Nippon Kayaku Kabushiki Kaisha

Other

Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai

Tadashi Shirai

Yasuhisa Tashiro

Hamao Umezawa

Masao Suzuki

Takaaki Aoyagi

Tetsushi Saino

Shigeru Aoki

Rinzo Nishizawa

Akio Fujii

Hideo Sugimura

Yasushi Takahashi

Yuzo Aboshi

Toshiro Narita

Toshiaki Arai

A process for producing threo-3-amino-2-hydroxybutanoylaminoacetic acids comprises the steps of allowing to react a starting compound represented by the general formula: ##STR1## wherein R.sub.1 represents a naphthyl or a group of the formula: ##STR2## in which R.sub.6 and R.sub.7 represent individually hydrogen, halogen, amino or a protected amino, hydroxy or a protected hydroxy, a lower alkoxy or a lower alkyl and R.sub.2 represents a protected amino, with a starting compound represented by the general formula: ##STR3## wherein R.sub.3 represents hydrogen or an ester residue, to obtain threo-3-protected amino-2-hydroxy-4-oxobutanoic acid or its ester represented by the general formula: ##STR4## wherein R.sub.1, R.sub.2 and R.sub.3 have the same meanings as above, and then reducing the same into threo-3-protected amino-2-hydroxybutanoic acid or its ester represented by the general formula: ##STR5## wherein R.sub.1, R.sub.2 and R.sub.3 have the same meanings as above, and further converting the above compound into 3-amino-2-hydroxybutanoic acid represented by the general formula: ##STR6## wherein R.sub.2 ' represents amino or a protected amino, thereafter condensing the same, in a conventional manner for forming a peptide coupling, with a compound represented by the general formula: ##STR7## wherein R.sub.4 represents an alkyl having 3-4 carbon atom or 3-guanidinopropyl, while previously protecting as required those groups not relevant to the reaction, and removing the protecting groups for the functional groups to produce threo-3-amino-2-hydroxybutanoylaminoacetic acids represented by the general formula: ##STR8## wherein R.sub.1 and R.sub.4 have the same meanings as above. This invention also provides the compounds represented by the general formula (III) as novel intermediates for the above aimed compounds and a process for producing the intermediates.

Process for producing threo-3-amino-2-hydroxy-butanoyl-aminoacetic acids

Threo-3-protected amino-2-hydroxy-4-oxobutanoic acid or its esters represented by the formula: ##STR1## wherein R.sub.1 represents naphthyl or a group of the formula ##STR2## in which R.sub.6 and R.sub.7 represent individually hydrogen, halogen, amino, an amino protected with acyl, lower alkyloxycarbonyl or carbamoyl, hydroxy or protected with acyl, lower alkyloxycarbonyl or carbamoyl, lower alkoxy, lower alkyl or phenyl group; R.sub.2 represents an amine protected with acyl, lower alkyloxycarbonyl or carbamoyl; and R.sub.3 represents hydrogen, lower alkyl having 1 to 6 carbon atoms or benzyl.

Process for producing threo-3-amino-2-hydroxybutanoyl-aminoacetic acids,

DL- .alpha.-phenylglycine can be combined with benzene-sulfonic acid, p-ethylbenzenesulfonic acid or m-xylenesulfonic acid to give the salt. The salt of the racemate may be more soluble in a sulfuric acid solution than the salt of the optically active isomer by suitably choosing the concentration of the sulfuric acid solution, and then the optical resolution by fractional crystallization is carried out. The D- or L- .alpha.-phenylglycine sulfonate is easily liberated of the sulfonic acid portion to give optically active D- or L- .alpha.-phenylglycine.

Process for the preparation of optically active .alpha.-phenylglycine

In order to separate optically active D- or L-.alpha.-phenylglycine hydrochloride from a supersaturated solution of DL-.alpha.-phenylglycine hydrochloride seed crystals of the desired D- or L-isomer are added to the solution in the presence of a metal chloride.

Optical resolution of DL-.alpha.-phenylglycine hydrochloride

Optically active p-hydroxyphenylglycine is prepared by reacting a racemic compound of a specified p-hydroxyphenylglycine derivative with optically active .alpha.-phenylethylamine to form a corresponding salt, obtaining two types of optically active salts therefrom by fractional crystallization, and obtaining optically active p-hydroxyphenylglycine by decomposition and hydrolysis of at least one of the optically active salts.

Process for the preparation of optically active p-hydroxyphenylglycine

Optically active p-hydroxyphenylglycine is manufactured by inoculating a supersaturated solution of a p-hydroxyphenylglycine sulfonic acid derivative salt comprising a mixture of the two optically active enantiomers of said salt with an optically active enantiomer of the same salt, said mixture being either racemic or else one in which the predominant enantiomer is that of the inoculant. In this manner the enantiomer having the form of the inoculant is selectively crystallized. The selectively crystallized salt is thereafter treated for removal of the sulfonic acid derivative.

Method of manufacturing optically active p-hydroxyphenylglycine

A process for preparing bleomycinic acid having a melting point of 228.degree.-230.degree.C. (decomposition) and an analysis of C : 40.80%, H : 5.29%, N : 16.45%, O : 24.78%, S : 4.53%, Cl : 3.37%, and Cu : 4.78% which is characterized by being soluble in water, difficultly soluble in methanol, acetic acid and dimethylsulfoxide, and insoluble in ethanol, ethyl acetate, acetone and ether, and which tests positive to Pauly and Ehrlich reactions but tests negative to ninhydrin, Sakaguchi, Dragendorf, Tollens, ferric chloride, Fehling and Molish reactions, and which has a maximum ultraviolet absorption spectrum at 246 m.mu. and 292 m.mu. and which has an infrared absorption spectrum bands at 3350, 1720, 1670, 1640, 1580, 1460, 1365, 1050, 770 (cm.sup.-.sup.1), and which can be hydrolyzed to yield 2'-(2-aminoethyl)-2,4'-bithiazole-4-carboxylic acid, L-threonine, 4-amino-3-hydroxy-2-methyl-.eta.-valeric acid, .beta.-hydroxy-histidine, .beta.-amino-.beta.-(4-amino-6-carboxy-5-methylpyrimidine-2-yl)-propionic acid, L-.beta.-amino-alanine, L-gulose and 3-0-carbamoyl-D-mannose, which comprises hydrolyzing bleomycin in the presence of a mycelium mass or enzyme.

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Musashino, Japan

Tadashi Shirai