Chemical process
The present invention relates to a process for the preparation of umeclidinium bromide, and to processes for preparing intermediates used in the preparation of umeclidinium bromide.
1. A process for the preparation of umeclidinium bromide, which comprises:
a) reacting ((2-bromoethoxy)methyl)benzene, of formula (II)
with diphenyl(quinuclidin-4-yl)methanol, of formula (III)
in a dipolar aprotic solvent with a boiling point greater than about 90° C. or an alcohol with a boiling point greater than about 80° C.; and optionally
b) re-crystallising the product of step (a).
2. A process according to claim 1 , wherein the alcohol is n-propanol.
3. A process according to claim 1 , wherein the dipolar aprotic solvent is DMF, DMA, DMSO or NMP.
4. A process according to claim 1 , wherein the re-crystallisation is performed in an aqueous n-propanol solution.
5. A process according to claim 4 , wherein the ratio of water to n-propanol is 2 to 1.
6. A process according to claim 1 , wherein the compound of formula (III) is prepared by a process comprising reacting phenyl lithium in dibutyl ether with a compound of formula (IV)
wherein R 1 is C 1-6 alkyl, aryl or benzyl, in a suitable solvent.
7. A process according to claim 6 , wherein the solvent is toluene.
8. A process according to claim 6 , wherein the compound of formula (IV) is prepared by a process comprising reacting a compound of formula (V)
wherein R 1 is C 1-6 alkyl, aryl or benzyl and Y is a leaving group, with a suitable base selected from KHMDS, LiHMDS and NaHMDS, in a suitable solvent.
9. A process according to claim 8 , wherein Y is —OTs, —OMs, —OTf, Cl or Br.
10. A process according to claim 9 , wherein Y is Cl.
11. A process according to claim 8 , wherein the solvent is toluene.
12. A process according to claim 8 , wherein the base is KHMDS.
13. A process according to claim 8 , wherein the compound of formula (V) is prepared by a process which comprises:
a) reacting a compound of formula (VI)
wherein R 1 is C 1-6 alkyl, aryl or benzyl, with a compound of formula (VII)
wherein X is a leaving group, in the presence of a suitable base; and
b) converting the product of step (a) to the compound of formula (V) with a suitable reagent.
14. A process according to claim 13 , wherein X is Cl or Br.
15. A process according to claim 13 , wherein the reagent in step (b) is selected from the group consisting of thionyl chloride, sulfonyl halides, such as sulfonyl chlorides, sulfonyl anhydrides and phosphorus halides.
16. A process according to claim 13 , wherein the reagent in step (b) is selected from the group consisting of thionyl chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride, trifluoromethanesulfonic anhydride, phosphoryl chloride, phosphorus tribromide and phosphorus pentachloride.
17. A process according to claim 15 , wherein the reagent is thionyl chloride.
18. A process according to claim 13 , wherein steps (a) and (b) are carried out in a suitable solvent.
19. A process according to claim 18 , wherein the solvent is toluene.
20. A process according to claim 13 , wherein the base is DBU.
21. A process according to claim 5 , wherein R 1 is ethyl.