NAS-181

(2R)-2-[[[3-(4-吗啉基甲基)-2H-1-苯并吡喃-8-基]氧基]甲基]吗啉二甲烷磺酸盐Chemical Name: (+)-2(R)-[3-(Morpholin-4-ylmethyl)-2H-1-benzopyran-8-yloxymethyl]morpholine methanesulfonate
CAS No. 205242-62-2, 205242-61-1 (free base), 205584-77-6 (free base, (S)-isomer)
项目整合开发状态: Preclinical
项目研究机构: AstraZeneca (Originator)
合成路线:The condensation of 3-(4-morpholinylmethyl)-2H-1-benzopyran-8-ol (VI) with 2(R)-(p-toluenesulfonyloxymethyl)-4-(triphenylmethyl)morpholine (XVI) by means of K2CO3 in DMF gives the protected target compound (XVII),which is finally deprotected with acetic acid and salified with methanesulfonic acid.The intermediates benzopyran (VI) and morpholine (XVI) have been obtained as follows:Benzopyran (VI): The reaction of 8-methoxy-4H-1-benzopyran-3-carboxylic acid (I) with SOCl2 in refluxing toluene gives the acyl chloride (II),which is condensed with morpholine (III) in dioxane yielding the methanone (IV).The reaction of (IV) with BBr3 in dichloromethane affords the 1-(8-hydroxy-2H-1-benzopyran-3-yl)-1-(4-morpholinyl)methanone (V),which is reduced with LiAlH4 in THF giving the desired intermediate benzopyran (VI).Morpholine (XVI): The reaction of benzyl (S)-glycicyl ether (VII) with benzylamine (VIII) gives 1-(benzylamino)-3-(benzyloxy)-2(R)-propanol (IX),which is cyclized with chloroacetyl chloride (X) and triethylamine in dichloromethane yielding the morpholinone (XI).The reduction of (XI) with LiAlH4 in ethyl ether affords the fully protected morpholine (XII),which is debenzylated with H2 over Pd/C in ethanol giving 2(R)-(hydroxyethyl)morpholine (XIII).The reaction of (XIII) with trityl chloride (XIV) and TEA in dichloromethane yields the N-tritylmorpholine (XV),which is finally tosylated with tosyl chloridde and pyridine affording the desired intermediate morpholine (XVI).