BMS-068645, ATL-146e, DWH-146e

Chemical Name: 4-[3-[6-Amino-9-[(2R,3R,4S,5S)-5-(N-ethylcarbamoyl)-3,4-dihydroxytetrahydrofuran-2-yl]-9H-purin-2-yl]-2-propynyl]cyclohexanecarboxylic acid methyl ester
项目整合开发状态: Phase II
项目研究机构: Adenosine Therapeutics (Originator), University of Virginia (Originator), Adenosine Therapeutics (Licensee), Bristol-Myers Squibb (Licensee)
合成路线:The intermediate iodopurine (IX) was prepared as follows.Acetylation of guanosine (I) afforded the triacetate ester (II).Subsequent chlorination of (II) to the 6-chloropurine (III) was accomplished by treatment with phosphoryl chloride and N,N-dimethylaniline.Diazotization of (III) with isoamyl nitrite in the presence of CuI furnished the 6-chloro-2-iodopurine (IV).Displacement of the 6-chloro group of (IV) in liquid ammonia with concomitant ammonolysis of the acetate esters gave rise to the 6-amino derivative (V).The dioxolane ketal (VI) was then formed by treatment of (V) with 2,2-dimethoxypropane in the presence of p-toluenesulfonic acid.After oxidation of the primary alcohol of (VI) with alkaline KMnO4 to give (VII),its ketal hydrolysis using 50% formic acid produced the carboxylic acid (VIII).The required N-ethyl amide (IX) was then obtained by esterification with SOCl2/EtOH,followed by treatment with liquid ethylamine.

合成路线:1,4-Cyclohexanedimethanol (X) was converted to the mono-tosylate (XI),which was then condensed with lithium acetylide ethylenediamine complex to furnish (4-propargylcyclohexyl)methanol (XII).This procedure was further improved with the protection of diol (X) as the mono-silyl ether (XIII).Tosylation of (XIII) and subsequent reaction with lithium acetylide afforded (XIV),which was then desilylated to (XII) by means of tetrabutylammonium fluoride.Alcohol (XII) was oxidized by Jones reagent to the corresponding carboxylic acid (XV).This was converted into the methyl ester (XVI) by treatment with trimethylsilyl diazomethane.Finally,palladium-catalyzed coupling of the iodopurine (IX) with acetylene (XVI) gave rise to the title compound.