[(2,2-dimethyl-4-methylene-4H-1,3-dioxin-6-yl)oxy](trimethyl)silane; 2,2-dimethyl-4-methylene-4H-1,3-dioxin-6-yl trimethylsilyl ether -Drug Synthesis Database

【结构式】

【分子编号】53651

【品名】[(2,2-dimethyl-4-methylene-4H-1,3-dioxin-6-yl)oxy](trimethyl)silane; 2,2-dimethyl-4-methylene-4H-1,3-dioxin-6-yl trimethylsilyl ether

【CA登记号】n/a

【分子式】C₁₀H₁₈O₃Si

【分子量】214.33662

【元素组成】C 56.04% H 8.46% O 22.39% Si 13.1%

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：(VI)

The chiral tetrahydropyran intermediate (XI) has been obtained as follows. The reaction of (-)-pseudoephedrine propionamide (I) with the allyl bromide (II) by the Myers' method gives pentenamide (III), which is reduced with LiNH2BH3 in THF to yield 2(S)-methyl-4-penten-1-ol (IV). Swern oxidation of (IV) affords the corresponding aldehyde (V), which is submitted to an asymmetric aldol condensation with the silyl enol ether (VI) catalyzed by Cu(OTf)2, (S)-Tol-BINAP and (Bu4N)Ph3SiF2 in THF to provide the adduct (VII). The methanolysis of (VII) with Me-OH in refluxing toluene gives the beta-keto ester (VIII), which is treated with Et2BOMe, NaBH4 and HF to yield the chiral hydroxy lactone (IX). The reduction of (IX) with DIBAL in THF affords the lactol (X), which is finally methylated with Ts-OH in refluxing methanol to provide the target tetrahydropyran intermediate (XI).

参考文献中间体

合成目标

【1】 Bauer, M.; Maier, M.E.; Synthesis of the core structure of salicylihalamide A by intramolecular Suzuki reaction. Org Lett 2002, 4, 13, 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)	56935	N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N-methylpropanamide		C₁₃H₁₉NO₂	详情	详情
(II)	11463	3-Bromo-1-propene; 3-Bromopropene；allyl bromide	106-95-6	C₃H₅Br	详情	详情
(III)	56936	(2S)-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N,2-dimethyl-4-pentenamide		C₁₆H₂₃NO₂	详情	详情
(IV)	56937	(2S)-2-methyl-4-penten-1-ol		C₆H₁₂O	详情	详情
(V)	26241	(2S)-2-methyl-4-pentenal		C₆H₁₀O	详情	详情
(VI)	53651	[(2,2-dimethyl-4-methylene-4H-1,3-dioxin-6-yl)oxy](trimethyl)silane; 2,2-dimethyl-4-methylene-4H-1,3-dioxin-6-yl trimethylsilyl ether	n/a	C₁₀H₁₈O₃Si	详情	详情
(VII)	56938	6-[(2R,3S)-2-hydroxy-3-methyl-5-hexenyl]-2,2-dimethyl-4H-1,3-dioxin-4-one		C₁₃H₂₀O₄	详情	详情
(VIII)	56939	methyl (5R,6S)-5-hydroxy-6-methyl-3-oxo-8-nonenoate		C₁₁H₁₈O₄	详情	详情
(IX)	56940	(4S,6R)-4-hydroxy-6-[(1S)-1-methyl-3-butenyl]tetrahydro-2H-pyran-2-one		C₁₀H₁₆O₃	详情	详情
(X)	56941	(4S,6R)-6-[(1S)-1-methyl-3-butenyl]tetrahydro-2H-pyran-2,4-diol		C₁₀H₁₈O₃	详情	详情
(XI)	56942	(4S,6R)-2-methoxy-6-[(1S)-1-methyl-3-butenyl]tetrahydro-2H-pyran-4-ol		C₁₁H₂₀O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XIX)

The silylation of the acetonide (XVIII) with Tms-Cl and LDA in THF gives dienolate (XIX), which is enantioselectively condensed with acrolein (XX) by means of Carreira's Ti catalyst in ethyl ether to yield the chiral allyl alcohol (XXI). The reaction of (XXI), N,O-dimethylhydroxylamine (XXII) and Me2AlCl affords the amide (XXIII), which is selectively reduced with Me4NBH(OAc)3 in HOAc/acetonitrile to provide the dihydroxyamide (XXIV). The silylation of the OH groups of (XXIV) with Tbdms-Cl and imidazole gives the disilylated compound (XXV), which is submitted to a Grignard reaction with vinylmagnesium bromide (XXVI) in THF to yield the vinyl ketone (XXVII). The Michael addition reaction with Ph2P(O)-Li and simultaneous triflation with (XXVIII) in THF affords the enol triflate (XXIX), which is cyclized by means of Pd(OAc)2, PPh3 and TEA in THF to provide the phosphorane (XXXa-b) as an inseparable mixture of the (Z)- and (E)-isomers. Finally, this mixture is submitted to photochemical isomerization with a medium-pressure UV mercury lamp in the presence of 9-fluorenone, furnishing the target intermediate, the (Z)-isomer (X) with a 95 % yield.

参考文献中间体

合成目标

【1】 Anné, S.; et al.; Enantioselective syntheses of key A-ring precursors of 1alpha,25-dihydroxyvitamin D3 and analogues. Synlett 1999, 9, 1435.
【2】 Hiyamizu, H.; et al.; A concise enantioselective synthesis of a key A-ring synthon for 1alpha-hydroxyvitamin D3 compounds. Org Lett 2001, 3, 3, 473.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XXXa),(X)	42574	[2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl](oxo)diphenylphosphorane; 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl(diphenyl)phosphine oxide		C₃₃H₅₁O₃PSi₂	详情	详情
(XXXb)	53658	(E)-2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethyl(diphenyl)phosphine oxide; (E)-[2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethyl](oxo)diphenylphosphorane	n/a	C₃₃H₅₁O₃PSi₂	详情	详情
(XVIII)	13327	2,2,6-Trimethyl-4H-1,3-dioxin-4-one；2,2,6-trimethyl-1,3-dioxin-4-one；2,2,6-trimethyl-m-Dioxin-4-one;3-(1-hydroxy-1-methylethoxy)-d-lactone Crotonicacid	5394-63-8	C₇H₁₀O₃	详情	详情
(XIX)	53651	[(2,2-dimethyl-4-methylene-4H-1,3-dioxin-6-yl)oxy](trimethyl)silane; 2,2-dimethyl-4-methylene-4H-1,3-dioxin-6-yl trimethylsilyl ether	n/a	C₁₀H₁₈O₃Si	详情	详情
(XX)	17668	acrylaldehyde; Acrolein	107-02-8	C₃H₄O	详情	详情
(XXI)	53652	6-[(2S)-2-hydroxy-3-butenyl]-2,2-dimethyl-4H-1,3-dioxin-4-one	n/a	C₁₀H₁₄O₄	详情	详情
(XXII)	13361	(Methoxyamino)methane; N,O-Dimethylhydroxylamine	1117-97-1	C₂H₇NO	详情	详情
(XXIII)	53653	(5S)-5-hydroxy-N-methoxy-N-methyl-3-oxo-6-heptenamide	n/a	C₉H₁₅NO₄	详情	详情
(XXIV)	53654	(3S,5S)-3,5-dihydroxy-N-methoxy-N-methyl-6-heptenamide	n/a	C₉H₁₇NO₄	详情	详情
(XXV)	53655	(3S,5S)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-N-methoxy-N-methyl-6-heptenamide	n/a	C₂₁H₄₅NO₄Si₂	详情	详情
(XXVI)	16524	bromo(vinyl)magnesium	1826-67-1	C₂H₃BrMg	详情	详情
(XXVII)	53626	(4S)-3,3-diethyl-4-{4-[(4-methyl-1-piperazinyl)carbonyl]phenoxy}-2-azetidinone	n/a	C₁₉H₂₇N₃O₃	详情	详情
(XXVIII)	34685	N-(5-chloro-2-pyridinyl)(trifluoro)-N-[(trifluoromethyl)sulfonyl]methanesulfonamide	145100-51-2	C₇H₃ClF₆N₂O₄S₂	详情	详情
(XXIX)	53657	(3S,5S)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-1-[(E)-2-(diphenylphosphoryl)ethylidene]-6-heptenyl trifluoromethanesulfonate	n/a	C₃₄H₅₂F₃O₆PSSi₂	详情	详情

Extended Information