1, 25-Dihydroxy-19-norvitamin D3, -Drug Synthesis Database

【结构式】

【药物名称】1, 25-Dihydroxy-19-norvitamin D3

【化学名称】1alpha,25-Dihydroxy-19-norvitamin D3

【CA登记号】130447-37-9

【分子式】C₂₆H₄₄O₃

【分子量】404.63878

【开发单位】Wisconsin Alumni Research Foundation (Originator)

【药理作用】Oncolytic Drugs

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

The reaction of vitamin D3 (I) with Ts-Cl in pyridine gives the tosylate (II), which is treated with NaHCO3 in hot methanol to yield 3,5-cyclovitamin D3 (III). The oxidation of (III) with SeO2 and tBu-OOH in dichloromethane, followed by acetylation affords 1-alpha-acetoxy-25-hydroxy-3,5-cyclovitamin D3 (IV). The dihydroxylation of the exo-double bond of (IV) with OsO4 in pyridine affords the alpha diol (V), which is oxidized with NaIO4 in methanol to provide the oxo cyclovitamin (VI). The reduction of (VI) with NaBH4 in ethanol gives the secondary alcohol (VII), which is mesylated with Ms-Cl and TEA in dichloromethane to yield the mesylate (VIII). The crude (VIII) is treated with LiAlH4 in THF to afford 1-alpha,25-dihydroxy-3,5-cyclovitamin D3 (IX). The cycloreversion of (IX) by means of hot acetic acid provides a mixture of the two monoacetylated vitamins (X) and (XI), which, without separation is hydrolyzed with KOH in methanol/ethyl ether to give the target 1-alpha,25-dihydroxy-19-nor-vitamin D3.

参考文献中间体

【1】 Paaren, H.E.; et al.; Direct C(1) hydroxylation of vitamin D3 and related compounds. J Org Chem 1980, 45, 16, 3253.
【2】 DeLuca, H.F.; Schnoes, H.K.; Perlman, K.L.; Sicinski, R.R.; Prahl, J.M. (Wisconsin Alumni Research Foundation); 19-Nor vitamin D cpds. EP 0387077; JP 1991505330; US 5246925; WO 9010620 .
【3】 Perlman, K.L.; et al.; 1alpha,25-Dihydroxy-19-nor-vitamin D3, a novel vitamin D-related compound with potential therapeutic activity. Tetrahedron Lett 1990, 31, 13, 1823.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	57127	(1S)-3-((Z)-2-{(1R,7aR)-1-[(1R)-5-hydroxy-1,5-dimethylhexyl]-7a-methyloctahydro-4H-inden-4-ylidene}ethylidene)-4-methylenecyclohexanol	C₂₇H₄₄O₂	详情	详情
(II)	57128	(1S)-3-((Z)-2-{(1R,7aR)-1-[(1R)-5-hydroxy-1,5-dimethylhexyl]-7a-methyloctahydro-4H-inden-4-ylidene}ethylidene)-4-methylenecyclohexyl 4-methylbenzenesulfonate	C₃₄H₅₀O₄S	详情	详情
(III)	57129	(6R)-6-((1R,7aR)-4-{(E,2R)-2-methoxy-2-[(5R)-2-methylenebicyclo[3.1.0]hex-1-yl]ethylidene}-7a-methyloctahydro-1H-inden-1-yl)-2-methyl-2-heptanol	C₂₈H₄₆O₂	详情	详情
(IV)	57130	(1R,3S,5S)-1-((1R)-2-{(1R,7aR)-1-[(1R)-5-hydroxy-1,5-dimethylhexyl]-7a-methyloctahydro-4H-inden-4-ylidene}-1-methoxyethyl)-2-methylenebicyclo[3.1.0]hex-3-yl acetate	C₃₀H₄₈O₄	详情	详情
(V)	57131	(1S,3S,5S)-1-((1R)-2-{(1R,7aR)-1-[(1R)-5-hydroxy-1,5-dimethylhexyl]-7a-methyloctahydro-4H-inden-4-ylidene}-1-methoxyethyl)-2-hydroxy-2-(hydroxymethyl)bicyclo[3.1.0]hex-3-yl acetate	C₃₀H₅₀O₆	详情	详情
(VI)	57132	(1S,3S,5S)-1-((1R)-2-{(1R,7aR)-1-[(1R)-5-hydroxy-1,5-dimethylhexyl]-7a-methyloctahydro-4H-inden-4-ylidene}-1-methoxyethyl)-2-oxobicyclo[3.1.0]hex-3-yl acetate	C₂₉H₄₆O₅	详情	详情
(VII)	57133	(1R,3S,5S)-1-((1R)-2-{(1R,7aR)-1-[(1R)-5-hydroxy-1,5-dimethylhexyl]-7a-methyloctahydro-4H-inden-4-ylidene}-1-methoxyethyl)-2-hydroxybicyclo[3.1.0]hex-3-yl acetate	C₂₉H₄₈O₅	详情	详情
(VIII)	57134	(1S,3S,5S)-1-((1R)-2-{(1R,7aR)-1-[(1R)-5-hydroxy-1,5-dimethylhexyl]-7a-methyloctahydro-4H-inden-4-ylidene}-1-methoxyethyl)-2-[(methylsulfonyl)oxy]bicyclo[3.1.0]hex-3-yl acetate	C₃₀H₅₀O₇S	详情	详情
(IX)	57135	(1S,3S,5S)-1-((1R)-2-{(1R,7aR)-1-[(1R)-5-hydroxy-1,5-dimethylhexyl]-7a-methyloctahydro-4H-inden-4-ylidene}-1-methoxyethyl)bicyclo[3.1.0]hexan-3-ol	C₂₇H₄₆O₃	详情	详情
(X)	57136	(1R,5R)-3-((E)-2-{(1R,7aR)-1-[(1R)-5-hydroxy-1,5-dimethylhexyl]-7a-methyloctahydro-4H-inden-4-ylidene}ethylidene)-5-hydroxycyclohexyl acetate	C₂₈H₄₆O₄	详情	详情
(XI)	57137	(1R,5R)-3-((Z)-2-{(1R,7aR)-1-[(1R)-5-hydroxy-1,5-dimethylhexyl]-7a-methyloctahydro-4H-inden-4-ylidene}ethylidene)-5-hydroxycyclohexyl acetate	C₂₈H₄₆O₄	详情	详情

合成路线2

The reaction of the chiral cyclohexenone (I) with H2O2 and NaOH in methanol gives the epoxide (II), which is submitted to a Wittig olefination with the phosphonium bromide (III) and KHMDS in toluene to yield the bromomethylene derivative (IV). The opening of the epoxide ring by means of DIBAL in hexane affords the cyclohexanol (V), which is silylated with Tbdms-Cl and imidazole to provide the bis silyl ether (VI). The reaction of (VI), triisopropyl borate and pinacol by means of t-BuLi in ethyl ether gives the boronic ester (VII), which is condensed with alkyl bromide intermediate (VIII) and catalyzed by PdCl2(dppf) and KOH in THF/water to yield the silylated precursor (IX). Finally, this compound is desilylated by means of aq. HF in THF to provide the target 1-alpha,25-dihydroxy-19-nor-vitamin D3. Alternatively, the intermediate (VIII) is reacted with triisiopropyl borate and pinacol, as before, to give the boronic ester (X), which is condensed with the cyclohexylidenemethyl bromide (VI) and catalyzed by PdCl2(dppf) and KOH in THF/water to yield the already reported silylated precursor (IX).

参考文献中间体

【1】 Hanazawa, T.; et al.; Novel synthetic approach to 19-nor-1alpha,25-dihydroxyvitamin D3 and its derivatives by Suzuki-Miyaura coupling in solution and on solid support. Org Lett 2001, 3, 24, 3975.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	57138	(5S)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclohexen-1-one	C₁₂H₂₂O₂Si	详情	详情
(II)	57139	(1S,4S,6S)-4-{[tert-butyl(dimethyl)silyl]oxy}-7-oxabicyclo[4.1.0]heptan-2-one	C₁₂H₂₂O₃Si	详情	详情
(III)	57140	(bromomethyl)(trimethyl)phosphonium bromide	C₄H₁₁Br₂P	详情	详情
(IV)	57141	({(1S,3R,6R)-5-[(E)-bromomethylidene]-7-oxabicyclo[4.1.0]hept-3-yl}oxy)(tert-butyl)dimethylsilane; (1S,3R,6R)-5-[(E)-bromomethylidene]-7-oxabicyclo[4.1.0]hept-3-yl tert-butyl(dimethyl)silyl ether	C₁₃H₂₃BrO₂Si	详情	详情
(V)	57142	(1R,5R)-3-[(Z)-bromomethylidene]-5-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanol	C₁₃H₂₅BrO₂Si	详情	详情
(VI)	57143	(1R,5R)-3-(bromomethylene)-5-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl tert-butyl(dimethyl)silyl ether; [((1R,5R)-3-(bromomethylene)-5-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)oxy](tert-butyl)dimethylsilane	C₁₉H₃₉BrO₂Si₂	详情	详情
(VII)	57144	tert-butyl(dimethyl)silyl (1R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]cyclohexyl ether; tert-butyl({(1R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]cyclohexyl}oxy)dimethylsilane	C₂₅H₅₁BO₄Si₂	详情	详情
(VIII)	57145	(5R)-5-{(1R,7aR)-4-[(E)-bromomethylidene]-7a-methyloctahydro-1H-inden-1-yl}-1,1-dimethylhexyl trimethylsilyl ether; [((5R)-5-{(1R,7aR)-4-[(E)-bromomethylidene]-7a-methyloctahydro-1H-inden-1-yl}-1,1-dimethylhexyl)oxy](trimethyl)silane	C₂₂H₄₁BrOSi	详情	详情
(IX)	57147	[((1R,5R)-3-[2-((1R,7aR)-1-{(1R)-1,5-dimethyl-5-[(trimethylsilyl)oxy]hexyl}-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene]-5-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)oxy](tert-butyl)dimethylsilane; (5R)-5-{(1R,7aR)-4-[(E)-2-((3R,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}cyclohexylidene)ethylidene]-7a-methyloctahydro-4H-inden-1-yl}-1,1-dimethylhexyl trimethylsilyl ether	C₄₁H₈₀O₃Si₃	详情	详情
(X)	57146	(5R)-5-{(1R,7aR)-7a-methyl-4-[(E)-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylidene]octahydro-1H-inden-1-yl}-1,1-dimethylhexyl trimethylsilyl ether; [((5R)-5-{(1R,7aR)-7a-methyl-4-[(E)-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylidene]octahydro-1H-inden-1-yl}-1,1-dimethylhexyl)oxy](trimethyl)silane	C₂₈H₅₃BO₃Si	详情	详情

合成路线3

The epoxidation of the chiral cyclohexenone (I) with H2O2 and NaOH in methanol gives the epoxide (II), which is condensed with triethyl phosphonoacetate (III) by means of NaH in THF to yield the cyclohexylidene acetate (IV). The regioselective opening of the epoxide ring of (V) by means of formic acid, Pd2(dba)3 and Bu3P in chloroform affords the cyclohexanol derivative (V), which is silylated by means of Tbdms-Cl and imidazole to provide the fully silylated compound (VI). The reduction of the ester group of (VI) by means of DIBAL in toluene gives the primary alcohol (VII) (1), which is treated with NCS and Me2S in dichloromethane to yield the chloride compound (VIII). The reaction of (VIII) with lithium diphenylphosphide, followed by oxidation with H2O2 affords the phosphine oxide (IX), which is condensed with the known synthon (X) by means of BuLi in THF to provide the silylated precursor (XI). Finally, this compound is desilylated by means of TBAF in THF to afford the target 1-alpha,25-dihydroxy-19-nor-vitamin D3.

参考文献中间体

【1】 Hanazawa, T.; et al.; Efficient and practical synthesis of the A-ring precursor of 19-nor-1alpha,25-dihydroxyvitamin D3 and its (3C- or 2H-labeled derivative. Org Lett 2001, 3, 14, 2205.

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)	57138	(5S)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclohexen-1-one		C₁₂H₂₂O₂Si	详情	详情
(II)	57139	(1S,4S,6S)-4-{[tert-butyl(dimethyl)silyl]oxy}-7-oxabicyclo[4.1.0]heptan-2-one		C₁₂H₂₂O₃Si	详情	详情
(III)	10019	Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate	867-13-0	C₈H₁₇O₅P	详情	详情
(IV)	57148	ethyl 2-((1R,4R,6S)-4-{[tert-butyl(dimethyl)silyl]oxy}-7-oxabicyclo[4.1.0]hept-2-ylidene)acetate		C₁₆H₂₈O₄Si	详情	详情
(V)	57149	ethyl 2-((3R,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-hydroxycyclohexylidene)acetate		C₁₆H₃₀O₄Si	详情	详情
(VI)	49047	ethyl 2-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)acetate		C₂₂H₄₄O₄Si₂	详情	详情
(VII)	49048	2-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)-1-ethanol		C₂₀H₄₂O₃Si₂	详情	详情
(VIII)	57150	tert-butyl(dimethyl)silyl (1R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-(2-chloroethylidene)cyclohexyl ether; tert-butyl{[(1R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-(2-chloroethylidene)cyclohexyl]oxy}dimethylsilane		C₂₀H₄₁ClO₂Si₂	详情	详情
(IX)	30302	[2-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)ethyl](oxo)diphenylphosphorane; 2-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)ethyl(diphenyl)phosphine oxide		C₃₂H₅₁O₃PSi₂	详情	详情
(X)	47151	ethyl 4-[[4-(benzyloxy)-2-hydroxy-3,6-dimethylbenzoyl]oxy]-2-hydroxy-3,6-dimethylbenzoate		C₂₇H₂₈O₇	详情	详情
(XI)	57147	[((1R,5R)-3-[2-((1R,7aR)-1-{(1R)-1,5-dimethyl-5-[(trimethylsilyl)oxy]hexyl}-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene]-5-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)oxy](tert-butyl)dimethylsilane; (5R)-5-{(1R,7aR)-4-[(E)-2-((3R,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}cyclohexylidene)ethylidene]-7a-methyloctahydro-4H-inden-1-yl}-1,1-dimethylhexyl trimethylsilyl ether		C₄₁H₈₀O₃Si₃	详情	详情

合成路线4

The reaction of cis,cis-cyclohexane-1,3,5-triol (I) with Ac2O and pyridine gives the triacetate (II), which is monodeacylated by means of porcine liver esterase at pH 7 to yield the diacetate (III). The silylation of the OH group of (III) with Tbdms-Cl , TEA and DMAP in dichloromethane affords the silyl ether (IV), which is submitted to desymmetrization by enzymatic hydrolysis with porcine liver esterase to provide the chiral cyclohexanol derivative (V). The oxidation of (V) by means of PCC in dichloromethane gives the chiral cyclohexanone (VI), which is finally treated with DBU in dichloromethane to yield the intermediate 5(S)-(Tbdms-O)-2-cyclohexenone (VII).

参考文献中间体

【1】 Kalkote, U.R.; et al.; Simple, efficient chemoenzymatic synthesis of (S)-5-(tert-butyldimethylsilyloxy)-2-cyclohexenone and enantiomeric ketone intermediates of 19-Nor-1alpha,25-dihydroxyvitamin D3. J Org Chem 2001, 66, 24, 8277.

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)	11800	1,3,5-Cyclohexanetriol; cis,cis-1,3,5-Cyclohexanetriol dihydrate	50409-12-6	C₆H₁₂O₃	详情	详情
(II)	49040	3,5-bis(acetoxy)cyclohexyl acetate		C₁₂H₁₈O₆	详情	详情
(III)	57152	(1R,3S)-3-(acetyloxy)-5-hydroxycyclohexyl acetate		C₁₀H₁₆O₅	详情	详情
(IV)	57153	(1R,3S)-3-(acetyloxy)-5-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl acetate		C₁₆H₃₀O₅Si	详情	详情
(V)	57154	(1S,3R,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-hydroxycyclohexyl acetate		C₁₄H₂₈O₄Si	详情	详情
(VI)	57155	(1R,3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-oxocyclohexyl acetate		C₁₄H₂₆O₄Si	详情	详情
(VII)	57138	(5S)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclohexen-1-one		C₁₂H₂₂O₂Si	详情	详情

Extended Information