CN1068316C

CN1068316C - Process for synthesizing 5-methyl-isoxazole-3-carboxamide

Info

Publication number: CN1068316C
Application number: CN96116560A
Authority: CN
Inventors: 王皆胜; 马明华; 吴艺明; 潘雪龙; 李建国; 黄桂荣
Original assignee: KUNSHAN GENERAL PHARMACEUTICAL FACTORY
Current assignee: Kunshan Shuanghe Pharmaceutical Co., Ltd.
Priority date: 1996-10-31
Filing date: 1996-10-31
Publication date: 2001-07-11
Anticipated expiration: 2016-10-31
Also published as: CN1156723A

Abstract

The present invention discloses a new process for synthesizing 5-methyl-isoxazole-3-carboxamide. Dimethyl oxalate is used as raw materials; under the action of sodium methoxide, the dimethyl oxalate and acetone are condensed into acetopyruvic acid methyl ester condensed together with hydroxylamine salt without separation to obtain 5-methyl-isoxazole-3-methyl formate directly introduced into liquid ammonia without separation to obtain 5-methyl-isoxazole-3-carboxamide. The price of raw materials used for the process is low, and intermediate compounds in each step do not need to be separated, so the present invention shortens the production period, enhances the product yield and reduces the production cost.

Description

5-methyl-isoxazoles-3-methane amide pot method synthesis technique

The present invention relates to the synthesis technique of 5-methyl-isoxazoles-3-methane amide.

5-methyl-isoxazoles-3-methane amide is the key intermediate of synthetic sulfa drug Sulfamethoxazole, existing production technology is to be raw material with the oxalic acid diethyl ester, this technology shortcoming is an oxalic acid diethyl ester unit price height, consume high, thereby cause the production cost height, and produce the by product alcohol mixture, bring problems such as reclaiming difficulty, abroad all be to continue the next step again after the intermediate product separation and purification, operate cumbersome, yield is not high, German Patent (DE3,126,394) intermediate 2.4-dioxy methyl valerate is separated, yield 88%, Czech-Slovakia's patent (CS175,335) and Romanian patent (Rom67,529) etc. 2.4-dioxy methyl valerate and oxammonium hydrochloride are contracted encircle yield 76%, Romania's patent (Rom67,530) is with 5-methyl-isoxazoles-3-methyl-formiate and ammoniacal liquor ammonification, and yield does not appear in the newspapers, whole process of preparation divided for three steps carried out, and operated cumbersome, production cycle is long, yield is not high.

The objective of the invention is: a kind of 5-methyl-isoxazoles-3-methane amide pot method synthesis technique is provided, and it is raw material with the dimethyl oxalate, and cost is low, consumption is few, and each goes on foot intermediate needn't separate, and has shortened the production cycle, has improved yield.

Technical scheme of the present invention is: a kind of 5-methyl-isoxazoles-3-methane amide pot method synthesis technique, this technology is raw material with dimethyl oxalate, acetone, sodium methylate, methanol solution, hydroxylammonium salt, through claisen condensation, get 5-methyl-isoxzzole-3-methane amide without separating, get product without separating direct ammonification with hydroxylammonium salt condensation-ring-closure reaction.

The further technical scheme of the present invention is: a kind of 5-methyl-isoxazoles-3-methane amide pot method synthesis technique, this technology is raw material with dimethyl oxalate, acetone, sodium methylate, methanol solution, hydroxylammonium salt, through claisen condensation, get 5-methyl-isoxazoles-3-methane amide without separating, get product without separating direct ammonification with hydroxylammonium salt condensation-ring-closure reaction; Dimethyl oxalate, acetone, sodium methylate, methanol solution, hydroxylammonium salt be blended in-5-120 ℃ reaction 0.5-25 hour, optimal reaction temperature-5-60 ℃ was reacted 0.5-10 hour, condensation-cyclization was 0-80 ℃ of reaction 2-10 hour, the ammonification temperature was 0-50 ℃ of reaction 1-10 hour, the mole proportioning is a dimethyl oxalate: acetone: hydroxylammonium salt: sodium methylate=1: (1-4): (1-3): (1-4), best proportioning is: dimethyl oxalate: acetone: hydroxylammonium salt: sodium methylate=1: (1-1.5): (1-1.5): (1-2); Reaction can be at polar solvent methyl alcohol, ethanol, propyl alcohol, butanols or these pure mixed solutions, and non-polar solvent benzene, toluene, chlorobenzene carry out among aprotic polar solvent DMF, the DMSO, and consumption is 1-15 times (weight ratio) of dimethyl oxalate.

In the such scheme, hydroxylammonium salt can be used oxammonium sulfate, oxammonium hydrochloride.

In the such scheme, ammonification can be carried out with ammoniacal liquor and liquefied ammonia, and consumption is a dimethyl oxalate: ammonia=1: (3--20).

Advantage of the present invention is: the dimethyl oxalate price is more inexpensive than oxalic acid diethyl ester, consumes to lack, and each goes on foot intermediate needn't separate, thereby has shortened the production cycle, has improved product yield, has reduced production cost.

The invention will be further described below in conjunction with embodiment:

Embodiment: a kind of 5-methyl-isoxazole-3-methane amide pot method synthesis technique, this technology is raw material with dimethyl oxalate, acetone, sodium methylate, methanol solution, hydroxylammonium salt, through Ke Shi, condensation-cyclization, aminating reaction and get, reaction formula is as follows:

Sodium methylate 180 grams (content 28%) are stirred down at 0-10 ℃ of mixed solution that drips dimethyl oxalate 59 grams, acetone 45 grams and methyl alcohol 100ml, dripped off in about 2 hours, isothermal reaction 3 hours is cooled to 10 ℃, slowly drip the vitriol oil to PH4-5, add oxammonium hydrochloride 45 grams, back flow reaction 8 hours finishes, be cooled to 10 ℃, feed ammonia to saturated, temperature is controlled at 20-25 ℃, finishes, reclaim methyl alcohol to doing, add 500ml water, be heated to 70 ℃, stirred 2 hours, be cooled to 20 ℃ again, filter, be washed to neutrality, dry 48.5 grams, yield 77%, mp168-169 ℃.

Claims

1. 5-methyl-isoxazole-3-methane amide pot method synthesis technique, it is characterized in that: this technology is raw material with dimethyl oxalate, acetone, sodium methylate, methanol solution, hydroxylammonium salt, through claisen condensation, get 5-methyl-isoxzzole-3-methane amide without separating, get product without separating direct ammonification with hydroxylammonium salt condensation-cyclization.

2. 5-methyl-isoxazoles according to claim 1-3-methane amide pot method synthesis technique, it is characterized in that: dimethyl oxalate, acetone, sodium methylate, methanol solution, hydroxylammonium salt be blended in-5-120 ℃ reaction 0.5-25 hour, condensation-cyclization 0-80 ℃ was reacted 2-10 hour, 0-50 ℃ of reaction of ammonification temperature 1-10 hour, the mole proportioning is a dimethyl oxalate: acetone: hydroxylammonium salt: sodium methylate=1: (1-4): (1-3): (1-4).

3. 5-methyl-isoxazoles according to claim 1-3-methane amide pot method synthesis technique, it is characterized in that: reaction can be at polar solvent methyl alcohol, ethanol, propyl alcohol, butanols or these pure mixed solutions, non-polar solvent benzene, toluene, chlorobenzene, carry out among aprotic polar solvent DMF, the DMSO, consumption is 1-15 times (weight ratio) of dimethyl oxalate.

4. 5-methyl-isoxazole according to claim 1-3-methane amide pot method synthesis technique, it is characterized in that: hydroxylammonium salt can be used oxammonium sulfate, oxammonium hydrochloride.

5. 5-methyl-isoxazole according to claim 1-3-methane amide pot method synthesis technique, it is characterized in that: ammonification can be carried out with ammoniacal liquor and liquefied ammonia, and consumption is a dimethyl oxalate: ammonia=1: (3-20).