Patent Application
20180312612
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,6H-Octakis-S-(2-carboxyethyl)-6A,6B,6C,6D,6E,6F,6G,6H-octathio-γ-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. 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 Dec. 15, 2015.
U.S. Pat. No. RE 44,733 (the 733 patent) describes a preparation method of sugammadax as shown in Scheme 1 below:
Sugammadex is prepared by dissolving γ-cyclodextrin in X2 (Cl2 or Br2)/PPh3/NaOMe in DMF followed by adding NaH and 3-mercapto propionic acid or NaOH/Cs2CO3/3-mercapto propionic acid.
A similar approach for sugammadax preparation is reported in U.S. Pat. No. 9,120,876B2 (the '876 patent, Scheme 2 below). Sugammadex is prepared by dissolving γ-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, PPh3 is used to produce the intermediate, and a significant amount of side product PPh3O2 is produced. PPh3O2 is hard to remove, and the intermediate is hard to isolate.
Another synthetic route is reported in Chinese Patent Application CN105273095A (Scheme 3 below). Sugammadex is prepared by dissolving γ-cyclodextrin in oxalyl chloride or SOCl2 in DMF followed by adding NaH and 3-mercapto propionic acid. When oxalyl chloride or SOCl2 is added into the mixture, exothermic heat and HCl are produced.
Bull Soc Chim Fr 1995 132 857-866 discloses that halide-γ-cyclodextrin can be prepared by reacting γ-cyclodextrin with MsCl in DMF.
In view of the above, there remains a need for the development of improved processes for the preparation of sugammadax sodium.
In one aspect, the present application provides a process for preparing a compound of formula II:
wherein X represents a halogen group, preferably chloro.
II
The process comprises reacting a γ-cyclodextrin of formula I with a halogenating agent in the presence of N-methyl-2-pyrrolidone:
In a second aspect, the present application provides a process for preparing a sugammadex salt of formula IIIa
wherein M represents Na or K, and the process comprises:
wherein X is a halogen group, preferably chloro;
and
In a third aspect, the present application provides a one-pot process for preparing sugammadex sodium salt of formula III comprising:
wherein X is a halogen group, preferably chloro; and
and
The abbreviations used in the present application are defined as following:
DMF: dimethylformamide.
DMSO: dimethyl sulfoxide.
DMAc: dimethylacetamide.
NMP: N-methyl-2-pyrrolidone.
In one aspect, the present application provides a process for preparing a compound of formula II:
wherein X is a halogen group, preferably chloro.
The process comprises reacting a γ-cyclodextrin of formula I with a halogenating agent in presence of N-methyl-2-pyrrolidone:
In some embodiments, the temperature of this reaction is maintained from 50-80° C. In some embodiments, the temperature is about 60-70° C. 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.
In another aspect, the present application provides a process for preparing sugammadex salt of formula IIIa
wherein M represents Na or K and the process comprises:
wherein X is a halogen group, preferably chloro;
and
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.
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).
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.
In some embodiments, the purification process of sugammadex salt of formula IIIa comprises: c-1) reacting sugammadex salt of formula IIIa 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.
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.
In yet another aspect, the present application provides a one-pot process for preparing sugammadex sodium salt of formula III:
and the process comprises:
wherein X is a halogen group, preferably chloro;
and
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.
In some embodiments, the sodium base is selected from sodium hydroxide, sodium tert-butoxide (NaOtBu) or sodium methoxide (NaOMe).
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.
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 HCl, TFA, H3PO4, or HOAc.
The following examples are provided to further illustrate, but not to limit this invention.
γ-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.
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 70-80° C. 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° C. and stirred for 1 hr. The crude sugammadex sodium was isolated and purified as a white solid.
γ-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.
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° C. 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° C. and stirred for 1 hr. The crude sugammadex sodium was isolated and purified as a white solid.
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° C. 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° C. and stirred for 1 hr. The crude sugammadex sodium was isolated and purified as a white solid.
The compound of formula III was purified with IPA/H2O/HCl 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.
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.
The compound of formula IV was purified with EtOH/H2O/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.
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 paragraph of Bull Soc Chim Fr 1995 132 857-866.
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 γ-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.
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.
This application is a continuation-in-part application of U.S. application Ser. No. 15/873,505 filed on Jan. 17, 2018, which claims priority from U.S. Provisional Patent Application Ser. No. 62/449,139, which was filed on Jan. 23, 2017. The entire content of this provisional application is incorporated herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| 62449139 | Jan 2017 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 15873505 | Jan 2018 | US |
| Child | 16031083 | US |
