Title of Invention	''PROCESS FOR PREPARATION OF 2-ETHOXY-5-(4-METHYLPOPERAZIN-1-YLSULPHONYL) BENZOIC ACID (A PRECURSOR FOR PREPARATION OF AN INTERMEDIATE TO SILDENAFIL)'';
Abstract	The invention relates to a process for preparation of 4-[2 -ethoxy-5-(4-methylpiperazin-l-ylsulphonyl)benzamidol]-l-methyl-3-n-propylpyrazole-5- carboxamide by (i) reaching N,N''-carbonyldimidazole and 2-Ethoxy-5-(4-methylpiperazin-l-ylsulpphonyl)benzoic acid in a solvent, preferably an ester, followed by heating the resulting mixture at about 55" C for about 0.5 hr, followed by refluxation for an additional duration of about 2 hours followed by cooling, preferably to room temperature (ii) reaching resulting mixture with 4 Amino-l-l-methyl-3-n-propylpyra2ole-5-carboxamide, preferably in additional amount of said solvent stirring the resulting mixture at room temperature for 72 hours or till claimed compound is obtained and later on it is purified.

Title of Invention

''PROCESS FOR PREPARATION OF 2-ETHOXY-5-(4-METHYLPOPERAZIN-1-YLSULPHONYL) BENZOIC ACID (A PRECURSOR FOR PREPARATION OF AN INTERMEDIATE TO SILDENAFIL)'';

Abstract

The invention relates to a process for preparation of 4-[2 -ethoxy-5-(4-methylpiperazin-l-ylsulphonyl)benzamidol]-l-methyl-3-n-propylpyrazole-5- carboxamide by (i) reaching N,N''-carbonyldimidazole and 2-Ethoxy-5-(4-methylpiperazin-l-ylsulpphonyl)benzoic acid in a solvent, preferably an ester, followed by heating the resulting mixture at about 55" C for about 0.5 hr, followed by refluxation for an additional duration of about 2 hours followed by cooling, preferably to room temperature (ii) reaching resulting mixture with 4 Amino-l-l-methyl-3-n-propylpyra2ole-5-carboxamide, preferably in additional amount of said solvent stirring the resulting mixture at room temperature for 72 hours or till claimed compound is obtained and later on it is purified.

Full Text	This application is divisional patent application out of the main Indian patent application no. 1548/Del/97. The present invention relates to a process for preparation of a compound of formula (11) [please see in the scheme given on page 6] named as 4-[2-ethoxy- 5 -(4-methy Ipiperazin-1 -ylsulphonyl)benzamidol] -1 -methyl-3 -n-propylpyrazole- 5 -carboxamide, particularly the present invention relates to a process for preparation of an intermediate used to prepare the sildenafil. More specifically, the present invention concerns a process for preparation of an intermediate to sildenafil, wherein such intermediate can result in more efficient sildenafil than that disclosed in EP-A-0463756 and such intermediate, surprisingly, can provide directly sildenafil of clinical quality standard, thus obviating the need for subsequent purification steps. In this context, sildenafil of clinical quality standard means material of sufficient purity for administration to humans. Sildenafil, which was originally disclosed in the above referred European patent (EP-A-04637.56), has been found to be particularly usefial in the treatment of, inter alia, male erectile dysfimction [WO-A-94/28902]. The presently disclosed process involves treatment of an imidazole, particularly of a diimidazole, more particularly of substituted diimidazole, even more particularly of N,N'-Carbonyldiimidazole with substituted benzoic acid, particularly with disubstituted benzoic acid, more particularly with 2, 5-disubstituted benzoic acid, even more particularly with 2-Ethoxy-5-(4-methylpiperazin-l-ylsulphonyl)benzoic acid (compound of formula V, please see in the scheme on page 6) in a solvent, preferably an ester, followed by heating the resulting mixture at about 55oC for about 0.5 hr, followed by refluxation for an additional duration of about 2 hours followed by cooling, preferably to room temperature in step-1, and treating the resulting reaction mixture from said step-1 with 4-Amino-l-methyl-3-n-propylpyrazole-5-carboxamide, preferably in additional amount of said solvent in step-2, and stirring the resulting reaction mixture fi"om said step-2 preferably at room temperature for about 72 hours or till a solid compound of formula II is obtained, wherein N,N'-Carbonyldiimidazole is taken in an amount of about 1.30 mol and 2-Ethoxy-5-(4-methylpiperazin-l-ylsulphonyl)benzoic acid is taken in an amount of about 1.30 mol in said step-1, and 4-Amino-l-methyl-3-n-propylpyrazole-5-carboxamide is taken in an amount of about 1.12 mol. In accordance with preferred embodiment of the present invention said solvent is preferably ethyl acetate. The key step in the over-all process for preparation of sildenafil involves the ring-closure of the immediate precursor to sildenafil, i.e. the bis-amide of formula (II) : (Formula Removed) Thus the invention provides a process for the preparation of a compound of formula (I) which comprises cyclisation of a compound of formula (II). In a preferred embodiment, the cyclisation is carried out in the presence of a base, preferably in a solvent, optionally in the presence of hydrogen peroxide or a peroxide salt, and is followed, where necessary, by neutralisation of the reaction mixture. Accordingly, present invention makes a disclosure of a process for preparation of 4-[2-Ethoxy-5-(4-methylpiperazln-1-ylsulphonyl)benzamidol]-1-methyl-3-n-propylpyrazole-5-carboxamide of formula (II): (Formula Removed) wherein said process comprises reacting N,N'-Carbonyldiimidazole and 2-Ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)benzoic acid in a solvent, preferably an ester, followed by heating the resulting mixture at about 55°C for about 0.5 hr, followed by refiuxatlon for an additional duration of about 2 hours followed by cooling, preferably to room temperature in step-1, and reacting the resulting reaction mixture from said step-1 with 4-Amino-1-methyl-3-n-propylpyrazole-5-carboxamlde, preferably in additional amount of said solvent in step-2, and stirring the resulting reaction mixture from said step-2 preferably at room temperature for about 72 hours or till a solid compound of formula II is obtained and said compound of formula (II) is isolated and purified as described hereinbefore, wherein N,N'-Carbonyldiimidazole is taken in an amount of about 1.30 mol and 2-Ethoxy-5-(4-methylpipera2in-1-yIsulphonyl)benzoic acid is taken in an amount of about 1.30 mol In said step-1, and 4-Amino-1-methyl-3-n-propylpyrazole-5-carboxamide is taken in an amount of about 1.12 mol. A suitable base may be selected from the group consisting of a metal salt of a C1-C12 alkanol, a C3-C12 cycioaikanol, a (C3-C8 cycloalkyl)C1-C6 aikanol, ammonia, a C1-C12 alkyiamine, a di(C1-C12 alkyl)amine, a C3-C8 cycioalkylamine, a N-{C3-C8 cycloalkyi)-N-(C1-C12 alkyl)amine, a di(C3-C8 cycIoalkyl)amine, a (C3-C8 cycloalkyl)C1-C6 alkyiamine, a N~(C3-C8 cycioalkyl)C1-C6 alkyl-N-(C1-C12 alkyl)amine, a N-(C3-C8 cycloalkyl)C1-C6 alkyl-N-{C3-C8 cycloalkyl)amine, a di[(C3-C8 cycioalky)C1-C6 alkyljamine and a heterocyclic amine selected from the group consisting of imidazole, triazole, pyrrolidine, piperidine, heptamethyleneimine, morpholine, thiomorpholine and a 1-(C1-C4 alkyi)piperazine; a metal hydride, fluoride, hydroxide, oxide,, carbonate and bicarbonate; wherein the metal is selected from the group consisting of lithium, sodium, potassium, rubidium, cesium, beryllium, magnesium, calcium, strontium, barium, aluminium, indium, thallium, titanium, zirconium, cobalt, copper, silver, zinc, cadmium, mercuny and cerium; and a C7-C12 bicyclic amidine. Preferably the base is selected from the group consisting of an alkali or alkaline earth metal salt of a C1-C12 alkanoi, a C3-C12 cycloaikanol and a (C3-C, cycloalkyi) C1-C6 alkanoi; an alkali metal salt of ammonia, a N-(secondary or tertiary C3-C6 alkyl)-N-(pnimary, secondary or tertiary C3-C6 alkyl)amine, a C3-C8 cycloalkylamine, a N-(C3-C8 cycloalkyl)-N-(primary, secondary or tertiary C3-C8 alkyl)amine, a di(C3-C8 cycloalkyi)amine and l-methylplperazine; and an alkali or alkaline earth metal hydride, hydroxide, oxide, carbonate and bicarbonate; 1,5-diazabicyclo[4.3.0]non-5-ene and 1,8-dia2abicyclo[5.4.0]undec-7-ene. A suitable solvent may be selected from the group consisting of a C1-C12 alkanoi, a C3-C12 cycloaikanol, a (C3-C8 cycloalkyl)C1-C6 alkanoi, a C3-C9 aikanone, a C4-C10 cycloalkanone, a C5-C12 alkyl ether, 1,2-dimethoxyethane, 1,2-diethoxyethane, digiyme, tetrahydrofuran, 1,4-dioxan, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, acetonitrile, dimethyl sulphoxide, sulpholane, dimethylformamide, dimethylacetamide, N-methylpyrrolidin-2-one, pyrrolidin-2-cne, pyridine and water, and mixtures thereof. Preferably the solvent is selected from the group consisting of ethanoi, 2-propanol, a secondary or tertiary C1-C12 alkanoi, a C3-C12 cycloaikanol, a tertiary C4-C12 cycloaikanol, a secondan/ or tertiarv (C3-C7- cycloalkyl)C2-C3 alkanol a C -C8 aikanone, 1,2-dimethoxyethane, 1,2-diethoxyethane, digiyme, tetrahydrofuran. 1,4-dioxan, toluene, xylene, chlorobenzene, 1,2-dichiorobenzene, acetonitrile, dimethyl sulphoxide, sulpholane, dimethylformamide, N-methylpyrrolidin-2-one, pyridine and water, and mixtures thereof. Further preferred features are that the quantity of base employed is from 1.0 to 5,0 molecular equivalents and that the reaction is carried out at from 50 to 170°C for from 3 to 170 hours. In a more preferred process the base is selected from the group consisting of the lithium, sodium and potassium salts of a C1-C12 alkanoi, a C4-C12 cycloaikanol, ammonia, cyclohexylamine and l-methylpipe.'-azine; the hydride salts of lithium, sodium and potassium; cesium carbonate; and barium oxide; the solvent is selected from the group consisting of ethanoi, a tertiary C4-C10 alcohol, a tertiary C5-C3 cycioatl Even more preferred is a process wherein the base is selected from the group consisting of the C1-C12 alkoxide and hydride salts of lithium, sodium and potassium, sodamide, sodium cyclohexylamide and cesium carbonate; the solvent is selected from the group consisting of ethanol, t-butanol, t-amyl alcohol, 1-methylcyclohexanol, tetrahydrofuran and 1,4-dioxan; and the reaction is conducted for from 3 to 60 hours. A particularly preferred process is that wherein the base is selected from the group consisting of sodium ethoxide, sodium t-butoxide, potassium t-butoxide and sodium hydride; and the solvent is selected from the group consisting of ethanol, t-butanol, t-amyl alcohol and tetrahydrofuran. In the above definitions, unless otherwise stated, an alkyl chain or cycloalkvl rinc may branched or unbranched. The compound of formula (I) may be isolated and purified by conventiona; techniques. For example, when (I) is produced in the form of a salt, by neutralisation of the optionally prediluted reaction mixture, followed by collection of the product by filtration/extraction and optional crystallisation thereof. Alternatively, the compound of formula (I) may be conveniently isolated and/or purified by standard chromatographic procedures. The compound of formula (II) required for the preparation of the compound of formula (I) may be obtained by the route depicted in the following reaction scheme using conventional procedures. SCHEME (Scheme Removed) Thus the compound of formula (iV) may be prepared by chlorosulphonylation of 2-ethoxybenzoic acid, i.e. the compound of formula (III). Typically, (III) is added to an ice-cooled mixture of about 1 mol. equiv. of thionyj chloride and about 4 moi. equivs. of chlorosuiphonic acid, whilst maintaining the reaction temperature below 25°C; the reaction is then allowed to continue at room temperature until complete Conversion of (IV) to the compound of formula (V) is achieved by N-sulphonylation of 1-methylpiperazine and may be conducted in a one-step or two-step procedure. In a one-step procedure, about 2.3 mol. equivs. of 1-methylpiperazine are added to an aqueous suspension of (IV) at about 10°C, whilst maintaining the reaction temperature below 20°C; the temperature of the resulting reaction mixture is then held at about 10°C. Alternatively, the quantity of 1-methylpiperazine can be reduced to about 1.1 miol. equiv. by employing about 1 mol. equiv. of sodium hydroxide as auxilian/ base. In a two-step procedure, a solution of (IV) in a suitable solvent, e.g. acetone, is added to a mixture of about a 10% 6X0633 of 1-methylpipefazipe and about a 10% excess of a suitable acid acceptor, e.g. a tertiary base such as triethylamine, whilst maintaining the reacticn temoerature below 20X. When triethylamine Is employed as auxiliany base, an intermediate hydrochloride-triethylamine double salt of (V), identified as the compound of formula (VA), is isolated. This salt may be transformed to (V) by treatment with water. A convenient alternative route to (V) is to employ a C1-C4 aikyl 2-ethoxybenzoate (obtained by conventional esterification of (III)) as the chlorosulphonylation substrate, followed by treatment of the resulting sulphonyl chlonde with 1-methylpiperazine as described above, then subsequent standard hydrolysis of the ester group. Other synthetic options for obtaining (V) from salicylic acid and its derivatives will be apparent to the person skilled in the art Coupling of (V) with the compound of formula (VII) may be achieved by any of the plethora of amide bond-forming reactions well known to those skilled in the art. For example, the carboxylic acid function of (V) is first of all activated using about a 5% excess of a reagent such as N,N'- carbonyldiimidazole in a suitable solvent, e.g. ethyl acetate, at from about room temperature to about SOX, followed by reaction of the intermediate imidazolide with (VI!) at from about 20 to about 60°C. The aminopyrazole (VII) is obtainable by conventional reduction of the corresponding nitropyrazole (VI), e.g. using palladium-catalysed hydrogenation in a suitable solvent such as ethyl acetate. The resulting solution of (VII) may be used directly, after filtration, in the coupling reaction with (V). The cyclisation reaction of (II) to provide the compound of formula (I) has been achieved in yields of up to 95%. Thus the over-all yield of (I) based on the benzoic acid derivative (III) as starting material, depending on v/hetherthe one-step or two-step sulphonylation procedure is used, can be as high as 51.7% or 47.8% respectively. This compares very favourably with the process disclosed in E:P-vV0463756 in which the over-all yield of (i; from 2-ethoxyDenzoyl chloride (anc tnus from (111) also, assumiing that the acid chioride derivative can be generated quantitatively therefrom) is 27.6%. In an alternative comparison, the over-all yieid of (I) based on the nitropyrazole (VI) can be as high as 85.2% in the presently disclosed process whilst, in the process disclosed in EP-A-0463756, the over-all yield of (I) from (VI) is 23.1%. Clearly then, the alternative process to (I) disclosed hereinbefore can be considerably more efficient and advantageous than that previously disclosed, and the intermediates of formulae (II), (V) and (VA) also form part of the invention. Alternatively, the cyclisation of a compound of formula (II) to a compound of formula (I) may be conducted under neutral or acidic conditions. Under neutral conditions, the compound of formula (II) is heated, optionally in the presence of a solvent and/or optionally in the presence of a dehydratina agent and/or mechanical water-removal system, e.g. a Dean-Stark apparatus A suitable solvent may be selected from the group consisting of 1,2-dichlorobenzene, dimethyl sulphoxide, sulpholane, N-methylpyrrolidin-2-one and pyrrolidin-2-one, and mixtures thereof. Preferably the solvent is 1,2-dichlorobenzene, sulpholane or N-methylpyrrolidin-2-one. A suitable dehydrating agent may be selected from the group consisting of anhydrous potassium carbonate, anhydrous sodium carbonate, anhydrous magnesium sulphate, anhydrous sodium sulphate, phosphorus pentoxide and molecular sieves. Preferably the dehydrating agent is molecular sieves. Preferably also, the reaction is carried out at from 180 to 220°C for from 0.5 to 72 hours. Under acidic conditions, the cyclisation is carried out by reaction of a compound of formula (II) with a protic acid or Lewis acid, optionally in the presence of a solvent. A suitable protic acid may be selected from the group consisting of an inr-nanic acid, an organo-sulphonic acid, an organo-phosohonic acid and an orcsno-carboxylic acid. Preferably the protic acid is concentrated sulphuric acid, phosphoric acid or i2-toluenesulphonic acid. A suitable Lewis acid may be selected from the group consisting of boron trifluoride, boron trichloride, boron tribromide, aluminium chloride, aluminium bromide, silicon tetrachloride, silicon tetrabromide, stannic chloride, stannic bromide, phosphorus pentachloride, phosphorus pentabromide, titanium tetrafluoride, titanium tetrachloride, titanium tetrabromide, ferric chloride, zinc fluoride, zinc chloride, zinc bromide, zinc iodide, mercuric chloride, mercuric bromide and mercuric iodide. Preferably the Lewis acid is boron trifluoride, aluminium chloride, silicon tetrachloride, stannic chloride, titanium tetrachloride, ferric chloride or zinc chloride. A suitable solvent may be selected from the group consisting of a C5-C.2 alkane, a C5-C8 cycloalkane, a C1-C12 alkanoic acid, a C1-C4 alkanol, a C3-C9 alkanone, a C5-C12 aikyi ether, 1,2-dimethoxyethane, 1,2-diethoxyethane, diglyme, tetrahydrofuran, 1,4-dioxan, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, nitrobenzene, dichloromethane, dibromomethane, 1,2-dichloroethane, acetonitrile, dimethyl sulphoxide, sulpholane, dimethylformamide, dimethyiacetamide, N-methylpyrrolidin-2-one and pyrroiidin-2-one, and mixtures thereof. Preferably the solvent is glacial acetic acid, tetrahydrofuran, 1,4-dioxan or chlorobenzene. Preferably also, the reaction is carried out at from 65 to 210°C for from 6 to 300 hours. The syntheses of the compound of formula (I) and the intermediates thereto iescrioed in the following Examples and Preparations, in cases where the comcound of formula (I) was not isolated and (if necessary) purified, the yields there of were determined, and reaction mixtures analysed, by quantitative thin layer chromatography (TLC), using Merck silica gel 60 plates and toluene:methylated spirit:0880 aqueous ammonia mixtures as solvent systems, and/or high performance liquid chromatography (HPLC), using Gilson equipment with a 15 cm reverse phase C18 column and thethylamine:phosphoric acid buffer in aqueous acetonitrile:methanol mixtures as mobile phases. 1H Nuclear magnetic resonance (NMR) spectra were recorded using a Vanan Unity 300 spectrometer and were in all cases consistent with the proposed structures. Characteristic chemiical shifts (6) are given in parts-per-million downfield from tetramethylsiiane using conventional abbreviations for designation of significant peaks: e.g. s, singlet; d, doublet; t, thplet; q, quartet; h, hextet; mi, multiplet; br, broad. Room temperature means 20-25X. TITLE COMPOUND 5-[2-Ethoxv-5-(4-methylpiperazin-1-ylsulphonyl)phenvl]-1-methvl-3-n-oropyl-1,6-dihvdro-7H-Dyrazolo[4.3-d]pyrimidin-7-one EXAMPLE 1 Potassium t-butoxide (3.37 g, 0.030 mol) was added to a stirred suspension of the title compound of Preparation 4 (12.32 g, 0.025 mol) in t-butanol (61 ml) and the resulting mixture heated under reflux for 8 hours, then allowed to cool to room temperature. Water (62.5 ml) was added and then the resulting solution filtered into a speck-free flask and treated dropwise with a speck-free solution of concentrated hydrochloric acid (2.3 ml) in water (62.5 ml). The precipitated product was granulated at pH = 7 and 10°C for 1 hour, collected by filtration, v/ashed with water and dried under vacuum to give the title compound (10.70 g, 90.2% m.p 139-190X. Found: C,55.55; H,6.34; N,17.69, C22H30N6O4S requires C.50.63; H,6.37; N,17.71%. δ (CD3SOCD3): 0.94(3H,t), 1.32(3H,t), 1.73(2H,h), 2.15(3H) 2 35(4H,brs), 2.76(2H,t), 2.88(4H.hr s)4.14(3H,s), 4.18(2H,q), 7,36(1H,d), 7,80(2H,m), 12.16(1H,br s). Analysis of the product by HPLC and quantitativeTLC indicated that clinical quality material had been obtained directly from the reaction. The yield of clinical quality material can be increased to 95% by conducting the cyclisation under more concentrated conditions. EXAMPLES 2-5 Clinical quality material was obtained by variation of the solvent, using procedures similar to that described in Example 1, as summarised in Table 1 As for Example 1, the reactions were carried out at reflux temperature, except in the cases of Examples 2 and 5 where a temperature of 100°C was employed. TABLE 1 (Table Removed) EXAMPLES 6-9 Clinical quality material was obtained by variation of the solvent and the base, using procedures similar to that described in Example 1, as summarised in Table 2. The reactions were carried out at reflux temperature, except in the case of Example 9 where a temperature of 100°C was empioyea. TABLE 2 (Table Removed) EXAMPLE 10 Clinical quality material (88%) was obtained by variation of the cation, using a procedure similar to that described in Example 1, when sodium t-butoxide was used as base and the reaction was conducted for 24 hours. EXAMPLE 11 Clinical quality material (71%) was obtained by vahation of the molar ratio of base, using a procedure similar to that described in Example 1, when potassium t-butoxide (5,0 mol.equiv.) was used and the reaction was conducted at reflux temperature for 18 hours. EXAMPLE 12 Further variation of the reaction conditions of Example 1, using 1.6 mol. equiv. of potassium t-butoxide (4.49 g, 0.040 mol) at 60°C for 55 hours, provided the title compound (87%) of purity >99% by HPLC and TLC analyses. EXAMPLE 13 Title compound (87%) of purity >99% by HPLC and TLC analyses was obtained, using a procedure similar to that described in Example 1, when 1,4-dioxan was used as solvent and the reaction was conducted at 100°C for 4 hours. EXAMPLE 14 Title compound (85%i) of purity >99% by HPLC and TLC analyses was obtained, using a procedure similar to that described in Example 1, when 1,2-dimethoxyethane was used as solvent and the reaction was conducted for 30 hours. EXAMPLE 15 Title compound (83%) of purity >99% by HPLC and TLC analyses was obtained, using a procedure similar to that described in Example 1, when 3,7-dimethyloctan-3-ol was used as solvent and the reaction was conducted at 100°C for 16 hours. EXAMPLE 16 Title compound (74%) of purity >99%) by HPLC and TLC analyses was obtained, using a procedure similar to that described in Example 1, when sodium n-decoxide was used as base, 1,4-dioxan was used as solvent and the reaction was conducted at 100°C for 20 hours. EXAMPLE 17 Title compound (85%) of purity >99% by HPLC and TLC analyses was obtauned, using a procedure similar to that described in Example 1, whe.n sodamide was used as base, 1,4-dioxan was used as solveru and the reaction was conducted at 100°C for 18 hours. EXAMPLE 18 Title compound (91%) of purity >99% by HPLC and TLC analyses was obtained, using a procedure similar to that described in Example 1, when sodium cyclohexylamide was used as base, 1,4-dioxan was used as solvent and the reaction was conducted at 100°C for 6.5 hours. EXAMPLE 19 Title compound (84%i) of purity >99% by HPLC and TLC analyses was obtained, using a procedure similar to that described in Example 1, when sodium 4-methylpiperazide was used as base, 1,4-dioxan was used as solvent and the reaction was conducted at 100°C for 8 hours. EXAMPLES 20-21 Under reaction conditions similar to those described in Example 1, the use of sodium methoxide in methanol for 32 hours furnished a four-component mixture from which the title compound was isolated in a chromatographed yield of 34.5%, whilst the use of potassium t-butoxide in methanol for 40 hours afforded a product mixture which, by TLC and NMR spectroscopic analyses, contained an estimated yield of 69% of the title compound. EXAMPLE 22 Under reaction conditions similar to those described in Example 1, the use of potassium t-butoxide in anhydrous dimethyl sulphoxide at 100°C for 50 hours afforded a crude product (88% wt. yield) which, by TLC and HPLC analyses, contained an estimated yield of 24% of the title compound. EXAMPLE 23 Under react;on conditions similar to those described in Example 1, the use or rnagnesiurn ethoxide in pyridine at reflux temperature for 96 hcjrs gave a c.rude product (79% wt. yield) which, by TLC and HPLC analyses, contained an estimated yield of 16% of the title compound. EXAMPLE 24 Under reaction conditions similar to those described in Example 1, the use of barium ethoxide (as a 10% w/v solution in ethanol) in t-amyl alcohol at 100°C for 20 hours provided a crude product (76.5% wt. yield) which, by TLC and HPLC analyses, contained an estimated yield of 75.5%) of the title compound. EXAMPLE 25 Under reaction conditions similar to those described in Example 1, the use of titanium ethoxide in pyridine at 100°C for 90 hours furnished a crude product (82%c wt. yield) which, by TLC and HFLC analyses, contained an estimated yield of 32°/o of the title compound. EXAMPLE 26 Under reaction conditions similar to those described in Example 1, the use of cupric ethoxide in pyridine at 100°C for 98 hours afforded a crude product (89.5% wt. yield) which, by TLC and HPLC analyses, contained an estimated yield of 18.5% of the title compound. EXAMPLE 27 Under reaction conditions similar to those described in Example 1, the use of aluminium tri-t-butoxide in pyridine at 100°C for 72 hours gave a crude product which, by TLC and HPLC analyses, contained a maximum (due to aluminium salt contamination) estimated yield of 66% of the title compound. EXAMPLE 28 Under reaction conditions similar to those described in Example 1, the use or a iciai of 3.6 mol. equiv. (1.2 mol. equiv. added in three stages) of lithium diisopropyiarnide (as a 1.5M solution of the mono(tetrahydrofuran) complex in cyclchexane 'n anhydrous 14-dioxan, initially at 0°C for 15 minutes, then temperature for 1 hour and subsequently at 100°C for a total of 140 hours, furnished a crude product (60.5% wt. yield) which, by TLC and HPLC analyses, contained an estimated yield of 55.5% of the title compound. EXAMPLE 29 Under reaction conditions similar to those described in Example 1, the use of 2.0 moi.equiv. of 1,8-diazabicyclo[5.4.0]undec-7-ene in pyridine at 100°C for 44 hours afforded a crude product (6.5% wt. yield) which, by TLC and HPLC analyses, contained an estimated yield of 3.3% of the title compound. EXAMPLE 30 Under reaction conditions similar to those described in Example 1, the use of potassium fluoride in t-amyi alcohol at 100°C for 44 hours gave a crude product (85% wt. yield) which, by TLC and HPLC analyses, contained an estimated yield of 3.5% of the title compound. EXAMPLE 31 85% Potassium hydroxide pellets (3.96 g, 0.06 mol) were added to a stirred suspension of the title compound of Preparation 4 (9.85 g, 0.02 mol) in ethanol (30 ml), followed by the addition of water (30 ml) which produced a clear solution. The reaction mixture was heated under reflux for 5 hours and then the bulk of the ethanol removed by evaporation under reduced pressure. The resulting mixture was diluted with water (60 ml), its pH adjusted to 7 using dilute sulphuric acid and the precipitated product granulated for 30 minutes. The solid was collected by riitration, v/ashed with water and dried under vacuum to provide a product (7.96 g), 96.4% of which was shown, by HPLC analysis, to be the title compound. EXAMPLES 32-34 Under reaction conditions similar to those described in Example 1, the use of barium oxide in acetonithle at reflux temperature for 52 hours gave the title compound (89%) of purity >99% by HPLC and TLC analyses. Repetition using dimethylformamide as solvent at 100°C for 31 hours provided a crude product (75.5% wt. yield) which, by TLC and HPLC analyses, contained an estimated yield of 54% of the title compound. Further repetition using pyridine as solvent at 100°C for 16 hours furnished a crude product which, by TLC and HPLC analyses, contained a maximum (due to barium salt contamination) estimated yield of 90% of the title compound. EXAMPLE 35 Under reaction conditions similar to those described in Example 1, the use of cesium carbonate in 4-methylpentan-2-one (methyl isobutyl ketone) at 100°C for 96 hours afforded a crude product (18.5% wt. yield) which, by TLC and HPLC analyses, contained an estimated yield of 13% of the title compound. EXAMPLE 36 Under reaction conditions similar to those described in Example 1, the use of potassium bicarbonate in t-amyl alcohol at 1G0°C for 115 hours gave a crude product (82.5% wt. yield) which, by TLC and HPLC analyses, contained an estimated yield of 20% of the title compound. EXAMPLE 37 The title compound of Preparation 4 (12.32 g, 0.025 mol) was heatea at 215 for 40 minutes and the resulting meit allowed to cool to room temperature. The tarry crude product was dissolved in dichloromethane (25 ml) and the.n purified by chromatography on silica gei, using increasingly polar mixiureo .: methanol in dichloromethane as eluant. Evaporation under vacuum of the appropriate single component fractions provided the pure (by ^H nmr analysis) title compound (1.76 g, 14.8%), whilst a batch of less pure title compound (0.87 g, 7.3 %) was obtained from further fractions. Further chromatographic processing of the latter gave an additional quantity (0.48 g) of pure title compound, the total yield being 2.24 g, 18.8%. EXAMPLES 38-40 A stirred mixture of the title compound of Preparation 4 (12.32 g, 0.025 mol) and 1,2-dichlorobenzene (61 ml) was heated under reflux for 72 hours. The resulting dark brown reaction mixture was allowed to cool, diluted with dichloromethane (60 ml) and filtered. Evaporation under reduced pressure of the filtrate gave a solvent-containing dark brown oil (17.51 g), 28.2% of the solvent- excluded material of which was shown, by TLC and HPLC analyses, to be the title compound. Repetition using sulpholane as solvent at about 205°C for 5 hours provided a crude product (14% wt. yield) which, by TLC and HPLC analyses, contained an estimated yield of 12% of the title compound. Further repetition using N-methylpyrrolidin-2-one as solvent at 205-210°C for 3 hours provided a crude product (21.5% wt. yield) which, by TLC and HPLC analyses, contained an estimated yield of 6.5% of the title compound. EXAMPLE 41 Under reaction conditions similar to those described in Example 38, except that the reaction was conducted for 24 hours in the presence of 4A molecular sieves, a solvent-containing product was obtained, 6.0% of the solvent-excluded material of which was shown, by HPLC analysis, to be the title compound. EXAMPLE 42 Concentrated sulphuric ac;d (1.0 ml, 1.S4 g, 18.75 mmoi) was adcec lo a stirred suspension of the title compound of Preparation 4 (12.32 g, 0.025 mol) in chlorobenzene (61 ml) and then the resulting mixture heated until solvent began to distil out. When the distillate was no longer cloudy (after collection of ca. 20 ml), the reaction mixture was allowed to cool to room temperature and a further quantity (20 ml) of chlorobenzene added before it was heated under reflux for 20 hours. The cool reaction mixture was treated with dichloromethane (100 ml) to form a solution, followed by water (100 ml). The pH of the resulting mixture was adjusted to 7 using 5M aqueous sodium hydroxide solution, then the organic phase separated, combined with a dichloromethane extract (50 ml) of the aqueous phase and evaporated under reduced pressure to furnish a solid (9.51 g), 5.5% of which was shown, by HPLC analysis, to be the title compound. EXAMPLE 43 Concentrated sulphuric acid (1.0 ml, 1.84g, 18.75 mmol) was added to a stirred solution of the title compound of Preparation 4 (6.16g, 12.5 mmol) in glacial acetic acid (31 ml) and the resulting mixture heated at 100°C for 115 hours. The solvent was removed by evaporation under reduced pressure, the residue "azeotroped" with toluene (2 x 50 ml) and the resulting oil (10.5 g) shaken with water (60 ml) to give a crystalline solid which was collected, washed with water (10 ml) and dried. This crop (2.03 g) was combined with a second crop (3.48g) obtained by neutralisation of the filtrate with 20% aqueous sodium hydroxide solution, followed by collection, washing and drying as before, to provide the crude product (5.51 g) which, by TLC and HPLC analyses, contained an estimated yield of 38% of the title compound. EXAMPLE 4^ A stirred mixture of rhe Liiie compound of Preparation 4 (6.16 g, 12.5 mrnoi) and glacial acetic acid (31 ml) was heated at 100°C for 7 hours and the resulting solution allov/ed to cod. TLC analysis of the reaction mixture showed thai wov.^ j\ the title compound was present at this stage. 85%) Aqueous phosphohc acid solution (0.5 ml) was added and the resulting mixture heated at 100°C, intermittently, for a total of 300 hours, then evaporated under reduced pressure. The residue was "azeotroped" with toluene and dissolved in water (50 ml), then the pH of the stirred aqueous solution adjusted to 7 with 20% aqueous sodium hydroxide solution. Stirring was continued for 2 hours, then the precipitate collected, washed with water (20 ml) and dried under vacuum at 50°C, to give the crude product (5.21 g) which, by TLC and HPLC analyses, contained an estimated yield of 9.1% of the title compound. EXAMPLE 45 A stirred mixture of o-tcluenesulphonic acid monohydrate (5.71 g, 0.030 mol) and chlorobenzene (100 ml) was heated under reflux until all the water had been removed, using a Dean-Stark trap, and then allowed to cool to room temperature The title compound of Preparation 4 (24.64 g, 0.050 mol) was added and the reaction mixture stirred under reflux for 24 hours, then allowed to cool. To the resulting mixture was added dichloromethane (200 ml) and water (200 ml), the pH was adjusted to 7 using 2M aqueous sodium hydroxide solution, and the organic phase separated and combined with a dichloromethane extract (100 ml) of the aqueous phase. The combined organic phases were washed with water (100 ml) and evaporated under reduced pressure to afford an off-white solid (24.86 g), 7.3% of which was shown, by TLC and HPLC analyses, to be the title compound. EXAMPLE 46 Titanium tetrachloride (3.3 ml, 5.69 g, 0.030 mol) was added to a stirred suspension of the title compound of Preparation 4 (12.32 g, 0.025 mol) in anhydrous 1,4-dioxan (61 ml), during which vigorous evolution of a gas was noiec. T(;e stirred reaction mixture was neaiea ai about 70°C for 7.5 hours, ailov^ed lo cool to room temperature and then treated with water (200 ml) and conceniraied hydrochloric acid (50 ml) to give a clear sciution. The solution was washec v,;;:h dichloromethane and its pH adjusted to 12 using 40% aqueous sodium hydroxide solution; it was then stirred for 10 minutes and its pH further adjusted to 7 using 5M hydrochloric acid. The precipitate was removed by filtration and washed with dichloromethane (2 x 200 ml), then the combined dichloromethane washings were used to extract the aqueous filtrate and evaporated under reduced pressure to give a solid (11.36 g), 33.7% of which was shown, by TLC and HPLC analyses, to be the title compound. EXAMPLES 47-52 Under reaction conditions similar to those described in Example 46, the variations of which are summarised in Table 3, alternative Lewis acids provided the corrected yields of title compound shown. TABLE 3 (Table Removed) as the diethyl etherate PREPARATION 1 5-ChlQrosulDhonyl-2-ethoxybenzoic acid Molten 2-ethoxybenzoic acid (25.0 g, 0.150 mol) was added to a stirred, ice-cooled mixture of thionyl chloride (11 ml, 0.151 mol) and chlorosulphonic acid (41.3 ml, 0.621 mol), whilst maintaining the temperature of the reaction mixture below 25°C. The resulting mixture was stirred at room temperature for 18 hours and then poured into a stirred mixture of ice (270 g) and water (60 ml) to give an off-white precipitate. Stirring v/as continued for 1 hour, then the product was collected by filtration, washed with water and dried under vacuum to provide the title compound (36.08 g). A reference sample, m.p. 115-116°C, was obtained by crystallisation from hexane:toluene. Found: C,41.02; H,3.27. C9H9CIO5S requires C,40.84; H,3.43%. δ (CDCI3): 1.64(3H,t), 4.45(2H,q), 7.26(1H,d), 8.20(1H,dd), 8.80(1H,d). FREPARATION 2 2-Ethoxv-5-(4-methylpiper3zin-1-visulphonvl)benzoic acid (a) one-step procedure 1-Methylpiperazine ('33.6 ml, 0.303 mol) was added to a stirred suspension of the title compound of Preparation 1 (34.4 g, 0.130 mol) in water (124 ml) at about 10°C, whilst maintaining the temperature of the reaction mixture below 20°C. The resulting solution was cooled to about 10°C and, after 5 minutes, crystallisation of a solid commenced. After a further 2 hours, the solid was collected by filtration, washed with ice-water and dried under vacuum to furnish the crude product (36.7 g). A sample (15.0 g) was purified by stirring it in refluxing acetone for 1 hour; the resulting suspension was allowed to cool to room temperature and the crystalline solid collected by filtration and dried under vacuum to afford the title compound (11.7 g), m.p. 198-199°C, whose 1H nmr spectrum is identical with that obtained for the product of procedure (b) below. (bi: two-steo procedure A solution of the title comipound of Preparation 1 (50.0 g, 0.189 mol) in acetone (150 ml) was added dropwise to a stirred mixture of l-methylpiperazine (20.81 g, 0.208 mol) and triethylamine (28.9 ml, 0.207 mol), whilst maintaining the temperature of the reaction mixture below 20°C. A white crystalline solid formed dunng the addition and stirhng was continued for a further 1.5 hours. Filtration, followed by washing with acetone and drying under vacuum of the product, provided the hydrochloride-triethylamine double salt of the title compound (78.97 g), m.p. 166-169°C. Found: C,51.33; H,8.14; N,9.06; CI,8.02. C14H20N2O5S; C6H15N; HCI requires C,51.55; H,7.79; N,9.02; CI, 7.61%. δ (CD3SOCD3): 1.17(9H,t), 1.32(3H,t), 2.15(3H.s), 2.47(6H,br s), 2.86(2H, br s), 3.02(6H,q), 4.18(2H,q), 7.32(1H,d), 7.78(1H,dd), 7.85(1H,d). The double salt (30.0 g) was stirred in water (120 ml) to produce an almost clear solution, from which crystallisation cf a solid rapidly occurred. After 2 hours. oclid was collected by filtration, washed with water and dried under vacuum give the title compound (14.61 c) as a white solid. A reference sample, m.p. 20 °C was obtained by recr/stai!isation from aqueous ethanol. Found: C,51.0" H.6.16; N,8.43. C14H20N2O5S requires 0,51.21; H,6.14; N,8.53%. δ (CD3SOCD;): 1.31(3H,t), 2.12(3H,s), 2.34(4H,brs), 2.84(4H, br s), 4.20(2H,q), 7.32(1 H,d), 7.80(1H,dd), 7.86(1H,d). PREPARATION 3 4-Amino-1-methyl-3-n-propylpyrazole-5-carboxamide A stirred suspension of 1-methyl-4-nitro-3-n-propylpyrazole-5-carboxamide (EP-A-0463756; 237.7 g, 1.12 rnol) and 5% palladium on charcoal (47.5 g) in ethyl acetate (2.02 1) was hydrogenated at 344.7 kPa (50 psi) and 50°C for 4 hours, when the uptake of hydrogen was complete. The cool reaction mixture was filtered, then the filter pad washed with ethyl acetate, the combined filtrate and washings thus furnishing an ethyl acetate solution of the title compound (EF-A-C463756) which was of sufficient purity to use directly in the next stage of the reaction sequence (see Preparation 4). PREPARATION 4 4-[2-Ethoxy-5-(4-methylpioerazin-1-vlsulDhonvl)benzamido1-1-methyl-3-n-propylpyrazole-5-carboxamide N.N'-Carbonyldiimidazole (210.8 g, 1.30 mol) was washed into a stirred suspension of the title compound of Preparation 2 (408.6 g, 1.24 mol) in ethyl acetate (1.50 I) using ethyl acetate (1.36 I) and the resulting mixture heated at 55'C for 0.5 hour and then under reflux for a further 2 hours before being allowed to cool to room temperature. An ethyl acetate solution of the title compound of Preparation 3 (2.185 Kg of solution containing 204 g, 1.12 mol of amine) was added and the reaction mixture stirred at room temperature for 72 hours to afford a crystalline solid which was collected by filtration and dried under vacuum. The title compound (425 g), m.p. 204-206°C, thus obtained was combined with a further crop (70 g) which was recovered by concentration of the mother liquor. A reference sample, m.p. 206-208°C, was obtained by recrystaliisation from aqyebiys methanol. Found: C,53.65; H 6.54 N,17,07. C22H32N5O5S requires C,53,64; H,6.55; N,17.06%. δ (CDCI3): G.96(3H,t), 1.58(3H,t), 1.66(2H,m), 2.27(3H.s) 2.45(4H,m), 2.52(2H,t), 3.05(4H,hr s), 4,05(3H,s;. 4.40(2H,q), 5.61(1H, brs), 7.61(1H,d), 7.65(1H, brs), 7,90(1H,dd), 8.62(1H,d), 9.25(1H,br s). PREPARATION 5 Methyl 2-ethoxybenzoate Concentrated sulphuric acid (0.5 ml) was added to a solution of 2-ethoxybenzoic acid (50 g, 0.301 mol) in methanol (500 ml) and the resulting mixture heated under reflux for 70 hours, then evaporated under reduced pressure to give an oil which was dissolved in dichloromethane (300 ml). This solution was washed successively with water (150 ml), aqueous sodium bicarbonate solution (150 ml) and water (150 ml), then evaporated under reduced pressure to give the title compound (49.7 g) as an oil. δ (CDCU): 1.44 (3H,t), 3.90 (3H,s), 4.12 (2H,q), 6.95 (2H,m), 7.44 (1H,t), 7.78 (1H,d). -2S PREPARATION 6 Methvl 5-chlorosulphonyl-2-ethoxvbenzoate The title compound of Preparation 5 (36.04 g, 0.20 mol) was added dropwise over 10 minutes to stirred, ice-cooled chlorosulphonic acid (59.8 ml, 0.90 mol), whilst maintaining the temperature of the reaction mixture below 22°C. The reaction mixture was stirred at room temperature for 18 hours, then thionyl chlonde (14.6 ml, 0.20 mol) added and the resulting solution stirred at room temperature for 6 hours, then poured into a stirred mixture of ice (530 g) and water (120 ml). The quenched mixture was extracted with dichloromethane (2 x 200 ml) and the combined extracts evaporated under reduced pressure to give the crude title compound (44.87 g) as a white solid. A reference sample, m.p. 99-100°C, was obtained by crystallisation from toluene. δ (CDCI3): 1.52 (3H,t), 3.93 (3H,s), 4.25 (2H,q), 4.25 (2H,q), 7.12 (1H,d), 8.12 (1H,dd), 8.46 (1H,d). PREPARATION 7 Methyl 2-ethoxy-5-(4-methylpiperazin-1-yisulphonyl)benzoate - solution of the crude title compound of Preparation 5 (27.87 g) in acetone^ (140 ml) was added dropwise over 10 minutes to a stirred, ice-cooled solution of 1-methylpiperazine (11.02 g, 0.11 mol) and triethylamine (15.3 ml, 0.11 mol) in acetone (140 ml), whilst maintaining the temperature of the reaction mixture below 20°C. A white precipitate formed during the addition and stirring was continued for a further 4 hours. The resulting mixture was filtered, the filtrate evaporated under reduced pressure and the residue azeotroped with toluene to provide a pale brown gum (41.9 g). This crude product was granulated by stirring with water (100 ml) for 2 hours and the resulting material collected by filtration, washed with water (2 x 50 ml) and dhed under vacuum at 50°C to furnish the title compound, m.p. 110-111°C. δ(CDCl3): 1.48 (3H,t). 2.27 (3H,s), 2.47 (4H,t), 3.03 (4H,t), 3.90 (3H,s), 4.18 (2H,q), 7.04 (1H,d), 7.81 (1H,dd), 8.15 (1H,d). The compound obtained as above was shown to be identical with that produced by conventional methyl esterification of the title compound of Preparation 2. Furthermore, conventional base hydrolysis of the compound obtained as above afforded a product identical with that of Preparation 2. WE CLAIM: 1. A process for preparation of 4-[2-Ethoxy-5-(4-methylpiperazin-1- ylsulphonyl)benzamidol]-1-methyl-3-n-propylpyra2ole-5-carboxamide of formula (II): (Formula Removed) wherein said process comprises reacting N,N'-Carbonyldiimidazole and 2-Ethoxy-5-(4-methylplperazin-1-ylsulphonyl)benzoic acid in a solvent, preferably an ester, followed by heating the resulting mixture at about 55°C for about 0.5 hr, followed by refluxation for an additional duration of about 2 hours followed by cooling, preferably to room temperature in step-1, and reacting the resulting reaction mixture from said step-1 with 4-Amino-l-methyl-3-n-propylpyrazole-5-carboxamide, preferably in additional amount of said solvent in step-2, and stirring the resulting reaction mixture from said step-2 preferably at room temperature for about 72 hours or till a solid compound of formula II is obtained and said compound of formula (II) is isolated and purified as described hereinbefore, wherein N,N'-Carbonyldiimidazole is taken in an amount of about 1.30 mol and 2-Ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)benzoic acid is taken in an amount of about 1.30 mol in said step-1, and 4-Amino-1-methyl-3-n-propylpyra2ole-5-carboxamide is taken in an amount of about 1.12 mol. 2. A process, as claimed in claim 1, wherein said solvent is preferably ethyl acetate. 3. A process for the preparation of a compound of formula II substantially as herein described with reference to the foregoing examples.

Full Text

This application is divisional patent application out of the main Indian patent application no. 1548/Del/97. The present invention relates to a process for preparation of a compound of formula (11) [please see in the scheme given on page 6] named as 4-[2-ethoxy- 5 -(4-methy Ipiperazin-1 -ylsulphonyl)benzamidol] -1 -methyl-3 -n-propylpyrazole- 5 -carboxamide, particularly the present invention relates to a process for preparation of an intermediate used to prepare the sildenafil. More specifically, the present invention concerns a process for preparation of an intermediate to sildenafil, wherein such intermediate can result in more efficient sildenafil than that disclosed in EP-A-0463756 and such intermediate, surprisingly, can provide directly sildenafil of clinical quality standard, thus obviating the need for subsequent purification steps. In this context, sildenafil of clinical quality standard means material of sufficient purity for administration to humans. Sildenafil, which was originally disclosed in the above referred European patent (EP-A-04637.56), has been found to be particularly usefial in the treatment of, inter alia, male erectile dysfimction [WO-A-94/28902].
The presently disclosed process involves treatment of an imidazole, particularly of a diimidazole, more particularly of substituted diimidazole, even more particularly of N,N'-Carbonyldiimidazole with substituted benzoic acid, particularly with disubstituted benzoic acid, more particularly with 2, 5-disubstituted benzoic acid, even more particularly with 2-Ethoxy-5-(4-methylpiperazin-l-ylsulphonyl)benzoic acid (compound of formula V, please see in the scheme on page 6) in a solvent, preferably an ester, followed by heating the resulting mixture at about 55oC for about 0.5 hr, followed by refluxation for an additional duration of about 2 hours followed by cooling, preferably to room temperature in step-1, and treating the resulting reaction mixture from said step-1 with 4-Amino-l-methyl-3-n-propylpyrazole-5-carboxamide, preferably in additional amount of said solvent in step-2, and stirring the resulting reaction mixture fi"om said step-2 preferably at room temperature for about 72 hours or till a solid compound of formula II is obtained, wherein N,N'-Carbonyldiimidazole is taken in an amount of about 1.30 mol and 2-Ethoxy-5-(4-methylpiperazin-l-ylsulphonyl)benzoic acid is taken in an amount of about 1.30 mol in said step-1, and 4-Amino-l-methyl-3-n-propylpyrazole-5-carboxamide is taken in an amount of about 1.12 mol. In accordance with preferred embodiment of the present invention said solvent is preferably ethyl acetate.
The key step in the over-all process for preparation of sildenafil involves the ring-closure of the immediate precursor to sildenafil, i.e. the bis-amide of formula (II) :
(Formula Removed)
Thus the invention provides a process for the preparation of a compound of formula (I) which comprises cyclisation of a compound of formula (II).
In a preferred embodiment, the cyclisation is carried out in the presence of a base, preferably in a solvent, optionally in the presence of hydrogen peroxide or a peroxide salt, and is followed, where necessary, by neutralisation of the reaction mixture.
Accordingly, present invention makes a disclosure of a process for preparation of 4-[2-Ethoxy-5-(4-methylpiperazln-1-ylsulphonyl)benzamidol]-1-methyl-3-n-propylpyrazole-5-carboxamide of formula (II):
(Formula Removed)
wherein said process comprises reacting N,N'-Carbonyldiimidazole and 2-Ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)benzoic acid in a solvent, preferably
an ester, followed by heating the resulting mixture at about 55°C for about 0.5 hr, followed by refiuxatlon for an additional duration of about 2 hours followed by cooling, preferably to room temperature in step-1, and reacting the resulting reaction mixture from said step-1 with 4-Amino-1-methyl-3-n-propylpyrazole-5-carboxamlde, preferably in additional amount of said solvent in step-2, and stirring the resulting reaction mixture from said step-2 preferably at room temperature for about 72 hours or till a solid compound of formula II is obtained and said compound of formula (II) is isolated and purified as described hereinbefore, wherein N,N'-Carbonyldiimidazole is taken in an amount of about 1.30 mol and 2-Ethoxy-5-(4-methylpipera2in-1-yIsulphonyl)benzoic acid is taken in an amount of about 1.30 mol In said step-1, and 4-Amino-1-methyl-3-n-propylpyrazole-5-carboxamide is taken in an amount of about 1.12 mol.
A suitable base may be selected from the group consisting of a metal salt of a C1-C12 alkanol, a C3-C12 cycioaikanol, a (C3-C8 cycloalkyl)C1-C6 aikanol, ammonia, a C1-C12 alkyiamine, a di(C1-C12 alkyl)amine, a C3-C8 cycioalkylamine, a N-{C3-C8 cycloalkyi)-N-(C1-C12 alkyl)amine, a di(C3-C8 cycIoalkyl)amine, a (C3-C8 cycloalkyl)C1-C6 alkyiamine, a N~(C3-C8 cycioalkyl)C1-C6 alkyl-N-(C1-C12 alkyl)amine, a N-(C3-C8 cycloalkyl)C1-C6 alkyl-N-{C3-C8 cycloalkyl)amine, a di[(C3-C8 cycioalky)C1-C6 alkyljamine and a heterocyclic amine selected from the group consisting of imidazole, triazole, pyrrolidine, piperidine, heptamethyleneimine, morpholine, thiomorpholine and a 1-(C1-C4 alkyi)piperazine; a metal hydride, fluoride, hydroxide, oxide,, carbonate and bicarbonate; wherein the metal is selected from the group consisting of lithium, sodium, potassium, rubidium, cesium, beryllium, magnesium, calcium, strontium, barium, aluminium, indium, thallium, titanium, zirconium, cobalt, copper, silver, zinc, cadmium, mercuny and cerium; and a C7-C12 bicyclic amidine.
Preferably the base is selected from the group consisting of an alkali or
alkaline earth metal salt of a C1-C12 alkanoi, a C3-C12 cycloaikanol and a (C3-C, cycloalkyi) C1-C6 alkanoi; an alkali metal salt of ammonia, a N-(secondary or tertiary C3-C6 alkyl)-N-(pnimary, secondary or tertiary C3-C6 alkyl)amine, a C3-C8 cycloalkylamine, a N-(C3-C8 cycloalkyl)-N-(primary, secondary or tertiary C3-C8 alkyl)amine, a di(C3-C8 cycloalkyi)amine and l-methylplperazine; and an alkali or alkaline earth metal hydride, hydroxide, oxide, carbonate and bicarbonate; 1,5-diazabicyclo[4.3.0]non-5-ene and 1,8-dia2abicyclo[5.4.0]undec-7-ene.
A suitable solvent may be selected from the group consisting of a C1-C12 alkanoi, a C3-C12 cycloaikanol, a (C3-C8 cycloalkyl)C1-C6 alkanoi, a C3-C9 aikanone, a C4-C10 cycloalkanone, a C5-C12 alkyl ether, 1,2-dimethoxyethane, 1,2-diethoxyethane, digiyme, tetrahydrofuran, 1,4-dioxan, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, acetonitrile, dimethyl sulphoxide, sulpholane, dimethylformamide, dimethylacetamide, N-methylpyrrolidin-2-one, pyrrolidin-2-cne, pyridine and water, and mixtures thereof.
Preferably the solvent is selected from the group consisting of ethanoi, 2-propanol, a secondary or tertiary C1-C12 alkanoi, a C3-C12 cycloaikanol, a tertiary C4-C12 cycloaikanol, a secondan/ or tertiarv (C3-C7- cycloalkyl)C2-C3 alkanol a C -C8 aikanone, 1,2-dimethoxyethane, 1,2-diethoxyethane, digiyme, tetrahydrofuran. 1,4-dioxan, toluene, xylene, chlorobenzene, 1,2-dichiorobenzene, acetonitrile, dimethyl sulphoxide, sulpholane, dimethylformamide, N-methylpyrrolidin-2-one, pyridine and water, and mixtures thereof.
Further preferred features are that the quantity of base employed is from 1.0 to 5,0 molecular equivalents and that the reaction is carried out at from 50 to 170°C for from 3 to 170 hours.
In a more preferred process the base is selected from the group consisting of the lithium, sodium and potassium salts of a C1-C12 alkanoi, a C4-C12 cycloaikanol, ammonia, cyclohexylamine and l-methylpipe.'-azine; the hydride salts of lithium, sodium and potassium; cesium carbonate; and barium oxide; the solvent is selected from the group consisting of ethanoi, a tertiary C4-C10 alcohol, a tertiary
C5-C3 cycioatl Even more preferred is a process wherein the base is selected from the group consisting of the C1-C12 alkoxide and hydride salts of lithium, sodium and potassium, sodamide, sodium cyclohexylamide and cesium carbonate; the solvent is selected from the group consisting of ethanol, t-butanol, t-amyl alcohol, 1-methylcyclohexanol, tetrahydrofuran and 1,4-dioxan; and the reaction is conducted for from 3 to 60 hours.
A particularly preferred process is that wherein the base is selected from the group consisting of sodium ethoxide, sodium t-butoxide, potassium t-butoxide and sodium hydride; and the solvent is selected from the group consisting of ethanol, t-butanol, t-amyl alcohol and tetrahydrofuran.
In the above definitions, unless otherwise stated, an alkyl chain or cycloalkvl rinc may branched or unbranched.
The compound of formula (I) may be isolated and purified by conventiona; techniques. For example, when (I) is produced in the form of a salt, by neutralisation of the optionally prediluted reaction mixture, followed by collection of the product by filtration/extraction and optional crystallisation thereof.
Alternatively, the compound of formula (I) may be conveniently isolated and/or purified by standard chromatographic procedures.
The compound of formula (II) required for the preparation of the compound of formula (I) may be obtained by the route depicted in the following reaction scheme using conventional procedures.
SCHEME
(Scheme Removed)
Thus the compound of formula (iV) may be prepared by chlorosulphonylation of 2-ethoxybenzoic acid, i.e. the compound of formula (III). Typically, (III) is added to an ice-cooled mixture of about 1 mol. equiv. of thionyj chloride and about 4 moi. equivs. of chlorosuiphonic acid, whilst maintaining the reaction temperature below 25°C; the reaction is then allowed to continue at room temperature until complete
Conversion of (IV) to the compound of formula (V) is achieved by N-sulphonylation of 1-methylpiperazine and may be conducted in a one-step or two-step procedure. In a one-step procedure, about 2.3 mol. equivs. of 1-methylpiperazine are added to an aqueous suspension of (IV) at about 10°C, whilst maintaining the reaction temperature below 20°C; the temperature of the resulting reaction mixture is then held at about 10°C. Alternatively, the quantity of 1-methylpiperazine can be reduced to about 1.1 miol. equiv. by employing about 1 mol. equiv. of sodium hydroxide as auxilian/ base. In a two-step procedure, a solution of (IV) in a suitable solvent, e.g. acetone, is added to a mixture of about a 10% 6X0633 of 1-methylpipefazipe and about a 10% excess of a suitable acid acceptor, e.g. a tertiary base such as triethylamine, whilst maintaining the reacticn temoerature below 20X. When triethylamine Is employed as auxiliany base, an intermediate hydrochloride-triethylamine double salt of (V), identified as the compound of formula (VA), is isolated. This salt may be transformed to (V) by treatment with water.
A convenient alternative route to (V) is to employ a C1-C4 aikyl 2-ethoxybenzoate (obtained by conventional esterification of (III)) as the chlorosulphonylation substrate, followed by treatment of the resulting sulphonyl chlonde with 1-methylpiperazine as described above, then subsequent standard hydrolysis of the ester group. Other synthetic options for obtaining (V) from salicylic acid and its derivatives will be apparent to the person skilled in the art
Coupling of (V) with the compound of formula (VII) may be achieved by any of the plethora of amide bond-forming reactions well known to those skilled in the
art. For example, the carboxylic acid function of (V) is first of all activated using about a 5% excess of a reagent such as N,N'- carbonyldiimidazole in a suitable solvent, e.g. ethyl acetate, at from about room temperature to about SOX, followed by reaction of the intermediate imidazolide with (VI!) at from about 20 to about 60°C.
The aminopyrazole (VII) is obtainable by conventional reduction of the corresponding nitropyrazole (VI), e.g. using palladium-catalysed hydrogenation in a suitable solvent such as ethyl acetate. The resulting solution of (VII) may be used directly, after filtration, in the coupling reaction with (V).
The cyclisation reaction of (II) to provide the compound of formula (I) has been achieved in yields of up to 95%. Thus the over-all yield of (I) based on the benzoic acid derivative (III) as starting material, depending on v/hetherthe one-step or two-step sulphonylation procedure is used, can be as high as 51.7% or 47.8% respectively. This compares very favourably with the process disclosed in E:P-vV0463756 in which the over-all yield of (i; from 2-ethoxyDenzoyl chloride (anc tnus from (111) also, assumiing that the acid chioride derivative can be generated quantitatively therefrom) is 27.6%. In an alternative comparison, the over-all yieid of (I) based on the nitropyrazole (VI) can be as high as 85.2% in the presently disclosed process whilst, in the process disclosed in EP-A-0463756, the over-all yield of (I) from (VI) is 23.1%.
Clearly then, the alternative process to (I) disclosed hereinbefore can be considerably more efficient and advantageous than that previously disclosed, and the intermediates of formulae (II), (V) and (VA) also form part of the invention.
Alternatively, the cyclisation of a compound of formula (II) to a compound of formula (I) may be conducted under neutral or acidic conditions.
Under neutral conditions, the compound of formula (II) is heated, optionally in the presence of a solvent and/or optionally in the presence of a dehydratina agent and/or mechanical water-removal system, e.g. a Dean-Stark apparatus
A suitable solvent may be selected from the group consisting of 1,2-dichlorobenzene, dimethyl sulphoxide, sulpholane, N-methylpyrrolidin-2-one and pyrrolidin-2-one, and mixtures thereof.
Preferably the solvent is 1,2-dichlorobenzene, sulpholane or N-methylpyrrolidin-2-one.
A suitable dehydrating agent may be selected from the group consisting of anhydrous potassium carbonate, anhydrous sodium carbonate, anhydrous magnesium sulphate, anhydrous sodium sulphate, phosphorus pentoxide and molecular sieves.
Preferably the dehydrating agent is molecular sieves.
Preferably also, the reaction is carried out at from 180 to 220°C for from 0.5 to 72 hours.
Under acidic conditions, the cyclisation is carried out by reaction of a compound of formula (II) with a protic acid or Lewis acid, optionally in the presence of a solvent.
A suitable protic acid may be selected from the group consisting of an inr-nanic acid, an organo-sulphonic acid, an organo-phosohonic acid and an orcsno-carboxylic acid.
Preferably the protic acid is concentrated sulphuric acid, phosphoric acid or i2-toluenesulphonic acid.
A suitable Lewis acid may be selected from the group consisting of boron trifluoride, boron trichloride, boron tribromide, aluminium chloride, aluminium bromide, silicon tetrachloride, silicon tetrabromide, stannic chloride, stannic bromide, phosphorus pentachloride, phosphorus pentabromide, titanium tetrafluoride, titanium tetrachloride, titanium tetrabromide, ferric chloride, zinc fluoride, zinc chloride, zinc bromide, zinc iodide, mercuric chloride, mercuric bromide and mercuric iodide.
Preferably the Lewis acid is boron trifluoride, aluminium chloride, silicon tetrachloride, stannic chloride, titanium tetrachloride, ferric chloride or zinc chloride.
A suitable solvent may be selected from the group consisting of a C5-C.2 alkane, a C5-C8 cycloalkane, a C1-C12 alkanoic acid, a C1-C4 alkanol, a C3-C9 alkanone, a C5-C12 aikyi ether, 1,2-dimethoxyethane, 1,2-diethoxyethane, diglyme, tetrahydrofuran, 1,4-dioxan, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, nitrobenzene, dichloromethane, dibromomethane, 1,2-dichloroethane, acetonitrile, dimethyl sulphoxide, sulpholane, dimethylformamide, dimethyiacetamide, N-methylpyrrolidin-2-one and pyrroiidin-2-one, and mixtures thereof.
Preferably the solvent is glacial acetic acid, tetrahydrofuran, 1,4-dioxan or chlorobenzene.
Preferably also, the reaction is carried out at from 65 to 210°C for from 6 to 300 hours.
The syntheses of the compound of formula (I) and the intermediates thereto iescrioed in the following Examples and Preparations, in cases where the comcound of formula (I) was not isolated and (if necessary) purified, the yields there of were determined, and reaction mixtures analysed, by quantitative thin layer chromatography (TLC), using Merck silica gel 60 plates and toluene:methylated spirit:0880 aqueous ammonia mixtures as solvent systems, and/or high performance liquid chromatography (HPLC), using Gilson equipment with a 15 cm reverse phase C18 column and thethylamine:phosphoric acid buffer in aqueous acetonitrile:methanol mixtures as mobile phases.
1H Nuclear magnetic resonance (NMR) spectra were recorded using a Vanan Unity 300 spectrometer and were in all cases consistent with the proposed structures. Characteristic chemiical shifts (6) are given in parts-per-million downfield from tetramethylsiiane using conventional abbreviations for designation of significant peaks: e.g. s, singlet; d, doublet; t, thplet; q, quartet; h, hextet; mi, multiplet; br, broad.
Room temperature means 20-25X.
TITLE COMPOUND
5-[2-Ethoxv-5-(4-methylpiperazin-1-ylsulphonyl)phenvl]-1-methvl-3-n-oropyl-1,6-dihvdro-7H-Dyrazolo[4.3-d]pyrimidin-7-one
EXAMPLE 1 Potassium t-butoxide (3.37 g, 0.030 mol) was added to a stirred suspension of the title compound of Preparation 4 (12.32 g, 0.025 mol) in t-butanol (61 ml) and the resulting mixture heated under reflux for 8 hours, then allowed to cool to room temperature. Water (62.5 ml) was added and then the resulting solution filtered into a speck-free flask and treated dropwise with a speck-free solution of concentrated hydrochloric acid (2.3 ml) in water (62.5 ml). The precipitated product was granulated at pH = 7 and 10°C for 1 hour, collected by filtration, v/ashed with water and dried under vacuum to give the title compound (10.70 g, 90.2% m.p 139-190X. Found: C,55.55; H,6.34; N,17.69, C22H30N6O4S requires C.50.63; H,6.37; N,17.71%. δ (CD3SOCD3): 0.94(3H,t), 1.32(3H,t), 1.73(2H,h), 2.15(3H) 2 35(4H,brs), 2.76(2H,t), 2.88(4H.hr s)4.14(3H,s), 4.18(2H,q), 7,36(1H,d), 7,80(2H,m), 12.16(1H,br s).
Analysis of the product by HPLC and quantitativeTLC indicated that clinical quality material had been obtained directly from the reaction.
The yield of clinical quality material can be increased to 95% by conducting the cyclisation under more concentrated conditions.
EXAMPLES 2-5 Clinical quality material was obtained by variation of the solvent, using procedures similar to that described in Example 1, as summarised in Table 1 As for Example 1, the reactions were carried out at reflux temperature, except in the cases of Examples 2 and 5 where a temperature of 100°C was employed.
TABLE 1
(Table Removed)
EXAMPLES 6-9 Clinical quality material was obtained by variation of the solvent and the base, using procedures similar to that described in Example 1, as summarised in
Table 2. The reactions were carried out at reflux temperature, except in the case of Example 9 where a temperature of 100°C was empioyea.
TABLE 2

(Table Removed)
EXAMPLE 10 Clinical quality material (88%) was obtained by variation of the cation, using a procedure similar to that described in Example 1, when sodium t-butoxide was used as base and the reaction was conducted for 24 hours.
EXAMPLE 11 Clinical quality material (71%) was obtained by vahation of the molar ratio of base, using a procedure similar to that described in Example 1, when potassium t-butoxide (5,0 mol.equiv.) was used and the reaction was conducted at reflux temperature for 18 hours.
EXAMPLE 12
Further variation of the reaction conditions of Example 1, using 1.6 mol. equiv. of potassium t-butoxide (4.49 g, 0.040 mol) at 60°C for 55 hours, provided the title compound (87%) of purity >99% by HPLC and TLC analyses.
EXAMPLE 13 Title compound (87%) of purity >99% by HPLC and TLC analyses was obtained, using a procedure similar to that described in Example 1, when 1,4-dioxan was used as solvent and the reaction was conducted at 100°C for 4 hours.
EXAMPLE 14
Title compound (85%i) of purity >99% by HPLC and TLC analyses was obtained, using a procedure similar to that described in Example 1, when 1,2-dimethoxyethane was used as solvent and the reaction was conducted for 30 hours.
EXAMPLE 15 Title compound (83%) of purity >99% by HPLC and TLC analyses was obtained, using a procedure similar to that described in Example 1, when 3,7-dimethyloctan-3-ol was used as solvent and the reaction was conducted at 100°C for 16 hours.
EXAMPLE 16 Title compound (74%) of purity >99%) by HPLC and TLC analyses was obtained, using a procedure similar to that described in Example 1, when sodium n-decoxide was used as base, 1,4-dioxan was used as solvent and the reaction was conducted at 100°C for 20 hours.
EXAMPLE 17
Title compound (85%) of purity >99% by HPLC and TLC analyses was
obtauned, using a procedure similar to that described in Example 1, whe.n sodamide was used as base, 1,4-dioxan was used as solveru and the reaction was conducted at 100°C for 18 hours.
EXAMPLE 18 Title compound (91%) of purity >99% by HPLC and TLC analyses was obtained, using a procedure similar to that described in Example 1, when sodium cyclohexylamide was used as base, 1,4-dioxan was used as solvent and the reaction was conducted at 100°C for 6.5 hours.
EXAMPLE 19 Title compound (84%i) of purity >99% by HPLC and TLC analyses was obtained, using a procedure similar to that described in Example 1, when sodium 4-methylpiperazide was used as base, 1,4-dioxan was used as solvent and the reaction was conducted at 100°C for 8 hours.
EXAMPLES 20-21 Under reaction conditions similar to those described in Example 1, the use of sodium methoxide in methanol for 32 hours furnished a four-component mixture from which the title compound was isolated in a chromatographed yield of 34.5%, whilst the use of potassium t-butoxide in methanol for 40 hours afforded a product mixture which, by TLC and NMR spectroscopic analyses, contained an estimated yield of 69% of the title compound.
EXAMPLE 22
Under reaction conditions similar to those described in Example 1, the use of potassium t-butoxide in anhydrous dimethyl sulphoxide at 100°C for 50 hours afforded a crude product (88% wt. yield) which, by TLC and HPLC analyses, contained an estimated yield of 24% of the title compound.
EXAMPLE 23 Under react;on conditions similar to those described in Example 1, the use or rnagnesiurn ethoxide in pyridine at reflux temperature for 96 hcjrs gave a c.rude product (79% wt. yield) which, by TLC and HPLC analyses, contained an estimated yield of 16% of the title compound.
EXAMPLE 24 Under reaction conditions similar to those described in Example 1, the use of barium ethoxide (as a 10% w/v solution in ethanol) in t-amyl alcohol at 100°C for 20 hours provided a crude product (76.5% wt. yield) which, by TLC and HPLC analyses, contained an estimated yield of 75.5%) of the title compound.
EXAMPLE 25 Under reaction conditions similar to those described in Example 1, the use of titanium ethoxide in pyridine at 100°C for 90 hours furnished a crude product (82%c wt. yield) which, by TLC and HFLC analyses, contained an estimated yield of 32°/o of the title compound.

EXAMPLE 26 Under reaction conditions similar to those described in Example 1, the use of cupric ethoxide in pyridine at 100°C for 98 hours afforded a crude product (89.5% wt. yield) which, by TLC and HPLC analyses, contained an estimated yield of 18.5% of the title compound.
EXAMPLE 27 Under reaction conditions similar to those described in Example 1, the use of aluminium tri-t-butoxide in pyridine at 100°C for 72 hours gave a crude product which, by TLC and HPLC analyses, contained a maximum (due to aluminium salt contamination) estimated yield of 66% of the title compound.
EXAMPLE 28
Under reaction conditions similar to those described in Example 1, the use or a iciai of 3.6 mol. equiv. (1.2 mol. equiv. added in three stages) of lithium diisopropyiarnide (as a 1.5M solution of the mono(tetrahydrofuran) complex in cyclchexane 'n anhydrous 14-dioxan, initially at 0°C for 15 minutes, then temperature for 1 hour and subsequently at 100°C for a total of 140 hours, furnished a crude product (60.5% wt. yield) which, by TLC and HPLC analyses, contained an estimated yield of 55.5% of the title compound.
EXAMPLE 29 Under reaction conditions similar to those described in Example 1, the use of 2.0 moi.equiv. of 1,8-diazabicyclo[5.4.0]undec-7-ene in pyridine at 100°C for 44 hours afforded a crude product (6.5% wt. yield) which, by TLC and HPLC analyses, contained an estimated yield of 3.3% of the title compound.
EXAMPLE 30 Under reaction conditions similar to those described in Example 1, the use of potassium fluoride in t-amyi alcohol at 100°C for 44 hours gave a crude product (85% wt. yield) which, by TLC and HPLC analyses, contained an estimated yield of 3.5% of the title compound.
EXAMPLE 31 85% Potassium hydroxide pellets (3.96 g, 0.06 mol) were added to a stirred suspension of the title compound of Preparation 4 (9.85 g, 0.02 mol) in ethanol (30 ml), followed by the addition of water (30 ml) which produced a clear solution. The reaction mixture was heated under reflux for 5 hours and then the bulk of the ethanol removed by evaporation under reduced pressure. The resulting mixture was diluted with water (60 ml), its pH adjusted to 7 using dilute sulphuric acid and the precipitated product granulated for 30 minutes. The solid was collected by riitration, v/ashed with water and dried under vacuum to provide a product (7.96 g), 96.4% of which was shown, by HPLC analysis, to be the title compound.
EXAMPLES 32-34
Under reaction conditions similar to those described in Example 1, the use of barium oxide in acetonithle at reflux temperature for 52 hours gave the title compound (89%) of purity >99% by HPLC and TLC analyses.
Repetition using dimethylformamide as solvent at 100°C for 31 hours provided a crude product (75.5% wt. yield) which, by TLC and HPLC analyses, contained an estimated yield of 54% of the title compound.
Further repetition using pyridine as solvent at 100°C for 16 hours furnished a crude product which, by TLC and HPLC analyses, contained a maximum (due to barium salt contamination) estimated yield of 90% of the title compound.
EXAMPLE 35 Under reaction conditions similar to those described in Example 1, the use of cesium carbonate in 4-methylpentan-2-one (methyl isobutyl ketone) at 100°C for 96 hours afforded a crude product (18.5% wt. yield) which, by TLC and HPLC analyses, contained an estimated yield of 13% of the title compound.
EXAMPLE 36 Under reaction conditions similar to those described in Example 1, the use of potassium bicarbonate in t-amyl alcohol at 1G0°C for 115 hours gave a crude product (82.5% wt. yield) which, by TLC and HPLC analyses, contained an estimated yield of 20% of the title compound.
EXAMPLE 37
The title compound of Preparation 4 (12.32 g, 0.025 mol) was heatea at 215 for 40 minutes and the resulting meit allowed to cool to room temperature. The tarry crude product was dissolved in dichloromethane (25 ml) and the.n purified by chromatography on silica gei, using increasingly polar mixiureo .: methanol in dichloromethane as eluant. Evaporation under vacuum of the appropriate single component fractions provided the pure (by ^H nmr analysis) title compound (1.76 g, 14.8%), whilst a batch of less pure title compound (0.87 g, 7.3 %) was obtained from further fractions. Further chromatographic processing of the latter gave an additional quantity (0.48 g) of pure title compound, the total yield being 2.24 g, 18.8%.
EXAMPLES 38-40 A stirred mixture of the title compound of Preparation 4 (12.32 g, 0.025 mol) and 1,2-dichlorobenzene (61 ml) was heated under reflux for 72 hours. The resulting dark brown reaction mixture was allowed to cool, diluted with dichloromethane (60 ml) and filtered. Evaporation under reduced pressure of the filtrate gave a solvent-containing dark brown oil (17.51 g), 28.2% of the solvent-
excluded material of which was shown, by TLC and HPLC analyses, to be the title compound.
Repetition using sulpholane as solvent at about 205°C for 5 hours provided a crude product (14% wt. yield) which, by TLC and HPLC analyses, contained an estimated yield of 12% of the title compound.
Further repetition using N-methylpyrrolidin-2-one as solvent at 205-210°C for 3 hours provided a crude product (21.5% wt. yield) which, by TLC and HPLC analyses, contained an estimated yield of 6.5% of the title compound.
EXAMPLE 41 Under reaction conditions similar to those described in Example 38, except that the reaction was conducted for 24 hours in the presence of 4A molecular sieves, a solvent-containing product was obtained, 6.0% of the solvent-excluded material of which was shown, by HPLC analysis, to be the title compound.
EXAMPLE 42 Concentrated sulphuric ac;d (1.0 ml, 1.S4 g, 18.75 mmoi) was adcec lo a stirred suspension of the title compound of Preparation 4 (12.32 g, 0.025 mol) in chlorobenzene (61 ml) and then the resulting mixture heated until solvent began to distil out. When the distillate was no longer cloudy (after collection of ca. 20 ml), the reaction mixture was allowed to cool to room temperature and a further quantity (20 ml) of chlorobenzene added before it was heated under reflux for 20 hours. The cool reaction mixture was treated with dichloromethane (100 ml) to form a solution, followed by water (100 ml). The pH of the resulting mixture was adjusted to 7 using 5M aqueous sodium hydroxide solution, then the organic phase separated, combined with a dichloromethane extract (50 ml) of the aqueous phase and evaporated under reduced pressure to furnish a solid (9.51 g), 5.5% of which was shown, by HPLC analysis, to be the title compound.
EXAMPLE 43 Concentrated sulphuric acid (1.0 ml, 1.84g, 18.75 mmol) was added to a stirred solution of the title compound of Preparation 4 (6.16g, 12.5 mmol) in glacial acetic acid (31 ml) and the resulting mixture heated at 100°C for 115 hours. The solvent was removed by evaporation under reduced pressure, the residue "azeotroped" with toluene (2 x 50 ml) and the resulting oil (10.5 g) shaken with water (60 ml) to give a crystalline solid which was collected, washed with water (10 ml) and dried. This crop (2.03 g) was combined with a second crop (3.48g) obtained by neutralisation of the filtrate with 20% aqueous sodium hydroxide solution, followed by collection, washing and drying as before, to provide the crude product (5.51 g) which, by TLC and HPLC analyses, contained an estimated yield of 38% of the title compound.
EXAMPLE 4^
A stirred mixture of rhe Liiie compound of Preparation 4 (6.16 g, 12.5 mrnoi) and glacial acetic acid (31 ml) was heated at 100°C for 7 hours and the resulting solution allov/ed to cod. TLC analysis of the reaction mixture showed thai wov.^ j\ the title compound was present at this stage.
85%) Aqueous phosphohc acid solution (0.5 ml) was added and the resulting mixture heated at 100°C, intermittently, for a total of 300 hours, then evaporated under reduced pressure. The residue was "azeotroped" with toluene and dissolved in water (50 ml), then the pH of the stirred aqueous solution adjusted to 7 with 20% aqueous sodium hydroxide solution. Stirring was continued for 2 hours, then the precipitate collected, washed with water (20 ml) and dried under vacuum at 50°C, to give the crude product (5.21 g) which, by TLC and HPLC analyses, contained an estimated yield of 9.1% of the title compound.
EXAMPLE 45 A stirred mixture of o-tcluenesulphonic acid monohydrate (5.71 g, 0.030 mol) and chlorobenzene (100 ml) was heated under reflux until all the water had been
removed, using a Dean-Stark trap, and then allowed to cool to room temperature The title compound of Preparation 4 (24.64 g, 0.050 mol) was added and the reaction mixture stirred under reflux for 24 hours, then allowed to cool. To the resulting mixture was added dichloromethane (200 ml) and water (200 ml), the pH was adjusted to 7 using 2M aqueous sodium hydroxide solution, and the organic phase separated and combined with a dichloromethane extract (100 ml) of the aqueous phase. The combined organic phases were washed with water (100 ml) and evaporated under reduced pressure to afford an off-white solid (24.86 g), 7.3% of which was shown, by TLC and HPLC analyses, to be the title compound.
EXAMPLE 46 Titanium tetrachloride (3.3 ml, 5.69 g, 0.030 mol) was added to a stirred suspension of the title compound of Preparation 4 (12.32 g, 0.025 mol) in anhydrous 1,4-dioxan (61 ml), during which vigorous evolution of a gas was noiec. T(;e stirred reaction mixture was neaiea ai about 70°C for 7.5 hours, ailov^ed lo cool to room temperature and then treated with water (200 ml) and conceniraied hydrochloric acid (50 ml) to give a clear sciution. The solution was washec v,;;:h dichloromethane and its pH adjusted to 12 using 40% aqueous sodium hydroxide solution; it was then stirred for 10 minutes and its pH further adjusted to 7 using 5M hydrochloric acid. The precipitate was removed by filtration and washed with dichloromethane (2 x 200 ml), then the combined dichloromethane washings were used to extract the aqueous filtrate and evaporated under reduced pressure to give a solid (11.36 g), 33.7% of which was shown, by TLC and HPLC analyses, to be the title compound.
EXAMPLES 47-52 Under reaction conditions similar to those described in Example 46, the variations of which are summarised in Table 3, alternative Lewis acids provided the corrected yields of title compound shown.
TABLE 3

(Table Removed)
as the diethyl etherate
PREPARATION 1 5-ChlQrosulDhonyl-2-ethoxybenzoic acid
Molten 2-ethoxybenzoic acid (25.0 g, 0.150 mol) was added to a stirred, ice-cooled mixture of thionyl chloride (11 ml, 0.151 mol) and chlorosulphonic acid (41.3 ml, 0.621 mol), whilst maintaining the temperature of the reaction mixture below 25°C. The resulting mixture was stirred at room temperature for 18 hours and then poured into a stirred mixture of ice (270 g) and water (60 ml) to give an off-white precipitate. Stirring v/as continued for 1 hour, then the product was collected by filtration, washed with water and dried under vacuum to provide the title compound (36.08 g). A reference sample, m.p. 115-116°C, was obtained by crystallisation from hexane:toluene. Found: C,41.02; H,3.27. C9H9CIO5S requires C,40.84; H,3.43%. δ (CDCI3): 1.64(3H,t), 4.45(2H,q), 7.26(1H,d), 8.20(1H,dd), 8.80(1H,d).
FREPARATION 2 2-Ethoxv-5-(4-methylpiper3zin-1-visulphonvl)benzoic acid (a) one-step procedure
1-Methylpiperazine ('33.6 ml, 0.303 mol) was added to a stirred suspension of the title compound of Preparation 1 (34.4 g, 0.130 mol) in water (124 ml) at about 10°C, whilst maintaining the temperature of the reaction mixture below 20°C. The resulting solution was cooled to about 10°C and, after 5 minutes, crystallisation of a solid commenced. After a further 2 hours, the solid was collected by filtration, washed with ice-water and dried under vacuum to furnish the crude product (36.7 g). A sample (15.0 g) was purified by stirring it in refluxing acetone for 1 hour; the resulting suspension was allowed to cool to room temperature and the crystalline solid collected by filtration and dried under vacuum to afford the title compound (11.7 g), m.p. 198-199°C, whose 1H nmr spectrum is identical with that obtained for the product of procedure (b) below.
(bi: two-steo procedure
A solution of the title comipound of Preparation 1 (50.0 g, 0.189 mol) in acetone (150 ml) was added dropwise to a stirred mixture of l-methylpiperazine (20.81 g, 0.208 mol) and triethylamine (28.9 ml, 0.207 mol), whilst maintaining the temperature of the reaction mixture below 20°C. A white crystalline solid formed dunng the addition and stirhng was continued for a further 1.5 hours. Filtration, followed by washing with acetone and drying under vacuum of the product, provided the hydrochloride-triethylamine double salt of the title compound (78.97 g), m.p. 166-169°C. Found: C,51.33; H,8.14; N,9.06; CI,8.02. C14H20N2O5S; C6H15N; HCI requires C,51.55; H,7.79; N,9.02; CI, 7.61%. δ (CD3SOCD3): 1.17(9H,t), 1.32(3H,t), 2.15(3H.s), 2.47(6H,br s), 2.86(2H, br s), 3.02(6H,q), 4.18(2H,q), 7.32(1H,d), 7.78(1H,dd), 7.85(1H,d).
The double salt (30.0 g) was stirred in water (120 ml) to produce an almost clear solution, from which crystallisation cf a solid rapidly occurred. After 2 hours. oclid was collected by filtration, washed with water and dried under vacuum give the title compound (14.61 c) as a white solid. A reference sample, m.p. 20 °C was obtained by recr/stai!isation from aqueous ethanol. Found: C,51.0" H.6.16; N,8.43. C14H20N2O5S requires 0,51.21; H,6.14; N,8.53%. δ (CD3SOCD;): 1.31(3H,t), 2.12(3H,s), 2.34(4H,brs), 2.84(4H, br s), 4.20(2H,q), 7.32(1 H,d), 7.80(1H,dd), 7.86(1H,d).
PREPARATION 3 4-Amino-1-methyl-3-n-propylpyrazole-5-carboxamide
A stirred suspension of 1-methyl-4-nitro-3-n-propylpyrazole-5-carboxamide (EP-A-0463756; 237.7 g, 1.12 rnol) and 5% palladium on charcoal (47.5 g) in ethyl acetate (2.02 1) was hydrogenated at 344.7 kPa (50 psi) and 50°C for 4 hours, when the uptake of hydrogen was complete. The cool reaction mixture was filtered, then the filter pad washed with ethyl acetate, the combined filtrate and washings thus furnishing an ethyl acetate solution of the title compound (EF-A-C463756) which was of sufficient purity to use directly in the next stage of the reaction sequence (see Preparation 4).
PREPARATION 4 4-[2-Ethoxy-5-(4-methylpioerazin-1-vlsulDhonvl)benzamido1-1-methyl-3-n-propylpyrazole-5-carboxamide
N.N'-Carbonyldiimidazole (210.8 g, 1.30 mol) was washed into a stirred suspension of the title compound of Preparation 2 (408.6 g, 1.24 mol) in ethyl acetate (1.50 I) using ethyl acetate (1.36 I) and the resulting mixture heated at 55'C for 0.5 hour and then under reflux for a further 2 hours before being allowed to cool to room temperature. An ethyl acetate solution of the title compound of Preparation 3 (2.185 Kg of solution containing 204 g, 1.12 mol of amine) was added and the reaction mixture stirred at room temperature for 72 hours to afford a crystalline solid which was collected by filtration and dried under vacuum. The title compound (425 g), m.p. 204-206°C, thus obtained was combined with a further crop (70 g) which was recovered by concentration of the mother liquor. A reference sample, m.p. 206-208°C, was obtained by recrystaliisation from aqyebiys methanol. Found: C,53.65; H 6.54 N,17,07. C22H32N5O5S requires C,53,64; H,6.55; N,17.06%. δ (CDCI3): G.96(3H,t), 1.58(3H,t), 1.66(2H,m), 2.27(3H.s) 2.45(4H,m), 2.52(2H,t), 3.05(4H,hr s), 4,05(3H,s;. 4.40(2H,q), 5.61(1H, brs), 7.61(1H,d), 7.65(1H, brs), 7,90(1H,dd), 8.62(1H,d), 9.25(1H,br s).
PREPARATION 5 Methyl 2-ethoxybenzoate
Concentrated sulphuric acid (0.5 ml) was added to a solution of 2-ethoxybenzoic acid (50 g, 0.301 mol) in methanol (500 ml) and the resulting mixture heated under reflux for 70 hours, then evaporated under reduced pressure to give an oil which was dissolved in dichloromethane (300 ml). This solution was washed successively with water (150 ml), aqueous sodium bicarbonate solution (150 ml) and water (150 ml), then evaporated under reduced pressure to give the title compound (49.7 g) as an oil. δ (CDCU): 1.44 (3H,t), 3.90 (3H,s), 4.12 (2H,q), 6.95 (2H,m), 7.44 (1H,t), 7.78 (1H,d).
-2S PREPARATION 6 Methvl 5-chlorosulphonyl-2-ethoxvbenzoate
The title compound of Preparation 5 (36.04 g, 0.20 mol) was added dropwise over 10 minutes to stirred, ice-cooled chlorosulphonic acid (59.8 ml, 0.90 mol), whilst maintaining the temperature of the reaction mixture below 22°C. The reaction mixture was stirred at room temperature for 18 hours, then thionyl chlonde (14.6 ml, 0.20 mol) added and the resulting solution stirred at room temperature for 6 hours, then poured into a stirred mixture of ice (530 g) and water (120 ml). The quenched mixture was extracted with dichloromethane (2 x 200 ml) and the combined extracts evaporated under reduced pressure to give the crude title compound (44.87 g) as a white solid. A reference sample, m.p. 99-100°C, was obtained by crystallisation from toluene. δ (CDCI3): 1.52 (3H,t), 3.93 (3H,s), 4.25 (2H,q), 4.25 (2H,q), 7.12 (1H,d), 8.12 (1H,dd), 8.46 (1H,d).
PREPARATION 7 Methyl 2-ethoxy-5-(4-methylpiperazin-1-yisulphonyl)benzoate
- solution of the crude title compound of Preparation 5 (27.87 g) in acetone^ (140 ml) was added dropwise over 10 minutes to a stirred, ice-cooled solution of 1-methylpiperazine (11.02 g, 0.11 mol) and triethylamine (15.3 ml, 0.11 mol) in acetone (140 ml), whilst maintaining the temperature of the reaction mixture below 20°C. A white precipitate formed during the addition and stirring was continued for a further 4 hours. The resulting mixture was filtered, the filtrate evaporated under reduced pressure and the residue azeotroped with toluene to provide a pale brown gum (41.9 g). This crude product was granulated by stirring with water (100 ml) for 2 hours and the resulting material collected by filtration, washed with water (2 x 50 ml) and dhed under vacuum at 50°C to furnish the title compound, m.p. 110-111°C. δ(CDCl3): 1.48 (3H,t). 2.27 (3H,s), 2.47 (4H,t), 3.03 (4H,t), 3.90 (3H,s), 4.18 (2H,q), 7.04 (1H,d), 7.81 (1H,dd), 8.15 (1H,d).
The compound obtained as above was shown to be identical with that produced by conventional methyl esterification of the title compound of Preparation 2.
Furthermore, conventional base hydrolysis of the compound obtained as above afforded a product identical with that of Preparation 2.

WE CLAIM:
1. A process for preparation of 4-[2-Ethoxy-5-(4-methylpiperazin-1-
ylsulphonyl)benzamidol]-1-methyl-3-n-propylpyra2ole-5-carboxamide of
formula (II):
(Formula Removed)
wherein said process comprises reacting N,N'-Carbonyldiimidazole and 2-Ethoxy-5-(4-methylplperazin-1-ylsulphonyl)benzoic acid in a solvent, preferably an ester, followed by heating the resulting mixture at about 55°C for about 0.5 hr, followed by refluxation for an additional duration of about 2 hours followed by cooling, preferably to room temperature in step-1, and reacting the resulting reaction mixture from said step-1 with 4-Amino-l-methyl-3-n-propylpyrazole-5-carboxamide, preferably in additional amount of said solvent in step-2, and stirring the resulting reaction mixture from said step-2 preferably at room temperature for about 72 hours or till a solid compound of formula II is obtained and said compound of formula (II) is isolated and purified as described hereinbefore, wherein N,N'-Carbonyldiimidazole is taken in an amount of about 1.30 mol and 2-Ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)benzoic acid is taken in an amount of about 1.30 mol in said step-1, and 4-Amino-1-methyl-3-n-propylpyra2ole-5-carboxamide is taken in an amount of about 1.12 mol. 2. A process, as claimed in claim 1, wherein said solvent is preferably ethyl acetate.
3. A process for the preparation of a compound of formula II substantially as herein described with reference to the foregoing examples.

Documents:

517-del-2001-abstract.pdf

517-del-2001-Assignment-(22-12-2011).pdf

517-del-2001-assignment.pdf

517-DEL-2001-Claims.pdf

517-del-2001-complete specification (granted).pdf

517-del-2001-Correspondence Others-(22-12-2011).pdf

517-DEL-2001-Correspondence-Others.pdf

517-del-2001-correspondence-po.pdf

517-del-2001-description (complete).pdf

517-del-2001-form-1.pdf

517-del-2001-form-13.pdf

517-del-2001-Form-16-(22-12-2011)-1.pdf

517-del-2001-Form-16-(22-12-2011).pdf

517-DEL-2001-Form-2.pdf

517-del-2001-form-3.pdf

517-del-2001-form-5.pdf

517-del-2001-form-6.pdf

517-del-2001-GPA-(22-12-2011).pdf

517-del-2001-gpa.pdf

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Patent Number

187317

Indian Patent Application Number

517/DEL/2001

PG Journal Number

12/2002

Publication Date

23-Mar-2002

Grant Date

25-Oct-2002

Date of Filing

24-Apr-2001

Name of Patentee

PFIZER RESEARCH AND DEVELOPMENT COMPANY,

Applicant Address

LA TOUSHE HOUSE, INTERNATIONAL FINANCIAL SERVICES CENTRE, DUBLIN, 1,IRELAND

Inventors:

#	Inventor's Name	Inventor's Address
1	NA	NA
2	PETER JAMES DUNN	PFIZER CENTRAL RESEARCH, RAMSGATE ROAD, SANDWICH, KENY, CT13 9NJ, UNITED KINGDOM.
3	ALBERT SHAW WOOD;	India Karnataka India

PCT International Classification Number

A61K 31/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	9612514.1	1996-06-14	U.K.