(1R)-1-(4-isobutylphenyl)-1-butanol -Drug Synthesis Database

【结构式】

【分子编号】49223

【品名】(1R)-1-(4-isobutylphenyl)-1-butanol

【CA登记号】

【分子式】C₁₄H₂₂O

【分子量】206.32808

【元素组成】C 81.5% H 10.75% O 7.75%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VIII)

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.

参考文献中间体

合成目标

【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

该中间体在本合成路线中的序号：(VIII)

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.

参考文献中间体

合成目标

【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

Extended Information