Synthesis of ethambutol
AssigneeAmerican Cyanamid Company
InventorBalwant Singh
Life of this patent
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Abstract
D-2-Amino-1-butanol, for the synthesis of ethambutol hydrochloride, d,d'-2,2'-(ethylenediimino)di-1-butanol dihydrochloride, is produced in high purity and good yields by the reaction of butene-1, a nitrile, preferably an excess of acetonitrile, and chlorine to form N-[1-(chloromethyl)propyl]acetimidoyl chloride which is hydrolyzed to dl-2-amino-1-butanol, which can be isolated as the hydrochloride, or free base, or a mixture, resolved with L(+)-tartaric acid and the d-2-amino-1-butanol reacted with ethylene dichloride and then hydrochloric acid to form ethambutol hydrochloride. A minimum of by-products which are conveniently split out permits the economical synthesis of a pharmaceutical grade product.
Claims9
The process of the synthesis of d,d'-2,2'-(ethylenediimino)di-1-butanol which comprises mixing dl-2-amino-1-butanol containing dl-1-amino-2-butanol with L(+)- tartaric acid in anhydrous methanol, separating the crystalline acid L(+)- tartrate of d-2-amino-1-butanol from the salts of dl-2-amino-1-butanol and d- and l- 1-amino-2-butanol which remain in solution in the methanol, dissolving said d-2-amino-1-butanol L(+)- tartrate in water, adding an alkali or alkaline earth hydroxide, separating out the resultant alkali or alkaline earth L(+)- tartrate, thus isolating d-2-amino-1-butanol, evaporating off remaining water, adding ethylene dichloride, and reacting to form d,d'-2,2'-(ethylenediimino)di-1-butanol, and isolating the thus formed d,d'-2,2'-(ethylenediimino)di-1-butanol as the dihydrochloride salt.
A process for the synthesis of d,d'-2,2'-(ethylenediimino)di-1-butanol which comprises adding chlorine and butene-1 to an excess of acetonitrile to form N-[1-(chloromethyl)propyl]acetimidoyl chloride, with the concurrent production of 1,2-dichlorobutane, adding water to hydrolyze the N-[1-(chloromethyl)propyl]acetimidoyl chloride to N-[1-(chloromethyl)propyl]acetamide, distilling off and recovering for recycle the excess acetonitrile, adding water and azeotropically distilling off at least the last part of by-product 1,2-dichlorobutane, adding methanol and hydrochloric acid to the partially hydrolyzed mixture containing at least some N-[1-(chloromethyl)propyl]acetamide and dl-2-amino-1-butanol hydrochloride, refluxing to complete hydrolysis to dl-2-amino-1-butanol hydrochloride, and distilling off the residual water, and by-product methyl acetate, dissolving said dl-2-amino-1-butanol hydrochloride in methanol, adding anhydrous ammonia, separating out solid ammonium chloride, thereby leaving dl-2-amino-1-butanol as a mixture of the free base and its hydrochloride salt, adding L(+)- tartaric acid, separating crystalline d-2-amino-1-butanol L(+)- tartrate from the solution, leaving behind l-2-amino-1-butanol and d- and l- 1-amino-2-butanol as hydrochloride and/or L(+)- tartrate salts, dissolving the said d-2-amino-1-butanol L(+)- tartrate in a solvent, adding potassium hydroxide, separating out potassium L(+)- tartrate, thus isolating the d-2-amino-1-butanol, evaporating off the solvent, distilling off purified d-2-amino-1-butanol;
- adding not more than 1/6 mole of ethylene dichloride per mole of the thus distilled d-2-amino-1-butanol, adding finely-divided sodium hydroxide to react with the hydrogen chloride present, distilling off the unreacted d-2-amino-1-butanol, adding a 2 to 4 carbon alkanol, separating the sodium chloride from the solution, adding hydrogen chloride to convert the product d,d'-2,2'-(ethylenediimino)-di-1-butanol to its dihydrochloride salt, and separating said salt from the solution, in a pharmaceutically elegant form.
Dependencies are inferred from the claim text.