N-formylation of amino carboxylic compounds with formamide

#The invention relates to N-formylation of certain amino carboxylic acids. An amino carboxylic acid, e.g., aspartic acid, is reacted with formamide to convert the amine group to a formyl group, -NH-CHO. With the amine group protected (by the N-formylation), the compound can then be used in conventional dipeptide synthesis or in other chemical or enzymatic reactions. The protecting formyl group may be removed by mild hydrolysis.

#N-formylation of amino carboxylic acids is not new and a number of reagents have been employed to protect the amine group in this manner. However, the prior art processes are complex, expensive and/or do not provide adequate yields. For example: L-phenylalanine has been N-formylated by treating its sodium salt with chloral, Chem. Abs. 102(11):96080z. D-phenylalanine, glycine, valine and glutamic acid have been N-formylated with HCO.sub.2.SO.sub.3.Na, Chem. Abs. 85(1):6043t. Acetic anhydride has been added to amino acid in formic acid, Sheehan et al., J. Am. Chem. Soc., Vol. 80, p. 1154 (1958); Gensler et al., J. Org. Chem., Vol. 21, p. 336 (1956). Benzyl esters of amino acid derivatives can be N-formylated with formic acid in the presence of N,N'-dicyclohexylcarbodiimide, Thomas, Tetrah. Let. 335 (1967). N-formylation of t-butylamine with ethyl formate has been reported in yields of 29.4 to 84%, Moffatt et al., J. Org. Chem., Vol. 27, p. 4058 (1962). Pettit et al., J. Org. Chem., Vol. 24, p. 895 (1959), reports that sodium methoxide, aniline and dimethylformamide may be heated to yield formanilide. Galat et al., J. Am. Chem. Soc., Vol. 65, pp. 1566-67 (1944), disclose the reaction:

#RNH.sub.2.HCl+R'--C(:O)--NH.sub.2 =RNH--C(:O)--R'+NH.sub.4 Cl.

#Under a nitrogen atmosphere, a slurry of 2.7 gm (20 mmol) L-aspartic acid in 4.0 ml (100 mmol) formamide was heated at 95.degree.-100.degree. C. for 2 hours. Examination of the resulting homogeneous mixture by proton NMR showed that the L-aspartic acid had been completely converted to its N-formyl derivative.

#Under a nitrogen atmosphere, a slurry of 0.75 gm (10 mmol) glycine in 4.0 ml (100 mmol) formamide was heated at 90.degree. C. for 30 minutes. Examination of the resulting homogeneous mixture by proton NMR showed that the glycine had been completely converted to N-formyl glycine.

#Under a nitrogen atmosphere, a slurry of 0.89 gm (10 mmol) alanine in 4.0 ml (100 mmol) formamide was heated at 90.degree. C. for 65 minutes. Examination of the resulting homogeneous mixture by proton NMR showed an 80% conversion of the alanine to its N-formyl derivative.