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【结 构 式】

【分子编号】46308

【品名】(2R,3S)-1,4-bis(benzyloxy)-3-(3-hydroxypropoxy)-2-butanol

【CA登记号】

【 分 子 式 】C21H28O5

【 分 子 量 】360.45032

【元素组成】C 69.98% H 7.83% O 22.19%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XXXVI)

Preparation of the allyl alcohol precursor (XXX) was further reported by an alternative method described in the two following schemes: The symmetrical epoxide (XXXV) was cleaved by 1,3-propanediol (II) in the presence of potassium tert-butoxide to give the diol (XXXVI). After protection of the primary alcohol of (XXXVI) as the pivalate ester (XXXVII), the benzyl ether groups of (XXXVII) were removed by hydrogenation in the presence of palladium hydroxide to provide (XXXVIII). Protection of the vicinal diol moiety of (XXXVII) as the corresponding acetonide (XXXIX) was achieved by treatment with 2,2-dimethoxypropane and p-TsOH. Subsequent Swern oxidation of the primary alcohol function of (XXXIX) gave aldehyde (XL). Addition of vinylmagnesium bromide to aldehyde (XL) afforded the allylic alcohol (XLI) as a diastereomeric mixture. Esterification of (XLI) with pivaloyl chloride provided dipivalate ester (XLII). Epoxide (XLIII) was then prepared by acidic acetonide (XLII) hydrolysis, followed by cyclization of the resultant vicinal diol under Mitsunobu conditions to afford epoxide (XLIII). Addition of the O-protected lithium acetylide (XLIV) to epoxide (XLIII) furnished the acetylene adduct (XLV)

1 Hatakeyama, S.; Ikeda, T.; Maeyama, J.; Esumi, T.; Iwabuchi, Y.; Irie, H.; Convergent synthesis of 1alpha, 25-dihydroxy-2beta-(3-hydroxypropoxy)vitamin D3 (ED-71). Bioorg Med Chem Lett 1997, 7, 22, 2871.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II) 14685 1,3-propanediol; Trimethylene Glycol 504-63-2 C3H8O2 详情 详情
(XXXV) 25266 benzyl [(2S,3S)-3-[(benzyloxy)methyl]oxiranyl]methyl ether; (2S,3S)-2,3-bis[(benzyloxy)methyl]oxirane C18H20O3 详情 详情
(XXXVI) 46308 (2R,3S)-1,4-bis(benzyloxy)-3-(3-hydroxypropoxy)-2-butanol C21H28O5 详情 详情
(XXXVII) 46309 3-([(1S,2R)-3-(benzyloxy)-1-[(benzyloxy)methyl]-2-hydroxypropyl]oxy)propyl pivalate C26H36O6 详情 详情
(XXXVIII) 59880 3-{[(1S,2R)-2,3-dihydroxy-1-(hydroxymethyl)propyl]oxy}propyl pivalate C12H24O6 详情 详情
(XXXIX) 46310 3-([(1S)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxyethyl]oxy)propyl pivalate C15H28O6 详情 详情
(XL) 46311 3-([(1R)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxoethyl]oxy)propyl pivalate C15H26O6 详情 详情
(XLI) 46312 3-([(1S)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxy-3-butenyl]oxy)propyl pivalate C17H30O6 详情 详情
(XLII) 59883 3-({(1R)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-[(2,2-dimethylpropanoyl)oxy]-3-butenyl}oxy)propyl pivalate C22H38O7 详情 详情
(XLIII) 46314 3-([(1R)-2-[(2,2-dimethylpropanoyl)oxy]-1-[(2R)oxiranyl]-3-butenyl]oxy)propyl pivalate C19H32O6 详情 详情
(XLIV) 59881 {3-[(4-methoxybenzyl)oxy]-1-propynyl}lithium C11H11LiO2 详情 详情
(XLV) 59882 3-({(1R,2R)-1-{1-[(2,2-dimethylpropanoyl)oxy]-2-propenyl}-2-hydroxy-6-[(4-methoxybenzyl)oxy]-4-hexynyl}oxy)propyl pivalate C30H44O8 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XV)

The A ring fragment (XXV) was synthesized as follows. Ring opening of epoxide (XIII) with 1,3-propanediol (XIV) in the presence of potassium tert-butoxide afforded the hydroxy ether (XV). The primary alcohol group of (XV) was then esterified with pivaloyl chloride (XVI) in the presence of pyridine to give (XVII). After hydrogenolysis of the benzyl ethers of (XVII), the 1,2-diol moiety was protected as the corresponding acetonide (XVIII) by means of 2,2-dimethoxypropane. Swern oxidation of the free alcohol group of (XVIII) generated aldehyde (XIX), and subsequent addition of vinylmagnesium bromide to (XIX) provided the allylic alcohol (XX) as a diastereomeric mixture. After protection of the hydroxyl group of (XX) as the pivalate ester, acid hydrolysis of the acetonide furnished diol (XXI). This was then converted to epoxide (XXII) under Mitsunobu conditions. Addition of lithium trimethylsilylacetylide (XXIII) to the epoxide (XXII) and then hydrolysis of the pivalate esters yielded (XXIV). This compound was protected as the tris(tert-butyldimethylsilyl) ether, and the diastereomeric mixture was separated by flash chromatography to provide intermediate (XXV).

1 Hatakeyama, S.; et al.; Synthesis and biological characterization of 1alpha,24,25-trihydroxy-2beta-(3-hydroxypropoxy)vitamin D3 (24-hydroxylated ED-71). Steroids 2001, 66, 3-5, 267.
2 Watanabe, H.; Hatakeyama, S.; Kawase, A. (Chugai Pharmaceutical Co. Ltd.); 24-Hydroxyvitamin D derivs.. EP 1061070; WO 9943645 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIII) 46307 benzyl [(2R,3S)-3-[(benzyloxy)methyl]oxiranyl]methyl ether; (2R,3S)-2,3-bis[(benzyloxy)methyl]oxirane C18H20O3 详情 详情
(XIV) 14685 1,3-propanediol; Trimethylene Glycol 504-63-2 C3H8O2 详情 详情
(XV) 46308 (2R,3S)-1,4-bis(benzyloxy)-3-(3-hydroxypropoxy)-2-butanol C21H28O5 详情 详情
(XVI) 13597 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride 3282-30-2 C5H9ClO 详情 详情
(XVII) 46309 3-([(1S,2R)-3-(benzyloxy)-1-[(benzyloxy)methyl]-2-hydroxypropyl]oxy)propyl pivalate C26H36O6 详情 详情
(XVIII) 46310 3-([(1S)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxyethyl]oxy)propyl pivalate C15H28O6 详情 详情
(XIX) 46311 3-([(1R)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxoethyl]oxy)propyl pivalate C15H26O6 详情 详情
(XX) 46312 3-([(1S)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxy-3-butenyl]oxy)propyl pivalate C17H30O6 详情 详情
(XXI) 46313 3-([(1R)-1-[(1R)-1,2-dihydroxyethyl]-2-[(2,2-dimethylpropanoyl)oxy]-3-butenyl]oxy)propyl pivalate C19H34O7 详情 详情
(XXII) 46314 3-([(1R)-2-[(2,2-dimethylpropanoyl)oxy]-1-[(2R)oxiranyl]-3-butenyl]oxy)propyl pivalate C19H32O6 详情 详情
(XXIII) 16299 Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium 54655-07-1 C5H9LiSi 详情 详情
(XXIV) 46315 (4R,5R)-4-(3-hydroxypropoxy)-1-octen-7-yne-3,5-diol C11H18O4 详情 详情
(XXV) 46316 (5R,6R)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]-3-butynyl)-2,2,3,3,12,12,13,13-octamethyl-5-vinyl-4,7,11-trioxa-3,12-disilatetradecane; tert-butyl(dimethyl)silyl 3-[[(1R,2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]-2-propenyl)-4-pentynyl]oxy]propyl ether C29H60O4Si3 详情 详情
Extended Information