Process for preparing diltiazem intermediate

A technology for diltiazem and intermediates, applied in the field of preparation of diltiazem intermediates, can solve the problems of being difficult to use, difficult to obtain, etc., and achieve the effects of easy industrial production and high optical yield

Inactive Publication Date: 2007-02-07
NINGBO UNIVERSITY OF TECHNOLOGY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, through the asymmetric reduction method of latent chiral ketones, J Org Chem, 1996, 61: 8586-8590 reported that under the action of amino acid chiral ligands such as teleucine, the intermediate I, namely 2- (4-methoxyphenyl)-1,5-benzothiazepine-3,4-(2H,5H)-dione is asymmetrically reduced to intermediate II of (2S,3S), but it is very bright Amino acid is a special amino acid, which is difficult to obtain, so the asymmetric reduction method is difficult to be practical

Method used

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  • Process for preparing diltiazem intermediate
  • Process for preparing diltiazem intermediate
  • Process for preparing diltiazem intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0025] In a 125 ml Erlenmeyer flask with a stirring reflux device, under the protection of nitrogen, add 100 ml of anhydrous tetrahydrofuran solvent, 0.457 g (0.012 mol) of NaBH 4 and 2.6 g (0.016 mol) of optically active R-mandelic acid ([α] 25 D =-150°, c=2, water), NaBH 4 The molar ratio with the optically active R-type mandelic acid derivative is 1: 1.3, heat and reflux for 3 hours, then cool the reaction solution with ice-salt water, add 3 grams (0.01 mole) of diltiazem intermediate I at 0 ° C, optical The mol ratio of active R-type mandelic acid and diltiazem intermediate I is 1: 0.62, and the solution is continued to be cooled to -10~-20 DEG C, kept stirring at this temperature for 3 hours, then stop the reaction with a small amount of room temperature water, reduce Add 100 milliliters of water after removing tetrahydrofuran by pressure distillation, stir for 0.5 hour, make the product become powdery solid in water at room temperature, vacuum filter the precipitated s...

Embodiment 2

[0028] 1 g of the crude product of diltiazem intermediate II obtained in Example 1 was recrystallized with 40 ml of absolute ethanol to obtain 0.88 g of white crystals of diltiazem intermediate II with a yield of 88%, m.p.171°C to 177°C , [α] 23 D =+74.3° (c=0.3, absolute ethanol), chiral HPLC analysis: (2R, 3R) isomer is 0.9%, (2S, 3S) isomer is 99.1%.

Embodiment 3

[0030] In a dry 125 ml three-necked flask with stirring reflux, under N 2 Under protection, add 100 ml of anhydrous tetrahydrofuran, 0.609 g (0.016 mol) of NaBH 4 , 6.5 g (0.04 mol) of R-mandelic acid, NaBH 4 The molar ratio with the optically active R-type mandelic acid derivative is 1: 2.5, heat and reflux for 3 hours, then cool the reaction solution with ice-salt water, add 9.6g (0.032mol) diltiazem intermediate I at 0°C, the optically active The mol ratio of R-type mandelic acid and diltiazem intermediate is 1: 0.8, and continue to cool the solution to -10~-20°C, keep stirring at this temperature for 3 hours, then stop the reaction with a small amount of water at room temperature, and The tetrahydrofuran was removed, and 100 ml of water was added to the residue. Stir for 0.5 hours to make the product a powdery solid in water at room temperature, vacuum filter the precipitated solid, and dry to obtain diltiazem intermediate II, namely d-cis-3-(4-methoxyphenyl)-3-hydroxyl-...

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Abstract

The invention discloses a preparing method of Dierliuzhuo intermediate, which comprises the following steps: adding NaBH4 and optical activated amygdalic derivant in the flask with anhydrous tetrahydropyran solvent and nitrogen condition through stirring; heating to reflux for 3 h to obtain chiral ligand compound; cooling to 0 deg.c; adding Dierliuzhuo intermediate I; cooling until -10- -20 deg.c; insulating to stir for 3 h; adding water with indoor temperature to stop reacting; removing tetrahydropyran solvent through decompressing and distilling; evolving product to obtain isomer of 88% Dierliuzhuo intermediate II (2S,3S).

Description

technical field [0001] The present invention relates to the method for preparing medicine intermediate, particularly relate to the preparation method of diltiazem (diltiazem) intermediate. Background technique [0002] Diltiazem (diltiazem) is a benzothiazepine-type calcium straw antagonist, clinically used to treat various angina pectoris, tachycardia, supraventricular arrhythmia and hypertension. Diltiazem can be prepared from intermediates in which 3-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one is the synthesis of diltiazem The key intermediate, which has four stereoisomers, only the (2S, 3S) type of intermediate II is d-cis-3-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro Only -1,5-benzothiazepin-4(5H)-one has medicinal effect, therefore, people carry out a lot of work around how to obtain the (2S, 3S) type intermediate II. US 5256803, EP 320532 proposed to obtain its intermediate III, i.e. d-cis-3-(4-methoxyphenyl)-3-(2-aminophenylthio)-2-hydroxyprop...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D281/10
Inventor 王家荣彭阳峰何佺赵红亮
Owner NINGBO UNIVERSITY OF TECHNOLOGY
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