HK1033459B - Intermediate compound for preparing sildenafil - Google Patents

Description

Intermediate compound for preparing xibo ketone

The present invention relates to a process for the preparation of a compound of formula (I):

the compound is named 5- [ 2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl ] -1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one or sildenafil; the invention also relates to intermediates used in the preparation. Xiboketon was originally disclosed in EP-A-0463756 and has now been found to be particularly useful in the treatment of male erectile dysfunction: see WO-A-94/28902.

More particularly, the present invention relates to ｃA process for the preparation of sildenafil, which is more efficient than the process disclosed in EP- ｃA-0463756 and by which sildenafil meeting clinical quality criteriｃA can be obtained directly, unexpectedly, without subsequent purification steps. Herein, sildenafil, a clinical quality standard, refers to a substance of sufficient purity to be suitable for administration to humans.

In the overall process, the key step involves a ring closure reaction to form the boombone from the intermediate precursor, i.e., the diamide of formula (II).

Accordingly, the present invention provides a process for the preparation of a compound of formula (I), said process comprising a cyclisation reaction of a compound of formula (II).

In a preferred embodiment, the cyclization reaction is carried out in the presence of a base, preferably in a solvent, optionally in the presence of hydrogen peroxide or a peroxygenated salt, and the reaction mixture is then neutralized if desired.

Suitable bases may be selected from C₁-C₁₂Alcohol, C₃-C₁₂Cycloalkanol, (C)₃-C₈Cycloalkyl) C₁-C₆Alcohol, ammonia, C₁-C₁₂Alkylamine, di (C)₁-C₁₂Alkyl) amine, C₃-C₈Cycloalkylamine, N- (C)₃-C₈Cycloalkyl) -N- (C₁-C₁₂Alkyl) amine, di (C)₃-C₈Cycloalkyl) amine, (C)₃-C₈Cycloalkyl) C₁-C₆Alkylamine, N- (C)₃-C₈Cycloalkyl) C₁-C₆alkyl-N- (C)₁-C₁₂Alkyl) amine, N- (C)₃-C₈Cycloalkyl) C₁-C₆alkyl-N- (C)₃-C₈Cycloalkyl) amine, bis [ (C)₃-C₈Cycloalkyl) C₁-C₆Alkyl radical]An amine and a metal salt of a heterocyclic amine selected from the group consisting of: imidazole, triazole, pyrrolidine, piperidine, cycloheptylamine, morpholine, thiomorpholine and 1- (C)₁-C₄Alkyl) piperazine; metal hydrides, fluorides, hydroxides, oxides, carbonates and bicarbonates; wherein the metal is selected from the group consisting of lithium, sodium, potassium, rubidium, cesium, beryllium, magnesium, calcium, strontium, barium, aluminum, indium, thallium, titanium, zirconium, cobalt, copper, silver, zinc, cadmium, mercury, and cerium; and C₇-C₁₂Bicyclic amidines.

Preferred bases are selected from C₁-C₁₂Alcohol, C₃-C₁₂Cycloalkanol and (C)₃-C₈Cycloalkyl) C₁-C₆Alkali or alkaline earth metal salts of alcohols; ammonia, N- (secondary or tertiary C)₃-C₆Alkyl) -N- (primary, secondary or tertiary C₃-C₆Alkyl) amine, C₃-C₈Cycloalkylamine, N- (C)₃-C₈Cycloalkyl) -N- (primary, secondary or tertiary C₃-C₆Alkyl) amine, di (C)₃-C₈Cycloalkyl) amines and alkali metal salts of 1-methylpiperazine; and alkali or alkaline earth metal hydrides, hydroxides, oxides, carbonates and bicarbonates; 1, 5-diazabicyclo [4.3.0 ]]Non-5-ene and 1, 8-diazabicyclo [5.4.0]Undec-7-ene.

Suitable solvents may be selected from C₁-C₁₂Alcohol, C₃-C₁₂Cycloalkanol, (C)₃-C₈Cycloalkyl) C₁-C₆Alcohol, C₃-C₉Alkanones, C₄-C₁₀Cycloalkanone, C₅-C₁₂Alkyl ethers, 1, 2-dimethoxyethane, 1, 2-diethoxyethane, diglyme, tetrahydrofuran, 1, 4-dioxane, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, acetonitrile, dimethyl sulfoxide, sulfolane, dimethylformamide, dimethylacetamide, N-methylpyrrolidin-2-one, pyrrolidin-2-one, pyridine and water, and mixtures thereof.

Preferred solvents are selected from ethanol, 2-propanol, secondary or tertiary C₄-C₁₂Alcohol, C₃-C₁₂Cycloalkanol, tertiary C₄-C₁₂Cycloalkanol, secondary or tertiary (C)₃-C₇Cycloalkyl) C₂-C₆Alcohol, C₃-C₉Alkanones, 1, 2-dimethoxyethane, 1, 2-diethoxyethane, diglyme, tetrahydrofuran, 1, 4-dioxane, toluene, xylene, chlorobenzene, 1, 2-dichlorobenzene, acetonitrile, dimethyl sulfoxide, sulfolane dimethylformamide, N-methylpyrrolidin-2-one, pyridine and water, and mixtures thereof.

Further preferred features are that the base is used in an amount of 1.0 to 5.0 molar equivalents and that the reaction is carried out at 50 to 170 ℃ for 3 to 170 hours.

In a more preferred process, the base is selected from C₁-C₁₂Alcohol, C₄-C₁₂Lithium, sodium and potassium salts of cycloalkanol, ammonia, cyclohexylamine and 1-methylpiperazine; hydrides of lithium, sodium and potassium; cesium carbonate and barium oxide; the solvent is selected from ethanol and tertiary C₄-C₁₀Alcohol, tertiary C₅-C₈Cycloalkanol, tetrahydrofuran, 1, 4-dioxane and acetonitrile, the reaction being carried out at 60 to 105 ℃ and the amount of base used being 1.1 to 2.0 molar equivalents.

More preferably, the process is one wherein the base is selected from the group consisting of lithium, sodium and potassium C₁-C₁₂Alkoxides and hydride salts, sodium amide, sodium cyclohexylamide, and cesium carbonate; the solvent is selected from ethanol, tert-butanol, tert-amyl alcohol, 1-methylcyclohexanol, tetrahydrofuran and 1, 4-dioxane; the reaction is carried out for 3 to 60 hours.

A particularly preferred process is one wherein the base is selected from the group consisting of sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide and sodium hydride; the solvent is selected from ethanol, tert-butanol, tert-amyl alcohol and tetrahydrofuran.

In the above definitions, unless otherwise stated, an alkyl or cycloalkyl chain may be branched or straight.

The compounds of formula (I) may be isolated and purified by conventional techniques. For example, when (I) is produced in the form of a salt, the product is collected by neutralization of the optionally pre-diluted reaction mixture, followed by filtration/extraction and optionally crystallization.

Alternatively, the compounds of formula (I) may be conveniently isolated and/or purified by conventional chromatographic methods.

The compounds of formula (II) required for the preparation of the compounds of formula (I) can be prepared by conventional methods via the routes described in the following reaction schemes.

Scheme(s)

Thus, the compounds of formula (IV) can be prepared by chlorosulfonation of 2-ethoxybenzoic acid, i.e., a compound of formula (III). Generally, (III) is added to a mixture of about 1 molar equivalent of thionyl chloride and about 4 molar equivalents of chlorosulfonic acid cooled in an ice bath while maintaining the reaction temperature below 25 ℃; the reaction was then continued at room temperature until the end of the reaction.

The conversion of (IV) into the compound of formula (V) is accomplished by N-sulfonation of 1-methylpiperazine and can be carried out in one or two steps. In a one-step process, about 2.3 molar equivalents of 1-methylpiperazine are added to the aqueous suspension of (IV) at about 10 ℃ while maintaining the reaction temperature below 20 ℃; the temperature of the resulting reaction mixture was then maintained at about 10 ℃. Alternatively, the amount of 1-methylpiperazine can be reduced to about 1.1 molar equivalents by using about 1 molar equivalent of sodium hydroxide as auxiliary base. In the two-step process, a solution of (IV) in a suitable solvent (e.g. acetone) is added to a mixture consisting of about 10% excess of 1-methylpiperazine and about 10% excess of a suitable acid acceptor (e.g. a tertiary base such as triethylamine) while maintaining the reaction temperature below 20 ℃. When triethylamine was used as the auxiliary base, the hydrochloric acid-triethylamine double salt intermediate of (V) was isolated and identified as the compound of structural formula (VA). The salt can be converted to the compound of formula (V) by treatment with water.

A convenient alternative route to (V) is the use of 2-ethoxybenzoic acid C₁-C₄Alkyl esters [ obtained by the conventional esterification reaction of (III) ] as substrates for the chlorosulfonation reaction, the sulfonyl chlorides obtained are subsequently treated with 1-methylpiperazine in the manner described above, and the ester groups are then subjected to conventional hydrolysis. Other synthetic routes to (V) from salicylic acid and its derivatives will be apparent to those skilled in the art.

The coupling of (V) to the compound of formula (VII) may be accomplished by any of a number of amide bond forming reactions well known to those skilled in the art. For example, the carboxylic acid functional group of (V) is first activated with an about 5% excess of a reagent (e.g., N' -carbonyldiimidazole) in a suitable solvent (e.g., ethyl acetate) at a temperature of from room temperature to about 80 ℃, followed by reaction of the imidazole intermediate with (VII) at a temperature of from about 20 to about 60 ℃.

The corresponding aminopyrazole (VII) is prepared by conventional reduction of the nitropyrazole (VI), for example by palladium-catalyzed hydrogenation in a suitable solvent, for example ethyl acetate. The resulting solution of (VII) can be used directly after filtration for the coupling reaction with (V).

(II) the cyclization reaction to form the compound of formula (I) can be accomplished in up to 95% yield. Thus, the overall yield can be as high as 51.7% or 47.8%, respectively, calculated on the benzoic acid derivative as starting material and depending on the one-step or two-step sulfonation process used. This process works better than the process disclosed in EP-A-0463756, which gives an overall yield of 27.6% for (I) from 2-ethoxybenzoyl chloride [ i.e.from (III), which is assumed to give the acid chloride derivative in quantitative yield ]. In other comparisons, the process disclosed in the present invention gives overall yields of up to 85.2% based on the nitropyrazole (VI), whereas the process disclosed in EP-A-0463756 gives an overall yield of 23.1% from (VI) to (I).

It is clear that the alternative processes disclosed above for preparing (I) are more efficient and advantageous than previously disclosed processes, while intermediates of formula (II), (V) and (VA) also form part of the present invention.

In addition, the cyclization of the compound of formula (II) to form the compound of formula (I) can also be carried out under neutral or acidic conditions.

The compound of formula (II) is heated under neutral conditions, optionally in the presence of a solvent and/or optionally in the presence of a dehydrating agent and/or a mechanical dehydration system (e.g. Dean-Stark trap).

Suitable solvents may be selected from 1, 2-dichlorobenzene, dimethyl sulfoxide, sulfolane, N-methylpyrrolidin-2-one and pyrrolidin-2-one, and mixtures thereof.

Preferred solvents are 1, 2-dichlorobenzene, sulfolane or N-methylpyrrolidin-2-one.

Suitable dehydrating agents may be selected from potassium carbonate, anhydrous sodium carbonate, anhydrous magnesium sulfate, anhydrous sodium sulfate, phosphorus pentoxide, and molecular sieves.

Preferred dehydrating agents are molecular sieves.

The reaction is preferably carried out at 180 to 220 ℃ for 0.5 to 72 hours.

Under acidic conditions, the cyclization reaction is carried out by reacting a compound of formula (II) with a protic or Lewis acid, optionally in the presence of a solvent.

Suitable protic acids may be selected from inorganic acids, organic sulfonic acids, organic phosphonic acids and organic carboxylic acids.

Preferred protic acids are concentrated sulfuric acid, phosphoric acid or p-toluenesulfonic acid.

Suitable Lewis acids may be selected from the group consisting of boron trifluoride, boron trichloride, boron tribromide, aluminum trichloride, aluminum bromide, silicon tetrachloride, silicon tetrabromide, tin chloride, tin 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.

Preferred Lewis acids are boron trifluoride, aluminum trichloride, silicon tetrachloride, tin chloride, titanium tetrafluoride, titanium tetrachloride, iron chloride or zinc chloride.

Suitable solvents may be selected from C₅-C₁₂Alkane, C₅-C₈Cycloalkanes, C₁-C₁₂Alkanoic acid, C₁-C₄Alkanol, C₃-C₉Ketones, C₅-C₁₂Alkyl ethers, 1, 2-dimethoxyethane, 1, 2-diethoxyethane, diglyme, tetrahydrofuran, 1, 4-dioxane, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, nitrobenzene, dichloromethane, dibromomethane, 1, 2-dichloroethane, acetonitrile, dimethyl sulfoxide, sulfolane, dimethylformamide, dimethylacetamide, N-methylpyrrolidin-2-one, pyrrolidin-2-one, and mixtures thereof.

Preferred solvents are glacial acetic acid, tetrahydrofuran, 1, 4-dioxane or chlorobenzene.

The reaction is also preferably carried out at 65 to 210 ℃ for 6 to 300 hours.

The preparation of the compounds of structural formula (I) and intermediates thereof is described in the following examples and preparations. If the compound of formula (I) is not isolated and purified, if desired, the determination of the yield and the analysis of the reaction mixture is carried out by quantitative thin-layer chromatography (TLC) using Merck silica gel 60 plates and using a mixture of toluene: methylated spirit: 0880 aqueous ammonia as solvent system and/or High Performance Liquid Chromatography (HPLC) using a Gilson instrument equipped with a 15cm reverse phase C18 column and using a mixture of triethylamine: aqueous acetonitrile in phosphate buffer: methanol as mobile phase.

¹H Nuclear Magnetic Resonance (NMR) spectra were recorded with a Varian Unity 300 spectrometer and all spectra were consistent with the proposed structure. The characteristic chemical shift (δ) is one part per million moving from trimethylsilane to low field and the characteristic peaks are indicated by the conventional abbreviations: for example, s, singlet; d, doublet; t, triplet; q, quartet; h, six-fold peak; m, multiplet; br, broad peak.

The room temperature means 20-25 ℃.

The title Compound

5- [ 2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl]-1-methyl-3-n-propyl-1, 6- dihydro-7H-pyrazolo [4, 3-d]Pyrimidin-7-ones

Example 1

Potassium tert-butoxide (3.37g, 0.030mol) was added to a suspension of the title compound of preparation 4 (12.32g, 0.025mol) in tert-butanol (61ml) with stirring, and the resulting mixture was heated under reflux for 8 hours and then cooled to room temperature. Water (62.5ml) was added and the resulting solution was filtered into a dust-free (speck-free) flask and treated dropwise with a solution of concentrated, dust-free hydrochloric acid (2.3ml) in water (62.5 ml). The precipitated product was granulated at pH 7 and 10 ℃ for 1 hour, collected by filtration, washed with water and dried under vacuum to give the title compound (10.70g, 90.2%) m.p.189-190 ℃. Fruit of Chinese wolfberryMeasuring: c, 55.55; h, 6.34; n, 17.69. C₂₂H₃₀N₆O₄S requires C, 55.68; h, 6.37; n, 17.71 percent. Delta (CD)₃SOCD₃)：0.94(3H，t)，1.32(3H，t)，1.73(2H，h)，2.15(3H，s)，2.35(4H，br s)，2.76(2H，t)，2.88(4H，br 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 quantitative TLC showed that the substance was directly obtained from the reaction as a clinical quality standard.

By carrying out the cyclization reaction at greater concentrations, the yield of the substance of clinical quality standard can be increased to 95%.

Examples 2 to 5

Substances of clinical quality standards were prepared by varying the solvents using a similar method to that described in example 1, as shown in table 1. The reaction was carried out at reflux temperature as in example 1, except that temperatures of 100 ℃ were used in examples 2 and 5.

TABLE 1

Examples	Solvent(s)	Reaction time (hours)	% yield
				2	Tert-amyl alcohol	5	78
3	Ethanol	9.5	83
				4	Tetrahydrofuran (THF)	32	81
5	1-methylcyclohexanol	4	65

Examples 6 to 9

Substances of clinical quality standards were prepared using a similar method to that described in example 1, by varying the solvent and base, as shown in table 2. The reaction was carried out at reflux temperature except that the temperature used in example 9 was 100 ℃.

TABLE 2

Examples

Alkali

Solvent(s)

Reaction time

% yield

			(hours)
					6	Sodium ethoxide	Tert-butyl alcohol	10	86
7	Sodium ethoxide	Ethanol	7	82.5
					8	Sodium hydride	Tetrahydrofuran (THF)	48	84
9	Cesium carbonate	Tert-amyl alcohol	17	71

Example 10

Using a similar procedure and varying the cation as described in example 1, with sodium tert-butoxide as base and the reaction was carried out for 24 hours, a substance of clinical quality standard (88%) was prepared.

Example 11

Using a similar method and varying the molar ratio of the base as described in example 1, potassium tert-butoxide (5.0 molar equivalents) was used as the base and the reaction was carried out at reflux temperature for 18 hours, a material of clinical quality standard (71%) was obtained.

Example 12

Further varying the reaction conditions of example 1, 1.6 molar equivalents of potassium tert-butoxide (4.49g, 0.040mol) were reacted at 60 ℃ for 55 hours to afford the title compound (87%) in a purity of > 99% (HPLC and TLC analysis).

Example 13

Using a similar procedure to that described in example 1, using 1, 4-dioxane as solvent and carrying out the reaction at 100 ℃ for 4 h, the title compound was obtained in a purity of > 99% (87%) (HPLC and TLC analysis).

Example 14

Using a similar procedure as described in example 1, using 1, 2-dimethoxyethane as solvent and the reaction was carried out for 30 hours, the title compound was obtained in a purity of > 99% (85%) (HPLC and TLC analysis).

Example 15

Using a similar procedure to that described in example 1, using 3, 7-dimethyloctan-3-ol as solvent and carrying out the reaction at 100 ℃ for 16 h, the title compound was obtained in a purity of > 99% (83%) (HPLC and TLC analysis).

Example 16

Using a similar procedure as described in example 1, with sodium n-decanol as the base and 1, 4-dioxane as the solvent and carrying out the reaction at 100 ℃ for 20 h, the title compound was obtained in a purity of > 99% (74%) (HPLC and TLC analysis).

Example 17

Using a similar procedure as described in example 1, with sodium amide as base, 1, 4-dioxane as solvent and the reaction carried out at 100 ℃ for 18 h, the title compound was obtained in a purity of > 99% (85%) (HPLC and TLC analysis).

Example 18

Using a similar procedure as described in example 1, with sodium cyclohexylamide as base and 1, 4-dioxane as solvent and carrying out the reaction at 100 ℃ for 6.5 h, the title compound was obtained in a purity of > 99% (91%) (HPLC and TLC analysis).

Example 19

Using a similar procedure to that described in example 1, with sodium 4-methylpiperazine as base and 1, 4-dioxane as solvent and the reaction carried out at 100 ℃ for 8 h, the title compound was obtained in a purity of > 99% (84%) (HPLC and TLC analysis).

Examples 20 to 21

Under similar reaction conditions as described in example 1, after 32 hours of reaction with sodium methoxide in methanol a four-component mixture is obtained, from which the title compound is isolated in 34.5% chromatographic yield; at the same time, after 40 hours of reaction in methanol using potassium tert-butoxide, a mixture of the products is obtained which, by TLC and NMR spectroscopy, contains the title compound in an estimated yield of 69%.

Example 22

After 50 hours at 100 ℃ in anhydrous dimethyl sulfoxide using potassium tert-butoxide under similar reaction conditions as described in example 1, the crude product (88% by weight yield) is obtained which, by TLC and HPLC analysis, contains the title compound in an estimated yield of 24%.

Example 23

The crude product (79% yield by weight) was obtained after 96 hours of reaction with magnesium ethoxide in pyridine at reflux temperature under similar reaction conditions as described in example 1 and contained 16% of the estimated yield of the title compound by TLC and HPLC analysis.

Example 24

Under similar reaction conditions as described in example 1, after reaction for 20 h in t-amyl alcohol using barium ethoxide (10% w/v in ethanol) at 100 ℃ crude product (76.5% weight yield) was obtained which contained 75.5% of the estimated yield of the title compound by TLC and HPLC analysis.

Example 25

The crude product (82% by weight yield) was obtained after 90 hours reaction in pyridine using titanium ethoxide under similar reaction conditions as described in example 1 at 100 ℃ and was analyzed by TLC and HPLC, containing the title compound in an estimated yield of 32%.

Example 26

After 98 hours reaction in pyridine at 100 ℃ using copper ethoxide under similar reaction conditions as described in example 1, the crude product (89.5% w/w yield) was obtained, which contained 18.5% of the estimated yield of the title compound by TLC and HPLC analysis.

Example 27

The crude product, which contains the title compound in the maximum (due to contamination with aluminum salts) estimated yield of 66% by TLC and HPLC analysis, was obtained after 72 hours of reaction in pyridine using aluminum tri-tert-butoxide under similar reaction conditions as described in example 1.

Example 28

Using a total of 3.6 molar equivalents (1.2 molar equivalents each time added in three stages) of a solution of lithium diisopropylamide [ 1.5M in cyclohexane of the mono (tetrahydrofuran) complex ] in anhydrous 1, 4-dioxane under similar reaction conditions as described in example 1, the reaction was first carried out at 0 ℃ for 15 minutes, then at room temperature for 1 hour and then at 100 ℃ for 140 hours to give the crude product (60.5% weight yield) which contained 55.5% of the estimated yield of the title compound by TLC and HPLC analysis.

Example 29

Under similar reaction conditions as described in example 1, 2.0 molar equivalents of 1, 8-diazabicyclo [5.4.0] undec-7-ene gave, after reaction in pyridine at 100 ℃ for 44 hours, the crude product (6.5% weight yield) which, by TLC and HPLC analysis, contained the title compound in an estimated yield of 3.3%.

Example 30

Under similar reaction conditions as described in example 1, after 44 hours reaction using potassium fluoride in t-amyl alcohol at 100 ℃ crude product (85% yield by weight) was obtained containing the title compound in an estimated yield of 3.5% by TLC and HPLC analysis.

Example 31

An 85% potassium hydroxide tablet (3.96g, 0.06mol) was added to a suspension of the title compound of preparation 4 (9.85g, 0.02mol) in ethanol (30ml) with stirring, followed by addition of water (30ml) to form a clear solution. The reaction mixture was heated to reflux for 5 hours, then most of the ethanol was distilled off under reduced pressure. The resulting mixture was diluted with water (60ml), its pH was adjusted to 7 with dilute sulfuric acid and the precipitated product was granulated for 30 minutes. The solid was collected by filtration, washed with water and dried in vacuo to give the product (7.96g) which was 96.4% by HPLC analysis as the title compound.

Examples 32 to 34

After 52 hours at reflux temperature using barium oxide in acetonitrile under similar reaction conditions as described in example 1, the title compound (89%) was obtained in a purity of > 99% by HPLC and TLC analysis.

The above experiment was repeated using dimethylformamide as solvent to give the crude product (75.5% by weight yield) after 31 hours at 100 ℃ which contained 54% of the estimated yield of the title compound by TLC and HPLC analysis.

The above experiment was repeated again using pyridine as solvent and after 16 hours at 100 ℃ the crude product was obtained, which contained the title compound in a maximum (due to contamination with barium salts) estimated yield of 90% by TLC and HPLC analysis.

Example 35

After 96 hours at 100 ℃ in 4-methylpent-2-one (methylisobutylketone) using cesium carbonate under similar reaction conditions as described in example 1, the crude product (18.5% by weight yield) was obtained which contained 13% of the estimated yield of the title compound by TLC and HPLC analysis.

Example 36

Under similar reaction conditions as described in example 1, after 115 hours at 100 ℃ using potassium bicarbonate in tert-amyl alcohol, the crude product (82.5% by weight yield) was obtained, which contained 20% of the estimated yield of the title compound, analyzed by TLC and HPLC.

Example 37

The title compound of preparation 4 (12.32g, 0.025mol) was heated at 215-220 ℃ for 40 minutes and the resulting melt was then cooled to room temperature. The crude product, which is tar-like, is dissolved in dichloromethane (25ml) and then purified by chromatography on silica gel using a methanol/dichloromethane mixture of increasing polarity as eluent. The appropriate single-component fractions were evaporated in vacuo to give pure fractions (by¹H NMR analysis) (1.76g, 14.8%) while obtaining a batch of less pure title compound (0.87g, 7.3%) from the other fractions. The latter was further chromatographed to give another batch (0.48g) of the pure title compound in 2.24g, 18.8% overall yield.

Examples 38 to 40

A mixture of the title compound of preparation 4 (12.32g, 0.025mol) and 1, 2-dichlorobenzene (61ml) was heated under reflux with stirring for 72 hours. The resulting dark brown reaction mixture was cooled, diluted with dichloromethane (60ml) and filtered. The filtrate was evaporated under reduced pressure to give a solvent-containing black brown oil (17.51g), which was analyzed by TLC and HPLC and 28.2% of the material except solvent was the title compound.

The above experiment was repeated using sulfolane as solvent to give the crude product (14% by weight yield) after 5 hours at about 205 c, which contained the title compound in an estimated yield of 12% by TLC and HPLC analysis.

The above experiment was repeated again using N-methylpyrrolidin-2-one as solvent and after 3 hours at 205 ℃ and 210 ℃ the crude product (21.5% by weight yield) was obtained which contained 6.5% of the estimated yield of the title compound by TLC and HPLC analysis.

EXAMPLE 41

Similar reaction conditions as described in example 38 were used except that the reaction was carried out in the presence of 4A molecular sieve for 24 hours to give a solvent-containing product, which was analyzed by HPLC and showed 6.0% of the material other than the solvent to be the title compound.

Example 42

Concentrated sulfuric acid (1.0ml, 1.84g, 18.75mmol) was added to a suspension of the title compound of preparation 4 (12.32g, 0.025mol) in chlorobenzene (61ml) with stirring and the resulting mixture was heated to the point where the solvent began to distill off. When the distillate was no longer turbid (after collection of about 20ml), the reaction mixture was cooled to room temperature, chlorobenzene (20ml) was added again and heated under reflux for 20 hours. The cooled reaction mixture was treated with dichloromethane (100ml) to form a solution, followed by treatment with water (100 ml). The pH of the resulting mixture was adjusted to 7 with 5M aqueous sodium hydroxide, the organic phase was separated and combined with an aqueous dichloromethane extract (50ml), and evaporated under reduced pressure to give a solid (9.51g) of which 5.5% was the title compound by HPLC analysis.

Example 43

Concentrated sulfuric acid (1.0ml, 1.84g, 18.75mmol) was added to a solution of the title compound of preparation 4 (6.16g, 12.5mmol) in glacial acetic acid (31ml) with stirring and the resulting mixture was heated at 100 ℃ for 115 h. The solvent was distilled off under reduced pressure, the residue azeotroped with toluene (2X 50ml) and the resulting oil (10.5g) shaken with water (60ml) to form a crystalline solid which was filtered, washed with water (10ml) and dried to give the first product (2.03 g). The filtrate was neutralized with 20% aqueous sodium hydroxide solution and then collected, washed and dried as before to give a second crop of product (3.48g), which was combined with the first crop to give the crude product (5.51g) which contained 38% of the estimated yield of the title compound by TLC and HPLC analysis.

Example 44

A mixture of preparation 4 of the title compound (6.16g, 12.5mmol) and glacial acetic acid (31ml) was heated at 100 ℃ for 7 hours with stirring and the resulting solution was then cooled. TLC analysis of the reaction mixture showed no title compound formed at this stage.

An 85% phosphoric acid aqueous solution (0.5ml) was added and the resulting mixture was heated at 100 ℃ for 300 hours intermittently, and then evaporated under reduced pressure. The residue was azeotroped with toluene and dissolved in water (50ml), and the pH of the aqueous solution was adjusted to 7 with 20 ℃ aqueous sodium hydroxide solution under stirring. After stirring for an additional 2 hours the precipitate was collected, washed with water (20ml) and dried in vacuo at 50 ℃ to give the crude product (5.21g) which contained 9.1% of the estimated yield of the title compound by TLC and HPLC analysis.

Example 45

A mixture of p-toluenesulfonic acid monohydrate (5.71g, 0.030mol) and chlorobenzene (100ml) was heated under reflux with stirring until all water was removed (using a Dean-Stark trap) and then cooled to room temperature. The title compound of preparation 4 (24.64g, 0.050mol) was added and the reaction mixture was heated under reflux for 24 hours and cooled. To the resulting mixture were added dichloromethane (200ml) and water (200ml), the pH was adjusted to 7 with a 2M aqueous solution of sodium hydroxide, the organic phase was separated and combined with a dichloromethane extract (100ml) of the aqueous phase. The combined organic phases were washed with water (100ml) and evaporated under reduced pressure to give an off-white solid (24.86g) of which 7.3% by TLC and HPLC analysis was the title compound.

Example 46

Titanium tetrachloride (3.3ml, 5.69g, 0.030mol) was added to a suspension of the title compound (12.32g, 0.025mol) in anhydrous 1, 4-dioxane (61ml) under stirring, during which time a large amount of gas was evolved. The reaction mixture was heated at about 70 ℃ for 7.5 hours with stirring, cooled to room temperature and treated with water (200ml) and concentrated hydrochloric acid (50ml) to give a clear solution. The solution was washed with dichloromethane and then adjusted to pH 12 with 40% aqueous sodium hydroxide; after stirring for 10 minutes, the pH was adjusted to 7 with 5M hydrochloric acid. The precipitate was filtered off and washed with dichloromethane (2X 200ml), then the permanent solution filtrate was extracted with combined dichloromethane washes and evaporated under reduced pressure to give a solid (11.36g) of which 33.7% was the title compound by TLC and HPLC analysis.

Examples 47 to 52

Using similar reaction conditions to those described in example 46, with the variations listed in Table 3, the title compound was prepared in corrected yield from different Lewis acids.

TABLE 3

Examples Lewis acid solvent reaction time% yield

(hours)

47 BF₃ ^*Tetrahydrofuran 72 7.0

48 AlCl₃1, 4-dioxane 307.8

49 FeCl₃Tetrahydrofuran 246.3

50 ZnCl₂Tetrahydrofuran 722.8

51 SiCl₄1, 4-dioxane 4420.5

52 SnCl₄1, 4-dioxane 4830.8

In the form of a diethyl ether complex

Preparation 1

5-chlorosulfonyl-2-ethoxybenzoic acid

Molten 2-ethoxybenzoic acid (25.0g, 0.150mol) was added to an ice-bath cooled mixture of thionyl chloride (11ml, 0.151mol) and chlorosulfonic acid (41.3ml, 0.621mol) with stirring, while maintaining the temperature of the reaction mixture below 25 ℃. The resulting mixture was stirred at room temperature for 18 hours, then poured into a stirred mixture of ice (270g) and water (60ml) to give a beige precipitate. After stirring for an additional 1 hour the product was collected by filtration, washed with water and dried under vacuum to give the title compound (36.08 g). Using a mixture of hexane: toluene recrystallization gave a standard sample, m.p.115-116 ℃. Measured value: c, 41.02; h, 3.27; . C₉H₉ClO₅S requires C, 40.84; h, 3.43 percent. Delta (CDCl)₃)：1.64(3H，t)，4.45(2H，q)，7.26(1H，d)，8.20(1H，dd)，8.80(1H，d)。

Preparation 2

2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) benzoic acid

(a) The method comprises the following steps One-step process

1-methylpiperazine (33.6ml, 0.303mol) was added to a suspension of the title compound of preparation 1 (34.4g, 0.130mol) in water (124ml) at about 10 ℃ with stirring, while keeping the temperature of the reaction mixture below 20 ℃. The resulting solution was cooled to about 10 ℃ and solid crystallization began to occur after 5 minutes. After an additional 2 hours, the solid was collected by filtration, washed with ice water and dried in vacuo to give the crude product (36.7 g). A portion of the sample (15.0g) was purified by stirring in refluxing acetone for 1 hour; the resulting suspension was cooled to room temperature, and the crystalline solid was collected by filtration and dried in vacuo to give the title compound (11.7g), m.p.198-199 ℃ with a 1H NMR spectrum identical to that of the product obtained in method (b) below.

(b) The method comprises the following steps Two-step process

A solution of the title compound of preparation 1 (50.0g, 0.189mol) in acetone (150ml) was added dropwise to a mixture of 1-methylpiperazine (20.81g, 0.208mol) and triethylamine (28.9ml, 0.207mol) with stirring, while keeping the temperature of the reaction mixture below 20 ℃. During the addition a white crystalline solid formed and stirring was continued for 1.5 hours. Filtration and washing of the product with acetone and drying in vacuo gave the title compound as a triethylamine hydrochloride double salt (78.97g), m.p.166-169 ℃. Measured value: c, 51.33; h, 8.14; n, 9.06; cl, 8.02. C₁₄H₂₀N₂O₅S；C₆H₁₅N; HCl requires C, 51.55; h, 7.79; n, 9.02; cl, 7.61%. Delta (CD)₃SOCD₃)：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 (30.0g) was stirred in water (120ml) to form a near clear solution in which solid crystals rapidly formed.After 2 hours, the solid was collected by filtration, washed with water and dried in vacuo to give the title compound (14.61g) as a white solid. Recrystallization from ethanol water gave a standard sample, m.p.201 ℃. Measured value: c, 51.09; h, 6.16; n, 8.43. C₁₄H₂₀N₂O₅S requires C, 51.21; h, 6.14; n, 8.53 percent. Delta (CD)₃SOCD₃)：1.31(3H，t)，2.12(3H，s)，2.34(4H，br s)，2.84(4H，br s)，4.20(2H，q)，7.32(1H，d)，7.80(1H，dd)，7.86(1H，d)。

Preparation 3

4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide

A suspension of 1-methyl-4-nitro-3-n-propylpyrazole-5-carboxamide (EP-A-0463756; 237.7g, 1.12mol) and 5% palladium on charcoal (47.5g) in ethyl acetate (2.02l) was hydrogenated at 344.7kPｃA (50 psi) and 50 ℃ for 4 hours with stirring, at which time the uptake of hydrogen was stopped. The reaction mixture was cooled and filtered, the filter cake was washed with ethyl acetate, and the filtrate and washings were combined to give an ethyl acetate solution of the title compound (EP-A-0463756) which was of sufficient purity to be used directly in the next reaction (see preparation 4).

Preparation 4

4- [ 2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) benzoylamino group]-1-methyl-3-n-propyl Pyrazole-5-carboxamides

N, N' -carbonyldiimidazole (210.8g, 1.30mol) was washed with ethyl acetate (1.36l) with stirring to prepare a suspension of the title compound 2 (408.6g, 1.24mol) in ethyl acetate (1.50l), and the resulting mixture was heated at 55 ℃ for 0.5 hour and then further heated under reflux for 2 hours and then cooled to room temperature. An ethyl acetate solution of the title compound of preparation 3 (2.185Kg solution containing 204g of amine, 1.12mol) was added, and the reaction mixture was then cooled at room temperatureAfter stirring for 72 hours, the resulting crystalline solid was filtered and dried in vacuo. The title compound thus obtained (425g, m.p.204-206 ℃ C.) was combined with another batch of the product obtained by concentrating the mother liquor (70 g). Recrystallizing with methanol water to obtain standard sample, m.p.206-208 deg.C. Measured value: c, 53.65; h, 6.54; and N, 17.07. C₂₂H₃₂N₆O₅S requires C, 53.64; h, 6.55; and N, 17.06%. Delta (CDCl)₃)：0.96(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，br s)，4.05(3H，s)，4.40(2H，q)，5.61(1H，br s)，7.61(1H，d)，7.65(1H，br s)，7.90(1H，dd)，8.62(1H，d)9.25(1H，br s)。

Preparation 5

2-Ethoxybenzoic acid methyl ester

Concentrated sulfuric acid (0.5ml) was added to a solution of 2-ethoxybenzoic acid (50g, 0.301mol) in methanol (500ml) and the resulting mixture was heated under reflux for 70 hours, then evaporated under reduced pressure to give an oil which was dissolved in dichloromethane (300 ml). The solution was washed successively with water (150ml), an aqueous sodium hydrogencarbonate solution (150ml) and water (150ml), and then evaporated under reduced pressure to give the title compound (49.7g) as an oil. Delta (CDCl)₃)：1.44(3H，t)，3.90(3H，s)，4.12(2H，q)，6.95(2H，m)，7.44(1H，t)，7.78(1H，d)。

Preparation 6

5-Chlorosulfonyl-2-ethoxybenzoic acid methyl ester

The title compound of preparation 5 (36.04g, 0.20mol) was added dropwise to ice-cooled chlorosulfonic acid (59.8ml, 0.90mol) over 10 minutes while maintaining the temperature of the reaction mixture below 22 ℃ with stirring. The reaction mixture was stirred at room temperature for 18 hours, then thionyl chloride (14.6ml, 0.20mol) was added and the resulting solution was stirred at room temperature for 6 hours, thenIt was poured into a stirred mixture of ice (530g) and water (120 ml). The mixture was extracted with dichloromethane (2X 200ml) and the combined extracts evaporated under reduced pressure to give the crude title compound as a white solid (44.87 g). Crystallizing with toluene to obtain standard sample at m.p.99-100 deg.C. Delta (CDCl)₃)：1.52(3H，t)，3.93(3H，s)，4.25(2H，q)，7.12(1H，d)，8.12(1H，dd)，8.46(1H，d)。

Preparation 7

2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) benzoic acid methyl ester

A solution of the crude compound of preparation 6 (27.87g) in acetone (140ml) was added dropwise over 10 minutes to a solution of 1-methylpiperazine (11.02g, 0.11mol) and triethylamine (15.3ml, 0.11mol) in acetone (140ml) cooled in an ice bath, while maintaining the temperature of the reaction mixture below 20 ℃ with stirring. A white precipitate formed during the addition and stirring was continued for 4 hours. The resulting mixture was filtered, the filtrate evaporated under reduced pressure and the residue azeotroped with toluene to give a light brown gum (41.9 g). The crude product was granulated with water (100ml) under stirring for 2 hours and the resulting material collected by filtration, washed with water (2X 50ml) and dried under vacuum at 50 ℃ to give the title compound, m.p.110-111 ℃. Delta (CDCl)₃)：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)。

It was confirmed that the compound obtained by the above method was the same as the compound obtained by the conventional methyl esterification reaction using the title compound of preparation 2.

Further, the compound prepared above can give the same product as the compound of preparation 2 by conventional alkaline hydrolysis.

Claims (1)

1. A compound of structural formula (V):

or a hydrochloric acid-triethylamine double salt thereof, or C thereof₁-C₄An alkyl ester.