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Preparation method for key intermediate of Barnidipine

A technology for barnidipine and intermediates, which is applied in the field of preparation of key intermediates of barnidipine, can solve the problems of low resolution efficiency and low yield, and achieve easy separation, high product yield, and good optical purity Effect

Active Publication Date: 2019-09-27
贵州中森医药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The purpose of the present invention is to provide a key intermediate of barnidipine (R) 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-methoxycarbonyl-3 - A new preparation method of pyridinecarboxylic acid to solve the problems of low resolution efficiency and low yield in the above-mentioned prior art

Method used

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  • Preparation method for key intermediate of Barnidipine
  • Preparation method for key intermediate of Barnidipine
  • Preparation method for key intermediate of Barnidipine

Examples

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Effect test

Embodiment 1

[0035] Preparation of Barnidipine Key Intermediate (R)1,4-Dihydro-2,6-Dimethyl-4-(3-nitrophenyl)-5 Using L-Lactic Acid as Chiral Hydroxy Acid as Starting Material -Methoxycarbonyl-3-pyridinecarboxylic acid, the specific preparation steps are as follows:

[0036] Step 1: Preparation of L-isopropyl lactate (intermediate 1)

[0037] Take 225g of isopropanol, cool in an ice bath for 15min, add 3ml of concentrated sulfuric acid dropwise, add 106g of L-lactic acid and 500ml of toluene, conduct azeotropic dehydration reaction at 140°C for 12h, then evaporate the solvent under reduced pressure at 50°C, and add ethyl acetate to the residue 500ml of ester, 500ml of saturated sodium bicarbonate solution, stirred for 10min, separated the water layer, washed the organic layer with 500ml of saturated sodium chloride, dried over anhydrous sodium sulfate, and distilled off the solvent at 40°C under reduced pressure to obtain L - Isopropyl lactate, weighing 80g, yield 60.6%, directly dropped ...

Embodiment 2

[0047] Preparation of the key intermediate of barnidipine (R)1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)- 5-methoxycarbonyl-3-pyridinecarboxylic acid, the specific preparation steps are as follows:

[0048] Step 1: Preparation of S-isopropyl phenyllactate (intermediate 1)

[0049] Put 16.6g of S-phenyllactic acid and 300ml of isopropanol into the reaction flask in turn, add 1.7g of boric acid under stirring, stir at room temperature for 24h, evaporate the solvent under reduced pressure at 40°C, add 500ml of dichloromethane to the residue to dissolve, and then use saturated Wash with 500ml of sodium bicarbonate solution, 500ml of saturated sodium chloride, dry over anhydrous sodium sulfate, and evaporate the solvent under reduced pressure at 40°C to obtain S-isopropyl phenyllactate as a colorless transparent paste, weighing 18.9g, yield 91%, put directly into the next step reaction.

[0050] Step 2: Preparation of (S)-α-3-oxobutyryloxyphenylpropionate isopropyl (intermediate 2...

Embodiment 3

[0059] Preparation of the key intermediate of barnidipine (R)1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)- 5-methoxycarbonyl-3-pyridinecarboxylic acid, the specific preparation steps are as follows:

[0060] Step 1: Preparation of S-isopropyl mandelate (intermediate 1)

[0061] Put 15.2g of S-mandelic acid and 300ml of isopropanol into the reaction flask in turn, add 1.7g of boric acid under stirring, stir at room temperature for 24h, evaporate the solvent at 40°C under reduced pressure, add 500ml of dichloromethane to the residue to dissolve, and use saturated Wash with 500ml of sodium bicarbonate solution, 500ml of saturated sodium chloride, dry over anhydrous sodium sulfate, and evaporate the solvent under reduced pressure at 40°C to obtain S-isopropyl mandelate as a colorless transparent paste, weighing 18.0g, yield 93%, put directly into the next step reaction.

[0062] Step 2: Preparation of (S)-α-3-oxobutanoyloxyphenylacetic acid isopropyl ester (intermediate 2)

[006...

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Abstract

he preparation method of the intermediate is characterized by comprising the following steps: with chiral hydroxy acid as a starting material, the chiral hydroxy acid reacts with isopropanol under the catalysis of lewis acid, then reacts with an acetoacetic acid reagent, and is directly cyclized with m-nitrobenzaldehyde and methyl 3-aminocrotonate in an alcohol solvent, then crystallization is performed in a low temperature environment for realizing chiral resolution, hydrolysis is performed by sodium hydroxide, and then acidization is performed by hydrochloric acid to obtain a product. the intermediate is characterized by being prepared by the following steps: with chiral hydroxy acid as a starting material,the chiral hydroxy acid reacts with isopropanol under the catalysis of lewis acid, then reacts with an acetoacetic acid reagent, and is directly cyclized with m-nitrobenzaldehyde and methyl 3-aminocrotonate in an alcohol solvent, crystallization and chiral resolution are realized in a low temperature environment, hydrolysis is performed by sodium hydroxide, and then acidization is performed by hydrochloric acid to obtain a product. The preparation method disclosed by the invention has the advantages that the preparation technology is simple, the resolution is easy, the product yield is high, the optical purity is good, the quality is stable, and the large-scale industrial production is easy.

Description

technical field [0001] The invention belongs to the field of pharmaceutical technology, and in particular relates to a method for preparing a key intermediate of barnidipine, which is (R)1,4-dihydro-2,6-dimethyl-4-( 3-nitrophenyl)-5-methoxycarbonyl-3-pyridinecarboxylic acid. Background technique [0002] Barnidipine hydrochloride (barnidipine hydrochloride), chemical name (3S)-1-benzyl-3-pyrrolidinylmethyl-(4S)-2,6-dimethyl-4-(3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylate hydrochloride, developed by Japan Yamanouchi Company, first listed in Japan in 1992, is the first new long-acting dihydropyridine with a single optical isomer Calcium antagonists. Barnidipine specifically acts on calcium channels, inhibits the influx of calcium ions, selectively relaxes the smooth muscles of peripheral blood vessels and coronary vessels, and has a lasting and significant antihypertensive effect. [0003] At present, the main synthesis method of barnidipine is after preparing 1,4-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/90
CPCC07D211/90
Inventor 汤磊王建塔张吉泉毛远湖
Owner 贵州中森医药有限公司
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