Selective synthesis method of diltiazem chiral intermediate

A chiral intermediate, diltiazem technology, applied in the field of selective synthesis of diltiazem chiral intermediates, can solve the problem of high cost, achieve the effect of increasing yield, improving utilization rate, and reducing cost

Active Publication Date: 2019-03-26
SUZHOU KAIYUAN MINSHENG SCI & TECH CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Most of these routes are more complicated, and the reaction requires the use of expensive reagents, and the cost is relatively high

Method used

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  • Selective synthesis method of diltiazem chiral intermediate
  • Selective synthesis method of diltiazem chiral intermediate
  • Selective synthesis method of diltiazem chiral intermediate

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preparation example Construction

[0036] The selective synthesis method of diltiazem chiral intermediate of the present invention, such as Figure 1 to Figure 5 As shown, using anisaldehyde as the main raw material, it is first condensed with the intermediate product 1 formed by the reaction of chloroacetyl chloride and L-menthol, after purification, it reacts with o-aminothiophenol and undergoes hydrolysis and ring-forming steps to obtain the diltiazem chiral intermediate body, including the following steps:

[0037]Step 1. Add L-menthol, 0.01-0.1 equivalent (moles / L-menthol moles) of DMAP (N,N-dimethyl-4-aminopyridine) and the first solvent into the reactor, and stir After dissolving, add 1.0-2.0 equivalents (moles / L-menthol moles) of acid-binding agent, then dropwise add 1.0-2.0 equivalents (moles / L-menthol moles) of chloroacetyl chloride, and stir after the addition reaction, after the reaction is completed, add water to separate the layers, remove the water layer and then dry the remaining organic layer ...

Embodiment 1

[0049] Add 62.5g of L-menthol, 0.5g of N,N-dimethylaminopyridine (DMAP), and 200mL of dichloromethane into a 1L reaction flask, and stir to dissolve. Add 63.0 g of sodium carbonate, add 56.5 g of chloroacetyl chloride dropwise at a controlled temperature of 25°C to 30°C, and keep stirring at 25°C to 30°C for 2 hours after dropping. After the reaction was completed, 400 mL of water was added, and after stirring and separating, the organic layer was dried by adding 10 g of anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure to obtain intermediate product 1, which was directly used in the next reaction without purification.

Embodiment 2

[0051] Add 62.5g of L-menthol, 0.5g of N,N-dimethylaminopyridine (DMAP), and 200mL of chloroform into a 1L reaction bottle, and stir to dissolve. Add 63.0 g of sodium bicarbonate, add 56.5 g of chloroacetyl chloride dropwise at a controlled temperature of 25°C to 30°C, and keep stirring at 25°C to 30°C for 2 hours after dropping. After the reaction was completed, 400 mL of water was added, and after stirring and separating, the organic layer was dried by adding 10 g of anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure to obtain intermediate product 1, which was directly used in the next reaction without purification.

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Abstract

The invention provides a selective synthesis method of diltiazem chiral intermediate. The method is as below: using anisic aldehyde, chloroacetyl chloride and L-menthol as raw materials; first subjecting chloroacetyl chloride and L-menthol to an esterification reaction to obtain an intermediate 1; then subjecting the intermediate 1 with anisic aldehyde to a Darzens condensation reaction to produce diastereomer intermediates 2 and 3; refining to obtain an optically pure intermediate 3; reacting the intermediate 3 with o-aminothiophenol to obtain an intermediate 4; hydrolyzing the intermediate 4 to obtain an intermediate 5; and cyclizing the intermediate 5 to obtain a product. The invention has the advantages that the ester formed by chloroacetyl chloride and L-menthol is selective in the Darzens condensation reaction with anisic aldehyde to generate the more target product, and solubility difference between the target product and the isomer is used to directly obtain optically pure intermediate, without a complicated resolution process, and the yield is greatly improved. The method substantially increases the utilization rate of the main raw material anisic aldehyde and reduces cost.

Description

technical field [0001] The invention relates to a selective synthesis method of 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 D-cis-2-(4-methoxyphenyl)-3-hydroxyl-2,3-dihydro-1,5-benzothiazepine-4(5H) -ketone, and then through N-alkylation, O-acetylation two-step reaction to obtain the product. The target product of the p...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D281/10C07D303/48C07D301/02
CPCC07D281/10C07D301/02C07D303/48
Inventor 赵飞陈玮吴一尘曾淼徐剑锋
Owner SUZHOU KAIYUAN MINSHENG SCI & TECH CORP
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