-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】2beta-(3-Hydroxypropoxy)-1alpha,24(S),25-trihydroxyvitamin D3

【CA登记号】

【分子式】C₃₀H₅₀O₆

【分子量】506.7294

【开发单位】Chugai (Originator)

【药理作用】Bone Diseases, Treatment of, METABOLIC DRUGS, ONCOLYTIC DRUGS, Vitamin D Analogs

合成路线1 合成路线2 合成路线3

合成路线1

The title compound was synthesized by coupling two structural moieties. The C/D ring fragment (XII) was prepared as shown in Scheme 28478101a. Indane derivative (I) was protected as the acetate ester (II) and subsequently alkylated at the alpha position of the sulfone group with the chiral tosylate (III) to afford (IV). Reductive cleavage of the sulfone group of (IV) by means of sodium amalgam yielded diol (V), which was protected as the acetonide (VI) using 2,2-dimethoxypropane and p-toluenesulfonic acid. Reprotection of the free hydroxyl group of (VI) as the acetate ester (VII), followed by ketal hydrolysis with iodine in MeOH, produced diol (VIII). This was then silylated with tert-butyldimethylsilyl triflate, giving bis-silyl ether (IX). The acetyl group of (IX) was reductively cleaved with LiAlH4, and the resulting alcohol (X) was oxidized to the corresponding ketone (XI) employing N-methylmorpholine-N-oxide in the presence of tetra-n-propylammonium perruthenate (TPAP). Then, Wittig reaction of ketone (XI) with (bromomethylene)triphenylphosphorane furnished the required bromo olefin (XII).

参考文献中间体

【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	分子式	供应商	用于合成
(I)	46295	(1R,3aR,4S,7aR)-7a-methyl-1-[(1S)-1-methyl-2-(phenylsulfonyl)ethyl]octahydro-1H-inden-4-ol	C₁₉H₂₈O₃S	详情	详情
(II)	46296	(1R,3aR,4S,7aR)-7a-methyl-1-[(1S)-1-methyl-2-(phenylsulfonyl)ethyl]octahydro-1H-inden-4-yl acetate	C₂₁H₃₀O₄S	详情	详情
(III)	46297	(2S)-2,3-dihydroxy-3-methylbutyl 4-methylbenzenesulfonate	C₁₂H₁₈O₅S	详情	详情
(IV)	46298	(3S,6S)-6-[(1R,3aR,4S,7aR)-4-hydroxy-7a-methyloctahydro-1H-inden-1-yl]-2-methyl-5-(phenylsulfonyl)-2,3-heptanediol	C₂₄H₃₈O₅S	详情	详情
(V)	46299	(3S,6R)-6-[(1R,3aR,4S,7aR)-4-hydroxy-7a-methyloctahydro-1H-inden-1-yl]-2-methyl-2,3-heptanediol	C₁₈H₃₄O₃	详情	详情
(VI)	46300	(1R,3aR,4S,7aR)-7a-methyl-1-[(1R)-1-methyl-3-[(4S)-2,2,5,5-tetramethyl-1,3-dioxolan-4-yl]propyl]octahydro-1H-inden-4-ol	C₂₁H₃₈O₃	详情	详情
(VII)	46301	(1R,3aR,4S,7aR)-7a-methyl-1-[(1R)-1-methyl-3-[(4S)-2,2,5,5-tetramethyl-1,3-dioxolan-4-yl]propyl]octahydro-1H-inden-4-yl acetate	C₂₃H₄₀O₄	详情	详情
(VIII)	46302	(1R,3aR,4S,7aR)-1-[(1R,4S)-4,5-dihydroxy-1,5-dimethylhexyl]-7a-methyloctahydro-1H-inden-4-yl acetate	C₂₀H₃₆O₄	详情	详情
(IX)	46303	(1R,3aR,4S,7aR)-1-((1R,4S)-4,5-bis[[tert-butyl(dimethyl)silyl]oxy]-1,5-dimethylhexyl)-7a-methyloctahydro-1H-inden-4-yl acetate	C₃₂H₆₄O₄Si₂	详情	详情
(X)	46304	(1R,3aR,4S,7aR)-1-((1R,4S)-4,5-bis[[tert-butyl(dimethyl)silyl]oxy]-1,5-dimethylhexyl)-7a-methyloctahydro-1H-inden-4-ol	C₃₀H₆₂O₃Si₂	详情	详情
(XI)	46305	(1R,3aR,7aR)-1-((1R,4S)-4,5-bis[[tert-butyl(dimethyl)silyl]oxy]-1,5-dimethylhexyl)-7a-methyloctahydro-4H-inden-4-one	C₃₀H₆₀O₃Si₂	详情	详情
(XII)	46306	(6S)-6-((3R)-3-[(1R,3aR,7aR)-4-[(E)-bromomethylidene]-7a-methyloctahydro-1H-inden-1-yl]butyl)-2,2,3,3,5,5,8,8,9,9-decamethyl-4,7-dioxa-3,8-disiladecane; (2S,5R)-5-[(1R,3aR,7aR)-4-[(E)-bromomethylidene]-7a-methyloctahydro-1H-inden-1-yl]-2-[[tert-butyl(dimethyl)silyl]oxy]-1,1-dimethylhexyl tert-butyl(dimethyl)silyl ether	C₃₁H₆₁BrO₂Si₂	详情	详情

合成路线2

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).

参考文献中间体

【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

合成路线3

Coupling of the A-ring fragment (XXV) and the C/D-ring fragment (XII) to give adduct (XXVI) was carried out in the presence of tris(dibenzylideneacetone) (chloroform)dipalladium and triphenylphosphine. The silyl protecting groups were finally removed by treatment with tetrabutylammonium fluoride.

参考文献中间体

【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	分子式	供应商	用于合成
(XII)	46306	(6S)-6-((3R)-3-[(1R,3aR,7aR)-4-[(E)-bromomethylidene]-7a-methyloctahydro-1H-inden-1-yl]butyl)-2,2,3,3,5,5,8,8,9,9-decamethyl-4,7-dioxa-3,8-disiladecane; (2S,5R)-5-[(1R,3aR,7aR)-4-[(E)-bromomethylidene]-7a-methyloctahydro-1H-inden-1-yl]-2-[[tert-butyl(dimethyl)silyl]oxy]-1,1-dimethylhexyl tert-butyl(dimethyl)silyl ether	C₃₁H₆₁BrO₂Si₂	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
(XXVI)	46317	(1S,4R)-4-((1R,3aR,7aR)-4-[(E)-2-[(3R,4R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-(3-[[tert-butyl(dimethyl)silyl]oxy]propoxy)-2-methylenecyclohexylidene]ethylidene]-7a-methyloctahydro-1H-inden-1-yl)-1-(1-[[tert-butyl(dimethyl)silyl]oxy]-1-methylethyl)pentyl tert-butyl(dimethyl)silyl ether; (6S)-6-[(3R)-3-((1R,3aR,7aR)-4-[(E)-2-[(3R,4R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-(3-[[tert-butyl(dimethyl)silyl]oxy]propoxy)-2-methylenecyclohexylidene]ethylidene]-7a-methyloctahydro-1H-inden-1-yl)butyl]-2,2,3,3,5,5,8,8,9,9-decamethyl-4,7-dioxa-3,8-disiladecane	C₆₀H₁₂₀O₆Si₅	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)