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Preparation method for (S)-1,4-dihydropyridine calcium ion antagonist

A technology of calcium dihydropyridine and antagonists, applied in chemical instruments and methods, organic compound/hydride/coordination complex catalysts, physical/chemical process catalysts, etc., can solve problems such as cumbersome operations

Inactive Publication Date: 2015-08-26
SHIJIAZHUANG UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Preparation of formula (I) by resolution method involves repeated steps such as (R)-isomer racemization, recrystallization, and salt solution, and the operation is cumbersome

Method used

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  • Preparation method for (S)-1,4-dihydropyridine calcium ion antagonist
  • Preparation method for (S)-1,4-dihydropyridine calcium ion antagonist
  • Preparation method for (S)-1,4-dihydropyridine calcium ion antagonist

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Preparation of (S)-1,4-dihydropyridine-2,6-dimethyl-4-(2-nitrophenyl)piperidine-3,5-dicarboxylic acid isobutylmethyl ester (1)

[0029] The structure of compound (1) and catalyst (1) used is shown in the following formula:

[0030]

[0031] N 2 Under protection, in the reactor, add 2.33g (0.01moL) 2-(2-nitrobenzylidene) methyl acetoacetate, catalyst (1) 0.5g (1 mmoL, Merrifield resin chiral phosphoric acid content 2mmol / g) and 20 mL of acetonitrile, stirred at room temperature for 10 minutes, added 1.72 g (0.011 moL) of isobutyl β-aminocrotonate, heated to 50°C, and reacted for 24 hours. Cool, add 1 mL of water to quench the reaction, filter with suction, wash the catalyst with 3 mLх3 acetonitrile, dry, recover the catalyst, and recycle it. The washing solution and the reaction solution were combined, the solvent was spinned out, the residue was added with 10mL of water, extracted with 10mLх3 chloroform, dried, filtered with suction, and evaporated to dryness to o...

Embodiment 2

[0033] Preparation of (S)-1,4-dihydropyridine-2,6-dimethyl-4-(3-nitrophenyl)piperidine-3,5-dicarboxylic acid ethylmethyl ester (2)

[0034] The structure of compound (2) and catalyst (2) used is shown in the following formula:

[0035]

[0036] N 2 Under protection, add 2.33g (0.01moL) methyl 2-(3-nitrobenzylidene)acetoacetate, catalyst (2) 0.77g (1 mmol) and 21mL chloroform into the reactor, and stir at room temperature for 10 minutes , add 1.29 g (0.011moL) ethyl β-aminocrotonate, heat to 50°C, and react for 24 hours. Cool, and use 6mL of 2mol L for the reaction solution -1 Adjust the pH of the NaOH solution to 11, separate layers, extract the aqueous phase with 10mLх3 chloroform, dry, filter with suction, evaporate the solvent to obtain a solid, and recrystallize the solid with ethanol-water (w / w=95:5) to obtain light yellow Compound (2). Yield 87%, ee value 91%, [a] D 25 = +13.6°(c = 0.5, C 2 h 5 OH), mp: 158-159°C. For the aqueous phase, use 6mL of 2mol·L -1...

Embodiment 3

[0038] (S)-1,4-Dihydropyridine-2,6-dimethyl-4-(3-nitrophenyl)piperidine-3,5-dicarboxylate isopropylmethyl ester (3) preparation

[0039] The structure of compound (3) and the structure of catalyst (3) are shown in the following formula:

[0040]

[0041] N 2 Under protection, in the reactor, add 2.33g (0.01moL) 2-(3-nitrobenzylidene) methyl acetoacetate, catalyst (3) 0.45g (1 mmolL, chiral phosphoric acid content in Merrifield resin 2.2 mmol / g) and 20mL acetonitrile, stirred at room temperature for 10 minutes, added 1.56 g (0.011moL) isopropyl β-aminocrotonate, heated to 50°C, and reacted for 24 hours. Cool, add 1 mL of water to quench the reaction, filter with suction, wash the catalyst with 3 mLх3 acetonitrile, dry, recover the catalyst, and recycle it. Combine the washing solution and the reaction solution, spin out the solvent, add 10mL of water to the residue, extract with 10mLх3 chloroform, dry, filter with suction, evaporate the solvent to dryness, and obtain a so...

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Abstract

The invention relates to a preparation method for a (S)-1,4-dihydropyridine calcium ion antagonist as shown in a formula (I); the (S)-1,4-dihydropyridine calcium ion antagonist is an anti-hypertension medicine. The preparation method comprises a step of condensing substituted benzylidene acetoacetate and beta-amino crotonate, wherein substituted benzylidene acetoacetate is catalyzed by chiral phosphoric acid as shown in a formula (IV) or a formula (V). The preparation method is mild in reaction condition, high in yield and optical purity, and suitable for industrialized production.

Description

technical field [0001] The invention relates to a preparation method of an antihypertensive drug (S)-1,4-dihydropyridine calcium ion antagonist, which includes the steps of adding raw materials and closing the ring. Background technique [0002] At present, there are about 150 million hypertensive patients over the age of 15 in China, and the prevalence rate is increasing year by year. Clinically commonly used antihypertensive drugs include 1.4-dihydropyridine calcium antagonists, angiotensin II antagonists, converting enzyme inhibitors, and β-blockers. Among them, 1.4-dihydropyridine calcium antagonists can be used for various types of hypertension, and are welcomed by clinicians and patients because of their definite antihypertensive effect, convenient administration and low price. Except for nifedipine, all 1.4-dihydropyridine calcium antagonists have one or more chiral centers and exist multiple isomers. Studies have shown that the S-isomer is an active ingredient in t...

Claims

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Application Information

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IPC IPC(8): C07D211/90B01J31/06
CPCC07D211/90B01J31/06B01J2231/42
Inventor 张宝华刘斯婕史兰香郭瑞霞
Owner SHIJIAZHUANG UNIVERSITY
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