合成路线1

Condensation of S-methylisothiourea (I) and cyano acetate derivative (II) by means of NaOMe in MeOH affords pyrimidine derivative (III), whose hydroxy group is converted into chloro by means of refluxing POCl3, yielding derivative (IV). Alkylation of (IV) with cyclopentylamine (V) and Et3N in CH2Cl2 provides derivative (VI), whose nitrile group is then reduced by means of LiAlH4 in THF to afford aminomethyl compound (VII). Treatment of (VII) with 1,1-carbonyldiimidazole (CDI) in refluxing THF gives pyrimidopyrimidinone (VIII), whose methylsulfanyl group is oxidized with 3-phenyl-2-(phenylsulfonyl)oxaziridine (IX) in CHCl3 to afford methyl sulfoxide derivative (X). Displacement of the methyl sulfoxide group of (X) with substituted aniline (XI) in TFA/acetonitrile yields 3,4-dihydropyrimidopyrimidinone (XII), which is finally oxidized by means of KOtBu in THF or DMSO.

合成路线2

Reaction of 2-nitro-5-chlorophenylhidrazyne (I) with ethyl 2-cyano-3-ethoxypropenoate (II) in EtOH and catalytic HOAc affords derivative (III), which is simultaneously hydrolyzed and cyclized to the triazine system (IV) in aqueous NaOH. Treatment of (IV) with SOCl2 followed by addition of alcohol (V) in chloroform allows obtention of the desired product.

合成路线3

Reaction of 2-nitro-5-chlorophenylhidrazyne (I) with ethyl 2-cyano-3-ethoxypropenoate (II) in EtOH and catalytic AcOH affords derivative (III), which is simultaneously hydrolyzed and cyclized to the triazine system (IV) in aqueous NaOH. Treatment of (IV) with SOCl2, followed by addition of alcohol (V) in chloroform, allows obtention of the desired product.

合成路线4

合成路线5

Condensation of ethyl(ethoxymethylene)cyanoacetate (I) with diethyl aminomalonate hydrochloride (II) in the presence of NaOMe in refluxing MeOH gives the pyrrole derivative (III), which is cyclized with formamidine acetate (IV) in refluxing EtOH to yield methyl 4-hydroxy-pyrrolo[3,2-d]pyrimidine-7-carboxylate (V). Decarbomethoxylation of ester (V) by means of aqueous KOH at reflux provides 4-hydroxy-pyrrolo[3,2-d]pyrimidine (VI), which by chlorination with POCl3 at reflux and subsequent chloride displacement with NaOBn in refluxing benzyl alcohol leads to 4-(benzyloxy)pyrrolo[3,2-d]pyrimidine (VII). Mannich reaction of deazapurine derivative (VII) with 4(R)-(hydroxymethyl)pyrrolidin-3(R)-ol (VIII) [obtained by debenzylation of compound (IX) with H2 and Pd/C in EtOH at 58 °C and formaldehyde in H2O at 58 °C yields the O-benzyl ulodesine derivative (X), which is finally deprotected by hydrogenolysis over Pd/C in aqueous ammonia .
In a related procedure, Mannich reaction of 4-hydroxypyrrolo-[3,2-d]pyrimidine (VI) with 4(R)-(hydroxymethyl)pyrrolidin-3(R)-ol hydrochloride (XI) [obtained by N-deprotection of 1-Boc-4(R)-(hydroxymethyl)pyrrolidin-3(R)-ol (XII) using HCl in MeOH (4)] and formaldehyde in the presence of NaOAc in H2O at 95 °C provides ulodesine as the corresponding acetate salt .
Alternatively, ulodesine can be obtained by deprotection of precursor (XIII) with H2 and Pd(OH)2/C in EtOH/AcOH .