[Studies on the efficient syntheses of the drug metabolites].
This review summarizes our recent findings in the syntheses of drug metabolites. The metabolites of Grepafloxacin (1) and OPC-14117 (10) were prepared from the common intermediates (5) and (21), respectively. Moreover, treatment of 10 with a model P450 system led to a benzyl alcohol derivative (11) in one step. OPC-31260 (22) was efficiently N-dealkylated using several metalloporphyrins with oxidants to afford three metabolites (23-25). In addition, I succeeded in obtaining the metabolite (23) in high yield from N-oxide (26) not only as an oxygen donor but also as a substrate, there after, in the model P450 system. Optically active metabolites of OPC-29030 (27) were prepared by enzyme-catalyzed enantioselective transesterification of racemic sulfinyl metabolites. On the other hand, a chiral 1,1'-bi-2-naphthol derivative (38a) was found to be an efficient asymmetric acylating agent for a secondary alcohol (36) which is a valuable intermediate for preparing optically active metabolites of 22. Furthermore, metabolites (45) and (47) of OPC-21268 (44) were prepared using SmI2-induced cyclization and oxidative decarboxylation with Pb(OAc)4 as key steps, respectively.
Otsubo
K
K
Medicinal Chemistry Research Institute, Otsuka Pharmaceutical Co., Ltd., 463-10, Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan.
D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000378:metabolism; D001552:Benzazepines / Q000138:chemical synthesis / Q000378:metabolism; D002625:Chemistry, Organic; D003577:Cytochrome P-450 Enzyme System; D024841:Fluoroquinolones; D007093:Imidazoles; D007189:Indans / Q000138:chemical synthesis / Q000378:metabolism; D008049:Lipase; D055601:Organic Chemistry Phenomena; D010879:Piperazines / Q000138:chemical synthesis / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000378:metabolism; D015363:Quinolones / Q000138:chemical synthesis / Q000378:metabolism; D013237:Stereoisomerism; D013457:Sulfur Compounds
D000890:Anti-Infective Agents; D001552:Benzazepines; D024841:Fluoroquinolones; D007093:Imidazoles; D007189:Indans; C404198:OPC 29030; D010879:Piperazines; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D015363:Quinolones; D013457:Sulfur Compounds; C068644:OPC 21268; C076251:mozavaptan; C074852:OPC 14117; D003577:Cytochrome P-450 Enzyme System; D008049:Lipase; C075375:grepafloxacin