Processes for the preparation of sugammadex
The present invention provides processes for the preparation of sugammadex: (I) In one aspect, there is provided a process for the preparation of sugammadex from 8-per-deoxy-8-bromo-γ-cyclodextrin and 3-mercaptopropionic acid. In another aspect, there is provided an alternative process for the preparation of sugammadex from 8-per-deoxy-8-bromo-γ-cyclodextrin and disodium 3 -mercaptopropionate. In another aspect, there is provided a process for the preparation of 8-per-deoxy-8-bromo-γ-cyclod extrin, which may be used in the production of sugammadex. In one such aspect, there is provided a process for the preparation of 8-per-deoxy-8-bromo-y-cyclodextrin from γ-cyclodextrin and a brominating agent. In another such aspect, there is provided a process for the preparation of 8-per-deoxy-8-bromo-γ-cyclodextrin comprising, inter alia, reacting γ-cyclodextrin with an electrophilic brominating agent, a deoxygenating agent, and an acid in the presence of an organic solvent.
1. A process for the preparation of a sugammadex:
comprising:
reacting γ-cyclodextrin of the formula:
with an electrophilic brominating agent to brominate γ-cyclodextrin, a deoxygenating agent, and an acid in the presence of an organic solvent;
heating the resulting mixture;
adding to the mixture a solution comprising water and an acid and mixing the resulting solution to produce the 8-per-deoxy-8-bromo-γ-cyclodextrin of the formula:
dissolving 8-per-deoxy-8-bromo-γ-cyclodextrin in 1-methyl-2-pyrrolidinone;
adding 3-mercaptopropionic acid to form a first solution;
dissolving a base in water to form a base-water solution;
adding the base-water solution to the first solution at a rate sufficient to maintain the temperature of the resulting solution between about 5° C. and 40° C., wherein the base in the base-water solution is selected sodium hydroxide, sodium carbonate, and sodium phosphate;
stirring the resulting solution in the presence of heat;
adjusting the pH of the resulting mixture to from 7 to 13; and
isolating the sugammadex product.
2. The process of claim 1 , wherein the concentration of base in the base-water solution ranges from 6% to 24%.
3. The process of claim 2 , wherein the concentration of base in the base-water solution ranges from 13% to 14%.
4. The process of claim 2 , wherein the base-water solution is added to the first solution over at least 1 hour.
5. The process of claim 3 , wherein the resulting solution is heated to a temperature between 20 and 100° C. and then stirred for from 2 h to 30 hours.
6. The process of claim 1 , wherein the sugammadex is isolated by the addition of antisolvent or a mixture of antisolvent and water.
7. The process of claim 1 , wherein the γ-cyclodextrin has been dried through azeotropic distillation with DMF until the Karl Fischer titration value is less than 0.1%.
8. The process of claim 1 , wherein the electrophilic brominating agent is combined with the organic solvent, and the resulting solution is added to a solution comprising the γ-cyclodextrin, the deoxygenating agent, acid, and the organic solvent.
9. The process of claim 8 , wherein the electrophilic brominating agent is 1,3-dibromo-5,5-dimethylhydantoin, N-bromoacetamide, N-bromosuccinimide, N-bromophthalimide, N-bromosaccharin, dibromoisocyanuric acid, monosodium bromoisocyanurate hydrate, bromodimethylsulfonium, bromide, 5,5-dibromomeldrum's acid, 2,4,4,6-tetrabromo-2,5-cyclohexadienone, bis(2,4,6-trimethylpyridine)-bromonium hexafluorophosphate or N-(bromomethylene)-N-methylmethanaminium.
10. The process of claim 9 , wherein the electrophilic brominating agent is 1,3-dibromo-5,5-dimethylhydantoin.
11. The process of claim 8 , wherein the deoxygenating agent is an optionally substituted monophenyl, diphenyl and triphenyl compound selected from:
wherein each of R 1 , R 2 , and R 3 is independently selected from H, F, Cl, CH 3 , OCH 3 , and CF 3 ;
R 4 is selected from methyl, ethyl, and benzyl;
each R 5 is independently selected from methyl and ethyl; and
each R 6 is independently selected from methyl, ethyl, n-butyl, and O-phenyl.
12. The process of claim 11 , wherein the deoxygenating agent is methyldiphenylphosphine.
13. The process of claim 8 , wherein the acid is selected from methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, acetic acid, sulfuric acid, phosphoric acid, and hydrobromic acid.
14. The process of claim 8 , wherein the organic solvent is N,N-dimethylformamide (DMF), N,N-diethylformamide (DEF), N,N-dibutylformamide, N,N-dimethylacetamide (DMA), N,N-diethylacetamide, 1-methyl-2-pyrrolidinone (NMP), 1-ethyl-2-pyrrolidone, 1-butyl-2-pyrrolidone, 1-octyl-2-pyrrolidone, 1-cyclohexyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone (DMI), or 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), or a mixture thereof.
15. The process of claim 8 , wherein the solution is heated to at least about 25° C. and allowed to react from 4 to 48 hours, and then quenched by the addition of water and acid while stirring for 2 to 24 hours at a temperature from 25° C. to 70° C.
16. The process of claim 15 , wherein the 8-per-deoxy-8-bromo-γ-cyclodextrin is isolated by precipitation with an antisolvent.
17. A process for the preparation of a sugammadex:
comprising:
forming a solution comprising γ-cyclodextrin of the formula:
an organic solvent; and
a brominating agent;
heating the resulting solution to brominate γ-cyclodextrin; wherein the mixture is heated to and maintained at a temperature between 40 and 80° C. and allowed to react from 4 hours to 48 hours and then quenched with water while maintaining the temperature between 25° C. to 70° C. to produce the 8-per-deoxy-8-bromo-γ-cyclodextrin of the formula:
dissolving 8-per-deoxy-8-bromo-γ-cyclodextrin in 1-methyl-2-pyrrolidinone;
adding 3-mercaptopropionic acid to form a first solution;
dissolving a base in water to form a base-water solution;
adding the base-water solution to the first solution at a rate sufficient to maintain the temperature of the resulting solution between about 5° C. and 40° C., wherein the base in the base-water solution is selected sodium hydroxide, sodium carbonate, and sodium phosphate;
stirring the resulting solution in the presence of heat;
adjusting the pH of the resulting mixture to from 7 to 13; and
isolating the sugammadex product.
18. The process of claim 17 , wherein the γ-cyclodextrin is has been dried through azeotropic distillation with DMF until the Karl Fischer titration value is less than 0.1%.
19. The process of claim 18 , wherein the organic solvent is N,N-dimethylformamide, N,N-diethylformamide, N,N-dibutylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone, 1-ethyl-2-pyrrolidone, 1-octyl-2-pyrrolidone, or 1-cyclohexyl-2-pyrrolidone, or mixtures thereof.
20. The process of claim 19 , wherein the brominating agent is an N-(bromomethylene)-N-alkylmethanaminium bromide or a bromomethylenemorpholinium bromide.
21. The process of claim 17 , wherein the 8-per-deoxy-8-bromo-γ-cyclodextrin is isolated by precipitation with an antisolvent.