The intermediate oxadiazole (VIII) has been obtained as follows: The reaction of methyl pivalate (I) with refluxing hydrazine hydrate gives the corresponding hydrazide (II), which is cyclized with methyl orthoformate catalyzed by Ts-OH to yield 2-tert-butyl-1,3,4-oxadiazole (III). The condensation of (III) with N2-(tert-butoxycarbonyl)-N1-methoxy-N1-methyl-DL-valinamide (VI) by means of LDA in THF affords the acylated oxadiazole (VII), which is finally deprotected with HCl in ethyl acetate to provide the target intermediate (VIII).
The reaction of 3-(2,2-dimethoxyethyl)-2-phenyl-4-oxo-3,4-dihydropyrimidine-5-carboxylic acid (IX) with isobutyl chloroformate and hydroxylamine gives the corresponding hydroxamic acid (X), which is acylated with Ac2O in pyridine to yield the acetoxy compound (XI). The degradation of (XI) by reaction with DBU in refluxing THF affords the amine (XII), which is protected with benzyl chloroformate (XIII) and NaHCO3, providing the carbamate (XIV). The hydrolysis of the dimethylacetal group of (XIV) with HCl in hot acetic acid gives the acetaldehyde derivative (XV), which is oxidized with NaClO2 in tert-butanol/water yielding the corresponding acetic acid derivative (XVI). The condensation of (XVI) with the intermediate amine (VIII) by means of ethyl chloroformate and NMM in THF affords the amide (XVII), which is hydrogenolyzed with H2 over Pd/C in order to eliminate its carbamate protecting group and provide the target racemic 285811.
The intermediate 2-(5-nitro-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)acetic acid (IV) has been obtained by several related ways: 1. The cyclization of N-(tert-butoxycarbonylmethyl)benzamidine (I) with 3-methoxy-2-nitro-2-propenoic acid methyl ester (II) by means of Na2CO3 gives 2-(5-nitro-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)acetic acid tert-butyl ester (III), which is hydrolyzed by means of TFA to the target intermediate acid (IV). 2. The direct cyclization of N-(carboxymethyl)benzamidine (V) with propenoic ester (II) by means of NaOH gives the target intermediate (IV). 3. The cyclization of N-allylbenzamidine (VI) with propenoic ester (II) by means of HCl in methanol gives the allyl pyrimidinone (VII), which is oxidized with NaIO4 and RhCl3 to afford the target intermediate acid (IV). 4. The cyclization of N-(2-furylmethyl)benzamidine (VIII) with propenoic ester (II) by means of HCl in toluene/methanol gives the furylmethyl pyrimidinone (IX), with is treated with ozone, NaIO4 and RhCl3 in acetonitrile to yield the target intermediate acid (IV). 5. The cyclization of N-(2,2-dimethoxyethyl(benzamidine (X) with propenoic ester (II) in methanol gives the pyrimidinone acetaldehyde dimethylacetal (XI), which is hydrolyzed with TFA to the corresponding aldehyde (XII). Finally, this compound is oxidized with NaClO2 to afford the target intermediate acid (IV).
The condensation of intermediate acetic acid (IV) with 2-tert-butyl-5-(DL-valyl)-1,3,4-oxadiazole (XIII) by means of methyl chloroformate and NMM gives the corresponding amide (XIV), which is finally reduced with H2 over Pd/C in MeOH.
The reaction of methyl pivalate (I) with hydrazine gives the expected hydrazide (II), which is cyclized with methyl or ethyl orthoformate and Ts-OH, yielding the 2-tert-butyl-1,3,4-oxadiazole (III). The condensation of (III) with N-(tert-butoxycarbonyl)-L-valinal (IV) by means of BuLi and MgBr2 in THF affords the alcohol (V), which is treated with HCl in dioxane to provide the amino alcohol (VI). The condensation of (VI) with 2-[5-(benzyloxycarbonyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl]acetic acid (VII) by means of EDC, HOBT and NMM in DMF gives the corresponding amide (VIII), which is treated with DMP or (COCl)2 in order to oxidize the secondary OH group to the ketone (IX). Finally, this compound is deprotected by means of AlCl3 and anisole or HBr in HOAc to afford the target compound.