Patent GB-828694-A (GB)
Title: New -a-amino--ß-hydroxycarboxylic acid amides and a process for their manufacture
IPC: C07C237/00
Filed: 1956-03-05
Abstract: The invention comprises amides of the formula R-CHOH-CHNH2-CO-NR2R2 where R is C1-C4 alkyl or phenyl, R1 is hydrogen or C1-C4 alkyl and R2 is phenyl optionally substituted by methoxy, ethoxy or carbalkoxy of 2-4 carbon atoms; alternatively NR1R1 may represent a saturated ring system; also acid addition salts of these amides.  Preferred amides are the anilides and p-alkoxyanilides. The compounds are made from keto acid amides R-CO-CH2-CO-NR1R2 by treatment with nitrous acid to form the isonitroso derivatives and reduction of the isonitroso and keto groups simultaneously or successively. Reduction of both groups is effected by catalytic hydrogenation (e.g. with a precious metal or nickel catalyst), by nascent hydrogen produced from sodium amalgam or aluminium amalgam and alcohol, by lithium aluminium hydride or sodium borohydride, or by electrolytic means. Alternatively the isonitroso group may be reduced to amino with nascent hydrogen obtained from a metal and acid, with sodium hydrosulphite or stannous chloride and the keto group then reduced to hydroxy in the same way as above.  It is preferable to protect the amino group in the amino-keto-acid amides by acylation, e.g. with acetic, propionic, benzoic or phylacetic anhydride or chloride; this may be done without isolation of the aminoketo amide or of the isonitroso compound. The acyl group is removed after reduction by hydrolysis with dilute acid.  The products form salts with inorganic and organic acids (several specified) and are of value therapeutically.  The examples describe the preparation of the following: (1) isonitroso-acetoacetic p-phenetidide, a -phenacetylamino-acetoacetic p-phenetidide, a -phenacetylamino - b  - hydroxybutyro - p-phenetidide, a  - amino - b  - hydroxybutyro - p-phenetidide and its hydrochloride; (2) as (1) without N-acylation, followed by formation of a salt of the product with phenyldimethylpyrazolone methylaminomethanesulphonic acid; (3) as (1) via a -acetylamino-acetoacetic p-phenetidide and a -acetylamino-b -hydroxybutyro - p - phenetidide; (4) isonitroso-acetoacetanilide, a - phenacetylamino - acetoacetanilide, a  - phenacetylamino - b  - hydroxybutyranilide and a  - amino - b  - hydroxybutyranilide; (5) isonitroso-benzoylacetic p-phenetidide, a  - amino - b  - hydroxy - b -phenylpropionic p-phenetidide and its hydrochloride; (6) isonitroso - acetoacetic N - methyl - p - phenetidide, a  - amino - b  - hydroxybutyric N - methyl - p - phenetidide and its maleate; (7) isonitroso - acetoacetic N - n-butyl - p - anisidide and a  - amino - b  - hydroxybutyric N-n-butyl-p-anisidide maleate; (8) isonitroso-acetoacetic N-methylanilide and a  - amino - b  - hydroxybutyric N - methylanilide maleate; (9) N-ethyl analogues of (8); (10) isonitroso-acetoacetic 4-phenyl-4-carbethoxy - piperidide and a  - amino - b  - hydroxybutyric 4 - phenyl - 4 - carbethoxy - piperidide; (11) isonitroso - acetoacetic p - carbethoxyanilide and a - amino - b  - hydroxybutyric p-carbethoxyanilide.  A list is given of other suitable starting materials where R is methyl and phenyl, and either R1 is H, methyl, ethyl, n- and iso-propyl, n- and iso-butyl and R2 is phenyl, p - methoxyphenyl, p - ethoxyphenyl, p - carbomethoxyphenyl, o - and p - carbethoxyphenyl and p - carbopropoxyphenyl, or NR1R2 is piperidino, pyrrolidino, morpholino, thiazolidino, pipecolino (3 isomers), decahydroqiunolino and decahydro-isoquinolino.  The following acetoacetic amides are prepared from the amine and diketene: N-methylanilide, N - ethylanilide, N - n - butyl - p-anisidide, p - carbethoxyanilide and 4-phenyl-4-carbethoxypiperidide.