阅读说明：本技术 用于制备舒更葡糖的方法 (Process for preparing sugammadex ) 是由 J·M·麦凯布·邓恩 N·库尔 W·陈 Y·曹 D·R·小高蒂尔 A·M·海德 S·L· 于 2019-06-03 设计创作，主要内容包括：本发明提供了用于制备式(I)的舒更葡糖的方法。在一个方面,提供了从八全脱氧-八溴-γ-环糊精和3-巯基丙酸制备舒更葡糖的方法。在另一个方面,提供了从八全脱氧-八溴-γ-环糊精和3-巯基丙酸二钠制备舒更葡糖的替代方法。在另一个方面,提供了制备八全脱氧-八溴-γ-环糊精的方法,其可以在舒更葡糖的生产中使用。在一个这种方面,提供了从γ-环糊精和溴化剂制备八全脱氧-八溴-γ-环糊精的方法。在另一个这种方面,提供了用于制备八全脱氧-八溴-γ-环糊精的方法,其尤其包括在有机溶剂的存在下,使γ-环糊精与亲电溴化剂、脱氧剂和酸反应。(The present invention provides a process for the preparation of sugammadex of formula (I). In one aspect, a process for preparing sugammadex from octa-per-deoxy-octabromo-gamma-cyclodextrin and 3-mercaptopropionic acid is provided. In another aspect, an alternative method for preparing sugammadex from octa-per-deoxy-octabromo-gamma-cyclodextrin and disodium 3-mercaptopropionate is provided. In another aspect, a process for preparing octaper-deoxy-octabromo-gamma-cyclodextrin is provided, which may be used in the production of sugammadex. In one such aspect, a process for preparing octaper-deoxy-octabromo-gamma-cyclodextrin from gamma-cyclodextrin and a brominating agent is provided. In another such aspect, there is provided a process for preparing octaper-deoxy-octabromo-gamma-cyclodextrinA process which comprises, inter alia, reacting gamma-cyclodextrin with an electrophilic brominating agent, a de-oxidant and an acid in the presence of an organic solvent.)

1. Process for the preparation of sugammadex:

it includes:

dissolving octa-full-deoxy-octabromo-gamma-cyclodextrin in a solvent;

adding 3-mercaptopropionic acid to form a first solution;

adding a base-water solution to the first solution at a rate sufficient to maintain the temperature of the resulting solution between about 5 ℃ and 40 ℃;

stirring the resulting solution in the presence of heat;

adjusting the pH of the resulting mixture to 7 to 13; and

isolating the sugammadex product.

2. The method of claim 1, wherein the solvent used to form the first solution is 1-methyl-2-pyrrolidone, N-dimethylformamide; n, N-diethylformamide; 1, 3-dimethyl-2-imidazolidinone; 1, 3-dimethyl-, 3,4,5, 6-tetrahydro-2 (1H) -pyrimidinone; pyridine; 1, 2-dimethoxyethane; 1,1,3, 3-tetramethylurea; triethylene glycol; dimethyl sulfoxide; water; diethyl carbonate; methanol; n, N-dibutylformamide; n, N-dimethylacetamide; n, N-diethylacetamide; 1-ethyl-2-pyrrolidone; 1-octyl-2-pyrrolidone; or 1-cyclohexyl-2-pyrrolidone; or mixtures thereof.

3. The method of claim 2, wherein the solvent is 1-methyl-2-pyrrolidone.

4. The process of claim 3, wherein the base in the base-water solution is sodium hydroxide, sodium carbonate, sodium phosphate, sodium bis (trimethylsilyl) amide, sodium tert-butoxide or sodium tert-amylate, or a mixture thereof.

5. The method of claim 4, wherein the concentration of base in the base-water solution is in the range of 6% to 24%.

6. The method of claim 5, wherein the concentration of base in the base-water solution is in the range of 13% to 14%.

7. The method of claim 6, wherein the base-water solution is added to the first solution over at least 1 hour.

8. The process of claim 7, wherein the resulting solution is heated to a temperature between 20 and 100 ℃ and then stirred for 1 to 30 hours.

9. The method of claim 8, wherein the sugammadex is isolated by adding an anti-solvent or a mixture of an anti-solvent and water.

10. Process for preparing sugammadex

It includes:

dissolving a solubility enhancing agent in a solvent mixture to form a first solution;

adding disodium 3-mercaptopropionate to the first solution to form a second solution;

adding octa-per-deoxy-octabromo-gamma-cyclodextrin to the second solution to form a third solution;

stirring the third solution in the presence of heat; and

isolating the sugammadex product.

11. The method of claim 10, wherein the solubility enhancer is selected from the group consisting of sodium 4-toluene sulfonate, sodium 3-toluene sulfonate, sodium 2, 4-xylene sulfonate, sodium 3, 5-xylene sulfonate, sodium 4-isopropyl benzene sulfonate, sodium 4-ethyl benzene sulfonate, sodium 3-ethyl benzene sulfonate, sodium 2-ethyl benzene sulfonate, sodium 4-bromobenzene sulfonate, sodium 3-bromobenzene sulfonate, sodium 2-bromobenzene sulfonate, sodium 4-chlorobenzene sulfonate, sodium 3-chlorobenzene sulfonate, sodium 2-chlorobenzene sulfonate, sodium 4-fluorobenzene sulfonate, sodium 3-fluorobenzene sulfonate, sodium 2-fluorobenzene sulfonate, sodium 4-methoxybenzene sulfonate, sodium 2-methoxybenzene sulfonate, sodium benzene sulfonate, sodium toluene sulfonate, sodium 2-toluene sulfonate, sodium 1-hexanesulfonate, sodium 1-heptanesulfonate, N-lauroylsarcosine, sodium dodecylsulfate, sodium taurocholate and sodium benzoate.

12. The method of claim 11, wherein the solubility enhancer is sodium 4-toluene sulfonate.

13. The method of claim 11, wherein the solvent of the first solution is selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1, 2-dimethoxyethane, dichloromethane, diethyl ether, anisole, cyclopentyl methyl ether, tert-amyl alcohol, ethylene glycol diethyl ether, ethylene glycol dimethyl ether, or a mixture of two or more of any of the foregoing solvents, optionally further mixed with water.

14. The method of claim 13, wherein the third solution is heated to a temperature between 20 and 100 ℃.

15. The method of claim 14, wherein the third solution is stirred for at least 2 hours.

16. The method of claim 15, wherein the sugammadex is isolated by precipitation with an anti-solvent or with a mixture of an anti-solvent and water.

17. The method of claim 15, wherein the anti-solvent is selected from the group consisting of methanol, ethanol, isopropanol, and tetrahydrofuran.

18. The process of any one of claims 1-17, wherein octaper-deoxy-octabromo-gamma-cyclodextrin of the formula:

prepared by a process comprising:

forming a gamma-cyclodextrin comprising the formula:

an organic solvent; and

a solution of a brominating agent;

heating the resulting solution;

adding an amount of water sufficient to quench the reaction; and

separating the octa-deoxy-octabromo-gamma-cyclodextrin.

19. The process of claim 18, wherein the gamma-cyclodextrin is dried by azeotropic distillation with DMF until the karl fischer titration value is less than 0.1%.

20. The process of claim 19, wherein the organic solvent is N, N-dimethylformamide, N-diethylformamide, N-dibutylformamide, N-dimethylacetamide, 1-methyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, 1-octyl-2-pyrrolidone, or 1-cyclohexyl-2-pyrrolidone, or a mixture thereof.

21. The process of claim 20, wherein the brominating agent is N- (bromomethylene) -N-alkylammonium bromide or bromomethylmorpholium bromide.

22. The process of claim 21 wherein the brominating agent is N- (bromomethylene) -N-alkylammonium bromide having the following structural formula:

wherein each R¹Independently is (C)₁-C₆) An alkyl group.

23. The process of claim 21, wherein the brominating agent is bromomethylmorpholium bromide having the structure:

24. the method of claim 21, wherein the mixture is heated to a temperature between 40 and 80 ℃.

25. The method of claim 24, wherein the mixture is allowed to react for 4 to 48 hours while maintaining the reaction temperature at 40 to 80 ℃.

26. The method of claim 25, wherein the reaction is quenched with water.

27. The method of claim 26, wherein water is added while maintaining the temperature between 25 ℃ and 70 ℃.

28. The method of claim 27, wherein the mixture is stirred for 1 hour to 24 hours.

29. The process of claim 28, wherein the octaper-deoxy-octabromo-gamma-cyclodextrin is isolated by precipitation with an anti-solvent.

30. The process of any one of claims 1-17, wherein octaper-deoxy-octabromo-gamma-cyclodextrin of the formula:

prepared by a process comprising:

reacting in the presence of an organic solvent a gamma-cyclodextrin of the formula:

reacting with electrophilic brominating agent, deoxidant and acid;

heating the resulting mixture;

adding a solution comprising water and an acid to the mixture and mixing the resulting solution; and

separating the octa-deoxy-octabromo-gamma-cyclodextrin.

31. The process of claim 30, wherein the gamma-cyclodextrin is dried by azeotropic distillation with DMF until the karl fischer titration value is less than 0.1%.

32. The method of claim 30, wherein the electrophilic brominating agent is combined with the organic solvent and the resulting solution is slowly added to a solution comprising γ -cyclodextrin, a deoxygenating agent, an acid, and an organic solvent.

33. The method of claim 32, wherein the electrophilic brominating agent is 1, 3-dibromo-5, 5-dimethylhydantoin, N-bromoacetamide, N-bromosuccinimide, N-bromophthalimide, N-bromosaccharin, dibromoisocyanuric acid, bromoisocyanuric acid monosodium hydrate, bromodimethylsulfonium bromide, 5-dibromomeldrum's acid, 2,4,4, 6-tetrabromo-2, 5-cyclohexadieneone, or bis (2,4, 6-trimethylpyridine) -bromonium hexafluorophosphate.

34. The method of claim 33, wherein the electrophilic brominating agent is 1, 3-dibromo-5, 5-dimethylhydantoin.

35. The method of claim 30, wherein the oxygen scavenger is an optionally substituted monophenyl, diphenyl, and triphenyl compound selected from the group consisting of: wherein R is¹、R²And R³Each independently selected from H, F, Cl, CH₃、OCH₃And CF₃；

R⁴Selected from methyl, ethyl and benzyl;

each R⁵Independently selected from methyl and ethyl; and

each R⁶Independently selected from methyl, ethyl, n-butyl and O-phenyl.

36. The method of claim 30, wherein the oxygen scavenger is methyl diphenyl phosphine.

37. The process of claim 30, wherein the acid is selected from the group consisting of methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, acetic acid, sulfuric acid, phosphoric acid, and hydrobromic acid.

38. The process of claim 30, wherein the organic solvent is N, N-Dimethylformamide (DMF), N-Diethylformamide (DEF), N-dibutylformamide, N-Dimethylacetamide (DMA), N-diethylacetamide, 1-methyl-2-pyrrolidone (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 mixtures thereof.

39. The method of claim 30, wherein the mixture is heated to at least about 30 ℃.

40. The method of claim 39, wherein the heated mixture is allowed to react for 4 to 48 hours.

41. The method of claim 40, wherein the reaction is quenched by the addition of water and an acid.

42. The method of claim 41, wherein the mixture is stirred for 2 to 24 hours after the addition of water and acid.

43. The method of claim 42, wherein the mixture is stirred while maintaining the temperature at 25 ℃ to 70 ℃.

44. The process of claim 43, wherein the octaper-deoxy-octabromo-gamma-cyclodextrin is isolated by precipitation with an anti-solvent.

45. The method of claim 44, wherein the mixture is cooled to room temperature prior to separation.

Technical Field

The present invention relates to a novel process for the preparation of the pharmaceutical product sugammadex.

Background

Sugammadex is a modified cyclodextrin having the structure:

EMEA in 2008, and USFDA approved sugammadex in 2015 for reversal of neuromuscular blockade induced by rocuronium and vecuronium bromide in adults undergoing surgery. It has the trade nameThe following are marketed in the form of sterile solutions for intravenous injection. Sugammadex and a method for its synthesis are disclosed and protected in WO2001/040316, published 6/7/2001. There remains a need in the art for improved synthesis of sugammadex. The present invention addresses this need.

Disclosure of Invention

The present invention provides a process for the preparation of sugammadex. In one aspect, a process for preparing sugammadex is provided:

it includes:

dissolving octa-per-deoxy-octabromo-gamma-cyclodextrin (8-per-deoxy-8-bromo-gamma-cyclodextrin) in a solvent;

adding 3-mercaptopropionic acid to form a first solution;

adding a base-water solution to the first solution at a rate sufficient to maintain the temperature of the resulting solution between about 5 ℃ and 40 ℃;

stirring the resulting solution in the presence of heat;

adjusting the pH of the resulting mixture to 7 to 13; and

isolating the sugammadex product.

In another aspect, a process for preparing sugammadex is provided

It includes:

dissolving a solubility enhancing agent in a solvent mixture to form a first solution;

adding disodium 3-mercaptopropionate to the first solution to form a second solution;

adding octa-per-deoxy-octabromo-gamma-cyclodextrin to the second solution to form a third solution;

stirring the third solution in the presence of heat; and

isolating the sugammadex product.

In another aspect, a process for preparing octaper-deoxy-octabromo-gamma-cyclodextrin of the formula:

it includes:

forming a gamma-cyclodextrin comprising:

an organic solvent; and

a solution of a brominating agent;

heating the resulting solution; and

separating the octa-deoxy-octabromo-gamma-cyclodextrin. The product octaper-deoxy-octabromo-gamma-cyclodextrin from gamma-cyclodextrin may be used in any of the above aspects of the invention as starting material for the production of sugammadex.

In another aspect, an alternative process for preparing octaper-deoxy-octabromo-gamma-cyclodextrin of the formula:

it includes:

reacting in the presence of an organic solvent a gamma-cyclodextrin of the formula:

reacting with electrophilic brominating agent, deoxidant and acid;

heating the resulting mixture;

adding a solution comprising water and an acid to the mixture and mixing the resulting solution; and

separating the octa-deoxy-octabromo-gamma-cyclodextrin. The product octaper-deoxy-octabromo-gamma-cyclodextrin from gamma-cyclodextrin may be used in any of the above aspects of the invention as starting material for the production of sugammadex.

The examples provided herein are for illustrative purposes only so that the present invention may be more fully understood. These examples should not be construed as limiting the invention in any way.

Detailed Description

Abbreviations

r.t. (or R.T.): at room temperature

DEF: n, N-diethylformamide

DMF: n, N-dimethylformamide

DMA: n, N-dimethyl acetamide

DMI: 1, 3-dimethyl-2-imidazolidinone

DMPU: 1, 3-dimethyl-, 3,4,5, 6-tetrahydro-2 (1H) -pyrimidinone

DMSO, DMSO: dimethyl sulfoxide

DME: 1, 2-dimethoxyethane

H (or H): hour(s)

HPLC: high pressure liquid chromatography

KF: karl Fischer titration

NMP: 1-methyl-2-pyrrolidone

Py: pyridine compound

TMU: 1,1,3, 3-tetramethylurea

TEG: triethylene glycol

V: volume is defined as the amount of solvent used based on the amount of relevant limiting reagent; i.e. 1V (or 1V) ═ 1ml of solvent used per gram of limiting reagent.

Commercially available solvents and reagents were used as received. All solvents and reagents indicated as commercially available are available from a number of commercial suppliers including, for example, Sigma Aldrich, st.

Preparation of sugammadex from octa-deoxy-octabromo-gamma-cyclodextrin and 3-mercaptopropionic acid

In one aspect, a process for preparing sugammadex is provided:

it includes:

dissolving octa-full-deoxy-octabromo-gamma-cyclodextrin in a solvent;

adding 3-mercaptopropionic acid to form a first solution;

adding a base-water solution to the first solution at a rate sufficient to maintain the temperature of the resulting solution between about 5 ℃ and 40 ℃;

stirring the resulting solution in the presence of heat;

adjusting the pH of the resulting mixture to 7 to 13; and

isolating the sugammadex product.

Conveniently, the base-water solution and the first solution may be prepared in separate reactors (or other suitable containers or vessels) prior to combining them. Suitable reactors, vessels or vessels are well known to those of ordinary skill in the art.

As described above, octa-per-deoxy-octabromo- γ -cyclodextrin is dissolved in a solvent and 3-mercaptopropionic acid is added to form a first solution. Suitable solvents for forming the first solution are commercially available. In one embodiment, the solvent is an organic solvent. In another embodiment, the solvent is 1-methyl-2-pyrrolidone (NMP), N-Dimethylformamide (DMF); n, N-Diethylformamide (DEF); 1, 3-dimethyl-2-imidazolidinone (DMI); 1, 3-dimethyl-, 3,4,5, 6-tetrahydro-2 (1H) -pyrimidinone (DMPU); pyridine (Py); 1, 2-Dimethoxyethane (DME); 1,1,3, 3-Tetramethylurea (TMU); triethylene glycol (TEG); dimethylsulfoxide (DMSO); water; diethyl carbonate; methanol; n, N-dibutylformamide; n, N-Dimethylacetamide (DMA); n, N-diethylacetamide; 1-ethyl-2-pyrrolidone; 1-octyl-2-pyrrolidone; or 1-cyclohexyl-2-pyrrolidone; or mixtures thereof. In a preferred embodiment, the solvent is 1-methyl-2-pyrrolidone (NMP).

In one embodiment, the temperature of the first solution comprising octaper-deoxy-octabromo-gamma-cyclodextrin, solvent, and 3-mercaptopropionic acid is controlled during the addition of the base-water solution. In one embodiment, the temperature of the first solution is maintained (or adjusted) to be within the range of 18 ℃ to 35 ℃. In another such embodiment, the temperature of the first solution is maintained in the range of 25 ℃ to 32 ℃. In another such embodiment, the temperature of the first solution is maintained in the range of 5 ℃ to 40 ℃. In another such embodiment, the temperature of the first solution is maintained in the range of 10 ℃ to 30 ℃. In another such embodiment, the temperature of the first solution is maintained in the range of 15 ℃ to 25 ℃. In another such embodiment, the temperature of the first solution is maintained at 20 ℃.

Base-water solutions suitable for use in the present invention can be purchased or prepared by methods known to those skilled in the art. In one non-limiting embodiment, the base-water solution can be prepared by mixing a suitable base and water. Bases suitable for use in the base-water solution are commercially available. In one embodiment, the base is sodium hydroxide, sodium carbonate, sodium phosphate, sodium bis (trimethylsilyl) amide, sodium tert-butoxide or sodium tert-amylate or a mixture thereof. In a preferred embodiment, the base is sodium hydroxide. In an alternative to each of the foregoing embodiments, the concentration of the base in the water is in the range of 6% to 24%. In another alternative of each of the foregoing embodiments, the concentration of the base in the water is in the range of 10% to 15%. In an alternative to each of the foregoing embodiments, the concentration of the base in the water is in the range of 13% to 14%.

In one embodiment, the base-water solution according to any one of the above embodiments is slowly added to the first solution. In one such embodiment, the base-water solution according to any of the above embodiments is added over a period of at least 1 hour or more.

After the addition of the base-water solution according to any one of the above embodiments to the first solution is complete, the resulting solution is stirred in the presence of heat. In one embodiment, after the addition of the base-water solution to the first solution is complete, the resulting solution is heated to a temperature of at least 20 ℃. In another embodiment, the solution is heated to a temperature between 20 and 100 ℃. In another embodiment, the solution is heated to a temperature between 40 and 70 ℃. In another embodiment, the solution is heated to a temperature between 40 and 60 ℃. In another embodiment, the solution is heated to a temperature between 45 and 65 ℃. In one embodiment, the solution is heated to a temperature of about 50 ℃. In one embodiment, the solution is stirred for at least 1 hour (in another embodiment, at least 2 hours) while maintaining the temperature according to any one of the embodiments described in the preceding paragraph. In another embodiment, the solution is stirred for 1 to 30 hours (in another embodiment, 2 to 30 hours) while maintaining the temperature according to any one of the embodiments described in the preceding paragraph. In another embodiment, the solution is stirred at about 50 ℃ for about 10 hours. In another embodiment, the solution is stirred at about 50 ℃ for about 4 hours.

Then, the pH of the resulting solution is adjusted to 6 to 13 by adding an appropriate amount of acid or base as needed. In one embodiment, the pH of the resulting solution is adjusted to 6.7 to 13. In another embodiment, the pH of the resulting solution is adjusted to 7 to 13. In one embodiment, the pH of the resulting solution is adjusted to 7 to 9.5. In another embodiment, the pH of the resulting solution is adjusted to 7 to 10. In another embodiment, the pH of the resulting solution is adjusted to 7.5 to 8. In another embodiment, the pH of the resulting solution is adjusted to 8.5 to 9.5. Suitable acids and bases are commercially available and known to the skilled person. In one embodiment, the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid (all acids available from Sigma Aldrich), and mixtures thereof; the base (if desired) is sodium hydroxide, sodium carbonate, sodium phosphate, sodium bicarbonate, sodium hydrogen phosphate, sodium ethoxide or sodium methoxide (all bases are available from Sigma Aldrich) and mixtures thereof. In one embodiment, the acid is aqueous hydrochloric acid and the base (if desired) is sodium hydroxide.

Optionally isolating the sugammadex thus produced. In one embodiment, the separation is achieved by adding an anti-solvent to the solution to precipitate sugammadex. Suitable anti-solvents are commercially available. In one embodiment, the anti-solvent is methanol, ethanol, isopropanol, or tetrahydrofuran. In a preferred embodiment, the anti-solvent is methanol.

Preferably, the anti-solvent is added slowly. In one embodiment, the anti-solvent, which may be selected from any of the above embodiments, is added over at least 20 minutes.

After the addition of the antisolvent is complete, the resulting solution is optionally stirred to form a slurry. In one embodiment, the solution is stirred for at least 30 minutes. In another embodiment, the solution is stirred for 30 minutes to 24 hours. In a preferred embodiment, the solution is stirred for 2 hours after the addition of the anti-solvent.

The resulting slurry is filtered and the collected solids are washed with a solvent or a mixture of water and solvent. Suitable solvents are commercially available and include, but are not limited to, methanol, ethanol, isopropanol, NMP, and mixtures thereof, as well as mixtures of such solvents and water. The resulting solid may be dried (e.g., under vacuum) to obtain the desired product.

Example 1: preparation of sugammadex from octa-deoxy-octabromo-gamma-cyclodextrin and 3-mercaptopropionic acid

In a 10L reactor, octa-per-deoxy-octabromo-gamma-cyclodextrin (400.0g, 196.64mmol, 88.5 wt%) was dissolved in NMP (2000ml) and 3-mercaptopropionic acid (273.6ml, 3144mmol) was added. The solution was cooled to 20 ℃. Sodium hydroxide-water solution (1600mL, 6080mmol, 13.4 wt%) was added to the solution in the 10L reactor over 1.5h while maintaining the temperature between 20-23 ℃. After the addition was complete, the reaction was heated to 50 ℃ and stirred for 3 h. The desired product is isolated. Isolation was achieved by adjusting the pH to 7-8 using 6N aqueous HCl (231.2mL, 1141.4 mmol). Then, methanol (2800mL) was added over 2h at 18-20 ℃ and the mixture was stirred at 18-20 ℃ for 2 h. The slurry was filtered and washed with 8:1 methanol: the solid was washed with water (v/v) (2000 mL). The resulting solid was dried under vacuum to obtain 449.2g of the desired sugammadex product (87.74 wt%, 92% isolated yield). Analytical data characterizing the resulting sugammadex are consistent with the characterization of sugammadex provided in the literature (Adam, j.m., et al, j.med.chem.2002,45, 1806-1816).

Example 1A: preparation of sugammadex from octa-deoxy-octabromo-gamma-cyclodextrin and 3-mercaptopropionic acid

In a 30L reactor, octa-per-deoxy-octabromo-gamma-cyclodextrin (1000.0g, 493.8mmol, 88.9 wt%) was dissolved in NMP (5L) and 3-mercaptopropionic acid (721mL, 8292mmol) was added. The solution was cooled to 20 ℃. Sodium hydroxide-water solution (4L, 16.06mol, 13.8 wt%) was added to the solution in a 30L reactor over 4 hours while maintaining the temperature between 18 ℃ and 23 ℃. After the addition was complete, the reaction mixture was heated to 50 ℃ and stirred for 3 h. The desired product is isolated. The separation was achieved by adjusting the pH to 8.5 to 9.5 using 6N aqueous HCl (597mL, 3.581 mol). Methanol (6L) was then added over 4h at 18 ℃ to 20 ℃ and the mixture was stirred at 18 ℃ to 20 ℃ for about 2 h. The slurry was then filtered and washed with 8:1 methanol: the solid was washed with water (v/v) (5L). The resulting solid was dried under vacuum to obtain 1.041kg of the desired sugammadex product (93.76 wt%, 91.4% isolated yield).

Preparation of sugammadex from octa-deoxy-octabromo-gamma-cyclodextrin and disodium 3-mercaptopropionate

In another aspect, a process for preparing sugammadex is provided

It includes:

dissolving a solubility enhancing agent in a solvent mixture to form a first solution;

adding disodium 3-mercaptopropionate to the first solution to form a second solution;

adding octa-per-deoxy-octabromo-gamma-cyclodextrin to the second solution to form a third solution;

stirring the third solution in the presence of heat; and

isolating the sugammadex product.

Solubility enhancers suitable for use in the process are commercially available. In one embodiment, the solubility enhancer is selected from the group consisting of sodium 4-toluenesulfonate, sodium 3-toluenesulfonate, sodium 2, 4-dimethylbenzenesulfonate, sodium 4-isopropylbenzenesulfonate, sodium 4-ethylbenzenesulfonate, sodium 3-ethylbenzenesulfonate, sodium 2-ethylbenzenesulfonate, sodium 4-bromobenzenesulfonate, sodium 3-bromobenzenesulfonate, sodium 2-bromobenzenesulfonate, sodium 4-chlorobenzenesulfonate, sodium 3-chlorobenzenesulfonate, sodium 2-chlorobenzenesulfonate, sodium 4-fluorobenzenesulfonate, sodium 2-fluorobenzenesulfonate, sodium 4-methoxybenzenesulfonate, sodium 3-methoxybenzenesulfonate, sodium 1-hexanesulfonate, sodium 1-heptanesulfonate, N-lauroylsarcosine, N-hydroxysuccinimide, N-hydroxyben-ethyl-zene, Sodium dodecyl sulfate, sodium taurocholate, sodium benzenesulfonate, 3, 5-xylene sulfonate, 4-isopropylbenzene sulfonate and sodium benzoate. In a preferred embodiment, the solubility enhancer is sodium 4-toluenesulfonate.

Suitable solvents for forming the first solution are commercially available. In one embodiment, the solvent is a mixture of water and an organic solvent. In another embodiment, the solvent is an organic solvent. In one embodiment, the organic solvent is selected from Tetrahydrofuran (THF), 2-methyltetrahydrofuran (MeTHF), 1, 2-Dimethoxyethane (DME), Dichloromethane (DCM), diethyl ether (Et)₂O), anisole, cyclopentyl methyl ether (CPME), t-amyl alcohol, ethylene glycol diethyl ether, ethylene glycol dimethyl ether, or a mixture of two or more of any of the foregoing solvents, optionally further mixed with water. In a preferred embodiment, the solvent is a mixture of water and Tetrahydrofuran (THF).

The third solution is stirred in the presence of heat, as described above. In one embodiment, the solution is heated to a temperature between 20 and 100 ℃. In another embodiment, the solution is heated to a temperature between 40 and 60 ℃. In one embodiment, the solution is heated to a temperature of about 50 ℃. In one embodiment, the solution is stirred for at least 2 hours while maintaining the temperature according to any of the above temperatures. In another embodiment, the solution is stirred for 2 to 30 hours while maintaining the temperature according to any of the above temperatures. In another embodiment, the solution is stirred at about 50 ℃ for about 10 hours.

Sugammadex was isolated by precipitation with an anti-solvent. Suitable anti-solvents are commercially available. In one embodiment, the anti-solvent is selected from the group consisting of methanol, ethanol, isopropanol, and tetrahydrofuran. In a preferred embodiment, the anti-solvent is methanol. Preferably, the anti-solvent is added slowly. In one embodiment, the anti-solvent is added over at least 20 minutes. In another embodiment, the anti-solvent is added over a period of 20 minutes to 20 hours. In another embodiment, the anti-solvent is added over about 50 minutes.

After addition of the anti-solvent according to any of the above embodiments, the resulting solution is optionally stirred to form a slurry. In one embodiment, the solution is stirred for at least 30 minutes. In another embodiment, the solution is stirred for 30 minutes to 24 hours. In a preferred embodiment, the solution is stirred for about 16 hours after the addition of the anti-solvent.

The resulting slurry is then filtered and washed with an anti-solvent or a mixture of water and anti-solvent. The solid thus obtained may be dried (optionally under vacuum) to obtain the isolated sugammadex product. In one embodiment, 1 volume of an anti-solvent according to any of the above embodiments is used to wash the solid. In a preferred embodiment, 3 volumes of an anti-solvent/water mixture according to any of the above embodiments is used to wash sugammadex solids.

Example 2: preparation of sugammadex from octa-deoxy-octabromo-gamma-cyclodextrin and disodium 3-mercaptopropionate

Sodium 4-toluenesulfonate (1.53g, 7.50mmol, 95 wt%) was dissolved in a mixture of THF (42.5mL) and water (10mL) to form a first solution. Disodium 3-mercaptopropionate (9.04g, 37.5mmol, 62 wt%) was charged in two portions to the first solution to form a second solution. Octa-per-deoxy-octabromo-gamma-cyclodextrin (5.00g, 2.50mmol, 85 wt%) was charged in five portions to the second solution to form a third solution. The resulting solution was heated to 50 ℃ and maintained with stirring for 10 hours. The desired product is isolated. The separation was achieved by adjusting the pH to 7-14 using 18% aqueous HCl or 19% aqueous NaOH. After pH adjustment, water (5ml) was added and an aqueous layer and an organic layer were formed. And collecting the water layer. Methanol (18mL) was then added to the collected layer at 23 ℃ to form a precipitate. The slurry was stirred at 23 ℃ for 1h, then methanol (11mL) was added slowly to the slurry over 45 minutes. The slurry was filtered and the solid was washed with a mixture of methanol and water (15mL, 8: 1). The resulting solid was dried under vacuum to obtain the desired sugammadex product. Analytical data characterizing the resulting sugammadex are consistent with the characterization of sugammadex provided in the literature (Adam, j.m., et al, j.med.chem.2002,45, 1806-1816).

Preparation of octa-fully deoxy-octabromo-gamma-cyclodextrins from gamma-cyclodextrin

In another aspect, a process is provided for preparing octaper-deoxy-octabromo-gamma-cyclodextrin of the formula:

it includes:

forming a gamma-cyclodextrin comprising the formula:

an organic solvent; and

a solution of a brominating agent;

heating the resulting solution; and

separating the octa-deoxy-octabromo-gamma-cyclodextrin. In a preferred embodiment, an amount of water sufficient to quench the reaction is added to the resulting solution prior to separation.

Suitable gamma-cyclodextrins are commercially available. A typical commercially available gamma-cyclodextrin contains about 10% by weight of water. Preferably, the gamma-cyclodextrin is anhydrous, containing less than 10,000ppm by weight of water. More preferably, the gamma-cyclodextrin comprises less than 1000ppm by weight of water. Suitably, the gamma-cyclodextrin may be obtained commerciallyAre commercially available and dried to the desired extent by methods known to those of ordinary skill in the art. Such methods include, but are not limited to, azeotropic distillation with a suitable organic solvent, such as DMF, or by passage of P under vacuum at elevated temperature (e.g., 100 ℃ C.)₂O₅And (5) drying. In one embodiment, the gamma-cyclodextrin is dried by azeotropic distillation with DMF until KF (karl fischer titration) value is less than 0.1%.

Suitable organic solvents are commercially available. In one embodiment, the organic solvent is N, N-Dimethylformamide (DMF), N-Diethylformamide (DEF), N-dibutylformamide, N-Dimethylacetamide (DMA), 1-methyl-2-pyrrolidone (NMP), 1-ethyl-2-pyrrolidone, 1-octyl-2-pyrrolidone, or 1-cyclohexyl-2-pyrrolidone, or a mixture thereof. In a preferred embodiment, the organic solvent is N, N-Dimethylformamide (DMF). In another preferred embodiment, the gamma-cyclodextrin is anhydrous and the organic solvent is N, N-Dimethylformamide (DMF). As will be appreciated by those skilled in the art, the volume of the gamma-cyclodextrin and solvent solution can vary widely based on the desired amount. Typically and in one embodiment, the volume will be in the range between 5 and 20V. In another embodiment, the volume is 12V.

Suitable brominating agents include, but are not limited to, N- (bromomethylene) -N-alkylammonium bromide (N- (bromomethylene) -N-alkylmethanaminium bromide), which is commercially available or can be prepared by methods well known to those of ordinary skill in the art. See, for example, Giles, p.r. and Marson, C.M. (2001). dimethyl aminomethylene nitrile bromine.10.1002/047084289X.rd317m. Exemplary N- (bromomethylene) -N-alkylammonium bromides include those represented by the following structural formula:

wherein each R¹Independently is (C)₁-C₆) An alkyl group. In one embodiment, each R is¹Independently methyl (commercial), ethyl, n-propyl or n-butyl. In one embodiment, each R is¹Independently methyl, ethyl or n-butyl. Suitable brominating agents also include, but are not limited to, bromomethylene morpholinium bromide (or referred to as N- (bromomethylene) -N-morpholinium bromide) having the structure:

see, e.g., Chmurski, k.; defaye, j.; tetrahedron Letters 1997,38, 7365-.

Thus, in one embodiment, the brominating agent is selected from the group consisting of N- (bromomethylene) -N-alkylammonium bromides of the formula:

wherein each R¹Independently methyl, ethyl or N-butyl, and bromomethylene morpholinium bromide (or referred to as N- (bromomethylene) -N-morpholinium bromide) of the formula:

in a preferred embodiment, the brominating agent is N- (bromomethylene) -N-alkylammonium bromide of the formula:

wherein each R¹Is methyl. In such embodiments, N- (bromomethylene) -N-alkylammonium bromide refers herein to N- (bromomethylene) -N-methylammonium bromide.

As will be appreciated by those skilled in the art, the amount of brominating agent used will vary in proportion to the amount of gamma-cyclodextrin to be brominated. For example, the amount of N- (bromomethylene) -N-alkylammonium bromide will generally range from 12 to 24 equivalents relative to the amount of γ -cyclodextrin. In a preferred embodiment, the amount of N- (bromomethylene) -N-alkylammonium bromide is 20 equivalents relative to the amount of γ -cyclodextrin.

The solution comprising the gamma-cyclodextrin, the organic solvent, and the N- (bromomethylene) -N-alkylammonium bromide can be formed by any order of addition. Thus, in one embodiment, the gamma-cyclodextrin is added to the organic solvent prior to the addition of the N- (bromomethylene) -N-alkylammonium bromide. In another embodiment, the N- (bromomethylene) -N-alkylammonium bromide is added to the organic solvent prior to the addition of the gamma-cyclodextrin. In a preferred embodiment, anhydrous gamma-cyclodextrin is added to the organic solvent and solid N- (bromomethylene) -N-alkylammonium bromide is added to the solution in portions.

The resulting mixture is then heated at a temperature and for a time sufficient to replace each primary hydroxyl group of the gamma-cyclodextrin with bromine. The minimum and optimum time and temperature for bromination can be evaluated by methods known to those skilled in the art, such as by measuring (e.g., by HPLC) the amount of octa-per-deoxy-octabromo-gamma-cyclodextrin produced by the method at a selected time point at each temperature within a temperature range, and then selecting the combination of time and reaction temperature that results in an acceptable (or desired) amount and conversion. The amount of time required is generally inversely proportional to the temperature. In one embodiment, the mixture is heated to a temperature between 40 ℃ and 80 ℃. In another embodiment, the mixture is heated to a temperature of 70 ℃. In one embodiment, the reaction time is 4 to 48 hours, and the reaction temperature is maintained at 40 to 80 ℃. In another embodiment, the reaction time is 6 hours and the temperature is 70 ℃.

After reacting the heated mixture at a suitable temperature and time according to any of the above embodiments, the reaction is quenched by mixing the resulting mixture with water prior to isolating the octa-per-deoxy-octabromo-gamma-cyclodextrin. The amount of water is typically in the range of 10 to 500 equivalents (in some embodiments, in the range of 10 to 300 equivalents) relative to the amount of γ -cyclodextrin. In one embodiment, water is added while maintaining the temperature between 25 ℃ and 70 ℃. In another embodiment, water is added while maintaining the temperature at 50 ℃. Upon addition of the aqueous solution, the mixture is then stirred at the selected temperature for 1 to 24 hours (in another embodiment, 2 to 24 hours). In one non-limiting embodiment, the mixture is stirred at about 50 ℃ for about 2 hours. The mixture is then optionally allowed to cool to room temperature before separation.

The octa-fully deoxy-octabromo-gamma-cyclodextrin thus produced is then isolated. Isolation is achieved by precipitation of octa-per-deoxy-octabromo-gamma-cyclodextrin from the solution by addition of an anti-solvent, optionally followed by filtration and drying.

Suitable anti-solvents include water, water and methanol, water and ethanol, and mixtures of water and ethers. Non-limiting examples of ethers include dialkyl ethers such as diethyl ether, 2-methoxy-2-methylpropan-1-ol, cyclic ethers such as tetrahydrofuran, 2-methyltetrahydrofuran and 1, 4-dioxane, ethylene glycol derived ethers such as dimethoxyethane, diethylene glycol methyl ether, diethylene glycol diethyl ether and dipropylene glycol dimethyl ether (Proglyme). Water: methanol and water: ethanol and water: the ether ratios may each independently range from 1:99 to 99: 1. Suitably, the non-limiting amount of anti-solvent may be in the range of 3 volumes to 20 volumes based on the amount of octaper-deoxy-octabromo-gamma-cyclodextrin. In one embodiment, the solution is stirred with the addition of the anti-solvent. In a preferred embodiment, the anti-solvent is water.

In one embodiment, the temperature of the solution comprising octa-per-deoxy-octabromo- γ -cyclodextrin is maintained at (or cooled to) a first temperature range, optionally an anti-solvent is added to achieve some amount of precipitation, then optionally further cooled to a second temperature range, optionally with the addition of additional anti-solvent to achieve further precipitation of octa-per-deoxy-octabromo- γ -cyclodextrin. In another embodiment, the anti-solvent is added over a period of at least 30 minutes before cooling to the second temperature range. In one embodiment, the first temperature range is 20 ℃ to 70 ℃. In another embodiment, the first temperature is 30 ℃ to 70 ℃. In another embodiment, the first temperature is 40 ℃. In one embodiment, the second temperature range is 0 ℃ to 40 ℃. In another embodiment, the second temperature is room temperature. In another embodiment, additional anti-solvent according to any other of the above embodiments is added as the temperature cools to the second temperature range. In one embodiment, the solution is aged (age) prior to filtration and drying. If further cooling to the second temperature is used, the solution is optionally aged prior to further cooling. In each case including other embodiments, the solution is aged for at least one hour. In another embodiment, the solution is previously aged for 1 hour to 24 hours. In a preferred embodiment, water is added at 40 ℃, then cooled to room temperature and aged for at least 1 hour.

Optionally filtering and washing (optionally 1,2 or more times) the precipitated octaper-deoxy-octabromo-gamma-cyclodextrin with an anti-solvent. As above, suitable anti-solvents include water, water and methanol, water and ethanol, and mixtures of water and ethers. Non-limiting examples of ethers include dialkyl ethers such as diethyl ether, 2-methoxy-2-methylpropan-1-ol, cyclic ethers such as tetrahydrofuran, 2-methyltetrahydrofuran and 1, 4-dioxane, ethylene glycol derived ethers such as dimethoxyethane, diethylene glycol methyl ether, diethylene glycol diethyl ether and dipropylene glycol dimethyl ether. Water: methanol and water: ethanol and water: the ether ratios may each independently range from 1:99 to 99: 1. In a preferred embodiment, the precipitate is washed with water. The filtered precipitate is then optionally dried under vacuum before further use. As will be appreciated by those skilled in the art, the length of time required for drying will be inversely proportional to the temperature. Non-limiting examples of drying temperatures are in the range of 20 ℃ to 60 ℃ (or in the range of 25 ℃ to 50 ℃), and non-limiting examples of drying times can be in the range of about 1 hour up to 5 days or more. The product octaper-deoxy-octabromo-gamma-cyclodextrin from gamma-cyclodextrin may be used in any of the above aspects of the invention as starting material for the production of sugammadex.

Example 3: preparation of octa-fully deoxy-octabromo-gamma-cyclodextrins from gamma-cyclodextrin

Solid N- (bromomethylene) -N-methylammonium bromide (35.2g, 154mmol) was added portionwise to a solution of anhydrous gamma-cyclodextrin (10g, 7.71mmol) and DMF (120mL) at 10 ℃. After the addition was complete, the solution was heated at 70 ℃ for 6 h. The solution was then cooled to 50 ℃ and water (12.5mL, 694mmol) was added and the solution was stirred at 50 ℃ for 2 h. The solution was cooled to 40 ℃ and the product was precipitated by slowly adding water (80 mL). The resulting slurry was then cooled to room temperature and aged for at least one hour to precipitate octa-per-deoxy-octabromo-gamma-cyclodextrin. The precipitate was filtered and washed twice with water (60 mL). The solid octa-per-deoxy-octabromo-gamma-cyclodextrin thus obtained from gamma-cyclodextrin was dried under vacuum at 50 ℃ to obtain the desired product (13.85 g). The analytical data characterizing the obtained octa-deoxy-octabromo-gamma-cyclodextrin product are consistent with the characterization of octa-deoxy-octabromo-gamma-cyclodextrin as provided in the literature (Gorin, B.I.; Riopelle, R.J.; Thatcher, G.R.J. tetrahedron Lett.1996,37, 4647-one 4650).

Example 3A: preparation of octa-fully deoxy-octabromo-gamma-cyclodextrins from gamma-cyclodextrin

Solid N- (bromomethylene) -N-methylammonium bromide (3.18kg, 14.65mol) was added portionwise to a solution of anhydrous gamma-cyclodextrin (1kg, 0.77mol) and DMF (16L) at 0 ℃. After the addition was complete, the solution was heated at 70 ℃ for 6 hours. The solution was then cooled to 40 ℃ and water (1.4L, 77mmol) was added and the solution was stirred at 40 ℃ for 4 h. The product was precipitated by slowly adding water (12L). The resulting slurry was then cooled to room temperature and aged for at least one hour to precipitate octa-per-deoxy-octabromo-gamma-cyclodextrin. The precipitate was filtered and washed three times with water (4L). The solid octa-per-deoxy-octabromo-gamma-cyclodextrin thus obtained from gamma-cyclodextrin was dried under vacuum at room temperature to obtain the desired product (1.44 kg). The analytical data characterizing the obtained octa-deoxy-octabromo-gamma-cyclodextrin product are in accordance with the characterization of octa-deoxy-octabromo-gamma-cyclodextrin as provided in the literature (Gorin, B.L; Riopelle, R.J.; Thatcher, G.R.J. tetrahedron Lett.1996,37, 4647-one 4650).

Preparation of octa-fully deoxy-octabromo-gamma-cyclodextrins from gamma-cyclodextrin

In another aspect, an alternative process for preparing octaper-deoxy-octabromo-gamma-cyclodextrin of the formula:

it includes:

reacting in the presence of an organic solvent a gamma-cyclodextrin of the formula:

reacting with electrophilic brominating agent, deoxidant and acid;

heating the resulting mixture;

adding a solution comprising water and an acid to the mixture and mixing the resulting solution; and

separating the octa-deoxy-octabromo-gamma-cyclodextrin.

In a preferred embodiment, the electrophilic brominating agent is combined with an organic solvent and the resulting solution is slowly added to a solution comprising gamma-cyclodextrin, a deoxygenating agent, an acid, and an organic solvent. The resulting solution is then heated at a temperature of at least 30 ℃ for a time sufficient to fully brominate the primary hydroxyl groups of the gamma-cyclodextrin with bromine.

Suitable gamma-cyclodextrins are commercially available. A typical commercially available gamma-cyclodextrin contains about 10% by weight of water. Preferably, the gamma-cyclodextrin used in the process is anhydrous, comprising less than 10,000ppm by weight of water. More preferably, the gamma-cyclodextrin comprises less than 1000ppm by weight of water.

Suitable electrophilic brominating agents are commercially available. In one embodiment, 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-dibromomeldrum's acid, 2,4,4, 6-tetrabromo-2, 5-cyclohexadieneone, or bis (2,4, 6-trimethylpyridine) -bromonium hexafluorophosphate. In a preferred embodiment, the electrophilic brominating agent is 1, 3-dibromo-5, 5-dimethylhydantoin.

The amount of electrophilic brominating agent, deoxidizer, acid and solvent used will vary in proportion to the amount of gamma-cyclodextrin to be brominated. The amount of electrophilic brominating agent, which may be selected from any of those listed above, will generally range from 6 to 16 equivalents of γ -cyclodextrin. In one embodiment, the amount of electrophilic brominating agent is 10 equivalents. In another embodiment, the electrophilic brominating agent is 1, 3-dibromo-5, 5-dimethylhydantoin, and the amount ranges from 6 to 16 equivalents. In another embodiment, the electrophilic brominating agent is 10.5 equivalents of 1, 3-dibromo-5, 5-dimethylhydantoin.

Suitable deoxidizers are commercially available. In one embodiment, the oxygen scavenger is an optionally substituted mono-, di-, and tri-phenyl compound selected from the group consisting of: wherein R is¹、R²And R³Each independently selected from H, F, Cl, CH₃、OCH₃And CF₃；

R⁴Selected from methyl, ethyl and benzyl;

each R⁵Independently selected from methyl and ethyl; and

each R⁶Independently selected from methyl, ethyl, n-butyl and O-phenyl. In one embodiment, the oxygen scavenger is methyl diphenylphosphine.

The amount of oxygen scavenger used, which may be selected from any of those listed above, is generally in the range of 12 to 32 equivalents (of gamma-cyclodextrin). In one embodiment, the amount of deoxidizer is 20 equivalents. In another embodiment, the oxygen scavenger is methyldiphenylphosphine in an amount in the range of 12 to 32 equivalents. In another embodiment, the oxygen scavenger is 20 equivalents of methyldiphenylphosphine.

Suitable organic solvents are commercially available. In one embodiment, the organic solvent is N, N-Dimethylformamide (DMF), N-Diethylformamide (DEF), N-dibutylformamide, N-Dimethylacetamide (DMA), N-diethylacetamide, 1-methyl-2-pyrrolidone (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 of any of the foregoing organic solvents. In a preferred embodiment, the organic solvent is N, N-Dimethylformamide (DMF).

After combining the electrophilic brominating agent, the deoxygenator, the acid, and the organic solvent as described above, the mixture is allowed to react for a sufficient time to brominate each primary OH group of the γ -cyclodextrin. The minimum and optimum time and temperature for bromination can be evaluated by methods known to those skilled in the art, such as by measuring (e.g., by HPLC) the amount of octa-per-deoxy-octabromo-gamma-cyclodextrin produced by the method at a selected time point at each temperature within a temperature range, and then selecting the combination of time and reaction temperature that results in an acceptable (or desired) amount and conversion. The amount of time required is generally inversely proportional to the temperature. Minimally, the mixture is heated to at least about 30 ℃. In one embodiment, the mixture is heated to a temperature between 30 and 80 ℃. In another embodiment, the mixture is heated to a temperature between 50 and 70 ℃. In one embodiment, the reaction time is 4 to 48 hours, and the reaction temperature is maintained at 30 ℃ to 80 ℃. In another embodiment, the reaction time is 4 to 12 hours and the temperature is 50 to 70 ℃.

In some embodiments, it may be advantageous to use an acid when certain combinations of electrophilic brominating agents, deoxidizers, and solvents are used. In such embodiments, suitable acids include organic and inorganic acids. Non-limiting examples of these acids are commercially available and include, for example: methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, acetic acid, sulfuric acid, phosphoric acid and hydrobromic acid. In a preferred embodiment, the acid is methanesulfonic acid. The amount of such acid used, which may be selected from any of those listed above, is typically in the range of 0.1 mol% (0.001 equivalent) to 10 equivalents of γ -cyclodextrin. In one embodiment, the acid is selected from any of those listed above, and the amount of acid used is 2 mol% (0.02 equivalents). In one embodiment, the acid is methanesulfonic acid and is used in an amount of 2 mol%.

After reacting the heated mixture at a suitable temperature and time according to any of the above embodiments, the reaction is quenched by mixing the resulting mixture with a solution comprising water and an acid. Optionally, after adding the solution comprising water and acid, additional water is added. Suitable acids are commercially available. Non-limiting examples of such acids include hydrobromic acid, trifluoroacetic acid and trifluoromethanesulfonic acid. In one embodiment, the acid is an aqueous hydrobromic acid solution (e.g., a 48% aqueous hydrobromic acid solution). The amount of the aqueous solution of these acids is generally in the range of 6 to 20 equivalents, preferably 10 equivalents, relative to the amount of γ -cyclodextrin. In one embodiment, the water-acid solution is added while maintaining the temperature at 25 ℃ to 70 ℃. In another embodiment, the temperature is increased to 60 ℃. Once the water-acid solution is added, the mixture is then stirred at the selected temperature for 2 to 24 hours. In one non-limiting embodiment, the mixture is stirred at about 60 ℃ for about 6 hours. The mixture is then optionally allowed to cool to room temperature before separation.

The separation of octa-per-deoxy-octabromo-gamma-cyclodextrin can be achieved by precipitation. Precipitation may be achieved by slow addition of an anti-solvent. As above, suitable anti-solvents include water, water and methanol, water and ethanol, and mixtures of water and ethers. Non-limiting examples of ethers include dialkyl ethers such as diethyl ether, 2-methoxy-2-methylpropan-1-ol, cyclic ethers such as tetrahydrofuran, 2-methyltetrahydrofuran and 1, 4-dioxane, ethylene glycol derived ethers such as dimethoxyethane, diethylene glycol methyl ether, diethylene glycol diethyl ether and dipropylene glycol dimethyl ether. Water: methanol and water: ethanol and water: the ether ratios may each independently range from 1:99 to 99: 1. In one embodiment, the anti-solvent is 1:9(v: v) methanol: a water mixture. Optionally aging the resulting slurry for at least 1 hour and up to 24 hours. Optionally washing the octa-per-deoxy-octabromo-gamma-cyclodextrin thus precipitated with an anti-solvent 1 or two times. In one embodiment, the anti-solvent comprises a solution of water and methanol.

Optionally filtering the precipitated octa-per-deoxy-octabromo-gamma-cyclodextrin and optionally washing 1,2 or more times with an anti-solvent. As above, suitable anti-solvents include water, water and methanol, water and ethanol, and mixtures of water and ethers. Non-limiting examples of ethers include dialkyl ethers such as diethyl ether, 2-methoxy-2-methylpropan-1-ol, cyclic ethers such as tetrahydrofuran, 2-methyltetrahydrofuran and 1, 4-dioxane, ethylene glycol derived ethers such as dimethoxyethane, diethylene glycol methyl ether, diethylene glycol diethyl ether and dipropylene glycol dimethyl ether. Water: methanol and water: ethanol and water: the ether ratios may each independently range from 1:99 to 99: 1. In a preferred embodiment, the precipitate is washed with methanol, water, and then methanol. The filtered precipitate is then optionally dried under vacuum before further use. As will be appreciated by those skilled in the art, the length of time required for drying will be inversely proportional to the temperature. Non-limiting examples of drying temperatures are in the range of 20 ℃ to 60 ℃ (or in the range of 25 ℃ to 50 ℃), and non-limiting examples of drying times can be in the range of about 1 hour up to 5 days or more. The product octaper-deoxy-octabromo-gamma-cyclodextrin from gamma-cyclodextrin may be used in any of the above aspects of the invention as starting material for the production of sugammadex.

Example 4: preparation of octa-fully deoxy-octabromo-gamma-cyclodextrins from gamma-cyclodextrin

A solution of 1, 3-dibromo-5, 5-dimethylimidazolidine-2, 4-dione (23.0g, 81.0mmol) in DMF (24.0ml) was slowly added to a solution of anhydrous gamma-cyclodextrin (10g, 7.71mmol), methyl diphenylphosphine (28.7ml, 154.2mmol) in DMF (120ml) at 0 ℃. After the addition was complete, the mixture was heated at 55 ℃ for 9 h.

The mixture was then heated to 60 ℃. 48% hydrobromic acid/water (8.9mL, 77.1mmol) and water (15mL, 1.5 vol) were added sequentially. The resulting mixture was then stirred at 60 ℃ for 6h, then cooled to room temperature. The product was precipitated by slow addition of 1/9(v/v) methanol/water mixture (210 mL). Aging the slurry for at least 1 h; the precipitate was filtered and then washed twice with water, methanol 1/1(v/v) (40mL), and twice with methanol (30 mL). The solid was then dried at 50 ℃ under vacuum to give the desired product (14.8 g). The analytical data characterizing the obtained octa-deoxy-octabromo-gamma-cyclodextrin product are consistent with the characterization of octa-deoxy-octabromo-gamma-cyclodextrin as provided in the literature (Gorin, B.I.; Riopelle, R.J.; Thatcher, G.R.J. tetrahedron Lett.1996,37, 4647-one 4650).