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Preparation method of alcaftadine intermediate

A reaction system, methyl technology, applied in the direction of organic chemistry, etc., can solve the problems of reduced safety requirements, long route, low overall yield, etc., and achieve the effect of increased reaction yield, shortened reaction route, and simple operation

Active Publication Date: 2013-11-27
SHANGHAI PUKANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] Patents CN92105040.2 and CN96106116.2 report using ethyl 4-chlorocarboxy-1-piperidinecarboxylate as a raw material to obtain the target product through four steps of acylation, deprotection, methylation and ring-closing dehydration (synthesized as follows shown in route 2), this method improves the synthetic route and reduces the safety requirements for equipment and reagents, but the route is long and the overall yield is low

Method used

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  • Preparation method of alcaftadine intermediate
  • Preparation method of alcaftadine intermediate
  • Preparation method of alcaftadine intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] (1) Add 86g of 1-(2-phenylethyl)-1H-imidazole, 500ml of acetonitrile, and 120g of triethylamine into a 1000ml three-neck flask, cool down to 0-5°C in an ice-water bath, and slowly add N-methyl-4 - 108g of piperidinecarbonyl chloride, after the dropwise addition, warm up to room temperature (25-30°C), keep warm until the reaction is complete, add 1L of 20% sodium hydroxide and stir for 30min, extract with dichloromethane, dry over anhydrous sodium sulfate, filter, The solvent was recovered from the filtrate to obtain 134.1 g of the product [1-(2-phenylethyl)-1H-imidazol-2-yl](1-methyl-4-piperidinyl)methanone, with a yield of 90.3%.

[0034] (2) Add 87g of [1-(2-phenylethyl)-1H-imidazol-2-yl](1-methyl-4-piperidinyl)methanone into a 500ml three-necked flask, and then add 350ml of polyphosphoric acid , heated to 110°C, kept warm for 12 hours, after the reaction was completed, cooled to room temperature, poured into 500ml of ice water, 40% sodium hydroxide solution to pH=10-...

Embodiment 2

[0036] (1) Add 86g of 1-(2-phenylethyl)-1H-imidazole, 200ml of pyridine, and 60g of triethylamine into a 500ml three-neck flask, cool down to 0-5°C in an ice-water bath, and slowly add N-methyl-4 - 161g of piperidinecarbonyl chloride, after the dropwise addition, heat up to 65°C, keep warm until the reaction is complete, spin dry the solvent, add 100ml of 20% sodium hydroxide and stir for 30 minutes, extract with dichloromethane, dry over anhydrous sodium sulfate, filter , The solvent was recovered from the filtrate to obtain 139.7 g of the product [1-(2-phenylethyl)-1H-imidazol-2-yl](1-methyl-4-piperidinyl)methanone, with a yield of 94.1%.

[0037] (2) Add 90g of [1-(2-phenylethyl)-1H-imidazol-2-yl](1-methyl-4-piperidinyl)methanone into a 1000ml three-necked flask, and then add 48% hydrogen Bromic acid 500ml, heated to reflux, heated to 120°C and kept warm until the reaction was complete, the reaction time was 5-17 hours, evaporated the solvent, added 500ml isopropanol to ref...

Embodiment 3

[0039] (1) Add 86g of 1-(2-phenylethyl)-1H-imidazole, 200ml of toluene, and 160g of pyridine into a 500ml three-neck flask, cool down to 0-5°C in an ice-water bath, and slowly add N-methyl-4-piperide dropwise 161g of picoyl chloride, after the dropwise addition, heat up to 95°C, keep warm until the reaction is complete, spin to dry the solvent, add 100ml of 20% sodium hydroxide and stir for 30 minutes, extract with dichloromethane, dry over anhydrous sodium sulfate, filter, and the filtrate The solvent was recovered to obtain 135.7 g of the product [1-(2-phenylethyl)-1H-imidazol-2-yl](1-methyl-4-piperidinyl)methanone, with a yield of 91.4%.

[0040] (2) Add 56g of [1-(2-phenylethyl)-1H-imidazol-2-yl](1-methyl-4-piperidinyl)methanone into a 500ml three-necked flask, and then add trifluoroform 350ml of sulfonic acid, heat to 100°C, keep warm until the reaction is complete, the reaction time is 3-7 hours, cool to room temperature, pour 500ml of ice water, 40% sodium hydroxide sol...

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Abstract

The invention provides a preparation method of 6,11-dihydro-11-(1-methyl-4-subpiperidyl)-5H-imidazole[2,1-b][3] benzo azepine shown in a formula (I). The preparation method comprises the following steps of: with N-methyl-4-piperidine formyl chloride hydrochloride and 1-phenethyl-1H-imidazole as raw materials, carrying out an acylation reaction under the action of alkali to obtain [1-(2- phenethyl)-1H-imidazole-2-yl] (1-methyl-4-piperidyl) ketone, and then synthesizing 6,11-dihydro-11-(1-methyl-4-subpiperidyl)-5H-imidazole[2,1-b][3] benzo azepine. The invention provides a simple and efficient preparation method of 6,11-dihydro-11-(1-methyl-4-subpiperidyl)-5H-imidazole[2,1-b][3] benzo azepine, the preparation method is short in route and easy in operation, and can be used for avoiding a grignard reaction and introduction of precious metal, greatly shortening the existing reaction route and greatly increasing the reaction yield.

Description

technical field [0001] The present invention relates to the field of chemical pharmacy, in particular, to a method for preparing an important intermediate of alcaftadine, and more specifically, to a 6,11-dihydro-11-(1-methyl-4-methylidene A preparation method of piperidinyl)-5H-imidazol[2,1-b][3]benzazepine. Background technique [0002] Alcaftadine, whose English name is Alcaftadine, and whose trade name is Lastacaft, is a molecular entity drug used to prevent itching caused by allergic conjunctivitis. Alcaftadine is a histamine H1-receptor antagonist and a mast cell stabilizer, which can inhibit the release of histamine from mast cells and prevent the action of histamine, thereby reducing allergic reactions; in addition, it can reduce chemotaxis and inhibit the activity of eosinophils , its chemical name is 6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazol[2,1-b][3]benzazepine-3-carbaldehyde formula (III ), the important intermediate for the synthesis of this com...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
Inventor 汪迅李新涓子李勇刚高艳吕兴红沈小良田良闪
Owner SHANGHAI PUKANG PHARMA
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