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 dealkoxycarbonylating a 4-oxo-1,6-dihydro-pyrimidinyl carboxylic acid ester of formula (II):
wherein R is C 1-4 alkyl.
2. A process for preparing a compound of formula (I), as defined in claim 1 , wherein the compound of formula (I) is prepared by condensing the guanidine of formula (III) with an alkoxymethylene malonic acid ester of formula (IV), thus obtaining an intermediate (II), which is dealkoxycarbonylated 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:
3. A process according to claim 2 wherein the conversion from (III) over (II) to obtain (I) is conducted in a one-pot reaction, without isolation of intermediate (II).
4. A process according to claim 1 wherein R is methyl or ethyl.
5. A process according to claim 1 wherein the process is conducted in the presence of a salt.
6. A process according to claim 5 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.
7. A process according to claim 6 wherein M is an alkali metal, ammonium or substituted ammonium and X is a halide, cyanide or C 1-4 alkylcarboxylate.
8. A process according to claim 1 wherein the process is conducted in a dipolar aprotic solvent.
9. A process according to claim 8 wherein the solvent is selected from dimethylformamide (DMF), dimethylacetamide (DMA), hexamethylphosphoric acid triamide (HMPT), N-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO) and acetonitrile.
10. A process according to claim 1 wherein at the end of the dealkoxycarbonylation step an acid is added to the reaction mixture.
11. The process according to claim 6 , wherein M is an alkali metal and X is C 1-4 alkylcarboxylate.
12. The process according to claim 10 , wherein the acid is an alkylcarbonic acid.
13. The process according to claim 12 wherein the acid is C 1-4 alkylcarbonic acid.
14. The process according to claim 13 wherein the acid is acetic acid.
15. The process according to claim 5 wherein the salt is sodium acetate.
16. The process according to claim 9 wherein the solvent is N-methylpyrrolidone.
17. A process to prepare (E)-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile, wherein the process encompasses a process for preparing a compound of formula (I)
wherein the compound of formula (I) is prepared by dealkoxycarbonylating a 4-oxo-1,6-dihydro-pyrimidinyl carboxylic acid ester of formula (II):
wherein R is C 1-4 alkyl;
followed by halogenation of the obtained compound of formula (I) resulting in a compound of formula (C);
followed by coupling (E)-4-amino-3,5-dimethylcinnamonitrile (compound of formula B) with the obtained compound of formula (C) to give (E)-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile (compound of formula A)