(3R)-3-[(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]butanal -Drug Synthesis Database

【结构式】

【分子编号】25263

【品名】(3R)-3-[(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]butanal

【CA登记号】

【分子式】C₃₅H₆₂O₃Si₂

【分子量】587.04648

【元素组成】C 71.61% H 10.65% O 8.18% Si 9.57%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(I)

The Grignard condensation of carbaldehyde (I) with methylmagnesium bromide in ethyl ether gives the secondary alcohol (II), which is oxidized with TPAP and NMO in dichloromethane to yield the methyl ketone (III). The aldol reaction of (III) with hexafluoroacetone (IV) by means of LiHMDS in THF affords the hexafluorohydroxy ketone (V), which is reduced with NaBH4 in THF/methanol to provide the diol (VI). The selective acetylation of the secondary OH group of (VI) with Ac2O and pyridine gives the monoacetate (VII), which is treated with Mom-Cl and DIEA in order to protect its tertiary OH group, yielding (VIII). The deacetylation of (VIII) with KOH in methanol affords the secondary alcohol (IX), which is treated with CS2, NaH and Me-I to provide the thionocarbonate (X). The reduction of (X) with Bu3SnH in refluxing toluene gives the protected intermediate (XI), which is finally deprotected by reaction with methanesulfonic acid in methanol to yield the target vitamin D3 derivative.

参考文献中间体

合成目标

【1】 Ikeda, M.; et al.; Synthesis and biological evaluations of A-ring isomers of 26,26,26,27,27,27-hexafluoro-1,25-dihydroxyvitamin D3. Bioorg Med Chem 2000, 8, 8, 2157.

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)	25263	(3R)-3-[(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]butanal		C₃₅H₆₂O₃Si₂	详情	详情
(II)	55446	(4R)-4-{(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl}-2-pentanol		C₃₆H₆₆O₃Si₂	详情	详情
(III)	55447	(4R)-4-{(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl}-2-pentanone		C₃₆H₆₄O₃Si₂	详情	详情
(IV)	44260	1,1,1,3,3,3-hexafluoroacetone	684-16-2	C₃F₆O	详情	详情
(V)	55448	(6R)-6-{(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl}-1,1,1-trifluoro-2-hydroxy-2-(trifluoromethyl)-4-heptanone		C₃₉H₆₄F₆O₄Si₂	详情	详情
(VI)	55449	(6R)-6-{(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl}-1,1,1-trifluoro-2-(trifluoromethyl)-2,4-heptanediol		C₃₉H₆₆F₆O₄Si₂	详情	详情
(VII)	55450	1-((2R)-2-{(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl}propyl)-4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butyl acetate		C₄₁H₆₈F₆O₅Si₂	详情	详情
(VIII)	55451	1-((2R)-2-{(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl}propyl)-4,4,4-trifluoro-3-(methoxymethoxy)-3-(trifluoromethyl)butyl acetate		C₄₃H₇₂F₆O₆Si₂	详情	详情
(IX)	55452	(6R)-6-{(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl}-1,1,1-trifluoro-2-(methoxymethoxy)-2-(trifluoromethyl)-4-heptanol		C₄₁H₇₀F₆O₅Si₂	详情	详情
(X)	55453	O-[1-((2R)-2-{(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl}propyl)-4,4,4-trifluoro-3-(methoxymethoxy)-3-(trifluoromethyl)butyl] S-methyl carbonodithioa		C₄₃H₇₂F₆O₅S₂Si₂	详情	详情
(XI)	55454	(1R,5S)-3-((Z)-2-{(1R,3aR,7aR)-7a-methyl-1-[(1R)-6,6,6-trifluoro-5-(methoxymethoxy)-1-methyl-5-(trifluoromethyl)hexyl]octahydro-4H-inden-4-ylidene}ethylidene)-5-{[tert-butyl(dimethyl)silyl]oxy}-4-methylenecyclohexyl tert-butyl(dimethyl)silyl ether; [((1R,5S)-3-((Z)-2-{(1R,3aR,7aR)-7a-methyl-1-[(1R)-6,6,6-trifluoro-5-(methoxymethoxy)-1-methyl-5-(trifluoromethyl)hexyl]octahydro-4H-inden-4-ylidene}ethylidene)-5-{[tert-butyl(dimethyl)silyl]oxy}-4-methylenecyclohexyl)oxy](tert-butyl)dimethylsilane		C₄₁H₇₀F₆O₄Si₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Aldehyde (I), derived from vitamin D2, was submitted to a Reformatsky reaction with ethyl bromodifluoroacetate and activated Zn to produce a mixture of diastereomeric b-hydroxyesters (II). After chromatographic separation, the required (23S)-isomer was condensed with MeMgBr to give tertiary alcohol (III). Finally, desilylation of (III) with tetra n-butylammonium fluoride in THF provided the title compound.

参考文献中间体

合成目标

【1】 Iwasaki, H.; Miyamoto, Y.; Hosotani, R.; Nakano, Y.; Konno, K.; Takayama, H.; Synthesis and biological evaluation of (23R)- and (23S)-24,24-difluoro-1alpha,23,25-trihydroxyvitamin D3. Chem Pharm Bull 1998, 46, 12, 1932.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	40673	ethyl 2-bromo-2,2-difluoroacetate; Ethylbromodifluoroacetate; 2-bromo-2,2-difluoroacetic acid ethyl ester; bromodifluoroacetic acid ethyl ester	667-27-6	C₄H₅BrF₂O₂	详情	详情
(I)	25263	(3R)-3-[(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]butanal		C₃₅H₆₂O₃Si₂	详情	详情
(II)	25264	ethyl (5R)-5-[(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]-2,2-difluoro-3-hydroxyhexanoate		C₃₉H₆₈F₂O₅Si₂	详情	详情
(III)	25321	(4R,6R)-6-[(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]-3,3-difluoro-2-methyl-2,4-heptanediol		C₃₉H₇₀F₂O₄Si₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

参考文献中间体

合成目标

【1】 Iwasaki, H.; Miyamoto, Y.; Hosotani, R.; Nakano, Y.; Konno, K.; Takayama, H.; Synthesis and biological evaluation of (23R)- and (23S)-24,24-difluoro-1alpha,23,25-trihydroxyvitamin D3. Chem Pharm Bull 1998, 46, 12, 1932.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	40673	ethyl 2-bromo-2,2-difluoroacetate; Ethylbromodifluoroacetate; 2-bromo-2,2-difluoroacetic acid ethyl ester; bromodifluoroacetic acid ethyl ester	667-27-6	C₄H₅BrF₂O₂	详情	详情
(I)	25263	(3R)-3-[(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]butanal		C₃₅H₆₂O₃Si₂	详情	详情
(II)	25264	ethyl (5R)-5-[(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]-2,2-difluoro-3-hydroxyhexanoate		C₃₉H₆₈F₂O₅Si₂	详情	详情
(III)	25265	(4S,6R)-6-[(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]-3,3-difluoro-2-methyl-2,4-heptanediol		C₃₉H₇₀F₂O₄Si₂	详情	详情

Extended Information