FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. TITLE OF THE INVENTION: - "Process for preparation of Sugammadex Sodium an
intermediates thereof "
2. APPLICANT
(a) NAME
(b) NATIONALITY
(c) ADDRESS : Omgene Life Sciences Pvt. Ltd
: Indian company
: 333-334, GIDC Makarpura, Vadodara-India. -390 010 Gujarat,
3. PREAMBLE TO THE DESCRIPTION
The following specification is to be performed. particularly describes the invention and the manner in which it

Process for preparation of Sugammadex sodium and intermediates thereof Field of the invention
The present invention relates to process for preparation of 6-perdeoxy-6-per-chloro gamma cyclodextrin which is a key intermediate useful in the synthesis of Sugammadex sodium. The present invention further relates to a process for preparation of Sugammadex sodium. Background of the invention
Sugammadex (Org 25969, Bridion) is chemically known as Cyclooctakis-(l->4)-[6-S-(2-carboxyethyl)-6-thio-a-D-glucopyranosyl]. Sugammadex is an agent for reversal of neuromuscular blockade by the neuromuscular blocking agents (NMBAs) rocuronium, vecuronium, pancuronium in general anaesthesia. It is the first selective relaxant binding agent (SRBA). SRBAs are a new class of drugs that selectively encapsulates and binds NMBAs.
The word Sugammadex is derived from Su= Sugar and Gammacyclodex = Cyclodextrin. Sugammadex is inert chemically and does not bind to any receptor. It acts by rapidly encapsulating steroidal NMBDs to form a stable complex at a 1:1 ratio and thus decreasing the free concentration of the drug from the plasma. This creates a concentration gradient favouring the movement of the remaining rocuronium molecules from the neuromuscular junction back into the plasma, where they are encapsulated by free Sugammadex molecules. The latter molecules also enter the tissues and form a complex with rocuronium. Therefore, the neuromuscular blockade of rocuronium is terminated rapidly by the diffusion of rocuronium away from the neuromuscular junction back into the plasma. NMBDs are quaternary ammonium compounds with at least one charged nitrogen atom. Cyclodextrins have a lipophilic centre but a hydrophilic outer core, attributable to negatively charged ions on their surface. These negatively charged ions on the surface of Sugammadex attract the positive charges of the quaternary ammonium relaxant, drawing the drug in to the central core of the cyclodextrin. The binding of the guest molecule into the host cyclodextrin occurs because of Vander Waal's forces, hydrophobic and electrostatic interactions. The structure of the cyclodextrin is such that all four hydrophobic rings of the steroidal relaxant fit

tightly within the concentric doughnut forming an inclusion complex. This has been confirmed by calorimetry and X-ray crystallography. Such a reaction occurs in the plasma not at the neuromuscular junction and the concentration of free rocuronium in the plasma decrease rapidly after Sugammadex administration. US 6670340 disclose process for preparation of Sugammadex sodium. The process as disclosed in example 4 of this patent involves reaction of iodo y-cyclodextrin intermediate with 3-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). The preparation of iodo intermediate, 6-per-deoxy-6-per-iodo-y-cyclodextrin is as given in example 3 which involves reaction of y-cyclodextrin with iodine in presence of triphenylphosphine (PPh3) and DMF. In practise, and to develop a process that has to be taken from lab scale to manufacturing scale, purity is one of the most important criteria. Since this process involves use of triphenylphosphine reagent there is formation of triphenylphosphine oxide as a by-product. Removal of triphenylphosphine oxide from the reaction mass is very difficult as it requires repeated washing with the solvent, which leads to inconsistency in yield of final product Sugammadex sodium. Furthermore, the product was dialysed for 36 hours to get pure compound. The dialysis purification is expensive and provides product in lower yield and hence such processes are not feasible and economical at industrial scale.
Another process for preparing the intermediate compound, 6-perdeoxy-6-per-chloro gamma cyclodextrin as disclosed in WO2012025937 involves use of phosphorous halide in particular, phosphorous pentachloride. WO2012025937 also disclose process for preparation of Sugammadex sodium using this intermediate which involves 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 chloro gamma cyclodextrin intermediate using phosphorous pentachloride is associated with formation of phosphorous

impurities during the reaction, which are difficult to remove and also it involves tedious workup procedure.
WO2014125501 discloses preparation of 6-perdeoxy-6-per-chloro gamma cyclodextrin using phosphorous pentachloride (see example 1). The process as given in example 1 of this patent application was repeated by the present inventors. The first step provided yellow to brown mass which lacked the powder form and the flow properties. The mass was pasty at times and difficult to filter. Thus the process was unclean and tedious. Overall, no consistent product was obtained. WO2014125501 also disclose preparation of Sugammadex sodium using this intermediate which involves reaction of 6-perdeoxy-6-per-halo-gamma-cyclodextrin with 3-mercapto propionic acid in presence of alkali metal alkoxide such as sodium methoxide and organic solvent, the drawback of this this reaction is that it needs anhydrous conditions for completion of the reaction. It has been reported that the generation of impurities and obtaining less pure compounds are major concerns with Sugammadex.
Applicant Nippon Organon K.K.in their "Report on the Deliberation Results" submitted to Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau, Ministry of Health, Labour and Welfare, mentions as follows: For related substances, specifications for 14 different related substances (Related Substance A, Org 48301, Related Substance B, Related Substance D, Related Substance E, Related Substance F, Related Substance G, Related Substance H, Related Substance I, Related Substance J, Related Substance K, Related Substance L, Related Substance M, Related Substance N), other individual related substances, and total related substances have been set. In the course of regulatory review, the specifications limits for 4 different related substances (Related Substance A, Related Substance D, Related Substance F, Related Substance G) have been changed based on the results of batch analyses.
For related substances (degradation products), specifications for Related Substance E, Related Substance I, Related Substance C, Related Substance G, Related Substance D, Related Substance K, other individual degradation products, and total degradation products have been established. In the course of regulatory review, a

specification for Impurity A which arises in *** (hidden part) step has been newly
set and the specification limits for individual degradation products have been
changed based on the results of batch analyses and stability studies.
The cause for change of the colour of the drug product (the light yellow-brown
colour darkened) was investigated using liquid chromatography-ultraviolet-visible
spectrophotometry (LC-UV/VIS) and liquid chromatography-mass spectrometry
(LC-MS), which suggested that trace amounts of varieties of unspecified
degradation products (unidentified), instead of a single degradation product, were
involved and in addition to *** investigated in formulation development, *** and
*** content of the drug substance, *** and *** during the manufacture of the drug
product, and *** were considered to affect the color of the drug product. Therefore,
*** and *** have been included in the drug substance specification and the relevant
manufacturing process steps have been improved.
In view of the above it is clear that Sugammadex is not only prone to degradation
but traces of degradation impurities affect and change the colour to yellowish brown
and makes it unacceptable in quality. Therefore, it is crucial to carefully select the
process to prepare pure Sugammadex sodium.
The reported purification techniques for Sugammadex sodium employ column
chromatographic and membrane dialysis which are costly and not convenient in
large scale operations. Therefore, the reported processes for preparation of
Sugammadex sodium as discussed herein are time consuming and not economically
and industrially viable.
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 the one which provides Sugammadex sodium in good yield and high purity.
Object of the invention
An object of the present invention is to provide a process for preparation of 6-
perdeoxy-6-per-haIo gamma cyclodextrin which is a key intermediate used for
preparation of Sugammadex sodium.
Another object of the present invention is to provide process for preparation of
Sugammadex sodium.

Another object of the present invention is to provide novel process for preparation
of Sugammadex sodium with good yield and high purity.
Another object of the present invention is to provide simple process for preparation
of Sugammadex sodium which involves use of reagents which are conveniently
used at industrial scale.
Summary of the Invention
According to an aspect, the present invention provides process for preparation of 6-
perdeoxy-6-per-halo gamma cyclodextrin, hereinafter also halo intermediate of
Sugammadex preferably perdeoxy-6-per-chloro gamma cyclodextrin hereinafter
also chloro intermediate of Sugammadex using oxalyl halide, preferably oxalyl
chloride.
In another aspect, the present invention provides process for preparation of
Sugammadex from corresponding acid involving a step having preparation of
potassium salt of such acid.
In another aspect, the present invention provides pure Sugammadex with purity
more than 90 %, preferably more than 95%.
Brief description of the drawings
Figure 1 is HPLC profile of 6-perdeoxy-6-per-chloro gamma cyclodextrin
Figure 2 is 1HNMR of 6-perdeoxy-6-per-chloro gamma cyclodextrin
Figure 3 is 13CNMR of 6-perdeoxy-6-per-chloro gamma cyclodextrin
Figure 4 is HPLC profile of Sugammadex sodium prepared according to example 3
Figure 5 is 1HNMR of Sugammadex prepared according to example 3
Figure 6 is 13CNMR of Sugammadex prepared according to example 3
Figure 7 is HPLC profile of Sugammadex acid (compound of formula IV)
Figure 8 is 1HNMR of compound of formula IV
Figure 9 is 13CNMR of compound of formula IV
Figure 10 is HPLC profile of Sugammadex prepared according to example 5
Figure 11 is 1HNMR of Sugammadex prepared according to example 5
Figure 12 is HPLC profile of Sugammadex prepared according to process of
example 1 of WO2014125501.

Detailed description of the invention
The present invention provides a process for preparation of halo intermediate of Sugammadex, preferably, chloro intermediate of Sugammadex which is a key intermediate useful in the synthesis of Sugammadex. Further the present invention provides preparation of Sugammadex using this intermediate. According to first aspect, the present invention provides a process for preparation of halo intermediate of Sugammadex comprising reacting gamma-cyclodextrin of formula II with oxalyl halide, preferably oxalyl chloride in presence of dimethylformamide to obtain halo intermediate of Sugammadex, preferably chloro intermediate of Sugammadex. (Ill)
According to second aspect, the present invention provides process for preparation of Sugammadex comprising reacting halo intermediate of Sugammadex, preferably chloro intermediate of Sugammadex of formula III with 3-mercapto propionic acid and sodium hydroxide to obtain Sugammadex of formula (I).


According to third aspect, the present invention provides process for preparation of acid of Sugammadex of formula (IV) comprising
a) reacting halo intermediate of Sugammadex, preferably chloro intermediate of Sugammadex of formula III with 3-mercapto propionic acid and potassium hydroxide to get the product containing potassium salt of acid of Sugammadex.
b) treating the compound obtained in step a) with acid to form the compound of formula (IV);

According to fourth aspect, the present invention provides process for preparation of Sugammadex comprising reacting the acid of Sugammadex of formula (IV) with sodium hydroxide to form Sugammadex sodium of formula (I).


The terms 'compound of formula (I) and 'Sugammadex' and 'Sugammadex
sodium' are used herein interchangeably and the terms 'compound of formula (IV)
and 'Sugammadex acid' and acid of Sugammadex are used herein interchangeably.
The compound, 6-perdeoxy-6-per-halo gamma cyclodextrin and halo intermediate
of Sugammadex are used herein interchangeably.
6-perdeoxy-6-per-chloro gamma cyclodextrin and chloro intermediate of
Sugammadex are used herein interchangeably.
The present invention is described in details in the following embodiments.
According to an embodiment of present invention the process for preparation of 6-
perdeoxy-6-per-chloro gamma cyclodextrin which is a key intermediate used for
preparing Sugammadex sodium, the process comprises:
a) reacting gamma-cyclodextrin of formula (II) with oxalyl chloride in
presence of dimethylformamide (DMF) to obtain chloro intermediate of
Sugammadex and optionally purifying chloro intermediate of Sugammadex .
The reaction of step a) is performed at temperature in the range of 60-80 °C.
The reaction of step a) is carried out for 12-18 hours.
The purification of perdeoxy-6-per-chloro gamma cyclodextrin in step b) involves
suspending perdeoxy-6-per-chloro gamma cyclodextrin in alcoholic solvent such
as methanol, stirring the suspension and filtering to obtain pure perdeoxy-6-per-
chloro gamma cyclodextrin.

The pure perdeoxy-6-per-chloro gamma cyclodextrin obtained according to present
invention has purity more than 98%.
This process is depicted in below scheme 1.

According to another embodiment of the present invention, the process for preparation of Sugammadex sodium comprises a) reacting gamma-cyclodextrin with oxalyl chloride in presence of DMF at temperature in the range of 60-80°C for 12-18hr to obtain chloro intermediate of Sugammadex; b) converting chloro intermediate of Sugammadex to Sugammadex sodium.
According to another embodiment of the present invention, the conversion of chloro intermediate of Sugammadex to Sugammadex sodium comprises either reacting chloro intermediate of Sugammadex with 3-mercapto propionic acid in presence of sodium hydroxide to obtain Sugammadex sodium; OR
a) reacting chloro intermediate of Sugammadex with 3-mercapto propionic acid in presence of potassium hydroxide to obtain a product containing the potassium salt of acid of Sugammadex;
b) treating the product obtained in step a) with acid to obtain the compound of formula (IV);
c) reacting the compound of formula (IV) with sodium hydroxide to obtain Sugammadex sodium of formula (I).

According to another embodiment, the process for preparation of Sugammadex
sodium comprises reaction of perdeoxy-6-per-chloro gamma cyclodextrin with 3-
mercapto propionic acid in presence of sodium hydroxide to form Sugammadex
sodium.
The reaction is carried out in presence of organic solvent selected from the group
consisting solvent selected from dimethylformamide (DMF), dimethylacetamide
(DMA), N-methyl pyrrolidone (NMP) and dimethylsulfoxide (DMSO).
The reaction is performed at temperature in the range of 70-90°C for 16-20 hrs.
This process is depicted in below scheme 2.

According to another embodiment, the present invention provides process for preparation of Sugammadex sodium comprising the steps of:
a) reacting gamma-cyclodextrin with oxalyl chloride in presence of dimethylformamide to obtain perdeoxy-6-per-chloro gamma cyclodextrin;
b) reacting perdeoxy-6-per-chloro gamma cyclodextrin with 3-mercapto propionic acid in presence of sodium hydroxide to form Sugammadex sodium;
c) optionally purifying Sugammadex sodium.
The reaction of step a) is performed at temperature in the range of 60-80 °C. The reaction of step a) is carried out for 12-18 hours.

The reaction of step b) is carried out in presence of organic solvent selected from
the group consisting of dimethylformamide (DMF), dimethylacetamide (DMA),
N-methyl pyrrolidone.(NMP) and dimethylsulfoxide (DMSO).
The reaction of step b) is performed at temperature in the range of 70-90 °C.
The reaction of step b) is carried out for 16-20 hours.
The purification of Sugammadex in step c) involves the following steps;
i. dissolving Sugammadex sodium in first solvent to obtain a solution ii. treating the solution obtained with activated carbon iii. filtering the solution of step ii) and separating the filtrate and iv. adding second solvent to the filtrate of step iii) to get pure Sugammadex sodium.
The first solvent used in the purification process is selected from the group
consisting of water, acetone, DMF, alcohol such as methanol, ethanol and
isopropanol and/or mixtures thereof.
The second solvent used in the purification process is selected from acetone,
methanol, acetonitrile or mixtures thereof.
The purification step is carried out at temperature in the range of 50-80°C.
Sugammadex sodium obtained by this purification has purity more than 90%.
In an alternative method Sugammadex is purified by preparative HPLC method.
This process for preparation of Sugammadex sodium is illustrated by the following reaction scheme 3.


According to another embodiment, the present invention provides process for preparation of Sugammadex sodium comprising the steps of
a) reacting gamma-cyclodextrin with oxalyl chloride in presence of
dimethylformamide to obtain chloro derivative of Sugammadex of formula
(in);
b) reacting chloro derivative of Sugammadex of formula (III) with 3-mercapto propionic acid in presence of potassium hydroxide to give a product containing the potassium salt of acid of Sugammadex;
c) treating the compound of step b) with acid to obtain the compound of formula (IV);
d) reacting the compound of formula (IV) with sodium hydroxide to obtain Sugammadex sodium.
The reaction of step a) is performed at temperature in the range of 60-80°C. The reaction of step a) is carried out for 12-18 hours.

The reaction of step b) is carried out in presence of organic solvent selected from
dimethylformamide (DMF), dimethylacetamide (DMA), N-methyl
pyrrolidone.(NMP) and dimethylsulfoxide (DMSO).
In the reaction of step b) halo intermediate compound and mercapto propionic acid
and halo intermediate compound and potassium hydroxide are used in a molar ratio
of at least 1: 15 and at least 1:30 respectively, preferably at least 1:20 and 1:40
respectively and most preferably at least 1:25 and at least 1:50 respectively. The
ratio of mercapto propionic acid and potassium hydroxide is about x: y preferably
1:2.
The reaction of step b) is performed at temperature in the range of 80-140°C,
preferably at temperature from 110-120°C. The reaction of step b) is carried out
for 2 to 6hr, preferably for 1.5 - 2hr.
The acid used in step c) is hydrochloric acid. The reaction of step c) is performed
at temperature from 25-35°C. The reaction of step c) is carried out for 1.5-2hr.
The reaction of step d) is performed at temperature in the range of 25-35°C. The
reaction of step d) is carried out 0.5-2 hrs. The process is as depicted in scheme 4.


The process of preparation of Sugammadex sodium according to above scheme 4 involves the following steps; Step 1:
In this step a mixture of anhydrous dimethylformamide (DMF) and oxalyl chloride is stirred for lhr at temperature below 5°C and a solution of dry gamma-cyclodextrin dissolved in DMF is added slowly into this mixture. The solution is heated at 65-70°C for 16 hrs. After the completion of reaction, the reaction mixture is cooled to room temperature and solvent such as diisopropyl ether is added to the reaction mixture with stirring. The solvent is removed and the precipitated gummy solid so obtained is cooled to 0 to 5°C and neutralized to about pH 8 with slow addition of aqueous sodium hydroxide solution. The reaction mass is stirred for l hr

at temperature 0 to 5°C and the precipitated material is filtered, washed with the water. The residue is then suspended into solvent such as methanol, stirred, filtered, washed with solvent such as diisopropyl ether and dried to give 6-deoxy-6-chloro gamma cyclodextrin.
Step 2
In this step a solution of potassium hydroxide in solvent such as DMF is cooled at 0-5 °C and to this a solution of 3-mercapto propionic acid in solvent such as DMF is added maintaining the temperature of reaction mixture between 0-5°C. The reaction mixture is then stirred at this temperature for about 60 minutes followed by addition of a solution of 6-deoxy-6-chloro gamma cyclodextrin in DMF. The mixture is heated, at about 110-120°C for about 2hr. After completion of the reaction, the reaction mixture is cooled to about 40-50°C and diluted with solvent such as methanol. The resulting precipitate is stirred at 20-25°C for about lhr and filtered under vacuum. The wet solid is then dissolved in water with vigorous stirring and acidified with concentrated hydrochloric acid (HC1). The precipitated solid of Sugammadex acid is filtered and suspended in solvent such as ethyl acetate, stirred for 30 minutes, filtered and dried. Sugammadex acid obtained has purity more than 95% as measured by HPLC.
Step 3
In this step the compound, Sugammadex acid is dissolved in a solution of sodium hydroxide in a mixture of solvent, preferably water and methanol. The pH of reaction mixture is maintained between 8-10 and anti-solvent such as methanol is added to the mixture. The precipitated solid of Sugammadex sodium is filtered, washed with solvent such as methanol and dried at 50°C under vacuum oven.
According to another embodiment, the present invention provides process for preparation of Sugammadex sodium comprising treating the compound of formula (IV) with a solution of sodium hydroxide at temperature from 25-35°C to obtain a solution and precipitating pure Sugammadex sodium using organic solvent. The

solution of sodium hydroxide is prepared by dissolving sodium hydroxide in a mixture of solvent. The mixture of solvent used is water and methanol. The solution of sodium hydroxide is added in such an amount that the pH of the reaction is maintained between 8 to 10. The organic solvent used for precipitation of sodium salt of Sugammadex is selected from methanol, ethanol, isopropanol etc. or mixtures thereof. This process is depicted in below scheme 5.

Sugammadex sodium prepared according to the present invention is characterized
by HPLC profile representing high purity more than 90%, preferably more than
95%.
According to the present invention, pure Sugammadex sodium is prepared using a
simple and convenient process with simple work up process and avoiding the
formation of by-product/impurities and purification techniques such as column
chromatography and dialysis as used in the reported processes.
As it has been discussed that applicant Nippon Organon K.K. reported 14 different
related substances for Sugammadex from A to N. Also it is stated that traces of
impurities may remain in the product which may result in yellow to brown colored
product. The coloured impurities cannot be washed out with simple washings. It

requires special techniques such as purification by column chromatography or
dialysis or some tedious work up processes. The inventors of the present invention
followed the reported processes and found that the desired product with high purity
could not be achieved. In fact it is very tricky to obtain pure and white desired
product.
The inventors of the present invention found that it was easy to handle the large
scale operations when they used oxalyl chloride to prepare perdeoxy-6-per-chloro
gamma cyclodextrin and sodium hydroxide for the preparation of Sugammadex
from 6-perdeoxy-6-per-halo gamma cyclodextrin. The resulted reaction mixture in
such reaction was easy for work up after the completion of the reaction.
The process of the present invention is convenient as oxalyl chloride is used instead
of reported phosphorous pentachloride (PCls), triphenylphosphine (PPI13) and
provides a white pure solid which gives upon drying white free flowing material as
compared to yellow to brown pasty compound which is obtained when inventors of
present invention repeated the process disclosed in WO2014125501.
The process of the present invention provides pure Sugammadex sodium using
sodium hydroxide than reported bases such as sodium hydride and sodium
methoxide used for making Sugammadex sodium.
Interestingly, none of the WO2014125501 and WO2012025937 mentions about
different impurities present in the final product Sugammadex sodium prepared
under the respective process.
Sugammadex sodium prepared according to the present invention is characterized
by HPLC profile representing high purity more than 95%.
The formation of the reaction products is monitored by HPLC. Sugammadex
sodium prepared according to the present invention is subjected to purification to
get pure Sugammadex sodium having more than 95% HPLC purity.
The purification techniques in the prior arts employ column chromatographic
/membrane dialysis techniques which are costly and not convenient in large scale
operations. The process of the present invention further provides Sugammadex
sodium with high purity.

According to present invention, Sugammadex sodium obtained by present process
is further purified to get Sugammadex sodium with high purity.
The process of the present invention provides pure Sugammadex having purity at
least 90%, preferably more than 95%.
In another embodiment, Sugammadex is purified by the preparative HPLC method.
Advantageously it is found by the present inventors that Sugammadex is purified
by subjecting the Sugammadex acid to preparative HPLC method. The advantage
of the present process is that more than 95% pure Sugammadex is produced from
free acid of Sugammadex by preparative HPLC.
General conditions of HPLC method:
Chromatographic conditions of the basic preparative separation are
Reagents: (1) Acetonitrile (HPLC Grade), (2) Methanol (HPLC Grade), (3) MilliQ
Water (4) Formic acid.
Diluent: Dimethyl formamide
Crude solution:
Prepare 500 mg/ml of acid of Sugammadex solution by taking appropriate quantity
of acid of Sugammadex and dissolve it in DMF, sonicate for 5 minutes and filter if
necessary,
Mobile Phase- A
Transfer 2.0 ml of Formic acid in 1000 ml of Milli-Q water and mix well, degas by
sonication and use.
Mobile Phase- B
Mixture of Acetonitrile, Methanol (70:30) respectively.
Chromatographic Conditions:
Column : Luna C18 (3), 10 urn particle size. Packed in a 50 mm id stainless steel
preparative Column.
Flow rate: 35 ml/min.
Detection: UV at 210 nm
Inj. Vol. : 20 ml (Depending on concentration inject ~ lO.Ogms/ injection)

Run time : 115 minutes Gradient Program:

Time in minutes % Mobile Phase A % Mobile Phase B
0.01 85 15
10.00 85 15
20.0 80 20
80.00 70 30
100.00 65 35
101.00 0 100
110.00 0 100
110.10 85 15
115.00 85 15
Approximate Retention time (RT) for Sugammadex peak is 85 minutes. Nuclear magnetic resonance spectroscopy (NMR) was performed using Avance III 400 MHz NMR spectrometer (for the 13C NMR spectra acquired at 100 MHz) and the chemical shifts were reported in 5 (ppm).
Advantages of process of present invention:
1. Use of oxalyl chloride for preparation chloro gamma cyclodextrin in present process significantly simplifies the work up procedure as no byproducts are formed and the compound obtained is having purity more than 98%. This process avoids phosphorous reagents such as PPh3, PC15 which produces phosphorous impurities and are difficult to remove from reaction mixture. Further use of these reagents is undesirable on large scale commercial processes.
2. The inorganic base such as potassium hydroxide (KOH), sodium hydroxide (NaOH) are used in the present process for making the reaction efficient and clean. Reported use of sodium hydride and sodium methoxide require anhydrous reaction conditions. The present process do not require rigorous anhydrous conditions for carrying out the reaction.
3. Greatly reduces the reaction time required for completion of reaction.

4. Simple acid base work up procedure furnishes the desired compounds with high purity of more than 95%.
Aspects and embodiments of the present invention are illustrated by the following examples. It is to be understood, that the aspects and embodiments of the invention are not limiting the scope of invention described herein. Examples Example 1
Preparation of 6-perdeoxy-6-per-chloro gamma-cyclodextrin In a 5L four-necked flask equipped with stirrer, dropping funnel, nitrogen inlet, and thermometer with pocket, oxalyl chloride (293.8g, 198.5ml, 2315mmol) was added to DMF (1200 ml) and maintained the mixture at 0-5 °C under nitrogen followed by stirring at 20-25°C for lhr. A solution of gamma-cyclodextrin (lOOg, 77.16mmol) in DMF (500ml) was added to above mixture at 5-10°C under nitrogen. The mixture was stirred at 65-70°C for 14-16 hr. After the completion of reaction, the reaction mixture was cooled to 20-25°C and diluted with diisopropyl ether (1.2L). The organic layer was decanted and the viscous residue was treated with 10% NaOH solution at 5-10°C until PH = 8. The resulting slurry was stirred for one hour at 20-25°C. The slurry was filtered under vacuum and the solid was washed with water (3 x 500ml) and dried under vacuum. The crude material was suspended in methanol (750ml), stirred for 30min, filtered under vacuum and washed with diisopropyl ether (500ml). The solid obtained was dried at 55- 60°C in an oven for 12-16hr to afford the titled compound (95g). Yield: 85%, Purity: 98%, melting point: 226-228°C
!H NMR (400 MHz, DMSO-d6): 8 6.0 (br s., 16 H), 4.99 (m, 8 H), 4.04 (d, J = 10 Hz, 8 H), 3.87 - 3.78 (m, 16H), 3.64 - 3.56 (m, 8 H), 3.46 - 3.34 (m, 16 H) ppm. 13C NMR (100 MHz, DMSO-d6): 5 101.98, 82.93, 72.30, 72.16, 71.11, 44.92 ppm. Mass: m/z (M+Na)+ calcd for C48H72C18O32Na: 1463.14; found: 1463.06.

Example 2
Preparation of 6-perdeoxy-6-per-chloro gamma-cyclodextrin In a clean, dried 50L glass reactor equipped with stirrer, dropping funnel, nitrogen inlet, and thermometer with pocket was charged anhydrous dimethyl formamide (15L, moisture content NMT 0,4%) while maintaining the temperature at 0-5°C (using dry ice acetone bath). Oxalyl chloride (2L, 23635mmol, 30eq) was added slowly over a period 4-5hr (while maintaining the temperature below 5°C) and stirring was continued for lhr at the same temperature. A solution of dry gamma-cyclodextrin (1.0 kg, 770.94mmol) dissolved in dimethyl formamide (5L) was added slowly into the above reaction mixture. The solution was heated at 65-70°C for 16hr. The reaction was monitored by TLC at regular intervals. After the completion of reaction, the reaction mixture was cooled to room temperature and diisopropyl ether (10L) was added to the reaction mixture with stirring. The gummy solid precipitate out. The upper layer solvent was decanted, the gummy brown material was cooled to 0 to 5°C and was neutralized (pH 8.0) with slow addition of aqueous sodium hydroxide solution (20%, 5L) with stirring. The slurry obtained was stirred for lhr at temperature 0 to 5°C. The precipitate was filtered, washed with the water (3 x 2L) and dried under vacuum. The wet cake was suspended into methanol (10L), stirred, filtered, washed with diisopropyl ether (2L) and dried in oven at 60°C for 14-16hr to give the titled compound (980g). . Yield: 87.9%, Purity: 98.1% as measured by HPLC.
Example 3
Preparation of Sugammadex sodium
A clean, dried 10L four neck flask equipped with stirrer, dropping funnel, nitrogen
inlet, and thermometer with pocket, was charged with a solution of sodium
hydroxide (83 g, 2077mmol) dissolved in water (100ml) followed by addition of
anhydrous DMF (2L) maintained under inert atmosphere using nitrogen. A solution
of 3-mercapto propionic acid (110g, 1037mmol) in DMF (1L) was added slowly
under nitrogen maintaining the temperature between 0-5°C. The mixture was stirred
for another lhr at this temperature. A mixture of 6-deoxy-6-chloro gamma

cyclodextrin (l00g, 69mmol) in DMF (1L) was added slowly at 5-10°C. The resulting mixture was heated to 75-80°C for 16-20hr. After the completion of reaction, the reaction mixture was cooled to 25-30°C and methanol (1.5L) was added into the reaction mixture, the resulting precipitate was stirred at 20-25 °C, filtered, and dried under vacuum. The dried solid was dissolved in water (1L), treated with activated carbon (50 g, 5%) at 50°C, stirred and filtered through celite. The filtrate was stirred at 60°C and excess methanol (2.5L) was added slowly to the filtrate to get the precipitate. The precipitated material was filtered under vacuum as white solid, washed with methanol (500ml) and dried in oven to give pure Sugammadex sodium (90 g). Yield: 90 g, Purity: 91.2%.
lH NMR (400 MHz, D2O): 5 5.09 (m, 8H); 3.98-3.94 (m, 8H); 3,88-3.83 (m, 8H); 3.58-3.52 (m, 16H); 3.07-3.01 (m, 8H); 2.92-2.87 (m, 8H); 2.78-2.74 (m, 16H); 2.34-2.47 (m, 16H)ppm.
13C NMR (100 MHz, D20): 8 180.18, 100.60, 81.96, 72.14, 71.84, 70.72, 37.24, 32.83, 29.06 ppm. Mass: m/z (M-Na7+H6)+ calcd for C72H110NaO48S8: 2023.12; found: 2023.39.
Example 4
Preparation of Sugammadex acid (Compound of formula IV) In a clean, dried 5L four neck flask equipped with stirrer, dropping funnel, nitrogen inlet, and thermometer with pocket was charged dimethyl formamide (1500ml) followed by addition of potassium hydroxide (194.0 g, 3464mmol) and the mixture maintained at 0-5°C. A solution of 3-mercapto propionic acid (186.35g, 153.0ml, 1756 mmol) in DMF (500ml) was added to the reactor over a period of 30 minutes under nitrogen while maintaining the temperature between 0-5 °C. The resulting mixture was stirred at this temperature for 60 minutes. A solution of 6-deoxy-6-chloro gamma cyclodextrin (l00g, 69.22mmol) in DMF (500ml) was added to the flask. The resulting mixture was heated at 110-120°C for 1.5 - 2.0hr while monitoring the progress of the reaction through HPLC. After completion of the reaction, the temperature of the reaction mixture was brought to 40-50°C and

methanol (1000ml) was added to the mixture. The resulted precipitate was stirred
at 20-25°C for lhr, filtered under vacuum and washed with methanol (500ml).
The wet solid was dissolved in water (2000ml) with vigorous stirring and the
solution was acidified with concentrated hydrochloric acid to give the white solid
precipitate. The precipitated solid was filtered and suspended in ethyl acetate (500
ml), stirred for 30 minutes and filtered. The solid was dried to afford the titled
compound (75 g).
Yield: 55%, Purity: 95.8% as measured by HPLC.
1H NMR (400 MHz, DMSO-d6): 8 5.94 (br. s, 16H), 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 (100 MHz, DMSO-d6): 5 173.00, 102.01, 83.94, 72.45, 72.33, 71.36,
34.53, 33.08, 27.87 ppm.
Mass: m/z (M-H2+K)+ calcd for CyiHnoCUsSgK: 2039.24; found: 2039.26.
Example 5
Preparation of Sugammadex Sodium
In a clean, dried 3L four neck flask equipped with stirrer, dropping funnel, nitrogen
inlet, and thermometer with pocket, the compound (75g) as obtained in example 4
was dissolved in solution of sodium hydroxide (37.5g, 0.937mol) in water (100ml)
and methanol (100ml). The pH of resultant mixture was maintained between 8-10.
To this mixture methanol (1.5L) was slowly added at room temperature and the
mixture was stirred for additional 30 minutes. The precipitated white solid was
filtered off under vacuum and thoroughly washed with methanol (500ml). The solid
was dried at 50°C under vacuum oven for 24hr to afford Sugammadex sodium (79
g). Yield: 96.9%, Purity: 95.5% measured by HPLC

We claim,
1. A process for preparation of Sugammadex sodium comprising reacting the
compound of formula (IV) with sodium hydroxide to obtain Sugammadex sodium
of formula (I).

2. The process as claimed in claim 1 wherein the reaction is carried out in
presence of water and methanol.

3. The process as claimed in claim 1 wherein the reaction is carried out at temperature from 25-35°C.
4. A process for preparation of Sugammadex sodium comprising

a) reacting gamma-cyclodextrin with oxalyl halide in presence of dimethylformamide to obtain halo intermediate of Sugammadex;
b) reacting halo intermediate of Sugammadex with 3-mercapto propionic acid in presence of potassium hydroxide to obtain a product containing the potassium salt of Sugammadex;
c) treating the compound of step b) with acid to obtain the compound of formula (IV);

d) reacting the compound of formula (IV) with sodium hydroxide to obtain
Sugammadex sodium.
5. The halo intermediate of Sugammadex according to claim 4 is chloro
intermediate of Sugammadex
6. The process as claimed in claim 4 wherein the reaction of step a) is carried out at temperature from 60-80°C and wherein the reaction of step b) is carried out at temperature from 80-140°C.
7. The process as claimed in claim 4 wherein the reaction of step b) is carried out in presence of solvent selected from dimethylformamide, dimethylacetamide, N-methyl pyrrolidone and dimethylsulfoxide.

8. The process as claimed in claim 4 wherein said acid in step c) is hydrochloric acid.
9. The process as claimed in claim 4 wherein the reaction of step d) is carried out in presence of mixture of solvent at temperature from 25-35°C.
10. The process as claimed in claim 9 wherein the mixture of solvent is mixture of methanol and water.
11. A process for preparation of Sugammadex sodium comprising a) reacting
gamma-cyclodextrin (II) with oxalyl chloride in presence of dimethylformamide to
obtain perdeoxy-6-per-chloro gamma cyclodextrin (III); b) converting perdeoxy-6-
per-chloro gamma cyclodextrin to Sugammadex sodium of formula (I).

12. The process as claimed in claim 11 wherein said step a) is carried out in
presence of dimethylformamide at temperature from 60-90°C.

13. The process as claimed in claim 11 wherein said conversion of perdeoxy-6-
per-chloro gamma cyclodextrin to Sugammadex sodium comprises either
reacting perdeoxy-6-per-chloro gamma cyclodextrin with 3-mercapto propionic
acid and sodium hydroxide to obtain Sugammadex sodium; OR
a) reacting perdeoxy-6-per-chloro gamma cyclodextrin with 3-mercapto propionic acid in presence of potassium hydroxide to obtain the compound containing potassium salt of Sugammadex;
b) treating the compound of step a) with acid to obtain the compound of formula (IV);
c) reacting the compound of formula (IV) with sodium hydroxide to obtain Sugammadex of formula (I).
14. The process as claimed in claim 13 wherein said reaction of perdeoxy-6-
per-chloro gamma cyclodextrin with 3-mercapto propionic acid is carried out in
presence of solvent selected from dimethylformamide, dimethylacetamide, N-
methyl pyrrolidone and dimethylsulfoxide.
15. The process as claimed in claim 13 wherein perdeoxy-6-per-chloro gamma
cyclodextrin and mercapto propionic acid and perdeoxy-6-per-chloro gamma
cyclodextrin and potassium hydroxide are used in a molar ratio of at least 1:15
and at least 1:30.
16. The process as claimed in claim 13 wherein said acid is hydrochloric acid.
17. The process as claimed in claim 13 further comprises purification of Sugammadex by preparative HPLC.
18. The process as claimed in claim 17 wherein acid of Sugammadex is used
for purification of Sugammadex.
19. A process for preparation of 6-perdeoxy-6-per-chloro gamma cyclodextrin comprising reacting gamma-cyclodextrin with oxalyl chloride to form perdeoxy-6-per-chloro gamma cyclodextrin.
20. The process as claimed in claim 19 wherein said reaction is carried out in presence of dimethylformamide at temperature from 60-90°C.

21. A process for preparation of Sugammadex acid of formula (IV) comprising
treating Sugammadex potassium salt with an acid to obtain Sugammadex acid of
formula (IV).

22. The process as claimed in claim 21 wherein said acid is hydrochloric acid.
23. Sugammadex having at least 95% purity prepared by a process comprising
reacting perdeoxy-6-per-chloro gamma cyclodextrin with 3-mercapto
propionic acid in presence of potassium hydroxide to obtain product
containing potassium salt of acid of Sugammadex which is subsequently
treated with an acid to convert it into an acid of Sugammadex which is
further converted into Sugammadex.