Form 2
THE PATENTS ACT, 1970
(39 of 1970)
& THE PATENTS RULE 2003
Provisional Specification
[See section 10 and rule 13]
1. TITLE OF THE INVENTION
"Process for preparation of Naratriptan hydrochloride"
2. APPLICANT
a) NAME: USV LIMITED
b) NATIONALITY: Indian Company incorporated under the Companies
ACT 1956
c) ADDRESS: B.S.D. Marg, Station Road, Govandi, Mumbai 400 088,
Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.

Technical field:
The present invention relates to an improved process for the preparation of N-methyl-3-( 1 -methyl-4-piperidinyl)-1 H-indole-5-ethanesulphonamide hydro chloride of formula (I).

Background of invention:
The compound N-methyl-3-(l-methyl-4-piperidinyl)-lH-indole-5-
ethanesulphonamide hydro chloride is also known by the name "Naratriptan hydrochloride." Naratriptan hydro chloride exhibits selective vasoconstrictor activity used as the active ingredient in pharmaceutical products and being sold using the trademark AMERGE, for treating migraine. Naratriptan hydro chloride is an indole derivative disc loosed in US 4997841 and 5066660.
US 4997841 describes three different processes for preparation of Naratriptan: Process A: A solution of 4-hydrazino-N-methyl-benzenethanesulphonamide (II) with l-mefhyl-4-piperidineacetaldehyde (A) in a mixture of water and 2N hydrochloric acid followed by stirring for 2 days at room temperature to yield the hydrazone compound which is treated with polyphosphate ester in chloroform to get crude Naratriptan base (IX). The crude base (IX) was purified by column chromatography on silica gel using mixture of dichloromethane, ethanol and ammonia. The main disadvantage of this process is use of the aldehyde intermediate which is commercially not available and there are no synthetically feasible routes available for its synthesis in the literature. The reaction is represented by scheme be low.


Process B: A mixture of 5-bromo indole (B), N-methyl-4-piperidone and potassium hydroxide in ethanol is refluxed to obtain compound of formula (C). Treating compound (C) with ethanolic HC1 followed by hydrogenation in the presence of Platinum oxide to obtain 5-Bromo-3-(l-methyl-4-piperidinyl)-lH-indole (D). The mixture of obtained compound (D), N-methyl vinyl sulphonamide, Pd(OAc)2 and tri-o-tolylphosphine&triethyl amine in acetonitrile is heated to get crude N-Methyl-2-[3-(l-methyl-4-piperidinyl)-lH-indole-5-yl]ethenesulphonamide (E) which is purified by column chromatography on silica gel using a mixture of dichloromethane, ethanol and ammonia. The purified compound (E) is hydrogenated in presence of 10% palladium on carbon in ethanolic hydrochloric acid and DMF to get N-methyl-3-(l-methyl-4-piperidinyl)-lH-indole-5-ethanesulphonamide (IX). Treating the obtained compound (IX) with ethanolic hydrochloric acid to obtained Naratriptan hydro chloride (I). The reaction is represented by scheme be low.

The disadvantage of this process is that cumbersome operations like Heck reaction is involved. Further N-methyl vinyl sulphonamide is an unstable compound, expensive and not easily available. Also it is difficult to produce N-methyl vinyl sulphonamide in at a commertial scale due to its unstability. Other reagents such as Pd(OAc)2 and

tri-o-tolylphosphine are very expensive. Besides the above process using these expensive intermediates and reagents yield only 5-7% of the final product.
Process C: A mixture of N-methyl-lH-indole-5-ethanesulphonamide (VII), N-methyl-4-piperidone and potassium hydroxide in methanol is refluxed to produce compound (VIII). The compound (VIII) is hydrogenated in the presence of 5% Pd/C to obtain N-Methyl-3-(4-piperidinyl)-lH-indole-5-ethanesulphonamide (IX). The compound (IX) is purified by column chromatography on silica gel using a mixture of dichloromethane, ethanol and ammonia. The reaction is represented by the below scheme.

The main disadvantage of the processes as described in Process A, B and C is use of column chromatography for purification of Naratriptan base thus these processes making the processes time consuming, impractical at industrial scale and economically not viable.
US Patent No.4994483 describes process for preparation of N-methyl-lH-indole-5-ethanesulphonamide (VII) which comprises heating the mixture of 5-bromo indole (B), N-methyl vinyl sulphonamide, Pd(OAc)2, tri-o-tolylphosphine, and triethylamine in acetonitrile to get crude 2-(lH-indol-5-yl)-N-methyl ethane sulfonamide (F) which is purified by column chromatography. The purified compound (F) is hydrogenated in the presence of 10% palladium oxide on charcoal in mixture of ethyl acetate and methanol to get N-methyl-lH-indole-5-ethanesulphonamide (VII). On fol l0wing the above process, the overall yield obtained is 18% and reported yield is 22-23%. The reaction is represented by the be low scheme.


Scheme 4
US 5659040 describes process for preparation of Naratriptan hydro chloride comprising heating the mixture of compound (C), N-methyl vinyl sulphonamide, Pd(OAc)2, tri-o-tolyphosphine and triethylamine in dimethylformamide to get (E)-N-Methyl-2-[3-(l,2,3,6-tetrahydro-l-methyl-4-pyridinyl)-lH-indol-5-yljethenesulphonamide (G). The compound (G) is hydrogenated in the presence of 10% palladium oxide on charcoal in a mixture of dimethylformamide, water and 2N hydrochloric acid to get crude Naratriptan hydrochloride, which was crystallized with hot IMS(Indstrial methylated spirit)/water to get pure Naratriptan hydro chloride (1). The reaction is represented by the scheme be low.

WO2006010079 describes process for preparation of Naratriptan hydro chloride comprising reacting diazoinium salt of N-Methyl-2-(4-aminophenyl)ethane sulfonamide with (3-ketoester compound , then after several stages to get Naratriptan hydro chloride (I). This process is time consuming and economically not viable as it involves many steps.

Advantages of the present process for preparation of Naratriptan hydro chloride are
1. Provides Naratriptan hydro chloride in high yield and high purity.
2. More suitable for scaled-up operations as it involves less number of steps.
3. Avoids use of column chromatography.

4. Avoids cumbersome operations like Heck reaction.
5. Avoid use of expensive reagents like palladium acetate, N-methyl-4-piperidine acetaldehyde and N-methyl vinyl sulfonamide.
6. It is simple, economical and industrially feasible process for the preparation Naratriptan hydrochloride.
7. Involves use of easily available raw materials and l0w operating cost, overcoming the problems of handling the reactants and reagents as used in the prior art.
Object of the invention:
The object of the present invention is to provide a simple and cost effective process for the preparation of Naratriptan hydro chloride i.e. N-methyl-3-(l-methyl-4-piperidinyl)-l H-indole-5-ethanesulfonamide hydro chloride in high yield and high purity.
Summary of the invention:
The present invention disc loses process for preparation of N-methyl-2-[3-(l-methyl-4-piperidinyl)-lH-indole-5-ethanesulfonamide hydro chloride of formula (I) in high yield and purity which comprises the following steps;
a) combining hydrazino derivative(II) with a pyruvic acid ester compound where R represents an alkyl group having 1 to 5 carbon atoms to yield hydrazone compound(IV);
b) cyclizing the obtained hydrazone compound (IV)to produce an indole carboxylic ester(V);
c) hydrolyzing the obtained carboxylic ester (V) to get carboxylic acid compound(VI);
d) decarboxylating the carboxylic acid compound (VI) to obtain indole sulfonamide(VII);
e) combining the indole sulfonamide (VII) with N-methyl-4-piperidone to obtain compound (VIII);
f) hydrogenating the compound (VIII) to produce Naratriptan base (IX) and purifying the base;
g) converting the obtained Naratriptan base into its acid addition salt and
h) purifying obtained salt to get Naratriptan hydro chloride (I) with purity of more


than 99.8%. The reaction of the present invention is represented by the scheme be low.

According to another aspect of the present invention there is provided process for preparation of key intermediate indole sulfonamide (VII) used for the preparation of Naratriptan hydro chloride comprises the steps of;
a) combining 5-bromo indole (B) with aryl vinyl sulphonate (C), to get crude
phenyl lH-indole-5-ethenesulfonate (X).
b) hydrogenating the compound (X) to get lH-indole-5-aryl
ethanesulfonamide (XI) followed by combining with methyl amine to produce
indole sulfonamide (VII)
OR
b) optionally combining the compound (X) with methyl amine to obtain N-methyl-lH-indole-5-ethenesulfonamide (XII) followed by hydrogenating it to produce indole sulfonamide (VII).


The present invention describes an improved process for the preparation of compound of formula (I).


The process for preparation of Naratriptan hydro chloride according to the present invention comprises the following steps;
a) reacting hydrazino derivative of compound (II) with a pyruvic acid ester
compound (III), where R represents an alkyl group having 1 to 5 carbon atoms
to obtain hydrazone compound (IV);

b) cyclizing the hydrazone derivative (IV) in the presence of an acid to give the indole derivative (V);

c) hydrolyzing the obtained compound (V) with base and acidifying with acid to


produce compound (VI);
d) decarboxylating the obtained compound (VI) to produce indole sulfonamide compound (VII);

e) reacting the obtained compound (VII) with N-methyl-4-piperidone to produce compound (VIII);

f) reducing the compound (VIII)) using noble metal catalyst to obtain Naratriptan base (IX);

g) treating the obtained Naratriptan base (IX) with alcoholic acid to get

Naratriptan salt and h) purifying the obtained salt to get the compound of Formula (I) having purity more than 99.8%.

According to an embodiment of the present invention the hydrazino derivative (II) is condensed with pyruvate ester (III) maintaining the temperature at about 25 to 100°C, preferably about 80°C for a period of about 2 to 4 hours to obtain hydrosome compound of formula (IV). The compound (IV) can be prepared by reacting the compound (II) with compound of formula (III) in the presence or absence of catalytic amount of acid in organic solvent. The acid used is selected from methane sulfonic acid, acetic acid, phosphoric acid, hydrochloric acid and sulfuric acid. The organic solvent used is alcohol selected from methanol, ethanol, propanol, isopropanol or mixtures thereof.
The hydrazone compound of formula (IV) is cyclized using an acid in presence or absence of solvent to get the indole derivative of formula (V). The acid used is selected from inorganic acid such as hydrochloric acid, sulfuric acid, and phosphoric acid, or organic acid such as acetic acid, methane sulphonic acid, para-toluenesulphonic acid or Lewis acids such as boron trifluoride. The solvent used is selected from dichloromethane, chloroform, methanol, ethanol, isopropanol or mixtures thereof.
The obtained indole derivative of formula (V) is hydrolyzed in the presence of base such as sodium hydroxide, potassium hydroxide, lithium hydroxide in water or mixture of water and organic solvents at reflux temperature to obtain the compound of formula (VI). The base used is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide. The solvent used is selected from methanol, ethanol, isopropanol, tetrahydrofuran, dioxane or mixtures thereof.

The compound of formula (VI) is decarboxylated in the presence of copper catalyst such as cuprous oxide, copper oxide, copper bronze at temperature in the range of about 140 to 220°C, or about 180 to 200°C for 2 to 5 hours, or about 3 to 5 hours to obtain compound of formula (VII) in the presence of quinoline. The obtained compound of formula (VII) is further condensed with N-methyl-4-piperidone at temperature of about 60 to 1000C, typically requiring period of about 8 to 14 hours, preferably 8 to 10 hours .in presence of base such as sodium hydroxide and potassium hydroxide in solvent such as alcohol selected from methanol, ethanol, propanol, isopropanol, or their mixtures, to obtain compound of formula (VIII).
The obtained compound of formula (VIII) is further reduced using catalyst in presence of hydrogen gas at temperature of about 25 to 80°C, preferably 40 to 50°C for about 5 to 12 hours, preferably 8 to 12 hours to obtain Naratriptan base (IX). The catalyst used is selected from palladium oxide/charcoal, palladium/charcoal, platinum oxide/charcoal, platinum/charcoal, rhodium/charcoal. The reduction can be carried out in solvent or mixtures of solvent and acid. The acid used is selected from acetic acid, methane sulphonic acid, hydrochloric acid, and the solvent used is selected from alcohol such as methanol, ethanol, propanol, isopropanol, ethers such as dioxane, esters such as ethyl acetate and an amide or mixtures thereof, more preferably mixture of methanol and acetic acid is used.
Naratriptan base (IX)obtained by the above process is characterized by XRPD having the following characteristic peaks :-

Pos[°2Th] Rel. Int. [%]
6.0313 0.69
11.9694 15.55
12.3020 4.89
12.9366 3.56
14.6488 2.81
15.0344 6.93
17.1859 9.51
17.9725 100.00
18.6130 73.66


19.4575 13.62
20.0776 8.19
22.5529 10.90
23.9735 8.02
24.4746 9.13
25.4455 5.77
Naratriptan base (IX) thus obtained is further converted into its acid addition salt (I) by treating it with alcoholic HC1. The alcohol is selected from ethanol, ethanol, propanol, isopropanol or mixtures thereof at temperatures about 0 to 30°C, preferably 10tol5°C.
The obtained Naratriptan salt is further purified by dissolving Naratriptan HC1 in a water or mixture of water and solvent at a temperature about 25 to 100°C, preferably 60 to 80°C and the obtained solution is charcoalized and cooled to obtain Naratriptan hydro chloride (I). The solvent used is selected from ethanol, propanol, isopropanol or acetonitrile or ether like tetrahydrofuran, dioxane, preferably a mixture of water and ethanol.
Naratriptan hydro chloride obtained according to the present invention has purity of more than 99.8% by HPLC.

Scheme 10
According to another embodiment, the present invention provides process for preparation of the key intermediate N-methyl-lH-indole-5-ethanesulfonamide (VII) used for the preparation of Naratriptan hydro chloride which comprises the steps of;

a) heating the mixture of 5-bromo indole (B), aryl vinylsulphonate having formula (XII), Pd(OAc)2 and tri-o-tolyphosphine in acetonitrile to get crude lH-indole-5-phenyl ethenesulfonamide (X);

b) hydrogenating the compound (X) in the presence of 10% palladium on charcoal in solvent to get phenyl lH-indole-5-ethanesulphonate (XI),

c) treating the compound (XI) with methyl amine to obtain N-methyl-lH-indole-5-ethanesulfonamide (VII);

Preferably, the sulfonate compound of formula (X) is prepared by reacting the compound (B) with aryl vinylsulphonate (XII), where aryl represents substituted or unsubstituted aromatic ring in the presence of Pd(OAc)2, tri-o-tolyphosphine and triethylamine in organic solvent at temperature of about 80 to 120°C, preferably about 80°C for a period of about 2 to 4 hours. The organic solvent is selected from acetonitrile, dimethylformamide.
The compound of formula (X) is reduced to a compound of formula (XI) at

temperature about 25 to 80 C, preferably 40 to 50 C for about 8 to 24 hours, preferably 14 to 16 hours in the presence of hydrogen gas using a catalyst such as palladium oxide/charcoal, palladium/charcoal, platinum oxide/charcoal, platinum/charcoal rhodium/charcoal. The reduction can be carried out in solvent or mixtures of solvents. The solvent used is selected from alcohol such as methanol, ethanol, propanol, isopropanol, ethers such as dioxane, tetrahydrofuran, esters such as ethyl acetate and an amide as dimethylformamide or mixtures thereof more preferably mixture of methanol and terahydrofuran.
The compound having formula (XI) can be converted into sulfonamide compound (VII) using methylamine in water or organic solvent or mixtures thereof at temperature of about 25 to 80°C preferably about 40 to 50°C. The reaction is carried out for 2 to 6 hours preferably about 3 to 4 hours. The organic solvent is selected from alcohol such as methanol, ethanol, propanol, isopropanol, ethers such as dioxane, tetrahydrofuran and amide as dimethylformamide or mixtures thereof more preferably mixture of methanol and tetrahydrofuran.
According to another embodiment, the present invention provides process of preparation of amorphous Naratriptan hydro chloride which comprises the steps of;
A] Naratriptan.HCl
a) dissolving Naratriptan.HCl in a suitable solvent and
b) lyophilizing the resultant clear solution to obtain the amorphous form.
B] From Naratriptan
a) suspending Naratriptan in suitable solvent and adding cone. HC1 to the suspension and
b) lyophilizing the resultant clear solution to get the amorphous form.
The dissolving solvent used in either of the above two process is water. The concentration of Naratriptan in solution used for lyophilization is 4-10% preferably 4-8 %. The solution of Naratriptan is lyophilized for 24 hrs to get an amorphous Form.
According to another embodiment of the present invention process of preparation of amorphous Naratriptan hydro chloride comprises the steps A] From Naratriptan. HC1
a) dissolving Naratriptan.HCl in a suitable solvent and


b) spray drying the resultant clear solution to get the amorphous form. B] From Naratriptan
a) suspending Naratriptan in suitable solvent and adding conc.HCl to the suspension and
b) spray drying the resultant clear solution to get the amorphous form..
The dissolving solvent used in either of the above two process is polar protect solvent like, water or C1-C4 alcohols or mixture thereof, preferably water. The alcohols used is methanol, ethanol preferably methanol. The concentration of Naratriptan in solution used for spray drying is 4-10% preferably 4-8 %. The solution of Naratriptan is spray dried at inlet temperature of 40 to 170°C and outlet temperature of 35-85°C.
According to another embodiment of the present invention process of preparation of amorphous Naratriptan HC1 comprises the steps
A] From Naratriptan. HC1
a) dissolving Naratriptan. HC1 in a suitable solvent and
b) evaporating the solvent under vacuum to get amorphous Naratriptan HC1.
B] From Naratriptan
a) suspending Naratriptan in suitable solvent and adding conc.HCl to the suspension and
b) evaporating the solvent under vacuum to get amorphous Naratriptan HC1.
The dissolving solvent used in either of the above two process is polar protic solvent like, water or C1-C4 alcohols or mixture thereof, preferably water. The alcohols used is methanol, ethanol preferably methanol. The solvent from the solution of Naratriptan is evaporated at 65°C, under vacuum to get the amorphous Naratriptan HC1.
The novel amorphous form of Naratriptan HC1 are characterized by X-ray powder diffraction. X-ray powder diffraction pattern has been obtained on Xpert'PRO, Panalytical, diffractometer equipped with accelerator detector using Copper Ka(X=1.5406A°) radiation with scanning range between 4-50 26 at scanning speed of 2°/min.


The following examples are for illustrative purposes only and are not intended, nor should they be interpreted, to limit the scope of the invention.
EXAMPLES:
Example 1
Preparation of Hydrazone of 4-Hydrazino-N-Methyl benzene ethane
sulfonamide hydrochloride(IV):
A mixture of 4-hydrazino-N-methyl benzene ethane sulfonamide hydro chloride (II) (150 g, 56.49 mmol), ethyl puruvate (III) (65.59 g, 56.49 mmol) in ethanol (1.5 lit) and methane sulphonic acid (7ml) was stirred for 2 to 3 h at temperature 80°C. From the obtained reaction mixture half volumes of ethanol was distilled off. The reaction mixture was further cooled to temperature 10°C for one hour to precipitate out the solid. The solid obtain was filtered, washed with chilled ethanol and dried. [Yield: 130 g, 70.58%]
Example 2
Preparation of Indole-2- ester (V):
A mixture of (130 g, 39.75 mmol) compound (IV), obtained in example 1 and methane sulphonic acid (3.06g, 44.78 mmol) in acetic acid (Hit) was refluxed for 2 to 3 h at temeprature 115°C. The acetic acid was distilled out and the solid obtained was neutralized with aqueous sodium carbonate, solid separated filtered, washed with water and dried. [Yield: 105 g, 85 %]
Example 3
Preparation of Indole -2-carboxylic acid (VI) :
A mixture of the compound (V) ( 95g, 30.64 mmol) obtained in example 2 and sodium hydroxide (36.78g,91.92 mmol) in water (570 ml) was refluxed for 2 h. The obtained reaction mixture was cooled and acidified with cone. HC1 . The precipitated solid was filtered, washed with water and dried. [ Yield: 85.5g, 90%]
Example 4
Preparation of N-methyl-lH-indole-5-ethanesulfonamide (VII) :
A mixture of the compound (VI) (85g, 30.14mmol) obtained in example 3 and


cuprous oxide (4.25 g) in quinoline (425 ml) was refluxed for 6h. The obtained reaction mixture was cooled down, ethyl acetate (400 ml) was added and filtered through hyflow The filtrate was washed with dilute hydrochloric acid, water and concentrated to get solid of compound (VII). [Yield : 55g,76.66%]
Example 5
Preparation of (E)-N-Methyl-2-[3-(l,2,3,6-tetrahydro-l-methyl-4-pyridinyl)-lH-
indol-5-yljethanesulfonamide (VIII):
A mixture of the compound (VII) (51 g, 21.42mmol) obtained in example 4, N-Methyl-4-pipperidone ( 60.6lg, 53.56mmol) and potassium hydroxide ( 30g, 53.57mmol) in ethanol (0.357 lit) was refluxed for 12 h. The obtained reaction mixture was cooled to 10°C and precipitated solid was filtered followed by washing with ethanol and further washed with water and dried. [Yield: 55g,77.07% ]
Example 6
Preparation of N-methyl-3-(l-methyl-4-piperidinyl)-l H-indole-5-ethanesulfon-
amide (IX):
A mixture of the compound (VIII) (38g, ll.Hmmol) obtained in example 5 was reduced using platinum oxide (7.6g) in a mixture of 50% acetic acid in methanol (600 ml) for 8h at 40 psi at 40°C. Then reaction mixture was filtered through hyflowThe filtrate was concentrated, basified with aqueous sodium carbonate solution and extracted with ethyl acetate (1 lit). The ethyl acetate layer was separated, washed with EDTA, water, concentrated to get the solid and dried. [ Yield 24.54g, 64.20%]
Example 7
Preparation of Nartriptan Hydro chloride (I):
The compound (IX) (24g, 716mmol) obtained in example 6 was dissolved in ethanol (150 ml) at refluxed temperature. The obtained solution was cooled at room temperature and mixture of ethanol-water (120 ml / 72 ml) was added and refluxed for 1 h. (0.24 g) activated charcoal was added to the refluxed solution and hot solution was filtered through hyflow The filtrate was stirred for 1 h at temperature 10°C, the


separated solid was filtered, washed with cooled ethanol and dried. [Yield: 14.4 g, 54.11%]
Example 8
Preparation of N-Methyl vinyl sulfonamide :
PART A:
A mixture of Isethnaoic acid sodium salt (0.250 Kg, 1689 mmol) was taken in DMF (0.32L) and dichloromethae (0.3L). To this mixture thionyl chloride (0.375L, 5186mmol) was added dropwise at 20-30°C.The reaction mixture was heated slowly from 30-60°C. After completion of the reaction 3.5 lit of chilled water was added. The reaction mixture was extracted with 3X0a.5L dichloromethae. Di chloroethane was distilled to get oil. [ Yield 0.250Kg, 90%]
Crude chloroethane sulfonyl chloride ( 250gm, 1533mmole) was distilled under high vacuum to get pure chloroethane sulfonyl chloride. (200gm, 90%)
PART B:
A mixture of chloroethane sulfonyl chloride (l00g, 613 mmole) and THF ( IL) was stirred under nitrogen atmosphere. The reaction mixture was cooled to -50 to -60°C. Hydroquinone was added in the catalytic amount to the reaction mixture. N-Methyl amine gas (142.ml, 1839mmol) was purged (Aqueous methyl amine was added in potassium hydroxide) in the reaction mixture maintaining temperature -50 to -60°C. The reaction was monitored on GC. After completion of the reaction, the reaction mixture was filtered and filtrate evaporated under vacuum not more than 50°C. Thick oil (crude) obtained stored under nitrogen atmosphere
Crude N-Methyl vinyl sulfonamide (50gm, 413mmol) was distilled using short path distillation to get pure compound. [Yield 50g, 67.35%]
Example 9
Preparation of Phenyl vinyl sulfonate :
PART A:
A mixture of Isethanoic acid sodium salt (0.250 Kg, 1689 mmol) was taken in DMF (0.32L) and dichloromethae (0.3L). To this mixture thionylchloride (0.375L, 5186mmol) was added dropwise at 20-30°C.The reaction mixture was heated slowly


from 30-60°C. After completion of the reaction 3.5 lit of chilled water was added. The reaction mixture was extracted with 3X0.5L dichloromethae. Di chloroethane was distilled to get oil.
Crude chloroethane sulfonyl chloride ( 250gm, 1533mmole) was distilled under high vacuum to get pure chloroethane sulfonyl chloride [ Yield 0.250Kg, 90%].
PART B:
A mixture of chloroethane sulfonyl chloride (l00g, 613 mmole) and dichloromethane (0.4 L) was stirred under nitrogen atmosphere. Hydroquinone was added in the catalytic amount to the reaction mixture. Reaction mixture was chilled to -15 to -20°C. A mixture of phenol (57.6gm, 613mmol) and Triethylamine (0.171 L, 813mmol) in dichloromethane(0.4L) was added to the above reaction mixture maintaining the temperature. After addition reaction was stirred at 25 to 30"C for one hour. Reaction mixture was monitored on GC. After completion of reaction dichloromethane ( 0.2L) was added. Organic layer was treated with hydrochloric acid (2%,1.5L) and followed by aqueous sodium hydroxide ( 1L, 5%) and water (2X1L). Organic layer was distilled to get oil (86gm, 76.78%).
Crude phenyl vinyl sulfonate (86gm,467 mmol) was distilled under vacuum to get pure colurless oil which gets solidified after cooling. [Yield 64gm, 74.41%].
Example 10
Preparation of (E)-2-(lH-indol-5-yl)-N-methyl ethene sulfonamide(VII):-
A mixture of palladium acetate ( 4gm, 17 mmol) and tri-o-tolyl phosphine (12gm, 39mmol) in dimethylformamide (0.2L) was stirred under nitrogen atmosphere. A mixture of 5-Bromo indole( 50gm, 255mmol), N-Methyl vinyl sulfonamide( 28gm, 231 mmol) and triethylamine (0.035L, 251mmol) in dimethylformamide (0.05L) was added to the reaction mixture. The reaction mixture was heated to 100-110°C for 8 to l0hrs. After completion of the reaction mixture cooled to 35 to 40°C and filtered through hyflow Filtrate was treated with hexane (0.2L). Reaction mixture was quenched in water (1L) stirred and water layer was treated with ethyl acetate ( 3 X 0.2 L) folwed by water. Ethyl acetate layer was evaporated to get solid. Solid was treated with ethyl acetate and hexane ( 80:20, 0.2L) to get pure solid. [ Yield 50gm, 83%]


Example 11
Preparation of 2-(lH-indol-5-yl)-N-methyl ethane sulfonamide (VIII):-
A mixture of indole sulfonamide (40g, 169mmol) was hydrogenated using 50 % wet
palladium on charcoal (63gm)) in a mixture of (Methanol: THF 0.2 L each) for 6 to 8h at 70-80°C at 70 psi Kg/cm2 hydrogen pressure.After completion of reaction was filterd through hyflow Filtrate was distilled to get solid. [ Yield 32 gm, 79.34%]
Example 12
Preparation of Phenyl (E)-2-(lH-indol-5-yl) ethene sulfonate (X):-
A mixture of palladium acetate ( 4gm, 17 mmol) and tri-o-tolyl phosphine (12gm, 39mmol) in dimethylformamide (0.2L) was stirred under nitrogen atmosphere. A mixture of 5-Bromo indole( 50gm, 255mmol), phenyl vinyl sulfonate ( 42.50gm, 231 mmol) and triethylamine (0.035L, 251 mmol) in dimethylformamide (0.05L) was added to the reaction mixture. The reaction mixture was heated to 100-110°C for 8 to l0hrs. After completion of the reaction mixture cooled to 35 to 40°C and filtered through hyflow Filtrate was treated with hexane (0.2L). Reaction mixture was quenched in water (1L) stirred and water layer was treated with ethyl acetate ( 3 X 0.2 L) followed by water. Ethyl acetate layer was evaporated to get solid. Solid was treated with ethyl acetate and hexane ( 80:20, 0.2L) to get pure solid. [ Yield 59.5gm, 78%]
Example 13
Preparation of Phenyl (E)-2-(lH-indol-5-yl) ethane sulfonate (XI):-
A mixture of phenyl sulfonate (40g, 133mmol) was hydrogenated using 50 % wet palladium on charcoal (63gm)) in a mixture of (Methanol: THF 0.2 L each) for 6 to 8h at 70-80°C at 70 psi Kg/cm2 hydrogen pressure. After completion of reaction was filtered through huff law. Filtrate was distilled to get solid. [ Yield 28 gm, 69.54%]


Example 14
Preparation of 2-(lH-indol-5-yl)-N-methyl ethane sulfonamide :-
A mixture of phenyl sulfonate (28gm, 93mmol) and methyl amine gas (8.65 gm,
280mmol) in pyridine (7.53ml, 93 mmol) was heated in autoclave at 100°C for 3
hrs. After reaction mixture was over the mixture was filtered and filtrate concentrated to get oil. [Yield 3gm, 13.55%].
Preparation of Amorphous Naratriptan hydrochloride Example 15
lg Naratriptan HC1 was dissolved in 40 ml water at 50-60°C. The hot solution was filtered to remove insoluble matter. The clear solution was lyophilized for 24 h to get amorphous form of Naratriptan HC1
Example 16
l0g Naratriptan was suspended in 250 ml water at 40-50°C. To this suspension 2.6 ml Cone. HC1 was added. The hot solution was filtered to remove insoluble matter. The clear solution was lyophilized for 24h to get amorphous form of Naratriptan HC1
Example 17
20g of Naratriptan.HC1 was dissolved in 400 ml water at 50-60°C. The solution was filtered to get clear solution. The clear solution was spray dried. Spray drying is carried out at the inlet temperature 120°C and outlet temperature 65°C to get Amorphous Naratriptan HC1.


Example 18
20g of Naratriptan was dissolved in 400 mL water at 50-60°C. To this suspension 5.2 ml Cone. HCl was added. The solution was filtered to get clear solution. The clear solution was spray dried. Spray drying is carried out at the inlet temperature 120°C and outlet temperature 65°C to get Amorphous Naratriptan HCl.
Example 19
5g Naratriptan HCl was dissolved in 150 ml water at a temperature range of 50-60°C. The clear solution is concentrated under vacuum at 65°C to get Amorphous Naratriptan HCl.
Example 20
l0g Naratriptan was suspended in 250 ml water at 40-50°C. To this suspension 2.6 ml Cone. HCl was added. The hot solution was filtered to remove insoluble matter. The clear solution is concentrated under vacuum at 65°C to get Amorphous Naratriptan. HCl.