(3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate -Drug Synthesis Database

【结构式】

【分子编号】35585

【品名】(3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate

【CA登记号】39746-01-5

【分子式】C₁₅H₁₄O₅

【分子量】274.27316

【元素组成】C 65.69% H 5.14% O 29.17%

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：(I)

Commercially available Corey aldehyde benzoate (I) was oxidized to carboxylic acid (II) by Jones reagent at 0 C. Subsequent chlorination of (II) with SOCl2 afforded acid chloride (III). The crude acid chloride (III) was condensed with 3-hydroxy-4-methylthiazole-2-thione (IV) to yield the thiohydroxamate ester (V). Decarboxylation of (V) by means of tris(phenylthio)antimony in a flask open to air furnished alcohol (VI). Alkylation of alcohol (VI) with allyl bromide (VII) afforded allyl ether (VIII), which by epoxidation using m-chloroperbenzoic acid provided the epoxide (IX). Regiospecific epoxide opening with the Grignard reagent (X) gave alcohol (XI) as a diastereomeric mixture. The hydroxyl groups of (XI) were then protected as the bis-tetrahydropyranyl ether (XII) using dihydropyran and p-toluenesulfonic acid. Lactone reduction with DIBAL in toluene at -78 C gave the lactol (XIII).

参考文献中间体

合成目标

【1】 Feng, Z.; et al.; Design and synthesis of 13-oxa prostaglandin analogs as antiglaucoma agents. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 236.
【2】 Feng, Z.; Hellberg, M.R. (Alcon Laboratories, Inc.); 13-Oxa prostaglandins for the treatment of glaucoma and ocular hypertension. US 6232344; WO 9932441 .

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)	35585	(3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate	39746-01-5	C₁₅H₁₄O₅	详情	详情
(II)	50695	(3aR,4R,5R,6aS)-5-(benzoyloxy)-2-oxohexahydro-2H-cyclopenta[b]furan-4-carboxylic acid		C₁₅H₁₄O₆	详情	详情
(III)	50696	(3aR,4R,5R,6aS)-4-(chlorocarbonyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate		C₁₅H₁₃ClO₅	详情	详情
(IV)	50697	3-Hydroxy-4-methyl-2(3H)thiazolethione; N-Hydroxy-4-methyl-2-thiazolethione; 2-Mercapto-4-methylthiazole 3-oxide	49762-08-5	C₄H₅NOS₂	详情	详情
(V)	50698	(3aR,4R,5R,6aS)-4-([[4-methyl-2-thioxo-1,3-thiazol-3(2H)-yl]oxy]carbonyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate		C₁₉H₁₇NO₆S₂	详情	详情
(VI)	50699	(3aR,4R,5R,6aS)-4-hydroxy-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate		C₁₄H₁₄O₅	详情	详情
(VII)	11463	3-Bromo-1-propene; 3-Bromopropene；allyl bromide	106-95-6	C₃H₅Br	详情	详情
(VIII)	50700	(3aR,4R,5R,6aS)-4-(allyloxy)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate		C₁₇H₁₈O₅	详情	详情
(IX)	50701	(3aR,4R,5R,6aS)-4-(2-oxiranylmethoxy)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate		C₁₇H₁₈O₆	详情	详情
(X)	50702	bromo[3-(trifluoromethyl)benzyl]magnesium		C₈H₆BrF₃Mg	详情	详情
(XI)	50703	(3aR,4R,5R,6aS)-5-hydroxy-4-[2-hydroxy-4-[3-(trifluoromethyl)phenyl]butoxy]hexahydro-2H-cyclopenta[b]furan-2-one		C₁₈H₂₁F₃O₅	详情	详情
(XII)	50704	(3aR,4R,5R,6aS)-5-(tetrahydro-2H-pyran-2-yloxy)-4-[2-(tetrahydro-2H-pyran-2-yloxy)-4-[3-(trifluoromethyl)phenyl]butoxy]hexahydro-2H-cyclopenta[b]furan-2-one		C₂₈H₃₇F₃O₇	详情	详情
(XIII)	50705	(3aR,4R,5R,6aS)-5-(tetrahydro-2H-pyran-2-yloxy)-4-[2-(tetrahydro-2H-pyran-2-yloxy)-4-[3-(trifluoromethyl)phenyl]butoxy]hexahydro-2H-cyclopenta[b]furan-2-ol		C₂₈H₃₉F₃O₇	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Commercially available aldehyde (I) was reduced to alcohol (II) with NaBH4. After protection of the hydroxyl group of (II) as the tert-butyldiphenylsilyl ether (III), hydrolysis of the benzoate ester of (III) using K2CO3 in MeOH afforded the 11R alcohol (IV). Displacement of the hydroxyl group of (IV), with inversion of the configuration, by means of (diethylamino)sulfur trifluoride generated the 11S fluoride (V), along with minor amounts of olefin (VI). Separation was achieved by dihydroxylation of the olefin (VI) with N-methylmorpholine-N-oxide and OsO4, followed by column chromatography. Reduction of the lactone group of (V) with diisobutylaluminum hydride at -78 C yielded lactol (VIII). Wittig condensation with the phosphorane resulting from phosphonium salt (IX) and t-BuOK furnished the Z-olefin (X). The carboxylate group was then converted to isopropyl ester (XI) by treatment with isopropyl iodide and DBU.

参考文献中间体

合成目标

【1】 Klimko, P.; Sharif, N.A.; Griffin, B.W.; Crider, J.Y.; AL-8810: A novel prostaglandin F2alpha analog with selective antagonist effects at the prostaglandin F2alpha (FP) receptor. J Pharmacol Exp Ther 1999, 290, 3, 1278.
【2】 Sallee, V.L.; Hellberg, M.R.; Klimko, P.G.; Zinke, P.W. (Alcon Laboratories, Inc.); 11-Halo prostaglandins for the treatment of glaucoma or ocular hypertension. WO 9820880 .

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)	35585	(3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate	39746-01-5	C₁₅H₁₄O₅	详情	详情
(II)	35586	(3aR,4S,5R,6aS)-4-(hydroxymethyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate		C₁₅H₁₆O₅	详情	详情
(III)	35587	(3aR,4S,5R,6aS)-4-([[tert-butyl(diphenyl)silyl]oxy]methyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate		C₃₁H₃₄O₅Si	详情	详情
(IV)	35588	(3aR,4S,5R,6aS)-4-([[tert-butyl(diphenyl)silyl]oxy]methyl)-5-hydroxyhexahydro-2H-cyclopenta[b]furan-2-one		C₂₄H₃₀O₄Si	详情	详情
(V)	35589	(3aR,4S,5S,6aS)-4-([[tert-butyl(diphenyl)silyl]oxy]methyl)-5-fluorohexahydro-2H-cyclopenta[b]furan-2-one		C₂₄H₂₉FO₃Si	详情	详情
(VI)	35590	(3aR,6aS)-4-([[tert-butyl(diphenyl)silyl]oxy]methyl)-3,3a,6,6a-tetrahydro-2H-cyclopenta[b]furan-2-one		C₂₄H₂₈O₃Si	详情	详情
(VII)	35591	(3aS,6aS)-4-([[tert-butyl(diphenyl)silyl]oxy]methyl)-4,5-dihydroxyhexahydro-2H-cyclopenta[b]furan-2-one		C₂₄H₃₀O₅Si	详情	详情
(VIII)	35592	(3aR,4S,5S,6aS)-4-([[tert-butyl(diphenyl)silyl]oxy]methyl)-5-fluorohexahydro-2H-cyclopenta[b]furan-2-ol		C₂₄H₃₁FO₃Si	详情	详情
(IX)	13616	(4-Carboxybutyl)triphenylphosphonium bromide	17814-85-6	C₂₃H₂₄BrO₂P	详情	详情
(X)	35593	(Z)-7-[(1R,2S,3S,5S)-2-([[tert-butyl(diphenyl)silyl]oxy]methyl)-3-fluoro-5-hydroxycyclopentyl]-5-heptenoic acid		C₂₉H₃₉FO₄Si	详情	详情
(XI)	35594	isopropyl (Z)-7-[(1R,2S,3S,5S)-2-([[tert-butyl(diphenyl)silyl]oxy]methyl)-3-fluoro-5-hydroxycyclopentyl]-5-heptenoate		C₃₂H₄₅FO₄Si	详情	详情

Extended Information