Patent GB-585089-A (GB)
Title: Improvements in or relating to the production of oxazolone methylene ethers
IPC: C07D263/42
Filed: 1944-03-04
Abstract: Oxazolone derivatives of the general formula:  <FORM:0585089/IV/1> wherein R represents an alkyl or aralkyl group and R1 represents a saturated or unsaturated, substituted or unsubstituted hydrocarbon group, are produced by condensing an appropriate N-acylated glycine with an alkyl or aralkyl orthoformate, e.g. ethy orthoformate, in the presence of an acid anhydride to yield products considered useful as intermediates in a synthesis of penicillin and similar substances. It is, in general, desirable and in some cases necessary, at least where R1 is an alkyl group other than methyl, to employ as condensing agent the anhydride corresponding to the acyl group of the acyl glycine.  Specified radicals represented by R are ethyl, propyl or benzyl and by R1, butenyl, amyl, phenyl, styryl, p-nitrophenyl and p-nitrostyryl.  Potentially active therapeutic substances are obtained by replacing the ether group in the -CHOR radial by other groups, e.g. by ammonia or by primary or secondary amines or hydrazines to yield compounds of the type:-  <FORM:0585089/IV/2> wherein R1 has the significance defined above and R4 and R5 represent monovalent radicals including hydrogen and substituted or unsubstituted alkyl groups or together form part of a closed ring, e.g. the piperidine ring, and which contain no functional groups interfering with the reaction or reating preferentially with substituent groups present in (I) or the group NR4R5 represents a hydrazine residue. Specified amines are aniline piperidine glycine ethyl ester and the aminoquinolines, and hydrazine and substituted hydrazines can be employed.  Reaction is effected by warming the two reactants together, optionally in the presence of a solvent such as pyridine, ethyl alcohol, benzene or water.  Compounds of general formula (I) may be treated with compounds carrying both an amino group (primary or secondary) and a thiol group, e.g. b b -dimethylcysteine and the carboxyl and/or the thiol group in such cysteine oxazolones may be protected to promote smoother further reaction, subsequently removing the covering atom or group.  Again, a 4-methylene-5-oxazolone carrying an ether group as in (I) may react with hydrogen sulphide or with a mercaptan to yield compounds of the type:- <FORM:0585089/IV/3> wherein R1 has the significance defined above and R6 is hydrogen or an organic radical, e.g. a hydrocarbon radical such as phenyl; benzyl mercaptan is specified.  Oxazolones of type (I) and amino derivatives thereof, may be converted into the corresponding 4-hydroxymethylene compounds, (a) directly, by treatment with concentrated hydrochloric acid; (b) indirectly, by basification with caustic alkalis and acidification of the resultant salts.  Such compounds and their alkali metal salts will react in aqueous solution with ammonia and with primary or secondary amines to yield compounds of type (II).  Numerous examples are given. 2-Styryl-4-ethoxymethylene-5-oxazolone is prepared by refluxing together cinnamoyl glycine, ethyl orthoformate and acetic anhydride at 135-140 DEG  C.  S-Benzyl penicillamine is prepared by adding 2-phenyl-4-isopropylidene-5-oxazolone, in dry benzene, to benzyl mercaptan, in methanolic sodium methoxide, acidifying, evaporating, heating the residue with an aqueous mixture of acetic and hydrochloric acids treating the evaporated solution with ether and normal hydrochloric acid and neutralising with ammonia. Specification 585,581 is referred to.