Process for manufacturing pyrimidine sulfamide derivatives
The invention relates to a process for manufacturing the compound of formula I wherein R is H, (C 1 -C 6 )alkyl or benzyl, or a salt thereof, said process comprising the reaction of the compound of formula I-1 wherein X is Br, Cl or F, or a salt thereof, with the compound of formula I-2 wherein R is H, (C 1 -C 6 )alkyl or benzyl, or a salt thereof, in the presence of a base, and, when X is Br or Cl, in the presence of tetra-n-butyl ammonium fluoride hydrate or cesium fluoride. The invention further relates to the compound of formula I-1 and uses thereof.
1. A method for manufacturing a compound of formula I
wherein R is H, or a salt thereof, said method comprising the reaction of the compound of formula I-1
wherein X is bromine, chlorine or fluorine, with the compound of formula I-2
wherein R is H, or a salt of said compound of formula I-2, said reaction being performed in the presence of a base in a polar aprotic organic solvent or a polar mixture of aprotic organic solvents, and, when X is bromine or chlorine, in the presence of tetra-n-butyl ammonium fluoride hydrate or cesium fluoride.
2. The method of claim 1 , wherein the base is NaOH, KOH, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, potassium text-butylate, Na 2 CO 3 K 2 CO 3 or Cs 2 CO 3 .
3. The method of claim 2 , wherein the base is K 2 CO 3 .
4. The method of claim 1 , wherein the polar aprotic organic solvent or polar mixture of aprotic organic solvents comprises dimethylsulfoxide.
5. The method of claim 4 , which is performed using dimethylsulfoxide as solvent.
6. The method of claim 1 , wherein X is chlorine and the reaction of the compound of formula I-1 with the compound of formula I-2 is performed in the presence of tetra-n-butyl ammonium fluoride hydrate and using dimethylsulfoxide as solvent.
7. A compound of formula I-1
wherein X is fluorine;
or a salt of said compound.
8. A method of manufacturing a compound of formula I,
wherein R is H, or a salt thereof, comprising reacting the compound of formula I-1
wherein X is chlorine, or a salt thereof; with a fluorination agent.
9. A method for manufacturing the compound of formula I
wherein R is H, or for manufacturing a salt thereof, said method comprising reacting a compound of formula I-1 Cl
or a salt thereof, with tetra n-butyl ammonium fluoride hydrate or cesium fluoride in the presence of a base in a polar aprotic organic solvent or a polar mixture of aprotic organic solvents, to yield the compound of formula I-1 F
and
reacting the compound of formula I-1 F with a compound of formula I-2
wherein R is H, or a salt thereof, in the presence of a base in a polar aprotic organic solvent or a polar mixture of aprotic organic solvents, to yield said compound of formula I or a salt thereof.
10. The method of claim 9 , wherein the compound of formula I-1 Cl is reacted with cesium fluoride.
11. The method of claim 8 , wherein the fluorination agent is tetra-n-butyl ammonium fluoride hydrate.
12. A method for manufacturing a compound of formula I
wherein R is n-propyl, or a salt thereof, said method comprising reacting a compound of formula I-1
wherein X is bromine, chlorine or fluorine, with a compound of formula I-2
wherein R is n-propyl, or a salt of said compound of formula I-2, said reaction being performed in the presence of a base in a polar aprotic organic solvent or a polar mixture of aprotic organic solvents, and, when X is bromine or chlorine, in the presence of tetra-n-butyl ammonium fluoride hydrate or cesium fluoride.
13. The method of claim 12 , wherein the base is NaOH, KOH, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, potassium tort-butylate, Na 2 CO 3 K 2 CO 3 or Cs 2 CO 3 .
14. The method of claim 13 , wherein the base is K 2 CO 3 .
15. The method of claim 12 , wherein the polar aprotic organic solvent or polar mixture of aprotic organic solvents comprises dimethylsulfoxide.
16. The method of claim 15 , wherein the dimethylsulfoxide is used as a solvent.
17. The method of claim 12 , wherein X is chlorine and the reaction of the compound of formula I-1 with the compound of formula I-2 is performed in the presence of tetra-n-butyl ammonium fluoride hydrate and using dimethylsulfoxide as solvent.
18. A method of manufacturing a compound of formula I,
wherein R is n-propyl, or a salt thereof, comprising reacting the compound of formula I-1
with a fluorination agent.
19. A method for manufacturing the compound of formula I
wherein R is n-propyl, or for manufacturing a salt thereof, said method comprising reacting a compound of formula I-1 Cl
or a salt thereof, with tetra n-butyl ammonium fluoride hydrate or cesium fluoride in the presence of a base in a polar aprotic organic solvent or a polar mixture of aprotic organic solvents, to yield the compound of formula I-1 F
and
reacting the compound of formula I-1 F with a compound of formula I-2
wherein R is n-propyl, or a salt thereof, in the presence of a base in a polar aprotic organic solvent or a polar mixture of aprotic organic solvents, to yield said compound of formula I or a salt thereof.
20. The method of claim 19 , wherein the compound of formula I-1 Cl is reacted with cesium fluoride.
21. The method of claim 18 , wherein the fluorination agent is tetra-n-butyl ammonium fluoride hydrate.