Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Patent
1997-12-11
1999-10-19
Burn, Brian M.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C07C22940
Patent
active
059691794
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a process for the preparation of one enantiomeric form of 2-amino-3-(4-alkylaminophenyl)propanoic acid of general formula: ##STR2## in which Alk represents an alkyl radical containing 1 to 2 carbon atoms, and salts thereof.
The preparation of (2S)-2-amino-3-(4-methylaminophenyl)propanoic acid has been described in patent application WO 94/08014, by the action of an N-methyltransferase on p-amino-(L)-phenylalanine. However, this preparation would not be exploitable industrially on account of the very low yields.
The preparation of racemic 2-amino-3-(4-methylaminophenyl)propanoic acid has been described by B. L. Moldaver and Z. V. Pushkareva, Chem. Abstr., 55, 22226g; furthermore, the specificity of this reaction does not guarantee the production of N-monomethylated compound (on synthesizing diethyl p-dimethylaminobenzyl-N-acetylaminomalonate, the presence is observed, after crystallization, of a mixture of p-aminophenylalanine and its mono- and dimethyl derivatives in the crystallization mother liquors).
It has now been found that the enantiomeric forms of this acid can be prepared directly from (L)-phenylalanine or from (D)-phenylalanine, depending on whether it is desired to obtain the (S) or (R) form of the acid respectively, in high yields and with a product of good quality.
According to the invention, (L)- or (D)-phenylalanine, whose amine function is optionally protected, is nitrated, and the nitro radical of the 4-nitrophenylalanine obtained, of general formula: ##STR3## in which R is a hydrogen atom or a protecting radical, is then converted into an alkylamino radical, after protection (if R is hydrogen) of the amine function of the phenylalanine.
The nitration is carried out by nitric acid in sulphuric medium, at a temperature of between -10 and -20.degree. C.
The protection of the amino radical is carried out according to the known methods, by a protecting radical R whose installation and removal do not affect the rest of the molecule. In particular, the process is performed according to the methods described by T. W. Greene, Protective Groups in Organic Synthesis, A. Wiley-Interscience Publication (1981), or by McOmie, Protective Groups in Organic Chemistry, Plenum Press (1973). Preferably, the amino radical is protected in the form of amide by a radical R=acyl, more particularly by an acetyl radical; or alternatively the amino radical is protected in the form of carbamate by a radical R=alkyloxycarbonyl.
The conversion of the nitro radical into an alkylamino radical is carried out by reductive alkylation when the radical Alk is a methyl or ethyl radical, or by reduction, formulation of the amine obtained and subsequent reduction of the formylamino radical when the radical Alk represents methyl.
The reductive alkylation is carried out by hydrogenation, under a pressure of hydrogen in the presence of Raney nickel, working in methanol at a temperature of between 20 and 40.degree. C. and at a pressure of between 100 and 200 kPa.
The alkylation is carried out under hydrogen pressure by addition of benzaldehyde and then formaldehyde in the case where Alk is a methyl radical, or ethanal in the case where Alk is an ethyl radical.
The removal of the amino-protecting radical and the removal of the benzyl radical are carried out successively. When the amino-protecting radical is an acetyl radical, the removal is carried out by treatment in aqueous acid medium, in particular by hydrochloric acid. When Alk is a methyl or ethyl radical, the removal of the benzyl radical is carried out by hydrogenation under hydrogen in the presence of palladium-on-charcoal in aqueous acid medium, in particular aqueous hydrochloric acid, at a temperature of between 50 and 60.degree. C. and at a pressure of between 100 and 200 kPa. In this case, the phenylalanine derivative of general formula (I) is obtained in salt form. It may optionally be released from its salt according to the usual methods which do not affect the rest of the molecule.
When it is desired to obtain a phenylalanine derivative
REFERENCES:
patent: 4647694 (1987-03-01), Hosztafi et al.
Chemical Abstracts, vol. 55, No. 22, Abstract No. 22226g (1961).
F. Bergel et al., 19. Cyto-Active Amino Acids and Peptides. Part V. Derivatives of p-Amino and p-Mercapto-phenylalanine, J. Chem. Soc. (1959), pp. 90-97. (with Chemical Abstract vol. 53, No. 13, Abstract No. 12202g (1959).
Burn Brian M.
Davis Brian J.
Rhone-Poulenc Rorer S.A.
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