Synthesis of ethambutol

Claim 2

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.

Claim 3

The process of claim 1 in which about 1/3 of the dl-2-amino-1-butanol is present as the hydrochloride.

Claim 4

The process of claim 1 in which the dl-2-amino-1-butanol is synthesized by heating N-[1-(chloromethyl)propyl]acetamide in the presence of a lower alkanol and water whereby the N-[1-(chloromethyl)propyl]acetamide is hydrolyzed to dl-2-amino-1-butanol, and distilling off the coproduced alkanol acetate, whereby side reactions are suppressed, and the hydrolysis to dl-2-amino-1-butanol is essentially quantitative.

Claim 5

The process of claim 3 in which the water is added first, the mixture refluxed, and then methanol as the lower alkanol is added.

Claim 6

The process of claim 3 in which the N-[1-(chloromethyl)propyl]acetamide is synthesized by reacting N-[1-(chloromethyl)propyl]acetimidoyl chloride with water, in the presence of a weak base, thereby hydrolyzing N-[1-(chloromethyl)propyl]acetimidoyl chloride to N-[1-(chloromethyl)propyl]acetamide.

Claim 7

The process of claim 3 in which the N-[1-(chloromethyl)propyl]acetamide is synthesized by reacting at least about 2 moles of acetonitrile with about 1 mole of chlorine and about 1 mole of butene-1, to produce N-[1-(chloromethyl)propyl]acetimidoyl chloride with the concurrent production of 1,2-dichlorobutane, adding water, thereby hydrolyzing said N-[1-(chloromethyl)propyl]acetimidoyl chloride to N-[1-(chloromethyl)propyl]acetamide, and after the synthesis of said N-[1-(chloromethyl)propyl]acetamide, distilling off under reduced pressure and recovering the excess acetonitrile.

Claim 8

The process of claim 6 in which water is added at about the same rate as N-[1-(chloromethyl)propyl]acetimidoyl chloride is produced, thereby hydrolyzing N-[1-(chloromethyl)propyl]acetamide before said N-[1-(chloromethyl)propyl]acetimidoyl chloride can be additionally chlorinated, and also releasing the heat of hydrolysis over the course of the reaction, thus controlling isothermal temperature rise.

Claim 9

The process of claim 7 in which the separated acetonitrile is recycled without additional purification.

Claim 10

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.

Claim 11

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.