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Prepn of ebastine

A technology of ebastine and intermediates, which is applied to the production and preparation of antiallergic drug ebastine, and the field of raw material drug synthesis technology, can solve the problems that the purification process affects the yield and the reaction cannot be completely carried out.

Active Publication Date: 2007-01-03
杭州仟源保灵药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the third step condensation process in the above-mentioned preparation method of ebastine, a bromide with strong corrosiveness and toxicity, i.e. brominated diphenylmethane, is used, and the reaction cannot be carried out completely, and a more complicated salt-forming process is required in the process. The purification process of free separation again affects the yield, and the small test yield is generally about 50%

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0013] Example 1: Add 280ml of methyl isobutyl ketone, 18 grams (0.17mol) of anhydrous sodium carbonate, 1-[4-(1,1-dimethylethyl)phenyl]-4-[ 26 g (0.085 mol) of 4-hydroxy-1-piperidinyl]-butanone (intermediate 2), 0.5 g of phenylacetyl peroxide (BPO), and 34 g (0.17 mol) of chlorinated diphenylmethane were added. After reflux reaction was carried out for 20 hours. Add water to wash the reaction solution, add 300ml 2N hydrochloric acid to the separated organic layer, separate the organic layer, take the acidified solution, and neutralize it with 2N sodium hydroxide solution to pH=9. Solid precipitated out. Filter, wash and dry. 31 grams of Ebastine was obtained, yield 77.0%, mp83-85.5°C

Embodiment 2

[0014] Example 2: Add 150ml of toluene solution in the reaction flask, 1-[4-(1,1-dimethylethyl)phenyl]-4-[4-hydroxyl-1-piperidinyl]-butane Ketone (intermediate 2) 15 g (0.05 mol), anhydrous sodium carbonate 10.6 g (0.1 mol), add a small amount of phenylacetyl peroxide (BPO), add 20 g of chlorodiphenylmethane (0.1 mol), reflux for 20 Hour. Wash with 10% sodium chloride, separate layers, add 100 ml of 15% hydrochloric acid to the reaction solution, stir, add 10% sodium hydroxide solution to the separated acid solution to neutralize to pH=9. Filter, wash and dry. 18 g of ebastine crystals were obtained with a yield of 77.5%.

Embodiment 3

[0015] Example 3: Add 230ml of methyl isobutyl ketone, 21 grams (0.2mol) of anhydrous sodium carbonate, 1-[4-(1,1-dimethylethyl)phenyl]-4-[ 30.5 g (0.1 mol) of 4-hydroxy-1-piperidinyl]-butanone (intermediate 2), and an appropriate amount of phenylacetyl peroxide (BPO). Heat to reflux. 40 g (0.2 mol) of chlorinated diphenylmethane was dissolved in 50 ml of methyl isobutyl ketone and added dropwise to the reaction solution within 2 hours. The reaction was completed in 20 hours. Wash the reaction solution with saturated sodium chloride solution, add 300 ml of 2N hydrochloric acid to the separated organic layer, separate the acidified solution, and neutralize it to pH=9 with 2N sodium hydroxide solution. Ebastine precipitated. Filter, wash and dry. 36 grams of ebastine was obtained, and the yield was 76.2%.

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PUM

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Abstract

The preparation process of ebastine includes the following steps: 1. condensation of 4-chlorobutyryl chloride and tert-butyl benzene to produce 4-chloro-1-[4-(1,1-dimethylethyl) phenyl]-1-butanone as intermediate I; 2. condensation of the intermediate I and 4-hydroxypiperidine to produce 1-[4-(1,1-dimethylethyl) phenyl]-4-[4-hydroxyl-1-piperidino] -butane ketone as intermediate II; 3. reflux condensation of methylisobutyl ketone ortoluene, chloro diphenylmethane and the intermediate II in the presence one small amount of phenylacetyl peroxide as reaction initiator, and 4. adding 2N hydrochloric acid in the same volume as the reactant after finishing the reaction, shaking, eliminating organic layer, adding 2N sodium hydroxide solution to neutralize to pH9, stirring to separate solid matter, filtering, water washing to neutral and obtain the ebastine product. The present invention has the features of complete reaction, high yield and other advantages.

Description

technical field [0001] The invention relates to a production and preparation method of an antiallergic drug ebastine, which belongs to the raw material drug synthesis technology in the field of medicine and chemical industry. Background technique [0002] Ebastine belongs to an antiallergic drug, and its common production and preparation process is usually divided into the following three steps: [0003] 1. Condensation of 4-chlorobutyryl chloride and tert-butylbenzene to generate 4-chloro-1-[4-(1,1-dimethylethyl)phenyl]-1-butanone, which is intermediate 1; [0004] 2. Intermediate 1 is condensed with 4-hydroxypiperidine to obtain 1-[4-(1,1-dimethylethyl)phenyl]-4-[4-hydroxy-1-piperidinyl]-butane Ketone, this is intermediate 2; [0005] 3. Intermediate 2 is condensed with bromodiphenylmethane and then salted with fumaric acid, and the obtained solid is then freed to form 1-[4-(1,1-dimethylethyl)phenyl]-4- [4(diphenylmethoxy)-1-piperidinyl]-1-butanone is the product of eba...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/46
Inventor 陈松年冯乾健李娟
Owner 杭州仟源保灵药业有限公司
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