CN101987844B - Method for synthesizing 4-(4-chlorobenzyl)-2-(hexahydro-1-methyl-1H-diazepoxide-4-radical)-1-(2H)-phthalizine hydrochloride - Google Patents
Method for synthesizing 4-(4-chlorobenzyl)-2-(hexahydro-1-methyl-1H-diazepoxide-4-radical)-1-(2H)-phthalizine hydrochloride Download PDFInfo
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- CN101987844B CN101987844B CN 200910144407 CN200910144407A CN101987844B CN 101987844 B CN101987844 B CN 101987844B CN 200910144407 CN200910144407 CN 200910144407 CN 200910144407 A CN200910144407 A CN 200910144407A CN 101987844 B CN101987844 B CN 101987844B
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Abstract
The invention relates to a method for synthesizing 4-(4-chlorobenzyl)-2-(hexahydro-1-methyl-1H-diazepoxide-4-radical)-1-(2H)-phthalizine hydrochloride (azelastine). The method is characterized in that: common chemical raw materials comprising N-methyl hexahydrodiazepoxide-4-ketone hydrochloride and 4-(4-chlorobenzyl)-1-(2H)-phthalizine ketone are used as raw materials; the 4-(4-chlorobenzyl)-2-(hexahydro-1-methyl-1H-diazepoxide-4-radical)-1-(2H)-phthalizine hydrochloride (azelastine) is synthesized in one step by condensation reaction; the total yield is 67 percent and exceeds the yield reported by the conventional documents; and the production cost is reduced. The method avoids the combustible and explosive synthesis steps of ring expansion and hydrazide treatment in the conventional synthesis processes, and does not cause personal injury of operators. The method has mild reaction conditions, and is easy to control and realize industrialization.
Description
Affiliated technical field
The present invention relates to the synthetic method of a kind of 4-(4-chlorobenzyl)-2-(six hydrogen-1-methyl isophthalic acid H-nitrogen Zhuo-4-yl)-1-(2H)-phthalazinium hydrochlorate (W-2979M), belong to the fine chemistry industry production field.
Background technology
4-(4-chlorobenzyl)-2-(six hydrogen-1-methyl isophthalic acid H-nitrogen Zhuo-4-yl)-1-(2H)-phthalazinium hydrochlorate (W-2979M) is developed by German Asta-Werke AG company and Japanese Wei Cai company, and is in widespread attention since the listing.This product all has production in states such as U.S., moral, English, day and methods at present, and takes in British Pharmacopoeia.Estimate that the listing of anti-asthma new drug W-2979M will change the structure of present treatment of allergic rhinitis and asthma medication greatly, this product is widely used in treatment of allergic rhinitis and skin pruritus and asthma clinically, in addition, recent years abroad has also been obtained good curative effect with its treatment allergic skin itch, eczema and various dermatitis, has huge market capacity, wide market outlook and the powerful market competitiveness.
2003 34 (1) reports of Chinese Journal of Pharmaceuticals are take N-methyl piperidine-4-ketone as raw material. synthesized the allergy preparations W-2979M through reactions such as ring expansion, hydrazides, condensations. and overall yield of reaction 48.6%, equation is as follows:
Summary of the invention
The object of the invention is to adopt that raw material is easy to get, synthetic route is short, avoided ring expansion, these inflammable and explosive synthesis steps of hydrazidesization.Provide a kind of and can not cause personal injury to operator, synthetic route is short, reaction conditions is gentle, safety easily the row, yield is high, cost is low, be easy to realize industrialized synthetic method.
The present invention realizes above-mentioned purpose by following technical solution:
Adopting in the present invention N-methyl six hydrogen azatropylidene-4-keto hydrochloride and 4-(4-chlorobenzyl)-1-(2H)-phthalazone is raw material, through condensation reaction one-step synthesis 4-(4-chlorobenzyl)-2-(six hydrogen-1-methyl isophthalic acid H-nitrogen Zhuo-4-yl)-1-(2H)-phthalazinium hydrochlorate (W-2979M), its chemical equation is as follows:
The present invention compared with prior art has following beneficial effect: the present invention is take N-methyl six hydrogen azatropylidene-4-keto hydrochloride as raw material, and through condensation reaction one-step synthesis W-2979M, total recovery reaches yield 67%, surpasses the yield of existing bibliographical information; Avoid adopting in the conventional building-up process ring expansion, these inflammable and explosive synthesis steps of hydrazidesization, can not cause personal injury to operator.
Description of drawings
Fig. 1 is the chemical structural formula of W-2979M;
Fig. 2 is the reacting flow chart of synthetic hydrochloric acid azelastine.
Embodiment
The present invention can realize by following concrete steps:
Getting 350g N-methyl six hydrogen azatropylidene-4-keto hydrochloride puts in 10～12 times of dehydrated alcohols and dissolves, be cooled to 5 ℃, add the 100g POTASSIUM BOROHYDRIDE, add the fashionable Bubble formation that has, to slowly add, be warming up to 20-25 ℃ after adding, keep adding after 12 hours 4-(4-chlorobenzyl)-1-(2H)-phthalazone, then solution temperature rising reflux 3 hours is cooled to 0～5 ℃ and stirred 2 hours, filters out solid, filtrate decompression is distilled to dried, the dope of gained is dissolved in the acetone, adds activated carbon decolorizing, filter.Filtrate is regulated PH=1--2 with hydrochloric acid, remains on 0-5 ℃ of lower the stirring 5 hours, filters washing with acetone, absolute ethanol washing, dry white powder solid, the W-2979M 600g of getting.Yield 67%.Content 99%, fusing point 222-225 ℃.
Claims (1)
1. the synthetic method of an azelastine Hcl, it is characterized in that: get 350g N-methyl six hydrogen azepine-4-keto hydrochloride and put in 10～12 times of dehydrated alcohols and dissolve, be cooled to 5 ℃, add the 100g POTASSIUM BOROHYDRIDE, add the fashionable Bubble formation that has, to slowly add, be warming up to 20-25 ℃ after adding, keep adding after 12 hours 4-(4-chlorobenzyl)-1-(2H)-phthalazone, solution temperature rising reflux 3 hours, then being cooled to 0～5 ℃ stirred 2 hours, filter out solid, filtrate decompression is distilled to dried, and the dope of gained is dissolved in the acetone, add activated carbon decolorizing, filter; Filtrate is regulated pH=1-2 with hydrochloric acid, remains on 0-5 ℃ of lower the stirring 5 hours, filters washing with acetone, absolute ethanol washing, dry white powder solid, azelastine Hcl 600g, yield 67%, content 99%, fusing point 222-225 ℃ of getting.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200910144407 CN101987844B (en) | 2009-08-04 | 2009-08-04 | Method for synthesizing 4-(4-chlorobenzyl)-2-(hexahydro-1-methyl-1H-diazepoxide-4-radical)-1-(2H)-phthalizine hydrochloride |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200910144407 CN101987844B (en) | 2009-08-04 | 2009-08-04 | Method for synthesizing 4-(4-chlorobenzyl)-2-(hexahydro-1-methyl-1H-diazepoxide-4-radical)-1-(2H)-phthalizine hydrochloride |
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| CN101987844A CN101987844A (en) | 2011-03-23 |
| CN101987844B true CN101987844B (en) | 2013-04-03 |
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| CN 200910144407 Active CN101987844B (en) | 2009-08-04 | 2009-08-04 | Method for synthesizing 4-(4-chlorobenzyl)-2-(hexahydro-1-methyl-1H-diazepoxide-4-radical)-1-(2H)-phthalizine hydrochloride |
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102391253A (en) * | 2011-10-24 | 2012-03-28 | 贵州云峰药业有限公司 | Synthetic technology of azelastine hydrochloride |
| CN102702108A (en) * | 2012-06-27 | 2012-10-03 | 上海大学 | 1,2-dihydrophthalazin compound and synthetic method thereof |
| CN102863393A (en) * | 2012-09-26 | 2013-01-09 | 上海大学 | 1,2-dihydro phthalazine compound and synthetic method thereof |
| CN104173352B (en) * | 2014-09-10 | 2016-06-01 | 贵州云峰药业有限公司 | W-2979M pharmaceutical composition |
| CN113045547B (en) * | 2019-12-27 | 2023-03-28 | 武汉先路医药科技股份有限公司 | Preparation method of azelastine hydrochloride |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0488209A1 (en) * | 1990-11-28 | 1992-06-03 | Eisai Chemical Co., Ltd. | Process for producing benzylphthalazinone derivatives and salts thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH05230056A (en) * | 1992-02-19 | 1993-09-07 | Sumika Fine Kemu Kk | Production of 4-substituted benzyl-2-(n-substituted hexahydroazepinyl)-1(2h)-phthalazinone derivative |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0488209A1 (en) * | 1990-11-28 | 1992-06-03 | Eisai Chemical Co., Ltd. | Process for producing benzylphthalazinone derivatives and salts thereof |
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| JP特开平5-230056A 1993.09.07 |
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