公开(公告)号：JPS61257962A

公开(公告)日：1986-11-15

申请号：JP9847985

申请日：1985-05-09

Applicant: FUJISAWA PHARMACEUTICAL CO

Inventor： YAZAWA HISATOYO ,  KAGARA KOUJI ,  KAWAI NOBUTAKA ,  KAKIMOTO SATOSHI

IPC: C07D263/42 ,  B01J23/00 ,  B01J23/04 ,  B01J31/00 ,  B01J31/02 ,  C07B61/00 ,  C07C67/00 ,  C07C313/00 ,  C07C319/20 ,  C07C323/62

Abstract: PURPOSE:To obtain the titled compound useful as a synthetic intermediate for dibenzothiepin derivatives simply at a low cost, by passing a benzaldehyde compound and a thiophenol compound as raw materials through novel intermediates. CONSTITUTION:A novel compound expressed by formula I (R is H or halogen) is reacted with a compound expressed by formula II (R is lower alkyl or aryl) or a salt thereof to give a novel compound expressed by formula III, which is then subjected to hydrolysis reaction to afford a novel intermediate expressed by formula IV or a salt thereof. The resultant compound expressed by formula IV or salt thereof is treated with hydrogen peroxide in the presence of a base to give the aimed compound, expressed by formula V and useful as a synthetic intermediate for dibenzothiepin derivatives useful as a remedy for schizophrenia. The novel compound expressed by formula I can be obtained from an inexpensive benzaldehyde compound and thiophenol compound and the production process is industrially advantageous.

公开(公告)号：JPH029842A

公开(公告)日：1990-01-12

申请号：JP15892688

申请日：1988-06-27

Applicant: FUJISAWA PHARMACEUTICAL CO

Inventor： KAGARA KOUJI ,  YAMAZAKI HIROSHI ,  FUJI TATSUO

IPC: C07C201/06 ,  C07C67/00 ,  C07C201/00 ,  C07C201/12 ,  C07C205/12 ,  C07C205/58 ,  C07C253/30 ,  C07C255/38 ,  C07C255/41

Abstract: PURPOSE:To obtain the title compound useful as an intermediate for synthesizing pyrrolnitrin, antimicrobial agent in high yield by oxidizing a substituted aniline as a starting raw material, reacting the resultant compound with a specific compound, successively hydrolyzing and carrying out the decarboxylation reaction. CONSTITUTION:A substituted aniline shown by formula I (X is halogen) such as 2,6-dichloroaniline is treated with NaNO2, etc., in the presence of an inorganic acid into a diazonium salt, which is reacted with NaNO2, etc., in the presence of a copper compound and oxidized to give a compound shown by formula II. This compound is reacted with a compound such as methyl cyanoacetate shown by formula III (R and R are cyano or esterified carboxyl group) in the presence of a base to give a compound shown by formula IV. Then this compound is hydrolyzed in the presence of an acid or a base to give a compound shown by formula V or a salt thereof, which is further decarboxylated in a solvent such as dimethylformamide under heating to give the aimed compound shown by formula VI such as 3-chloro-2-nitroroluene.

公开(公告)号：JPH06172318A

公开(公告)日：1994-06-21

申请号：JP32348392

申请日：1992-12-02

Applicant: FUJISAWA PHARMACEUTICAL CO

Inventor： KAGARA KOUJI ,  KAWAI NOBUTAKA ,  MACHITANI KOJI ,  KODERA TETSUO ,  NAKAMURA TAKASHI ,  OMORI HIROKI

IPC: A61K31/415 ,  A61P9/04 ,  A61P35/00 ,  A61P43/00 ,  C07D233/64

Abstract: PURPOSE:To industrially advantageously produce a amino acid derivative having a renin-inhibiting activity in high yield from inexpensive starting raw materials through a new synthetic intermediate. CONSTITUTION:The compound of formula I [R is alkyl or aryl which may be substituted with one or more substituents selected from acyl, OH, alkoxy, aryl, alkylthio, and group of formula II (R is H, acyl; R is H, alkyl), amino which may be substituted with alkyl or acyl; R and R form a substitutable heterocyclic group together with the adjacent nitrogen atom; R , R are H, alkyl; R is H, N-protected group; R'' is H, carboxy-protecting group], e.g. Nalpha-[2(S)-[N-methyl-N-[2-{N-(morpholinocarbonyl)-N- methylamino}ethyl]aminocarbonyloxy]-3-phenylpropionyl]-N -trityl-L- histidine. The compound is produced by reacting a compound of formula III with a compound of formula IV, and can be converted into an amino acid derivative of formula VI by reacting the compound of formula I with a compound of formula V (R is alkyl) and, if necessary, releasing the N-protecting group.

公开(公告)号：JPH0489452A

公开(公告)日：1992-03-23

申请号：JP20422390

申请日：1990-07-31

Applicant: FUJISAWA PHARMACEUTICAL CO

Inventor： KAGARA KOUJI ,  MACHITANI KOJI ,  TAKASUKA KIYOAKI

IPC: C07D215/14 ,  A61K31/47 ,  A61P29/00 ,  A61P37/08 ,  C07C67/14 ,  C07C69/708 ,  C07D309/12

Abstract: NEW MATERIAL:Cyclic compounds of formula {A is =C=O or =CHOR [R is cyclic terpenoxy(lower)alkanoyl]; R is oxygen-containing heterocycle or cyclic terpenoxy(lower)alkanoyl; Both R are H or lower alkyl}. EXAMPLE:5-[2H-3,4,5,6-tetrahydropyran-2-yloxy]-alpha-tetrarone. USE:An intermediate for production of a 1,2,3,4-tetrahydro-1-naphthol derivative, etc. PREPARATION:For example, a compound of formula III is added to a compound of formula II to obtain a compound of formula Ia (Z is alkylene containing 0 at terminal or on its middle part) belonging to a group of compounds of formula I.

公开(公告)号：JPH02117658A

公开(公告)日：1990-05-02

申请号：JP27171188

申请日：1988-10-27

Applicant: FUJISAWA PHARMACEUTICAL CO

Inventor： KAGARA KOUJI ,  GOSHIMA SHUNSUKE ,  MUKAI KOJI

IPC: C07D211/90 ,  A61K31/445 ,  A61K31/451 ,  A61P9/08 ,  A61P9/10 ,  A61P9/12

Abstract: NEW MATERIAL:Light-stabilized crystal of (+)-2-cyano-6-methyl-4-(3- nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 5-isopropyl 3-methyl ester having physical properties characterized by a melting point of 133-135 deg.C and a specific powder X-ray diffraction pattern. USE:The crystal exhibits hypotensive action and coronary vasodilating action, etc., and is useful as a drug. It has high light-stability and high stability as a drug and exhibits good powder handleability in drug-preparation process. PREPARATION:The objective light-stabilized crystal compound can be produced by converting a racemic compound of 5-carboxy-2-cyano-6-methyl-4-(3- nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid methyl ester to a diastereomer salt with an optically active base such as cinchronine, precipitating required diastereomer with a solvent and treating the diastereomer with an acid.

公开(公告)号：JPH01301660A

公开(公告)日：1989-12-05

申请号：JP13219888

申请日：1988-05-30

Applicant: FUJISAWA PHARMACEUTICAL CO

Inventor： KAGARA KOUJI ,  MOMONAGA SHINJI ,  MACHITANI KOJI ,  TAKASUKA KIYOAKI

IPC: C07D213/55 ,  A61K31/44 ,  A61K31/4402 ,  A61K31/4418 ,  A61P7/02 ,  C07D521/00 ,  C12P41/00

Abstract: PURPOSE:To obtain the subject compound useful for intermediate of drug in optically high purity and high yield without reagent of high cost, by reacting a mixture of D-modification and L-modification of a monocyclic heterocyclic alanine esters containing 3-nitrogen with an enzyme having esterase activity. CONSTITUTION:A mixture of D- and L-modifications of monocyclic heterocyclic alanine ester containing 3-nitrogen and salts of said ester (e.g., salt of HCl, H2SO4, nitric acid or phosphoric acid) is reacted with an enzyme having esterase activity (e.g., alpha-chymotrypsin, subtilisin) preferably at about neutral and a temperature of near 37 deg.C, in a solvent having no adverse effect to the reaction. By said method, only L-modification of said mixture is selectively deesterified and D-modificationis obtained.

公开(公告)号：JPH0616645A

公开(公告)日：1994-01-25

申请号：JP17580692

申请日：1992-07-02

Applicant: FUJISAWA PHARMACEUTICAL CO

Inventor： KAGARA KOUJI ,  KAWAI NOBUTAKA ,  MACHITANI KOJI ,  KODERA TETSUO ,  NAKAMURA TAKASHI

IPC: C07D233/64

Abstract: PURPOSE:To obtain a new synthetic intermediate useful for producing an amino acid derivative having renin inhibiting activity in good yield at a reduced cost. CONSTITUTION:The compound of formula I [R is lower alkyl which may be substituted with a substituent group selected from acyl, OH, lower alkoxy, aryl, lower alkylthio and formula II (R is H or acyl; R is H or lower alkyl), aryl or amino which may be substituted with lower alkyl or acyl; R is H or lower alkyl or R and R , together with the adjacent N atom, form a heterocyclic group which may be substituted (with alkyl, hydroxyalkyl, acyl, etc.); R is H or lower alkyl; R is H or N-protecting group; R is H or carboxy- protecting group]. This compound is obtained by reacting a compound of formula III with a compound of formula IV. The objective amino acid derivative of formula VI is prepared by reacting the compound of formula I or a reactive derivative at the carboxyl group thereof with a compound of formula V (R is lower alkyl) and, as necessary, releasing the N-protecting group.

公开(公告)号：JPH0558974A

公开(公告)日：1993-03-09

申请号：JP29855491

申请日：1991-08-27

Applicant: FUJISAWA PHARMACEUTICAL CO

Inventor： KAGARA KOUJI ,  GOSHIMA SHUNSUKE ,  KODERA TETSUO ,  TSUBOI HIROYUKI

IPC: C07C227/06 ,  C07C229/56

Abstract: PURPOSE:To safely and easily obtain the subject compound useful as a raw material for quinazoline derivatives and medicines at low cost and in high yield by reducing a nitrobenzoic acid derivative. CONSTITUTION:The objective compound of formula II can be obtained by reacting a compound of formula I (R is H, halogen or lower alkoxy) or its salt with a reducing agent (e.g. hydrazine) in the presence of a catalyst (e.g. ferric chloride-activated carbon) in a solvent (e.g. isopropyl alcohol) at room temperature to higher temperatures. The compound of the formula I can be prepared by oxidation of a compound of formula III.

公开(公告)号：JPH0525111A

公开(公告)日：1993-02-02

申请号：JP29820791

申请日：1991-10-17

Applicant: FUJISAWA PHARMACEUTICAL CO

Inventor： KAGARA KOUJI ,  KAWAI NOBUTAKA ,  MACHITANI KOJI ,  TAKASUKA KIYOAKI

IPC: C07C249/06 ,  C07C251/40

Abstract: PURPOSE:To obtain the subject compound in a short process and good yield by reacting an aliphatic aldehyde or salt thereof with a wittig reagent having a carbamoyl group and then reacting the reactional product with dinitrogen trioxide or with a nitrous acid salt in the presence of an acid. CONSTITUTION:An aliphatic aldehyde expressed by formula I (R to R are H or lower alkyl) or salt thereof (especially preferably 2-ethylcrotonaldehyde, etc.) is reacted with a Wittig reagent (especially preferably diethylphosphonoacetoamide) and then with dinitrogen trioxide without isolating the intermediate product. Otherwise, the reactional product with the Wittig reagent is reacted with nitrous acid salt in the presence of an acid to provide an aliphatic amide expressed by formula II or salt thereof [especially preferably (+ or -)-(E)-4-ethyl-2 [(E)-hydroxyimino]-5-nitro-3-hexeneamide]. The compound expressed by formula II is useful as a treating agent for vasodilation, antithrombotic agent, treating agent for angina pectoris, etc.

公开(公告)号：JPH02256669A

公开(公告)日：1990-10-17

申请号：JP34211489

申请日：1989-12-27

Applicant: FUJISAWA PHARMACEUTICAL CO

Inventor： KAGARA KOUJI ,  GOSHIMA SHUNSUKE ,  TSUBOI HIROYUKI

IPC: C07D239/47

Abstract: PURPOSE:To obtain the subject substance in a simple process by reacting 6-(3,4- dimethoxyphenyl)-3-methyl-2,4(1H,3H)-pyrimidinedione, etc., with 2,4,6- trimethylaniline, etc., in the presence of a reagent for activating oxo groups. CONSTITUTION:A compound expressed by formula I (R and R are H or lower alkyl; R is aryl which may have a substituent group) is reacted with a compound expressed by formula II (R is aryl which may have a substituent group) or salt thereof in the presence of a reagent (e.g. PCl3, P2O5, thionyl chloride or phosgene) capable of activating oxo groups of the compound expressed by formula I to afford a compound expressed by formula III. The compound, expressed by formula III and having cardiotonic action, etc., can be readily obtained in high yield for a short time according to the above-mentioned method without using H2S, alkyl halides, etc., which are toxic substances and considered as industrially undesirable.