AL-16049

Chemical Name: 7-[(1S,2R,3R,5S)-3,5-Dihydroxy-2-[2(S)-hydroxy-4-[3-(trifluoromethyl)phenyl]butoxy]cyclopentyl]-5(Z)-heptenoic acid isopropyl ester; 17-[3-(Trifluoromethyl)phenyl]-13,14-dihydro-18,19,20-trinor-13-oxaprostaglandin F2alpha isopropyl ester
项目整合开发状态: Preclinical
项目研究机构: Alcon (Originator)
合成路线: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).

合成路线: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.