WO2020013759A1 - Method for preparing sugammadex sodium - Google Patents

Method for preparing sugammadex sodium Download PDF

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WO2020013759A1
WO2020013759A1 PCT/SG2018/050346 SG2018050346W WO2020013759A1 WO 2020013759 A1 WO2020013759 A1 WO 2020013759A1 SG 2018050346 W SG2018050346 W SG 2018050346W WO 2020013759 A1 WO2020013759 A1 WO 2020013759A1
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formula
sugammadex
process according
sodium
reacting
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PCT/SG2018/050346
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French (fr)
Inventor
Chiaying Lee
Shanghong Chen
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Scinopharm Taiwan Ltd.
Scinopharm Singapore Pte Ltd
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Priority to PCT/SG2018/050346 priority Critical patent/WO2020013759A1/en
Publication of WO2020013759A1 publication Critical patent/WO2020013759A1/en

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/16—Cyclodextrin; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof

Definitions

  • the present invention relates to a process for preparing sugammadex sodium, a modified gamma cyclodextrin chemically designated as 6A,6B,6C,6D,6E,6F,6G,6FI- Octakis-S-(2-carboxyethyl)-6A,6B,6C,6D,6E,6F,6G,6H-octathio-Y-cyclodextrin sodium salt (1 :8) with a molecular weight of 2178.01 and a formula as shown below:
  • Sugammadex sodium (marked as BRIDION®) is a modified gamma
  • cyclodextrin forms a complex with neuromuscular blocking agents rocuronium and vecuronium, and it reduces the amount of neuromuscular blocking agent available to bind to nicotinic cholinergic receptors in the neuromuscular junction. This results in reversal of neuromuscular blockade induced by rocuronium and vecuronium.
  • BRIDION® was approved by the U.S. Food and Drug Administration (FDA) on
  • Sugammadex is prepared by dissolving g-cyclodextrin in X2 (CI2 or
  • Sugammadex is prepared by dissolving g-cyclodextrin in PX3 or PX5 in DMF followed by adding NaH and 3-mercapto propionic acid.
  • PPfi3 is used to produce the intermediate, and a significant amount of side product PPfi302 is produced.
  • PPfi302 is hard to remove, and the intermediate is hard to isolate.
  • Sugammadex is prepared by dissolving g- cyclodextrin in oxalyl chloride or SOCI2 in DMF followed by adding NaH and 3-mercapto propionic acid. When oxalyl chloride or SOCI2 is added into the mixture, exothermic heat and HCI are produced.
  • halide-Y-cyclodextrin can be prepared by reacting g-cyclodextrin with MsCI in DMF.
  • the present application provides a process for preparing a compound of formula II:
  • X represents a halogen group preferably chloro.
  • the process comprises reacting a g-cyclodextrin of formula I with a halogenating agent in the presence of N-methyl-2-pyrrolidone:
  • the present application provides a process for preparing a sugammadex salt of formula Ilia
  • M represents Na or K
  • the process comprises: a) reacting a g-cyclodextrin of formula I with a halogenating agent in the presence of N- methyl-2-pyrrolidone to provide a compound of formula II :
  • X is a halogen group, preferably chloro; b) reacting the compound of formula II with 3-mercapto propionic acid in the presence of a base and an organic solvent to provide a sugammadex salt of formula Ilia. c) optionally purifying the sugammadex salt of formula Ilia.
  • the present application provides a one-pot process for preparing sugammadex sodium salt of formula III comprising:
  • X is a halogen group, preferalby chloro; and b) reacting the compound of formula II with 3-mercapto propionic acid in the presence of an sodium base and an organic solvent to a provide sugammadex sodium of formula III.
  • DMSO dimethyl sulfoxide
  • DMAc dimethylacetamide
  • NMP N-methyl-2-pyrrolidone
  • the present application provides a process for preparing a compound of formula II:
  • X is a halogen group, preferably chloro.
  • the process comprises reacting a g-cyclodextrin of formula I with a halogenating agent in presence of N-methyl-2-pyrrolidone:
  • the temperature of this reaction is maintained from 50- 80°C. In some embodiments, the temperature is about QO-TO ⁇ .
  • the halogenating agent is selected from the group consisting of methanesulfonyl chloride, bromine, iodine, N-iodosuccinimide, oxalyl chloride, oxalyl bromide, thionyl chorlide, thionyl bromide, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphoruspentabromide, phosphoryl chloride, phosphoryl bromide, and triphosgene.
  • the halogenating agent is preferably
  • the present application provides a process for preparing sugammadex salt of formula Il ia
  • the halogenating agent is selected from the group consisting of methanesulfonyl chloride, bromine, iodine, N-iodosuccinimide, oxalyl chloride, oxalyl bromide, thionyl chorlide, thionyl bromide, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus pentabromide, phosphoryl chloride, phosphoryl bromide and triphosgene.
  • the halogenating agent is preferably methanesulfonyl chloride or triphosgene.
  • the base of step (b) is selected from alkali metal hydroxide and metal alkoxy.
  • alkali metal hydroxide is selected from the group consisting of sodium hydroxide, lithium hydroxide, and potassium hydroxide.
  • the alkali metal hydroxide of step (b) is sodium hydroxide.
  • the metal alkoxy of step (b) is selected from the group consisting of sodium tert-butoxide (NaOtBu) and sodium methoxide (NaOMe).
  • the metal alkoxy of step (b) is sodium tert-butoxide (NaOtBu).
  • the solvent of step (b) is selected from the group consisting of polar aprotic solvents, C1 -5 esters, acetonitrile, dimethylformamide, and dimethylsulfoxide. In some embodiments, the solvent of step (b) is preferably dimethylformamide.
  • the purification process of sugammadex salt of formula Ilia comprises: c-1 ) reacting sugammadex salt of formula Ilia with an acid in the presence of a first solvent to provide sugammadex free acid of formula IV: c-2) optionally, purifying the sugammadex free acid of formula IV with chromatograph column or active carbon: and c-3) treating the sugammadex free acid of formula IV with alkali metal hydroxide in the presence of a second solvent.
  • the first solvent and/or the second solvent is selected from C1 -4 alkyl-alcohols, for example EtOH, MeOH, and IPA.
  • the first solvent is IPA
  • the second solvent is EtOH or MeOH.
  • the alkali metal hydroxide is sodium hydroxide.
  • the present application provides a one-pot process for preparing sugammadex sodium salt of formula III:
  • the process comprises: a) reacting a g-cyclodextrin of formula I with a halogenating agent in the presene of N-methyl-2-pyrrolidone to provide the compound of formula II :
  • the halogenating agent is selected from the group consisting of methanesulfonyl chloride, bromine, iodine, N-iodosuccinimide, oxalyl chloride, oxalyl bromide, thionyl chorlide, thionyl bromide, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus pentabromide, phosphoryl chloride, phosphoryl bromide, and triphosgene.
  • the halogenating agent is preferably methanesulfonyl chloride or triphosgene.
  • the sodim base is selected from sodium hydroxide, sodium tert-butoxide (NaOtBu) or sodium methoxide (NaOMe).
  • the solvent of step (b) is selected from the group consisting of polar aprotic solvents, C1 -5 esters, acetonitrile, dimethylformamide, and dimethylsulfoxide. In some embodiments, the solvent of step (b) is preferably dimethylformamide.
  • the purification process of sugammadex sodium of formula III comprises: c-1 ) reacting sugammadex sodium of formula III with an acid in the presence of a first solvent to provide sugammadex free acid of formula IV: c-2) optionally, purifying the sugammadex free acid of formula IV with chromatograph column or active carbon: and c-3) treating the sugammadex free acid of formula IV with sodium hydroxide in the presence of a second solvent.
  • the acid may be HCI, TFA, Fi 3 P0 4 , or HOAc.
  • sugammadex sodium was isolated and purified as a white solid.
  • g-Cyclodextrin of formula I, methanesulfonyl chloride and N-Methyl-2- pyrrolidone were added into a 500 mL 3-neecked-R-flask at 20-30°C. The mixture was heat to 60-70°C and stirred for NLT 20 hr. After the reaction was completed, 3-mercapto propionic acid and NaOH were added into the mixture. The mixture was heated to 70- 80°C and stirred for NLT 12 hr. After the reaction was completed, MeOH was added at 60-80 °C. Then the mixture was cooled to 20-30 °C and stirred for 1 hr. The crude sugammadex sodium was isolated and purified as a white solid.
  • sugammadex sodium was isolated and purified as a white solid.
  • N-Methyl-2-pyrrolidone (220 ml_) was added into a 500 ml_ 3-neecked-R-flask. After triphosgene (22.9 g, 10 equiv) was added at -10 to 0°C, the mixture was heated to 20-30°C and stirred for NLT 2 hr before g-Cyclodextrin (10 g, 1.0 equiv) of formula I was added. The mixture was heated to 60-70°C and stirred for NLT 3 hr. After the reaction was completed, MeOH (20 mL, 2 vol) and NaOH (237 mL) were added into the mixture. The compound of formula II was isolated in about 90% yield.

Abstract

A process for preparing sugammadex sodium comprising: reacting a γ-cyclodextrin of formula (I) with triphosgene in the presence of N-methyl-2-pyrrolidone to provide a compound of formula (II); and reacting the compound of formula (II) with 3-mercapto propionic acid in the presence of a sodium base and an organic solvent to provide sugammadex sodium formula (III): wherein X in formula (II) is chloro.

Description

METHOD FOR PREPARING SUGAMMADEX SODIUM
BACKGROUND OF THE INVENTION
[0001 ] The present invention relates to a process for preparing sugammadex sodium, a modified gamma cyclodextrin chemically designated as 6A,6B,6C,6D,6E,6F,6G,6FI- Octakis-S-(2-carboxyethyl)-6A,6B,6C,6D,6E,6F,6G,6H-octathio-Y-cyclodextrin sodium salt (1 :8) with a molecular weight of 2178.01 and a formula as shown below:
Figure imgf000003_0001
[0002] Sugammadex sodium (marked as BRIDION®) is a modified gamma
cyclodextrin. It forms a complex with neuromuscular blocking agents rocuronium and vecuronium, and it reduces the amount of neuromuscular blocking agent available to bind to nicotinic cholinergic receptors in the neuromuscular junction. This results in reversal of neuromuscular blockade induced by rocuronium and vecuronium.
BRIDION® was approved by the U.S. Food and Drug Administration (FDA) on
December 15, 2015. [0003] U.S. Patent No. RE 44,733 (the‘733 patent) describes a preparation method of sugammadax as shown in Scheme 1 below:
Figure imgf000004_0001
Scheme 1 : Preparation of Sugammadax Disclosed in USRE44733E
[0004] Sugammadex is prepared by dissolving g-cyclodextrin in X2 (CI2 or
Br2)/PPh3/NaOMe in DMF followed by adding NaH and 3-mercapto propionic acid or NaOH/Cs2C03/3-mercapto propionic acid.
[0005] A similar approach for sugammadax preparation is reported in U.S. Patent No. 9,120,876B2 (the‘876 patent, Scheme 2 below). Sugammadex is prepared by dissolving g-cyclodextrin in PX3 or PX5 in DMF followed by adding NaH and 3-mercapto propionic acid. Based on the‘733 patent and the‘876 patent, PPfi3 is used to produce the intermediate, and a significant amount of side product PPfi302 is produced. PPfi302 is hard to remove, and the intermediate is hard to isolate.
Figure imgf000005_0001
Scheme 2: Preparation of Sugammadax Disclosed in US9120876B2
[0006] Another synthetic route is reported in Chinese Patent Application
CN105273095A (Scheme 3 below). Sugammadex is prepared by dissolving g- cyclodextrin in oxalyl chloride or SOCI2 in DMF followed by adding NaH and 3-mercapto propionic acid. When oxalyl chloride or SOCI2 is added into the mixture, exothermic heat and HCI are produced.
Figure imgf000006_0001
Scheme 3: Preparation of Sugammadax Disclosed in CN105273059A
[0001] Bull Soc Chim Fr 1995 132 857-866 discloses that halide-Y-cyclodextrin can be prepared by reacting g-cyclodextrin with MsCI in DMF.
Figure imgf000006_0002
Scheme 4: Preparation of halide-y-cyclodextrin Disclosed in Bull Soc Chim Fr 1995 132
857-866
[0007] In view of the above, there remains a need for the development of improved processes for the preparation of sugammadax sodium. SUMMARY OF THE INVENTION
[0008] In one aspect, the present application provides a process for preparing a compound of formula II:
Figure imgf000007_0001
wherein X represents a halogen group preferably chloro.
II
[0009] The process comprises reacting a g-cyclodextrin of formula I with a halogenating agent in the presence of N-methyl-2-pyrrolidone:
Figure imgf000008_0001
I
[0010] In a second aspect, the present application provides a process for preparing a sugammadex salt of formula Ilia
Figure imgf000008_0002
wherein M represents Na or K, and the process comprises: a) reacting a g-cyclodextrin of formula I with a halogenating agent in the presence of N- methyl-2-pyrrolidone to provide a compound of formula II :
Figure imgf000009_0001
II
wherein X is a halogen group, preferably chloro; b) reacting the compound of formula II with 3-mercapto propionic acid in the presence of a base and an organic solvent to provide a sugammadex salt of formula Ilia.
Figure imgf000010_0001
c) optionally purifying the sugammadex salt of formula Ilia.
[001 1 ] In a third aspect, the present application provides a one-pot process for preparing sugammadex sodium salt of formula III comprising:
Figure imgf000011_0001
III a) reacting a g-cyclodextrin of formula I with a halogenating agent in the presence of N- methyl-2-pyrrolidone to provide a compound of formula II :
Figure imgf000012_0001
II
wherein X is a halogen group, preferalby chloro; and b) reacting the compound of formula II with 3-mercapto propionic acid in the presence of an sodium base and an organic solvent to a provide sugammadex sodium of formula III.
Figure imgf000013_0001
III ; and
c) optionally purifying the sugammadex sodium of formula III. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION
[0012] The abbreviations used in the present application are defined as following: [0013] DMF: dimethylformamide.
[0014] DMSO: dimethyl sulfoxide.
[0015] DMAc: dimethylacetamide.
[0016] NMP: N-methyl-2-pyrrolidone.
[0017] In one aspect, the present application provides a process for preparing a compound of formula II:
Figure imgf000014_0001
II wherein X is a halogen group, preferably chloro.
[0018] The process comprises reacting a g-cyclodextrin of formula I with a halogenating agent in presence of N-methyl-2-pyrrolidone:
Figure imgf000015_0001
I
[0019] In some embodiments, the temperature of this reaction is maintained from 50- 80°C. In some embodiments, the temperature is about QO-TOΌ. In some embodiments, the halogenating agent is selected from the group consisting of methanesulfonyl chloride, bromine, iodine, N-iodosuccinimide, oxalyl chloride, oxalyl bromide, thionyl chorlide, thionyl bromide, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphoruspentabromide, phosphoryl chloride, phosphoryl bromide, and triphosgene. In some embodiments, the halogenating agent is preferably
methanesulfonyl chloride or triphosgene.
[0020] In another aspect, the present application provides a process for preparing sugammadex salt of formula Il ia
Figure imgf000016_0001
Ilia wherein M represents Na or K and the process comprises: a) reacting a g-cyclodextrin of formula I with a halogenating agent in the presence of N-methyl-2-pyrrolidone to provide the compound of formula II :
Figure imgf000016_0002
Figure imgf000017_0001
II wherein X is a halogen group, preferably chloro; b) reacting the compound of formula II with 3-mercapto propionic acid in the
presence of a base and an organic solvent to provide the compound of formula Ilia.
Figure imgf000017_0002
Figure imgf000018_0001
Ilia ; and c) optionally, purifying the sugammadex salt of formula Ilia.
[0021 ] In some embodiments, the halogenating agent is selected from the group consisting of methanesulfonyl chloride, bromine, iodine, N-iodosuccinimide, oxalyl chloride, oxalyl bromide, thionyl chorlide, thionyl bromide, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus pentabromide, phosphoryl chloride, phosphoryl bromide and triphosgene. In some embodiments, the halogenating agent is preferably methanesulfonyl chloride or triphosgene.
[0022] In some embodiments, the base of step (b) is selected from alkali metal hydroxide and metal alkoxy. In some embodiments, alkali metal hydroxide is selected from the group consisting of sodium hydroxide, lithium hydroxide, and potassium hydroxide. In some embodiments, the alkali metal hydroxide of step (b) is sodium hydroxide. In some embodiments, the metal alkoxy of step (b) is selected from the group consisting of sodium tert-butoxide (NaOtBu) and sodium methoxide (NaOMe). In some embodiments, the metal alkoxy of step (b) is sodium tert-butoxide (NaOtBu).
[0023] In some embodiments, the solvent of step (b) is selected from the group consisting of polar aprotic solvents, C1 -5 esters, acetonitrile, dimethylformamide, and dimethylsulfoxide. In some embodiments, the solvent of step (b) is preferably dimethylformamide.
[0024] In some embodiments, the purification process of sugammadex salt of formula Ilia comprises: c-1 ) reacting sugammadex salt of formula Ilia with an acid in the presence of a first solvent to provide sugammadex free acid of formula IV: c-2) optionally, purifying the sugammadex free acid of formula IV with chromatograph column or active carbon: and c-3) treating the sugammadex free acid of formula IV with alkali metal hydroxide in the presence of a second solvent.
[0025] In some embodiments, the first solvent and/or the second solvent is selected from C1 -4 alkyl-alcohols, for example EtOH, MeOH, and IPA. In some embodiments, the first solvent is IPA, and the second solvent is EtOH or MeOH. In some embodiments, the alkali metal hydroxide is sodium hydroxide.
Figure imgf000019_0001
IV
[0026] In yet another aspect, the present application provides a one-pot process for preparing sugammadex sodium salt of formula III:
Figure imgf000020_0001
I, and the process comprises: a) reacting a g-cyclodextrin of formula I with a halogenating agent in the presene of N-methyl-2-pyrrolidone to provide the compound of formula II :
Figure imgf000020_0002
Figure imgf000021_0001
II wherein X is a halogen group, preferably chloro; b) reacting the compound of formula II with 3-mercapto propionic acid in the presence of a sodium base and an organic solvent to provide the compound of formula III
Figure imgf000021_0002
Figure imgf000022_0001
III ; and c) optionally purifying the sugammadex sodium of formula III.
[0027] In some embodiments, the halogenating agent is selected from the group consisting of methanesulfonyl chloride, bromine, iodine, N-iodosuccinimide, oxalyl chloride, oxalyl bromide, thionyl chorlide, thionyl bromide, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus pentabromide, phosphoryl chloride, phosphoryl bromide, and triphosgene. In some embodiments, the halogenating agent is preferably methanesulfonyl chloride or triphosgene.
[0028] In some embodiments, the sodim base is selected from sodium hydroxide, sodium tert-butoxide (NaOtBu) or sodium methoxide (NaOMe).
[0029] In some embodiments, the solvent of step (b) is selected from the group consisting of polar aprotic solvents, C1 -5 esters, acetonitrile, dimethylformamide, and dimethylsulfoxide. In some embodiments, the solvent of step (b) is preferably dimethylformamide.
[0030] In some embodiments, the purification process of sugammadex sodium of formula III comprises: c-1 ) reacting sugammadex sodium of formula III with an acid in the presence of a first solvent to provide sugammadex free acid of formula IV: c-2) optionally, purifying the sugammadex free acid of formula IV with chromatograph column or active carbon: and c-3) treating the sugammadex free acid of formula IV with sodium hydroxide in the presence of a second solvent. The acid may be HCI, TFA, Fi3P04, or HOAc.
Figure imgf000023_0001
EXAMPLES
[0031 ] The following examples are provided to further illustrate, but not to limit this invention.
Example 1
[0032] g-Cyclodextrin of formula I, methanesulfonyl chloride and N-Methyl-2- pyrrolidone were added into a 500 ml_ 3-neecked-R-flask at 20-30°C. The mixture was heat to 60-70°C and stirred for NLT 20 hr. After the reaction was completed, the mixture was cooled to 45-55 °C. H2O and NaOH were added into the mixture at the temperature. The mixture was stirred at 45-55 °C for 1 hr and another H2O was added. The mixture was cooled to 0-10°C and stirred for NLT 1 hr. The compound of formula II was isolated in 82% yield. Example 2
[0033] 3-Mercapto propionic acid, DMSO and NaOH were added into a 50 mL 3- neecked-R-flask at 20-30°C and the mixture was stirred for 1 hr. The compound of formula II was added at 20-30°C. The mixture was warmed to 70-80Ό and stirred for NLT 12 hr. After the reaction was completed, MeOH was added at 60-80 °C and stirred for 1 hr. The mixture was cooled to 20-30 Ό and stirred for 1 hr. The crude
sugammadex sodium was isolated and purified as a white solid.
Example 3
[0034] g-Cyclodextrin of formula I, methanesulfonyl chloride and N-Methyl-2- pyrrolidone were added into a 500 mL 3-neecked-R-flask at 20-30°C. The mixture was heat to 60-70°C and stirred for NLT 20 hr. After the reaction was completed, 3-mercapto propionic acid and NaOH were added into the mixture. The mixture was heated to 70- 80°C and stirred for NLT 12 hr. After the reaction was completed, MeOH was added at 60-80 °C. Then the mixture was cooled to 20-30 °C and stirred for 1 hr. The crude sugammadex sodium was isolated and purified as a white solid.
Example 4
[0035] 3-Mercapto propionic acid, DMSO and NaOtBu were added into a 50 ml_ 3- neecked-R-flask at 20-30°C and the mixture was stirred for 1 hr. The compound of formula II was added at 20-30°C. The mixture was warmed to 70-80^0 and stirred for NLT 12 hr. After the reaction was completed, MeOH was added at 60-80 °C and stirred for 1 hr. The mixture was cooled to 20-30 Ό and stirred for 1 hr. The crude
sugammadex sodium was isolated and purified as a white solid.
Example 5
[0036] 3-Mercapto propionic acid, DMSO and NaOMe were added into a 50 ml_ 3- neecked-R-flask at 20-30°C and the mixture was stirred for 1 hr. The compound of formula II was added at 20-30°C. The mixture was warmed to 70-80^0 and stirred for NLT 12 hr. After the reaction was completed, MeOH was added at 60-80 °C and stirred for 1 hr. The mixture was cooled to 20-30 Ό and stirred for 1 hr. The crude sugammadex sodium was isolated and purified as a white solid.
Example 6
[0037] The compound of formula III was purified with IPA/H2O/HCI at 40-50°C, and the pH was maintained at 3-4, the resulting the formula IV (sugammadex free acid) was isolated in 60-70% yield.
Example 7
[0038] The compound of formula IV was purified with RP-18 silica gel (or active carbon). The resulting the formula IV (sugammadex free acid) was isolated in 50-70% yield.
Example 8
[0039] The compound of formula IV was purified with EtOH/H20/NaOH at 40-50 °C, and the pH was maintained at 7-9. The resulting the formula III (sugammadex sodium) was isolated in 60-70% yield.
Comparative Examples 1 -3
[0040] Several other solvents were used to replace N-Methyl-2-pyrrolidone tested in Example 1 above. The specific conditions are listed Table 1 below. Except for the conditions that are explicitly listed in Table 1 below, other conditions and process steps for Comparative Examples 1 -3 are the same as those described in Example 1 .
Specifically, comparative Example 1 was conducted based on page 862, left column, second full pagraph of Bull Soc Chim Fr 1995 132 857-866. Table 1
Figure imgf000026_0001
Example 9
[0041 ] N-Methyl-2-pyrrolidone (220 ml_) was added into a 500 ml_ 3-neecked-R-flask. After triphosgene (22.9 g, 10 equiv) was added at -10 to 0°C, the mixture was heated to 20-30°C and stirred for NLT 2 hr before g-Cyclodextrin (10 g, 1.0 equiv) of formula I was added. The mixture was heated to 60-70°C and stirred for NLT 3 hr. After the reaction was completed, MeOH (20 mL, 2 vol) and NaOH (237 mL) were added into the mixture. The compound of formula II was isolated in about 90% yield.
Comparative Example 4
[0042] DMF was used to replace N-Methyl-2-pyrrolidone tested in Example 9 above. Except for the conditions that are explicitly listed in Table 2 below, other conditions and process steps for Comparative Example 4 are the same as those described in Example 9.
Table 2
Figure imgf000026_0002

Claims

CLAIMS WHAT IS CLAIMED IS:
1 . A process for preparing a compound of formula II:
Figure imgf000027_0001
wherein X is chloro said process comprising reacting a g-cyclodextrin of formula I with triphosgene in presence of N-Methyl-2-pyrrolidone
Figure imgf000027_0002
2. The process according to claim 1 comprising conducting the reacting step at about 50-80 °C.
3. The process according to claim 1 comprising conducting the reacting step at about 60-70°C.
4. A process for preparing a sugammadex salt of formula Ilia
Figure imgf000028_0001
wherein M represents Na or K, and the process comprises : a) reacting a g-cyclodextrin of formula I with triphosgene in presence of N- methyl-2-pyrrolidone to provide a compound of formula II :
Figure imgf000029_0001
wherein X is chloro
b) reacting the compound of formula II with 3-mercapto propionic acid in presence of a base and an organic solvent to provide a sugammadex salt of formula Il ia:
Figure imgf000030_0001
c) optionally purifying the sugammadex salt of formula Ilia.
5. The process according to claim 4, wherein the base of step (b) is selected from the group consisting of alkali metal hydroxides and metal alkoxides.
6. The process according to claim 5, wherein the alkali metal hydroxides comprise sodium hydroxide, lithium hydroxide, and potassium hydroxide.
7. The process according to claim 4, wherein the base of step (b) is sodium hydroxide.
8. The process according to claim 5, wherein the metal alkoxides comprise sodium teri-butoxide (NaOtBu) and sodium methoxide (NaOMe).
9. The process according to claim 4, wherein the base of step (b) is sodium teri-butoxide (NaOtBu).
10. The process according to claim 4, wherein the solvent of step (b) is selected from the group consisting of polar aprotic solvents, C1 -5 esters, acetonitrile, dimethylformamide, and dimethylsulfoxide.
11 . The process according to claim 4, wherein the organic solvent is dimethylformamide.
12. The process according to claim 4 wherein the step c) is conducted and comprises: c-1 ) reacting the sugammadex salt of formula Ilia obtained in step b) with an acid in the presence of a first solvent to provide sugammadex free acid of formula IV
Figure imgf000032_0001
IV c-2) optionally purifying the sugammadex free acid of formula IV with chromatograph column or active carbon; and c-3) treating the sugammadex free acid of formula IV with an alkali metal hydroxide in presence of a second solvent.
13. The process according to claim 12, wherein the first and second solvent are both independently selected from Ci-4 alkyl alcohols.
14. The process according to claim 12, wherein the first solvent is isopropyl alcohol, and the second solvent is MeOH.
15. The process according to claim 12, wherein the alkali metal hydroxide is sodium hydroxide.
16. A one-pot process for preparing a sugammadex sodium salt of formula III comprising:
Figure imgf000033_0001
a) reacting a g-cyclodextrin of formula I with triphosgene in presence of N- methyl-2-pyrrolidone to provide a compound of formula II:
Figure imgf000033_0002
Figure imgf000034_0001
II wherein X is chloro, b) reacting the compound of formula II with 3-mercapto propionic acid in presence of a sodium base and an organic solvent to provide the compound of formula
Figure imgf000034_0002
Figure imgf000035_0001
; and
c) optionally purifying the sugammadex sodium of formula III.
17. The process according to claim 16, wherein the sodim base is selected from the group consisting of sodium hydroxide, sodium tert- butoxide (NaOtBu), and sodium methoxide (NaOMe).
18. The process according to claim 16, wherein the step c) is conducted and comprises: c-1 ) reacting the sugammadex sodium of formula III with an acid in the presence of a first solvent to provide a sugammadex free acid of formula IV
Figure imgf000036_0001
c-2) optionally purifying the sugammadex free acid of formula IV with chromatograph column or active carbon; and c-3) treating the sugammadex free acid of formula IV with sodium hydroxide in the presence of a second solvent.
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CN111607020A (en) * 2020-06-23 2020-09-01 湖南如虹制药有限公司 Method for removing turbidity and visible foreign matters of sugammadex sodium
CN113527544A (en) * 2021-08-06 2021-10-22 吉林省博大伟业制药有限公司 Preparation method of high-purity sugammadex sodium

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WO2016194001A1 (en) * 2015-05-29 2016-12-08 Alaparthi Lakshmi Prasad Processes for preparation of sugammadex and intermediates thereof
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CN111607020A (en) * 2020-06-23 2020-09-01 湖南如虹制药有限公司 Method for removing turbidity and visible foreign matters of sugammadex sodium
CN111607020B (en) * 2020-06-23 2021-03-09 湖南如虹制药有限公司 Method for removing turbidity and visible foreign matters of sugammadex sodium
CN113527544A (en) * 2021-08-06 2021-10-22 吉林省博大伟业制药有限公司 Preparation method of high-purity sugammadex sodium
CN113527544B (en) * 2021-08-06 2022-12-30 吉林省博大伟业制药有限公司 Preparation method of high-purity sugammadex sodium

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