Process for preparing [4,6-bis-dimethylamino-2-[4-(4-trifluoromethylbenzoylamino)benzyl]pyrimidin-5-yl]acetic acid
View Patent ↗The present invention relates to a process for preparing a compound of formula (I).
1. A process for preparing a compound of formula (I)
the process comprising reacting a compound of formula (III)
with 4-trifluoromethylbenzoyl chloride in the presence of a second base and methanol to obtain a compound of formula (II)
and then hydrolyzing the compounds of formula (II) in the presence of a first base and of a solvent or of a mixture of solvents to obtain the compound of formula (I).
2. The process according to claim 1 , wherein the first base is the monohydrate of LiOH.
3. The process according to claim 1 , wherein the solvent or the mixture of solvents is a mixture of tetrahydrofuran, methanol, and water.
4. The process according to claim 1 , wherein the obtained reaction mixture comprising a salt of the compound of formula (I) is subsequently neutralized with acetic acid.
5. The process according to claim 1 , wherein the second base is diisopropylethylamine.
6. The process according to claim 1 , wherein the compound of formula (III) is obtained by hydrogenation of a compound of formula (IV)
7. The process according to claim 6 , wherein the hydrogenation takes place in the presence of palladium on activated charcoal.
8. The process according to claim 6 , wherein the compound of formula (III) is isolated from isopropanol as its free base.
9. The process according to claim 6 , wherein the compound of formula (IV) is obtained by reacting a compound of formula (V)
with an excess of dimethylamine in the presence of a solvent or of a mixture of solvents.
10. The process according to claim 9 , wherein the solvent or the mixture of solvents is isopropyl acetate.
11. The process according to claim 9 , wherein the hydrogenation of the compound of formula (IV) is subsequently performed without prior isolation.
12. The process according to claim 11 , wherein the reaction mixture is washed with water prior to performing the hydrogenation.
13. The process according to claim 9 , wherein the compound of formula (V) is obtained by reacting a compound of formula (VI)
with a chlorinating agent in the presence of a third base.
14. The process according to claim 13 , wherein the chlorinating agent is POCl 3 .
15. The process according to claim 13 , wherein the third base is triethylamine.
16. The process according to claim 9 , wherein the compound of formula (VI) is obtained by reacting a compound of formula (VII) or a hydrohalogenide thereof
with trimethyl 1,1,2-ethantricarboxylate in the presence of a fourth base.
17. The process according to claim 16 wherein the fourth base is sodium methylate.
18. The process according to claim 16 , wherein the compound of formula (VII) or the hydrohalogenide thereof is obtained by reacting 4-nitrophenylacetonitril in the presence of methanol and acetyl chloride and subsequently reacting the obtained intermediate with ammonia.