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Preparation method of 2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepine

A technology of methoxyphenyl and benzothiazide, which is applied in the field of chemical pharmaceuticals, can solve the problems of high cost and achieve the effects of high yield, high optical purity and high product purity

Active Publication Date: 2021-04-02
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 needs to use expensive reagents, and the cost is higher than

Method used

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  • Preparation method of 2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepine
  • Preparation method of 2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepine
  • Preparation method of 2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepine

Examples

Experimental program
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Effect test

Embodiment 1

[0048] Intermediate 1:

[0049] 1000ml reaction flask, under nitrogen protection, add o-aminothiophenol (62.6g, 0.5mol, 1.0eq), toluene 500ml, triethylamine (10.1g, 0.1mol, 0.2eq), cool down to -18°C, add acetone dropwise Methyl alkynoate (46.2g, 0.55mol, 1.1eq), control the temperature at -18°C, stir well, keep warm for half an hour, until the reaction of o-aminothiophenol is complete, heat up, evaporate the low boiling point substances, and then heat up to toluene Reflux, react for 2 hours, cool, wash with water, concentrate and cool, precipitate crystals, filter with suction, and dry to obtain intermediate product 1, 69.9g, with a yield of 78.9% and a purity of 99.2%.

Embodiment 2

[0051] Intermediate 2:

[0052] In a 1000ml reactor, add 500ml of dichloromethane, catalyst 1 (10g, a mixture of titanium tetraisopropoxide and L-(+)-diisopropyl tartrate in a mass ratio of 1:1), and intermediate 1 (53g , 0.3mol, 1.0eq), cooled to 0°C, controlled the internal temperature to 0°C, then added dropwise tert-butanol peroxide (28.4g, 0.315mol, 1.05eq) to react for half an hour, filtered, washed with water, concentrated to obtain the intermediate product 2 (44.1g, 0.228mol), yield 76%, purity 98.5%.

Embodiment 3

[0054] In a 1000ml reaction flask, under the protection of nitrogen, add 300ml of tetrahydrofuran, 12g of magnesium chips, 0.1g of iodine, and a small amount of 4-methoxybromobenzene. -Methoxybromobenzene (39.3g, 0.21mol), refluxed for 1 hour to obtain a solution of (4-methoxyphenyl)magnesium bromide in tetrahydrofuran.

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Abstract

The invention provides a preparation method of 2-(4-methoxyphenyl)-3-hydroxyl-2,3-dihydro-1,5-benzothiazepine. The preparation method uses o-aminothiophenol and methyl propiolate as raw materials to synthesize an intermediate product 1, and then obtains an intermediate product 2 through selective epoxidation, and reacts the intermediate product 2 and 4-methoxyphenyl anion, and then Mitsunobu reaction afforded intermediate 3, which was then hydrolyzed to yield the product. During the ring formation process of the intermediate product 1, the tension of the Z-structure olefin is small, so the yield is high, and the subsequent epoxidation is an asymmetric epoxidation reaction, and the intermediate product 2 is obtained with high optical purity and high yield. The oxyphenyl anion is SN 2 Reaction, and then the ortho position undergoes configuration inversion to obtain the product. The whole process does not need to be split, and the total yield of the route is high and economical.

Description

technical field [0001] The invention relates to a preparation method of a compound, in particular to a preparation method of a diltiazem chiral intermediate, and belongs to the technical field of chemical pharmacy. Background technique [0002] Diltiazem (diltiazem) is a benzothiazepine calcium antagonist, a selective calcium channel blocker, the chemical name is cis-(+)-5-[(2-dimethylamino)ethyl]-2- (4-Methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine-4-(5H)-one hydrochloride. Diltiazem was developed and marketed by Japan Tanabe Company in the early 1970s. 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 (i.e. 2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepinone), followed by N-alkylation, O-acetyl A two-step reaction yields the product. [0003] As the key chiral intermediate in the synthesis of diltiazem, the existing synthetic methods of 2...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D281/10
CPCC07D281/10Y02P20/584
Inventor 沈冰良赵飞陈玮朱家可徐剑锋
Owner SUZHOU KAIYUAN MINSHENG SCI & TECH CORP
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