合成路线1

BI-1356 can be synthesized as follows. Cyclization of 2-aminoacetophenone (I) with chloroacetonitrile (II) in the presence of HCl in dioxane gives 2-(chloromethyl)-4-methylquinazoline (III) (1), which can also be prepared by reaction of 2-(chloromethyl)-4-methylquinazoline-3-oxide (IV) with PCl3 in refluxing chloroform (2). Coupling of the quinazoline derivative (III) with 3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine (V) –prepared by treatment of 8-bromo-3-methylxanthine (VI) with butyn-2-yl bromide (VII) in the presence of TEA or DIEA in DMF (3)–, in the presence of Na2CO3 or K2CO3 provides 1-(4-methylquinazolin-2-ylmethyl)-3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine (VIII). Condensation of bromoxanthine (VIII) with (R)-3-(phthalimido)piperidine D-tartrate (IX) affords the adduct (X), which is deprotected by heating with 2-aminoethanol in either toluene at 85 ºC or in THF at 65 ºC (1). Scheme 1.
The title compound can also be prepared by coupling of the bromoxanthine (VIII) with 3(R)-(tert-butoxycarbonylamino)piperidine (XI) by means of K2CO3 in DMF to give the N-protected piperidine derivative (XII), which is deprotected with TFA in CH2Cl2 (2, 3). Scheme 1.