Patent GB-917435-A (GB)
Title: Phenylalanine derivatives and methods for their preparation
Filed: 1959-11-20
Abstract: The invention comprises compounds of the general formula <FORM:0917435/IV (b)/1> wherein R1 is a hydrogen atom or a C1-4 alkyl group; R2 is a hydroxy group, a C1-4 alkoxy group, an alkanoyloxy group having at most 4 carbon atoms or a phenoxy group, R3 is a carboxy group, a carbalkoxy group having at most 4 carbon atoms, a cyano or a carboxamido group, R4 is a hydrogen atom, a C1-4-alkyl group or a C1-4-alkoxy group, and R5 is a hydrogen atom, an alkanoyl group having at most 4 carbon atoms or a benzoyl group, their acid addition salts and the preparation thereof (a) by hydrolysing and simultaneously or subsequently decarboxylating substituted acylamido malonic acid esters of the formula:  <FORM:0917435/IV (b)/2> wherein R11 is a C1-4 alkyl or a benzyl group and X is an acylamido or acylimido group; (b) by reducing substituted b -phenylpropionic acid derivatives of the formula <FORM:0917435/IV (b)/3> wherein Y is a bivalent nitrogen containing group which can be converted into the amino group by reduction or reductive cleavage, in particular the imino, oximino, benzylimino or phenylhydrazono group, and Z is a monovalent nitrogen containing group which can be converted into the amino group by reduction or reductive cleavage, in particular the nitro group, the azido group or the benzylamino group; (c) treating with an alkali metal hypohalite, according to Hofmann, substituted benzylmalonamic esters of the general formula <FORM:0917435/IV (b)/4> (d) treating aldehydes of the general formula <FORM:0917435/IV (b)/5> with an alkali metal cyanide and ammonia or an ammonium salt and hydrolysing the intermediate aminonitrile; and (e) reducing and hydrolysing or reductively cleaving substituted 4-benzylidene hydantoins of the formula <FORM:0917435/IV (b)/6> or substituted 3,6-bis-benzylidene-2,5-diketopiperazines of the formula <FORM:0917435/IV (b)/7> or substituted 4-benzylidene-oxazolones of the formula <FORM:0917435/IV (b)/8> wherein R51 represents an alkyl or phenyl group.  The compounds of the invention may also be prepared by converting, according to the Schmidt reaction with hydrazoic acid, substituted a -benzyl aceto acetic acid esters of the formula <FORM:0917435/IV (b)/9> into the a -acetamido-b -phenylpropionic acid or esters which may be hydrolysed to give compounds of the free amino group; or by reacting substituted a -halo-b -phenylpropionic acids and esters with ammonia or with a salt of a dicarboxylic acid imide or diacylimide followed by hydrolytic cleavage of the acyl radical. The oxazolones XII used as starting materials may also be partially hydrolysed to the a -acylamido-cinnamic acids which may be reduced. In addition when R2 is alkoxy the group may be hydrolysed to a free hydroxy group and similarly R3 as carboxy may be esterified. Condensation of halomethyl compounds <FORM:0917435/IV (b)/10> with metal compounds of acylamido or acylimido malonic acid esters <FORM:0917435/IV (b)/11> gives the substituted acylamido malonic acid compounds (II).  By analogous condensation with acetoacetic acid esters compounds (III) are obtained.  Reaction of compounds III with alkyl nitrite or with an alkali metal and benzene diazonium chloride gives compounds (IV).  Further, compounds (XIV), are condensed with metal compounds of cyanoacetic acid esters and the substituted benzylcyano acetic acid esters so obtained partially hydrolysed give compounds (VI).  a -Halo-b -phenylpropionic acids and esters are prepared by halogenation, hydrolysis subsequent or concomitant, decarboxylation and, if desired, esterification of condensation products of compounds XIV with acetoacetic acid esters or cyanoacetic acid esters or analogous condensation products with malonic acid esters.  Compounds (V) are prepared from the a -halo-b -phenylpropionic acids or esters and an alkali metal azide or nitrite.  Compounds (VIII) are prepared by reacting the halomethyl compounds (XIV) with an alkali metal cyanide and reducing the nitrile with stannous chloride and hydrogen chloride (Stephen).  Formyl salicyclic acids and their derivatives of the formula <FORM:0917435/IV (b)/12> are condensed with hydantoin or thiohydantoin to give compounds (X) or substituted thiohydantoins which can be converted into hydantoins by acid.  Compounds (XVI) condensed with 2,5-diketo-piperazine or acetylglycine anhydride in the presence of acetic anhydride and sodium acetate give compounds (XI), or with acylglycines such as acetylglycine or hippuric acid give compounds (XII).  Compounds (XII) may be hydrolysed with a non reducing acid to form the phenylpyruvic acids which may be converted into compounds (IV) by reaction with ammonia, hydroxylamine or benzylamine.  By reacting the formyl compounds (XVI) with nitroacetic acid esters, substituted a -nitro-b -hydroxy-b -phenylpropionic acid esters are obtained which may be dehydrated to form a -nitro-cinnamic acid esters which, in turn, may be reduced to compounds (V). Compounds (XVI) condensed with cyanoacetic acid esters followed by reduction of the benzylidene cyanoacetic acid esters also form benzylcyanoacetic acid esters.  Halomethyl compounds (XIV) are prepared by halogenation of the corresponding substituted-toluene or by reacting a substituted benzene with formaldehyde and a hydrohalide.