(3aR,4R,5R,6aS)-4-[(E,3R)-4,4-dimethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-5-methylhexahydro-2H-cyclopenta[b]furan-2-ol -Drug Synthesis Database

【结构式】

【分子编号】37403

【品名】(3aR,4R,5R,6aS)-4-[(E,3R)-4,4-dimethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-5-methylhexahydro-2H-cyclopenta[b]furan-2-ol

【CA登记号】

【分子式】C₂₄H₄₂O₄

【分子量】394.59508

【元素组成】C 73.05% H 10.73% O 16.22%

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：(XI)

The resolution of racemic 3,3alpha-beta,4,5,6,6alpha-beta-hexahydro-4beta-nitromethyl-5alpha-carboxy-2H-cyclopenta[b]furan-2-one (I), with R(+)-alpha-methyl-p-nitrobenzylamine gives optical active 3,3aR,4,5,6,6aS-hexahydro-4R-nitromethyl-5R-carboxy-2H-cyclopenta[b]furan-2-one (I), which is reduced with borane-methyl sulfide complex in ethyl acetate yielding the corresponding hydroxymethyl compound (II). The reaction of (II) with I2 and triphenylphosphine in HMPT affords the iodomethyl derivative (III), which is finally reduced with sodium cyanoborohydride in the same solvent to give 3,3aR,4,5,6,6aS-hexahydro-4S-nitromethyl-5R-methyl-2H-cyclopenta[b]furan-2-one (IV). The treatment of (IV) with sodium methoxide in methanol and with H2SO4-methanol yields the 4S-dimethoxymethyl derivative (V), which is hydrolyzed with trifluoro acetic acid in water-CHCl3 to afford the corresponding 4S-formyl compound (VI). The Wittig reaction of (VI) with dimethyl (3,3-dimethyl-2-oxoheptyl)phosphonate (VII) in 1,2-dimethoxyethane affords 3,3aR,4,5,6,6aS-hexahydro-4R-(4,4-dimethyl-3-oxo-1-trans-octenyl)-5R-methyl-2H-cyclopenta[b]furan-2-one (VIII), which is reduced with NaBH4 in methanol to yield the corresponding 3S-hydroxy compound (IX). The protection of the hydroxy group of (IX) with dihydropyran/p-toluenesulfonic acid in CH2Cl2 affords the 3S-tetrahydropyranyloxy compound (X), which is reduced again with diisobutyl aluminum hydride in toluene to afford 3,3aR,4,5,6,6-hexahydro-4R-(4,4-dimethyl-3R-tetrahydropyranyloxy-1-trans-octenyl)-5R-methyl-2H-cyclopenta[b]furan-2-ol (XI).

参考文献中间体

合成目标

【1】 Holland, G.W.; et al.; US 4112225 .
【2】 Hillier, K.; Blancafort, P.; Serradell, M.N.; Castaner, J.; RO-21-6937/000. Drugs Fut 1981, 6, 1, 42.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	39393	(4S)-4-benzyl-3-(2-chloroacetyl)-1,3-oxazolidin-2-one	C₁₂H₁₂ClNO₃	详情	详情
(II)	37394	(3aR,4S,5R,6aS)-5-(hydroxymethyl)-4-(nitromethyl)hexahydro-2H-cyclopenta[b]furan-2-one	C₉H₁₃NO₅	详情	详情
(III)	37395	(3aR,4R,5R,6aS)-5-(iodomethyl)-4-(nitromethyl)hexahydro-2H-cyclopenta[b]furan-2-one	C₉H₁₂INO₄	详情	详情
(IV)	37396	(3aR,4S,5R,6aS)-5-methyl-4-(nitromethyl)hexahydro-2H-cyclopenta[b]furan-2-one	C₉H₁₃NO₄	详情	详情
(V)	37397	(3aR,4S,5R,6aS)-4-(dimethoxymethyl)-5-methylhexahydro-2H-cyclopenta[b]furan-2-one	C₁₁H₁₈O₄	详情	详情
(VI)	37398	(3aR,4S,5R,6aS)-5-methyl-2-oxohexahydro-2H-cyclopenta[b]furan-4-carbaldehyde	C₉H₁₂O₃	详情	详情
(VII)	37399	dimethyl 3,3-dimethyl-2-oxoheptylphosphonate	C₁₁H₂₃O₄P	详情	详情
(VIII)	37400	(3aR,4R,5R,6aS)-4-[(E)-4,4-dimethyl-3-oxo-1-octenyl]-5-methylhexahydro-2H-cyclopenta[b]furan-2-one	C₁₈H₂₈O₃	详情	详情
(IX)	37401	(3aR,4R,5R,6aS)-4-[(E,3R)-3-hydroxy-4,4-dimethyl-1-octenyl]-5-methylhexahydro-2H-cyclopenta[b]furan-2-one	C₁₈H₃₀O₃	详情	详情
(X)	37402	(3aR,4R,5R,6aS)-4-[(E,3R)-4,4-dimethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-5-methylhexahydro-2H-cyclopenta[b]furan-2-one	C₂₄H₄₀O₄	详情	详情
(XI)	37403	(3aR,4R,5R,6aS)-4-[(E,3R)-4,4-dimethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-5-methylhexahydro-2H-cyclopenta[b]furan-2-ol	C₂₄H₄₂O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XI)

The Wittig reaction of (XI) with (4-carboxybutyl)triphenylphosphonium bromide (XII) in HMPT gives nat-11R,16,16-trimethyl-15R-(2-tetrahydropyranyloxy)-9S-hydroxyprosta-cis-5-trans-13-dienoic acid (XIII), which is oxidized with Jones reagent (CrO3-H2SO4) affording the corresponding 9-oxo compound (XIV). Finally, this compound is hydrolyzed with acetic acid in a mixture THF-water.

参考文献中间体

合成目标

【1】 Holland, G.W.; et al.; US 4112225 .
【2】 Hillier, K.; Blancafort, P.; Serradell, M.N.; Castaner, J.; RO-21-6937/000. Drugs Fut 1981, 6, 1, 42.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XI)	37403	(3aR,4R,5R,6aS)-4-[(E,3R)-4,4-dimethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-5-methylhexahydro-2H-cyclopenta[b]furan-2-ol		C₂₄H₄₂O₄	详情	详情
(XII)	37404	(3-carboxypropyl)(triphenyl)phosphonium bromide	17857-14-6	C₂₂H₂₂BrO₂P	详情	详情
(XIII)	37405	(Z)-7-((1R,2R,3R,5S)-2-[(E,3R)-4,4-dimethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-5-hydroxy-3-methylcyclopentyl)-5-heptenoic acid		C₂₉H₅₀O₅	详情	详情
(XIV)	37406	(Z)-7-((1R,2R,3R)-2-[(E,3R)-4,4-dimethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-3-methyl-5-oxocyclopentyl)-5-heptenoic acid		C₂₉H₄₈O₅	详情	详情

Extended Information