By condensation of the sodium salt of 1,3-dibutyl-xantine (I) with chloroacetone (II) in refluxing ethanol.
The condensation of pyruvic aldehyde dimethyl acetal (I) with dimethylformamide dimethyl acetal (II) afforded ketoenamine (III), which was condensed with N-methyl guanidine (IV) to give pyrimidine (V). Acid hydrolysis of the acetal function of (V) yielded pyrimidine carboxaldehyde (VI), which was converted to the imine (VIII) by treatment with 1-Boc-4-aminopiperidine (VII). Isonitrile (XII) was prepared by condensation of 4-fluorobenzaldehyde (IX) with formamide and p-thiocresol (X), followed by dehydration of the resulting formamide (XI) by means of POCl3 and Et3N. Reaction of isonitrile (XII) with imine (VIII) in the presence of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) produced imidazole (XIII). Finally, acid deprotection of the Boc group of (XIII) provided the title compound.
In a related procedure, condensation of 4-fluorobenzaldehyde (IX) with formamide and p-toluenesulfinic acid (XIV) produced the tosyl formamide (XV), which was dehydrated by means of POCl3 and Et3N to give isonitrile (XVI). Imidazole (XIII) was then obtained by reaction of this isonitrile with imine (VIII). Finally, the Boc protecting group of (XIII) was removed by acid treatment as above.
Two related syntheses have been reported for this compound. The intermediate alpha-tosyl-(4-fluorobenzyl)isonitrile (V) was prepared by condensation of 4-fluorobenzaldehyde (I), p-toluenesulfinic acid (II) and formamide (III) in the presence of chlorotrimethylsilane (1-4), followed by dehydration of the resulting formamide derivative (IV) with POCl3 and triethylamine.
In the original procedure, pyruvic aldehyde dimethyl acetal (VI) was condensed with N,N-dimethylformamide dimethyl acetal to give enaminoketone (VII). Subsequent reaction of (VII) with guanidine (VIII) provided 2-aminopyrimidine-4-carboxaldehyde dimethyl acetal (IX), which was hydrolyzed to the corresponding aldehyde (X) with 3 N HCl at 48 C. This was condensed with 4-amino-2,2,6,6-tetramethylpiperidine (XI) to produce imine (XII). Finally, reaction between imine (XII) and tosyl isonitrile (V) in the presence of K2CO3 generated the target imidazole.
Condensation between p-fluorobenzaldehyde (I), p-toluenesulfinic acid (II) and formamide in the presence of camphorsulfonic acid afforded 4-fluorophenyltosylmethyl formamide (III). Subsequent dehydration of (III) by means of POCl3 and Et3N produced isonitrile (IV). Imine (VII) was prepared by condensation of pyridine-4-carboxaldehyde (V) with 1-Boc-4-aminopiperidine (VI) using MgSO4 as the dehydrating reagent. Dipolar cycloaddition of this imine with the anion of tosyl isonitrile (IV) generated the trisubstituted imidazole (VIII). Finally, acid cleavage of the Boc protecting group furnished the title compound.
A new procedure, which avoided the unstable pyrimidine aldehye (X), started by condensing pyruvic aldehyde (XIII) with aminopiperidine (XI). The resulting imine (XIV) was reacted with tosyl isonitrile (V) to form the acetyl imidazole (XV). Subsequent treatment of (XV) with N,N-dimethylformamide dimethyl acetal gave enaminoketone (XVI), which was then condensed with guanidine (VIII) to produce the required pyrimidine ring.
Condensation of pyruvic aldehyde dimethyl acetal (I) with dimethylformamide dimehylacetal provided ketoenamine (II). This was cyclized with guanidine to afford aminopyrimidine (III). Then, hydrolysis of the dimethyl acetal of (III) with 3 M HCl yielded aldehyde (IV). 4-Fluorobenzaldehyde (V) was condensed with thiocresol (VI) and formamide in refluxing toluene to give 4-fluorophenyl-tolylthiomethyl formamide (VII), which was dehydrated to isocyanide (VIII) with POCl3 and Et3N at -30 C. Finally, imine (X), (obtained from pyrimidine aldehyde (IV) and 4-(3-aminopropyl)morpholine (IX)), was condensed with isocyanide (VIII) in the presence of 1,5,7-triazabicyclo[4.4.0]dec-5-ene to furnish the title imidazole.