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【结 构 式】 
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【药物名称】FK-687, TF-505, FR-146687 【化学名称】4-[1-[4-[1(S)-(4-Isobutylphenyl)butoxy]benzoyl]indolizin-3-yl]butyric acid 【CA登记号】146939-64-2 【 分 子 式 】C33H37NO4 【 分 子 量 】511.66714 |
【开发单位】Fujisawa (Originator), Taiho (Licensee) 【药理作用】Benign Prostatic Hyperplasia Therapy, RENAL-UROLOGIC DRUGS, Steroid 5alpha-Reductase Type 1 Inhibitors, Steroid 5alpha-Reductase Type 2 Inhibitors |
合成路线1
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.
| 【1】 Okada, S.; Kuroda, A.; Sawada, K.; Sawada, Y.; Watanabe, S.; Tanaka, H.; 4-(Benzoylindolizinyl)butyric acids; novel nonsteroidal inhibitors of steroid 5alpha-reductase. III. Chem Pharm Bull 2001, 49, 7, 779. |
| 【2】 Okada, S.; Sawada, K.; Kuroda, A.; Watanabe, S.; Tanaka, H. (Fujisawa Pharmaceutical Co., Ltd.); Indolizin derivs., process for their preparation and pharmaceutical compsn. containing them. EP 0519353; JP 1993178856; US 5334716 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 49217 | Indolizine | C8H7N | 详情 | 详情 | |
| (II) | 40684 | ethyl 4-chloro-4-oxobutanoate; Ethyl succinyl chloride | 14794-31-1 | C6H9ClO3 | 详情 | 详情 |
| (III) | 49218 | ethyl 4-(3-indolizinyl)-4-oxobutanoate | C14H15NO3 | 详情 | 详情 | |
| (IV) | 49219 | ethyl 4-(3-indolizinyl)butanoate | C14H17NO2 | 详情 | 详情 | |
| (V) | 49220 | 4-(chlorocarbonyl)phenyl acetate | C9H7ClO3 | 详情 | 详情 | |
| (VI) | 49221 | ethyl 4-[1-[4-(acetoxy)benzoyl]-3-indolizinyl]butanoate | C23H23NO5 | 详情 | 详情 | |
| (VII) | 49222 | ethyl 4-[1-(4-hydroxybenzoyl)-3-indolizinyl]butanoate | C21H21NO4 | 详情 | 详情 | |
| (VIII) | 49223 | (1R)-1-(4-isobutylphenyl)-1-butanol | C14H22O | 详情 | 详情 | |
| (IX) | 49224 | ethyl 4-[1-(4-[[(1S)-1-(4-isobutylphenyl)butyl]oxy]benzoyl)-3-indolizinyl]butanoate | C35H41NO4 | 详情 | 详情 | |
| (X) | 49225 | 1-Phenylisobutane; Isobutylbenzene; 2-Methyl-1-phenylpropane | 538-93-2 | C10H14 | 详情 | 详情 |
| (XI) | 10792 | Butanoyl chloride; Butyryl chloride | 141-75-3 | C4H7ClO | 详情 | 详情 |
| (XII) | 49226 | 1-(4-isobutylphenyl)-1-butanone | C14H20O | 详情 | 详情 |
合成路线2
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.
| 【1】 Sawada, K.; Tanaka, H.; Watanabe, S.; Kuroda, A.; Okada, S. (Fujisawa Pharmaceutical Co., Ltd.); Process for the preparation of indolizine derivs.. WO 9507279 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 49223 | (1R)-1-(4-isobutylphenyl)-1-butanol | C14H22O | 详情 | 详情 | |
| (XIII) | 49227 | 6-methoxy-6-oxohexanoic acid | C7H12O4 | 详情 | 详情 | |
| (XIV) | 49228 | methyl 6-chloro-6-oxohexanoate | C7H11ClO3 | 详情 | 详情 | |
| (XV) | 49229 | methyl 5-bromo-6-chloro-6-oxohexanoate | C7H10BrClO3 | 详情 | 详情 | |
| (XVI) | 23540 | Phenol | 108-95-2 | C6H6O | 详情 | 详情 |
| (XVII) | 49230 | 6-methyl 1-phenyl 2-bromohexanedioate | C13H15BrO4 | 详情 | 详情 | |
| (XVIII) | 49231 | methyl 5-bromo-6-oxohexanoate | C7H11BrO3 | 详情 | 详情 | |
| (XIX) | 49232 | 1-(4-[[(1S)-1-(4-isobutylphenyl)butyl]oxy]phenyl)-2-(2-pyridinyl)-1-ethanone | C27H31NO2 | 详情 | 详情 | |
| (XX) | 49233 | methyl 4-[1-(4-[[(1S)-1-(4-isobutylphenyl)butyl]oxy]benzoyl)-3-indolizinyl]butanoate | C34H39NO4 | 详情 | 详情 | |
| (XXI) | 10251 | methyl 4-hydroxybenzoate; Methyl p-hydroxybenzoate | 99-76-3 | C8H8O3 | 详情 | 详情 |
| (XXII) | 49234 | methyl 4-[[(1S)-1-(4-isobutylphenyl)butyl]oxy]benzoate | C22H28O3 | 详情 | 详情 | |
| (XXIII) | 17590 | 2-methylpyridine; 2-picoline | 109-06-8 | C6H7N | 详情 | 详情 |