Minoru Uchida

Hydroxyl radical scavenging by rebamipide and related compounds: Electron paramagnetic resonance study

We studied the scavenging activity of rebamipide, a novel antipeptic ulcer agent, and seven related compounds against hydroxyl radicals using the electron paramagnetic resonance (EPR) spin trapping technique. 5,5-Dimethyl-1-pyrroline-N-oxide (DMPO) was used as a spin trapping agent. We estimated the second order rate constant for the reaction between the agents tested and hydroxyl radical at pH 7.8 by kinetic competition studies. All compounds tested scavenged the hydroxyl radicals with a certain relationship between concentration and scavenging efficacy. A structure-scavenging activity relationship was derived from the kinetic evidence available on the formation and inhibition of the DMPO spin adduct EPR signal of hydroxyl radicals (DMPO-OH). Important determinants for scavenging hydroxyl radicals were the 3,4-double bond of the quinolinone ring in conjunction with a 2-oxo function and the carbonyl portion of the amido group in conjunction with a para-chlorobenzoyl function.

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.

An efficient synthesis of a key intermediate towards (S)-(−)-nadifloxacin

Abstract 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 .

Synthesis of N-Acetylhemiaminal metabolites of opc-21268, vasopressin V1 receptor antagonist

Abstract N-Acetylhemiaminal metabolites of 1-{1-[4-(3-acetylaminopropoxy)benzoyl]-4-piperidyl}-3,4-dihydro-2(1 H )-quinolinone (OPC-21268) ( 1 ), which is a new vasopressin V1 receptor antagonist were synthesized by oxidative decarboxylation of the corresponding α - amino acid derivatives with lead tetraacetate.