Yoshikazu Kawano

Practical application of the palladium-catalyzed amination in phenylpiperazine synthesis: An efficient synthesis of a metabolite of the antipsychotic agent aripiprazole

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.

Synthesis of a key intermediate, (S)-2-[(3-hydroxypropyl)sulfinyl]-1-(o-tolyl)imidazole, for the platelet aggregation inhibitor, OPC-29030 via lipase-catalyzed enantioselective transesterification

Abstract 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.

Enantioselective Synthesis of the Metabolites of Vasopressin V2 Receptor Antagonist OPC-31260 via Lipase-Catalyzed Transesterification

Abstract 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.

An efficient synthesis of optically active metabolites of platelet adhesion inhibitor OPC-29030 by lipase-catalyzed enantioselective transesterification

Abstract The optically active metabolites of ( S )-3,4-dihydro-6-[3-(1- o -tolyl-2-imidazolyl)sulfinyl-propoxy]-2(1 H )-quinolinone (OPC-29030, 1 ), which is a new anti-platelet agent (platelet adhesion inhibitor), were effectively synthesized by the enzyme-catalyzed enantioselective transesterification of the racemic sulfinyl metabolites. The enzymes can recognize a stereogenic sulfur atom remote from the reaction site.

Efficient Synthesis of Functionalized Benzazepine Derivatives Utilizing Intramolecular Mitsunobu Reaction

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.