CN102391253A

CN102391253A - Synthetic technology of azelastine hydrochloride

Info

Publication number: CN102391253A
Application number: CN201110324488XA
Authority: CN
Inventors: 陈友; 黄忠文; 刘诚; 李占胜; 倪全平
Original assignee: GUIZHOU YUNFENG PHARMACEUTICAL CO Ltd
Current assignee: GUIZHOU YUNFENG PHARMACEUTICAL CO Ltd
Priority date: 2011-10-24
Filing date: 2011-10-24
Publication date: 2012-03-28

Abstract

The invention discloses a synthetic technology of azelastine hydrochloride, which is characterized in that acylhydrazone is formed by N-Methylhexahydroazepin-4-one hydrochloride and benzoyl hydrazine and then is reduced with potassium borohydride, and finally is condensed with 2-(para chlorobenzene acetyl) benzoic acid into 4-( chlorine benzyl)-2-piperazidine-1- methyl-1H-azelastine-4- radical)-1-(2H)-phthalazine hydrochloride. The synthetic technology has the advantages of simple process and higher yield.

Description

A kind of synthesis technique of W-2979M

Technical field

The invention belongs to the fine chemistry industry production field, be specifically related to a kind of synthesis technique of W-2979M.

Background technology

The chemical formula of W-2979M is 4-(4-benzyl chloride base)-2-(six hydrogen-1-methyl isophthalic acid H-nitrogen Zhuo-4-yl)-1-(2H)-phthalazinium hydrochlorate; Be by German Asta-Werker AG company and the research and development exploitation of Japanese Wei Cai company, received extensive attention since the listing.This product all has production in states such as U.S.A, moral, English, day and methods at present, and takes in British Pharmacopoeia.Estimate the structure of the listing of asthma new drug W-2979M, have the huge market space and prospect present treatment of allergic rhinitis of big about-face and asthma medication, significant to the research of its technology.

Chinese Journal of Pharmaceuticals reported that with N-methyl piperidine-4-ketone be raw material in 2003, had synthesized W-2979M through reactions such as ring expansion, hydrazidesization, condensations, and overall yield of reaction is 48.6%, and this method synthetic W-2979M yield is not high.

Chinese patent CN20091014407.0 in 2009 adopts N-methyl six hydrogen, and azatropylidene-the 4-keto hydrochloride is a raw material, and through condensation one-step synthesis W-2979M, total recovery reaches 67%, but the raw material that this method adopts is more difficult to get, and yield is not high.

Summary of the invention

The present invention provides a yield height, and the simple W-2979M synthetic route of technology is one and is easy to industrialized synthetic route.

The synthesis technique of a kind of W-2979M of the present invention; Adopt N-methyl six hydrogen azatropylidene-4-keto hydrochloride and benzoyl hydrazine to form acylhydrazone; Use potassium borohydride reduction again; At last again and 2-(to chloro acetyl) phenylformic acid be condensed into 4-(4-benzyl chloride base)-2-(six hydrogen-1-methyl isophthalic acid H-nitrogen Zhuo-4-yl)-1-(2H)-phthalazinium hydrochlorate, its reaction equation is following:

Figure 201110324488X100002DEST_PATH_IMAGE002

。

The synthesis technique of a kind of W-2979M of the present invention; The reaction conditions of N-methyl six hydrogen azatropylidene-4-keto hydrochloride and benzoyl hydrazine is: the mol ratio is 1: (1 ~ 1.2); Stirring reaction 1-5h at room temperature bathes with icy salt solution or cryosel then and is chilled to-10-20 ℃.

The new synthetic process of a kind of W-2979M of the present invention; Use the condition of potassium borohydride reduction to be: the methanol solution that drips 0.5 ~ 2 mol/L KOH; 1 ~ 6h adds POTASSIUM BOROHYDRIDE 97MIN again, and the amount that adds POTASSIUM BOROHYDRIDE 97MIN is 1 ~ 1.5 times of N-methyl six hydrogen azatropylidene-4-keto hydrochloride add-on; Continue cooling and stirring after 5-50 minute, 10-50 ℃ of following stirring reaction 5 ~ 10h.

The synthesis technique of a kind of W-2979M of the present invention is used CH with the product behind the potassium borohydride reduction ₂Cl ₂MgSO is used in extraction ₄After the drying, again with adding the diethyl ether solution salify that contains HCl, precipitation; Add pure water and 2-(to chloro acetyl) phenylformic acid again; Add-on is 0.8 ~ 1.2 times of N-methyl six hydrogen azatropylidene-4-keto hydrochloride add-on; Using 10 ~ 30% NaOH solution accent pH again is 5 ~ 9, stirring and refluxing 1 ~ 3h, under agitation cooling; Make oily matter become solid particulate, the NaOH with 10 ~ 30% transfers PH>7, the W-2979M free alkali is fully separated out, leave standstill, filter the washing after drying.

The synthesis technique of a kind of W-2979M of the present invention, dried 4-(4-benzyl chloride base)-2-(six hydrogen-1-methyl isophthalic acid H-nitrogen Zhuo-4-yl)-1-(2H)-phthalazinium hydrochlorate uses earlier the acetone heating for dissolving; Add gac, stirring and refluxing 10-80min, filtered while hot; Filter residue washs with hot acetone, and filtrating is used the aqueous isopropanol salify that contains HCl under cooling and stirring, freezing, filtration; Solids is used the cold acetone thorough washing, drains.80 ~ 105 ℃ of following dryings, distinguish recrystallization once with acetone and ethanol again, obtain 4-(4-benzyl chloride base)-2-(six hydrogen-1-methyl isophthalic acid H-nitrogen Zhuo-4-yl)-1-(2H)-phthalazinium hydrochlorate product.

The beneficial effect that the present invention reaches: the present invention adopts N-methyl six hydrogen azatropylidene-4-keto hydrochloride and benzoyl hydrazine to form acylhydrazone; Use potassium borohydride reduction again; At last again and 2-(to chloro acetyl) phenylformic acid be condensed into 4-(4-benzyl chloride base)-2-(six hydrogen-1-methyl isophthalic acid H-nitrogen Zhuo-4-yl)-1-(2H)-phthalazinium hydrochlorate, it is simple to have technology, yield is high; Total recovery reaches 70% ~ 80%, and the product content that obtains behind the recrystallization reaches more than 98.5%.

Embodiment

The synthesis technique of a kind of W-2979M of the present invention; Adopt N-methyl six hydrogen azatropylidene-4-keto hydrochloride and benzoyl hydrazine to form acylhydrazone; Use potassium borohydride reduction again, at last again and 2-(to chloro acetyl) phenylformic acid be condensed into 4-(4-benzyl chloride base)-2-(six hydrogen-1-methyl isophthalic acid H-nitrogen Zhuo-4-yl)-1-(2H)-phthalazinium hydrochlorate.

In reaction kettle, add N-methyl six hydrogen azatropylidene-4-keto hydrochloride 100 mol and benzoyl hydrazine 110mol, at room temperature stirring reaction 1-5h bathes with icy salt solution or cryosel then and is chilled to 0 ~ 20 ℃; Drip the methanol solution 50L of 2 mol/L KOH, the dropping time is 5h, adds POTASSIUM BOROHYDRIDE 97MIN 130mol again, continues cooling and stirring after 30 minutes, 40 ~ 50 ℃ of following stirring reaction 6h; Use CH again ₂Cl _{2 (}50kg MgSO is used in extraction (1000ml * 3) ₄After the drying, again with adding the diethyl ether solution salify that contains HCl, precipitation; Add 1000kg pure water and 2-(to chloro acetyl) phenylformic acid 100mol again, using 20% NaOH solution accent pH again is 7, stirring and refluxing 2h; Under agitation cooling makes oily matter become solid particulate, and using 20% NaOH accent PH is 9; The W-2979M free alkali is fully separated out; Leave standstill, filter, the washing after drying; Dried 4-(4-benzyl chloride base)-2-(six hydrogen-1-methyl isophthalic acid H-nitrogen Zhuo-4-yl)-1-(2H)-phthalazinium hydrochlorate uses earlier the acetone heating for dissolving, adds gac; Stirring and refluxing 60min, filtered while hot, filter residue washs with hot acetone; With the aqueous isopropanol salify that contains HCl, the cold acetone thorough washing is used in freezing, filtration to filtrating again under cooling and stirring; Drain,, distinguish recrystallization once with acetone and ethanol again 100 ℃ of following dryings; Obtain 4-(4-benzyl chloride base)-2-(six hydrogen-1-methyl isophthalic acid H-nitrogen Zhuo-4-yl)-1-(2H)-phthalazinium hydrochlorate (72kmol), content reaches: 99.1%.

Claims

1. the synthesis technique of a W-2979M; It is characterized in that: adopt N-methyl six hydrogen azatropylidene-4-keto hydrochloride and benzoyl hydrazine to form acylhydrazone; Use potassium borohydride reduction again; At last again and 2-(to chloro acetyl) phenylformic acid be condensed into 4-(4-benzyl chloride base)-2-(six hydrogen-1-methyl isophthalic acid H-nitrogen Zhuo-4-yl)-1-(2H)-phthalazinium hydrochlorate, its reaction equation is following:

Figure 201110324488X100001DEST_PATH_IMAGE002

。

2. the synthesis technique of a kind of W-2979M according to claim 1; It is characterized in that: the reaction conditions of N-methyl six hydrogen azatropylidene-4-keto hydrochloride and benzoyl hydrazine is: the mol ratio is 1: (1 ~ 1.2); Stirring reaction 1-5h at room temperature bathes with icy salt solution or cryosel then and is chilled to-10-20 ℃.

3. the new synthetic process of a kind of W-2979M according to claim 1; It is characterized in that: use the condition of potassium borohydride reduction to be: the methanol solution that drips 0.5 ~ 2 mol/L KOH; 1 ~ 6h adds POTASSIUM BOROHYDRIDE 97MIN again, and the amount that adds POTASSIUM BOROHYDRIDE 97MIN is 1 ~ 1.5 times of N-methyl six hydrogen azatropylidene-4-keto hydrochloride add-on; Continue cooling and stirring after 5-50 minute, 10-50 ℃ of following stirring reaction 5 ~ 10h.

4. the synthesis technique of a kind of W-2979M according to claim 3, it is characterized in that: the product with behind the potassium borohydride reduction is used CH ₂Cl ₂MgSO is used in extraction ₄After the drying, again with adding the diethyl ether solution salify that contains HCl, precipitation; Add pure water and 2-(to chloro acetyl) phenylformic acid again; Add-on is 0.8 ~ 1.2 times of N-methyl six hydrogen azatropylidene-4-keto hydrochloride add-on; Using 10 ~ 30% NaOH solution accent pH again is 5 ~ 9, stirring and refluxing 1 ~ 3h, under agitation cooling; Make oily matter become solid particulate, the NaOH with 10 ~ 30% transfers PH>7, the W-2979M free alkali is fully separated out, leave standstill, filter the washing after drying.

5. the synthesis technique of a kind of W-2979M according to claim 1 is characterized in that: dried 4-(4-benzyl chloride base)-2-(six hydrogen-1-methyl isophthalic acid H-nitrogen Zhuo-4-yl)-1-(2H)-phthalazinium hydrochlorate, the first acetone heating for dissolving of using; Add gac, stirring and refluxing 10-80min, filtered while hot; Filter residue washs with hot acetone, and filtrating is used the aqueous isopropanol salify that contains HCl under cooling and stirring, freezing, filtration; Solids is used the cold acetone thorough washing, drains.

6. 80 ~ 105 ℃ of following dryings, distinguish recrystallization once with acetone and ethanol again, obtain 4-(4-benzyl chloride base)-2-(six hydrogen-1-methyl isophthalic acid H-nitrogen Zhuo-4-yl)-1-(2H)-phthalazinium hydrochlorate product.