FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION (See section 10 and rule 13)


PROCESS FOR THE PREPARATION OF
N-METHYL-2-[3-(l-METHYL-4~PIPERIDYL)-lH-ND0L-5-YL]-ETHANESULF0NAMIDE
AND ITS ACID ADDITION SALTS
SUN PHARMACEUTICAL INDUSTRIES LTD.

A company incorporated under the laws of India having their office at 17/B. MAHAL INDUSTRIAL ESTATE. MAHAKALl CAVES ROAD, ANDHERI (E), MUMBAI-400093,
MAHARASHTRA, INDIA.

The following specification describes the nature of this invention.
.148613&I2008
ki5. JULZ0Q8

FIELD OF INVENTION
The present invention relates to an improved process for preparing N-methyI-2-[3-
(l-methyl-4-piperidyl)-lH-indol-5-yl]-ethanesulfonamide1 a compound of formula 1 or its acid addition salts.

Formula 1
The compound of formula I. commonly known as Naratriptan. is a selective 5-HTi receptor agonist, which binds to the 5-HTI receptors located on the intracranial bJood vessels with high affinity and produces vasoconstriction.
BACKGROUND OF THE INVENTION
United States patent no. 4.997,841 (referred to as '841 hereinafter) describes naratriptan and related compounds and salts thereof as being useful in the treatment of migraine, cluster headache and headache associated with vascular disorders. The hydrochloride salt of naratriptan is an approved drug which is marketed in several countries worldwide for the acute treatment of migraine attacks in adults. In United States it is sold under the trade name AMERGE* (Glaxo Smithkline Beecham).
The '841 patent discloses process for preparing naratriptan and related compounds. One of the processes for preparing naratriptan involves reaction of 2-(4-Hydrazino-pheny])-ethanesulfonic acid methylamide, & compound of formula 2, with (l-Methyl-pJperidin-4-yl)-acelaldehyde, a compound of formula 3. (See Scheme I).
2


Scheme I
This reaction suffers from several limitations, such as:
• it requires a prolonged reaction time of about 2 days;
• the intermediate hydrazone product of the reaction of compound of formula 2 with compound of formula 3, is isolated as a crude oil and requires addition of further quantities of Lewis acid such as polyphosphate ester for its further conversion to naratriptan,
• The process involves use of flash chromatography for the purification of naratriptan. which is not feasible for large scale production,
• the yields obtained are poor (about 7%).
European Patent Application No. 0581538 (referred to as EP'538 hereinafter) discloses a method of preparing (l-Methyl-piperidin-4-y])-acetaldehyde, the compound of formula 3, starting from l-methyl-piperidin-4-one, a compound of formula 4. The process involves four steps as outlined in Scheme II and are as follows:
1. Reaction of l-methyl-piperidin-4-one, a compound of formula 4, with methyl diethyl phosphonoacetate, a compound of formula 5, in presence of sodium hydride and tetrahydrofuran (THF) to yield l-methyl-piperidin-4-ylidene-acetic acid methyl ester, a compound of formula 6.
2. Reduction of l-methyl-piperidin-4-yridene-acetic acid methyl ester, a compound of formula 6 using Pd/C, hydrogen at high atmospheric pressure
3

(40psi) and in acidic conditions to yield (l-methyl piperidin-4-yl) acetic acid methyl ester, a compound of formula 7.
3. Reduction of (l-methyl-piperidin-4-yl) acetic acid methyl ester, a compound of formula 7, to 2(l-methyl-piperidin-4-yI)-ethanol, a compound of formula 8, using D1BAL-H (Diisobutyl aluminium hydride) at sub-zero temperature of -35 °C.
4. Oxidation of 2-(l-methyl-piperidin-4-yl)-ethanoI, a compound of formula 8, to (l-Methyl-piperidin-4-yl)-acetaldehyde. a compound of formula 3, using DMSO and oxalyl chloride

Scheme II
In another reference. Borne et al J, Met. Chem., 869, 1972, l-methyl-piperidin-4-ylidene-acetic acid ethyl ester, the compound of formula 6, is prepared in a manner
4

similar to that in '538 patent using monoglyme as a solvent.
These prior art process for preparing compound of formula 3 have a number of limitations, such as:
• The reaction in step 1 involves use of hazardous and highly reactive base such as sodium hydride, which is very sensitive towards moisture and warrants absolute anhydrous conditions.
• The reaction in step 2 involves reduction using elevated pressure and acidic conditions and step 3 employs sub-zero temperatures upto -35°C for the reduction of the ester compound of Formula 7.
• The overall yield of acetaldehydc intermediate, a compound of formula 3, is only about 6-7%.
These [imitations in combination with the high cost of reagents and solvents, seriously jeopardize the industrial applicability of the process.
Therefore, there is a strong need for a commercially viable process for preparing
N-methyl-2-[3-(l-methyl-4-piperidinyl)-lH-indol-5yl]-ethanesuIfonamide, a
compound of formula 1, or acid addition salt thereof, which uses safer reagents, milder conditions of temperature, produces high yield of quality material and is suitable for large scale production. The commercial feasibility of such a process for preparing compound of formula 1 is highly dependent on an industrially viable and economical method for preparing (l-Methyl-pipeHdin-4-yl)-acetaldehyde, the compound of formula 3, which is a key intermediate in the synthesis of compound of formula 1, naratriptan.
The present invention provides a process for preparation of N-methyl-2-[3-(l-methyl-4-piperidy])-lH-indol-5yl]-ethanesulfonamide, the compound of formula 1, or acid addition salt thereof by using safer reagents and milder conditions of
5

temperature to produce high yield of quality material and is suitable for large scale production.
The present invention also provides a process for the preparation of (1—Methyl— piperidin-4-yl)-acetaldehyde, a compound of formula 3.
The process of the present invention for preparing compound of formula 3 is advantageous as step 1 is carried out using innocuous base like potassium hydroxide in place of hazardous base like sodium hydride and obviates the need of absolute anhydrous conditions. Further the hydrogenation of the olefinic ester in the second step requires atmospheric pressure or very low pressure of upto lKg/cma as compared to high atmospheric pressure of 40psi used by the EP'538 process. Further, the hydrogenation is carried out under non-acid conditions as compared to use of mineral acid by EP'538 process. Also, the reduction of the ester in the third step is carried out at temperatures in the range of -5°C to 10°C as compared to the drastic sub-zero temperature of -35°C required in the EP'538 process. The present invention provides 6 times higher yield of the compound of formula 3 as compared to the process disclosed in EP'838 patent. Further, in one aspect the method of preparation of compound of formula 3 involves lesser number of steps as compared to the process of prior art. Thus the process of the present invention uses safer reagents and milder conditions of temperature.
The reaction of compound of formula 2 with compound of formula 3 to give compound of formula 1 is a single pot reaction which does not require isolation of the intermediate hydrazone product and addition of any further quantities of acid like polyphosphates, which is an added advantage over the prior known process for the said step. Further, the process requires considerably lesser time as compared to the '841 process which requires a time period of 2 days. A substantially higher yield of 66% is obtained in this step as compared to 7% yield obtained in the '841 patent.
6

DESCRIPTION OF THE INVENTION
The present invention relates to a process for the preparation of compound of
formula 1 or acid addition salt thereof

Formula 1

Formula 4
One aspect of the present invention relates to an improved process for preparing compound of formula 1 or salts thereof, wherein the process comprises the steps of: (a) Reacting a compound of formula 4
with a compound of formula 5,

Formula 5
in the presence of a base selected from the group consisting of alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates or mixtures thereof, to obtain a compound of formula 6
7


Formula 6
wherein each RL in Formula 5 and Formula 6 is independently selected from C1-C5 alkyl.
(b) catalytically hydrogenating the compound of formula 6 under atmospheric
conditions to obtain a compound of formula 7

wherein R1 has the meaning as defined above
(c) reacting the compound of formula 7, with sodium bis(2-methoxyethoxy)
aluminum hydride, to a compound of formula 8

(d) reacting the compound of formula 8, with dimethyl sulfoxide and oxalyl
chloride in presence of an organic base to obtain compound of formula 3, and
8


(e) converting the compound of formula 3, to a compound of formula 1 or its salt.
Scheme ill represents the process outlined above in steps a.b.c.d and e.
In another aspect, the present invention related to a novel process for preparing
N-methyl-2-[3-(l-methyl-4-piperidyl)-lHindol-5-yl]-ethanesulfonamide, a
compound of formula 1 or acid addition salts thereof.

Formula 1
9
wherein the process comprises the steps of: (a) reacting a compound of formula 4


with a compound of formula 5,
o
Formula 5
in the presence of a base selected from the group consisting of alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates or mixtures thereof, to obtain a compound of formula 6

wherein each Ri in Formula 5 and Formula 6 is independently selected from Ci-C5 alkyl.
(b) catalytically hydrogenating the compound of formula 6 under atmospheric conditions to obtain a compound of formula 7

wherein R1 has the meaning as defined above,
(c') reacting compound of formula 7, with diisobutyl aluminium hydride in presence of an alkali metal alkoxide to obtain a compound of formula 3, and
10


Formula 3
(e) converting the compound of formula 3, to compound of formula 1 or its salt.
Scheme IV represents the process outlined above in steps a,b,c' and e.

The processes of the present, invention for preparation of compound of formula 1 or salts thereof, as illustrated in Schemes III and IV, are described herein in detail. The processes as summarized above and as outlined in Scheme III and IV, involve the
11

steps a, b and e which are common for both the processes and hence each of these steps are described herein in context to both the schemes III and IV.
As per scheme III of the present invention, the process involves the steps a, b, c, d and e. Step a involves reaction of N-methyl piperidin-4-one i.e. the compound of formula 4 with a phosphonate ester i.e. the compound of formula 5, in the presence of a base selected from the group consisting of alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates or mixtures thereof, to obtain an olefinic ester, a compound of formula 6.
The alkali metal hydroxide may be selected from potassium hydroxide, sodium hydroxide, cesium hydroxide, barium hydroxide, lithium hydroxide or tetrabutylammonium hydroxide and the like. The preferred alkali metal hydroxide is potassium hydroxide.
The alkali carbonate may be selected from sodium carbonate, potassium carbonate, lithium carbonate and the like. The preferred alkali carbonate is potassium carbonate. The reaction may also be carried out in the presence of mixtures of an alkali metal hydroxide and an alkali metal carbonate, for example, in presence of mixture of potassium hydroxide and potassium carbonate.
Further, the reaction may be advantageously carried out in presence of an organic solvent in anhydrous conditions at about 60-65°C. Reaction temperature preferably should not exceed 70°C. A suitable organic solvent for the reaction may be selected from a poiar to moderately polar or non-pofar aprotic organic solvent, The solvent may be selected from a sulfoxide like dimethylsulfoxide; an amide like dimethylacetamide or dimethylformamide; a nitrile like acetonitrile, benzonitrile, an ether like diethylether or tetrahydrofuran, an aromatic or aliphatic hydrocarbon like toluene, chlorobenzene, heptane, hexane, etc. Preferably the organic solvent is
12

an aprotic non-polar organic solvent. More preferably, the aprotic non-polar organic solvent is toluene.
Suitable phosphonate esters which may be used according to the present invention are compounds of formula 5 wherein each R1 is independently selected from C1-C5 alkyl. For example, each R1 may be independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl. Accordingly, a suitable phosphonate ester may be triethyl phosphonoacetate, ethyl dimethyl phosphonoacetate or the like. The prefered phosphonate ester is triethyl phosphonoacetate.
The suitable phosphonate ester, a compound of formula 5, may be prepared from a trialkyl phosphite and a halo alkylester. For instance, triethyl phosphonoacetate may be prepared by reacting triethyl phosphite with ethyl bromoacetate. The reaction may be carried out with or without a solvent at a temperature ranging from 70-95 °C. Preferably, the reaction is carried out without a solvent at a temperature of 90-95 °C.
Step b involves hydrogenation of the olefinic ester of formula 6 obtained in step a above, to obtain a saturated ester derivative i.e. the compound of formula 7. The reaction may be carried out in presence of a metal catalyst and hydrogen gas in- a suitable organic solvent. Further, the reaction is preferably carried out in the absence of any mineral or organic acid.
A metal catalyst may be selected from the group of noble metal catalysts like palladium, platinum, rhodium etc. Preferably the metal catalyst is palladium supported on Carbon. Preferred grade of Pd/C being 39-C supplied by M/s Arora . Matthey (India). The reaction may be carried out by purging hydrogen gas to the reaction mixture containing the metal catalyst and the compound of formula 6, at atmospheric pressure or preferably at very low pressure of upto lKg/cm2.
13

The reaction may be carried out at a temperature ranging from 15—40°C. The reaction may be carried out in presence of a suitable organic solvent selected from group of alkanols like methanol, ethanol, isopropanol or n-butanol. The prefered solvent is Methanol.
Step c according to scheme HI, involves reduction of the saturated ester derivative of formula 7 to obtain 2-(l-methyl-piperidin-4-yl)-ethanol i.e. the compound of formula 8, in presence of sodium bis(2-melhoxyethoxy) aluminum hydride. The hydride, sodium bis(2-methoxyethoxy) aluminum hydride is commonly known as vitride.
The reaction may be carried out at a temperature ranging from subzero to 40°C, preferably from -5 °C to 10°C. The reaction may be carried out in presence of an organic solvent selected from the group consisting of aromatic hydrocarbons or ethers. The aromatic hydrocarbon may be selected from toluene, xylene and the like. Preferably the organic solvent is toluene.
Step d of scheme 111 involves reaction of 2-(l-methyl-piperidin-4-yl)-ethanol i.e. compound of formula 8 with dimethyl sulfoxide and oxalyl chloride in presence of an organic base, to obtain (1 —Methyl—piperidin—4—yl) acetaldehyde compound of formula 3.
The organic base may be selected from triethylamine, tri n-propylamine, tri n-butylamine, tri-n-pentylamine or diisopropyl ethyl amine. Triethylamine is preferred as the organic base. The reaction may be carried out at -70 to -50°C, preferably -65 to -60°C, in presence of Dichloromethane. This reaction is known as Swern oxidation. The present invention intends to cover the variations of Swern oxidation within its scope.
14

Step e of the process involves converting (1 -Methyl—piperidin—4-yl) acetaldehyde, a compound of formula 3, to N-meLhyl-2-[3-(l-methyI-4-piperidyI)-i^indol-5-yl]-ethanesulfonamide. compound of formula 1 or its salt. This process involves the reaction of a hydrazine compound of formula 2 with acetaldehyde intermediate compound of formula 3. The reaction may be carried out in acid catalysts in presence of an organic solvent.
Suitable acid catalyst for the reaction may be selected from mineral acids like hydrochloric acid, sulfuric acid, polyphosphorc acid, or lewis acid like zinc chloride, aluminium chloride and the like.
A suitable solvent can be selected from alkanols like methanol, ethanol, isopropanol etc. Preferably, the reaction is carriea' out using nydrocMoric acid as the acid catalysts and Ethanol as the solvent. Further, the reaction may be carried out at a temperature from 50 °C to 80 °C for a period of 10-15hrs, preferably between 70 °C to 80 °C for a period of 12-14hrs. According to a preferred aspect of the present invention the reaction is advantageously carried out in a single pot without isolating the intermediate hydrazone product.
Step (e) may yield compound of formula 1 in the form of base or salt. Alternatively, the compound of formula 1 may be converted to its salt. Since the compound of formula 1 possess a basic center (Tertiary amine) in its structure, it can form acid addition salts. The acid addition salts may be selected from mineral acid salts e.g. hydrochloride, hydrobromide. sulfate, organic acid salts e.g. citrate succinate, maleate, fumarate, malate, tartarate, myristate, pamoate, etc.. sulfonates e.g. methanesulfonates, benzenesulfonates. toluensulfonates and other salts which are customarily employed in pharmaceutical field in connection with the basic compounds. Preferably the salt is hydrochloride salt. The process of preparation of
15

such acid addition salt of a basic drug is well known in the art.
According to the second embodiment, the process of the present invention for the
preparation of N-methyl-2-[3-(l-methyN4-piperidyl)-lj^indol-5-yl]-
ethanesulfonamide(Naratriptan) i.e, the compound of formula 1, involves a four step reaction starting from N-methyl-piperidinone i.e. a compound of formula 4. The process, as summarized in Scheme IV above, is as described below.
According Lo Scheme IV the process involves the steps a, b, c' and e. As mentioned hereinabove, the process of steps a, b, and e according to the present invention, are common to both the Scheme III and IV, and hence, the same as described above is applicable to either of the routes disclosed in Schemes III and IV.
Step c" of the process, as per scheme 17, involves reaction of the saturated ester derivative obtained in step (b) with diisobutyl aluminium hydride in presence of an alkali metal alkoxide to obtain 1—methyl—piperidin—4—yl acetaldehyde compound of formula 3. The reaction may be carried out in presence of a suitable organic solvent.
The alkali metal alkoxide may be selected from sodium ^-butoxide, potassium- i-butoxide and the like, sodium-/-butoxide being the prefered alkali metal alkoxide.
A suitable organic soivent for the reaction may be selected from the group consisting of ethers. or aromatic and/or aliphatic hydrocarbons. Suitable ether may be diethylether, Diphenylether, tetrahydrofuran (THF). An aromatic and/or aliphatic hydrocarbon solvent may be Toluene. Cyclohexane. Hexane, Heptane and the likes or mixtures thereof. The prefered organic solvent is THF. The reaction can be carried out at a temperature range of -20 °C to 10°C, preferably in the temperature range of -5°C to OX.
16

The following examples illustrate the process of the present invention which should not be construed as constituting a limitation thereto.
Example t Preparation of (l-Methyl-piperidin-4-yIidene)-acetic acid ethyl ester
(a) Preparation of (Diethoxyphosphoryl)-acetic acid ethyl ester
To a 3-neck RBF, triethyl phosphate (99.7g, 0.59moles) was added, and the flask was gradually heated to 65-70°C under stirring. Ethyl bromoacetate (66.6ml, 0.59moles) was added to the flask in a drop-wise manner maintaining the temperature of the reaction mixture between 65-95'C. The reaction mixture was then heated to 70-75'C and maintained at this temperature for 2 to 3 hr. After the completion of the reaction, the mixture was allowed to cool to 45-50°C and degassed. The yield obtained is 100 %.
(b) Preparation of (1 -Melhyl-piperidin-4-ylidene)—acetic acid ethyl ester
Toluene (900ml) was added to a 3-neck RBF equipped with an overhead stirrer, powder funnel and stirrer. Sodium sulfate (Anhydrous) (134g), Potassium carbonate (83g, 0.600) and (diethoxy-phosphoryl)-acetic acid ethyl ester (134g, 0.59moles ) (as prepared above in example la) were gradually added in a series to the flask to form a suspension. 1-Methyl piperidin-4-one(68g, 0.600moles) in 440mL Toluene. (80g, 1.42moles) was added to the suspension, followed by addition of potassium hydroxide (pellets, 85%). The reaction mixture was stirred and was maintained with stirring for 30min, maintaining the temperature of the reaction below 70°C. The reaction was quenched by addition of solution of. sodium bisulphite (15.5g) in 1300ml DM water, The toluene layer was separated and washed with 1300mL sodium bisulphite solution, DM water (2xl340mL) and warm water (2xl340mL). Toluene was distilled out at a temperature of 35-45'C under vacuum. The syrup obtained was degassed for 1-2 hrs to obtain the product as pale yellow colored syrup Yield 52.9%
17

Example 2 Preparation of (l-Methyl-piperidin-4-yl)-acetic acid ethyl ester
To a 3-neck RBF equipped over magnetic stirrer, powder funnel, hydrogen bubbler and thermometer pocket, was added (1 -Methyl—piperidin-4-ylidene)-acetic acid ethyl ester (tOOg, 0.54moles) (prepared in example 1 above) and lOOOmL of methanol. The flask was stirred at 25-30'C to obtain clear solution. lOg of palladium suspended in lOmL of DM water was added to the clear solution and the flask was purged with nitrogen and then with hydrogen gas at 25-30'C. The flask was maintained at 25-30°C with continuous bubbling of hydrogen gas at atmospheric pressure for 3-5 hrs. After completion of the reaction, the reaction mixture was filtered and the methanolic solution was collected. The methanolic solution was distilled at 35-45°C under vacuum, followed by co-distillation with toluene. The syrup obtained was degassed for 1.0-2.0hr under vacuum at 35-45°C to yield product as pale yellow syrup. Yield- 95.4%
Example 3 Preparation of 2-(l-Methyl-piperidin-4-yi)-ethanol
(l-Methyl-piperidin-4-y!)-acetic acid ethyl ester (lOOg, 0.54moles) in 600mL of tetrahydrofuran was stirred under nitrogen atmosphere to obtain a clear solution. The solution was cooled to 10-15 °C and vitride solution (670mL, 65% solution in toluene) was added to it with stirring, maintaining temperature of the reaction mixture below 30°C. The reaction mixture was maintained with stirring at 25-30°C for 3-4 hrs. After completion of reaction, the flask was cooled to 10—15°C and sodium hydroxide solution (10% solution in DM water) was added to the reaction mixture at a temperature below 30°C. the flask was maintained with stirring for 30min.to the flask, toluene (800ml) was added and stirring was continued for another 30min. The layers were separated and the toluene layer collected was distilled under vacuum.
18

The syrup obtained was degassed for l-2hr under vacuum at 35-45°C to obtain product as pale yellow colored syrup. Yield: 90 %
Example 4 Preparation of (l-Methyl-piperidin-4~yl)-acetaldehyde
Dimelhylsulfoxide (l20g. l-68moles) was charged to dichloromethane (5500mL) in a RBF and stirred to obtain a clear solution. The solution was cooled to -60 to -65 °C and oxalyl chloride (80mL, 0.84 moles) was added gradually to the above solution maintained at a temperature below -60 °C. A solution of 2-(l-Methyl-piperidin-4-yl)-ethanol (lOOg, 0.69moles) (prepared above in example 3) in dichloromethane (1500mL) was added to the reaction mixture, gradually over a period of about lhr. The reaction mixture was maintained with stirring at -60 to -65 °C for 25-30min. Triethylamine (500mL. 3.58moles) was added to the reaction flask and the reaction mixture was stirred for 15-20min. The temperature was gradually raised to 20-25'C and reaction mixture was stirred for 2 hrs. The reaction was quenched by addition of DM water (500mL) and the flask was maintained with stirring for 30 min. the layers were separated and the dichloromethane layer was collected. The dicholoromethane layer was distilled out under reduced pressure top obtain a syrup which was degassed for 1-2 hrs to obtain the product as pale yellow syrup. Yield—51%
Example 5 Preparation of (l-Methyl-piperidin-4-yl)-acetaldehyde
(a) Preparation of Sodium diisobutyW-butoxyaluminium hydride reagent; To a 3.01it 3-neck RB flask assembly equipped with overhead stirrer, powder funnel, nitrogen bubbler and thermometer pocket, sodium- feW-butoxide (80g, Q.83moles) and tetrahydrofuran (400mL) was added under nitrogen pressure. The suspension obtained was cooled to -5 to 0°C and DIBAH (20% solution in toluene, 680mL) was added to it maintaining the temperature between -5 to 0°C. The temperature of the
19

reaction mixture was allowed to increase gradually to 20-25°C and it was maintained at this temperature with stirring for 2hrs.
(b) To a 3-neck RB flask assembly equipped with overhead stirrer, powder funnel, nitrogen bubbler and thermometer pocket, (l-Methyl-piperidin-4—yl)-acetic acid ethyl ester (lOOg, 0.54moles) and tetrahydrofuran (400mL) was added at 25-30°C to obtain a solution. The reaction mixture was cooled to -5 to 0°C and sodium diisobutyl- /-butoxyaluminium hydride reagent (as prepared in step 6a above) was added to il, maintaining the temperature of the reaction mixture between -5 to 0°C. The reaction mixture was maintained at -5 to 0°C under nitrogen pressure for 2-3hrs. After completion of the reaction, the reaction was quenched by addition of methanol (80ml) maintaining the temperature between -5 to 0°C. The flask was stirred for 10-15 min at -5 to 0°C. D M water (400mL) was added to the reaction mixture maintaining the temperature below Z0°C. The product was extracted from the quenched reaction mixture using toluene (2xl000mL). The toluene layer was cooled, dried using anhydrous sodium sulphate and was distilled off completely under vacuum. The product obtained was degassed for 1-2 hr to yield the product as pale yellow syrup. Yield—75%
Example 6
Preparation of vVLmethyl-2-[3-(l-methyl-4-piperidyl)-lH-indol-5-yl]-
ethanesulfonamide hydrochloride (Naratriptan hydrochloride)
A solution of 2-(l-Methylpiperidin-4-yl)-acetaldehyde(100gm) and Ethanol(500ml)was mixed with 2-(4-Hydrazino-phenyl) ethane sulfonic acid methyl-amide hydrochloride (160 gm) and stirred at 25-30°C. Hydrochloric acid (100ml) and Acetic acid(lOOml) were added to the mixture and stirred at 25-30°C. The mixture was gradually heated to 60-65°C and stirred for 12-16 hour at that temperature. The reaction mixture was cooled to 25-30°C and water (20 Vol) was added with continued stirring. The stirred solution was basified with Caustic lye
20

solution (400ml) and the product was extracted into dichloromethane. The organic layer was dried over Sodium sulfate and distilled out under vacuum to obtain syrup. The syrup was solubilised in Ethanol(5 Vol.' wrt Naratriptan base syrup) and hydrochloric acid was added. The solution was stirred at 25-30QC for 10-12 hrs to obtain solid. Yield 66%.
The present invention can be summarized as follows:
I) A process of preparing a compound of formula 1 and its acid addition salts thereof

Formula 1
comprising the steps of :
(a) reacting a compound of formula 4

Formula 5
in the presence of a base selected from the group consisting of alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates or mixtures thereof, to obtain an olefinic ester, a compound of formula 6
21


wherein each Rt in Formula 5 and Formula 6 is independently selected from C1-C5 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.
(b) Hydrogenating the compound of formula 6 obtained in step (a) above, to
obtain a compound of formula 7

wherein R1 has the meaning as defined above
(c) Reacting the compound of formula 7 with sodium bis(2-methoxyethoxy)
aluminum hydride to obtain a compound of formula 8

(d) Reacting the compound of formula 8, with dimethyl sulfoxide and oxalyl
chloride in presence of an organic base to obtain a compound of formula 3,
22


Formula 3
(e) converting the compound of formula 3 to a compound of formula 1 or its acid addition salt.
II) The process as in I, wherein the phosphonate ester is selected from a group consisting of triethyl phosphonoacetate, ethyl dimethyl phosphonoacetate and ethyl diphenyl phosphonoacetate.
III) The process as in II, wherein the phosphonate ester is triethyl phosphonoacetate.
IV) The process as in I. wherein alkali metal hydroxide is selected from a group consisting of potassium hydroxide, sodium hydroxide, cesium hydroxide, barium hydroxide and Lithium hydroxide
V) The process as in IV, wherein the alkali metal hydroxide is potassium hydroxide.
VI) The process as in I, wherein the alkali metal carbonate is selected from a group consisting of potassium carbonate, sodium carbonate and lithium carbonate.
VII) The process as in VI wherein the alkali metal carbonate is potassium carbonate. VIII). The process as in I wherein step a is carried out in presence potassium hydroxide and potassium carbonate.
IX) The process as in I, wherein hydrogenation is carried out at atmospheric
pressure.
X) The process as in 1 wherein the organic base in step d is selected from a group consisting of triethylamine, tri n-propy!amine, tri n-butylamine, tri-n-pentylamine and diisopropyl ethyl amine.
XI) The process as in V11I wherein the organic base is triethylamine.
XII) The process as in i. wherein step e is carried out by reacting the compound of
23

formula 1
formula 3 with a hydrazine compound of formula 2
o

Scheme I
at a temperature of 50 °C to 80 °C for a period of 10—15hrs. XIII) A process of preparing a compound of formula 1 or its acid addition salts thereof

Formula 1
comprising the steps of :
(a) Reacting a compound of formula 4

Formula 5
in the presence of a base selected from the group consisting of alkali metal hydroxides or alkali metal carbonates, bicarbonates or mixtures thereof, to obtain an olefinic ester, a compound of formula 6
24


wherein each R1 in Formula 5 and Formula 6 is independently selected from C1-C5 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.
(b) Hydrogenating the compound of formula 6 obtained in step (a) above, to
obtain a compound of formula 7

wherein R1 has the meaning as defined above
(c) reacting the compound of formula 7 with diisobutyl aluminium hydride in
presence of an alkali metal alkoxide to obtain a compound of formula 3,

(d) converting the compound of formula 3 to a compound of formula 1 or
its acid addition salt.
XIV) The process as in XIII, wherein the alkali metal alkoxide used in step c, is
25

selected from sodium /-butoxide or potassium-/butoxide.
XV) The process as in XIII, wherein-step d is carried out by reacting the compound of formula 3 with a hydrazine compound of formula 2, at a temperature of 50 °C to 80 GC for a period of 10—15hrs.
Dated this 14ih Day of July, 2008 (Signature) "^S^Pr^T^M..^^.
DIL1P SHANGHVI
CHAIRMAN AND MANAGING DIRECTOR
SUN PHARMACEUTICAL INDUSTRIES LTD,
26