IL25044A - Process for production of amino-alkyl carboxylic acid amides - Google Patents

Description

Process production of carboxylic acid amides DE LA I NATIONAL LA RECHBRCHB MEDICALS 23960 THIS INVENTION relates to the production acid wherein and are each selected from and and represents 0 or and and are each selected from CHj or hare therapeutic Among these compounds those preferred from the standpoint of their therapeutic activity are the ethyl amides of acetic acid and acetic The preparation of these compounds by the reaction of the appropriate acetic acid chloride with the appropriate and precipitation or recr stallisation of the product as the under anhydrous whilst used an industrial nevertheless has certain Thus the method tends to afford variable results due possibly to local The excess often may lead to the formation of which impurities in the final product may have a deleterious effect on the products from the of their use as local and such impurities are difficult if not impossible to It is an object of the present invention to provide a new method for the production of such carboxylic acid and their in a condition of improved According to the present invention there is provided alkyl carboxylic acid a process the production of an amino amide of the general formula CO N Am wherein the benzene nucleus A may carry one or more further Y represents 0 or represents H or a lower alkyl n represents aa integer from 1 to 4 and Am represents a radical cr a residue of a primary or secondary amine or of a which comprises reacting an ester of the formula T wherein represents an alkyl or aralkyl with a diamine of the formula H n 2n in substantially equimolecular n the presence of an organic diluent liquid which is chemically inert with respect to the the diamine and the product of the reaction and which forma an azeotrope with the alcohol the reaction being carried out at a temperature lower than the boiling point of the said Additional substituents which may be present oa the nucleus A may for halogen lower alkyl groups lower alkoxy The term used in this specification in relation to alkyl and alkoxy groups implies a carbon content not exceeding The diluent may be employed in excess of the quantity theoretically required for entrainment of the alcohol in the form of its Preferably the diluent used is an aromatic most preferably the group is and the reaction is effected at a temperature of 110 to It has found despite the moderate temperature of the reaction the auxiliar particularly ensures the completion of the reaction at a relatively low temperature even with esters less reactive than the methyl and more effectively than when using an excess the and nevertheless by displacing the reaction equilibrium by eliminating the alcohol which is distilled off as azeotrope continuously with its When the diluent entrains no further alcohol reaction is the excess diluent may be distilled off at atmospheric pressure and the product may be in excellent by distillation at very low Salts of the may be prepared and recrystallised by known The salts are obtained as clean white solids and generally have melting points higher than the corresponding products obtained by the processes of the prior The following examples will serve to illustrate the acetic acid acetic acid ethyl ester g t 1 is heated for 5 hours with ί 1 in solution in dry toluene The reaction is effected in a vessel provided with a short distillation column or in any other suitable apparatus so that the ethanol liberated by the reaction may be as its azeotrope with the during the course of the reaction while the excess toluene is condensed and thus returned to the reaction When no further alcohol is produced the excess toluene is distilled off and the residual basic amide is distilled under reduced pressure 1 mm The amide thus obtained is dissolved in a mixture of 1 volune acetones and 3 volumes diethyl ether and treated with ezcess dry hydrochloric acid The precipitated after from melts at The yield of pure product is 75 EXAMPLE 2 phenoxy acetic acid amide phenoxy acetic acid ethyl ester is heated under reflux for 3 hours with ethylamine 1 in solution in toluene the azeotrope of ethanol and toluene being distilled off continuously with its The excess toluene is then distilled off and the residue distilled at low The base thus obtained is dissolved in anhydrous diethyl acetone added and a current of dry hydrochloric acid gas passed through the solution to precipitate the The after recrystallisation from anhydrous has and is obtained in a yield of EXAMPLE and acetic acid amide By proceeding as in Example 2 but replacing the methoxy phenoxy acetic acid ethyl ester by an equimolecular quantity of phenoxy acetic acid ethyl ester and para phenoxy acetic acid ethyl there are obtained phenoxy acetic acid hydrochloride and butoxyphenoxy acetic acid hydrochloride insufficientOCRQuality

Claims (6)

HAVING NOW particularly described and ascertained the nature of our said invention and in what manner the same is to he performed, we declare that what we claim ia: alkyl carboxylic acid

1. · A process for the production of an amino/amide of the general formula wherein the benzene nucleus A may carry one or more further conventional tsubstituents, Y represents 0 or SO,,, Z^ represents H or a lower alkyl group, n represents an integer from 1 to 4 and Am represents a radical ΈΕ^ or a residue of a primary or secondary amine or of a cycloamine, which comprises reacting an ester of the formula wherein represents an alkyl or aralkyl radical, with a diamine of the formula Z^ t H - N — C H. - Am n 2n in substantially equimolecular quantities, in the presence of an organic diluent liquid which is chemically inert with respect to the ester, the diamine and the product of the reaction and which forms an azeotrope with the alcohol Z^OH, the reaction being carried out at a temperature not lower than the boiling point of the said azeotrope.

2. A process according to claim 1 wherein the nucleus A is further substituted by one or more halogen atoms, lower alkyl groups and/or lower alkoxy groups*

3. · A process according to claim 1 or 2 wherein the diluent is an aromatic hydrocarbon.

4. · A process according to claim 3 wherein the diluent is toluene.

5. · Δ process according to any of claims 1-4 wherein the group Z≥ is an ethyl group.

6. A process according to claim 1 or 2 wherein the diluent is toluene, the group s a ethyl group and the reaction is effected at 110-130°C. 7· A process according to claim 1 or 2 substantially as hereinbefore described with reference to any one of the foregoing specific examples 1 to 3· alkyl carboxylic acid 8, An amino/amide as defined in claim 1 whenever prepared or produced by the processes hereinbefore described and claimed. Dated this 24th Day of January, 1966