DESC:FIELD OF THE INVENTION:
The present invention provides an improved process for the preparation of Sugammadex. More particularly, the invention relates to an improved process for the preparation of intermediate 6-per-deoxy-6-per-halo- ? -cyclodextrin wherein said halo is bromo, chloro or iodo. The invention further relates to new chemical intermediates for the synthesis of Sugammadex sodium.

BACKGROUND OF THE INVENTION:
Sugammadex (Trade name: Bridion) is first disclosed in U.S. Pat. No RE44,733 E assigned to Akzo Nobel. Sugammadex sodium was approved in EMEA as an agent for reversal of neuromuscular blockade by the agent rocuronium in general anaesthesia in 2008 and is the first selective relaxant binding agent (SRBA).

Sugammadex sodium contains 8 recurring glucose units each with 5 asymmetric carbon atoms, in total 40 asymmetric carbon atoms for the whole molecule. Sugammadex is a modified y-cyclodextrin, with a lipophilic core and a hydrophilic periphery. The gamma cyclodextrin has been modified from its natural state by placing eight carboxylpropyl thio ether groups at the sixth carbon positions.

The U.S.Pat. No US RE44,733 E discloses a process for preparing Sugammadex sodium as depicted in Scheme-I:

This patent discloses a process for preparation of sugammadex which involves iodination of dry ?-cyclodextrin by reacting with triphenylphosphine and iodine in dry dimethylformamide at 70°C for 24 hours to obtain 6-per-deoxy-6-per-iodo-?-cyclodextrin as a yellow solid. The 6-per-deoxy-6-per-iodo- ? -cyclodextrin was dissolved in dimethylformamide and added slowly to a mixture of 3-mercaptopropionic acid and sodium hydride in dry dimethylformamide. The obtained mixture was heated at 70°C for 12 hours. The mixture was cooled and water was added to the mixture. The volume of the mixture was reduced under vacuum by evaporation followed by addition of ethanol to precipitate Sugammadex sodium.

US 9,120,876 B2 (hereinafter referred as '876) discloses the preparation of Sugammadex by chlorination of ?-cyclodextrin with phosphorous pentachloride in dimethylformamide, after completion of the chlorination the solvent was removed to obtain a viscous residue. The viscous residue was diluted with water followed by adjusting the pH to 8 with 5M sodium hydroxide to obtain slurry, it was then filtered, washed with water and dried to give 6-per-deoxy-6-per-chloro-?- cyclodextrin. The chlorinated ? -cyclodextrin was dissolved in dimethylformamide and added slowly to a mixture of 3-mercaptopropionic acid and sodium hydride in dimethylformamide. The obtained mixture was heated at 70-75°C for 12 Hours. The dimethylformamide was partially removed then diluted with ethanol to obtain a precipitate. The precipitate is stirred for one hour and filtered to obtain crude Sugammadex sodium. The crude Sugammadex sodium was purified over silica gel and Sephadex G-25* column using water as eluent.

US 2016/0009827 A1 (hereinafter referred as '827) discloses the preparation of Sugammadex by chlorination of ? -cyclodextrin with phosphorous pentachloride in dimethylformamide. After completion of the chlorination, the mixture was quenched with water. The obtained mixture was hydrolyzed with aqueous sodium hydroxide solution, filtered, washed repeatedly with water and dried to give 6-per- deoxy-6-per-chloro- ? -cyclodextrin. The chlorinated ? -cyclodextrin was added slowly to a mixture of 3-mercaptopropionic acid and sodium methoxide in methanol and dimethylformamide, then heated to 75-80 °C and maintained at 75- 80°C for 12 to 14 Hours to give crude Sugammadex sodium. The crude Sugammadex sodium was purified by treating it with activated carbon in a mixture of water and methanol.
CNl 04844732A2 discloses an alternative process for the preparation of Sugammadex by reacting ?- cyclodextrin with thiourea in dimethylformamide at 90 °C for 12 Hours. After completion of the reaction, the solvent was partially evaporated followed by addition of ethanol to obtain a precipitate. The resulting solid precipitate was treated with aqueous sodium hydroxide solution followed by adjusting the pH 2 with hydrochloric acid. The ethanol was added to the mixture to obtain a solid residue, which was recrystallized in water to obtain 6-per-deoxy-6-per-mercapto- ? -cyclodextrin. The 6-per-deoxy-6-per-mercapto-y-cyclodextrin was reacted with acrylic acid in water under UV light exposure at 20 °C for 6 Hours. The pH of the solution was adjusted to 9 with aqueous sodium hydroxide solution followed by filtering the solution from nanofiltration membrane to obtain Sugammadex sodium.

The alternate process disclosed in CNl 04844732 A2 involves specific techniques and instrument for the preparation of Sugammadex, which are difficult to implement and control in the industrial scale.

Thus, the prior art procedures for the preparation of Sugammadex suffers from the following disadvantages outlined below;

(i) The use of pyrophoric reagents such as sodium hydride is also not recommended as their handling is difficult at large scale production of Sugammadex.
(ii) The use of special techniques such as chromatographic purification and utilization of UV light are difficult to implement and control in the industrial scale.
(iii) Finally, the longer time duration, handling of reagents, utilization of special techniques and lower purity of Sugammadex are not desirable for the preparation of Sugammadex.

An improvement in the process is disclosed in WO16194001, WO17089966, WO17089978 and WO17163165 publications.

WO16194001 discloses a process for preparation of Sugammadex sodium which comprises;
a) reacting gamma-cyclodextrin with either triphosgene or oxalyl chloride in presence of
dimethylformamide 65-70 °C for 14-16 hr to obtain perdeoxy-6-per-chloro-?- cyclodextrin;
b) reacting 3-mercapto propionic acid and potassium hydroxide in presence of dimethylformamide to obtain a solution of potassium salt of 3-mercapto propionic acid;
c) treating potassium salt of 3-mercapto propionic acid obtained in step b) with perdeoxy-6-per-chloro ?- cyclodextrin (III) at 110-120 °C for 1.5-2hr to obtain a product containing potassium salt of acid of Sugammadex;
d) treating the compound of step c) with acid to obtain a compound of formula (IV);
e) reacting the compound of formula (IV) with sodium hydroxide to obtain Sugammadex
sodium.

WO17089966 and WO17089978 discloses a process for preparation of Sugammadex sodium which comprises;
a) reacting ? -cyclodextrin with oxalyl chloride in presence of dimethylformamide at 65-70°C for 15 hr to obtain 6-perdeoxy-6-per-chloro- ?- cyclodextrin;
b) reacting 6-perdeoxy-6-per-chloro- ?- cyclodextrin with 3-mercapto propionic acid in the presence of Sodium tert-butoxide in DMSO at 70°C overnight. The obtained residue was lyophilized to obtain Sugammadex sodium.
Alternatively, the chlorinated ? -cyclodextrin was dissolved in dimethylformamide and added slowly to a mixture of 3-mercaptopropionic acid and sodium hydride in dimethylformamide. The obtained mixture was heated at 70-75°C for 12 Hours. The dimethylformamide was partially removed then diluted with ethanol to obtain a precipitate. The precipitate is stirred for one hour and filtered to obtain crude Sugammadex sodium. The crude Sugammadex sodium was purified over silica gel and Sephadex G-25* column using water as eluent.

WO17163165 discloses a process for preparation of Sugammadex sodium comprising the steps of,
a) reacting gamma-cyclodextrin with oxalyl chloride in presence of dimethylformamide at 65-70 °C for 15 hr to obtain perdeoxy-6-per-chloro- ?- cyclodextrin;
b) reacting perdeoxy-6-per-chloro- ?- cyclodextrin with disodium salt of 3-mercapto propionic acid in DMSO followed by heating the mixture at 70-75°C to obtain the reaction mixture containing crude Sugammadex sodium ;
c) de-oxygenating the reaction mixture with nitrogen in multiple cycles.

In view of the above it is pertinent to note that there is a continuous need in the art to develop a simple alternative process for making Sugammadex sodium of Formula I.

OBJECTS OF THE INVENTION:
The object of the present invention is to provide novel processes for preparing Sugammadex sodium of formula (I).

Yet another object of the present invention is to provide a novel process which proceeds via new chemical intermediates for the synthesis of Sugammadex sodium of formula (I).

Yet another object of the present invention is to provide a process for the synthesis of Sugammadex sodium of formula (I) which is simple, economical and suitable for industrial scale-up.

SUMMARY OF THE INVENTION:
According to a first aspect of the present invention, there is provided a process for preparing Sugammadex sodium of formula I comprising steps of:

i) reacting ?-cyclodextrin of formula III with N-halosuccinimide and trialkyl/aryl phosphine, wherein halo is selected from bromo, chloro and iodo, in a suitable organic solvent, to obtain 6-per-deoxy-6-per-halo- ?-cyclodextrin of formula II,

wherein X is halo selected from bromo, chloro and iodo, and,
ii) reacting the 6-per-deoxy-6-per-halo-?-cyclodextrin of formula II with 3-mercaptopropionic acid in the presence of a base in a suitable organic solvent to obtain Sugammadex sodium of formula I.

According to another aspect of the present invention, there is provided a process for preparing an intermediate II, namely 6-per-deoxy-6-per- halo- ?- cyclodextrin of formula II, wherein X is halo selected from bromo ,chloro and iodo, comprising steps of:

i) reacting ?-cyclodextrin of formula III with N-halosuccinimide and trialkyl/aryl phosphine in a suitable organic solvent, to obtain 6-per-deoxy-6-per-halo- ?- cyclodextrin of formula II, wherein halo is selected from bromo, chloro and iodo, and
ii) isolating 6-per-deoxy-6-per-halo- ? -cyclodextrin of formula II.

In yet another aspect, the present invention relates to an improved process for preparing Sugammadex sodium of formula I comprising steps of:
i) reacting ?-cyclodextrin of formula III with iodine in the presence of triphenyl phosphine in a suitable organic solvent, to obtain intermediate of formula IIA,

wherein at least one of X1 is iodo and at least one of X1 is hydroxy and each of the remaining X1 is independently selected from iodo and/or hydroxy;
iii) reacting intermediate of formula IIA with a halogenating agent in a suitable organic solvent, to obtain intermediate of formula IIB,

wherein at least one of X2 is iodo and each of the remaining X2 is independently selected from either bromo, chloro or iodo ; and
iv) reacting intermediate of formula IIB with 3-mercaptopropionic acid in the presence of a base in a suitable organic solvent to obtain Sugammadex sodium of formula I.

According to another aspect of the present invention, there is provided a process for preparing an intermediate of formula IIB, wherein at least one of X2 is iodo and each of the remaining X2 is independently selected from either bromo, chloro or iodo comprising steps of:
i) reacting ?-cyclodextrin of formula III with iodine in the presence of triphenyl phosphine in a suitable organic solvent, to obtain intermediate of formula IIA, wherein at least one of X1 is iodo and at least one of X1 is hydroxy and each of the remaining X1 is independently selected from iodo and/or hydroxy ;
ii) reacting intermediate of formula IIA with a halogenating agent, wherein halo is selected from bromo, chloro and iodo, in a suitable organic solvent, to obtain intermediate of formula IIB,and
iii) isolating intermediate of formula IIB.

According to another aspect of the present invention, there is provided a process for preparing an intermediate of formula IIA, wherein at least one of X1 is iodo and at least one of X1 is hydroxy and each of the remaining X1 is independently selected from iodo and/or hydroxy; comprising steps of:
i) reacting ?-cyclodextrin of formula III with iodine in the presence of triphenyl phosphine in a suitable organic solvent, to obtain intermediate of formula IIA,; and
ii) Isolating intermediate of formula IIA.

In another aspect, the present invention provides novel intermediate compounds of formula IIA and IIB as shown below;

wherein, at least one of X1 is iodo and at least one of X1 is hydroxy and each of the remaining X1 is independently selected from iodo and/or hydroxyl; and

wherein, at least one of X2 is iodo and each of the remaining X2 is independently selected from either bromo, chloro or iodo.

Further, the present invention provides Sugammadex sodium of formula (I), prepared according to the process described above, having a purity of more than about 95% .

Sugammadex sodium of formula (I) prepared according to the process of the present invention may be formulated with one or more pharmaceutically acceptable excipients to provide a pharmaceutical composition. Such excipients, compositions and methods of preparation are well known to those skilled in the art.

DETAILED DESCRIPTION OF THE INVENTION:
In an embodiment of the present invention, there is provided an improved synthesis of Sugammadex sodium of formula (I), as depicted below in reaction scheme 2.
Scheme 2

wherein X is halo selected from bromo, chloro and iodo.

In one embodiment of the invention, in step i) ?-cyclodextrin of formula III is reacted with N-halosuccinimide wherein halo is selected from bromo, chloro and iodo, and trialkyl/aryl phosphine in a suitable organic solvent, to obtain 6-per-deoxy-6-per-halo- ?-cyclodextrin of formula II. The reaction is preferably conducted in the absence of water, preferably less than 0.25% water, more preferably less than 0.20%, most preferably less than 0.1% water.

In an embodiment N-halosuccinimide is selected from a group consisting of N-chlorosuccinimide ( NCS), N-bromosuccinimide (NBS) and N-iodosuccinimide (NIS).

In an embodiment ?-cyclodextrin of formula III is preferably dried prior to the reaction with alkyl groups of the trialkyl/aryl phosphine, for example, by azeotropic distillation.

In an embodiment, ?-cyclodextrin of formula III is refluxed in a high boiling solvent selected from the group comprising of toluene, xylene, and the like under inert atmosphere, such as under nitrogen or argon, preferably nitrogen. The traces of water are removed by azeotropic distillation. The residue is stirred in an inert organic solvent.

The alkyl/aryl groups of the trialkyl/aryl phosphine can be the same or different and is preferably selected from the group consisting of C1-C6 straight or branched alkyls, C6-C 10 aryls, and arylalkyls wherein the alkyl contains 1-4 carbons, and the aryl contains 6-12 carbons; preferably methyl, ethyl, phenyl, and benzyl, more preferably phenyl.

In an embodiment trialkyl/aryl phosphine and halogenating agent are stirred in an inert organic solvent. A dry solution of ?-cyclodextrin of formula III is preferably added drop-wise to a dry solution of trialkyl/aryl phosphine and halogenating agent in an inert organic solvent.

An inert organic solvent may be selected from polar organic solvents such as C1-5 esters, acetonitrile, dimethylformamide, dimethylsulfoxide. Preferably the organic solvent is dimethylformamide or a mixture of dimethylformamide and polar organic solvents such as C1-C5 esters, acetonitrile.

The reaction is carried out at a temperature of about 0°C to about 250°C, preferably about 20°C to about 150°C, more preferably about 50°C to about 100°C; preferably, for about 20 minutes to about 30 hours, more preferably about an hour to about 28 hours, most preferably about 15 hours to about 25 hours.
Preferably, the reaction mixture is basified with liq. Ammonia, and the product is isolated, for example by filtration or extraction and distillation. The obtained product may be optionally purified in a suitable solvent by the methods known in the art.

The purification of 6-per-deoxy-6-per-halo- ?-cyclodextrin of formula II involves suspending 6-per-deoxy-6-per-halo- ?-cyclodextrin in alcoholic solvent such as methanol, ethanol, propanol, isopropyl alcohol, n-butanol, iso-butanol, tert-butanol, stirring the suspension and filtering to obtain pure perdeoxy-6-per-chloro- ?- cyclodextrin.

The pure perdeoxy-6-per-halo- ?-cyclodextrin obtained according to present invention has purity more than 98% by HPLC. The obtained yield is about 60% to about 90% w/w. Typically about 75% to about 87% w/w, more typically about 80% to about 85% w/w.

In an embodiment the 6-per-deoxy-6-per-halo- ?- cyclodextrin of formula II is reacted with 3-mercaptopropionic acid in the presence of base in a suitable organic solvent to obtain Sugammadex sodium of formula I.

The base can be selected from the group comprising of one or more of alkali metal hydroxide, metal amides, metal alkoxides, alkyllithiums, amine bases, Examples of suitable bases are: sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium methoxide, sodium ethoxide, potassium methoxide, sodium t-butoxide, potassium t-butoxide, carbonate, BuLi, and 1 ,8-diazabicyclo[ 5.4.0]undec-7 -ene. Most preferably, the base is selected from the group consisting of sodium methoxide, and sodium ethoxide.

The organic solvent in step (ii) may be selected from the group comprising of polar aprotic solvents such as dimethylsulfoxide, dimethylacetamide, dimethyl formamide and the like; alcohol solvents such as methanol, ethanol, n-propanol, isopropanol and n-butanol and the like; hydrocarbon solvents such as benzene, toluene, xylene, heptane, hexane and cyclohexane; ether solvents such as di-tert-butylether, diethylether, diisopropyl ether, 1,4-dioxane, methyl tert-butyl ether, ethyl tert-butyl ether, tetrahydrofuran and dimethoxyethane and mixtures thereof.

The reaction is carried out at a temperature of about 0°C to about 150°C, preferably about 20°C to about 120°C, more preferably about 50°C to about 100°C; preferably, for about an hour to about 30 hours, more preferably about 10 hours to about 28 hours, most preferably about 15 hours to about 25 hours.

Preferably, reaction mixture is stirred in an organic solvent such as alcohol solvent such as methanol, ethanol, propanol, isopropyl alcohol, n-butanol, iso-butanol, tert-butanol, preferably methanol and the Sugammadex sodium is isolated, for example by filtration.

The obtained Sugammadex sodium may be optionally purified in a suitable solvent by the methods known in the art. The purification of Sugammadex sodium involves dissolving Sugammadex sodium in a mixture of water and water miscible solvents; adding activated charcoal; clarifying the solution by filtration; adding water miscible solvents; stirring for sufficient time and isolating the obtained solid by filtration.

In an embodiment water miscible solvent is selected from water miscible alcohol, nitriles, ketones, DMF and the like. Preferably, the alcohol is the Cl-C4 alcohols such as methanol, ethanol propanol, isopropyl alcohol, n-butanol, iso-butanol, tert-butanol, and the likes and/or mixtures thereof. Preferably, the nitrile is acetonitrile, propionitrile, and the likes and/or mixtures thereof. Preferably, the ketone is acetone.

Sugammadex sodium obtained by the process of the present invention has purity of about 90% or more, more preferably with a purity of about 92% or more, most preferably with a purity of at least about 95% or more by weight.

In yet another embodiment, the present invention encompasses an alternative route for preparing Sugammadex of formula (I), which proceeds essentially as shown in the following scheme 3.
Scheme 3

wherein at least one of X1 is iodo and at least one of X1 is hydroxy and each of the remaining X1 is independently selected from iodo and/or hydroxy and wherein at least one of X2 is iodo and each of the remaining X2 is independently selected from either bromo, chloro or iodo.

It was found that the halogenation reaction specifically with iodine in the presence of triphenylphospine with ?-cyclodextrin of formula II as reported in the prior art US RE44,733 E, does not go to completion. At least 10 % hydroxy remains unreacted even after use of 15 equivalents of iodine. The partially halogenated compound gets carry forward in the subsequent steps and becomes difficult to remove even after repetitive purification and which in turn results in low yields and purity of the Sugammadex sodium (I). Such disadvantages mean that the disclosed process is difficult to implement industrially or economically.

Inventors of the present invention have developed a novel process to overcome this hydroxy impurity problem.

In an embodiment, ?- cyclodextrin of formula III is reacted with iodine in the presence of triphenyl phosphine in a suitable organic solvent, to obtain partially halogenated intermediate of formula IIA.

In an embodiment ?-cyclodextrin of formula III is preferably dried prior to the reaction with Iodine in presence of triphenyl phosphine , for example, by azeotropic distillation; as discussed with respect to the first reaction step of scheme 2.

In an embodiment triphenylphosphine and iodine are stirred in an inert organic solvent. A dry solution of ?-cyclodextrin of formula III is preferably added drop-wise to a dry solution of triphenylphosphine and iodine and the inert organic solvent.

An inert organic solvent may be selected from polar organic solvents such as C1-5 esters, acetonitrile, dimethylformamide, dimethylsulfoxide. Preferably the organic solvent is dimethylformamide or a mixture of dimethylformamide and polar organic solvents such as C1-C5 esters, acetonitrile. More preferably, the organic solvent is dimethylformamide.

The reaction is carried out at a temperature of about 0°C to about 250°C, preferably about 20°C to about 150°C, more preferably about 50°C to about 100°C; preferably, for about 20 minutes to about 30 hours, more preferably about an hour to about 28 hours, most preferably about 15 hours to about 25 hours.

Preferably, the reaction mixture is basified with liq. Ammonia, and the product is isolated, for example by filtration or extraction and distillation. The obtained product may be optionally purified in a suitable solvent by the methods known in the art.

The purification of partially halogenated intermediate of formula IIA involves suspending partially halogenated intermediate of formula IIA in polar solvents and polar protic solvents. Examples for polar solvents and polar protic solvents are: methanol, ethanol, propanol, acetone, ethyl acetate, tetrahydrofuran, isopropanol, n-butanol, tert-butanol, and isobutanol; stirring the suspension and filtering to obtain partially halogenated intermediate of formula IIA.

In an embodiment, the partially halogenated intermediate of formula IIA is further reacted with a halogenating agent in a suitable organic solvent, to obtain fully halogenated intermediate of formula IIB.

Preferably, a dry solution of intermediate of formula IIA in an inert organic solvent is added drop-wise to a dry solution of triphenylphosphine and halogenating agent and the inert organic solvent.

Preferably, the halogenating agent is selected from a group consisting of oxalyl chloride, oxalyl bromide, thionyl chloride and thionyl bromide, triphosgene, phosphorous halide such as PXs or PXs where X is an F, Cl, Br or iodine., N-halosuccinimide such as NCS, NBS or NIS. More preferably, the halogenating agent is N-halosuccinimide, most preferably N-halosuccinimide is NCS.

The amount of halogenating agent used varies from 1 to 8 equivalents based on partially halogenated intermediate of formula IIA.
The reaction is preferably conducted in the absence of water, preferably less than 0.25% water, more preferably less than 0.20%, most preferably less than 0.1% water.

An inert organic solvent may be selected from polar organic solvents such as C1-5 esters, acetonitrile, dimethylformamide, dimethylsulfoxide. Preferably the organic solvent is dimethylformamide or a mixture of dimethylformamide and polar organic solvents such as C1-C5 esters, acetonitrile. More preferably, the organic solvent is dimethylformamide.

The reaction is carried out at a temperature of about 0°C to about 250°C, preferably about 20°C to about 150°C, more preferably about 50°C to about 100°C; preferably, for about 20 minutes to about 30 hours, more preferably about an hour to about 28 hours, most preferably about 15 hours to about 25 hours.

Preferably, the reaction mixture is basified with liq. Ammonia , and the product is isolated, for example by filtration or extraction and distillation. The obtained product may be optionally purified in a suitable solvent by the methods known in the art .

The purification of fully halogenated intermediate of formula IIB involves suspending fully halogenated intermediate of formula IIB in polar solvents and polar protic solvents. Examples for polar solvents and polar protic solvents are: methanol, ethanol, propanol, acetone, ethyl acetate, tetrahydrofuran, isopropanol, n-butanol, tert-butanol, and isobutanol; stirring the suspension and filtering to obtain fully halogenated intermediate of formula IIB.

Intermediate compound IIB is then further reacted with 3-mercaptopropionic acid in the presence of base in a suitable organic solvent to obtain Sugammadex sodium of formula I.
The reaction conditions are the same as discussed with respect to the second reaction step of scheme 2.

Sugammadex sodium obtained by the process of the present invention has purity of about 90% or more, more preferably with a purity of about 92% or more, most preferably with a purity of at least about 95% or more by weight.

While considerable emphasis has been placed herein on the specific steps of the preferred process, it will be appreciated that many steps can be made and that many changes can be made in the preferred steps without departing from the principles of the invention. These and other changes in the preferred steps of the invention will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the invention and not as a limitation.

The invention will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limit to the scope of the reaction in any manner.

Example 1
Preparation of 6-perdeoxy-6-per-chloro- ?-cyclodextrin
An azeotropic distillation was performed by stirring ?- cyclodextrin (10.0 g 0.0077 mol) in toluene (50 ml) to remove traces of water. The reaction mixture was cooled to 25-30°C and stirred in 80ml DMF and stored under nitrogen.

To a stirred solution of triphenyl phosphine (40.4gm , 0.154 moles) in 80ml DMF was added N -chloro succinimide ( 20.58 g, 0.154 moles) The temperature of the reaction mixture was raised to 20-25°C and stirred for an hour. The above dry solution of ?- cyclodextrin was added to the reaction mixture at 20-25°C. Mixture was stirred at 65-70°C for 22-24 hrs. The reaction mixture was cooled to 5-10°C and basified with liq. Ammonia solution until pH 8. The reaction mixture was diluted with water ( 350 ml) and stirred for 1hr at 20-25°C. The slurry was filtered and dried.

The wet cake was stirred in 100ml Methanol for 1hr at 20-25°C, filtered and the solid dried at 55-60°C under vacuum for 8 hrs.
Yield - 60- 80%

Example 2
Preparation of Sugammadex sodium
To a stirred mixture of 30% solution of Sodium methoxide (14.95 gm, 0.082 moles) in 40 ml Dry DMF a solution of 3-mercapto propionic acid (3.6 ml, 0.041 moles) in DMF (50 ml) was added slowly under argon maintaining the temperature below 20°C. The resulting mixture was stirred at 20-25° C for about an hour . Then 6-deoxy-6-chloro- ?-cyclodextrin (2 g, 0.00138 moles) was added slowly at 20°C under argon and the resulting mixture was heated to 75-80°C for 14-16 hrs. Reaction mixture was cooled to 20-25° C and the reaction mixture was diluted with methanol (80 ml). The resulting precipitate was stirred at 20-25°C for 1 hr and filtered under vacuum and the solid dried to afford the crude Sugammdex sodium.
Yield – 3 gm

Example 3
Purification of Sugammadex sodium
The Sugammadex sodium (2gm) prepared from example 2 was dissolved in water (6 ml) and methanol (6 ml), treated with 20% activated carbon at 50-55°C and filtered the carbon cake through celite bed and the carbon cake was washed with purified water (2 mL). The filtrate was heated to 50-55°C and added methanol (90 ml) at the same temperature. The contents were cooled to 20 to 25°C and stirred for 2 hours at the same temperature. The resultant solid was washed with methanol and dried in vacuum at 60-65°C for 8-10 hrs. The obtained yield was 50%.
Yield - 50%
Purity > 95% by HPLC

Example 4
Preparation of intermediate IIA
An azeotropic distillation was performed by stirring ?-cyclodextrin (10.0 g 0.0077mol) in toluene (50 ml) to remove traces of water. The reaction mixture was cooled to 25-30°C and stirred in 80ml DMF and stored under nitrogen.

To a stirred solution of triphenyl phosphine ( 40.4gm , 0.0154 moles) in 80ml DMF was added iodine ( 29.4 g, 0.0154 moles). The temperature of the reaction mixture was raised to 20-25°C and stirred for an hour. The above dry solution of ?-cyclodextrin was added to the reaction mixture at 20-25°C. Mixture was stirred at 65-70°C for 22-24 hrs. The reaction mixture was cooled to 5-10°C and basified with liq. Ammonia solution until pH 8. The reaction mixture was diluted with water ( 350 ml) and stirred for 1hr at 20-25°C. The slurry was filtered and dried.

The wet cake was stirred in 20ml acetone for 1hr at 20-25°C, filtered and the solid dried at 60-65°C under vacuum for 8 hrs.
Yield – 10 g

Example 5
Preparation of intermediate IIB
To a stirred solution of triphenyl phosphine ( 1gm , 0.0038 moles) in 50ml DMF was added N -chloro succinimide ( 0.06 g, 0.0038 moles) .The temperature of the reaction mixture was raised to 20-25°C and stirred for an hour. The dry solution of Intermediate IIA ( 10 g) in 16 ml DMF was added to the reaction mixture at 20-25°C. Mixture was stirred at 65-70°C for 6-8 hrs. The reaction mixture was cooled to 5-10°C and basified with liq. Ammonia solution until pH 8. The reaction mixture was diluted with water ( 350 ml) and stirred for 1hr at 20-25°C. The slurry was filtered and dried.
The wet cake was stirred in 100ml Methanol for 1hr at 20-25°C, filtered and the solid dried at 60-65°C under vacuum for 8 hrs.
Yield - 60- 80%

Example 6
Preparation of Sugammadex sodium
To a stirred mixture of 30% solution of sodium methoxide (14.95 gm, 0.083 moles) in 40 ml Dry DMF a solution of 3-mercapto propionic acid (3.6 ml 0.041 moles) in DMF (50 ml) was added slowly under nitrogen maintaining the temperature below 20°C. The resulting mixture was stirred at 20-25° C for about an hour . Then intermediate IIB (2 g) was added slowly at 20°C under argon and the resulting mixture was heated to 75-80°C for 14-16 hrs. Reaction mixture was cooled to 20-25° C and the reaction mixture was diluted with methanol (80 ml). The resulting precipitate was stirred at 20-25°C for 1 hr and filtered under vacuum and the solid dried to afford the crude Sugammdex sodium.
Yield – 3 gm

Example 7
Purification of Sugammadex sodium
The Sugammadex sodium prepared from example 2 was dissolved in water (6 ml) and methanol (6 ml), treated with 20% activated carbon at 50-55°C and filtered the carbon cake through celite bed and the carbon cake was washed with purified water (2 mL). The filtrate was heated to 50-55°C and added methanol (90 ml) at the same temperature. The contents were cooled to 20 to 25°C and stirred for 2 hours at the same temperature. The resultant solid was washed with methanol and dried in vacuum at 60-65°C for 8-10 hrs. The obtained yield was 50%.
Yield – 1.5 g, 50%
Purity > 95% by HPLC
,CLAIMS:1. An improved process for preparing Sugammadex sodium of formula I

comprising steps of:
iii) reacting ?-cyclodextrin of formula III

with N-halosuccinimide and trialkyl/aryl phosphine, wherein halo is selected from bromo, chloro and iodo in a suitable organic solvent, to obtain 6-per-deoxy-6-per-halo- ?-cyclodextrin of formula II,

wherein X is halo selected from bromo, chloro and iodo, and,
iv) reacting the 6-per-deoxy-6-per-halo-?-cyclodextrin of formula II with 3-mercaptopropionic acid in the presence of a base in a suitable organic solvent to obtain Sugammadex sodium of formula I.

2. The process according to claim 1, wherein the N-halosuccinimide is selected from a group consisting of N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS) and N-iodosuccinimide (NIS).

3. The process according to claim 1, wherein the alkyl/aryl groups of the trialkyl/aryl phosphine are selected from the group consisting of C1-C6 straight or branched alkyls, C6-C 10 aryls, and arylalkyls wherein the alkyl contains 1-4 carbons, and the aryl contains 6-12 carbons.

4. The process according any one of the preceding claims, wherein the ?-cyclodextrin of formula III is dried by azeotropic distillation, prior to the reaction with N-halosuccinimide and trialkyl/arylphosphine.

5. The process according to claim 4, wherein the azeotropic distillation comprises refluxing ?-cyclodextrin of formula III, in a high boiling solvent selected from the group comprising of toluene, xylene, and the like under inert atmosphere, such as under nitrogen or argon.

6. The process according to claim 1, wherein the organic solvent in step (i) is selected from polar organic solvents such as C1-5 esters, acetonitrile, dimethylformamide, dimethylsulfoxide or a mixture thereof.

7. The process according to any one of the preceding claims, wherein the reaction is carried out at a temperature of about 0°C to about 250°C, preferably about 20°C to about 150°C, more preferably about 50°C to about 100°C.

8. The process according to any one of the preceding claims, wherein the 6-per-deoxy-6-per-halo- ?-cyclodextrin of formula II purified in a suitable alcoholic solvent such as methanol, ethanol, propanol, isopropyl alcohol, n-butanol, isobutanol and tert-butanol.

9. The process according to any one of the preceding claims, wherein the 6-per-deoxy-6-per-halo- ?-cyclodextrin has purity more than 98% by HPLC and the yield about 80% to about 85% w/w.

10. The process according to any one of the preceding claims, wherein the base in step (ii) is selected from the group comprising of one or more of alkali metal hydroxide, metal amides, metal alkoxides, alkyllithiums, and amine bases.

11. The process according claim 10, wherein the base is selected from the group comprising of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium methoxide, sodium ethoxide, potassium methoxide, sodium t-butoxide, potassium t-butoxide, carbonate, BuLi, and 1 ,8-diazabicyclo[ 5.4.0]undec-7 -ene.

12. The process according claim 11, wherein the base is selected from the group consisting of sodium methoxide, and sodium ethoxide.

13. The process according claim 1, wherein the organic solvent in step (ii) is selected from the group comprising of polar aprotic solvents such as dimethylsulfoxide, dimethylacetamide, dimethyl formamide and the like; alcohol solvents such as methanol, ethanol, n-propanol, isopropanol and n-butanol and the like; hydrocarbon solvents such as benzene, toluene, xylene, heptane, hexane and cyclohexane; ether solvents such as di-tert-butylether, diethylether, diisopropyl ether, 1,4-dioxane, methyl tert-butyl ether, ethyl tert-butyl ether, tetrahydrofuran and dimethoxyethane and mixtures thereof.

14. The process according claims 10 to 13, wherein the reaction is carried out at a temperature of about 0°C to about 150°C, preferably about 20°C to about 120°C, more preferably about 50°C to about 100°C.

15. A process for preparing 6-per-deoxy-6-per- halo- ?- cyclodextrin of formula II, wherein X is halo selected from bromo ,chloro and iodo, comprising steps of:
v) reacting ?-cyclodextrin of formula III with N-halosuccinimide and trialkyl/arylphosphine in a suitable organic solvent, to obtain 6-per-deoxy-6-per-halo- ?- cyclodextrin of formula II, wherein halo is selected from bromo, chloro and iodo, and
vi) isolating 6-per-deoxy-6-per-halo- ? -cyclodextrin of formula II.

16. The process according claim 15, wherein, the ?-cyclodextrin of formula III is dried by azeotropic distillation, prior to the reaction with N-halosuccinimide and trialkyl/arylphosphine.

17. The process according to claim 16, wherein, the azeotropic distillation comprises refluxing ?-cyclodextrin of formula III, in a high boiling solvent selected from the group comprising of toluene, xylene, and the like under inert atmosphere, such as under nitrogen or argon.

18. An improved process for preparing Sugammadex sodium of formula I

comprising steps of:
ii) reacting ?-cyclodextrin of formula III with iodine in the presence of triphenyl phosphine in a suitable organic solvent, to obtain intermediate of formula IIA,

wherein at least one of X1 is iodo and at least one of X1 is hydroxy and each of the remaining X1 is independently selected from iodo and/or hydroxy;
iii) reacting the intermediate of formula IIA with a halogenating agent in a suitable organic solvent, to obtain intermediate of formula IIB,

wherein at least one of X2 is iodo and each of the remaining X2 is independently selected from either bromo, chloro or iodo ; and
vii) Reacting the intermediate of formula IIB with 3-mercaptopropionic acid in the presence of a base in a suitable organic solvent to obtain Sugammadex sodium of formula I.

19. The process according claim 18, wherein the organic solvent in step (i) is selected from polar organic solvents such as C1-5 esters, acetonitrile, dimethylformamide, dimethylsulfoxide or mixture thereof .

20. The process according claims 18 to 19, wherein the reaction in step (i) is carried out at a temperature of about 0°C to about 250°C, preferably about 20°C to about 150°C, more preferably about 50°C to about 100°C.

21. The process according to claims 18 to 20, wherein the intermediate of formula IIA is purified in polar solvents and polar protic solvents such as methanol, ethanol, propanol acetone, ethyl acetate, tetrahydrofuran, isopropanol, n-butanol, tert-butanol, and isobutanol.

22. The process according to claim 18, wherein the halogenating agent in step (ii) is selected from a group consisting of oxalyl chloride, oxalyl bromide, thionyl chloride, thionyl bromide, triphosgene, phosphorous halide such as PXs or PXs where X is an F, Cl, Br or iodine; N-halosuccinimide such as NCS, NBS or NIS.

23. The process according to claim 22, wherein the amount of halogenating agent used varies from 1 to 8 equivalence based on partially halogenated intermediate of formula IIA.

24. The process according to claim 18, wherein the organic solvent of step (ii) is selected from polar organic solvents such as C1-C5 esters, acetonitrile, dimethylformamide, dimethylsulfoxide or a mixtures thereof.

25. The process according to claim 24, wherein the reaction is carried out at a temperature of about 0°C to about 250°C, preferably about 20°C to about 150°C, more preferably about 50°C to about 100°C.

26. The process according to any one of the preceding claims 18 to 25, wherein the purification of intermediate of formula IIB comprises suspending the intermediate of formula IIB in polar solvents and polar protic solvents selected from methanol, ethanol, propanol acetone, ethyl acetate, tetrahydrofuran, isopropanol, n-butanol, tert-butanol, and isobutanol ; stirring the suspension and isolating intermediate of formula IIB.

27. The process according claim 18, wherein, the base used in step (iii) is selected from the group comprising of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium methoxide, sodium ethoxide, potassium methoxide, sodium t-butoxide, potassium t-butoxide, carbonate, BuLi, and 1 ,8-diazabicyclo[ 5.4.0]undec-7 -ene.

28. The process as claimed in claim 18, wherein the organic solvent in step (iii) is selected from the group comprising of polar aprotic solvents such as dimethylsulfoxide, dimethylacetamide, dimethyl formamide and the like; alcohol solvents such as methanol, ethanol, n-propanol, isopropanol and n-butanol and the like; hydrocarbon solvents such as benzene, toluene, xylene, heptane, hexane and cyclohexane; ether solvents such as di-tert-butylether, diethylether, diisopropyl ether, 1,4-dioxane, methyl tert-butyl ether, ethyl tert-butyl ether, tetrahydrofuran and dimethoxyethane and mixtures thereof.

29. The process according to any one of the preceding claims, wherein prior to the isolation, the reaction mixture containing Sugammadex sodium is stirred in an organic solvent such as alcohol solvent selected from the group comprising of methanol, ethanol, propanol, isopropyl alcohol, n-butanol, iso-butanol, and tert-butanol; preferably methanol .

30. An intermediate compound of Formula IIB,

wherein at least one of X2 is iodo and each of the remaining X2 is independently selected from either bromo, chloro or iodo.

31. A process for preparing an intermediate compound of of formula IIB according to claim 30, wherein at least one of X2 is iodo and each of the remaining X2 is independently selected from either bromo, chloro or iodo comprising steps of:
iv) reacting ?-cyclodextrin of formula III with iodine in the presence of triphenyl phosphine in a suitable organic solvent, to obtain intermediate of formula IIA, wherein at least one of X1 is iodo and at least one of X1 is hyd roxy and each of the remaining X1 is independently selected from iodo and/or hydroxy ;
v) reacting intermediate of formula IIA with a halogenating agent in a suitable organic solvent, to obtain intermediate of formula IIB, and
vi) isolating intermediate of formula IIB.

32. An intermediate compound of Formula IIA,

wherein at least one of X1 is iodo and at least one of X1 is hydroxy and each of the remaining X1 is independently selected from iodo and/or hydroxyl.

33. A process for preparing an intermediate of formula IIA according to claim 32, wherein at least one of X1 is iodo and at least one of X1 is hydroxy and each of the remaining X1 is independently selected from iodo and/or hydroxy; comprising steps of:
iii) reacting ?-cyclodextrin of formula III with iodine in the presence of triphenyl phosphine in a suitable organic solvent, to obtain intermediate of formula IIA,; and
iv) Isolating intermediate of formula IIA.

34. A process for the purification of Sugammadex sodium comprising steps of :
i) dissolving Sugammadex sodium in a mixture of water and water miscible solvents;
ii) adding activated charcoal;
iii) clarifying the solution by filtration;
iv) adding water miscible solvents;
v) stirring for sufficient time; and
vi) isolating the obtained solid by filtration.

35. The process according to claim 34, wherein the water miscible solvent is selected from the group comprising of Cl-C4 alcohols such as methanol, ethanol propanol, isopropyl alcohol, n-butanol, iso-butanol, tert-butanol; nitriles such as acetonitrile, propionitrile; ketone such as acetone and the likes and/or mixtures thereof.

36. The process according to claim 35, wherein the water miscible solvent is methanol.

37. A process according to any one of the preceding claims wherein Sugammadex sodium has purity of about 90% or more, more preferably with a purity of about 92% or more, most preferably with a purity of at least about 95% or more by weight.