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A kind of method and application thereof for preparing phthaloyl amlodipine

A technology of phthaloyl ammonia chloride and dipine, applied in the direction of organic chemistry and the like, can solve the problems of long route, low final yield, complicated process and the like, and achieve the effects of short process, small amount of waste water and high yield

Active Publication Date: 2021-05-18
NANJING YUANSHU MEDICAL TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The characteristics of the synthetic route: the route is long, the process is cumbersome, and the final yield is low

Method used

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  • A kind of method and application thereof for preparing phthaloyl amlodipine
  • A kind of method and application thereof for preparing phthaloyl amlodipine
  • A kind of method and application thereof for preparing phthaloyl amlodipine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038]Example 1 Preparation of phthal amine chlorine chloride

[0039]1) 50 g of dihydropyridine, silica 3A molecular sieve 4g, N-bromide-butilimide (NBS) 70 g, stirred, 80 ° C is heated, and the reaction is 60 ° C, and the reaction is completed, stirred after the reaction is completed. To room temperature, it was stirred in an ice water bath for 1 h, filtered, and dried under vacuum at 50 ° C for 12 h, resulting in 74 g of a pale yellow solid powder (structural formula II), the crude rate of 90%, purity 98.375%.

[0040]2) 1000ml round bottom flask is added to 74 g, N-hydroxyethyl phthalamine 37.4 g, N-hydroxyethyl phthalamine 37.4 g, potassium carbonate 13g, N, N-dimethylformamide 1.3 g, methyl ethyl 300g, stirring, heat reflux at 80 ° C, reaction 8 h; After the reaction was completed, 200 g of water was added, stirred for 1 h, stirred, filter cake 50 ° C for 12 h, resulting 87.7 g of white solid powder (Structure III) ), The crude product rate was 95%, purity 97.932%.

[0041]3) 1000ml ro...

Embodiment 2

[0043]Example 2 Preparation of phthalophyllocytex form

[0044]The pale yellow solid powder 50g, a acetate, 400 g of ethyl acetate, stirred, stirred, stirred to 60 ° C, stirred, stirred, stirred, stirred to be heated to room temperature, stirred, stirred, stirred, stirred at room temperature, stirred with 50 g of ethanol, stir 2H, filtration, filter cake 50 ° C for 12 h, resulting in 49.6 g of pale yellow solid powder (phthalophenylel aminogenic crystalline type A), a crude rate of 99.2%, purity 99.758%. The phrochlorphrochlorine chloride formation A, the first melter was 138.1 ° C, and 138.7 ° C.

[0045]The X-ray pattern peak of phthalophyllocytex form Afigure 1 As shown: 5.7, 1107; 8.7, 10103; 11.3, 2912; 13.4, 759; 15.2, 463; 15.6, 786; 17.6, 1633; 18.0, 561; 19.5, 490; 20.2, 498; 21.8, 589 22.1,1159; 22.6,923; 24.5,849; 25.5,839; 26.1,1482; 26.3, 1167; 27.4,569; 27.7,1772.

Embodiment 3

[0046]Example 3 Preparation of phthalophylline Crystalline Type B

[0047]Add 49.6 g of the above pale yellow solid powder, add N, N-dimethylformamide, stirred, stirred to 60 ° C, stirred to 60 ° C, stirred to 60 ° C, stirred to heating, 0.20 g of water, stirred with 20 g of water, stir for 2 h, The solid was completely precipitated, filtered, and the filter cake was dried in vacuo for 12 h, resulting in 49.4 g of a pale yellow solid powder (phthal amyline chlorine), the crude rate of 99.6%, purity 99.862%. The o-phenylenedicanoyl amchlopine chloride was determined, the first melting was 147.2 ° C, and the final melted was 148.8 ° C.

[0048]X-ray map of amnoblobacine amine is likefigure 2 As shown: 7.0,5001; 8.5,945; 8.7,483; 10.1,274; 11.1,622; 11.9,3099; 12.2,405; 14.0,2107; 14.3,691; 14.6,371; 16.3,310; 16.9,1398 17.2,1656; 18.4,406; 20.5,905; 22.0,1891; 22.7,482; 23.1,515; 24.1,868; 24.2,1097; 24.6,588; 25.5,719; 25.7,804; 27.1,655; 27.7 , 954; 28.1, 1151.

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Abstract

The invention discloses a method for preparing phthaloyl amlodipine. The compound represented by the structural formula II is obtained by reacting the compound dihydropyridine represented by the structural formula I with N-bromosuccinimide under the action of a molecular sieve catalyst The compound shown in the compound II and the compound shown in the structural formula III use the benzophenone compound as a solvent, the inorganic carbonate as a catalyst, and the nitrogen-containing organic compound as a cocatalyst, and heat and reflux to obtain the compound shown in the structural formula IV; The compound shown in Tetrakis(triphenylphosphine) palladium and inorganic carbonate is used as catalyst, and benzene is used as solvent to react with 2-chlorophenylboronic acid to obtain phthaloyl amlodipine; the reaction steps of the preparation method of the present invention are simple , only three steps are required, the reaction conditions are mild, the post-reaction treatment is convenient, and the product purity is high. The present invention also provides a kind of amlodipine imine with different crystal forms obtained by various recrystallization methods, which meets different market demands and ensures Drug safety and efficacy.

Description

Technical field[0001]A method of preparing an obsmethyldiphenylel amnyl amine is a method of preparing an obsmethyidyl amnyl amine.Background technique[0002]The phosphhylaminthlorocetine is highly affinity with the membrane phospholipin of the biofilm, which can be aggregated in the depths of the vascular cell membrane lipid layer, and can slowly lasting the receptor of the calcium ion channel. It is an excellent calcium. Ion antagonist. At the same time, the NO generating enzyme activity can be restored to normal, and also has an anti-cell membrane oxidation. It is used to treat high blood pressure, angina pectoris, heart failure, etc., widely used, good market prospects, strict requirements for purity and crystal .[0003]At present, its synthetic methods are:[0004]1. Korean patent (patent number 86-1921)[0005][0006]The reaction step is concise, but its reaction rate is low and cannot meet the current production needs.[0007]2. U.S. Patent (6784297B2), U.S. Patent (6653481B2)[0008][0...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12
Inventor 金峰周太勇王凯肖亮淳清颜
Owner NANJING YUANSHU MEDICAL TECH CO LTD
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