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【结 构 式】

【分子编号】50705

【品名】(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

【CA登记号】

【 分 子 式 】C28H39F3O7

【 分 子 量 】544.6086696

【元素组成】C 61.75% H 7.22% F 10.47% O 20.56%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XIII)

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).

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:(XIII)

Wittig reaction of lactol (XIII) with the ylide generated from phosphonium salt (XIV) and potassium tert-butoxide afforded acid (XV), which was subsequently esterified with isopropyl iodide and DBU to give the isopropyl ester (XVI). Cleavage of the tetrahydropyranyl ethers of (XVI) under mildly acidic conditions followed by HPLC separation using a chiral column provided the desired alcohol diastereoisomer (XVII). Finally, hydrolysis of ester (XVII) under basic conditions provided the corresponding free acid.

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
(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
(XIV) 13616 (4-Carboxybutyl)triphenylphosphonium bromide 17814-85-6 C23H24BrO2P 详情 详情
(XV) 50706 (Z)-7-((1S,2R,3R,5S)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)-2-[2-(tetrahydro-2H-pyran-2-yloxy)-4-[3-(trifluoromethyl)phenyl]butoxy]cyclopentyl)-5-heptenoic acid C33H47F3O8 详情 详情
(XVI) 50707 isopropyl (Z)-7-((1S,2R,3R,5S)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)-2-[2-(tetrahydro-2H-pyran-2-yloxy)-4-[3-(trifluoromethyl)phenyl]butoxy]cyclopentyl)-5-heptenoate C36H53F3O8 详情 详情
(XVII) 50708 isopropyl (Z)-7-[(1S,2R,3R,5S)-3,5-dihydroxy-2-([(2S)-2-hydroxy-4-[3-(trifluoromethyl)phenyl]butyl]oxy)cyclopentyl]-5-heptenoate C26H37F3O6 详情 详情
Extended Information