"Process For Preparation Of Highly Pure Phenyl Hydrazine Derivative"

Abstract

The present invention relates to a process for the preparation and purification of N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride of formula I,a key intermediate in the preparation of naratriptan and its pharmaceutically acceptable salts, using a source of hydrochloric acid or a solvent to enhance the assay and purity of the intermediate.

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Specification

FIELD OF THE INVENTION
The present invention relates to a process for the preparation of highly pure phenyl hydrazine derivative. Particularly the present invention relates to a process for the preparation and purification of N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride of formula I,
(Formula removed)
a key intermediate in the preparation of naratriptan and its pharmaceutically acceptable salts.
BACKGROUND OF THE INVENTION
Naratriptan,is being sold as hydrochloride salt under the trade name AMERGE, for treating migraine and is chemically known as N-methyl-3-(l-methyl-4-piperidinyl)-l-H-indole-5-ethanesulfonamide and has following structure formula:
(Formula removed)
Naratriptan and its physiologically acceptable salts, solvates as well as its related compounds useful in the treatment of migraine were first disclosed in US patents 4,997,841 and 5,066,600. The patents also disclose the processes for preparation of these compounds.
US patent 4,997,841 describes several processes for synthesizing the naratriptan, and according to one of the processes, naratriptan is prepared by the reaction of N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide of formula I,
(Formula removed)

with l-methyl-4-piperidine acetaldehyde in mixture of water and 2N hydrochloric acid at room temperature to give an hydrazone intermediate, which is then cyclised in the presence of polyphosphate ester in chloroform to give naratriptan free base.
According to the above patent, ,N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride intermediate can be prepared by the reduction of corresponding 4-nitro compound with catalytic hydrogenation using a catalyst such as palladium charcoal to give amine intermediate, which is diazotized using nitrous acid followed by reduction using stannous chloride to give desired product. But no exemplified process is given wherein the purity or assay is reported.
US patent 4,994,483 discloses a process for the preparation of N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride starting from 4-nitobenzene sulfonyl chloride by the following reaction sequence:
(Formula removed)

In the exemplified process, the purity of hydrochloride salt of hydrazino compound of formula I, reported is only 66%, which is very less. Purity of the key intermediate is especially important in the synthesis of final API, so low purity of the intermediate makes the process not suitable for the commercial synthesis.
PCT publication WO2008/056378 exemplified a process for the preparation of N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride of formula I by diazotization of 4-amino-iV-methylbenzene-ethanesulfonamide hydrochloride using aqueous sodium nitrite followed by reduction using stannous chloride dihydrate and concentrated hydrochloride to give desired intermediate. The above patent application is completely silent about the purity and assay of the resulting intermediate.
The purity of the intermediates, used for the synthesis of the an API, as well as purity of the final API is very important in the pharmaceutical field, as even a minute amount of impurity can cause harm to the patient. Therefore before being formulated an API, should be free from all harmful impurities or should be present in acceptable amounts.
These impurities can be extraneous compounds or impurities that can come from many sources. They can be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. Impurities in naratriptan or any active pharmaceutical ingredient (API) are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API.
In addition, impurities introduced during commercial manufacturing processes must be limited to very small amounts, and are preferably substantially absent. For example, the ICH Q7A guidance for API manufacturers requires that process impurities be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time, and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.
Naratriptan, being a low dosage drug, is highly sensitive to the presence of even minute amount of impurity. So there is need to develop a process which minimize the undesired impurities present in the final API. It is always advantageous to use intermediates of high purity and free from the undesired impurities or such impurities should be present in acceptable amount. N-Methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride, is a key intermediate for the synthesis of naratriptan. The purity of the chemical compounds can be measured by chromatographic techniques such as high performance chromatography (HPLC). Purity of a compound as measured by HPLC is relative purity of the compound with respect to the presence of organic impurities. The impurities present are measured in the presence of the desired material. HPLC purity of the chemical compound does not provide any indication about the inorganic impurities present in the compound. So, assay of the chemical compound is also important, same as that of purity of the compound, which gives clear indication on the how much actual content of the desired compound is present in a sample. Assay is different from the purity. Assay provides an exact result on the content or potency of the analyte in a sample. Therefore, the product having 99% purity can even have assay of 40%. Therefore to provide the final API i.e. naratriptan or its pharmaceutically acceptable salts thereof in high purity and to make sure that is should be free from organic as well as inorganic impurities, the determination of assay of the intermediates before proceeding to next stage is also very important.
It is found by the present inventor that N-Methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride prepared by the prior art processes is highly impure and having low percentage of assay due to presence of inorganic impurities along with other undesired impurities. Also, purity of the N-Methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride, reported is only 66%, and silent about the assay of the intermediate. Another problem realized with iV-Methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride is that it is not easily commercially available.
As most of the prior art processes are either silent about the purity or proceed with the intermediate having less purity, assay of the desired intermediate is found to be very low on our hand. In addition to this intermediate compound of formula I is not easily commercial available. Therefore to fulfill the need in the art, there is an urgent need to develop a process which provide the high content of the intermediate (assay) as well as high purity to ensure the high purity of the final API i.e. naratriptan, either free from the undesired organic as well as inorganic impurities or impurities present in acceptable amount. Thus, present invention provides a process for the preparation and purification of intermediate compound of formula I, which makes the intermediate suitable for the using in the synthesis of naratriptan or its pharmaceutically acceptable salts.
OBJECT OF THE INVENTION
The foremost object of the present invention is to provide a process for the preparation and purification of N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride of formula I, a key intermediate for naratriptan, to improve assay and purity.
Another object of the invention is to provide a process for the purification of N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride of formula I using a source of hydrochloric acid.
Another object of the present invention is to provide a process for the purification of N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride of formula I by crystallization.
Another object of the present invention is to provide a process for the preparation of highly pure N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride of formula I.
SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation and purification of N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride of formula I,
(Formula removed)
which can be used as a key intermediate for synthesis of naratriptan and its pharmaceutically acceptable salts.
According to one embodiment, the present invention provides a process for the purification of N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride of formula I, which comprises the steps of:
a), providing N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride of formula I;
b). adding a source of hydrochloric acid to the reaction mixture;
c). recovering pure N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride of formula I there from; and
d). optionally, slurring the resulting product in a suitable solvent.
According to one embodiment, the present invention provides a process for the purification of N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride of formula I, which comprises the steps of:
a), providing N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride of formula I in a suitable solvent;
b). heating the reaction mixture till clear solution;
c). cooling the reaction mixture;
d). optionally, adding a second solvent;
e). recovering pure N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride of formula I there from;
f). optionally, repeating the steps a) to e); and
g). isolating pure N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride of formula I.
According to another embodiment, present invention provides a process for the preparation of highly pure N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride of formula I, comprises the steps of:
a), reacting 4-nitrophenylethyl bromide with sodium sulfite in a suitable solvent to form compound of formula II,
(Formula removed)
b). treating the compound of formula II with a suitable activating reagent like thionyl chloride to form compound of formula III;
(Formula removed)
c). reacting the compound of formula III with methyl amine to give compound of formula IV;
(Formula removed)
d). reducing compound of formula IV with a suitable reducing agent to give a compound of formula V;
(Formula removed)
e). diazotizing and reducing the compound of formula V to form N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride of formula I; and
f). purifying N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride of formula I.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of highly pure phenyl hydrazine derivative, specifically N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride of formula I,
(Formula removed)

a key intermediate in the preparation of naratriptan, to enhance the purity as well as assay of the intermediate.
According to one embodiment, present invention provides a process for the purification of the N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide
hydrochloride of formula I using a source of hydrochloric acid either in concentrated, aqueous or gaseous form or in combination with alcoholic solvents.
Specifically, the process involves treating the N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride with a source of hydrochloric acid in the presence or absence of a suitable solvent. Source of hydrochloric acid employed for the reaction includes concentrated or aqueous hydrochloric acid; hydrogen chloride gas; hydrogen chloride gas purged in an alcoholic solvents; or concentrated or aqueous hydrochloric acid in mixture with alcoholic solvent and the like or combination thereof, preferably alcoholic hydrochloride (prepared by purging hydrogen chloride gas in alcohol) or mixture of hydrochloric acid with alcoholic solvent can be used for the reaction. More preferably methanolic hydrochloride; ethanolic hydrochloride; aqueous hydrochloric acid; mixture of aqueous hydrochloric acid with methanol, ethanol or isopropanol and mixture thereof.
It is advantageous and optional to provide a solution of N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride in a suitable solvent, prior to the addition of source hydrochloric acid. Suitable solvent can be selected from alcohol such as methanol, ethanol, isopropanol and the like or mixture thereof. The solution of N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride in a suitable solvent can be heated from 25°C to 60°C for 10 minutes to 2 hours, preferably till the clear solution is obtained followed by addition of a suitable source of hydrochloric acid. The addition of hydrochloric acid may be carried out at a temperature lower than that used for preparing the solution in solvent. The reaction mixture can be obtained by adding a source of hydrochloric acid to iV-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride without adding any solvent to the reaction mixture.
Thereafter, resulting reaction mixture containing N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride in presence or absence of solvent and a source of hydrochloric acid can be stirred for few minutes to several hours from ambient
temperature to 35°C to give pure N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride. It is advantageous to cool the reaction mixture and further stir to ensure the complete precipitation of the desired product. The purified product can be isolated from the reaction mixture using a suitable technique such as filtration, centrifugation and the like.
According to another embodiment, N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride can be purified by crystallization or slurry wash using a suitable solvent.
In a preferred embodiment,N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride in a suitable solvent can be heated from 25°C to 60°C for 10 minutes to 2 hours, preferably, till the clear solution is obtained. More preferably, mixture is heated to a temperature of 30°C to 55°C for 1 hour. Suitable solvent can be selected from alcohol such as methanol, ethanol, isopropanol and the like or mixture thereof.
The desired product can be recovered from the reaction mixture by initiating crystallization on cooling the reaction mixture to a temperature of 0°C to 30°C, preferably reaction mixture is cooled to 5°C to 10°C. Alternatively, pure compound can be recovered from the reaction mixture by precipitating it from the mixture by the addition of second solvent in which the compound of formula I is insoluble or having low solubility. Second solvent includes but not limited to ethers such as isopropyl ether, methyl tertiary butyl ether and the like or mixture thereof. The compound of formula I can be isolated from the mixture by suitable techniques known in the art such as filtration, centrifugation and the like.
In another preferred embodiment, N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride can purified by stirring in a suitable solvent at room temperature. Suitable solvent can be selected from alcohol such as methanol, ethanol, isopropanol; ether such as isopropyl ether and the like or mixture thereof. The desired
product can be isolated from the mixture by suitable techniques known in the art such as filtration, centrifugation and the like.
The purification process as described in the present invention can be repeated to enhance the purity and content of the desired intermediate (assay); and to minimize the presence of undesired organic as well as inorganic impurities present in the compound; or to make it free from impurities. Specifically, the crystallization process can be repeated to increase the purity as well as assay of intermediate compound of formula I till the desired level of assay and purity is achieved. Similarly, any of the purification process can be carried out once or repeated or used in combination with other.
N-Methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride, thus obtained after the purification is highly pure and having comparatively high percentage of assay. The intermediate may have purity more than 90%, preferably more than 95%, more preferably 99% by HPLC. The intermediate thus obtained may have assay more than 65%), preferably more than 85%, more preferably up to 99%. However, it is advantageous to proceed further with the intermediate of purity more than 95% and assay more than 95% by HPLC to obtain naratriptan or its pharmaceutically acceptable salts thereof in high purity having undesired impurities in acceptable amount or free from the impurities.
N-Methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride, an intermediate in the synthesis of naratriptan can be prepared by any method known in the art, for example: US 4,994,483 or by the process described herein for reference.
Specifically, N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide and salts thereof can be prepared starting from 4-nitrophenylethyl bromide.
The process involves the reaction of 4-nitrophenylethyl bromide with sodium sulfite to give compound of formula II,
(Formula removed)

The reaction may be carried out in a suitable solvent at a temperature of 80 °C to reflux temperature for few minutes to several hours, preferably at a temperature of 100 °C till the completion of the reaction. Suitable solvent includes water, alcohol and the like or mixture thereof. After the completion of the reaction, the compound of formula II is isolated from the reaction mixture using suitable techniques such as distillation. Preferably, reaction mixture is successively washed with water immiscible solvent such as ester such as ethyl acetate; ether such as isopropyl ether and the like or mixture thereof followed by recovery of the desired product from the aqueous layer by suitable techniques such as distillation i.e. to provide compound of formula II. The resulting product can be used as such for the further reaction or can be purified with a solvent such as alcohol such as methanol, ethanol, isopropanol and the like or mixture thereof. Preferably, the resulting product can be stirred in a solvent or solvent mixture to provide the purified product.
Thereafter, compound of formula II, undergoes reaction with a suitable activating reagent such as oxalyl chloride or thionyl chloride to yield corresponding reactive derivative like compound of formula III,
(Formula removed)
followed by reaction with methylamine in a suitable solvent to give compound of formula IV.
(Formula removed)

The process involves the reaction of compound of formula II in a suitable solvent with an activating agent at a temperature of 70°C to 100 °C for 1 to 6 hours. Preferably, the reaction is carried out at a temperature of 75-85 °C for 3 to 5 hours, more preferably till the completion of the reaction. After the completion of reaction, the reaction mixture was diluted with a suitable solvent, which includes halogenated solvent such as dichloromethane and the like. The compound of formula III can be isolated from the reaction mixture or it can be proceed as such for the further reaction. The resulting mixture or the compound of formula III is then reacted with monomethyl amine at a temperature of 5°C to 20°C till the completion of reaction, preferably reaction is carried out at temperature from 10°C to 20°C. Monomethyl amine employed for the reaction can be gaseous or solvent saturated with monomethyl amine, wherein solvent is selected from halogenated hydrocarbon such as dichloromethane and the like. After the completion of the reaction, the compound of formula II can be isolated from the reaction mixture by suitable techniques such as solvent removal under vacuum, distillation or evaporation. It is optional to proceed the reaction without isolation of the intermediate. The isolated product can be used as such for the further reaction or can be optionally purified to enhance the purity of the product and to remove undesired impurities from the resulting product. Preferably, the compound of formula IV is purified using a suitable solvent such as methanol, ethanol and the like or mixture thereof.
Compound of formula IV, thus obtained can be further reduced using a suitable reducing agent to afford compound of formula V.
(Formula removed)

The process involves the reaction of compound of formula IV with a suitable reducing agent in a suitable solvent at ambient temperature to 40°C for 2 to 10 hours, preferably till the complete reduction. Suitable reducing agent includes hydrogen or hydrazine hydrate or source of hydrogen in the presence of catalyst such as palladium, Raney nickel and the like with or without support (carbon). The solvent employed for the reaction includes alcohol such as methanol, ethanol; water and the like or mixtures thereof. After the completion of the reaction, the catalyst is filtered off. The desired product can be recovered from the filtrate by the removal of solvent using suitable techniques like distillation, evaporation, concentration, or solvent removal under vacuum and the like to give compound of formula V. The isolated product can be used as such for the further reaction or can be purified using a suitable solvent that includes ether such as isopropyl ether, and the like or mixture thereof.
Finally, compound of formula V is converted to compound of formula I by diazotization followed by reduction. The process involves reaction of compound of formula V using sodium nitrite in the presence of acid at a temperature of-15 to 10°C till the complete diazotization reaction. The acid employed for the reaction includes inorganic acid such as hydrochloric acid and the like. It is advantageous to carry out reaction in water as a solvent. Thereafter, the temperature of the reaction mixture is raised and optionally, filtered to remove un-dissolved impurities. The resulting reaction mixture is treated with a reducing agent such as stannous chloride or stannous chloride dihydrate in the presence of acid at a temperature from -15 °C to 10 °C, preferably the reaction is carried out at a temperature below 0 °C. The acids employed for the reaction include inorganic acid such as hydrochloric acid and the like. The resulting product is then isolated in the form of hydrochloride salt.
Thereafter, highly pure N-Methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride of formula I prepared by the process of present invention can be converted to naratriptan or its pharmaceutically acceptable thereof by any method known in the art. Preferably pure N-Methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride of formula I, thus prepared can be converted to naratriptan or its pharmaceutically acceptable thereof by following the process as described in US 4,997,841; WO 2008/072257 and Indian application no. 1671/ DEL/2008.
The main advantage of the present invention is to provide highly pure N-Methyl-2-(4-hydrazino-phenyl)ethane sulfonamide hydrochloride, which is having high percentage of assay and having organic as well as inorganic impurities in minimum amount or free from such impurities.
Although, the following examples illustrate the practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of the invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification and examples. It is intended that the specification, including the examples, is considered exemplary only, with the scope and spirit of the invention being indicated by the claims, which follow.
Example 1: Preparation of N-Methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride
Step I: Preparation of 2-(4-nitrophenyl)-ethane sulfonic acid
A mixture of 4-nitrophenyl ethyl bromide (100 g, 0.43 moles) and sodium sulfite (57.5g, 0.46 moles) was suspended in water (400 ml) and refluxed for 3 hours. After the completion of reaction, the reaction mass was cooled to 40°C and washed with ethyl acetate (200 ml). Thereafter, aqueous layer was washed with isopropyl ether (100 ml). Aqueous layer was distilled and resulting residue was stirred with a mixture of methanol (100 ml) and isopropanol (200 ml) to give 115 g of title compound.
Step II: Preparation of N-methyl-2-(4-nitrophenyl)-ethane sulfonamide
2-(4-Nitrophenyl)-ethane sulfonic acid (115 g) was taken in toluene and heated at reflux temperature. Water was removed azeotropically from the reaction mixture. Thionyl chloride (100 ml, 0.84 mole) and dimethylformamide (10 ml, 0.14 mole) were added to the reaction mixture at 30-40 °C and heated to 75-85°C. The temperature of reaction mass was maintained for 4 hour and then toluene was distilled out completely. Thereafter, the reaction mass was diluted with dichloromethane (2.5 L) at 30°C and washed with water (800 ml). The separated organic layer was washed successively with aqueous sodium bicarbonate solution (40 g in 400 ml water) and aqueous sodium chloride solution (80 g in 400 ml water). Monomethyl amine gas (100 g, 3.23 mole) was purged in the organic layer at 10-18°C till the completion of reaction. After completion of reaction, the reaction mass was washed with water (2x800 ml), brine solution (400 ml water) and concentrated under vacuum. The resulting product was recrystallized with methanol to give 80 g (yield 75%) pure title compound having purity 98.5% by HPLC.
Step HI: Preparation of N-methyl-2-(4-aminophenyI) ethane sulfonamide
A solution of N-methyl-2-(4-nitrophenyl)-ethane sulfonamide (50 g, 0.2 mole) in methanol (1.0 L) was hydrogenated under hydrogen (4.5-5 Kg/cm2 pressure) for 6 hours using palladium on carbon (10 g, 50 % wet). After completion of reaction, the catalyst was removed by filtration through a hyflo bed. The filtrate was concentrated under vacuum and the resulting residue was stirred with isopropyl ether and filtered to give 38g (86.7%) of the title compound having 99.0% by HPLC.
Step IV: Preparation of N-Methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride
To a suspension of N-methyl-2-(4-aminophenyl) ethane sulfonamide (100 g, 0.47 mol) in water (600 ml), hydrochloric acid (150 ml) was added at 5-10°C. The reaction mixture was then cooled to 0°C and aqueous sodium nitrite solution (40 g in 200 ml
water) was added to the reaction mixture. The temperature of the reaction mass was raised to 15°C and filtered. The filtrate was slowly added to a solution of stannous chloride dihydrate (420 g, 1.86 mol) in cone, hydrochloric acid (840 ml) at -5 to 0°C. The temperature of the reaction mass was again raised slowly to 15-20°C and the precipitated product was filtered to give 300g of wet title compound.
A portion of material was dried and checked for the purity and assay. Purity 88% and assay 45 % by HPLC.
Example 2: Purification of Ar-Methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride
Method A: Crude N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride (30g of wet product) in methanol (40 ml) was heated till the clear solution obtained. The reaction mixture was cooled to 35°C followed by addition of ethanolic hydrochloride (25%w/w, 20 ml) slowly and stirred for 30 minutes. Further, reaction mixture was cooled tol5-20°C and stirred for 1 hour. The resulting product was filtered and slurry washed with chilled ethanol (5 ml) to give 7g of pure title compound having purity 99% and assay 99% by HPLC.
Method B; Crude iV-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride (30g of wet product) in isopropanol (40 ml) was heated till the clear solution obtained. The reaction mixture was cooled to 35°C followed by addition of ethanolic hydrochloride (25%w/w, 20 ml) slowly and stirred for 30 minutes. Further, reaction mixture was cooled tol5-20°C and stirred for 1 hour. The resulting product was filtered and slurry washed with chilled isopropanol (5 ml) to give 8.2g of pure title compound having purity 99% and assay 85% by HPLC.
Method C; Crude N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride (30g of wet product) in methanol (40 ml) was heated till the clear solution obtained. The reaction mixture was cooled to 10-20°C and stirred for 1 hour.
The resulting product was filtered and slurry washed with isopropyl ether (10 ml) to give 13g of title compound having purity 96.9% and assay 82% by HPLC.
The resulting product was again dissolved in methanol ( 25 ml) and heated till the clear solution obtained. The reaction mixture was cooled to 10-20°C and stirred for 1 hour. The resulting product was filtered and slurry washed with isopropyl ether (7 ml) to give 7g of the pure title compound having purity 98% and assay 95.6% by HPLC.
Method D: Crude N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride (30 g of wet product) in methanol (40 ml) was heated till the clear solution obtained. Isopropyl ether (60 ml) was added to the reaction mixture. The reaction mixture was cooled to 5-10°C and stirred for 1 hour. The resulting product was filtered to give 12g of pure title compound having purity 88.8% and assay 82% by HPLC.
Method E: Crude N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride (30g of wet product) was stirred with ethanolic hydrochloride (40 ml) at 25-30°C for 1 hour. The resulting product was filtered to give lOg of the title compound having purity 98% and assay 95% by HPLC.
Method F: Crude N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride (30g of wet product) in methanol (40 ml) was heated till the clear solution obtained. The reaction mixture was cooled to 35°C followed by addition of concentrated hydrochloric acid (20 ml) and stirred for 30 minutes. Further, reaction mixture was cooled to l5-20°C and stirred for 1 hour. The resulting product was filtered and slurry washed with chilled ethanol (5 ml) to give 6.5 g of the title compound having purity 97% and assay 98% by HPLC.
Method G: Crude N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride (30g of wet product) in methanol (40 ml) was heated till the clear solution obtained. The reaction mixture was cooled to 35°C followed by addition of mixture of concentrated hydrochloric acid (15 ml) and isopropanol (15 ml) and stirred
for 30 minutes. Further, reaction mixture was cooled tol5-20°C and stirred for 1 hour. The resulting product was filtered and slurry washed with isopropanol (10 ml) to give 6.8g of the title compound having purity 98% and assay 98% by HPLC.
Method H: Crude N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride (30g of wet product) in methanol (40 ml) was heated till the clear solution obtained. The reaction mixture was cooled to 35°C followed by addition of mixture of concentrated hydrochloric acid (15 ml) and methanol (15 ml) and stirred for 30 minutes. Further, reaction mixture was cooled to l5-20°C and stirred for 1 hour. The resulting product was filtered and slurry washed with methanol (10 ml) to give 7.0 g of the title compound having purity 99% and assay 95% by HPLC).
Method I: Crude N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride (30g of wet product) in methanol (40 ml) was heated till the clear solution obtained. The reaction mixture was cooled to 35°C followed by addition of mixture of concentrated hydrochloric acid (15 ml) and ethanol(15 ml) and stirred for 30 minutes. Further, reaction mixture was cooled tol5-20°C and stirred for 1 hour. The resulting product was filtered and slurry washed with ethanol (10 ml) to give 6.5g of the title compound having purity 99% and assay 99% by HPLC.

WE CLAIM:
1. A process for the purification of N-methyl-2-(4-hydrazino-phenyl) ethane
sulfonamide hydrochloride of formula I,
(Formula removed)

which comprises the steps of:
a), providing N-methyl-2-(4-hydrazino-phenyl)ethane sulfonamide hydrochloride
of formula I; b). adding a source of hydrochloric acid to the reaction mixture; c). recovering pure N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide
hydrochloride of formula I there from; and d). optionally, slurring the resulting product in a suitable solvent.
2. The process according to claim 1, wherein in step a) N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride of formula I is used in solution with a suitable alcoholic solvent such as methanol, ethanol, isopropanol and the like or mixture thereof.
3. The process according to claim 1, wherein in step b) source of hydrochloric acid is selected from concentrated or aqueous hydrochloric acid; hydrogen chloride gas, hydrogen chloride gas purged in an alcoholic solvents; or concentrated or aqueous hydrochloric acid in mixture with alcoholic solvent and the like or combination thereof such as methanolic hydrochloride; ethanolic hydrochloride; aqueous hydrochloric acid; mixture of aqueous hydrochloric acid with methanol, ethanol or isopropanol and mixture thereof; and in step d) suitable solvent is
alcohol such as methanol, ethanol, isopropanol; ether such as isopropyl ether; and the like or mixture thereof.
4. A process for the purification of N-methyl-2-(4-hydrazino-phenyl) ethane
sulfonamide hydrochloride of formula I, which comprises the steps of:
a), providing N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride
of formula I in a suitable solvent; b). heating the reaction mixture till clear solution; c). cooling the reaction mixture; d). optionally adding a second solvent; e). recovering pure N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide
hydrochloride of formula I there from; f). optionally, repeating the step a) to e); and g). isolating pure N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide
hydrochloride of formula I.
5. The process according to claim 4, wherein in step a) suitable solvent is alcohol such as methanol, ethanol, isopropanol and the like; in step d) second solvent is selected from ether such as isopropyl ether, methyl tertiary butyl ether and the like or mixture thereof.
6. A process for the preparation of pure N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride of formula I, comprises the steps of:
a), reacting 4-nitrophenylethyl bromide with sodium sulfite in a suitable solvent to form compound of formula II,
(Formula removed)
b). treating the compound of formula II with a suitable activating reagent like thionyl chloride to form compound of formula III;
(Formula removed)

c). reacting the compound of formula III with methyl amine to give compound of formula IV;
(Formula removed)
d). reducing compound of formula IV with a suitable reducing agent to give a compound of formula V;
(Formula removed)
e). diazotizing and reducing the compound of formula V to form N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride of formula I;
f). purifying N-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride of formula I.
7. The process according to claim 6, wherein in step a) suitable solvent is selected
from water, alcohol and the like or mixture thereof; and in step d) reducing agent
is hydrogen, hydrazine hydrate or source of hydrogen along with a catalyst such
as palladium, Raney nickel with or without support (carbon).
8. The process according to claim 6, where in step f) .N-methyl-2-(4-hydrazino-
phenyl) ethane sulfonamide hydrochloride of formula I is purified by at least one
method selected from crystallization using a alcoholic solvent; slurry washing
using a suitable solvent selected from alcohol, ether or mixture thereof; or using a source of hydrochloric acid or combination thereof.
9. The process according to claim 8, wherein source of hydrochloric acid is selected from concentrated or aqueous hydrochloric acid; hydrogen chloride gas; hydrogen chloride gas purged in an alcoholic solvents; or concentrated or aqueous hydrochloric acid in mixture with alcoholic solvent and the like or combination thereof such as methanolic hydrochloride; ethanolic hydrochloride; aqueous hydrochloric acid; mixture of aqueous hydrochloric acid with methanol, ethanol or isopropanol and mixture thereof.
10. The process according to claims 1, 4 and 6, further comprises converting pure JV-methyl-2-(4-hydrazino-phenyl) ethane sulfonamide hydrochloride of formula I in to naratriptan or its pharmaceutically acceptable salt thereof.

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