Process for preparing 4-[(1,6-dihydro-6-oxo-2-pyrimidinyl)amino]benzonitrile
View Patent ↗This invention relates to a process for preparing 4-[(1,6-dihydro-6-oxo-2-pyrimidinyl)-amino]benzonitrile (I) starting from a 4-oxo-1,6-dihydro-pyrimidinylcarboxylic acid ester (II) or starting from a guanidine derivative which is reacted with an alkoxy-methylene malonic acid ester to an ester (II) which is converted to (I), which reaction sequence may be a one-pot procedure.
1. A process for preparing a compound of formula (I)
wherein the compound of formula (I) is prepared by condensing the guanidine of formula (III) with an alkoxymethylene malonic acid ester of formula (IV), followed by a dealkoxycarbonylation to obtain the desired end product of formula (I), as outlined in the following reaction scheme, wherein each R, independently from the other radicals R, is C 1-4 alkyl:
2. A process according to claim 1 wherein the conversion from (III) to obtain (I) is conducted in a one-pot reaction.
3. A process according to claim 1 wherein R is methyl or ethyl.
4. A process according to claim 1 wherein the process is conducted in the presence of a salt.
5. A process according to claim 4 wherein the salt is represented by formula MX wherein M is a metal or ammonium or substituted ammonium, and X is an anion having nucleophilic properties.
6. A process according to claim 5 wherein M is an alkali metal, ammonium or substituted ammonium and X is a halide, cyanide or C 1-4 alkylcarboxylate.
7. A process according to claim 1 wherein the process is conducted in a dipolar aprotic solvent.
8. A process according to claim 7 wherein the solvent is selected from dimethylformamide (DMF), dimethylacetamide (DMA), hexamethylphosphoric acid triamide (HMPT), N-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO) and acetonitrile.
9. A process according to claim 1 wherein at the end of the dealkoxycarbonylation step an acid is added to the reaction mixture.
10. The process according to claim 6 , wherein M is an alkali metal and X is C 1-4 alkylcarboxylate.
11. The process according to claim 9 , wherein the acid is an alkylcarbonic acid.
12. A process according to claim 10 , wherein the solvent in N-methylpyrrolidone.
13. A process according to claim 11 , wherein the acid is a C 1-4 alkylcarbonic acid.
14. A process according to claim 13 , wherein the acid is acetic acid.
15. A process according to claim 4 , wherein the salt is sodium acetate.