Barnidipine hydrochloride compound and preparation method thereof

A technology of barnidipine hydrochloride and a compound, applied in the direction of organic chemistry and the like, can solve the problems of difficulty in obtaining, low efficiency, difficult industrialization, etc., and achieves the effects of mild reaction conditions, guaranteed optical purity, and short synthetic route.

A technology of barnidipine hydrochloride and a compound, applied in the direction of organic chemistry and the like, can solve the problems of difficulty in obtaining, low efficiency, difficult industrialization, etc., and achieves the effects of mild reaction conditions, guaranteed optical purity, and short synthetic route.

CN109111431AInactive Publication Date: 2019-01-01森淼(山东)药业有限公司
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  • Barnidipine hydrochloride compound and preparation method thereof
  • Barnidipine hydrochloride compound and preparation method thereof
  • Barnidipine hydrochloride compound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] The preparation of embodiment 1 barnidipine hydrochloride

[0043] (1) Add 600g of 3-hydroxypropionitrile, 400g of ethyl acetate, and 15g of pyridine into the reaction flask, raise the temperature to 80°C, and slowly add diketene (645g) / ethyl acetate solution (1100g) dropwise for about 1 to 2 hours The addition is completed; then the reaction is incubated for 1 to 2 hours, and the TLV detection reaction is completed.

[0044] Cool down to room temperature, add saturated sodium bicarbonate solution dropwise to the reaction solution, stir and separate the liquids, take the organic phase, wash with purified water, dry the organic phase, filter, and concentrate to obtain 776g of intermediate 1 with a yield of 65.2%.

[0045](2) Add intermediate 1 (750g), m-nitrobenzaldehyde 730.5g, 3-aminocrotonate methyl ester 556.2g and isopropanol 4500g into the reaction flask, heat up to 70-80°C for 10-14h; cool down to room temperature, then cool down at 0-5°C for 1-2 hours, filter wi...

Embodiment 2

[0056] The preparation of embodiment 2 barnidipine hydrochloride

[0057] (1) Add 600g of 3-hydroxypropionitrile, 400g of ethyl acetate, and 15g of triethylamine into the reaction flask, raise the temperature to 80°C, and slowly add diketene (645g) / ethyl acetate solution (1100g) dropwise at the same time, about 1~ The dropwise addition was completed in 2 hours; then the reaction was incubated for 1 to 2 hours, and the TLV detection reaction was completed.

[0058] Cool down to room temperature, add saturated sodium bicarbonate solution dropwise to the reaction solution, stir and separate the liquids, take the organic phase, wash with purified water, dry the organic phase, filter, and concentrate to obtain 1021g of intermediate 1 with a yield of 85.8%.

[0059] (2) Add intermediate 1 (1000g), m-nitrobenzaldehyde 974g, 3-aminocrotonate methyl ester 741.6g and isopropanol 6000g into the reaction flask, heat up to 70-80°C for 10-14h; cool down to room temperature , then cool down...

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Abstract

The invention discloses a barnidipine hydrochloride compound and a preparation method thereof. The preparation method comprises the following steps: (1) using 3-hydroxypropionitrile to react with diketene, to obtain an intermediate 1; (2) enabling the intermediate 1 to react with m-nitrobenzaldehyde and Beta-amino methyl crotonate, to obtain an intermediate 2; (3) enabling the intermediate 2 to behydrolyzed by strong base, to obtain an intermediate 3; (4) enabling the intermediate 3 to be resolved by chiral organic base, to obtain an intermediate 4; (5) enabling the intermediate 4 to react with thionyl chloride, (S)-1-benzyl-3-pyrrolidinol, and HCI ethanol solution, to obtain a crude product of barnidipine hydrochloride; and (6) performing ethyl alcohol pulping and refining, and ethyl alcohol recrystallization on the crude product of the barnidipine hydrochloride, to obtain the barnidipine hydrochloride.

Description

technical field [0001] The invention relates to a dihydropyridine calcium antagonist antihypertensive drug, in particular to a barnidipine hydrochloride compound and a preparation method thereof, belonging to the technical field of medicine. Background technique [0002] Barnidipine hydrochloride, its chemical name is: (S)-3-((S)-1-benzylpyrrolidinyl)-2,6-dimethyl-4-(3-nitrophenyl)-1 ,4-Dihydropyridine-3,5-dicarboxylate hydrochloride, molecular formula C 27 h 29 N 3 o 6 HCl, molecular weight 528, structural formula: [0003] [0004] Barnidipine Hydrochloride (Barnidipine Hydrochloride) is a powerful, long-acting, optically active third-generation dihydropyridine calcium antagonist antihypertensive drug developed by Japan Yamanouchi Company. It was first launched in Japan in 1992. Available in Korea, Philippines and Thailand. At present, this product has passed the mutual recognition procedure of the European Union, and has been approved for marketing in the Netherl...

Claims

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Application Information

Patent Timeline
01 Jan 2019
Publication
CN109111431A
IPC
C07D401/12
CPC
C07D401/12
Inventors
赵艳红