Patent GB-584918-A (GB)
Title: Improvements in and relating to the synthesis of thiazolidine compounds
IPC: C07D277/06
Filed: 1943-11-23
Abstract: Thiazolidine derivatives, some of which are suitable for use in the synthesis of compounds chemically related to penicillin, are obtained by the action of a cysteine derivative carrying at least one lower alkyl (C1 to C9) group in the b -position with (a) an aldehyde or (b) a ketone of higher molecular weight than acetone.  Such aldehyde or ketone may be substituted, e.g. by an amino or substituted amino group.  Alternatively, a compound furnishing such an aldehyde or ketone, e.g. an acetal, a half-acetal (such as an ethoxy methylene compound, or a haloacetal), a thioacetal or a bisulphite compound may be used. The corresponding nitro compound may be used in place of an aminoaldehyde or amino ketone, the nitro group being subsequently reduced.  Specified compounds for reaction with the b -alkyl cysteine are amino diethyl acetal, n-caproyl-amino diethyl acetal, benzoylamino diethyl acetal, phenylacetylamino diethyl acetal, p-toluenesulphonylamino diethyl acetal, N - carbethoxyamino diethyl acetal, ethyl b b -diethoxypropionate, ethyl a  - aldehyde - a  - phenylacetamino-acetate, the benzyl ester of aminodiethyl-acetal N - carboxylic acid, n - caproylamino acetaldehyde, ethyl - a  - formyl - N - n1 - caproylamino acetate, cyclohexanone, ethyl formyl acetate b -aminobutyraldehyde diethyl acetal, b  - aminopropionaldehyde diethyl acetal and 2 : 3-hexanedione.  Preferred compounds are obtained by condensing compounds of the general formula <FORM:0584918/IV/1> with cysteine derivatives of the general formula <FORM:0584918/IV/2> to form thiazolidine derivatives of the general formula <FORM:0584918/IV/3> wherein R2 represents hydrogen or carboxyl or an alkyl, aralkyl or aryl acyl or thioacyl radical or an alkyl, aralkyl or aryl ester radical, R3 represents hydrogen, or an alkyl, aralkyl or aryl ester readical, R4 represents hydrogen or a lower alkyl (C1 to C9) radical, R5 represents a lower alkyl (C1 to C9) radical, R6 and R7 each represent hydrogen or an alkyl, aralkyl or aryl radical and R8 represents hydrogen; X may be zero or 1 to 5.  In cases where R3 represents an ester group, this and the group COOR6 may subsequently be hydrolysed to carboxyl radicals. Preferably, the starting-material employed is a formyl aldehydic glycine derivative, X being zero and R3 representing an ester radical.  Where an amino ketone is employed in the condensation, R8 represents an alkyl, aryl or aralkyl group or R8 and R3 may together constitute part of an alicyclic ring when a cyclic amino ketone is used.  Numerous examples are given.  Caproylamino acetaldehyde is prepared (a) by hydrolysis of the corresponding diethyl acetal formed by reaction of amino diethyl acetal with n-caproyl chloride or by boiling caproic acid amide in xylene containing potassium and reaction of the product with bromacetal or (b) by reduction of the product of reaction of glycine with caproyl chloride.  Ethyl - a  - formyl - n - caproyl amino - acetate is obtained by reaction of caproyl glycine ethyl ester with ethyl formate and sodium in benzene.  N - Carbethoxy- and N - carbobenzyloxyamino - acetals are obtained by reaction of aminodiethyl acetal with ethyl and benzylchloroformates respectively. p - Toluenesulphonylamino - diethyl acetal is obtained by reaction of aminodiethyl acetal with p-toluenesulphonyl chloride in aqueous sodium hydroxide.  N - n - Caproylamino-b -aminopropionaldehyde-diethyl acetal is obtained by reaction of b -aminopropionaldehyde-diethyl acetal hydrochloride with n-caproyl chloride in aqueous sodium hydroxide.