WO2019159191A1

WO2019159191A1 - An improved process for preparation of sugammadex sodium

Info

Publication number: WO2019159191A1
Application number: PCT/IN2019/000007
Authority: WO
Inventors: Puta VENKATESH; Akiti Surendar; Kanuri Srinivas; Namani DR.VASU; Gali UDAY KUMAR REDDY; Khader ABDUL; Gona SHOBAN BABU; Indurtyi SRINIVAS REDDY
Original assignee: Extrovis AG Extrovis Private Ltd
Current assignee: Extrovis AG Extrovis Private Ltd
Priority date: 2018-02-19
Filing date: 2019-02-19
Publication date: 2019-08-22
Anticipated expiration: 2020-08-19

Abstract

The present invention provides an improved process for the preparation of Sugammadex sodium involving the step of reacting 6-perdeoxy-6-per halo-gamma-cyclodextrin with 3-Mercapto propionic acid in the presence of Lithium hydroxide in an organic solvents. The invention also provides a process relates to a process for preparation of Sugammadex sodium from its corresponding acid intermediate

Description

An improved process for preparation of Sugammadex sodium

FIELD OF INVENTION

This invention claims priority application 201841006247 filed on February 19, 2018.

Present invention relates to an improved process for preparation of Sugammadex Sodium or its pharmaceutically acceptable salts thereof. Specifically, present invention also relates to a process for preparation of Sugammadex sodium from its corresponding acid intermediate.

Sugammadex sodium is marketed as Bridion^® and structurally known as compound of formula 1.

BACKGROUND OF INVENTiON

Sugammadex is chemically known as Cyclooctakis-(l- 4)-[6-S-(2-carboxyethyl)-6-thio-a-D- glucopyranosyl]. It is first selective relaxant binding agent (SRBA). SRBA’s are a new class of drugs that selectively encapsulates and binds NMBA’s.

US 6670340 disclose process for preparation of Sugammadex sodium. Process of reparation of Sugammadex as disclosed in this patent involves reaction of cyclodextrin with iodine in presence of triphenylphosphine (PPh3) and DMF there by producing key intermediate compound, 6-per-deoxy-6-per-iodo-y-cyclodextrin (lodo intermediate). Obtained Iodo intermediate further reacting with Mercapto propionic acid in presence of sodium hydride and DMF to give 6-per-deoxy-6-per-(3-carboxyethyl) thio-Y-cyclodextrin, sodium salt (Sugammadex sodium). This process illustrates below as scheme- 1.

Scheme- 1

There are few disadvantages of process as disclosed in US 6670340 patent. For example, as disclosed process involves use of triphenylphosphine reagent, there is formation of triphenylphosphine oxide as a by-product. Removal of triphenylphosphine oxide from reaction mass is very difficult as it requires repeated washing with solvent, which leads to inconsistency in yield of final product Sugammadex sodium. Hence, such process is not feasible and economic disadvantage industrial scale.

WO2012025937 disclose process for preparation of Sugammadex sodium process involving following steps a) Reaction of gamma-cyclodextrin with phosphorous pentachloride and dimethylformamide to obtain 6-perdeoxy-6-per-chloro gamma cyclodextrin, and b) Reaction of 6-perdeoxy-6-per-chloro gamma cyclodextrin with 3-mercapto propionic acid in presence of alkali metal hydrides and an organic solvent to give Sugammadex sodium.

Preparation of choro gamma cyclodextrin intermediate using phosphorous pentachloride is associated with formation of phosphorous impurities during reaction, which are difficult to remove, and it also involves tedious workup procedure.

W02014125501 disclose preparation of Sugammadex sodium which involves reaction of 6- perdeoxy-6-per-ha!o-gamma-cyc!odextrin with 3-mercapto propionic acid in presence of alkali metal alkoxide such as sodium methoxide and organic solvent, however, drawback of this reaction is that it needs anhydrous conditions for completion of reaction.

Prior art methods of preparation of pure Sugammadex involves purification techniques employ column chromatographic and membrane dialysis which are costly and not convenient in large scale operations. Therefore, reported processes for preparation of Sugammadex sodium as discussed herein are time consuming and not economically and industrially viable.

Few of methods for chlorination are known in art which involve chlorination of corresponding hydroxyl compound by use of Vilsmeier-Haack reagent derived in-situ from various chlorinating agents such as phosphorus oxychloride, oxalyl chloride, phosphorus pentachloride etc, and a tertiary amide such as dimethyl formamide (DMF). However, they generate a large quantity of by-products, which are cumbersome to remove and dispose of.

Thus, there exist a need to provide a process of preparation of Sugammadex sodium which is simple, convenient, with easy work up procedure, economically efficient and one which provides Sugammadex sodium in good yield and high purity.

This invention describes a novel halogenations method for conversion of cyclodextrin to corresponding halo cyclodextrin and its further conversion to Sugammadex or its sodium salt thereof.

Summary of invention

Main object of invention is to provide an improved process for preparation of Sugammadex sodium.

Another object of invention is to provide improved method for carrying out preparation of 6- perdeoxy-6-per-halo gamma cyclodextrin from cyclodextrin by involving chlorinating agent, Vilsmeier reagent, whereby this intermediate is obtained in better purity and yield than has previously been possible. This intermediate further converted to Sugammadex and its salts thereof.

Another embodiment of invention is to provide improved method for carrying out preparation of 6-perdeoxy-6-per-bromo gamma cyclodextrin from its corresponding cyclodextrin by involving brominating agent and further conversion of obtained intermediate to Sugammadex or its alkali metal salts thereof.

Main aspect of invention is to provide an improved process for preparation of 6-perdeoxy-6- per-halo gamma cyclodextrin from cyclodextrin by using a chlorinating reagent of Vilsmeier type as a solid form derived from acid chlorides and conversion of 6-perdeoxy-6-per-halo gamma cyclodextrin to Sugammadex or its salts thereof.

Another aspect of invention describes a novel process for preparation of a halogenating reagent Vilsmeier type from various acid chlorides, acid bromides or acid iodides and a new method for halogenating, for example chlorination of corresponding hydroxyl compounds.

One more aspect of invention provides novel method for preparation of 6rperdeoxy-6-per- bromo gamma cyclodextrin from its corresponding gamma cyclodextrin by using brominating agent selected from group comprising bromine, N-bromosuccinamide (NBS), carbon tetrabromide, trimethylphenyl ammonium tribromide, bromotrichloromethane, N- bromoacetamide, N-bromosaccharin, N-Bromo phthalimide, boron tribromide and phosphorus tribromide.

Description of Drawings

Sheet 1: Chloro compound Sheet: 1/2

Sheet 2: Sugammadex Sodium Sheet:l/1

Detailed Description of Invention

In one embodiment of invention, Vilsmeier reagent is formed from acid chlorides in reaction with DMF optionally in presence of an adsorbent. For example, N,N-dimethyl formiminium chloride chlorosu!phite or N,N-dimethyl formiminium chloride chlorosulphate adducts formed respectively from thionyl chloride and sulphuryl chloride in reaction with dimethylformamide in presence of an adsorbent. Similarly, other Vilsmeier reagents are formed from other acid chlorides such as oxalyl chloride, phosphorus pentoxide, phosphorus oxychloride, phosgene etc.

Another embodiment of invention, Vilsmeier reagent is prepared from acid chlorides in reaction with DMF wherein process comprising, a) addition of acid chloride to mixture of dimethylformamide and an organic solvent under stirring at -25 to 0°C for about 20-40minutes;

b) stirring reaction mass of step, a) at - 10 to 0°C for about 25 to 45 minutes, and c) distilling off solvent from reaction mass of step b) under reduced pressure to get Vilsmeier reagent as solid compound.

Acid chloride of step a) is selected from oxalyl chloride, phosphorus oxychloride, phosgene, phosphorus pentachloride, sulphuryl chloride or thionyl chloride thereof. Organic solvent a) is selected from dichloromethane, dichloroethane, carbon tetrachloride, dimethylformamide and dimethysulphoxide.

Preferably, organic solvent of step a) is selected from group comprising amides, ethers, ketones, acetonitrile water or their combination. More preferably, solvent selected from amide solvents comprising dichloromethane, dimethyl acetamide, dimethyl formamide and dimethyl sulfoxide.

In a preferred embodiment (Chloromethylene) dimethyliminium chloride formed from oxalyl chloride solidifies easily at room temperature and can be separated and hence can be used as a separated and effective chlorinating reagent in chlorination reaction.

In another embodiment (Chloromethylene) dimethyliminium chloride formed from oxalyl chloride as formed in in-situ can be used for further reaction without separating out.

Reagent formed from acid chlorides is stable at room temperature, can be isolated as a solid and can be used for chlorinating various compounds Sugar derivatives, cyclodextrins etc.

Above explained process can be depicted by following synthetic scheme.

VH reagent

This invention describes an improved process for preparation of chlorinating reagent of Vilsmeier type as a solid form and its use in process for preparation for chlorinating gamma cyclodextrin to produce 6— perdeoxy-6-per-chloro gamma-cyclodextrin.

In yet another embodiment of this invention, Preparation of 6-perdeoxy-6-per-chloro gamma- cyclodextrin from cyclodextrin comprising, a) adding a solution of gamma cyclodextrin in an organic solvent to solution of Vilsmeier- Haack reagent at about 0-5°C under stirring for about 15-35 minutes;

b) stirring reaction mixture of step, a) at about 55-85°C for about 10-16 hours;

c) cooling reaction mass of step b) to 0-5°C and adding water to reaction mass followed by adjusting pH of reaction mass to 8 with aqueous basic solution at about 0- 15°C; d) stirring reaction solution of step c) at 0-20°C for about 30 minutes to 3 hours for solid separation, filtering separated solid and washing with water;

e) slurring obtained solid of step d) in an alcohol solvent for about 20 minutes, filtering solid and washing with alcohol and ether solvent, and

f) drying obtained solid of step e) at about 35 to 55°C under reduced pressure.

Organic solvent of step a) above is selected from group of amide solvents comprising dichloromethane, dimethyl acetamide, formamide and dimethyl sulfoxide.

Vilsmeier-Haack reagent of step a) above is preferably (Chloromethylene) dimethyliminium chloride.

Basic solution of above step c) comprising aqueous sodium hydroxide, aqueous potassium hydroxide and aqueous sodium bicarbonate solution.

Alcohol solvent of step e) comprising methanol, ethanol, propanol, isopropanol, butanol and tertiary butanol.

Above explained process can be depicted by following synthetic scheme.

In another embodiment present invention reaction can be proceeded for further step without isolation of 6-perdeoxy-6-per-chloro gamma-cyclodextrin to prepare Sugammadex acid. In yet another embodiment of this invention, this provides a process for preparation of Sugammadex acid from 6-perdeoxy-6-per-chloro gamma-cyclodextrin by conventional methods.

In another embodiment present invention provides a process for preparation of Sugammadex acid by reacting 6-perdeoxy-6-per-halo gamma cyclodextrin with mercapto propionic acid in presence of a base in a suitable solvent, process comprising of, a) addition of a solution of 3- mercapto propionic acid in an organic solvent to a solution of a base at 0-5°C under stirring for about 15-30 minutes;

b) stirring reaction mass of step, a) for about 45 to 90 minutes at about 0-5°C;

c) adding a solution of 6-perdeoxy-6-per-chloro gamma-cyclodextrin in an organic solvent to reaction mass of step b) for about 45 minutes;

d) stirring reaction mixture of step c) at about 90 to 120°C for about 10 to 15 hours; e) adding an alcohol solvent to reaction mass of step d) for about 30- 50 minutes and stirring reaction mass for about 45 to 90 minutes at about 40 to 65°C for separation of solid from reaction mass;

f) filtering separated solid of step e) and washing with alcohol solvent of step e) and drying solid at 40-60°C for about 1 hour;

g) dissolving solid of step f) in water and adjusting pH of solution to 2 with hydrochloric acid for separation of solid, and

h) filtering separated solid of step g) and drying solid at about 40-60°C for about 10-15 hours under reduced pressure to get Sugammadex acid solid.

Organic solvent of step a) above is selected from group of amide solvents comprising dichloromethane, dimethyl acetamide and formamide and dimethyl sulfoxide.

Base of step a) above is selected from group of inorganic bases selected from alkali or alkaline earth metal alkoxides, alkali or alkaline earth metal hydroxides, alkali or alkaline earth metal carbonates and alkali or alkaline earth metal bicarbonates. Specifically, base comprises sodium hydroxide, potassium hydroxide or lithium hydroxide their hydrates and mixtures thereof.

Organic solvent of step c) above is selected from group of amide solvents comprising dichloromethane, dimethyl acetamide and formamide and dimethyl sulfoxide.

Alcohol solvent of step e) comprising methanol, ethanol, propanol, isopropanol, butanol and tertiary butanol. In a preferred embodiment of present invention reaction between 6-perdeoxy-6-per-halo gamma cyclodextrin with mercapto propionic acid is performed at a temperature range between 50 -130°C for about 4 to 10 hours.

Above explained process can be depicted by following synthetic scheme.

In a preferred embodiment of present invention, Sugammadex acid as obtained by present invention may further purify by known conventional methods.

In yet another embodiment present invention provides a process for preparation of Sugammadex salt from corresponding Sugammadex acid in presence of a suitable base in a suitable solvent. .

In another embodiment of present invention, Sugammadex acid is reacted with a base in presence of a suitable solvent to give corresponding salt of Sugammadex. Process comprising of, a) add solution of a base in an organic solvent to Sugammadex acid in anorganic solvent for about 10 to 45 minutes at about 10-40°C;

b) stir reaction mixture of step a) for about 30 to 90 minutes at about 10-40°C;

c) filter separated solid of step b) and washing with an alcohol solvent; d) dissolving obtained solid of step c) in water and an alcohol solvent and adding activated carbon and stir for 20-45 minutes, filtering and washing with alcohol solvent;

e) stir filtrate as obtained by step d) at 35-70°C for about 10-20 minutes;

f) add alcohol solvent to reaction solution of step e) at 35-70°C for about 10-40 minutes for separation of solid;

g) cool reaction mass of step f) to 0 to 15°C and stir for about 45 to 90 minutes;

h) filter solid of step g) and washing with an alcohol solvent, and

i) dry obtained solid of step h) at 30-65°C under reduced pressure.

Base of step a) is selected from alkali or alkaline earth metal alkoxides, metal hydroxides, metal carbonates, metal bicarbonates or metal hydrides.

Solution of a base of step a) is a base in an alcoholic solvent and water.

Organic solvent of step a) above is selected from group of amide solvents comprising dichloromethane, dimethyl acetamide formamide and dimethyl sulfoxide.

Alcoholic solvent of steps a), c), d), f) and h) above is selected from methanol, propanol, isopropanol or tertiary butanol, preferably methanol.

Sugammadex salt is metal salt selected from sodium, potassium or Lithium, preferable sodium salt.

Above explained process can be depicted by the following synthetic scheme.

In an additional embodiment of the present invention, preparation of 6-perdeoxy-6-per-bromo gamma-cyclodextrin from cyclodextrin comprising, a) addition of triphenyl phosphate to an organic solvent and stir he contents for about 20 minutes;

b) cool reaction solution of step, a) to 0- 10°C and add brominating agent slowly for about 10 to 30 minutes at 0-10°C and stir reaction mass for about 25 to 90 minutes;

c) add gamma cyclodextrin solution to reaction mass of step b) at 0-5°C slowly for the about 1 -4 hours and stir for about 10-30 minutes;

d) heat reaction mass of step c) to 55 to 85°C and stir for about 3-5 hours;

e) distill off reaction mass of step d) to 10-16 volumes and cool reaction mass to 20-35°C; f) adjust reaction mass pH to 8.5 to 9.0 by adding aqueous solution of a weak base for about 10 to 20 minutes;

g) stir reaction mass of step f) for about I -3 hours at 20-35°C;

h) add alcohol solvent to reaction mass of step g) for about 2-5 hours and stir contents for about 3-60 mmutes;0- i) add water to reaction mass of step h) and stir contents for about 3-60 minutes;

j) filter separated solid of step i) and wash solid with alcohol solvent;

k) mix obtained solid of step k) with an organic solvent under stir;

l) add alcoholic solvent to reaction mass of step k) for about 2-5 hours at about 20-35°C; m) heat reaction mass of step I) to 40-60°C and add water for about 10-20 minutes and stir contents for about 3-6 hours at 40-60°C;

n) filter solid as separated out at step m) and wash solid with an alcoholic solvent, and o) repeat steps k) to n) to get solid compound of 6-perdeoxy-6-per-bromo gamma- cyclodextrin.

Brominating agent of step b) is selected from group comprising, bromine, N- bromosuccinamide (NBS), carbon tetrabromide, trimethylphenylammonium tribromide, bromotrichloromethane, N-bromoacetamide, N-bromosaccharin, N-Bromo phthalimide, boron tribromide and phosphorus tribromide. Gamma cyclodextrin solution of step c) is gamma cyclodextrin in an organic solvent of above step a);

Aqueous solution of a weak base of step f) is selected from group of alkali metal carbonates and alkaline earth metal carbonates comprising aqueous lithium carbonate, aqueous cesium carbonate, aqueous sodium bicarbonate, aqueous sodium carbonate, aqueous potassium carbonate and aqueous potassium bicarbonate.

Alcoholic solvent of steps h), j), 1), and n) above is selected from methanol, propanol, isopropanol, butanol and tertiary butanol, preferably isopropanol.

Above explained process can be depicted by following synthetic scheme.

In other embodiment present invention process of purifying the 6-perdeoxy-6-per-bromo gamma-cyclodextrin by conventional methods.

In yet other embodiment present invention provides crystalline 6-perdeoxy-6-per-bromo gamma-cyclodextrin.

In another embodiment present invention reaction can be proceeded for further step without isolation of 6-perdeoxy-6-per-bromo gamma-cyclodextrin to prepare Sugammadex acid.

In yet another embodiment of present invention, preparation of Sugammadex acid by reacting 6-perdeoxy-6-per-bromo gamma cyclodextrin with mercapto propionic acid in presence of a base in a suitable solvent, process comprising, a) add base to solution of 3- mercapto propionic acid in an organic solvent for about 2 hours at I5-35°C;

b) stir reaction mass of step a) for about 35 to 90 minutes at about 15-35°C;

c) add solution of 6-perdeoxy-6-per-bromo gamma-cyclodextrin in an organic solvent to reaction mass of step b) for about 40-85 minutes and stir contents for about 10-30 minutes;

d) stir reaction mixture of step c) at about 90 to 120°C for about 3-6 hours;

e) add ether solvent to reaction mass of step d) for about 20-35 minutes at about 15-35°C and stir reaction mass for about 2-5 hours for separation of solid from reaction mass; f) filter separated solid of step e) and washing with alcohol solvent;

g) dissolve obtained solid of step f) in water and adjust pH to 2 with an acid at about 20- 35°C for separation of solid;

h) stir reaction mass of step g) for about 45 to 90 minutes;

i) filter separated solid of step h) and suck dry material

j) dry obtained solid of step i) at 40-65°C for about 1-5 hours;

k) solid slurry from step j) in ester solvent for about 20-40 minutes;

L) filter solid of step k) by conventional methods;

m) solid slurry of step 1) in ketone solvent for about 20-40 minutes;

n) filter solid of step m) and suck dry material, and

o) dry obtained solid of step n) at 40-65°C for about 5 to 12 hours under reduced pressure to get Sugammadex acid.

Organic solvent of step a) above is selected from group of amide solvents comprising dichloromethane, dimethyl acetamide, and formamide and dimethyl sulfoxide.

Base of step a) & c) above is selected from group of inorganic bases selected from alkali or alkaline earth metal alkoxides, alkali or alkaline earth metal hydroxides, alkali or alkaline earth metal carbonates and alkali or alkaline earth metal bicarbonates. Specifically, base comprises sodium hydroxide, potassium hydroxide or lithium hydroxide their hydrates and mixtures thereof.

Ether solvent of step e) is selected from diisopropyl ether, methyl tent-butyl ether, dioxane, tetrahydrofuran and like. Alcohol solvent of step f) is selected from group comprising methanol, ethanol, propanol, isopropanol, butanol and tertiary butanol. Preferably, alcohol solvent is methanol.

Acid of step g) is selected such as aqueous sulfuric acid, hydrochloric acid or hydrobromic acid.

Ester solvent of step k) above is selected such as C 1-5 esters comprising ethyl acetate, methyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate and isobutyl acetate. Preferably ester solvent is ethyl acetate.

Ketone solvent of step m) above is selected such as acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone, 2-pentanone, 3-pentanone, cyclopentanone or cyclohexanone. Preferably, ketone is acetone.

Above explained process can be depicted by following synthetic scheme:

In yet another embodiment present invention provides a process for preparation of Sugammadex salt from corresponding Sugammadex acid as prepared by above process in presence of a suitable base in a suitable solvent.

Process for preparation of Sugammadex sodium salt from corresponding Sugammadex acid obtained from bromo compound, 6-perdeoxy-6-per-bromo gamma-cyclodextrin of presentinvention, process comprising of following steps, a) dissolve Sugammadex acid as obtained by above processes of present invention in an organic solvent; b) add solution of a base in an alcohol solvent to reaction solution of step a) under continuous stirring at pH of reaction solution maintaining between 8 and 9;

c) add alcohol solvent to reaction solution of step b) for about 25 to 45 minutes at 25 to 35°C;

d) stir reaction mass of step c) for about 45 minutes to 2 hours at 25 to 35°C;

e) filter solid as separated at step d) washing with an alcohol solvent;

f) dissolve obtained solid of step e) in a mixture of water and alcohol solvent, treat solution with activated carbon, filtering reaction solution and washing with water; g) heat filtrate of step f) to 45 to 60°C and stir for 20-40 minutes;

h) add alcohol solvent to reaction solution of step g) and stir for about 2 hours at 25 to 35°C;

i) filter solid as separated at step h) washing with an alcohol solvent, and

j) dry obtained solid of step i) at 45 to 65°C under reduced pressure for about 18-26 hours to get Sugammadex salt.

Base of.step b) is selected from group of alkali metal alkoxide or alkaline earth metal alkoxide, metal hydroxides, metal carbonate or metal bicarbonates and as like.

Preferably, base of step b) is an alkoxide, wherein alkoxide is comprising potassium isopropoxide, sodium tertiary butoxide, sodium methoxide, potassium methoxide, potassium butoxide, sodium butoxide, potassium tertiary amylate, sodium tertiary butylate and sodium tertiary amylate. Preferable alkoxide is sodium methoxide.

Alcohol solvent of steps b), c), e), f), h) and i) is selected from group comprising methanol, ethanol, propanol, isopropanol, butanol and tertiary butanol. Preferable, alcohol solvent is methanol.

Above explained process can be depicted by following synthetic scheme.

Examples described below serve as illustration on how to practice invention and do not limit scope of actual techniques used or scope of or range of reaction conditions or process conditions claimed

Example: 1

Preparation of (Chloromethylene) dimethyliminium chloride [VH reagent]

VH reagent

Ensured 10.0 L four-necked round bottom flask is clean and dry charged dichloromethane (5.0L) and dimethyl formamide (400mLor 541 mL) in to round bottom flask under nitrogen atmosphere. Cooled reaction mass to -10 to-0°C under continuous stirring for 15 to 20 minutes and added oxalyl chloride (300mLor 600 mL) slowly at- 15 to -0°C for 30-35 minutes. Stirred the reaction mass for another 30-35 min at - 15 to -0°C. The reaction mass temperature was raised to 20-35°C and distilled the solvent under reduced pressure, VH reagent (Chloromethylene) dimethyliminium chloride (600g or 735.0 g) was obtained as pale-yellow solid.

Ή NMR (500 MHz, CDCb): 5 3.93(s, 6H,), 10.89 (s, 1H). Example-2

Preparation of 6-perdeoxy-6-per-chloro gamma-cyclodextrin

Ensured the 10L four-necked round bottom flask ts clean and dry, charged (Chloromethylene) dimethyliminium chloride [VH reagent] (600g or 71 Og) and dimethyl formamtde (2500 mL or 3000m L) in to round bottom flask, cooled reaction mass to 0-15°C. Reaction mass stirred for 15-20 min. A solution of dry gamma-cyclodextrin (300 g) in dimethyl formamide (1 500 mL) was added to above reaction mass at 0-5 °C for 20-30 min. Reaction mass temperature was raised to 60-75 °C, stirred reaction mass for 12-16 hrs. After completion of the reaction, the reaction mass was cooled to 0-15°C, then chilled water was added slowly (3000 mL) for 20 to 30 min. Reaction mass pH was adjusted to 7-8 with NaOH solution at 0-5°C and stirred for 2-4 hrs at 20-25°C. The separated solid was filtered and the obtained solid was suspended in water (1200mL-l 500 mL) stirred for 1 -2hrs, then filtered and washed with water (1800 mL) and dried for^-S hrs under vacuum at 45-60 °C. Solid material is suspended in methanol (1500 mL), stirred for 30-35 min, filtered and washed with methanol (2 x 600 mL) and diisopropyl ether (2 x 600 mL). Obtained solid was dried at 45- 60°C in a vacuum oven for 24 h to obtain titled compound (300.6 g).

Purity: 95%, melting point: 226-228°C.

Mass:Tn/z(M+Na): 1467.12;IR: 3300 cm ¹.

*H NMR (500 MHz, DMSO-d₆): d 5.98-5.97(d, 8H,), 5.94-5.93(m, 8 H), 4.99-4.98 (m, 8 H), 4.03-4.01 (d, J = 10 Hz, 8 H), 3.85-3.81 (m, 16H), 3.62 - 3.58 (m, 8 H), 3.41- 3.38 (m, 16 H) ppm. Example-3

Preparation of Sugammadex acid

Ί(

0 0

Ensured the 10 L four-necked round bottom flask is clean and dry, charged Lithium hydroxide monohydride (250g-290.5 g) and dimethyl formamide ( 1200mL-1600 mL) in to round bottom flask, stirred for 15 min. Reaction mass was cooled to 0-15°C, a solution of 3- Mercapto propionic acid (293.98 g) in dimethyl formamide (600-800 mL) is added to reaction mass for 1-2 h at 0-5°C. Stirred the contents for 1 hour at 0-5°C then a solution of 6-deoxy- 6-chloro gamma cyclodextrin (200 g, 138.50mmol) in DMF (800 mL) was added to the reaction mixture for 30-40 minutes. Then reaction mass temperature was raised to 100-120°C and stirred for 6-8 hours, after completion of the reaction, the temperature was cooled to 50- 65°C, then methanol (2.0 L) was added to reaction mixture for30-45 min. Stirred for 1 hour at 50-65°C, precipitated solid was filtered under vacuum and washed with methanol (2x1.0 L). Crude solid was dissolved in water (4.0L) with continuous stirring for 30 min, the solution pH was adjusted to 2 with concentrated hydrochloric acid to afford solid precipitate, stir for 1 hour at room temperature. Obtained solid was filtered and dried under vacuum at 55-60°C for 2 hours, then the dried solid was suspended in ethyl acetate (1.2 L), stirred for 20-30 minutes and filtered the solid. Obtained solid was dried in vacuum oven at 50-55°C for 10- 12 hours to give (141.4 g) of Sugammadex acid.

HPLC Purity: 98.39 %. lR(KBr): 3396.70, 1708.96. Mass: m/z: 2001.4. Ή NMR (500 MHz, DMSO-de): d 12.2 (br. s, 8H) 5.94 (s, 16H), 4.91 (s, 8H), 3.82-3.73 (m, 8H), 3.63-3.54 (m, 8H), 3.43-3.32 (m, 16H), 3.08-3.02 (m, 8H), 2.89-2.81 (m, 8H), 2.78- 2.72 (m, 16H), 2.55-2.43 (m, 16H) ppm; ¹³C NMR (125 MHz, DMSO-de): d 173.48, 102.51, 84.44, 72.94, 72.82, 71.88, 34.97, 33.57, 28.35 ppm.

Example-4

Preparation of Sugammadex Sodium

Ensured 250mL four-necked round bottom flask is clean, dry, charged Sugammadex acid compound (5.0 g) in to round bottom flask then slowly dropwise added NaHCCb solution (23 mL) and Methanol (120-150 mL) was added slowly dropwise at room temperature for 20- 30 min and reaction mass was stirred for 1-2 h. Precipitated solid was filtered and washed with methanol (2x 15 mL) to obtain 4.5 g of Sugammadex sodium salt. Obtained salt was dissolved in 14 mL water and methanol (14 mL) add activated carbon 20% (1.35 g) stirred for 30-35 min at room temperature. The reaction mass was filtered through Celite bed and washed with water (5 mL). The filtrate was taken into RB flask, reaction mass temperature is raised to 55- 60°C and methanol was added slowly dropwise (130 mL), solid precipitated can be observed. ✓Slowly cooled to room temperature stirred for 2h, then filtered and washed with methanol (30 mL) to obtain white solid which was further dried in vacuum oven for 22-24 hours at 55- 60°C to give Sugammadex sodium (2.75 g)

Mass: m/z (. M+Na)\ 2023.4.

Ή NMR (500 MHz, D₂0): d 5.22-5.21 (m, 8H), 4.07-4.04 (m, 8H), 3.98-3.94 (m, 8H), 3.67- 3.62 (m, 16H), 3.20-3.17 (m, 8H), 3.02-2.98 (m, 8H), 2.92-2.86 (m, 16H), 2.59-2.56 (m, 16H) ppm. l³C NMR (125 MHz, D₂0): 5179.50, 100.67, 82.35, 72.65, 72.15, 71.16, 37.15, 33.32, 28.97 ppm.

Example-5

Preparation of Sugam adex Sodium

Ensured 250mL four-necked RB flask is dean, dty, charged Sugammadex acid (5.0 g) and DMF ( 1 mL) in to RJB flask then a solution of aOMe (1.348 g) in methanol (4.1 mL) as slowly added by dropwise addition and maintained the reaction mass pH at 8.0-9.0. Methanol (130 mL) was slowly added to the reaction mass at room temperature for 30 min and reaction mixture was stirred for 1 hour. Precipitated solid was filtered, washed with methanol (2x15 mL) to obtain 4.4 g of Sugammadex sodium salt. Obtained salt was dissolved in 14 mL of water and methanol (14 mL) and activated carbon 30%( 1.32g) was added and stirred for 30 min room temperature then filtered through Celite washed with water (5 L). The filtrate was taken into RB flask, temperature was raised to 45-60°C.To reaction mass methanol (130 L) was added, stirred for 2h at room temperature, filtered and washed with methanol (2x15 L) to obtain white solid which is further dried in vacuum oven for 22-24 hour at 55-60°C to give Sugammadex sodium (2.9 g).

Mass: m/z (M+Na) 2023.4. lH NMR (500 MHz, D₂0): 5 5.22-5.21 (m, 8H), 4.10-4.06 (m, 8H), 3.99-3.95 (m, 8H), 3.70- 3.64 (m, 16H), 3.16-3.13 (m, 8H), 3.04-2.99 (m, 8H), 2.89-2.86 (m, 16H), 2.56-2.46 (m, 16H) ppm. ^,3C NMR (125 MHz, D₂0): d180.64, 100.81, 82.1 1 , 72.56, 72.20, 71.14, 37.67, 33.31, 29.51 ppm.

Example-6

Preparation of Sugammadex Sodium

Ensured 250 mL four-necked round bottom flask is clean, dry, charged NaH (1.0 g) in to round bottom flask then slowly added a solution of Sugammadex acid compound (5.0 g) in DMF (15 L) and reaction mass pH was maintained at 7.0-9.0. Reaction mass is cooled to 0-15°C, methanol (13.0 mL) was added at 0-15°C, stirred for 1 hour. Precipitated solid was filtered and washed with methanol (2x15 mL) to give 4.6 g Sugammadex sodium salt. Obtained white solid was dissolved in 14 L water and methanol(14 mL),activated carbon 30%(1.38g) was added and stirred for 30 min then filtered, washed with water(5 mL), the filtrate was taken into RB flask, raised temperature to 45-60°C then methanol (135 L) was added, solid was precipitated, stirred for 2h at room temperature, filtered and washed with methanol(40mL) to obtain white solid which was further dried in vacuum oven for 22-24 hour at 55-60°C to give Sugammadex sodium (3.0 g).

Mass: mh (M+Na): 2023.4.

Ή NMR (500 MHz, D₂0): d 5.22-5.21 (m, 8H), 4.10-4.07 (m, 8H), 3.99-3.95 (m, 8H), 3.70- 3.64 (m, 16H), 3.16-3.13 (m, 8H), 3.04-2.99 (m, 8H), 2.89-2.86 (m, 16H), 2.56-2.46 (m,

16H) ppm.

^,3C NMR (125 MHz, D₂0): d180.64, 100.81, 82.12, 72.56, 72.20, 71.14, 37.68, 33.31, 29.51 ppm.

Example-7

Preparation of Sugammadex Sodium

Ensured 250 mL four-necked round bottom flask is clean and dry, charged Sugammadex acid (5.0 g) and dimethyl formamide (15 mL) in to round bottom flask then slowly a solution of NaOtBu (2.40 g) in methanol (7.5 mL) was added to reaction mixture, pH of the reaction mass was maintained at 7.0-9.0 Then methanol (130 m L) was slowly added for 30 min and reaction mixture was stirred for 1 hour. Precipitated solid was filtered and washed with methanol (30mL) to give 4.5 g of Sugammadex sodium salt. Obtained white solid was dissolved in 13 ml of water and methanol (13 mL) and activated carbon20% (1.35 g)was added, stirred for 30 min then filter and washed with water (5 mL), the filtrate was taken into RB flask, temperature raised to 55-60°C methanol(130 mL) was slowly added, stirred the contents for 2hours. Filtered the separated solid and washed with methanol (30 mL) to obtain white solid which was further dried in vacuum oven for 22-24 hours at 55-60°C to give Sugammadex sodium (2.85g).

Mass: m/z b4+Na): 2023.4.

Ή NMR (500 MHz, D₂0): d 5.21 -5.20 (m, 8H), 4.09-4.06 (m, 8H), 3.99-3.95 (m, 8H), 3.69- 3.64 (m, 16H), 3.16-3.13 (m, 8H), 3.03-2.99 (m, 8H), 2.89-2.86 (m, 16H), 2.56-2.46 (m, 16H) ppm.

^I3C NMR (125 MHz, D₂0): 5180.66, 100.96, 82.29, 72.58, 72.26, 71.16, 37.69, 33.29, 29.51 ppm.

Example-8

Preparation of Sugammadex Sodium

Ensured 250 mL four-necked round botom flask is clean, dry, Sugammadex acid (5.0 g) and dimethyl formamide (15 mL) were charged into round bottom flask, then slowly NaNH₂ (974 mg) in methanol (7 5 mL) was added to reaction mixture and pH was maintained at 7.0- 9.0. Then methanol (130 mL) was slowly added at room temperature for 30 min and stirred the reaction mass for 1 hour. The precipitated solid was filtered and washed with methanol (2x 15 mL) to give 4.0 g of Sugammadex sodium salt. Obtained salt was dissolved in 12 ml water and methanol (12 ml) added activated carbon (1.2 g, 30%W/W) stirred for 30 min then filtered and washed with water (4 mL). The filtrate was taken into RB flask, temperature was raised to 45-60°C then methanol was slowly added ( 120 mL) dropwise till separation of the solid, stirred for 2 hours at room temperature, filtered and washed with methanol (30mL) to obtain white solid which was further dried in vacuum oven for 22-24 hour at 55-60°C to give Sugammadex sodium (2.55 g, Yield: 47 %).

Mass: m/z b4+Na)\ 2023.4. Ή NMR (500 MHz, D₂0): d 5.22-5.21 (m, 8H), 4.09-4.05 (m, 8H), 3.99-3.95 (m, 8H), 3.70- 3.64 (m, 16H), 3.17-3.14 (m, 8H), 3.04-2.99 (m, 8H), 2.89-2.86 (m, 16H), 2.56-2.47 (m, 16H) ppm.

¹³C NMR (125 MHz, D₂0): 6180.54, 100.79, 82.1 1 , 72.55, 72.20, 71.16, 37.67, 33.40, 29.39 ppm.

Example-9

Preparation of Sugammadex Sodium

Ensured 250 mL four-necked round bottom flask is clean dry, Sugammadex acid (5.0 g) was added in to round bottom flask then slowly added a solution of Na₂C03 (2.1 g) solution (8.0mL) to reaction mass. Then methanol (125 mL) was added slowly for 30 min and stirred the reaction mass for 1 h. Precipitated solid was filtered and washed with methanol (30 mL) to obtain 4.8 g of Sugammadex sodium salt. Obtained salt was dissolved in 14 mL water and methanol (14 mL) then activated carbon 30%(1.44 g) was added and stirred for 30 min then filtered and washed with water(5 mL), the filtrate was taken into RB flask, stirred the reaction solution at 45-60°C then methanol (130 ml) was added and stirred for 2h at room temperature then filtered and washed with methanol (30 mL) to obtain white solid which was dried in vacuum oven for 22-24 hour at 55-60°C to give Sugammadex sodium (2.9 g).

Mass: m/z (M+Na)\ 2023.4.

Ή NMR (500 MHz, D₂0): 6 5.22-5.21 (m, 8H), 4.07-4.04 (m, 8H), 3:98-3.94 (m, 8H), 3.67- 3.62 (m, 16H), 3.20-3.17 (m, 8H), 3.02-2.98 (m, 8H), 2.92-2.86 (m, I 6H), 2.59-2.56 (m, 16H) ppm.

^{I 3}C NMR (125 MHz, D₂0): 6180.54, 100.79, 82.1 1 , 72.55, 72.20, 71.16, 37.67, 33.40, 29.39 ppm.

Example-10

Preparation of 6-perdeoxy-6-per-bromo- y-cyclodextrin

Ensured 5 Lfour-necked round botom flask is clean, dry, Gamma-cyclodextrin (100 g) and dimethyl formamide (1200-1500 mL) were charged in to round botom flask. Reaction mass heated to 80- 1 10°C and dimethyl formamide was distilled up to 50%(600-750mL). Reaction mass was allowed to temperature to 25-35°C. In another RBFIask, dimethyl formamide(1500mL) and Triphenyl phosphate(320-342.0g) were charged, stirred the reaction mass for 15-20 min. Reaction mass was cooled to 0- 15°C and N-Bromo succinimide was added into reaction mass. Stirred the reaction mass for 40-60min. Add Gamma cyclodextrin solution into reaction mass at 0-5°C for 2-3 hours, stirred the reaction mass at 60-80°C for 3-6 hours. Distilled the solvent of the reaction upto 12-18 volumes. The reaction mass pH was adjusted to 7.5-9.0 with 20-30% sodium carbonate solution. Stirred the reaction mass for 1 -2 hours, Isopropyl alcohol(3500mL) was added for 3-4 hours. Stirred the reaction mass 40-60 min and water (2500mL) was added into reaction mass for 40-60 min. Filtered the reaction mass and washed with Isopropyl alcohol(lOOmL) suck dry material and record the crude weight(X*). Charge Dimethyl formamide(X*8-10.0V) stir reaction mass 5-10 min and added Isopropyl alcohol (X*24-27.0V) for 3-4 hours at 25-35°C.Heat reaction mass 45- 55°C slowly added water(X*20-22.0V) stir reaction mass 4-5 hours filter reaction mass through Buchner funnel wash wet cake with Isopropyl alcohol (X* l .0V).Suck dry wet material and record weight(Y*). Charge dimethyl formamide(Y* 10.0V) stir reaction mass for 10-15 mins. Add Isopropyl alcohol (Y*23-27.0V). Heat reaction mass 45-55°C slowly add water(Y* 18-22.0 V) stir reaction mass 4-5 hours filter reaction mass through Buckner funnel wash wet cake with Isopropyl alcohol (Y* 1.0V). Suck dry wet material for 10-12 hours.

(65.0 g, yield 50 %) HPLC Purity: 94.6%. IR(KBr): 3367.7, 1669.4Mass: mh: 1800

Ή NMR (500 MHz, DMSO-d₆): 5 6.00(d, 8H,), 5.94-5.93(m, 8 H), 4.99-4.98 (m, 8 H), 4.03- 4.01 (d, J = 10 Hz, 8 H), 3.85-3.81 (m, 16H), 3.62 - 3.58 (m, 8 H), 3.41- 3.38 (m, ! 6 H) ppm. Exa ple-11

Preparation of Sugammadex Acid

Ensured 1.0 Liter four-necked round bottom flask is clean and dry, charged Dimethyl formamide (200-300mL) and 3-mercaptopropionic acid (30-35.3g) stirred the reaction mass for 5-10 min at 25-35°C. Lithium hydroxide monohydride (34.9g) was added for 1-2 hoprs at 25-35°C, stirred the reaction mass for 40-60 mins. Charged 6-perdeoxy-6-per-bromo gamma cyclodextrin(20g) solution into reaction mass for 40-60 min at 25-35°C, stirred the reaction mass for 10-15 min at same temperature. Then the reaction mass was stirred at 60- . 80°C for 4-5 hours. Allowed the reaction mass at 25-35°C. Charged Methanol(150.0mL) into reaction mass, stirred reaction mass for 3-4 hours and filtered and suck dry for 30-40 mins. Water was added and activated carbon into reaction mass stir reaction mass and filtered and washed with water, filtrate pH was adjusted with HCI. Stirred the reaction mass, filtered the solid and washed with water and suck dry reaction mass and added Ethyl acetate stirred the reaction mass filtered and suck dry the material. Acetone was charged to the above wet solid and stirred the reaction mass filtered through Celite bed washed with acetone and suck dry for 6-8 hours of Sugammadex acid.

HPLC Purity: 96.91%. IR(KBr): 3364.88, 1708.96. Mass: m/z 2001.25 Ή NMR (500 MHz, DMSO-d₆): 5 12.16 (br. s, 8H) 5.94 (s, 16H), 4.91 (s, 8H), 3.82-3.73 (m, 8H), 3.63-3.54 (m, 8H), 3.43-3.32 (m, 16H), 3.08-3.02 (m, 8H), 2.89-2.81 (m, 8H), 2.78-2.72 (m, 16H), 2.55-2.43 (m, 16H) ppm;^,3C NMR (125 MHz, DMSO-de): 8 173.48, 102.51 , 84.44, 72.94, 72.82, 71.88, 34.97, 33.57, 28.35 ppm.

Example-12

Preparation of Sugammadex Sodium

Ensured 250mL four-necked RB flask is clean, dry and equipped with a mechanical stirrer, argon inlet, dropping funnel and thermo socket, charged Sugammadex Acid (5.0 g) and dimethyl formamide (15 mL) in to RB flask stirred for 10 min clear solution observed then slowly dropwise added NaOMe (1.34g) in methanol (4, l mL) to reaction mass and maintained pH between 7.0-9.0, added methanol (130 mL) to reaction mass at room temperature for 30-40 min and reaction mixture was stirred for 1 hour. Precipitated solid was filtered, washed with methanol (30mL) to obtain 4.4 g of Sugammadex sodium salt. Obtained salt is dissolved in 14 mL of water, activated carbon (1.32g) was added and stirred for 30 min room temperature then filtered through celite bed, washed with water (5mL), the filtrate was taken into RB flask, warm to 40-45°C. and stirred the reaction solution for 30-40 mins and methanol (130 mL) was added and stirred for 2-3hr at room temperature, filtered and washed with methanol (30 mL) to obtain white solid which is further drjed in vacuum oven for 22-24 hours at 55-60°C to give Sugammadex sodium (2.17 g).

Purity: 97.90% measured by HPLC; Mass: m/z bί+Na) 2023.4. ^lH NMR (500 MHz, D₂0): 5 5.22-5.21 (m, 8H), 4.10-4.06 (m, 8H), 3.99-3.95 (m, 8H), 3.70- 3.64 (m, 16H), 3.16-3.13 (m, 8H), 3.04-2.99 (m, 8H), 2.89-2.86 (m, 16H), 2.56-2.46 (m, 16H) ppm.

¹³C NMR (125 MHz, D₂0): 8180.64, 100.81, 82.1 1, 72.56, 72.20, 71.14, 37.67, 33.31 , 29.51 ppm. Example-13

Preparation of Sugammadex Sodium

Ensured 250mL four-necked RB flask is clean dry and, charged Sugammadex Acid compound (5.0 g) and dimethyl formamide (50 mL) in to RB flask stirred for 10 min clear solution observed then slowly dropwise added NaOEt (1.39 g,) in methanol (50mL) to reaction mass and maintained pH between 8.0-9.0, added methanol (50 mL) to reaction mass at room temperature for 30-40 min and reaction mixture was stirred for 1 hour. Precipitated solid was filtered, washed with methanol (25 mL) to obtain 4 g of Sugammadex sodium salt. Obtained salt is dissolved in 10 mL of water, activated carbon 20% (I .Og) was added and stirred for 30 min room temperature then filtered through celite bed, washed with water (2.5mL), the filtrate was taken into RB flask, warm to 40-45°C. and stirred the reaction solution for 30-40 mins and methanol (125 mL) was added and stirred for 2-3 hr at room temperature, filtered and washed with methanol 25 mL) to obtain white solid which is further dried in vacuum oven for 22-24 hours at 55-60°C to give Sugammadex sodium (2.2-2.5g, Yield: 50-60 %).

Purity: 98.7% measured by HPLC; Mass: m/z (M+Na): 2023.4.

Ή NMR (500 MHz, D₂): d 5.22-5.21 (m, 8H), 4.10-4.06 (m, 8H), 3.99-3.95 (m, 8H), 3.70- 3.64 (m, 16H), 3.16-3.13 (m, 8H), 3.04-2.99 (m, 8H), 2.89-2.86 (m, I 6H), 2.56-2.46 (m, 16H) ppm.

^I3C NMR (125 MHz, D₂0): 6180.64, 100.81, 82.1 1 , 72.56, 72.20, 71.14, 37.67, 33.31, 29.51 ppm.

Claims

We claim:

1 . A process for preparation of 6-perdeoxy-6-per-haio gamma cyclodextrin from gamma cyclodextrin by using a solid Vilsmeier-Haack reagent comprising of following steps, a) adding a solution of gamma cyclodextrin in an organic solvent to solution of Vilsmeier-Haack reagent at about 0-5°C under continuous stirring for about 15-35 minutes;

b) stirring the reaction mixture of step, a) at about 55-85°C for about 10- 16 hours; c) cooling reaction mass of step b) to 0-5°C and addition of water to reaction mass followed by adjusting pH of reaction mass to 8 with aqueous basic solution at about 0-15°C;

d) stirring the reaction solution of step c) at 0-20°C for about 30 minutes to 3 hours for solid separation, filtering the separated solid and washing with water; e) addition of an alcohol solvent to the obtained solid of step d) stirring, filtering the solid and washing with alcohol and ether solvent, and

f) drying the obtained solid of step e) at about 35 to 55°C under reduced pressure.

2.· A Process according to claim 1, wherein organic solvent of step a) is selected from group of amide solvents comprising dichloromethane, dimethyl acetamide, formamide and dimethyl sulfoxide.

3. A Process according to claim 1, wherein Vilsmeier-Haack reagent of step a) is (Chloromethylene) dimethyliminium chloride.

4. A Process according to claim 3, wherein (Chloromethylene) dimethyliminium chloride is used as a solid compound

5. A Process according to claim 1, wherein basic solution of step c) is selected from aqueous sodium hydroxide, aqueous potassium hydroxide and aqueous sodium bicarbonate solution.

6. A Process according to claim I, wherein alcohol solvent of step e) is selected from methanol, ethanol, propanol, isopropano!, butanol and tertiary butanol.

7. A process for preparation of Sugammadex acid by reacting 6-perdeoxy-6-per-halo gamma cyclodextrin with mercapto propionic acid comprising steps of, a) addition of a solution of 3-mercapto propionic acid in an organic solvent to a solution of a base at 0-5°C under continuous stirring for about 15-30 minutes; b) stirring the reaction mass of step a) for about 45 to 90 minutes at about 0-5°C; c) addition of a solution of 6-perdeoxy-6-per-chloro gamma-cyclodextrin in an organic solvent to reaction mass of step b) for about 45 minutes;

d) stirring the reaction mixture of step c) at about 90 to 120°C for about 10 to 15 hours; e) addition of an alcohol solvent to reaction mass of step d) for about 30- 50 minutes and stirring for about 45 to 90 minutes at about 40 to 65°C for separation of solid from reaction mass;

f) filtering the separated solid of step e) and washing with alcohol solvent of step e) and drying at 40-60°C for about 1 hour;

g) dissolving the solid of step f) in water and adjusting pH of solution to 2 with hydrochloric acid for separation of solid, and

h) filtering the separated solid of step g) and drying the solid at about 40-60°C for about 10-15 hours under reduced pressure to get Sugammadex acid solid.

B. The process according to claim 7, wherein organic solvent of step a) is selected from amide solvents comprising, dimethyl acetamide, formamide and dimethyl sulfoxide.

9. The process according to claim 7, wherein base of step a) is selected from group of inorganic bases comprising alkali or alkaline earth metal alkoxides, alkali or alkaline earth metal hydroxides, alkali or alkaline earth metal carbonates and alkali or alkaline earth metal bicarbonates.

10. The process according to claim 9, wherein base is selected from sodium hydroxide, potassium hydroxide or lithium hydroxide, their hydrates and mixtures thereof.

1 1. The process according to claim 7, wherein organic solvent of step c) is selected from amide solvents comprising, dimethyl acetamide, formamide and dimethyl sulfoxide.

12. The process according to claim 7, wherein alcohol solvent of step e) is selected from methanol, ethanol, propanol, isopropanol, butanol and tertiary butanol.

13. The process according to claim 1 , wherein 6-perdeoxy-6-per-halo gamma cyclodextrin without its isolation can be used directly for further step of preparation of Sugammadex acid or Sugammadex salt.

14. A process for preparation of 6-perdeoxy-6-per-bromo gamma-cyclodextrin from gamma cyclodextrin comprising step of, a) addition of triphenyl phosphate to an organic solvent and stirring the contents for about 20 minutes;

b) cooling the reaction solution of step a) to 0-10°C and adding brominating agent slowly for about 10 to 30 minutes at 0-10°C and stirring the reaction mass for about 25 to 90 minutes;

c) adding gamma cyclodextrin solution to reaction mass of step b) at 0-5°C slowly for about 1-4 hours and stirring for about 10-30 minutes;

d) heating the reaction mass of step c) to 55 to 85°C and stirring for about 3-5 hours; e) distilling off the solvent from the reaction mass of step d) to 10-16 volumes and cooling the reaction mass to 20-35°C;

f) adjusting the reaction mass pH to 8.5 to 9.0 by addition of aqueous solution of a weak base for about 10 to 20 minutes;

g) stirring the reaction mass of step f) for about 1-3 hours at 20-35°C;

h) adding an alcohol solvent to the reaction mass of step g) for about 2-5_*hours and stirring the contents for about 3-60 minutes;

i) addition of water to reaction mass of step h) and stirring the contents for about 3- 60 minutes;

j) filtering the separated solid of step i) and washing the solid with alcohol solvent; k) mixing the obtained solid of step k) with an organic solvent under continuous stirring;

L) adding an alcoholic solvent to reaction mass of step k) for about 2-5 hours at about 20-35°C;

m) heating the reaction mass of step I) to 40-60°C and adding water for about 10-20 minutes and stirring the contents for about 3-6 hours at 40-60°C; n) filtering the solid as separated out at step m) and washing the solid with alcoholic solvent, and

o) repeating the steps k) to n) to get solid compound of 6-perdeoxy-6-per-bromo gamma-cyclodextrin.

15. The process according to claim 14, wherein organic solvent of step a) is selected from amide solvents comprising, dimethyl acetamide, formamide and dimethyl sulfoxide.

16. The process according to claim 14, wherein brominating agent of step b) is selected from group comprising, bromine, N-bromosuccinamide (NBS), carbon tetrabromide, trimethylphenylammonium tribromide, bromotrichloromethane, N-bromoacetamide, N-bromosaccharin, N-bromophthalimide, borontribromide and phosphorus tribromide.

17. The process according to claim 14, wherein gamma cyclodextrin solution of step c) is gamma cyclodextrin in an organic solvent of above step a);

18. The process according to claim 14, wherein aqueous solution of a weak base of step f) is selected from group of alkali metal carbonates and alkaline earth metal carbonates comprising aqueous lithium carbonate, aqueous cesium carbonate, aqueous sodium bicarbonate, aqueous sodium carbonate, aqueous potassium carbonate and aqueous potassium bicarbonate.

19. The process according to claim 14, wherein alcoholic solvent of steps h), j), I), and n) above is selected from methanol, propanol, isopropanol, butanol and tertiary butanol.

20. The process for preparation of Sugammadex acid from 6-perdeoxy-6-per-bromo gamma cyclodextrin as obtained by process according to claim 14.

21. The process according to claim 14, wherein 6-perdeoxy-6-per-bromo gamma cyclodextrin as obtained can be used directly without its isolation for preparation of Sugammadex acid or its salts.

22. A process for preparation of Sugammadex sodium from Sugammadex acid by reacting with a base in an organic solvent.

23. The process according to claim 22, wherein base is selected from group comprising alkali metal alkoxide or alkaline earth metal alkoxide, metal hydroxides, metal carbonate or metal bicarbonates and as like.

24. The process according to claim 23, wherein base is selected from potassium isopropoxide, sodium tertiary butoxide, sodium methoxide, potassium methoxide, potassium butoxide, sodium butoxide, potassium tertiary amylate, sodium tertiary butylate and sodium tertiary amylate.

25. The process according to claim 24, wherein the base is sodium methoxide.

26. A crystalline form of 6-perdeoxy-6-per-bromo gamma-cyclodextrin, is characterized in that, the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of -5.40,6.25,6.37, 8.37, 10.90, 16.70, 19.20,20,20, 25.50±0.2°.

27. The Crystalline form according to claim 26, characterized in differential scanning calorimetry analysis curve of said crystalline form shows an endothermic peak