合成路线1

Condensation of ethyl 3-(dimethylamino)acrylate (XVIII) with (benzyloxy)acetyl chloride (XIX) by means of pyridine in CH2Cl2 gives ethyl 2-[(benzyloxy)acetyl]-3-(dimethylamino)-2-propenoate (XX), which by cyclocondensation with ethyl oxalyl chloride (XXI) in the presence of LiHMDS in THF at –78 °C followed by heating with NH4OAc and AcOH affords pyridone derivative (XXII). Alkylation of pyridone (XXII) with bromoacetaldehyde dimethyl acetal (XXIII) and Cs2CO3 in DMF yields diethyl 1-(2,2-dimethoxyethyl)-3-(benzyloxy)-1,4-dihydropyridine-2,5-dicarboxylate (XXIV), which can also be obtained by condensation of diethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (XXV) with 2,2-dimethoxyethylamine (XXVI) in EtOH. Hydrolysis of acetal (XXIV) with H2SO4 and HCOOH in CH2Cl2 yields aldehyde (XXVII), which upon cyclocondensation with 3(R)-amino-1-butanol (XI) by means of AcOH in refluxing MeOH/toluene provides the hexahydropyrido[1’,2’:4,5]pyrazino[2,1-b][1,3]oxazine derivative (XXVIII). Hydrolysis of ester (XXVIII) with NaOH in THF/MeOH/H2O gives the corresponding free acid (XXIX), which is finally condensed with 2,4-difluorobenzylamine (XIV) in the presence of HATU and NMM in DMF .
Propenoate (XX) can also be prepared by condensation of ethyl 4-chloroacetoacetate (XXX) with PhCH2OH in the presence of t-AmONa to give benzyl ether (XXXI), which then reacts with N,N-dimethylformamide dimethyl acetal (XXXII) in toluene .