【药物名称】FK-687, TF-505, FR-146687
化学结构式(Chemical Structure):
参考文献No.19657
标题:Indolizin derivs., process for their preparation and pharmaceutical compsn. containing them
作者:Okada, S.; Sawada, K.; Kuroda, A.; Watanabe, S.; Tanaka, H. (Fujisawa Pharmaceutical Co., Ltd.)
来源:EP 0519353; JP 1993178856; US 5334716
合成路线图解说明:

The condensation of indolizine (I) with 4-chloro-4-oxobutyric acid ethyl ester (II) by means of AlCl3 in dichloromethane gives 4-(3-indolizinyl)-4-oxobutyric acid ethyl ester (III), which is reduced with borane in THF to yield 4-(3-indolizinyl)butyric acid ethyl ester (IV). The condensation of (IV) with 4-acetoxybenzoyl chloride (V) by means of AlCl3 in dichloromethane affords the 1-(4-acetoxybenzoyl)indolizine derivative (VI), which is demethylated with NaH in ethanol to provide the corresponding 4-hydroxybenzoyl derivative (VII). The condensation of (VII) with 1(R)-(4-isobutyl)phenyl-1-butanol under Mitsunobu conditions (DEAD, PPh3) gives the corresponding (S)-ether (XI), which is finally hydrolyzed to the target acid by means of NaOH in methanol/THF. The chiral intermediate alcohol (VIII) has been obtained as follows: The condensation of isobutylbenzene (X) with butyryl chloride (XI) by means of AlCl3 in dichloromethane gives the butyrophenone (XII), which is then enantioselectively reduced with (+)-B-chlorodiisopinocampheyl borane [(+)-DIP- chloride] in isopropanol.

参考文献No.50644
标题:Process for the preparation of indolizine derivs.
作者:Sawada, K.; Tanaka, H.; Watanabe, S.; Kuroda, A.; Okada, S. (Fujisawa Pharmaceutical Co., Ltd.)
来源:WO 9507279
合成路线图解说明:

The reaction of adipic acid monomethyl ester (XIII) with SOCl2 gives the acyl chloride (XIV), which is brominated with NBS in carbon tetrachloride to yield 5-bromo-5-(chloroformyl)pentanoic acid methyl ester (XV). The reaction of (XV) with phenol (XVI) by means of DIEA in ethyl ether affords the mixed diester (XVII), which is reduced with tri-tert-butoxylithiumaluminum hydride in THF to provide 5-bromo-5-formylpentanoic acid methyl ester (XVIII). The cyclization of (XVIII) with chiral ethanone (XIX) by means of DIEA in hot dioxane gives the methyl ester (XX) of the target compound, which is finally hydrolyzed with NaOH in ethanol/water to obtain the target acid . The intermediate chiral ethanone (XIX) has been obtained as follows: The reaction of the chiral alcohol (VIII) with 4-hydroxybenzoic acid methyl ester (XXI) under Mitsunobu conditions (DEAD, PPh3) gives the chiral ether (XXII), which is then condensed with 2-methylpyridine (XXIII) by means of LiHMDS in THF to yield the target ethanone.

参考文献No.628739
标题:4-(Benzoylindolizinyl)butyric acids; novel nonsteroidal inhibitors of steroid 5alpha-reductase. III
作者:Okada, S.; Kuroda, A.; Sawada, K.; Sawada, Y.; Watanabe, S.; Tanaka, H.
来源:Chem Pharm Bull 2001,49(7),779
合成路线图解说明:

The condensation of indolizine (I) with 4-chloro-4-oxobutyric acid ethyl ester (II) by means of AlCl3 in dichloromethane gives 4-(3-indolizinyl)-4-oxobutyric acid ethyl ester (III), which is reduced with borane in THF to yield 4-(3-indolizinyl)butyric acid ethyl ester (IV). The condensation of (IV) with 4-acetoxybenzoyl chloride (V) by means of AlCl3 in dichloromethane affords the 1-(4-acetoxybenzoyl)indolizine derivative (VI), which is demethylated with NaH in ethanol to provide the corresponding 4-hydroxybenzoyl derivative (VII). The condensation of (VII) with 1(R)-(4-isobutyl)phenyl-1-butanol under Mitsunobu conditions (DEAD, PPh3) gives the corresponding (S)-ether (XI), which is finally hydrolyzed to the target acid by means of NaOH in methanol/THF. The chiral intermediate alcohol (VIII) has been obtained as follows: The condensation of isobutylbenzene (X) with butyryl chloride (XI) by means of AlCl3 in dichloromethane gives the butyrophenone (XII), which is then enantioselectively reduced with (+)-B-chlorodiisopinocampheyl borane [(+)-DIP- chloride] in isopropanol.

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