合成路线1

1) The condensation of ethyl cyanoacetate (I) with 2-bromoacetaldehyde diethylacetal (II) by means of K2CO3 gives the alkylated cyanoacetate (III), which is cyclized with guanidine (IV) and sodium ethoxide to the pyrimidinone (V). The acidic cyclization of (V) by means of 0.5 N HCl affords the pyrrolopyrimidinone (VI), which is acylated with pivaloyl chloride (VII) to the heterocyclic amide (VIII). The iodination of (VIII) with N-iodosuccinimide (NIS) gives the diiodo derivative (IX), which by selective deiodination with Zn/acetic acid yields the 5-iodo derivative (X). The condensation of (X) with N-(4-ethynylbenzoyl)-L-glutamic acid dimethyl ester (XI) by means of tetrakis(triphenylphosphine)palladium and CuI affords the expected condensation product (XII), which is reduced with H2 over Pd/C in methanol/dichloromethane to the saturated compound (XIII). Finally, this compound is saponified with NaOH.

合成路线2

2-Pivaloylamino-pyrrolo[2,3-d]pyrimidine-4-one (I) is chlorinated to (II) in refluxing POCl3. Subsequent, Stille coupling of (II) with tributyl vinyltin gives the vinyl pyrrolopyrimidine (III), which is further reduced to the corresponding ethyl derivative (IV) by catalytic hydrogenation over Pd/C. Regioselective iodination of (IV) by means of N-iodosuccinimide provides (V). Aryl iodide (V) is then subjected to palladium-catalyzed cross-coupling with trimethylsilylacetylene (VI), leading to the silylethynyl adduct (VII). Desilylation of (VII) employing tetrabutylammonium fluoride furnishes intermediate (VIII).

合成路线3