product 3 was obtained.

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Abstract

The invention provides a method for selectively synthesizing a diltiazem chiral intermediate. P-methoxy cinnamyl aldehyde is used as a main raw material, firstly performs aldolization reaction with tartaric ester to produce an intermediate product 1, then epoxidation reaction is performed with hydrogen peroxide to form an intermediate product 2, oxidization is performed under acidic conditionby using potassium permanganate to obtain an intermediate product 3, ring closing reaction is performed with 2-amino-4-chloro thiophenol after purification to obtain (2S-cis)-(+)-2,3-dihydrogen-3-hydroxyl-2(4-methoxyphenyl)-1,5-benzosulfoazepine-4 (5H)-ketone, the total yield is up to 88.2%, and the optical purity is up to 99.1%.

Description

technical field [0001] The invention relates to a method for selectively synthesizing a diltiazem chiral intermediate, which belongs to the technical field of chemical pharmacy. Background technique [0002] The chemical name of diltiazem is cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3- Dihydro-1,5-benzothiazepine-4-(5H)-one hydrochloride is a selective calcium channel blocker. Diltiazem is a benzothiazepine-type calcium antagonist, originally developed by Tanabe Corporation of Japan, and first listed in Japan in the early 1970s, and then successively sold in the United States and Japan under the names of diltiazem, diltiazem, and Xierxin. , France, Spain and other countries listed. At present, the route of synthesizing diltiazem is mainly to first synthesize (2S-cis)-(+)-2,3-dihydro-3-hydroxyl-2(4-methoxyphenyl)-1,5-benzothiazepine Zol-4(5H)-one, and then the product is obtained through two steps of N-alkylation and O-acetylation. The target prod...

Claims

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Application Information

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IPC IPC(8): C07D281/10
CPCC07D281/10
Inventor 刘德斌韩博周超郭燕军陶思立巴娟张敏朱仁伟郭彦超陶锐尤敏孙春领
Owner 郭彦超
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