Tanabe Seiyaku Company, Limited

Takeji Shibatani

Hiroaki Matsumae

Ryuzo Yoshioka

Hiroyuki Akatsuka

Eri Kawai

Shin-ichi Yamada

Takuo Nishida

Eiji Takahashi

Ichiro Chibata

Tetsuya Tosa

Kenji Omori

Takao Mori

Taizo Watanabe

Masakatsu Furui

Yasuhiko Ozaki

Saburo Komatsubara

Satoshi Minobe

Hiroyasu Seko

Akio Nakao

Toshiyuki Furutani

Shinichi Yamada

Makoto Masuda

Kouji Yanagiya

Kouhei Takahashi

Motoyoshi Sato

Tadashi Kometani

Akiko Idei

Atsuhiko Tsujimura

Toshio Kakimoto

Yoshiaki Kakie

Noriyuki Nishimura

Powdery aggregate of 2-phenyl-1,5-benzothiazepin-3,4(2H,5H)-dione compound: ##STR1## wherein Ring A and Ring B are benzene ring having optionally substituent selected from lower alkyl, lower alkoxy and halogen, which is prepared by admixing solution of the compound (II) in polar organic solvent with solvent which does not substantially dissolve the compound (II) but is miscible with said polar organic solvent, and separating and collecting the resultant particles of the compound (II). Said aggregate of the compound (II) can be converted into optically active 3-hydroxy-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one compounds (I) on industrial scale, which are useful as intermediate for various medicaments.

Process for preparing optically active benzothiazepine compound and

An optically active salt of 1,5-benzothiazepine compound of the formula (I) or (II): ##STR1## wherein each of Ring A and Ring B is a substituted or unsubstituted benzene ring, and R.sup.1 and R.sup.2 are the same or different and each is a lower alkyl group, can be prepared by resolving a racemic salt of 1,5-benzothiazepine compound of the formula (I) or (II) by means of preferential crystallization.

Optically active benzothiazepine compounds and process for preparing the

Process for preparing optically active trans-3-phenylglycidamide compound, which comprises subjecting racemic trans-3-phenylglycidamide compound of the formula (I) ##STR1## wherein Ring A is substituted or unsubstituted benzene, and R.sup.1 is H or lower alkyl, to optical resolution using a microorganism having ability of preferentially hydrolyzing one of (2S,3R) isomer or (2R,3S) isomer thereof, and process for preparing an optically active 1,5-benzothiazepine derivative from the thus-obtained optically active trans-3-phenylglycidamide compound.

Process for preparing optically active trans-3-phenylglycidamide

A gene encoding a polypeptide which participates in the mechanism of secretion of esterase originated from a microorganism of the genus Serratia, a recombinant plasmid comprising a plasmid prepared by inserting said gene into a vector plasmid, a microorganism transformed with said recombinant plasmid, and a method for the production of an esterase which comprises cultivating the transformant microorganism as set forth above in a medium and collecting the produced esterase outside and inside the cells. Said transformed microorganism have remarkably excellent capability of extracellular secretion of esterase.

Gene participating in the mechanism of secretion of esterase

A novel process for preparing 1,5-benzothiazepine derivative �II!: ##STR1## wherein Ring A and Ring B are substituted or unsubstituted benzene ring, and R.sup.3 is H, (di-lower alkylamino)-lower alkyl or substituted or unsubstituted piperazinyl-lower alkyl, or a salt thereof, in high yield and in a single step from a novel 3-(2-amino-substituted or unsubstituted phenylthio)-2-hydroxy-3-substituted or unsubstituted phenylpropionamide compound. Said 1,5-benzothiazepine derivative �II! is useful as an intermediate for preparing medicaments such as diltiazem hydrochloride.

Process for preparing 1,5-benzothiazepine derivative

Disclosed is a process for preparing a D-amino acid selected from the group consisting of D-methionine, D-valine, D-leucine, D-isoleucine and D-histidine, which comprises the steps of:

Process for preparing D-amino acids

An optical resolution process of the compound of the formula (1): ##STR1## wherein Ring A and Ring B are a substituted or unsubstituted benzene ring and R.sup.1 and R.sup.2 are the same or different and a lower alkyl group, by utilizing difference in solubility between the two diastereoisomeric salts prepared by treating the racemic compound (1) with an acidic resolution agent. The present process is industrially advantageous with compared to conventional processes for preparing an optically active 3-hydroxy-1,5-benzothiazepine derivative which are useful as an intermediate for preparing medicines.

Process for preparing optically active 3-hydroxy-1,5-benzothiazepine

There is disclosed a method for determining an endotoxin by reacting the endotoxin adsorbed on an adsorbent having specific endotoxin adsorbability with an endotoxin detecting reagent, including the steps of:

Method for determining endotoxin and apparatus therefor

A gene encoding an esterase originated from a microorganism of the genus Serratia, a mutant strain having high esterase productivity containing said gene, a recombinant plasmid comprising said gene inserted into a vector plasmid, a novel microorganism transformed with said recombinant plasmid, and a method for the production of an esterase which comprises cultivating the mutant strain or the novel microorganism as set forth above in a medium and collecting the produced esterase outside and inside the cells. Said mutant strain having high esterase productivity and new transformed microorganism have excellent esterase productivity and can produce the desired esterase in high purity on a large scale.

Gene coding for esterase and novel microorganism containing said gene

A process for preparing optically active 3-phenylglycidic acid esters comprising reacting a racemic trans-3-phenylglycidic acid with an alkanol in the presence of a hydrolase to esterify preferentially either (2S, 3R) isomer or (2R, 3S) isomer of said racemic compound and isolating and collecting the resulting optically active 3-phenylglycidic acid ester from the reaction mixture, whereby the optically active ester can be produced in a single step and in a highly pure form. The optically active 3-phenylglycidic acid esters are useful for the preparation of 1,5-benzothiazepine derivatives having pharmacological activities such as platelet aggregation inhibitory activity.

Process for preparing (2S,3R)-3-alkyl-phenylglycidic acid esters using

A process for producing an esterase by cultivating an esterase-producing microorganism is disclosed. The cultivation is carried out in a medium to which has been added an ester of sorbitan or polyoxyethylene sorbitan and a substituted or unsubstituted fatty acid having 12 to 18 carbon atoms along with an amino acid which has the formula: ##STR1## wherein R.sup.1 is hydrogen or a lower alkyl group which may be substituted with a substituent selected from the group consisting of hydroxy, carboxy, amino, guanidino, carbamoyl, mercapto, methylthio, phenyl, hydroxyphenyl, imidazolyl and indolyl, and R.sup.2 is hydrogen, or R.sup.1 and R.sup.2 are combined to form trimethylene.

Production of an esterase in a culture medium containing an ester of

There is disclosed a process for preparing optically active 3-phenylglycidic acid ester compound, which comprises permitting a culture broth, cells or treated cells of a microorganism having an ability of stereoselectively hydrolyzing a (2R, 3S)-3-phenylglycidic acid ester compound to act on a racemic 3-phenylglycidic acid ester compound which may also have a substituent on the phenyl group, thereby hydrolyzing the (2R, 3S) optically active isomer and separating and collecting the (2S, 3R) antipode from the reaction mixture.

Process for preparing optically active 3-phenylglycidic acid esters

A novel esterase which is derived from Serratia marcescens is disclosed. Said esterase has the following physico-chemical properties and enzymatic characteristics: (1) Activity; it (i.e., said esterase) hydrolyzes an ester bond of organic carboxylates, (2) Substrate specificity; it acts on alkyl esters of organic carboxylic acids, triglycerides or thiol esters, (3) Optimum pH; its optimum pH is 7.5-9.0 when the hydrolysis is carried out by using olive oil as the substrate, (4) pH stability; it is stable at pH 5.0-9.0 when it is stored at 30.degree. C. for one hour, (5) Optimum temperature; its optimum temperature is 40.degree.-50.degree. C. when the hydrolysis is carried out by using olive oil as the substrate, (6) Heat stability; it is stable at a temperature of not higher than 50.degree. C. when it is stored at pH 8.0 for 30 minutes, (7) Molecular weight; 62,000.+-.2,000 (SDS-polyacrylamide gel electrophoresis), (8) Isoelectric point; 4.6.+-.0.1, (9) Effect of metal ions; it is activated in the presence of 1 mM calcium ion, and inhibited in the presence of 1 mM cobalt ion, nickel ion, iron ion or ethylenediamine-tetraacetic acid. Said esterase can widely be applied for organic synthetic reactions.

Esterase purified from serratia marcescens SR41 (FERM BP-No. 487)

Disclosed is a process for preparing 2-halogeno-3-hydroxy-3-phenylpropionic acid ester compounds represented by the formula (I): ##STR1## wherein Ring A is a phenyl group which may be substituted, R.sup.1 is an ester residue, and X is a halogen atom, which comprises permitting an enzyme having the ability of stereoselectively reducing oxo group to hydroxy group to act on 2-halogeno-3-oxo-3-phenylpropionic acid ester compounds represented by the formula (II): ##STR2## wherein Ring A, R.sup.1 and X have the same meanings as defined above.

Process for preparing 2-halogeno-3-hydroxy-3-phenyl-propionic acid ester

An aqueous solution of crude urokinase is contacted with a cross-linked diethylaminoethyl-agarose to have pyrogens adsorbed thereon. The effluent is then contacted with a water-insoluble, hydrophilic polysaccharide having a group of the formula:

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Kobe, Japan

Takeji Shibatani