|
【结 构 式】 
|
【药物名称】AL-16049 【化学名称】7-[(1S,2R,3R,5S)-3,5-Dihydroxy-2-[2(S)-hydroxy-4-[3-(trifluoromethyl)phenyl]butoxy]cyclopentyl]-5(Z)-heptenoic acid isopropyl ester 【CA登记号】 【 分 子 式 】C26H37F3O6 【 分 子 量 】502.57639 |
【开发单位】Alcon (Originator) 【药理作用】Antiglaucoma Agents, OCULAR MEDICATIONS, Ophthalmic Drugs, Prostaglandins, Prostanoid FP Agonists |
合成路线1
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
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 |