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An efficient and highly enantioselective synthesis of ( S )-(−)-5,6-difluoro-2-methyl-1,2,3,4-tetrahydroquinoline (4b) , a key intermediate in the synthesis of ( S )-(−)-nadifloxacin ( 2 ), was carried out by using a cross-coupling reaction. Also α,β-acetylenic ketones 14a,b underwent an asymmetric reduction using various chiral reagents to afford the corresponding propargylic alcohols 8a,b in good yield and excellent enantiomeric excess, which can be easily converted to butanol 9 .

In a search for inhibitors of gastric H+/K+ATPase, 4-(phenylamino)quinoline-3-carboxamides were synthesized and evaluated for antisecretory activity against histamine-induced gastric acid secretion in rats. These compounds were synthesized by condensation of aniline derivatives with N-substituted 4-chloroquinoline-3-carboxamides, which were obtained from treatment of 4(1H)-quinolinone-3-carboxylic acid with thionyl chloride. Most of the compounds inhibited histamine-induced gastric acid secretion in rats. Among them, N-allyl-4-(2-ethylphenylamino)quinoline-3-carboxamide (4h) was the most potent inhibitor and had the best profile as a candidate antiulcer agent. This compound showed reversible, K+-competitive gastric H+/K+-ATPase inhibitory activity.

The enantiomers of 7-fluoro-1-methyl-3-(methylsulfinyl)-4(1H)-quinolinone [(±)-1, flosequinan], a new drug for the treatment of heart failure, were synthesized from the optically active (R)-α-methylbenzylamine derivatives of quinoline. The key intermediates, (R)-α-methylbenzylamine derivatives, were prepared by diastereomeric separation. The configuration of (+)-1 was assigned on the basis of an X-ray crystallographic analysis of the synthetic precursor (4a). The absolute configuration was found to be (R)-(+)-1 and (S)-(-)-1.

A hydroxylated metabolite (5a) of 7-hydroxy-1-[[[4-(3-methoxyphenyl)-1-piperazinyl]acetyl]amino]-2,2,4,6-tetramethylindan (OPC-14117), which is a novel cerebroprotective agent with central nervous system-stimulating activity, was synthesized by use of a model cytochrome P-450 system. In order to confirm the structure of this compound it was prepared by another route. Tile structures of several metabolites (5a, 7 and 8) were identified by means of comparisons with the synthetic compounds.

Optically active 2-[(3-hydroxypropyl)sulfinyl]-1-( o -tolyl)imidazole (S)- 2 was synthesized by kinetic resolution of (±)- 2 with lipase and hydrolysis of the acetate (S)- 3 with potassium carbonate. The reaction mixture of the lipase-catalyzed transesterification was converted to the phthalic acid derivative (R)- 4 , and this (R)- 4 and the unreacted acetate (S)- 3 were fractionated without use of column chromatography. The unrequired recovered alcohol (R)- 2 was also racemized and (±)- 2 was repeatedly submitted to the lipase-catalyzed transesterification.

A metabolite of Aripiprazole (1), 7-[4-[4-(2,3-dichloro-4-hydroxyphenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2(1H)-quinolinone (2), was prepared by the coupling reaction of 1-(4-benzyloxy-2,3-dichlorophenyl)-piperazine (11) with 7-(4-chlorobutoxy)-3,4-dihydro-2(1H)-quinolinone (16). The palladium-catalyzed amination of contiguous tri- and tetra-substituted benzenes with piperazine derivatives was investigated. The key intermediate 11 was efficiently prepared using the palladium-catalyzed amination of phenyl bromide 15 with piperazine.

As an efficient and enantioselective synthesis of the 4,5-dihydroxy-benzazepine compounds, the syntheses of optically active 5-0-protected trans-4,5-dihydroxybenzazepine derivatives were accomplished. The trans-7-chloro-4-hydroxy-5-methoxymethoxy-1 -(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepine [(±)-4] was kinetically resolved by lipase-catalyzed transesterification. The optically active 4* was isomerized into the cis compound (6*) utilizing the Mitsunobu esterification followed by hydrolysis. The chiral compounds (4* and 6*) were converted to the 4,5-bismethoxymethoxy compounds (7*-10*), which were the intermediates for the compounds (2a, b and 3a, b).

The 5-hydroxy-2,3,4,5-tetrahydro-1H-benzazepine derivative (2), which is a typical metabolite of mozavaptan (1) having the 2,3,4,5-tetrahydro-1H-benzazepine skeleton, was synthesized by utilizing the intramolecular Mitsunobu reaction of the corresponding 2-(4-hydroxybutyl)aniline derivative. In the intramolecular Mitsunobu reaction, effect of the substituent group on nitrogen atom, influence of the functional group applying to synthesis of the other metabolites (3, 4 and 5) and utilization of synthesis of 2-substituent benzazepine derivatives were investigated.

The optical isomers of 5-dimethylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (OPC-31260, 1) and its metabolites (2, 3, 4, 5 and 6) were enantioselectively synthesized. The chiral acetate 8b and alcohol 7a were prepared via the resolution of the racemic alcohol (±)-7 using the lipase-mediated transesterification in vinyl acetate. The compounds 8b and 7a were converted to the hydroxy metabolites (2a and 2b), the methylamine metabolites (3a and 3b), the dimethylamines (1a and 1b), and the amine metabolites (4a and 4b) in several steps while maintaining their absolute configurations. The 4,5-diol metabolites (5a, 5b, 6a and 6b) were synthesized from the key intermediates obtained by the lipase-catalyzed transesterification.