WO2008056378A2

WO2008056378A2 - Novel process for the preparation of naratriptan hydrochloride

Info

Publication number: WO2008056378A2
Application number: PCT/IN2007/000534
Authority: WO
Inventors: Muddasani Pulla Reddy; Reddy Peddi Rajasekhara; Nannapaneni Venkaiah Chowdary
Original assignee: Natco Pharma Limited
Priority date: 2006-11-09
Filing date: 2007-11-09
Publication date: 2008-05-15
Also published as: WO2008056378A3

Abstract

Present invention provides a novel and improved process for the preparation of N- methyl-1H-indole-5-ethanesulfonamide of formula (I). Compound of formula (I) is a key intermediate used in the synthesis of naratriptan hydrochloride of formula (II). Hydrazone derivative of formula (XL) derived from the corresponding hydrazine and pyruvate ester is reacted with an acid catalyst to get the indole-2-carboxylate derivative of formula (XLI). Hydrolysis of this ester and decarboxylation gave the compound of formula (I). Naratriptan hydrochloride (Amerge) is widely used as anti-migraine drug in the market.

Description

FIELD OF INVENTION

Present invention relates to a novel and improved process for the preparation of N- methyl-lH-indole-5-ethanesulfonamide of formula I. Compound of formula I is a key intermediate used in the synthesis of naratriptan hydrochloride of formula II.

Naratriptan is a serotonin 5-HTW_ID receptor agonist and its pharmaceutical salts are widely used as anti-migraine agents and also for cluster headaches. Naratriptan hydrochloride (Amerge) is widely used as anti-migraine drug in the market.

BACKGROUND OF INVENTION

Naratriptan and its pharmaceutically acceptable salts and solvates are reported for the first time in GB2208646 (corresponding EP 303507 and US 4997841) by Glaxo. In the literature eight routes are disclosed for the preparation of naratriptan and its pharmaceutically acceptable salts. According to US 4997841, 5-bromoindole of formula III is reacted with N-methyl-4-piperidone of formula IV to get 3-substituted indole derivative of formula V (Scheme 1).

VII

Scheme 1 Hydrogenation of compound of formula V with platinum oxide gave the compound of formula VI. Heck reaction on compound of formula VI with N-methylvinylsulfonamide gave the indole derivative of formula VII. Hydrogenation of compound of formula VII in the presence of palladium catalyst followed by treatment with hydrochloric acid gave naratriptan hydrochloride of formula H.

According to another process of US 4997841, 5-bromoindole of formula III is reacted with N-methylvinylslfonamide under Heck reaction conditions to get the vinyl derivative of formula VIII (Scheme 2). Reduction of the vinyl group present in compound of formula VIII under hydrogenation conditions gave the compound of formula I. Condensation of compound of formula I with N-methyl-4-piperidone of formula IV gave the naratriptan precursor of formula IX. Hydrogenation of compound of formula IX under heterogeneous conditions gave naratriptan hydrochloride of formula II after treatment with HCl.

VIII

IX

Scheme 2

According to one more process disclosed in US 4997841 phenylhydrazine derivative of formula X is reacted with the aldehyde of formula XI under Fischer indolization conditions to get naratriptan base which on treatment with HCl gave its hydrochloride salt of formula II (Scheme 3).

Scheme 3

A process for the preparation of naratriptan hydrochloride of formula II is disclosed in US 5786473 involving a novel intermediate (Scheme 4). According to the process disclosed in this patent 5-bromoindole of formula III is reacted with N-methyl-4- piperidone of formula IV to get the known intermediate of formula V. Compound of formula V is reacted with N-methylvinylsulfone to get the novel intermediate of formula XII. Reduction of double bonds present in compound of formula XII under heterogeneous hydrogenation conditions gave naratriptan base which on treatment with HCl gave naratriptan hydrochloride of formula II.

XII Il

Scheme 4

WO 2006/010079 teaches a method for the preparation of naratriptan hydrochloride based on Zapp-Klingemann reaction as a key step in building the indole moiety.

Scheme 5

Accordingly, aniline derivative of formula XII is diazotized and reacted with a pyridyl/piperidinyl acetoacetate derivative to get the corresponding hydrazone derivative which on cyclization gave the indole-2 -carboxylase derivative of formulae XVI or XIX. These intermediates are converted to naratriptan hydrochloride by conventional chemistry.

A process for the preparation of naratriptan hydrochloride is reported by BeIa Pete (Heterocycles, 2003, 60, 2441) avoiding the earlier known Heck reaction. Accordingly,

XXI XXII XXIII

Scheme 6 p-nitrobenzaldehyde of formula XXI is reacted with isopropyl methanesulfonate to get the benzylalcohol derivative of formula XXII. Compound of formula XXII is reacted methanesulfonyl chloride in the presence of triethylamine to get the vinylsulfonate derivative of formula XXIII. Hydrolysis of this vinylsufonate ester with sodium iodide gave the corresponding sodium sulfonate of formula XXIV. Reaction of the sodium sulfonate of formula XXIV with thionyl chloride followed by N-methylbenzylamine gave the soulfonamide derivative of formula XXVI. Hydrogenation of compound of formula XXVI gave the aniline derivative of formula XXVII. Reductive N-alkylation of compound of formula XXVII with glyoxal monoacetal gave the compound of formula XXVIII which on reaction with trifluoroacetic anhydride gave the compound of formula XXIX. Reaction of compound of formula XXIX with titanium tetrachloride gave the required indole derivative of formula XXX. Hydrolysis with methanolic potassium hydroxide gave the compound of formula XXXI. Reaction of compound of formula XXXI with N-methyl-4-piperidone gave the compound of formula XXXII. Hydrogenation of compound of formula XXXII followed by N-debenzylation using sodium/liquid ammonia gave naratriptan base. Overall yield of naratriptan base is 3.6%.

A process for the preparation of naratriptan hydrochloride is recently described by Laszlo (Heterocycles, 2006, 68, 713). l-Benzylindoline-5-carboxaldehyde of formula XXXIII is oxidized to get the corresponding indole derivative of formula XXXIV (Scheme 7).

Scheme 7

Condensation of the aldehyde group present in compound of formula XXXIV with methanesulfonamide derivative gave the corresponding sulfonamide derivative of formula XXXV. Hydrogenation followed by condensation with N-methyl-4-piperidone gave the compound of formula XXXVII. Hydrogenation followed by deprotection of N- benzyl group with sodium/liquid ammonia gave naratriptan base.

Main drawback in the process disclosed in US 4997841 (Schemes 1&2) and US 5786473 (Scheme 4) is the requirement of palladium acetate and tri-o-tolylphosphine in the process. Both these raw materials are very expensive. Also N-methylvinylsulfonamide used in the process is not commercially available. Preparation of N- methylvinylsulfonamide is difficult due to its polymerization property. Main drawback in the process disclosed in US 4997841 (Scheme 3) is the preparation of the aldehyde intermediate of formula XI. Process for this intermediate requires more than six steps and the overall yield is very low. Also the yield of naratriptan produced in this process is less than 10%. Main drawback in the process disclosed in WO 2006/010079 (Scheme 5) is the usage of costly reagents like pyridine-4-carboxaldehyde and methyl iodide. Also the number of steps is more in this process. Process disclosed in Heterocycles, 2003, 60, 2441 (Scheme 6) is novel but not suitable for commercialization mainly due to number of steps involved in the synthesis, usage of costly reagents like p-nitrobenzaldehyde, trofluoroacetic anhydride, and potassium t-butoxide. Similarly process disclosed in Heterocycles, 2006, 68, 713 (Scheme 7) is novel but requires costly raw material like indoline-5-carboxaldehyde, titanium tetrachloride. This process is also not viable for commercialization due to pollution associated with titanium salts produced in the process.

Keeping in view of the difficulties in commercialization of the above-mentioned processes for the preparation of naratriptan hydrocholride, we aimed to develop a simple and economical process for commercial production of naratriptan hydrochloride.

We observed that a promising approach for a process for the preparation of naratriptan hydrochloride would be to (a) avoid the usage of costly and hazardous reagents like palladium acetate, tri-o-tolylphosphine, methyl iodide, p-nitrobenzaldehyde, indoline-5- carboxaldehyde, and N-methylvinylsulfonamide.

Accordingly, the main objective of the present invention is to provide an improved process for the preparation of naratriptan hydrochloride, which is commercially applicable. Another objective of the present invention is to provide an improved process for the preparation of naratriptan hydrochloride avoiding the usage of costly and hazardous reagents thereby making the process simple and economical.

PROCESS OF THE PRESENT INVENTION

The present invention has been developed based on our finding that if one forms the 5- substituted indole without a substitution at 3-postion via Fischer indolization procedure it would be easy and simple to commercialize. Introduction of the required substitution at 3-position can be made easily by following the prior art procedures. To meet this requirement we selected alkyl pyruvate and 4-hydrazino-N-methylbenzeneethane- sulfonamide as principal reactants to form the corresponding hydrazone. The resultant hydrazone is cyclized in the presence of an acid catalyst to get the 2,5-disubstituted indole. Removal of substitution at 2-position by conventional methods gave the required 5-substituted indole derivative. Process of the present invention is as shown in Scheme 8 below.

Scheme 8 Heating the hydrazine derivative of formula X with pyruvic acid esters of formula XXXIX in alcoholic solvent medium gave the corresponding hydrazone derivatives of formula XL. The hydrazone is dissolved in a solvent and treated with an acid catalyst to get the required indole-2-carboxylate of formula XLI. Hydrolysis of the ester group present in compound of formula XLI under basic conditions gave the indole-2-carboxylic acid of formula XLII in quantitative yield. Thermal decarboxylation of the acid group present in compound of formula XLII in the presence of a metal catalyst gave the required indole derivative of formula I in good yield.

Compound of formula I is reacted with N-methyl-4-piperidone of formula IV in alcoholic medium in the presence of a base to get the condensation product of formula IX in good yield. Reduction of the double bond present in compound of formula IX under heterogeneous hydrogenation conditions gave naratriptan base in high yield. Treatment of the naratriptan base with hydrochloric acid gave the pharmaceutically acceptable naratriptan hydrochloride of formula II.

Accordingly, present invention provides an improved process for the preparation of naratriptan hydrochloride of formula II,

Il which comprises:

(i) Reaction of the hydrazine derivative of formula X,

X with pyruvate esters of formula XXXIX,

O=

CO₂R XXXIX wherein R = Cj -Ci₀ alkyl or branched alkyl, C3-C₇ cycloalkyl, ArCH₂, phenyl, 1-5 substituted phenyl in a solvent medium at ambient to elevated temperature to get the hydrazone derivative of formula XL,

wherein R is as defined above

(ii) Indolization of the hydrazone of formula XL in a solvent medium and in the presence of an acid catalyst to get the indole derivative of formula XLI,

wherein R is as defined above

(iii) Hydrolysis of the compound of formula XLI using a base to get the compound of formula XLII,

(iv) Decarboxylation of compound of formula XLII at elevated temperature in the presence of a solvent and catalyst to get the indole derivative of formula I,

(v) Reaction of compound of formula I with N-methyl-4-pieridone of formula IV,

IV in the presence of a solvent and a base catalyst at ambient to elevated temperature to get the compound of formula IX,

IX

(vi) Hydrogenation of compound of formula IX in the presence of a metal catalyst to get naratriptan base

(vii) Reaction of naratriptan base with cone. Hydrochloric acid in a solvent medium to get the naratriptan hydrochloride of formula II

In a preferred embodiment of the present invention the alkyl pyruvate used in step (i) is ethyl or methyl pyruvate. Solvent used in step (i) is selected from a protic solvent such as methanol, ethanol, isopropanol, n-butanol; ethers like THF, dioxane, diethyl ether, diisopropyl ether; nitriles like acetonitrile; esters like ethyl acetate; halogenated solvents like methylene chloride, chloroform, ethylene dichloride. When ethyl pyruvate is used in the reaction corresponding hydrazone formed as a crystalline solid having a melting point of 155°C. When methanol is used as solvent and ethyl pyruvate as a reagent product consisted of ethyl and methyl ester. However when isopropanol is used as solvent product consisted of ethyl ester only.

The acid catalyst used in step (ii) is selected from acids like polyphosphoric acid (PPA), PPE (Polyphosphate ethyl ester), sulfuric acid, HCl, HBr, phosphoric acid, methanesulfonic acid, trifiuoromethanesulfonic acid, TiCl₄, ZnCl₂, SnCl₂, FeCl₃, AlCl₃, etc. The solvent employed in step (ii) is selected from halogenated solvent like methylene chloride, chloroform, ethylene dichloride; hydrocarbon solvents such as hexane, heptane, cyclohexane, toluene, xylenes; ethers like dioxane, THF, diethyl ether, diisopropyl ether, etc. Temperature of the reaction is in the range of 0-100⁰C. When the hydrazone derived from ethyl pyruvate is used in the reaction product formed as a crystalline solid in very high yield. Melting point of compound of formula XLI where R = ethyl is 162⁰C. The base used in hydrolysis step (iii) is selected from sodium or potassium carbonate, bicarbonate or hydroxide. The medium of reaction is water or aqueous alcohols. The temperature of the reaction is 25- 100⁰C. After the hydrolysis is over the compound is isolated by neutralization of reaction medium with acids such as sulfuric acid and HCl to get the required carboxylic acid of formula XLII. The yield of compound of formula XLII is almost quantitative. Melting point of compound of formula XLII is 227°C.

The catalyst used in decarboxylation step (iv) is selected from copper, copper oxides, or any other transition metals or their oxides. Temperature of the reaction is 150-250⁰C. The medium of the reaction is quinoline, picolines, and pyridine. After the reaction is over, product is isolated by vaccum distillation of solvent employed in the reaction, extraction of product into a suitable solvent such as methylene chloride, chloroform, ether, ethyl acetate, and isolation of product by crystallization from same solvent. Overall yield of the indole derivative of formula I from the hydrazine derivative is more than 50%.

The solvent employed in step (v) is selected from a protic solvent such as methanol, ethanol, isopropanol, n-butanol; ethers like THF, dioxane, diethyl ether, diisopropyl ether; nitriles like acetonitrile; hydrocarbon solvent like cyclohexane, heptane, toluene. Base catalyst employed in step (v) is selected from sodium or potassium hydroxide, carbonate, bicarbonate, sodium or potassium alkoxide. Temperature of the reaction is 25°C to reflux temperature of the solvent employed in the reaction. Metal catalyst employed in step (vi) is selected from Raney nickel, Pd/C, Platinum oxide. The solvent used in step (vi) is selected from alcoholic solvents such as methanol, ethanol, isopropanol; esters like ethyl acetate; hydrocarbon solvents like cyclohexane, heptane, and toluene. Solvent employed in step (vii) is selected from protic solvent such as methanol, ethanol, isopropanol, n-butanol; ethers like THF, dioxane, diethyl ether, diisopropyl ether; nitriles like acetonitrile; esters like ethyl acetate; halogenated solvents like methylene chloride, chloroform, ethylene dichloride. Overall yield of naratriptan hydrochloride of formula II is more than 40% and the purity of naratriptan hydrochloride is more than 99%. Present invention provides novel compounds of formulae XL, XLI, and XLII.

The details of the invention are given in the Examples given below which are provided to illustrate the invention only and therefore should not be construed to limit the scope of the present invention.

Example 1

Preparation of 2-(lH-indol-5-yl)-N-methyIethanesulfonamide of formula I (i) Preparation of 4-Hydrazino-N-methylbenzeneethanesuIfonamide Hydrochloride of the formula X

Into a IL, four-necked RB flask was charged lOOg of 4-amino-N-methylbenzene- ethanesulfonamide hydrochloride, 100ml of water and 375g of cone. HCl. The reaction mass was stirred and cooled to -10°C. A solution of sodium nitrite (37.6g dissolved in 185ml of water) was added to the reaction mass keeping the temperature below -5°C. After the addition, reaction mass was maintained below O⁰C for 2h. The reaction mass was filtered.

Into a 3L four-necked RB flask was charged 237g of stannous chloride dihydrate and 235ml of cone. HCl. The reaction mass was cooled to -10°C. Above diazonium solution was added to the reaction mass keeping the temperature below 0⁰C. The reaction mass was maintained below 0⁰C for 2h and filtered. The wet cake was washed with 100ml of IPA and dried at ambient temperature to get 103g of title compound.

(ii) Preparation of ethyl 2-(2-(4-(2-(N-methyIsulfamoyl)ethyl)phenyl)hydrazono)- propanoate of formula XL (R = Et)

Into a IL, three-necked RB flask was charged 75g of 4-hydrazino-N-methylbenzene- ethanesulfonamide hydrochloride and 500ml of ethanol. The reaction mass was heated to 50-55⁰C and added ethyl pyruvate (35.0g) slowly. After maintaining the reaction mass at 60-65⁰C for l-2h it was cooled to 5-1O⁰C. The reaction mass was filtered and washed the wet solid with 60ml of chilled ethanol. The wet material was dried in the oven at 60⁰C to yield 88g of the title compound as white crystalline solid. Purity by HPLC is 96.2%. M. P is 149-154°C. IR (KBr): 3309, 3286, 2984, 1692, 1614, 1566, 1526, 1509, 1370, 1309, 1244, 1141, 1090, 865, 810, and 571cm^"1. ¹H-NMR (CDCl₃, 300MHz): 9.78 (s, IH, exch with D₂O, =NNH); 7.19 (s, 4H, arom. H); 6.93 (s, IH, exch with D₂O, -SO₂NH); 4.17 (q, J = 7.2Hz, 2H, -CO₂CH₂CH₃); 3.20-3.22 (m, 2H, -SO₂CH₂-); 2.85-2.88 (m, 2H, ArCH₂-); 2.58 (d, J = 4.7Hz, 3H, -CH₃NH-); 2.04 (s, 3H, -=CCH₃); 1.25 (q, J = 7.2Hz, - COOCH₂CH₃). Mass: 328.2 [M+l].

(iii) Preparation of ethyl 5-(2-(N-methylsulfamoyl)ethyl)-lH-indoIe-2-carboxylate of formula XLI (R = Et) Into a 2L, four-necked RB flask was charged 4Og of ethyl 2-(2-(4-(2-(N- methylsulfamoyl)ethyl)phenyl)hydrazono)propanoate of formula XL ( R = Et) and 300ml of chloroform. The reaction mass was cooled to 5-10°C and added 30Og of polyphosphate ethyl ester (PPE). The reaction mass was heated to 55-60°C and maintained for 2h. The reaction mass was cooled to RT and added to 1300ml of chilled. The reaction mass pH was adjusted to 8.5-9.0 with potassium carbonate. The reaction mass temperature was raised to 25-30°C. Charged 1000ml of methylene chloride and separated the layers. Aqueous layer was extracted with methylene chloride and the combined organic layer was distilled to get 5Og of crude compound. Crude from one more batch was combined and taken for purification.

The above crude compound (10Og) was taken into a flask and charged 160ml of ethyl acetate. The reaction mass was heated to reflux temperature and maintained for 30min. The reaction mass was cooled to 5-10⁰C and maintained for Ih. The solid was filtered and washed with 30ml of chilled ethyl acetate. The wet compound was kept in the oven at 60⁰C to get 52g of the title compound as white crystalline solid. Purity by HPLC is 99.1%. Melting point is 161.2-162.8°C. IR (KBr): 3324, 2956, 1701, 1532, 1456, 1429, 1398, 1374, 1342, 1318, 1303, 1256, 1241, 1211, 1132, 1077, 1018, 847, 769, 745, 659, 584, and 511 cm^'1. ¹H-NMR (CDCl₃, 300MHz): 7.67 (s, IH, exch with D₂O, NH); 7.17 (s, 4H, arom. H); 4.32 (q, J = 6.8Hz, 2H, -COOCH₂CH₃); 3.84 (d, J = 4.8Hz, exch with D₂O, IH, NH); 3.26-3.29 (m, 2H, -SO₂CH₂); 3.06-3.09 (m, 2H, ArCH₂); 2.70 (d, J = 5.8Hz, 3H, -NCH₃); 2.11 (s, 3H, =CCH₃); 1.38 (t, J = 6.8Hz, -COOCH₂CH₃). Mass: 310.2 [M], 309.2 [M-I], and 237.2 [M-CO₂Et].

(iv) Preparation of 5-(2-(N-methylsulfamoyl)ethyl)-lH-indole-2-carboxylic acid of S formula XLII

Into a 2L, four-necked RB flask was charged 15.3g of KOH, 695ml of water, and 5Og of ethyl 5-(2-(N-methylsulfamoyl)ethyl)-lH-indole-2-carboxylate of formula XLI (R = Et). The reaction mass was heated to 65-70⁰C under stirring. After maintaining for Ih 5g of carbon was added and filtered and the filter bed washed with 100ml of water. The filtrate0 was taken into a flask and neutralized with cone. HCl to precipitate the acid. The reaction mass was filtered and the solid washed with water. The wet solid was dried at 50-60⁰C to get 43g of the title compound as white crystalline solid. Purity by HPLC is 99.8%. M.P is 229.8-230.3⁰C. IR (KBr): 3382, 3291, 2930, 2605, 1675, 1550, 1488, 1454, 1439, 1412, 1339, 1316, 1258, 1234, 1155, 1135, 1063, 821, 772, 744, 678, and 518cm-¹. ¹H-NMR5 (CDCl₃, 300MHz): 13.00 (br. s, IH, exch with D₂O, -COOH); 11.69 (s, IH, exch with D₂O, -NH); 7.52 (s, IH, arom H); 7.35 (d, J = 8.1Hz, IH, arom. H); 7.15 (d, J = 8.6Hz, arom H); 7.01 (s, IH, arom H); 6.96 (q, J = 4.8Hz, IH, exch with D₂O, NHCH₃); 3.26- 3.29 (m, 2H, SO₂CH₂); 2.97-3.01 (m, 2H, ArCH₂); 2.60 (d, J = 4.8Hz, NHCH₃). ¹³C- NMR (CDCl₃, 100MHz): 162.86 (C=O), 136.21 (C-8), 130.06 (C-9), 128.75 (C-5), 127.12 (C-2), 125.42 (C-6), 121.13 (C-4), 112.65 (C-7), 107.09 (C-3), 51.10 (SO₂CH₂), 29.39 (NHCH₃), and 28.69 (ArCH₂). Mass: 283.1 [M+l], 282.2 [M], 281.2 [M-I], and 237.1 [M-CO₂H].

(v) Preparation of 2-(lH-indol-5-yl)-N-methylethanesulfonamide of formula I Into a 1 L, four-necked RB flask was charged 25g of 5-(2-(N-methylsulfamoyl)ethyl)- 1 H- indole-2-carboxylic acid, 200ml of quinoline and 3.0gg of copper powder. The reaction mass was heated to 220-230⁰C. The reaction mass was maintained at 220-230⁰C for Ih and cooled to 25°C. Reaction mass from another batch of same size is combined with this one and proceeded for workup. The crude reaction mass was taken into a single necked RB flask. Quinoline was distilled out from the reaction mass under vaccum at 135⁰C. Hexane (80ml) was added to the residue, stirred for 15min, and decanted the hexane layer. This was repeated twice to remove traces of quinoline. Methylene chloride (800ml) was added to the residue and stirred for 20min. Carbon (5g) was added to the reaction mass, heated to 35-4O⁰C and filtered. Solvent was removed from the filtrate. Hexane (160ml) was added to the residue and heated to 50⁰C. The reaction mass was cooled to 25°C and filtered to get 46g of wet solid. The wet solid was recrystallized from methanol to get 27g of the title compound as pure white crystalline solid. Purity by HPLC is 99.8%. Melting point is 121.3-123.7°C. IR (KBr): 3416, 3290, 2975, 2954, 1477, 1459, 1415, 1401, 1339, 1308, 1270, 1226, 1151, 1134, 1 115, 1068, 982, 900, 860, 814, 793, 762, 746, 731, 650, 622, 603, 562, 528, 500, 466, and 427cm-¹. Mass: 238.3 [M], 237.3 [M-I].

Example 2 Preparation of N-methyl-2-(3-(l-methylpiperidin-4-yI)-lH-indol-5-yl)ethanesulfon- amide Hydrochloride (Naratriptan Hydrochloride) of formula II (i) Preparation of N-methyl-2-(3-(l-methyl-l,2,3,6-tetrahydropyridin-4-yI)-lH- indol-5-yI)ethanesulfonamide of formula XLIII Into a 250ml, three-necked RB flask was charged 8.3g of KOH and 100ml of IPA. The reaction mass was heated to reflux temperature to dissolve the KOH. The reaction mass was cooled to 60-65⁰C and charged 1Og of 2-(lH-indol-5-yl)-N-methylethanesulfon- amide, prepared according to the process given in Example 1 and 1 1.9g of N-methyl-4- piperidone. The reaction mass was maintained at 60-65⁰C for 3h. The reaction mass was cooled to 10-15⁰C and filtered the solids. The wet solid was washed with water and IPA. The wet solid was kept in the drier at 60⁰C to get 12.9g of title compound. Purity by HPLC is 97%. It is recrystallized from methanol to get 11.3g with 99.9% purity. M. P. is 218.6°C. IR (KBr): 3596, 3516, 3176, 3088, 3018, 2935, 2796, 2721, 2614, 1653, 1619, 1496, 1453, 1439, 1405, 1378, 1347, 1323, 1305, 1291, 1266, 1258, 1150, 1134, 1120, 1086, 1074, 1038, 963, 896, 876, 823, 805, 786, 751, 743, 662, 577, 518, and 482cm-'. Mass: 332.4 [M-I]. (H) Preparation of N-methyl-2-(3-(l-methylpiperidin-4-yl)-lH-indol-5-yl)ethane- sulfonamide Hydrochloride (Naratriptan Hydrochloride) of formula II

Into a 500ml, four-necked RB flask was charged 1Og of N-methyl-2-(3-(l-methyl- l,2,3,6-tetrahydropyridin-4-yl)-lH-indol-5-yl)ethanesulfonamide, 200ml of methanol, and LOg of 10% Pd/C. The reaction mass was stirred and started bubbling of hydrogen gas at 40-45⁰C. The reaction mass was maintained at same temperature under hydrogen bubbling for 6h. The reaction mass was cooled to 25°C and filtered. Methanol was distilled of from the filtrate. The residue was dissolved in ethyl acetate and added water.

Organic layer was separated and the aqueous layer extracted with ethyl acetate. Combined ethyl acetate layer was dried over sodium sulfate. Distillation of solvent afforded 9.5g of naratriptan base as white solid. Purity by HPLC is 99.84%.

The above naratriptan base (8.0g) was taken into a 250ml, three-necked RB flask and suspended in 80ml of methanol. The reaction mass pH was adjusted to 2.0-2.5 using IPA- HCl. The reaction mass was heated to reflux temperature and maintained for 45min. The reaction mass was cooled to RT and then to 5-10°C. The reaction mass was filtered and the wet solid washed with 5ml of chilled methanol. The wet solid was dried in the oven at 60°C to get 8.6g of the title compound as white crystalline solid. HPLC purity is 99.90%. M.P. is 245.9-246.2°C. IR (KBr): 3226, 3032, 2966, 2925, 2691, 2560, 2522, 1577, 1545, 1476, 1451, 1430, 1405, 1349, 1314, 1274, 1248, 1232, 1153, 1109, 1087, 1069, 1042, 1022, 984, 960, 955, 923, 888, 859, 834, 806, 778, 763, 694, 639, 586, 563, 541, 524, 478, 465, 452, and 430cm^"1. Powder XRD of the sample is given in Fig 1.

Example 3 Preparation of 2-(lH-indol-5-yl)-N-methylethanesulfonamide of formula I

(i) Preparation of methyl/ethyl 2-(2-(4-(2-(N-methyIsulfamoyl)ethyl)phenyl)- hydrazono)propanoate of formula XL (R = Me/Et)

Into a IL, three-necked RB flask was charged lOOg of 4-hydrazino-N-methylbenzene- ethanesulfonamide hydrochloride prepared according to Example 1 above and 350ml of methanol. Ethyl pyruvate (33.6g) was added to the reaction mass at 30°C and heated the reaction mass to reflux temperature. After maintaining the reaction mass at reflux for 5h it was cooled to 25°C. The reaction mass was filtered and washed the wet solid with 80ml of 5% aq methanol. The wet material was dried to yield 64.5g of title compound as white crystalline solid. HPLC of the sample showed 83% of methyl ester and 15% of ethyl ester of title compound. M.P is 163.3-169.O⁰C. IR (KBr): 3302, 3213, 2996, 2947, 1699, 1617, 1560, 1508, 1437, 1313, 1245, 1133, 845, 765, and 508cm^"1. ¹H-NMR (CDCl₃, 300MHz): 9.80 (d, J - 2.9Hz, IH, exch with D₂O, NH); 7.19 (s, 4H, arom H); 6.94 (d, J = 5.2Hz, IH, exch with D₂O, NH); 4.17 (q, J = 7.2Hz, 2H, -COOCH₂CH₃); 3.71 (s, 3H, COOCH₃); 3.21-3.24 (m, 2H, -SO₂CH₂); 2.85-2.88 (m, 2H, ArCH₂); 2.58 (d, J = 4.8, 3H, -NCH₃); 2.04 (s, 3H, =CCH₃); 1.25 (t, J = 6.8Hz, -COOCH₂CH₃). ¹³C-NMR (CDCl₃, 100MHz): 165.46 (C=O), 142.92 (C=N), 131.20 (C-4), 130.86 (C-4), 129.06 (C-3 & C- 5), 113.86 (C-2 & C-6), 51.73 (SO₂CH₂), 50.65 (OCH₃), 28.61 (NHCH₃), 28.53 (ArCH₂), and 11.80 (CH₃). Mass: 326.2 [M-I] of ethyl ester; 312.2 [M-I] of methyl ester.

(ii) Preparation of methyl/ethyl 5-(2-(N-methylsulfamoyl)ethyl)-lH-indole-2- car boxy late of formula XLI (R = Me/Et)

Into a IL, four-necked RB flask was charged 45g of crystalline phosphoric acid and 500ml of toluene. The reaction mass was heated to reflux temperature and removed water azeotropically. The reaction mass was cooled to 65-70⁰C and added 5Og of methyl/ethyl 2-(2-(4-(2-(N-methylsulfamoyl)ethyl)phenyl)hydrazono)propanoate of formula XLI (R = Me/Et). The reaction mass was heated to reflux temperature and maintained for 3h. The reaction mass was cooled to 65-70⁰C. Water (500ml) was added to the reaction mass and cooled to 25⁰C. The reaction mass was filtered and the wet cake washed with water and chilled IPA. The wet material was taken into a 500ml, four-necked RB flask and charged 165ml of IPA. The reaction mass was heated to 45-50⁰C. After maintaining for Ih reaction mass was cooled and filtered. The solid was washed with 30ml of chilled IPA and dried at 50-60⁰C to get 4Og of title compound as white crystalline solid. HPLC of the sample showed 80.77% of methyl ester and 18.59% of ethyl ester of title compound. M.P is 148.5-160.6⁰C. IR (KBr): 3331, 2954, 1703, 1534, 1451, 1437, 1418, 1376, 1344, - 1317, 1304, 1262, 1240, 1214, 1129, 1072,995, 847, 770, 745, 662, 638, and 512cm^"1. ¹H-NMR (CDCl₃, 300MHz): 8.95 (s, IH, exch with D₂O, NH); 7.55 (s, IH, arom H); 7.39 (d, J = 8.8Hz, IH, arom H); 7.17-7.21 (m, 2H, arom H); 3.95 (s, OCH₃); 3.92 (d, J = 4.9Hz, exch with D₂O, NHCH₃); 3.33-3.36 (m, 2H, SO₂CH₂); 3.20-3.24 (m, 2H, ArCH₂), 2.70 (d, J = 4.8Hz, 3H, NHCH₃). ¹³C-NMR (CDCl₃, 100MHz): 162.40 (C=O), 135.82 (C-9), 130.20 (C-5 & C-8), 127.75 (C-2), 126.00 (C-6), 121.80 (C-4), 112.44 (C-7), 108.34 (C-3), 52.65 (SO₂CH₂), 52.09 (OCH₃), 29.96 (NHCH₃), and 29.31 (ArCH₂). Mass: 309.1 [[M-I] of ethyl ester] and 295.2 [[M-I] of methyl ester].

(iii) Preparation of 5-(2-(N-methylsulfamoyl)ethyl)-lH-indole-2-carboxylic acid of formula XLII

Into a 2L, four-necked RB flask was charged 28g of KOH, 1000ml of water, and lOOg of methyl/ethyl 5-(2-(N-methylsulfamoyl)ethyl)-lH-indole-2-carboxylate. The reaction mass was heated to 65-70°C under stirring. After maintaining for Ih, 2Og of carbon was added and filtered. The filtrate was taken into a flask and neutralized with cone. HCl to precipitate the acid. The reaction mass was filtered and the solid washed with water. The wet solid was dried at 50-60⁰C to get 84.Og of the title compound as white crystalline solid. Purity by HPLC is 99.42%. M.P is 228.3-230.4⁰C. IR (KBr) is identical with that of Example 1.

(iv) Preparation of 2-(lH-indol-5-yl)-N-methylethanesulfonamide of formula I

Into a IL, four-necked RB flask was charged 7Og of 5-(2-(N-methylsulfamoyl)ethyl)-lH- indole-2-carboxylic acid, 350ml of quinoline and 31.5g of copper powder. The reaction mass was heated to 220-230⁰C. The reaction mass was maintained at 220-230⁰C for Ih and cooled to 25°C. The reaction mass filtered and the filtrate taken into a RB flask.

Quinoline was distilled of under vaccum keeping the temperature below 150⁰C. The residue was dissolved in ethyl acetate (IL) and washed with 500ml of IN HCl and water. Organic layer was dried with sodium sulfate and distilled of solvent completely. The residue was suspended in 100ml of IPA. The resulting slurry was heated to 40-45⁰C and cooled to 0-5⁰C. The solid was filtered and washed with 40ml of chilled IPA. The wet solid was dried in the oven at 60°C to get 46g of title compound as white crystalline solid. Purity by HPLC is 99.3%. M.P is 123.5-124.9⁰C. Example 4

Preparation of ethyl 5-(2-(N-methylsuIfamoyl)ethyl)-lH-indole-2-carboxylate of formula XLI (R = Et)

Into a 50ml, four-necked RB flask was charged l.Og of ethyl 2-(2-(4-(2-(N- methylsulfamoyl)ethyl)phenyl)hydrazono)-propanoate of formula XL (R = Et) prepared according to the process disclosed in Example 1 above and 5ml of 15% ethanolic HCl.

The reaction mass is heated to reflux temperature and maintained at this temperature for

5h. The reaction mass was cooled to 5-10⁰C diluted with water. The reaction mass pH was adjusted to 7.5-8.0 with sodium bicarbonate and extracted the product into methylene chloride. Methylene chloride layer was dried and evaporated to get 0.85g of residue. The residue was dissolved in 5ml of ethanol and cooled to 10-15⁰C. The solids were filtered and washed with ethanol to get 0.5g of title compound as white solid. M. P is 154-157⁰C.

Example 5 Preparation of ethyl 2-(2-(4-(2-(N-methylsulfamoyl)ethyl)phenyl)hydrazono)- propanoate of formula XL ( R = Et)

Into a 250ml, three-necked RB flask was charged 9.5g of 4-Hydrazino-N- methylbenzeneethanesulfonamide Hydrochloride of the formula X prepared according to the process given in Example 1 above and 70ml of IPA. The reaction mass was heated 50-60⁰C and added 4.3g of ethyl pyruvate. Reaction mass was maintained at this temperature for 2h and cooled to RT. The reaction mass was further cooled to 0-5⁰C and maintained for 2h. the solid was filtered and washed with chilled IPA. The wet solid was dried in the oven at ^'60⁰C to get 1Og of title compound as white solid. Melting point of the solid is 142.0-147⁰C. HPLC purity is 92.2%. ¹H-NMR spectrum of the sample did not show the presence of any isopropyl ester of required hydrazone.

Example 6

Preparation of N-methyl-2-(3-(l-methylpiperidin-4-yl)-lH-indol-5-yl)ethanesulfon- amide Hydrochloride (Naratriptan Hydrochloride) of formula II Naratriptan base (10. Og) prepared according to the process disclosed in Example 3 was taken into a 100ml, three-necked RB flask and suspended in 40ml of methanol. The reaction mass was heated to reflux temperature to get a clear solution. The solution was cooled to room temperature. Cone. HCl (4.2g) was added to the reaction mass. A clear solution formed and immediately solid precipitated from the reaction mass. The reaction mass was cooled to 10-15⁰C and filtered. The wet solid was dried in the oven at 60-65⁰C to get 10.8g of naratriptan hydrochloride as white crystalline solid. HPLC purity is 99.9%.

The above solid (8.0g) was taken into a 100ml, three-necked RB flask and added 24ml of water. The reaction mass was heated to 75-80⁰C. The resultant solution was slowly cooled to 25-30⁰C. The reaction mass was cooled to 5-10⁰C and maintained for Ih. The reaction mass was filtered and the solid washed with 5 ml of chilled water and 7ml of chilled methanol. The wet solid was dried in the oven at 60⁰C to get 7.Og of the title compound as white crystalline solid. Purity by HPLC is 99.9%. Melting point is 246.2- 246.5°C. IR (KBr) is identical to that of Example 2. Powder XRD of the sample is given in Fig 2.

Advantages of present invention:

1. Present process avoids the usage of costly reagents like palladium acetate; tri-o- tolylphosphine used in the prior art Heck reaction.

2. Present process does not require costly and hazardous reagents like pyridine-4- carboxaldehyde, methyl iodide, 4-nitrobenzaldehyde, N-methylvinylsulfonamide, etc used in the prior art processes.

3. Present process uses simple and readily available reagents like ethyl/methyl pyruvate and 4-hydrazino-N-methylbenzeneethanesulfonamide of formula X, and N-methyl-4- piperidone of formula IV in the process.

4. Overall yield of naratriptan hydrchloride is more than 40%. Purity of naratriptan hydrochloride produced according to the present process is more than 99% with all the impurities below 0.1% level. 5. Present process is economically and commercially viable.

Claims

WE CLAIM:

1. A novel and improved process for the preparation of 2-(lH-indol-5-yl)-N- methylethanesulfonamide of formula I,

which is useful for the preparation of anti-migraine drug naratriptan hydrochloride of formula II,

which comprises:

(i) Reaction of the hydrazine derivative of formula X,

with pyruvate esters of formula XXXIX,

O

CO₂R

XXXIX wherein R = C₁-CiO alkyl or branched alkyl, C₃-C₇ cycloalkyl, ArCH₂, phenyl, 1-5 substituted phenyl in a solvent medium at ambient to elevated temperature to get the hydrazone derivative of formula XL,

XL wherein R is as defined above (ii) Indolization of the hydrazone of formula XL in a solvent medium and in the presence of an acid catalyst to get the indole derivative of formula XLI,

wherein R = wherein R = Ci-Ci₀ alkyl or branched alkyl, C₃-C₇ cycloalkyl, ArCH₂, phenyl, 1 -5 substituted phenyl

(iii) Aqueous hydrolysis of the compound of formula XLI using a base to get the compound of formula XLII,

I

2. A process for the preparation of compound of formula I as claimed in claim 1 wherein the solvent used in step (i) is selected from a protic solvent such as methanol, ethanol, isopropanol, n-butanol; ethers like THF, dioxane, diethyl ether, diisopropyl ether; nitriles like acetonitrile; esters like ethyl acetate, halogenated solvents like methylene chloride, chloroform, ethylene dichloride.

3. A process for the preparation of compound of formula I as claimed in claims 1 and 2 wherein the elevated temperature used in step (i) is 25 °C to boiling point of the solvent employed, preferably the boiling point of the solvent.

4. A process for the preparation of compound of formula I as claimed in claims 1 to 3 wherein the acid catalyst used in step (ii) is selected from acids like polyphosphoric acid (PPA), PPE (Polyphosphate ethyl ester), sulfuric acid, HCl, HBr, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, TiCl₄, ZnCl₂, SnCl₂, FeCl₃, AlCl₃, preferably PPA or PPE.

5. A process for the preparation of compound of formula I as claimed in claims 1 to 4 wherein the solvent employed in step (ii) is selected from halogenated solvent like methylene chloride, chloroform, ethylene dichloride.

6. A process for the preparation of compound of formula I as claimed in claims 1 to 5 wherein the temperature of the reaction is in the range of 0-100⁰C, preferably 70-100⁰C.

7. A process for the preparation of compound of formula I as claimed in claims 1 to 6 wherein the base used in aqueous hydrolysis step (iii) is selected from sodium or potassium carbonate, bicarbonate or hydroxide.

8. A process for the preparation of compound of formula I as claimed in claims 1 to 7 wherein the catalyst used in decarboxylation step (iv) is selected from copper, copper oxides, or any other transition metals or their oxides, preferably copper powder.

9. A process for the preparation of compound of formula I as claimed in claims 1 to 8 wherein the temperature of the reaction in step (iv) is 150-250⁰C.

10. A process for the preparation of compound of formula I as claimed in claims 1 to 9 wherein the medium of the reaction in step (iv) is quinoline, picolines, and pyridine, preferably quinoline.

11. Improved process for the preparation of naratriptan hydrochloride of formula II,

" employing 2-(lH-indol-5-yl)-N-methylethanesulfonamide of formula I,

which comprises:

(i) Reaction of compound of formula I,

with N-methyl-4-pieridone of formula IV,

IX

(ii) Hydrogenation of compound of formula IX in the presence of a metal catalyst to get naratriptan base

(iii) Reaction of naratriptan base with cone, hydrochloric acid in a solvent medium to get the naratriptan hydrochloride of formula II

12. Improved process for the preparation of naratriptan hydrochloride of formula II as claimed in claim 11 wherein the solvent employed in step (i) is selected from a protic solvent such as methanol, ethanol, isopropanol, n-butanol; ethers like THF, dioxane, diethyl ether, diisopropyl ether; nitriles like acetonitrile; hydrocarbon solvent like cyclohexane, heptane toluene, preferably ethanol or methanol.

13. Improved process for the preparation of naratriptan hydrochloride of formula II as claimed in claims 11 and 12 wherein the base employed in step (i) is selected from sodium or potassium hydroxide, carbonate, bicarbonate, sodium or potassium alkoxide, preferably potassium hydroxide.

14. Improved process for the preparation of naratriptan hydrochloride of formula II as claimed in claims 11-13 wherein the quantity of base employed in step (i) is 1-6 molar equivalents to the compound of formula I, preferably 3-4 molar equivalents, more preferably 3 molar equivalents.

15. Improved process for the preparation of naratriptan hydrochloride of formula II as claimed in claims 11 -1C wherein the temperature of the reaction is 25 °C to reflux temperature of the solvent employed in the reaction, preferably 60-65 °C.

16. Improved process for the preparation of naratriptan hydrochloride of formula II as claimed in claims 11-15 wherein the metal catalyst employed in step (ii) is selected from Raney nickel, Pd/C, Platinum oxide.

17. Improved process for the preparation of naratriptan hydrochloride of formula II as claimed in claims 11-16 wherein the solvent used in step (ii) is selected from alcoholic solvents such as methanol, ethanol, isopropanol; esters like ethyl acetate; hydrocarbon solvents like cyclohexane, heptane, and toluene, preferably alcoholic solvent, more preferably, methanol. r

18. Improved process for the preparation of naratriptan hydrochloride of formula II as claimed in claims 11-17 wherein the solvent employed in step (iii) is selected from protic solvent such as methanol, ethanol, isopropanol, n-butanol; ethers like THF, dioxane, diethyl ether, diisopropyl ether; nitriles like acetonitrile; esters like ethyl acetate; halogenated solvents like methylene chloride, chloroform, ethylene dichloride.

19. Improved process for the preparation of naratriptan hydrochloride of formula II as claimed in claims 11-19 wherein the purity of naratriptan hydrochloride is more than 99%, preferably more than 99.5% by HPLC.

20. Novel compounds of formula XL

wherein R = Cj-Cio alkyl or branched alkyl, C₃-C₇ cycloalkyl, ArCH₂, phenyl, 1-5 substituted phenyl.

21. Novel compounds of formula XLI,

wherein R = wherein R = C₁-C₁₀ alkyl or branched alkyl, C₃-C₇ cycloalkyl, ArCH₂, phenyl, 1-5 substituted phenyl.

22. Novel compound of formula XLII