WO2006010079A2

WO2006010079A2 - Process for preparing naratriptan hydrochloride

Info

Publication number: WO2006010079A2
Application number: PCT/US2005/024436
Authority: WO
Inventors: Aminul Islam; Katam Sahadev; Madadi Vijaypal Reddy; Ruturaj Vijay Kulkarni; Mohammed Mohosin Layek; Chandan Bhar
Original assignee: Dr Reddys Laboratories Ltd; Dr Reddys Laboratories Inc
Current assignee: Dr Reddys Laboratories Ltd; Dr Reddys Laboratories Inc
Priority date: 2004-07-08
Filing date: 2005-07-08
Publication date: 2006-01-26
Anticipated expiration: 2007-01-08
Also published as: WO2006010079A3

Abstract

A process for preparing naratriptan hydrochloride, N-methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-ethanesulphonamide hydrochloride having formula (I).

Description

PROCESS FOR PREPARING NARATRIPTAN HYDROCHLORIDE

INTRODUCTION TO THE INVENTION

The present invention relates to a process for preparing N-methyl-3-(1- methyl-4-piperidinyl)-1 H-indole-5-ethanesulfonamide hydrochloride having formula (I).

The compound of formula (I) has the adopted name "naratriptan hydrochloride" and is being sold in pharmaceutical products using the trademark AMERGE, for treating migraine.

N-methyl-3-(1-methyl-4-piperidinyl)-1 H-indole-5-ethanesulfonamide and its physiologically acceptable salts and solvates are disclosed in GB 2208646. The compound exhibits selective vasoconstrictor activity and is indicated for use in the treatment of migraine.

U.S. Patents 4,997,841 and 5,066,600 disclose N-methyl-3-(1-methyl-4- piperidinyl)-1 H-indole-5-ethanesulfonamide hydrochloride and its related compounds useful in the treatment of migraine and process for preparation of compounds. In earlier disclosed processes, the key step is condensation of a 4- piperdone derivative with an appropriate substituted indole derivative in the presence of an acidic medium to obtain the compound of formula (I) and its related compounds.

The present invention relates to a process which has the following advantages over the earlier processes:

1 ) Earlier processes comprise cumbersome operations like Heck reactions and tin (II) chloride reduction. These are difficult to reproduce in larger scale. The process claimed in this application is relatively more suitable for scaled-up operations. 2) The intermediates and reagents used in earlier processes are more expensive than those used in the process claimed in this application. The process described herein is economically more viable.

SUMMARY OF THE INVENTION

A process for preparing a compound having formula (I)

comprises: (i) reacting a diazotized derivative of a compound having formula (II),

with a compound having formula (III), where R represents an alkyl group having 1 to 5 carbon atoms;

to produce a compound having formula (IV);

(ii) cyclizing the compound having formula (IV) in the presence of an acid to produce a compound having formula (V);

(V)

quaternizing the compound having formula (V) with an alkyl halide to produce a compound having formula (Vl), where X is a halogen;

(iv) reacting the compound having formula (Vl) with a reducing agent to produce a compound having formula (VII);

(v) hydrogenating the compound having formula (VII) to produce a compound having formula (VIII);

(vi) saponifying the compound having formula (VIII) with a base to produce a compound having formula (IX), where M is an alkali metal; and

(vii) decarboxylating the compound having formula (IX) with an acid to produce the compound having formula (I). An alternative process for preparing a compound having formula (I)

comprises:

(i) reacting a diazotized derivative of a compound having formula (II)

with a compound having formula (XIV), where R represents an alkyl group having 1 to 5 carbon atoms,

to produce a compound having formula (XV),

(ii) cyclizing the compound having formula (XV) to produce a compound having formula (VIII),

(iii) saponifying the compound having formula (VIII) with a base to produce a compound having formula (IX), where M is an alkali metal; and

(iv) decarboxylating the compound having formula (IX) in an acidic medium to produce the compound having formula (I).

DETAILED DESCRIPTION

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

comprising:

(i) diazotizing the aniline derivative of formula (II),

with the pyridine β-keto ester of formula (111), where R represents a straight or branched alkyl group having 1 to 5 carbon atoms,

under Japp-Klingemann coupling conditions to afford the hydrozone of formula (IV)

(ii) cyclizing the hydrazone derivative of the formula (IV) in the presence of an acid in a solvent to give the indole derivative of formula (V). Examples of acids that can be used are hydrochloric acid, sulfuric acid, phosphoric acid, and organic acids like para-toluene sulfonic acid or Lewis acids like boron trifluoride in solvents like dichloromethane, chloroform, and alcohols such as methanol, ethanol, propanol, iso propanol and the like.

(iii) quaternizing the compound of formula (V) with an alkyl halide such as methyl iodide or ethyl iodide in the presence of a solvent like dimethyl sulfoxide to give the compound of formula (Vl), where X is a halogen,

(iv) reducing the compound (Vl) with a reducing agent like sodium tetrahydridoborate in the presence of a solvent like alcohol such as methanol, ethanol and propanol and the like to give a compound of the formula (VII)

(v) reducing the compound of formula (VII) to the N-methyl piperidinyl derivative of the formula (VIII) by catalytic hydrogenation using a noble metal catalyst such as Raney nickel, palladium oxide/charcoal, palladium/charcoal, or rhodium/charcoal, in the presence of hydrogen gas and a solvent like ethanol, methanol, ethers like dioxane, esters such as ethyl acetate, or an amide

(vi) saponifying the ester group in formula (VIII) in presence of a base such as metal hydroxides like sodium hydroxide, potassium hydroxide, or metal carbonates like sodium or potassium carbonate, in the presence of a solvent like water to give the acid of formula (IX)

(vii) decarboxylating the compound of formula (IX) in an acidic medium such as in the presence of an acid like hydrochloric acid to give N-methyl-3-;(1- methyl-4-piperidinyl)-1 H-indole-5-ethanesulphonamide hydrochloride of the formula (I).

According to another aspect the present invention provides a process for preparing the compound of the formula (I)

comprising:

(i) diazotization of the aniline derivative of the formula (II) to the corresponding diazonium salt

with pyridine β-keto ester of formula (XIV), wherein R represents an alkyl group having 1 to about 5 carbon atoms, which is straight chained or branched, such as methyl, ethyl, propyl, isopropyl and the like,

under the Japp-Klingemann reaction conditions to afford the hydrazone of the formula (XV),

(ii) cyclization of the hydrazone of the formula (XV) in presence of acid and solvent to form the indole derivative of the formula (VIII), useful acids including, without limitation, inorganic acids like hydrochloric acid, sulfuric acid, phosphoric acid or organic acids like para-toluenesulphonic acid or Lewis acids like boron trifluoride and the like, in presence of solvents like alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol and the like or mixtures thereof,

(iii) saponifying the ester group in formula (VIII) in the presence of a base such as metal hydroxides like sodium hydroxide or potassium hydroxide, or metal carbonates like sodium or potassium carbonate, in the presence of a solvent like water, to give the compound of formula (IX), where M is a metal,

(iv) decarboxylating the compound of formula (IX) in an acidic medium such as an acid like hydrochloric acid to give N-methyl-3-(1-methyl-4-piperidinyl)- 1 H-indole-5-ethanesulphonamide hydrochloride of the formula (I).

According to another aspect, the present invention provides a process for preparing the compound of formula (XIV)

wherein R represents an alkyl group, which is straight chained or branched, such as methyl, ethyl, propyl, isopropyl and the like, the process comprising:

(i) dissolving a mixture of pyridine 4-carboxyldehyde and alkyl acetoacetate like methylacetoacetate, ethylacetoacetate, propylacetoacetate, isopropylacetoacetate and the like, in a solvent like n-hexane followed by addition of pyridinium para tolune sulfonate and refluxing the mixture to obtain the compound of formula (Ilia).

where R represents an alkyl group which is straight or branched chained, such as methyl, ethyl, propyl, isopropyl and the like.

(ii) reducing the compound of formula (Ilia) to the compound of formula (III) by catalytic hydrogenation using a noble metal catalyst like Raney nickel, palladium oxide/charcoal, palladium /charcoal, or rhodium/charcoal, such as at a hydrogen pressure of about 0.7 to 2.5 Kg/cm²

(iii) quatemizing the compound of formula (III) with an alkyl halide like methyl iodide,, ethyl iodide, propyl iodide and the like in the presence of a solvent like alcohols such as methanol, ethanol, propanol, butanol, or isobutanol to give the compound of formula (XIVa), where X is a halogen,

(iv) reducing the compound of formula (XIVa) to give the compound of formula (XIV) by catalytic hydrogenation, using a noble metal catalyst like Raney nickel, palladium oxide/charcoal, palladium/charcoal, rhodium/charcoal and the like in the presence of a solvent like methanol, ethanol, propanol, butanol, isopropanol, isobutanol, an ether like dioxane, or an ester such as ethyl acetate, and the like.

Scheme 1 illustrates a process for preparing N-methyl-3-(1-methyl-4- piperidinyl)-1H-indole-5-ethanesulphonamide hydrochloride of formula (I):

SCHEME 1

Diazotization of compound (II) can be conveniently carried out by conventional methods using reagents like sodium nitrite, amyl nitrite and the like. The reaction may be carried at a temperature of about -20 to 30⁰C, preferably about -15 to 25⁰C until the reaction is complete, such as for a period of about 15 to 45 minutes, or about 20 to 40 minutes. The compound of formula (IV) can be prepared by reacting the diazonium salt obtained, with a compound of formula (III) in the presence of metal hydroxides like sodium hydroxide, potassium hydroxide, barium hydroxide and the like, in the presence of a solvent like alcohols such as methanol, ethanol, propanol, isopropanol and the like, or mixtures thereof. The temperature of the reaction is usually maintained at about 0 to 5⁰C, or O⁰C, to reaction completion, such as for a period of about 1 to 4 hours, or about 2 to 4 hours.

Cyclization of the hydrozone compound of formula (IV) to form the indole derivative of formula (V) can be effected in the presence of an acid in a solvent. Useful acids include inorganic acids like hydrochloric acid, sulfuric acid, and phosphoric acid, or organic acids like para-toluenesulphonic acid, or Lewis acids like boron trifluoride, in the presence of a solvent like dichloromethane, chloroform, and alcohols such as methanol, ethanoljDropanol, isopropanol and the like, or mixtures thereof.. Alternatively, the cyclization may also be achieved by refluxing the compound of formula (IV) in a protic solvent like n-butanol and the like. The reaction temperature is typically about 45 to 70 ⁰C, or about 55 to 65 ⁰C. Completion of the reaction is typically achieved in about 8 to 15 hours, or about 12 to 14 hours. Quatemization of a compound of formula (V) can be carried out by reacting with an alkyl halide such as methyl iodide, ethyl iodide and the like, in the presence of a solvent like dimethyl sulfoxide, dimethylformamide and the like. The reaction can be carried out at a temperature of about 10 to 4O⁰C, or about 20 to 35⁰C and is usually complete in a period of about 2 to 10 hours, or about 4 to 5 hours.

Reduction of compound of formula (Vl) to a compound of formula (VII) is carried out in the presence of reducing agents like sodium tetrahydridoborate in the presence of a solvent such as alcohols such as methanol, ethanol, propanol, isopropanol and the like, or mixtures thereof. The temperature of the reaction can be in the range of about 20 to 4O⁰C, or about 25 to 35⁰C. Completion of the reaction can require about 2 to 5 hours, or about 3 to 5 hours.

Further reduction of the compound of formula (VII) to a compound of formula (VIII) can be carried out in the presence of a reducing agent such as hydrogen gas using a catalyst such as Raney nickel, palladium oxide/charcoal, palladium/charcoal, rhodium/charcoal, and the like. The reduction can be carried out in a solvent such as an alcohol such as methanol, ethanol, propanol, isopropanol, or their mixtures; ethers like dioxane; esters such as ethyl acetate; or an amide; at temperatures about 50 to 8O⁰C, or about 60 to 75⁰C. Completion of the reaction can require about 5 to 12 hours, or about 8 to 12 hours. Basic hydrolysis of compound (VIII) can be carried out in the presence of a base like metal hydroxides like sodium hydroxide and potassium hydroxide and the like, or metal carbonates like sodium carbonate, potassium carbonate and the like, in water at a temperature of about 10 to 12O⁰C, typically requiring a period of about 5 to 8 hours, or about 7 to 8 hours, followed by decarboxylation in an acidic medium like hydrochloric acid at about 40 to 14O⁰C to obtain a compound of formula (I), the reaction frequently requiring about 12 to 14 hours for completion. Scheme 2 illustrates an alternative process for preparing the compound of formula (I)

SCHEME 2

Diazotization of the compound of formula (II) can be conveniently carried out by conventional methods using reagents like sodium nitrite, amyl nitrite and the like. The reaction is usually carried at temperatures about -20 to 3O⁰C, or about -15 to 25⁰C and frequently requires about 15 to 45 minutes, or about 20 to 40 minutes. The compound of formula (XV) can be prepared by reacting the diazonium salt with a compound of formula (XIV) in the presence of a metal hydroxide like sodium hydroxide, potassium hydroxide, barium hydroxide and the like, in the presence of a solvent like alcohols such as methanol, ethanol, propanol, isopropanol and the like. The temperature of the reaction usually is maintained at about 0 to 5⁰C, or about O⁰C and the reaction requires about 1 to 4 hours, or about 2 to 4 hours.

The hydrazone intermediate of formula (XV) may or may not be isolated. The intermediate of formula (XV) can be converted in situ to the indole derivative of formula (VIII), through an acid catalyzed 3,3-sigmatropic shift in a moisture controlled medium. This cyclization step can be carried out in the presence of an alcohol such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol and the like or mixtures thereof, which is straight or branched chained, having free hydrogen ion dissolved in it (for example, hydrochloric acid) and may be affected by the presence of excess moisture (such as >20%) and also by lower concentrations of dissolved hydrogen ion (such as <5%).The temperature of reaction is normally in the range of about 45 to 125⁰C, or about 55 to 100⁰C. Completion of the reaction typically occurs within about 5 to 18 hours, or about 8 to 12 hours.

The final step can be a one-pot reaction wherein basic hydrolysis of compound (VIIl) is carried out in the presence of a base like metal hydroxides like sodium hydroxide, potassium hydroxide and the like or metal carbonates like sodium or potassium carbonate and the like, in presence of solvent like water at a temperature of about 10 to 12O⁰C, such as for period of about 5 to 8 hours, or about 7 to 8 hours, followed by decarboxylation in an acidic medium like hydrochloric acid at about 40 to 14O⁰C to obtain a compound of formula (I); the decarboxylation can require about 8 to 20 hours, or about 12 to 14 hours. If the one-pot option is used, compound (IX) will not be isolated.

Scheme 3 is an illustration of a process for preparing the compound of formula (II)

SCHEME 3

An appropriate starting material for producing the compound having formula (I) in the present invention includes compounds of formula (II), which is disclosed in US Patent 4,994,483, incorporated by reference herein. Accordingly, a process for preparing the compound of formula Il is described in Scheme 3.

Scheme 4 is an illustration of a representative process for preparing the intermediate compound of formula (XIV):

SCHEME 4 The compound of formula (Ilia), where R represents an alkyl group, which is straight or branched chain, such as methyl, ethyl, propyl, isopropyl and the like, can be prepared by dissolving a mixture of pyridine-4-carboxyaldehyde and an alkylacetoacetate like methylacetoacetate, ethylacetoacetate, propylacetoacetate, isopropylacetoacetate and the like, in a solvent like n-hexane and the like, and adding pyridinium p-toluene sulfonate. The mixture is refluxed to reaction completion, such as for a period of about 2 to 6 hours, or about 3 to 5 hours. Solvent is then removed from the reaction mixture and a solvent like ethyl acetate or water is added and the mixture stirred, such as for a period of about 10 to 15 minutes.

Reducing a compound of formula (Ilia) to a compound of formula (III) is accomplished by catalytic hydrogenation using a noble metal catalyst like Raney nickel, palladium oxide/charcoal, palladium /charcoal, rhodium/charcoal and the like, such as using a hydrogen pressure of about 0.5 to 2.5 Kg/cm², typically over a period of about 1 to 3 hours, or about 1.5 to 2.5 hours.

Quatemizing the compound of formula (III), to obtain the compound of formula (XIVa) is accomplished by reacting with an alkyl halide such as methyl iodide, ethyl iodide and the like, in the presence of a solvent like an alcohol such as methanol, ethanol, propanol, butanol, isopropanol, isobutanol and the like, or mixtures thereof. The reaction can require about 8 to 14 hours, or about 8 to 12 hours.

Reducing the compound of formula (XIVa) to the compound of formula (XIV) occurs using a reducing agent like hydrogen gas with a nobel metal catalyst such as Raney nickel, palladium oxide/charcoal, palladium/charcoal, rhodium/charcoal and the like. The reduction can be carried out in the presence of a suitable solvent like an alcohol such as methanol, ethanol, propanol, butanol, isopropanol, isobutanol and the like, or mixtures thereof; ethers like dioxane; esters like ethyl acetate and the like. The duration of the reaction is frequently about 5 to 7 hours, or about 5 to 6 hours. The manner in which the specific compounds can be prepared is illustrated in the following examples, which are illustrative only and should not be construed so as limiting the scope of the claimed invention in any manner. In these examples, the identities of final compounds and intermediates were confirmed by infrared (IR), nuclear magnetic resonance (NMR) spectral analysis, and/or mass spectral (MS) analysis as necessary.

Preparation of some starting materials is described below:

Preparation 1 : N-Methyl-2-(4-amino phenyl) ethane sulfonamide

Step 1 : Preparation of 2-(4-Nitro phenvO-1 -ethane sulfonic acid

A mixture of 4-nitrophenyl ethyl bromide, sodium sulfite and tetrabutyl ammonium bromide (25 grams, 20.54 grams, 1.168 grams, respectively) was suspended in water and refluxed for 3 hours. The reaction was monitored by thin layer chromatography (20% methanol in ethyl acetate). The reaction mass was cooled to 30 to 40⁰C and washed with 50 ml of ethyl acetate. The aqueous layer was acidified and concentrated as such to give a gummy residue. This residue was then stirred for 30 minutes with methanol (100 ml) and filtered. The residue was extracted with methanol (75 ml x 2). Combined filtrate was concentrated under reduced pressure to give the crude product, which was taken to the next step as such. Weight of crude compound: 37.0 grams, melting point: 250 ⁰C. ¹H NMR (DMSO-d₆, 200 MHz): δ 2.8 (m, 2H), 3.15 (m, 2H), 7.21 (d, 2H), 8.10 (d, 2H) MS (m/z): 150 (M⁺+ 1 )

Step 2: Preparation of 2-(4-Nitro phenvO-ethane sulfonyl chloride (XII)

The compound obtained in step 1 above was taken in toluene and refluxed, then residual methanol and water was removed through a Dean-Stark apparatus. When clear toluene was coming from condenser, the suspension was cooled to 1O⁰C and phosphorous pentachloride (83.08 grams, 0.4 moles) was added in small portions. The mixture was slowly heated to reflux temperature with stirring and maintained for 30 minutes. The reaction mixture was then brought to 30 to 40⁰C, dichloromethane was added (80 ml) to the reaction mixture. The formed salt was separated by filtration and washed with dichloromethane, and the combined filtrate was used for the next step.

Step 3: Preparation of N-Methyl-2-(4-nitro phenyl) ethane sulphonamide

Methylamine gas was passed into chilled dichloromethane at O⁰C over a period of 2 to 3 hours. After sufficiently saturating the dichloromethane with methylamine, the solution was cooled to 0 to -5⁰C. The dichloromethane/toluene solution of acid chloride obtained in step 2 above was added slowly to above methylamine solution, while maintaining a temperature below 0 ⁰C. The mixture was stirred at the same temperature for 30 minutes and then at 30 to 40⁰C for 3 hours. Reaction progress was checked by thin layer chromatography (40% ethyl acetate in petroleum ether). The separated solid was filtered and washed with dichloromethane. The combined filtrate was concentrated under reduced pressure to give a gummy solid, which was stirred with cold water (100 to 150 ml) for 30 minutes, filtered, washed with water, and then washed with 20% ethyl acetate in petroleum ether to remove impurities. Weight of compound: 15.50 grams Yield: 58.00 %, melting range: 132-136⁰C

¹H NMR: (CDCI₃, 200 MHz): δ 2.82 (d, 3H) 3.21 (m, 4H), 4.10 (br, 1 H, NH), 7.21 (d, 2H), 8.21 (d, 2H) MS (m/z): 245 (M⁺+1)

Step 4: Preparation of N-Methyl-2-(4-amino phenvDethanesulfonamide *

The compound (15.5 grams, 0.07 moles), obtained in step 3 above, was dissolved in methanol-ethyl acetate mixture (120:100 ml) and charged with 20% of Raney nickel catalyst into a hydrogenation flask. Hydrogen pressure was maintained at 4.7 to 5 Kg/cm² (temperature raised to 45 to 5O⁰C) for 4 to 5 hours. Progress of the reaction was monitored by thin layer chromatography (50% ethyl acetate in petroleum ether). Catalyst was removed by filtration through a celite bed and the bed was washed with methanol, then the combined filtrate was concentrated under vacuum to give a solid, which was triturated with 60% ethyl acetate in petroleum ether and filtered to recover the title compound. Weight of compound: 10.00 grams. Yield: 75.00%, melting range: 125 -128 ⁰C.

¹H NMR (DMSO-de, 200 MHz): δ 2.60 (d, 3H), 2.78 (m, 2H), 3.17 (m, 2H), 3.38 (s,

1 H), 4.91 (br, 2H), 6.52 (d, 2H), 6.95 (d, 2H),

MS (m/z): 215 (M⁺+1 )

Preparation 2: Methyl-2-acetyl-3-pyridyl propanoate

Step 1 : Preparation of (Cis-trans)-methyl-2-acetyl-3-pyridyl-2-propionoate

Pyridine 4-carboxyldehyde (200 grams, 1.87 moles) and methyl acetoacetate (217 grams, 1.87 moles) were taken in n-hexane (1000 ml), then 5 grams of pyridinium p-toluene sulfonate were added and the mixture was refluxed in a Dean-Stark apparatus for 3 to 4 hours. After reaction completion, n-hexane was removed from the reaction mixture under reduced pressure and ethyl acetate (1000 ml) and water (500 ml) were added, and stirred for 10 to 15 minutes, then the organic layer was separated, dried, and concentrated to get a crude mass of the title compound as a viscous liquid. Yield: 290 grams. ¹H NMR (CDCI₃, 200 MHz): δ 2.3 (2s, 3H), 2.4 (2s, 3H), 3.78 (2s, 3H), 3.82 (2s, 3H), 7.2 (t, 2H), 7.42 (2s, 1 H), 7.56 (2s, 1 H), 8.6 (t, 2H) MS (m/z): 206(M⁺+1)

Step 2: Preparation of Methyl-2-acetyl-3-pyridvlpropanoate (Cis-transJ-methyl^-acetyl-S-pyridyl^-propanoate (100 grams, 0.49 mole) obtained in step 1 above was taken in ethyl acetate (500 ml) and was hydrogenated in the presence of a catalytic amount of 10% palladium/charcoal (5 grams) at 0.8 to 1.5 Kg/cm² of hydrogen pressure for 1.5 to 2.5 hours. After completion of the reaction, catalyst was removed by filtration through a celite bed and the filtrate was concentrated under reduced pressure to give a thick mass, which was then crystallized from a heptane/ethyl acetate mixture (200 ml, 3:1 ) to give a pure solid product. Yield: 65 grams (65 %), melting range: 58-62 ⁰C ¹H NMR (CDCI₃, 200 MHz): δ 2.2 (s, 3H), 3.18 (dd, 2H) 3.7 (s, 3H), 3.8 (t, 1 H), 7.15 (d, 2H), 8.46 (d, 2H), MS (m/z): 208 (M+1).

Preparation 3: Ethyl-2-acetyl-3(4-N-methylperidinyl) propionate

Step 1 : Preparation of 4-(2-acetyl-2-ethoxycarbonyl-ethvO-1-methyl- pyridinium iodide

Ethyl-2-acetyl-3-pyridyl propionate (7.2 grams, 0.0324 moles), obtained according to preparation 2, except using ethylacetoacetate, was dissolved in 100 ml of tetrahydrofuran. To this, methyl iodide (11.45 grams, 0.0182 moles) was added and the mixture was stirred overnight. The reaction was monitored by thin layer chromatography (50% ethyl acetate: petroleum ether). Finally, ethanol was evaporated from the reaction mixture to get title product as a low melting point solid. Yield: 8 grams

¹H NMR (CDCI₃, 200 MHz): δ 1.24(t, 3H, J= 8.0 Hz), 2.36 (s, 3H), 3.41 (m, 4H), 4.22 (m, 4H), 8.07(d, 2H, J= 6.0 Hz), 9.09 (d, 2H, J=6.0 Hz). MS (m/z): 236 (M⁺+i).

Step 2: Preparation of Ethyl-2-acetyl-3(4-N-methylpiperidinvQ propionate

4-(2-Acetyl-2-ethoxycarbonyl-ethyl)-1 -methyl-pyridinium iodide (4.80 grams, 0.0203 moles) obtained in step 1 above, was dissolved in methanol, charged along with a platinum oxide catalyst (0.48 grams) into a hydrogenation flask and a 2.8 Kg/cm² hydrogen pressure was applied. Hydrogenation was continued for 6 hours. The mixture was filtered through a perlite bed, and the filtrate was concentrated to give a yellow colored liquid. Yield: 4.6 grams. ¹H NMR (CDCI₃, 200 MHz): δ 1.26 (t, 3H, J= 6.2 Hz), 16.4 (m, 2H), 2.23(s, 3H), 2.79 (s, 3H), 2.79(s, 3H), 2.95 (br, 2H), 3.44 (m, 4H), 4.20(q, 2H, J=6.0 Hz) MS (m/z): 242 (M⁺+1)

EXAMPLE 1

N-methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-ethanesulfonamide hydrochloride of the following formula:

was prepared, as follows:

Step 1 : Preparation of Methyl-5-methyl sulfamoylethyl-3-(4-pyridvO-1 H-2- indole carboxvlate

N-Methyl-2-(4-amino phenyl)ethanesulfonamide (5.23 grams, 0.025 moles), obtained in preparation 1 , was stirred in methanol (50 ml) and sodium acetate (16.5 grams, 0.2 moles) at 30 to 40⁰C for 2 hours. In another flask, the compound obtained in preparation 2 (5.0 grams, 0.023 moles) in water (100 ml) was treated with hydrochloric acid (3.4 grams, 9.7 ml, 0.093 moles) at -5 to O⁰C. To this was added sodium nitrite solution in water (4.7 grams, 0.23 moles, 10 ml) slowly at -5 to O⁰C. After addition, the reaction mixture was stirred at the same temperature for another hour. This solution of diazonium salt was added to methyl-2-acetyl-3- pyridyl propanoate, obtained in preparation 2, and sodium sulfate in methanol at 0⁰C for 30 minutes. The reaction mixture was stirred at 30 to 40⁰C for 3 hours. The reaction was monitored by thin layer chromatography (50% ethyl acetate in petroleum ether). Dichloromethane was added to the reaction mixture and the layers were separated; the aqueous layer was extracted with dichloromethane (two times). The combined organic layer was dried (sodium sulfate) and concentrated under reduced pressure to give a thick liquid (10 grams, crude compound (IV), where R represents the methyl group). The resultant compound was taken in 50 ml of methanolic hydrochloric acid (17.0%) and refluxed for 12 to 14 hours. The reaction was monitored by thin layer chromatography (50% ethyl acetate in petroleum ether). The reaction mass was cooled to 30 to 40⁰C, and the formed solid was filtered and washed with methanol to give 5.0 grams of the hydrochloride salt of methyl-5-methylsulfamoylethyl-3-(4-pyridyl)-1 H-2-indole carboxylate. The hydrochloride salt was taken into water and neutralized with sodium bicarbonate (pH 7-7.5); then the solid was filtered and dried under vacuum. Weight of the compound: 4.2 grams, yield: 48.2%, melting range: 222- 225⁰C IR (KBr, cm^"1): 3278, 2925, 2853, 1705, 1603, 1500, 1581 , 1440, 1322, 1231 , 1281 , 1130, 779, 625

¹H NMR (DMSO-de, 400 MHz): δ 2.59 (d, 3H, J= 5.2 Hz), 3.01 (m, 2H), 3.28 (m, 2H), 3.80 (s, 3H), 6.90 (q, 1 H J=5.2 Hz), 7.28 (dd, 1 H J= 8.8, 1.6 Hz), 7.45 (s, 1 H), 7.48 (d, 1H, J=8.4 Hz), 7.54 (d, 2H, J=5.6 Hz), 8.64 (d, 2H, J=6.4 Hz), 12.20 (bs). MS (m/z): 374(M⁺+1)

Step 2: Preparation of 1 -Methyl-4-(2-methoxy carbonyl-5-methyl sulphamoylethvi-1 H-3-indolvO pyridinium iodide

Mθthyl-5-methyl sulfamoylethyl-3-(4-pyridyl)-1 H-2-indole carboxylate, obtained in step 1 above, was dissolved in dimethylsulfoxide (200 ml). To the resultant mixture methyl iodide (38 grams, 0.26 moles) was added at one time at 30 to 4O⁰C and the mixture was stirred for 12 hours. 800 ml of ethyl acetate was added to the reaction mass and the solid was recovered by filtration and dried. Weight of the compound: 29.0 grams, yield: 85 %, melting range: 239-249⁰C IR (KBr, cm-¹): 3349, 3171 , 2946, 1698, 1638, 1549, 1511 , 1382, 1490, 1311, 1342, 1283, 1248, 1149, ¹H NMR (DMSO-d₆, 400 MHz): δ 2.60 (d, 3H, J= 4.8 Hz), 3.05 (m, 2H), 3.30 (m, 2H), 3.85 (s, 3H), 4.37 (s, 3H), 6.95 (q, 1H J=4.8 Hz), 7.36 (dd, 1H J= 8.8, 1.6 Hz), 7.55 (d, 1 H, J=8.8), 7.59 (br), 8.32 (d, 2H, J=6.8 Hz), 8.95 (d, 2H, J=6.4 Hz) 12.70 (bs).

MS (m/z):388(M⁺+1)

Step 3: Preparation of Methyl-5-methylsulfamolvethyl-3-(1-methyl-1 , 2.3,6- tetrahvdro-4-pyridvO-1 H-2-indole carboxylate

1-Methyl-4-(2-methoxycarbonyl-5-methylsulfamoylethyl-1H-3-indolyl) pyridinium iodide, (10.0 grams, 0.019 moles), obtained in step 2 above, was taken in methanol (300 ml) then sodium borohydride (2.95 grams, 0.077 moles) was added in small portions. After the addition, the mixture was stirred at 30 to 4O⁰C for 1 hour. The reaction was monitored by thin layer chromatography (ethyl acetate). Water (100 mL) was added to the reaction mass and the methanol was evaporated under reduced pressure. The compound was precipitated from water, then filtered and dried. Weight of the compound: 5.4 grams, yield: 71.0 %, melting range: 190-195 ⁰C

IR (KBr, cm-¹): 3340, 2947, 2796, 1710, 1540, 1462, 1332, 1305, 1242, 1145, 1112, 808, 752, 647 ¹H NMR (DMSO-d₆, 400 MHz): δ 2.32 (s, 3H), 2.44 (br, 2H), 2.60 (d, 3H, J = 4.8 Hz), 2.60 (t, 2H, J = 4.8 Hz), 3.01 (m, 2H), 3.07 (d, 2H, J = 2.8 Hz), 3.28 (m, 2H), 3.84 (s,3H), 5.67 (bs, 1 H), 6.92 (q, 1 H, J = 4.8 Hz), 7.19 (dd, 1 H J = 8.8, 1.6 Hz), 7.36 (d, 1 H, J = 8.4), 7.42 (s, 1 H)₁ 11.65 (bs, 1 H). MS (m/z):391(M⁺+1)

Step 4: Preparation of Methyl-3-(1-methyl-4-piperidyl)-5-methyl sulfamoyl ethyl-1 H-2-indole carboxylate

Methyl-3-(1-methyl-4-piperidyl)-5-methyl sulfamoyl ethyl-1 H-2-indole carboxylate (18.0 grams, 0.046 moles), obtained in step 3 above, was taken in methanol (1000 ml). Raney nickel catalyst was added and the compound was hydrogenated in an autoclave under 10.7 Kg/cm² hydrogen pressure at 5O⁰C for 12 hours. Reaction was monitored by mass spectrum and high performance liquid chromatography (HPLC) methods. Catalyst was removed by filtration through a celite bed, then the bed was washed with methanol and combined filtrate was concentrated under reduced pressure to give the solid title compound. Weight of the compound: 13.0 grams, yield: 72.0 %, melting range: 175-180 ⁰C IR (KBr, cm^"1): 3324, 2947, 1710, 1537, 1462, 1449, 1305, 1242, 1190, 1138, 782 ¹H NMR (DMSO-d₆, 200 MHz): δ 1.65 (bd, 2H), 2.05 (m, br, 4H), 2.10 (s, 3H), 2.60 (d, 3H, J = 4.8 Hz), 2.80- 3.05 (m, 4H), 3.30 (m, 2H), 3.60 (m, 1 H) 3.85 (s, 3H), 6.95 (br, 1H), 7.18 (d, 1 H, J= 8.8 Hz), 7.29 (d, 1H, J = 8.8 Hz), 7.65 (s, 1 H), 8.32 (s, 1 H), 11.50 (s, 1 H) MS (m/z): 394 (M⁺+1 ) Step 5: Preparation of N-methyl-3-(1-methyl-4-piperidinyl)-1 H-indole-5- ethanesulfonamide hydrochloride

Methyl-3-(1-methyl-4-piperidyl)-5-methylsulfanoylethyl-1 H-2-indole carboxylate (22.0 grams, 0.055 moles), obtained in step 4 above, was added to a stirred solution of sodium carbonate (29.6 grams, 0.27 moles) in water (300 ml) and was refluxed for 7 hours (clear solution observed; thin layer chromatography was used to check for an absence of starting material, with a methanol mobile phase). The reaction mass was cooled to 30 to 40⁰C, and concentrated hydrochloric acid was added slowly to obtain a pH about 2. After acidifying, the reaction mixture was refluxed for 12 hours. Formation of the compound of formula (IX) was checked by TLC using a 10% ammonia solution in methanol as the mobile phase. The reaction mass was cooled to 10 to 15⁰C and stirred for 30 to 40 minutes. The formed solid was separated by filtration, washed with methanol (2^χ25 ml), and dried under vacuum to get the title compound. Weight of the compound: 15.5 grams, yield: 75 %, melting range: 247-249 ⁰C. IR (KBr, cm-¹): 3328, 2965, 2993, 1474, 1315, 1153, 885, 779, 639 ¹H NMR: (DMSO-d₆, 400 MHz): δ 2.10 (m, br, 4H), 2.62 (d, 3H, J = 4.4), 2.78 (d, 3H, J= 5.2 Hz), 3.02 (m, 1H), 3.02 (m, br, 2H), 3.10 (m, br, 2H), 3.30 (m, br, 2H), 3.48 (m, bs, 2H), 6.95 (m, 1 H, NH), 6.98 (d, 1 H, J = 8.4 Hz), 7.10 (d, 1 H J = 2.4 Hz), 7.28 (d, 1 H, J=8.4), 7.58 (brs, 1 H), 10.50 (br, NH), 10.80 (s, 1H). MS (m/z): 336 (M⁺+1)

EXAMPLE 2

N-Methyl-3-(1 -methyl-4-piperidinyl)-1 H-indole-5-ethanesulfonamide hydrochloride

was prepared by the following procedure:

Step 1 : Preparation of Ethyl/methyl 3-(1-methyl-4-piperidvO-5-(2- methylsulfamoylethvD-1 H- 2-indolecarboxylate

Where R = Ethyl/Methyl

N-methyl-2-(4-aminophenyl)-1-ethanesulfonamide (3.5 grams, 0.016 moles), obtained in preparation 1 , was dissolved in methanol (35 ml) and cooled to 5 to 10⁰C, then concentrated hydrochloric acid (6.8 ml, 0.065 moles) was added dropwise to avoid heat generation and the mixture was stirred for 10 minutes. To this mixture a sodium nitrite (1.35 grams, 0.019 moles) solution in water (5ml) was added slowly at -5 to O⁰C. After addition, the solution was maintained under stirring at the same temperature for 30 minutes. This solution is called "Part A" below. Meanwhile, in a separate vessel, methyl-2-(1-methyl-4-piperidylmethyl)-3- oxobutanoate (4.0 grams, 0.017 moles), obtained in preparation 3, was taken in methanol (20ml), sodium acetate (10.7 grams, 0.13 moles) was added, and the mixture was stirred at 30 to 4O⁰C for 1 hour. The mixture was cooled to 0 to -5⁰C and Part A was added slowly. After addition, the mixture was stirred for 2 to 3 hours at 30 to 4O⁰C. After reaction completion, the reaction mass was extracted with dichloromethane several times. The combined dichloromethane layer was washed with water twice, dried over anhydrous sodium sulfate and concentrated. The crude residue (containing 2-(4-nitro phenyl)-1 -ethane sulfonic acid, characterized by spectral evidence) can be used directly for cyclization to form the indole moiety. To this crude residue (5.1 grams), 100ml of methanolic hydrochloric acid (about 15%) was added and the material was heated to reflux for 12 hours. The reaction mass was then cooled to 30 to 4O⁰C and concentrated to give the title compound. Melting Range: 175-18O⁰C IR (KBr, cm^'1): 3324, 2947, 1710, 1537, 1462, 1449, 1305, 1242, 1190, 1138, 782 ¹H NMR (DMSO-de, 200 MHz): δ 1.65 (bd, 2H), 2.05 (m, br, 4H), 2.10 (s, 3H), 2.60 (d, 3H, J = 4.8 Hz), 2.80- 3.05 (m, 4H), 3.30 (m, 2H), 3.60 (m, 1H) 3.85 (s, 3H), 6.95 (br, 1H), 7.18 (d, 1H, J= 8.8 Hz), 7.29 (d, 1H, J = 8.8 Hz), 7.65 (s, 1H), 8.32 (s, 1H), 11.50 (s, 1H) MS (m/z): 394 (M⁺+1)

Step 2: Preparation of N-Methyl-3-(1-methyl-4-piperidinvπ-1 H-indole-5- ethanesulfonamide hydrochloride of formula (\) Ethyl/methyl-3-(1-methyl-4-piperidyl)-5-methyl sulfamoyl ethyl- 1H-2-indole carboxylate (22.0 grams, 0.055 moles), obtained in step 1 above, was added to a stirred solution of sodium carbonate (29.6 grams, 0.27 moles) in water (300 ml) and was refluxed for 7 hours (clear solution observed, thin layer chromatography was used to check for an absence of starting material, using a methanol mobile phase). The reaction mass was cooled to 30 to 40⁰C, and concentrated hydrochloric acid was added slowly to obtain a pH about 2. After acidifying, the reaction mixture was refluxed for 12 hours. Formation of compound of formula (IX) was checked by TLC using a 10% ammonia solution in methanol mobile phase. The reaction mass was cooled to 10 to 15⁰C and to stirred for 30 to 40 minutes. The produced solid was filtered, washed with methanol (2*25 ml), and dried under vacuum to give the title compound. Weight of the compound: 15.5 grams, yield: 75 %, melting range: 247-249 ⁰C. IR (KBr, cm-¹): 3328, 2965, 2993, 1474, 1315, 1153, 885, 779, 639 ¹H NMR: (DMSO-de, 400 MHz): δ 2.10 (m, br, 4H), 2.62 (d, 3H₁ J = 4.4), 2.78 (d, 3H, J= 5.2 Hz), 3.02 (m, 1 H), 3.02 (m, br, 2H), 3.10 (m, br, 2H), 3.30 (m, br, 2H), 3.48 (m, bs, 2H), 6.95 (m, 1 H, NH), 6.98 (d, 1H, J = 8.4 Hz), 7.10 (d, 1H J = 2.4 Hz), 7.28 (d, 1H, J=8.4), 7.58 (brs, 1H), 10.50 (br, NH), 10.80 (s, 1 H). MS (m/z): 336 (M⁺+1)

EXAMPLE 3

N-methyl-3-(1-methyl-4-piperidinyl)-1 H-indole-5-ethanesulfonamide hydrochloride

was prepared using the following procedure: Step 1 : Preparation of Methyl-5-methylsulfamoylethyl-3-(4-pyridvO-1 H-2- indole carboxylate

N-Methyl-2-(4-aminophenyl) ethane sulfonamide (17 Kg), obtained in preparation 1 , was stirred in water (255 liters). Hydrochloric acid (20 liters) was added slowly and the mixture was maintained at a temperature at -5 to 8 ⁰C. To this, sodium nitrite solution in water (11 Kg in 35 liters) was added slowly at -5 to O⁰C. After this addition, methylene chloride (80 liters) was added slowly at -5 to 0⁰C to give a diazonium salt solution.

In another reactor Methyl-2-acetyl-3-pyridyl propanoate obtained in preparation 2 (16.5 Kg) was dissolved in methanol (35 liters). To this, caustic potash solution in water (11 Kg in 35 liters) was added slowly at -5 to O⁰C. The diazonium salt solution from above was added to the methyl-2-acetyl-3- pyridyl propanoate and caustic potash solution in methanol at -5 to O⁰C. The reaction mass was stired at -5 to 0⁰C for 30 to 50 minutes and then at 25 to 30⁰C for 1 hour. The reaction progress was monitored by thin layer chromatography. Dichloromethane (40 liters) was added to the reaction mixture and the layers were separated; the aqueous layer was extracted with dichloromethane (2 x 40 liters). The combined organic layer was dried using sodium sulfate and concentrated under reduced pressure to give a thick liquid. This liquid was taken into 170 liters of methanolic hydrochloric acid (13-18%), maintained at 15 to 20⁰C for 30 minutes, and heated to 61 to 62°C to distill off solvents. The reaction mass was maintained for 3 hours at 15 to 20⁰C. The formed solid was filtered and washed with ethyl acetate to give a wet cake of the hydrochloride salt of methyl-5- methylsulfamoylethyl-3-(4-pyridyl)-1 H-2-indole carboxylate. This hydrochloride salt was taken into water and neutralized with sodium bicarbonate (pH 7.5-8.5); filtered, and dried under vacuum. Weight of the compound: 12 Kg, yield: 40%, melting range: 222-225⁰C IR(KBr, cm-¹): 3278,2925, 2853, 1705, 1603, 1500, 1581, 1440, 1322, 1231,

1281, 1130,779,625

¹H NMR (DMSO-de, 400 MHz): δ 2.59 (d, 3H, J= 5.2 Hz), 3.01 (m, 2H), 3.28 (m,

2H), 3.80 (s, 3H), 6.90 (q, 1H J=5.2 Hz), 7.28 (dd, 1H J= 8.8, 1.6 Hz), 7.45 (S₁ 1H),

7.48 (d, 1 H, J=8.4 Hz), 7.54 (d, 2H, J=5.6 Hz), 8.64 (d, 2H₁ J=6.4 Hz), 12.20 (bs).

MS (m/z): 374(M⁺+1 )

Step 2: Preparation of 1-Methyl-4-(2-methoxy carbonyl-5-methyl sulfamoylethyl-1 H-3-indolvO pyridinium iodide

Methyl-5-methyl sulfamoylethyl-3-(4-pyridyl)~1 H-2-indole carboxylate (8

Kg), obtained in step 1 above, was dissolved in dimethyl sulfoxide (40 liters). To the resultant solution methyl iodide (12.2 Kg) was added slowly at 25 to 30⁰C and the mixture was stirred for 4 to 5 hours. The mixture was added to a vessel containing ethyl acetate (240 liters) and the resulting solid was filtered and dried.

Weight of the compound: 8.0 to 11.0 Kg, Yield: 85 to 100 %, Melting Range: 239-

249⁰C

IR (KBr, cm^"1): 3349, 3171 , 2946, 1698, 1638, 1549, 1511 , 1382, 1490, 1311 ,

1342, 1283, 1248, 1149 ¹H NMR (DMSO-de, 400 MHz): δ 2.60 (d, 3H, J= 4.8 Hz), 3.05 (m, 2H), 3.30 (m,

2H), 3.85 (s, 3H), 4.37 (s, 3H), 6.95 (q, 1 H J=4.8 Hz), 7.36 (dd, 1 H J= 8.8, 1.6 Hz),

7.55 (d, 1 H, J=8.8), 7.59 (br), 8.32 (d, 2H, J=6.8 Hz), 8.95 (d, 2H, J=6.4 Hz) 12.70

(bs).

MS (m/z):388(M⁺+1)

Step 3: Preparation of Methyl-5-methylsulfamolvethyl-3-(1-rnethyl-1 ,2,3,6- tetrahvdro-4-pyridvD-1 H-2-indole carboxvlate

1-Mθthyl-4-(2-methoxycarbonyl-5-methylsulfamoylethyl-1 H-3-indolyl) pyridinium iodide, (11 Kg), obtained in step 2 above, was taken in methanol (330 liters). Sodium borohydride (5.7 Kg) was added slowly to the reaction mass at 30 to 40⁰C. The mixture was stirred at 25 to 35°C for 4 to 6 hours. The reaction was monitored for completion by thin layer chromatography. A portion of the methanol (80 liters) was evaporated under reduced pressure at 35°C and water (110 liters) was added to the reaction mass. A solid precipitated and was filtered and dried. Weight of the compound: 5.7 to 8.3 Kg, Yield: 68 to 99 %, melting range: 190- 195⁰C.

IR (KBr, cm-¹): 3340, 2947, 2796, 1710, 1540, 1462, 1332, 1305, 1242, 1145, 1112, 808, 752, 647

¹H NMR (DMSO-de, 400 MHz): δ 2.32 (s, 3H), 2.44 (br, 2H), 2.60 (d, 3H, J = 4.8 Hz), 2.60 (t, 2H, J = 4.8 Hz), 3.01 (m, 2H), 3.07 (d, 2H, J = 2.8 Hz), 3.28 (m, 2H), 3.84 (s, 3H), 5.67 (bs, 1H), 6.92 (q, 1H, J = 4.8 Hz), 7.19 (dd, 1H J = 8.8, 1.6 Hz), 7.36 (d, 1 H, J = 8.4), 7.42 (s, 1 H), 11.65 (bs, 1 H). MS (m/z):391 (M⁺+1)

Step 4: Preparation of Methyl-3-(1-methyl-4-piperidvO-5-methyl sulfamoyl ethyl-1 H-2-indole carboxvlate

Methyl-3-(1-methyl-4-piperidyl)-5-methyl sulfamoyl ethyl-1 H-2-indole carboxylate (6.5 Kg), obtained in step 3 above, was taken in methanol (65 Kg). Raney nickel (6.5 Kg) in methanol (65 Kg) was added to the above reaction mixture and hydrogenation was conducted in an autoclave under 11 to 14 Kg/cm² pressure at 70 to 8O⁰C for 1 to 3 hours. The reaction progress was monitored by high performance liquid chromatography. Catalyst was removed by filtration through a celite bed, and the bed was washed with methanol or toluene and the combined filtrate was concentrated under reduced pressure to give the solid title compound. Weight of the compound: 3.9 to 6.5 Kg, Yield: 60 to 100.0 %, melting range: 175-18O ⁰C.

IR (KBr, cm^"1): 3324, 2947, 1710, 1537, 1462, 1449, 1305, 1242, 1190, 1138, 782 ¹H NMR (DMSO-Cl₆, 200 MHz): δ 1.65 (bd, 2H), 2.05 (m, br, 4H), 2.10 (s, 3H), 2.60 (d, 3H, J = 4.8 Hz), 2.80- 3.05 (m, 4H), 3.30 (m, 2H), 3.60 (m, 1 H) 3.85 (s, 3H), 6.95 (br, 1 H), 7.18 (d, 1H, J= 8.8 Hz), 7.29 (d, 1H, J = 8.8 Hz), 7.65 (s, 1H), 8.32 (s, 1H), 11.50 (s, 1H) MS (m/z): 394 (M⁺+i )

Step 5: Preparation of N-methvi-3-(1-methyl-4-piperidinvπ-1 H-indole-5- ethanesulfonamide hydrochloride Methyl-3-(1-methyl-4-piperidyl)-5-methylsulfanoylethyl-1 H-2-indole carboxylate (6.0 Kg), obtained in step 4 above, was added to a stirred solution of sodium carbonate (8.0 Kg) in water (12 liters) and was refluxed for 7 to 8 hours. The reaction mass was cooled to 50 to 55°C, and hydrochloric acid (17.5 liters) was added slowly. After acidifying, the reaction mixture was refluxed for 12 to 14 hour. The reaction mass was cooled to 10 to 15⁰C and stirred for 90 to 140 minutes. The produced solid was filtered, washed with methanol (2*12 liters) and dried under vacuum to give the title compound. Weight of the compound: 2 to 4 Kg, Yield: 40-75 %. The compound was further dissolved in methanol, the solution was treated with activated carbon, and the compound crystallized. Melting range: 247-249 ⁰C.

IR (KBr, cm^'1): 3328, 2965, 2993, 1474, 1315, 1153, 885, 779, 639 ¹H NMR: (DMSO-de, 400 MHz): δ 2.10 (m, br, 4H), 2.62 (d, 3H, J = 4.4), 2.78 (d, 3H, J= 5.2 Hz), 3.02 (m, 1 H), 3.02 (m, br, 2H), 3.10 (m, br, 2H)₁ 3.30 (m, br, 2H), 3.48 (m, bs, 2H), 6.95 (m, 1 H, NH), 6.98 (d, 1H, J = 8.4 Hz), 7.10 (d, 1H J = 2.4 Hz), 7.28 (d, 1 H, J=8.4), 7.58 (brs, 1H)₁ 10.50 (br, NH), 10.80 (s, 1 H). MS (m/z): 336 (M⁺+1)

Claims

CLAIMS:

1. A process for preparing a compound having formula (I)

comprising:

(i) reacting a diazotized derivative of a compound having formula (II),

to produce a compound having formula (IV);

(IV)

(iii) quatemizing the compound having formula (V) with an alkyl halide to produce a compound having formula (Vl), where X is a halogen;

(vii) decarboxylating the compound having formula (IX) with an acid to produce the compound having formula (I).

2. The process according to claim 1 , wherein the compound having formula (Vl) is not isolated prior to step (iv).

3. The process according to claim 1 , wherein steps (vi) and (vii) are conducted sequentially in a vessel, without isolating the compound having formula (IX).

4. A process for preparing a compound having formula (I)

comprising:

(i) reacting a diazotized derivative of a compound having formula (II)

to produce a compound having formula (XV),

(iii) saponifying the compound having formula (VIII) with a base to produce a compound having formula (IX), where M is an alkali metal, and

5. The process according to claim 4, wherein the compound having formula (XV) is not isolated, prior to conducting step (ii).

6. The process according to claim 4, wherein steps (iii) and (iv) are conducted sequentially in a vessel, without isolating the compound having formula (IX).

7. A compound having formula (XIV), where R is an alkyl group having 1 to 5 carbon atoms:

8. The compound according to claim 7, prepared by a process comprising:

(i) reacting a mixture of pyridine 4-carboxyldehyde and an alkyl acetoacetate to prepare a compound having formula (Ilia).

where R represents an alkyl group having 1 to 5 carbon atoms; (ii) hydrogenating the compound having formula (Ilia) to prepare a compound having formula (111);

(iii) quaternizing the compound having formula (III) with an alkyl halide to prepare a compound having formula (XIVa), where X is a halogen; and

(iv) hydrogenating the compound having formula (XIVa) to produce the compound having formula (XIV).

9. A compound having formula (VIII):

10. A compound having formula (IX), wherein M is an alkali metal: