Iclaprim, AR-101((R)-isomer), AR-102((S)-isomer), RO-48-2622, AR-100

艾拉普林Chemical Name: 5-(2-Cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-ylmethyl)pyrimidine-2,4-diamine
CAS No. 192314-93-5, 474793-41-4 (monomethanesufonate salt)
项目整合开发状态: Phase II
项目研究机构: Roche (Originator), Arpida (Licensee)
合成路线:The reaction of cyclopropanecarbonyl chloride (I) with bis(trimethylsilyl)acetylene (II) gives 1-cyclopropyl-3-(trimethylsilyl)-2-propyn-1-one (III),which is reduced with NaBH4 and CeCl3 in methanol to the corresponding propynol (IV).The condensation of (IV) with 3-hydroxy-4,5-dimethoxybenzaldehyde (V) by means of triphenylphosphine and dimethyl azodicarboxylate in toluene yields the expected propynyl ether (VI),which is cyclized in N,N-diethylaniline at 200 C affording 2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-carbaldehyde (VII).The condensation of (VII) with 3-anilinopropionitrile (VIII) by means of potassium tert-butoxide in DMSO gives the acrylonitrile (IX),which is finally cyclized with guanidine (X) by means of potassium tert-butoxide in ethanol.(1)

合成路线:The reaction of cyclopropanecarbonyl chloride (I) with bis(trimethylsilyl)acetylene (II) gives 1-cyclopropyl-3-(trimethylsilyl)-2-propyn-1-one (III),which is reduced with NaBH4 and CeCl3 in methanol to the corresponding propynol (IV).The condensation of propynol (IV) with 3-hydroxy-4,5-dimethoxybenzoic acid methyl ester (XI) by means of triphenylphosphine and dimethyl azodicarboxylate in toluene yields the expected propynyl ether (XII),which is cyclized in N,N-diethylaniline at 200 C affording 2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-carboxylic acid methyl ester (XIII).Finally,this compound is reduced with NaAlH2(OCH2CH2)2 and morpholine in toluene to give the previously described 2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-carbaldehyde (VII).The condensation of (VII) with 3-anilinopropionitrile (VIII) by means of potassium tert-butoxide in DMSO gives the acrylonitrile (IX),which is finally cyclized with guanidine (X) by means of potassium tert-butoxide in ethanol.