Process for the preparation of midodrine
a technology of midodrine and process, which is applied in the preparation of amino compounds, organic chemistry, carboxylic acid amides, etc., can solve the problems of dangerously explosive sodium azide and achieve the effect of no safety risks
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example 1
Preparation of 2-chloro-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamid- e
[0013] The reaction vessel is charged with 15.5 g 1-(2,5-dimethoxyphenyl)-- 2-amino-ethanol hydrochloride, 115 ml methylene chloride and 100 ml water. The mixture is stirred at 25.degree.-30.degree. C. to afford a clear two-phase mixture. The mixture is cooled to 5.degree.-10.degree. C. and a solution of 18.7 g of 50% potassium hydroxide and 18.5 ml water is added in portions at 5.degree.-10.degree. C.
[0014] The mixture is stirred at 5.degree.-10.degree. C. for 15 min. 8.0 ml of chloroacetyl chloride is added in portions at 5.degree.-10.degree. C. causing an exothermic reaction to occur. On completion of the addition, the pH should be adjusted to 3-6. The mixture is allowed to warm to 25.degree.-30.degree. C. and the pH is adjusted again to 3-6. After stirring for one hour at 25.degree.-30.degree. C., the pH is adjusted to 6-7 with 5% aqueous potassium hydroxide solution. The stirring is stopped and the lay...
example 2
Preparation of 2-dibenzylamino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]a- cetamide
[0016] The reaction vessel is charged with the methylene chloride solution of 2-chloro-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide prepared in example 1. The majority of the methylene chloride is distilled off at atmospheric pressure. On completion of the distillation 155 ml toluene are added. The mixture is stirred to obtain a solution. 45 to 50 ml of the toluene is distilled to remove the remainder of methylene chloride. The mixture is cooled to 85.degree.-90.degree. C. and 28.4 g dibenzylamine is added in portions at 85.degree.-90.degree. C. On completion of the addition, the mixture is heated to reflux for a period of 10 hours.
[0017] On completion of reaction, the resulting suspension is cooled to 45.degree.-50.degree. C. 110 ml water are added followed by 7.5 g of 50% potassium hydroxide. The mixture is stirred at 25.degree.-30.degree. C. for a period of 2-3 hours during which time the p...
example 3
Preparation of 2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide (Midodrine base)
[0021] An autoclave is charged with 15.0 g of 2-dibenzylamino-N-[2-(2,5-di- methoxyphenyl)-2-hydroxyethyl]acetamide, 200 ml ethanol and 1.5 g of 5% Pd / C catalyst. The system is flushed three times with nitrogen followed by hydrogen. The pressure of hydrogen is adjusted to 4-6 bar. The temperature is adjusted to 45.degree.-50.degree. C. The mixture is stirred and heated at 45.degree.-50.degree. C. for 24 hours.
[0022] On reaction completion, the mixture is cooled to 25.degree.-30.degree. C. and filtered through a Celite pad to separate the catalyst. The clear f / Uiltrate is transferred to a clean reaction vessel. About 1 / 2 of the ethanol is distilled out at atmospheric pressure. On cooling and seeding, Midodrine base will crystallize from solution. After cooling to 5.degree.-10.degree. C., the product is filtered to afford 6.3 g (71% yield) of white Midodrine base. The product is characterized as...
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