INTRODUCTION

One aspect of the present invention relates to a process for the preparation of
vardenafil and pharmaceutically acceptable salts thereof. More specifically it relates to a
process for preparing vardenafil hydrochloride trihydrate having low concentrations of
impurities. Vardenafil hydrochloride trihydrate is described chemically as 2-[2-ethoxy-5-
(4-ethyl-piperazine-l-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo [5,1-
fJ[l,2,4]triazin-4-one hydrochloride trihydrate and is structurally represented by formula I.

Formula I

Vardenafil hydrochloride is useful in the treatment of erectile dysfunction. It is commercially available in the market under the brand name Levitra® as capsules containing the 2.5, 5, 10 and 20 mg equivalent of vardenafil hydrochloride for oral administration. U.S. Patent No. 6,362,178 Bl describes the preparation of vardenafil and its hydrochloride salt.

The provision of a process for synthesis of the vardenafil hydrochloride in a pure form would address a much-felt need for the commercialization of this pharmaceutically important substance. The present invention thus provides a process for the synthesis of a pure vardenafil hydrochloride of formula I, which is substantially free of process and structural related impurities. The process of the present invention is simple, non-hazardous, and easily scalable for commercial production. The present invention is free from the technical problems associated with prior art, and is also cost effective, commercially viable, and well suited for industrial scale up.

SUMMARY

In one aspect, the present invention relates to a process for the preparation of vardenafil hydrochloride of formula I, which process comprises the steps of:

a) reaction of 2-ethoxy benzamidine hydrochloride of formula V with hydrazine hydrate in the presence of a suitable solvent to give 2-ethoxybenzohydrazonamide of formula XI, (which is optionally isolated);

Formula XI

b) 2-ethoxybenzohydrazonamide of formula XI can be further reacted with 3-
butyramido-l-ethoxy-l-oxobut-2-en-2-yl ethyl oxalate of formula VI in presence
of phosphorous trichloride and suitable organic solvent under suitable conditions
to afford 2-(2-ethoxy-phenyl)-5-methyl-7-propyl-3H-imidazo-[5,l-
fj[l,2,4]triazin-4-one of formula IV;

Formula IV

c) reaction of 2-(2-ethoxy-phenyl)-5-methyl-7-propyl-3H-imidazo-[5,l-
f][l,2,4]triazin-4-one of formula IV with chlorosulfonic acid afford the compound
4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydor-imidazo-[5,l-fJ[l,2,4]triazin-2-
yl)benzene sulfonyl chloride of formula III;

Formula III

d) condensation of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydor-imidazo-[5,l-
f][l,2,4]triazin-2-yl)benzene sulfonyl chloride of formula III with 1-ethyl-
piperazine in presence of suitable organic solvent to afford 2-[2-ethoxy-5-(4- ethyl-piperazine-1 -sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo [5,1 -f| [ 1,2,4] triazin-4-one of formula II;

Formula II

e) reaction of 2-[2-ethoxy-5-(4-ethyl-piperazine-l-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo [5,l-fJ[l,2,4] triazin-4-one with hydrochloric acid in presence of suitable organic solvents to afford 2-[2-ethoxy-5-(4-ethyl-piperazine-l-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,l-f][l,2,4]triazin-4-one hydrochloride trihydrate of formula I.

Formula I

In another aspect of the present invention relates to a process for the preparation of 2-ethoxybenzohydrazonamide of formula XI, which is a key intermediate for the preparation of vardenafil hydrochloride of formula I comprises the steps of:

a) reaction of 2-hydroxy benzonitrile of formula XII with diethyl sulfate in presence of suitable base and solvents to give the compound 2-ethoxybenzontirile of formula XVII

b) reaction of 2-ethoxy benzonitrile of formula XVII with hydroxylamine
hydrochloride in presence of suitable base and solvents to afford the compound 2-
ethoxy-N-hydroxy benzamidine of formula X;

Formula X

c) reduction of 2-ethoxy-N-hydroxy benzamidine of formula X with suitable
reducing agent in the presence of solvents under suitable reaction conditions to
afford the compound 2-ethoxy benzamidine hydrochloride of formula V;

Formula V

d) reaction of the 2-ethoxy benzamidine hydrochloride of formula V with hydrazine
hydrate in presence of suitable solvents to afford the 2-
ethoxybenzohydrazonamide of formula XI (which is optionally isolated).

Formula XI

In another aspect the present invention relates to a process for the preparation of 3-butyramido-l-ethoxy-l-oxobut-2-en-2-yl ethyl oxalate of formula VI, which is a key intermediate for the preparation of vardenafil hydrochloride of formula I comprising the steps of:

a) condensation of DL-alanine of formula IX with butyryl chloride of formula VIII in presence of suitable aqueous base and suitable solvents to afford the compound 2-butyrylamino propionic acid of formula VII;

rormula VII b) reaction 2-butyrylamino propionic acid of formula VII with ethyl oxalyl chloride in presence of suitable base and solvents to afford the compound 3-butyramido-l-ethoxy-l-oxobut-2-en-2-yl ethyl oxalate of formula VI;

Formula VI

The process of present invention is simple, improved, cost effective, eco-friendly, and reproducible and affords higher yield and purity of the final compound and is well suited on an industrial scale.

DETAILED DESCRIPTION

The present invention relates to an improved process for the preparation of vardenafil hydrochloride of formula I.

In one aspect, the present invention relates to a process for the preparation of vardenafil hydrochloride of formula I, which process comprises the steps of:

a) reaction of 2-ethoxy benzamidine hydrochloride of formula V with hydrazine hydrate in the presence of methanol solvent to give 2-ethoxybenzohydrazonamide of formula XI (which is optionally isolated);

Formula XI

b) 2-ethoxybenzohydrazonamide of formula XI can further reacted with 3-
butyramido-l-ethoxy-l-oxobut-2-en-2-yl ethyl oxalate of Formula VI in presence of phosphorous trichloride and suitable organic solvent under suitable conditions to afford 2-(2-ethoxy-phenyl)-5-methyl-7-propyl-3H-imidazo-[5,l-
f][l,2,4]triazin-4-one of Formula IV.

Formula IV

Suitably addition of 2-butyrylamino-l-ethoxycarbonyl propenyl ethyl oxalate solution with 2-ethoxybenzohydrazonamide is carried out slowly to control the exothermicity of the reaction and maintain the temperature of the reaction medium below about 10 °C to below about 0°C, as an increase in the temperature will cause the formation of side products and process related impurities. Suitable temperatures for conducting the reaction can range from about 10°C to about 80°C or for about 60°C to about 65°C and the suitable time for the completion of the reaction can range from about 30 minutes to about 5 hours or for about 3 hours to 4 hours.

Suitable organic solvents that can be used in this reaction include but are not limited to alcohols such as methanol, ethanol, isopropyl alcohol, n-butanol and the like; ketone solvents such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, t-butyl acetate and the like; or mixtures thereof in various proportions without limitation.

c) reaction of 2-(2-ethoxy-phenyl)-5-methyl-7-propyl-3H-imidazo-[5,l- f][l,2,4]triazin-4-one of Formula IV with chlorosulfonic acid to afford the
compound 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[l,5-
fJ[l,2,4]triazin-2-yl)benzene-l-sulfonyl chloride of Formula III.

Formula III

Suitable temperature for addition of 2-(2-ethoxy-phenyl)-5-methyl-7-propyl-3H-imidazo-[5,l-f][l,2,4]triazin-4-one with chlorosulfonic acid can range from 0°C to 20°C, or about 0°C to about 5°C; and the suitable temperatures for conducting the reaction can range from about 10°C to about 50°C or for about 20°C to about 30°C.

d) condensation of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo-[5,l-
fJ[l,2,4]triazin-2-yl)benzene sulfonyl chloride of formula III with 1-ethyl-
piperazine in presence of suitable organic solvent to afford 2-[2-ethoxy-5-(4-
ethyl-piperazine-1 -sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo [5,1 -f][ 1,2,4]
triazin-4-one of formula II.

Formula II

Suitable temperature for addition of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo-[5,l-f][l,2,4]triazin-2-yl)benzene sulfonyl chloride with 1-ethyl-piperazine in this step can range from 0°C to 20°C, or about 0°C to about 5°C and the suitable temperatures for conducting the reaction can range from about 10°C to about 50°C or for about 20 to about 30°C.

e) reaction of 2-[2-ethoxy-5-(4-ethyl-piperazine-1 -sulfonyl)-phenyl]-5-methyl-7-
propyl-3H-imidazo[5,l-f][l,2,4]triazin-4-one with hydrochloric acid in presence
of suitable organic solvents to afford 2-[2-ethoxy-5-(4-ethyl-piperazine-l-
sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1 -f] [ 1,2,4]triazin-4-one
hydrochloride trihydrate of Formula I.

Formula I

Suitable organic solvents that can be used in this reaction include but are not limited to alcohols such as methanol, ethanol, isopropyl alcohol, n-butanol and the like; ketone solvents such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, t-butyl acetate and the like; or mixtures thereof or their combination with water in various proportions without limitation.

In another aspect of the present invention relates to a process for the preparation of 2-ethoxybenzohydrazonamide of formula XI, which is a key intermediate for the preparation of vardenafil hydrochloride of Formula I comprising the steps of:
a) reaction of 2-hydroxy benzonitrile of formula XII with diethyl sulfate in presence
of suitable base and solvents to afford the compound 2-ethoxybenzontirile of
formula XVII;

Formula XII

Formula XVII

Suitable base include but are not limited to organic bases such as methylamine,
dimethylamine, triethylamine, ethyldiisopropylamine, butylamine and the like; inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium
carbonate, sodium bicarbonate, potassium bicarbonate and the like. Suitable organic solvents in step, which can be used to dissolve the 2-hydroxy benzonitrile include, but are not limited to alcohols such as methanol, ethanol, isopropyl alcohol, n-butanol and the like; ketone solvents such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; or mixtures thereof or their combination with water in various proportions.

b) reaction of 2-ethoxy benzonitrile of formula XVII with hydroxylamine
hydrochloride in presence of suitable base and solvents to afford the compound 2-
ethoxy-N'-hydroxybenzimidamide of formula X

Formula X

Suitable base that can be used include but are not limited to organic bases such as methylamine, dimethylamine, triethylamine, ethyldiisopropylamine, butylamine and the like; inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like. Suitable organic solvents that can be used in step include but are not limited to alcohols such as methanol, ethanol, isopropyl alcohol, n-butanol and the like; ketone solvents such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, t-butyl acetate and the like or mixtures thereof in various proportions without limitation.

Suitable temperatures for conducting the reaction can range from about 10°C to about 100°C or for about 80°C to about 90°C. The suitable time for the completion of the reaction can range from about 30 minutes to about 12 hours or for about 8 hours to about 9 hours.

c) reduction of 2-ethoxy-N-hydroxy benzamidine of formula X with suitable
reducing agent in the presence of suitable solvents to afford the compound 2-
ethoxy benzamidine hydrochloride of formula V.

Formula V

Suitable reducing agents that can be used include but are not limited to hydrogen in the presence of the catalysts Raney nickel™, palladium on carbon, platinum dioxide or the like. The suitable hydrogen pressure can range from 2 to 5 kg/cm and the temperature from about 0-35°C for the conversion of the compound of formula X to the compound of formula V. Suitable temperatures for conducting the reaction can range from about 30°C to about 80°C or for about 50°C to about 55°C. The suitable time for completion of the reaction can range from about 1 hour to about 6 hours or for about 4 hour to 5 hour.

d) reaction of the 2-ethoxy benzamidine hydrochloride of formula V with hydrazine hydrate in presence of suitable solvents under suitable reaction conditions to afford the 2-ethoxybenzohydrazonamide of formula XI (which is optionally isolated).

Formula XI

Suitable solvents that can be used include but are not limited to alcohols such as methanol, ethanol, isopropyl alcohol, n-butanol and the like; ketone solvents such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, t-butyl acetate and the like; Suitable temperature for addition of hydrazine hydrate can range from 0°C to 20°C, or about 0°C to about 5°C as an increase in the temperature and time will cause the formation of side products and process related impurities.

In another aspect of the present invention relates to a process for the preparation of 3-butyramido-l-ethoxy-l-oxobut-2-en-2-yl ethyl oxalate of formula VI, which is a key
intermediate for the preparation of vardenafil hydrochloride of formula I comprising the steps of:

a) condensation of DL-alanine of formula IX with butyryl chloride of formula VIII
in presence of suitable aqueous base and suitable solvents to afford the compound 2-butyrylamino propionic acid of formula VII.

Formula VII

Suitable aqueous bases that can be used in this step include but are not limited to inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like. Suitable temperature for addition of butyryl chloride can range from 0°C to 20°C, or about 0°C to about 5°C.

b) reaction of 2-butyrylamino propionic acid of formula VII with ethyl oxalyl
chloride in presence of suitable base and suitable solvents to afford the compound
3-butyramido-l-ethoxy-l-oxobut-2-en-2-yl ethyl oxalate of formula VI.

Suitable bases that can be used in this step include but are not limited to organic bases such as pyridine, methylamine, dimethylamine, triethylamine, ethyldiisopropylamine, butylamine and the like. Suitable temperatures for conducting the reaction in this step can range from about 10°C to about 80°C or for about 60°C to about 65°C. The suitable time for the completion of the reaction can range from about 30 minutes to about 5 hours or for about 3 hours to 4 hours.

In yet another embodiment of the present invention, vardenafil hydrochloride trihydrate of formula I substantially free from the potential process related benzoyl impurity 2-[2-ethoxy-5-(4-ethyl-piperazine-1 -sulfonyl)-phenyl]-5-methyl-7-phenyl-3H-imidazo[5,l-f][l,2,4]triazin-4-one of formula XIII at relative retention time (RRT) of about 1.30 as measured by HPLC.

Formula XIII

In yet another embodiment of the present invention, vardenafil hydrochloride trihydrate of formula I compound substantially free from the potential process related dimer impurity bis 2-[2-ethoxy-5-(pierazine-l-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,l-fJ[l,2,4]trazin-4-one of formula XIV at relative retention time of about 1.45 RRT as measured by HPLC.

Formula XIV

In yet another embodiment of the present invention, vardenafil hydrochloride trihydrate of formula I substantially free from the potential process related impurity 2-(2-ethoxy-phenyl)-5-methyl-7-propyl-3H-imidazo[5,l-fJ[l,2,4]trazin-4-one of formula XV at relative retention time of about 1.45 RRT as measured by HPLC.

Formula XV

In yet another embodiment of the present invention, vardenafil hydrochloride trihydrate of formula I substantially free from the potential process related impurity 2-(5-chloro-2-ethoxy-phenyl)-5-methyl-3H-imidazo[5,l-f][l,2,4]triazin-4-one of formula XVI at relative retention time of about 1.46 RRT as measured by HPLC.

Formula XVI

The above-mentioned impurity is analyzed by the high performance liquid chromatography (HPLC) method using water symmetry shield RP-8, 250x4.6 mm, 5. internal columns with the following parameters.

In yet another aspect, the present invention provides a particle size distribution of vardenafil hydrochloride trihydrate of formula I having a D (0.09) particle size of lesser than or equal to 25 microns or about 7 to about 8 microns.

The D10, and D90 values are useful ways for indicating a particle size distribution. D90 refers to at least 90 volume percent of the particles having a size smaller than the said value. Likewise D10 refers to 10 volume percent of the particles having a size smaller than the said value. D50 refers to at least 50 volume percent of the particles having a size smaller than the said value. Methods for determining D10, D50 and D90 include laser diffraction using Malvern equipment.

Vardenafil hydrochloride trihydrate according to the present invention has a D10 less than 100 um or less than 50 um; D50 less than 150 um or less than 100 um; and D90 less than 300 um or less than 200 um. There is no specific lower limit for any of the D values.

In still yet another embodiment of present invention there is provided vardenafil hydrochloride trihydrate substantially free of residual solvents.

Drying can be carried out under reduced pressure until the residual solvents reduce to an amount that is within the limits as specified by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines. As per the guidelines solvent level depends on the type of solvent but is not more than about 5000 ppm, or about 4000 ppm, or about 3000 ppm.

Vardenafil hydrochloride trihydrate of formula I obtained by the present invention has residual solvents; methanol less than or equal to 100 ppm (ICH limit: 3000 ppm); acetone less than or equal to 300 ppm (ICH limit: 5000ppm); dichloromethane: less than or equal to 200 ppm (ICH limit: 600 ppm); acetonitrile: not detected (ICH limit: 410 ppm); toluene; not detected (ICH limit 890 ppm).

The above-mentioned organic volatile impurities are analyzed by the gas chromatography method using the following parameters. Agilent 6890 series GC system, equipped with an FID detector and a split mode injector device. COLUMN: AT-Wax. 30m, ID=0.53mm, film thickness 1.0 um

The vardenafil hydrochloride trihydrate of formula I prepared according to the present invention is substantially free from the process related impurity. Typically the vardenafil hydrochloride trihydrate is of high purity such as at least 99.5 wt %, or at least 99.9 wt % pure. Correspondingly, the level of impurities may be less than about 1 wt %, 0.5 wt %, or 0.1 wt % by high performance liquid chromatography (HPLC).

Having thus described the invention with reference to particular preferred embodiments and illustrative example, those in the art may appreciate modification to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The examples are set for to aid in understanding the invention but are not intended to, and should not be construed to limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary skill in the art and are described in numerous publications. All references mentioned herein are incorporated in their entirety.

The following abbreviations and acronyms are used herein and have the indicated definitions: HPLC is high-pressure liquid chromatography and Ni(Ra) is Raney™ nickel, a sponge-metal catalyst produced when a block of nickel-aluminum alloy is treated with concentrated sodium hydroxide. Raney™ is a registered trademark of W. R. Grace and Company. Hyflow is flux-calcined diatomaceous earth treated with sodium carbonate. Hyflo Super Cel™ is a registered trademark of the Manville Corp.

Representative "pharmaceutically acceptable salts" include but are not limited to, e.g., water-soluble and water-insoluble salts, such as the acetate, aluminum, amsonate
(4,4-diaminostilbene-2,2-disulfonate), benzathine (N,N'-dibenzylethylenediamine),
benzenesulfonate, benzoate, bicarbonate, bismuth, bisulfate, bitartrate, borate, bromide,
butyrate, calcium, calcium edetate, camsylate (camphorsulfonate), carbonate, chloride,
choline, citrate, clavulariate, diethanolamine, dihydrochloride, diphosphate, edetate,
edisylate (camphorsulfonate), esylate (ethanesulfonate), ethylenediamine, fumarate,
gluceptate (glucoheptonate), gluconate, glucuronate, glutamate, hexafluorophosphate,
hexylresorcinate, hydrabamine (N.N'-bis(dehydroabietyl)ethylenediamine),
hydrobromide, hydrochloride, hydroxynaphthoate, l-hydroxy-2-naphthoate, 3-hydroxy-2-naphthoate, iodide, isothionate (2-hydroxyethanesulfonate), lactate, lactobionate, laurate, lauryl sulfate, lithium, magnesium, malate, maleate, mandelate, meglumine (1-deoxy-l-(methylamino)-D-glucitol), mesylate, methyl bromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, palmitate, pamoate (4,4'-methylenebis-3-hydroxy-2-naphthoate, or embonate), pantothenate, phosphate, picrate, polygalacturonate, potassium, propionate, p-toluenesulfonate, salicylate, sodium, stearate, subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate, tartrate, teoclate (8-chloro-3,7-dihydro-l,3-dimethyl-lH-purine-2,6-dione), triethiodide, tromethamine (2-amino-2-(hydroxymethyl)-l,3-propanediol), valerate, and zinc salts.

EXAMPLES

EXAMPLE 1: PREPRATION OF 2-BUTYRYL AMINO PROPIONIC ACID (FORMULA VII)

A 135 g portion of sodium hydroxide and 500 mL of water were charged into a clean and dry 4-neck round bottom flask followed by stirring for about 5 minutes. A 100 g portion of DL-alanine of formula IX was added slowly for about 0-5°C and stirred for about 5 minutes and 178.5 g of butyryl chloride of formula VIII was added slowly by drops for about 30-45 minutes at 0-5°C followed by stirring the reaction solution for about 45-60 minutes at 25-35°C and raise the temperature of the reaction solution to 25-35°C and stirred for about 3-4 hours until completion of the reaction. After completion of the reaction the reaction mass was cooled to 15-20°C and the pH of the reaction solution was adjusted to 1-2 by addition of 160 mL hydrochloric acid. A 1500 mL portion of ethyl acetate was added to the reaction solution and stirred for about 5-10 minutes. The organic and aqueous layers of the above solution were separated, the organic layer evaporated completely under vacuum to afford the crude product. To the resulting crude product, a 750 mL portion of cyclohexane was added and stirred at 20-30°C for about 1-2 hours as a solid separated. The separated solid was collected by filtration and washed with a 250 mL portion of cyclohexane and dried on the filter for about 10-15 minutes. The resulting solid was further dried under vacuum at 40-45°C to afford the 163.5 g of title compound. HPLC Purity: 99.87%.

EXAMPLE 2: PREPRATION OF 3-BUTYRAMIDO-1-ETHOXY-1-OXOBUT-2-EN-2-YL ETHYL OXALATE (FORMULA VI)

A 200 g portion of 2-butyrylamino propionic acid of formula VII, 6.5 g of dimethylaminopyridine, and 195 mL of pyridine was charged into a clean, dry, round-bottom flask containing 650 mL of toluene and stirred for about 10-15 minutes. The resulting reaction solution was cooled to about 0-5°C and 195 mL of ethyl oxalyl chloride was added into the reaction solution slowly by drops for about 4-5 hours and stirred for about 20-30 minutes at 20-30°C. The resulting reaction mass was heated to about 80-85°C and stirred for about 3-4 hours. After completion of the reaction, the reaction mass was cooled to about 25-30°C, water (100 mL) was added to the reaction mass, stirred for 10-15 minutes at 25-30°C, the organic and aqueous layers separated, and the organic layer was washed with (2X 1000 mL) water. The resulting neat organic layer was dried with sodium sulfate 10 g portion and evaporated completed by distillation under vacuum at 70-80°C to afford 231.5 g of the title compound. HPLC Purity: 99.87%

EXAMPLE 3: PREPRATION OF 2-ETHOXYBENZONITRILE (FORMULA XI)

A 100 g portion of 2-hydroxy benzonitrile of formula XII was charged into a clean, dry, round-bottom flask containing 1000 mL of isopropyl alcohol, stirred for about 10-15 minutes, 171 g of potassium carbonate was added into the reaction solution, and stirred for about 10-15 minutes. To the reaction mixture 111 mL of diethyl sulfate was added slowly by drops over about 20-30 minutes and stirred for about 7-8 hours at 30-35°C until completion of the reaction. The unwanted solid was removed by filtration, and the solid washed with isopropyl alcohol (40 mL). The resulting clear filtrate was removed completely under vacuum at 70-80°C to afford the 120 g of the crude title compound.

EXAMPLE 4; PREPARATION OF 2-ETHOXY BENZONITRILE (FORMULA X)

A 100 g portion of 2-ethoxy benzonitrile of formula XVII was charged in to a clean, dry, round-bottom flask containing 1000 mL of isopropyl alcohol and stirred for about 10-15 minutes, 140 g of potassium carbonate was added, and the resulting mixture stirred for about 10-15 minutes at 25-30°C. To the resulting reaction mixture 116 g of hydroxylamine hydrochloride was added, heated to about 80-85°C, and stirred for about 15-17 hours until completion of the reaction. After completion of the reaction, an unwanted solid was removed by filtration and washed with 200 mL of isopropyl alcohol. The resulting clear filtrate was evaporated up to 30 % under vacuum, the reaction mass cooled to 20-25°C, and stirred for 60-90 minutes. The separated solid was collected by filtration and washed with 100 mL isopropyl alcohol. The resulting solid was dried under vacuum at 40-45 °C for 2-3 hours to afford 93 g of the title compound.

EXAMPLE 5; PREPARATION OF 2-ETHOXY BENZAMINDINE HYDROCHLORIDE (FORMULA V)

A 80 g portion of 2-ethoxy-N-hydroxy benzamidine of formula X was charged into a hydrogenation apparatus containing 800 mL acetic acid and 80 g of wet palladium on carbon. The resulting reaction mixture was maintained at about 4-5 kg/cm hydrogen pressure for about 7-8 hours at 30-60°C until completion of the reaction. To the resulting filtrate, concentrated hydrochloric acid (67 mL) was added, and removed completely by distillation under vacuum below 80°C. The resultant crude was cooled to 20-30°C and 400 mL of toluene was added and stirred for solid separation for about 30-45 minutes. The separated solid was filtered and washed the solid with toluene 80 mL and dried under vacuum for about 40-45°C for 2-3 hours to afford 84.2 g of the title compound.

EXAMPLE 6; PREPARATION OF 2-(2-ETHOXY-PHENYL)-5-METHYL-7-
PROPYL-3H-IMIDAZO-[5,l-F][l,2,4]TRAZIN-4-ONE (FORMULA IV)

A 100 g portion of 2-ethoxy benzamidine hydrochloride of formula V was changed into a clean, dry, round-bottom flask containing 400 mL methanol and stirred for about 15-20 minutes at 25-30°C. To the resulting reaction solution hydrazine hydrate 33.3 mL was added slowly by drops for about 20-30 minutes at 20-30°C and stirred for about 1-2 hours at 20-30°C and 220 g of 3-butyramido-l-ethoxy-l-oxobut-2-en-2-yl ethyl oxalate compound of formula VI was added slowly into the reaction mass and heated to about 60-65 °C and stirred for 3-4 hours until completion of the reaction. After completion of the reaction, the volatiles were removed completely under vacuum to obtain the crude product. To the resultant crude product, toluene (2X 400 mL) was added and removed again completely under vacuum to afford crude IV.

The resulting crude was cooled to 25-30°C, phosphorous trichloride (56 mL) was added, heated to about 80-85°C, and stirred for 3-4 hours until completion of the reaction. After completion of the reaction, the reaction mass was removed completely under vacuum below 80°C, the crude product was cooled to 20-30°C, dichloromethane 500 mL was added, the pH of the reaction mass adjusted to 8-8.5 by addition of lye at 20-30°C, stirred for 15-20 minutes, and the resulting organic and aqueous layers separated. The aqueous layer resulting was washed with dichloromethane (75 mL), the combined organic phases were distilled under vacuum below 40°C to obtain the crude title compound.

The resulting crude compound was charged in to a clean, dry, round-bottom flask contain acetonitrile (600 mL), stirred for 10-15 minutes, heated to about 80-85°C for about 20-30 minutes, cooled to 0-5°C, and stirred until a solid separated. The separated solid collected by filtration and washed with acetonitrile (100 mL) to afford the title compound as a solid. The resulting solid was dried under vacuum at 40-45 °C for 2-3 hours to afford 72 g of the title compound.

EXAMPLE 7: PURIFICATION OF 2-(2-ETHOXY-PHENYL)-5-METHYL-7-PROPYL-3H-IMIDAZO-[5,l-F][l,2,4]TRAZIN-4-ONE (FORMULA IV)

A 20 g portion of 2-(2-ethoxy-phenyl)-5-methyl-7-propyl-3h-imidazo-[5,l-f][l,2,4]trazin-4-one of formula IV was charged into a clean, dry, round-bottom flask containing 200 mL of water, stirred for 5-10 minutes at 25-30°C, the pH of the reaction mass was adjusted to 13-13.5 by addition of lye (20 mL) at 25-30°C, heated to about 60-65°C, and stirred for 1-2 hours. The resulting reaction solutions were filtered through a Hyflow bed and the Hyflow bed was washed with water (20 mL).

The resulting reaction solution was charged into a clean, dry, round-bottom flask, cooled to 25-35°C, the pH of the reaction solution was adjusted to 10-10.5 by addition of concentrated HC1, and stirred for 45-60 minutes until a solid separated. The separated solid was collected bv filtration, washed with water (20 mL). and suction dried for 10
minutes. The resulting solid was further dried under vacuum at 60-65 °C until moisture content was less than 0.5%.

EXAMPLE 8; PREPARATION OF 4-ETHOXY-3(5-METHYL-4-OXO-7-PROPYL-
3,4-DIHYDRO-IMIDAZO[5,1 -F] [ 1,2,4]TRIAZIN-2-YL)BENZENE SULFONYL
CHLORIDE FORMULA (III)

A 20 g portion of 2-(2-ethoxy-phenyl)-5-methyl-7-propyl-3h-imidazo-[5,l-f][l,2,4]trazin-4-one of formula IV was charged into a clean, dry, round-bottom flask, cooled to 0-10°C, 69.6 g of chlorosulfonic acid was added slowly at 0-10°C, and stirred about 20-30 minutes. The resulting mixture was heated to 20-30°C and stirred for about 2 hours. The resulting reaction mass was cooled to 0-5°C, quenched with 400 mL of water, and extracted dichloromethane (2X 300 mL). The resulting clear organic solution was charged into a clean, dry, round-bottom flask, 14.6 g of N-ethyl-piperazine was added at 20-3 0°C, and stirred for 2 hours until completion of the reaction. The resulting reaction mass was washed with water (3X 100 mL), the organic layer separated, and evaporated completely under vacuum to afford the crude product. To the resulting crude product, 200 mL of 4% aqueous acetone was added and stirred until solid separation. The separated solid was collected by filtration, and washed with 4% aqueous acetone to afford 18.5 g of the title compound.

EXAMPLE 9; PREPARATION OF VARDENAFIL FREE BASE (FORMULA II)

A 60 g portion of 2-(2-ethoxy-phenyl)-5-methyl-7-propyl-3H-imidazo-[5,l-f] triazin-4-one of formula III was charged into a clean, dry, round-bottom flask containing 120 mL of chlorosulfonic acid. The resulting mixture was stirred for 20-30 minutes at 0-5°C, heated to 20-30°C, and stirred for an additional 1-2 hours until completion of the reaction. To the resulting reaction mass, 60 mL of water and 900 mL of dichloromethane were added, stirred for 5-10 minutes, and the organic and aqueous layers separated. The separated aqueous layer was washed with dichloromethane (2X 300 mL), the combined organic phases charged into a fresh dry round bottom flask, 48 mL of N-ethyl piperazine was added slowly by drops over about 20-30 minutes, and the resulting mixture stirred for 60-120 minutes at 20-30°C. After completion of the reaction, the reaction mass was quenched by addition 300 mL of water and stirred for about 10-15 minutes at 25-30°C.

The resulting organic and aqueous layers were separated and the organic layer was
washed with water (2X 300 mL). The combined organic layer was evaporated completely under vacuum below 50°C. To the resulting crude material, acetone (60 mL) was added and removed completely by distillation to remove any traces of N-ethylpiperazine to afford the title compound in crude form.

The resulting crude material was charged a clean, dry, round-bottom flask containing acetone (576 mL) and water (24 mL). The mixture was heated to 55-60°C and stirred for 20-30 minutes. The resulting reaction solution was cooled to about 0-5°C and stirred for solid separation for about 1-2 hours. The separated solid was collected by filtration, washed the solid with acetone (57.6 mL), washed with water (24 mL) dried by suction on the filter for 10-15 minutes, and dried under vacuum at 40-45 °C for 2-3 hours to afford 55.6 g of the title compound.

EXAMPLE 10: PREPRATION OF VARDENAFIL HYDROCHLORIDE TRIHYDRATE (FORMULA I)

A 45 g portion of vardenafil freebase of formula II was charged into a clean, dry, round-bottom flask containing 250 mL acetone and stirred for 10-15 minutes. Concentrated hydrochloric acid (9.2 mL) was added slowly by drops, the resulting mixture stirred for 10-15 minutes, and heated to about 50-55°C for complete dissolution. The resulting reaction solution was passed through cloth to make particle free and the cloth washed with acetone (41.5 mL) and water (2.5 mL). The resulting clear filtrate was charged in to the fresh round-bottom flask, cooled to 0-5°C, and stirred for 1-2 hours for solid separation. The separated solid was collected by filtration, washed the solid with acetone (41.5 mL) and washed with water 3.5 (mL). The resulting solid was dried under vacuum to afford the 47 g of title compound.

Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.

While particular embodiments of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention.

It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

Some intermediates within the present invention possess a chiral center, and the present invention includes each separate enantiomer of such compounds as well as mixtures of the enantiomers. All chiral and racemic forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials.

Some intermediates within the present invention possess double bonds. These double bonds can exist as geometric isomers, and the invention includes both E and Z isomers of such double bonds. All such stable isomers are contemplated in the present invention.

Formula XI Formula V

Scheme 1 represents a process for the preparation of the compound of formula XL

Scheme 2 represents a process for the preparation of the compound of formula VI.

Scheme 3 represents a process for the preparation of the compound of formula I.

We Claim:

1. A process for the preparing vardenafil hydrochloride trihydrate, the process comprising:

a) reacting 2-ethoxy benzamidine hydrochloride of formula V

Formula V with hydrazine hydrate in the presence of suitable organic solvent to give 2-ethoxybenzohydrazonamide of formula XI,

Formula XI

b) reacting the optionally isolated 2-ethoxybenzohydrazonamide of formula XI with
3-butyramido-l-ethoxy-l-oxobut-2-en-2-yl ethyl oxalate of formula VI in
presence of phosphorous trichloride and suitable organic solvent to afford 2-(2-
ethoxy-phenyl)-5 -methyl-7-propyl-3 H-imidazo- [5,1 -fj [ 1,2,4]triazin-4-one of
formula IV;

Formula IV

c) reacting 2-(2-ethoxy-phenyl)-5-methyl-7-propyl-3H-imidazo-[5,l-fJ[l,2,4]triazin-
4-one of formula IV with chlorosulfonic acid to afford 4-ethoxy-3-(5-methyl-4-
oxo-7-propyl-3,4-dihydor-imidazo- [5,1 -f] [ 1,2,4]triazin-2-yl)benzene sulfonyl
chloride of formula HI;

Formula III

d) condensing 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydor-imidazo-[5,l-
f][l,2,4]triazin-2-yl)benzene sulfonyl chloride of formula III with 1-ethyl-
piperazine in presence of a suitable organic solvent to afford 2-[2-ethoxy-5-(4-
ethyl-piperazine-l-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo [5,l-f][l,2,4]
triazin-4-one of formula II;

Formula II

e) reacting 2-[2-ethoxy-5-(4-ethyl-piperazine-1 -sulfonyl)-phenyl]-5-methyl-7- propyl-3H-imidazo [5,l-fJ[l,2,4] triazin-4-one with hydrochloric acid in presence of a suitable organic solvent to afford 2-[2-ethoxy-5-(4-ethyl-piperazine-l- sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,l-fj[l,2,4]triazin-4-one hydrochloride trihydrate of formula I.

2. A process for preparing vardenafil hydrochloride according to claim 1, wherein the suitable organic solvent is selected from a group consisting of alcohols such as methanol, ethanol, isopropyl alcohol, n-butanol and the like; ketone solvents such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, t-butyl acetate and the like; or mixtures thereof.

3. A process for the preparing 2-ethoxybenzohydrazonamide of formula XI, the process comprising:

a) reacting 2-hydroxy benzonitrile of formula XII with diethyl sulfate in presence of
a suitable base and a suitable organic solvent to give the compound 2-
ethoxybenzontirile of formula XVII

Formula XII Formula XVII

b) reacting 2-ethoxy benzonitrile of formula XVII with hydroxylamine
hydrochloride in presence of a suitable base and a suitable organic solvent to
afford the compound 2-ethoxy-N-hydroxy benzamidine of formula X;

Formula X

c) reducing 2-ethoxy-N-hydroxy benzamidine of formula X with suitable reducing
agent in the presence of a suitable organic solvent to afford the compound 2-
ethoxy benzamidine hydrochloride of formula V;

Formula V

d) reacting 2-ethoxy benzamidine hydrochloride of formula V with hydrazine
hydrate in presence of a suitable organic solvent to afford 2-
ethoxybenzohydrazonamide of formula XI.

Formula XI

4. A process for preparing 2-ethoxybenzohydrazonamide of formula XI according to claim 2, wherein the suitable base is selected from methylamine, dimethylamine, triethylamine, ethyldiisopropylamine, butylamine and the like; inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like.

5. A process for preparing 2-ethoxybenzohydrazonamide of formula XI according to claim 2, wherein the suitable organic solvent is selected from a group consisting of alcohols such as methanol, ethanol, isopropyl alcohol, n-butanol and the like; ketone solvents such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, t-butyl acetate and the like; or mixtures thereof.

6. A process for the preparing 3-butyramido-l-ethoxy-l-oxobut-2-en-2-yl ethyl oxalate of formula VI,

Formula VI

the process comprising:
a) condensing DL-alanine of formula IX with butyryl chloride of formula VIII in
presence of a suitable aqueous base and a suitable organic solvent to afford the
compound 2-butyrylamino propionic acid of formula VII;

Formula VII

b) reacting 2-butyrylamino propionic acid of formula VII with ethyl oxalyl chloride
in presence of a suitable base and a suitable organic solvent to afford the compound 3-butyramido-l-ethoxy-l-oxobut-2-en-2-yl ethyl oxalate of formula VI.

7. A process for preparing 3-butyramido-l-ethoxy-l-oxobut-2-en-2-yl ethyl oxalate of formula VI according to claim 6, wherein the suitable aqueous base for the step (a) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, I potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like.

8. A process for preparing 3-butyramido-l-ethoxy-l-oxobut-2-en-2-yl ethyl oxalate of formula VI according to claim 7, wherein the suitable aqueous base is aqueous sodium hydroxide.

9. A process for preparing 3-butyramido-l-ethoxy-l-oxobut-2-en-2-yl ethyl oxalate of formula VI according to claim 6, wherein the suitable base for step (b) is selected from methylamine, dimethylamine, triethylamine, ethyldiisopropylamine, butylamine and the like; inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like.

10. A process for preparing 3-butyramido-l-ethoxy-l-oxobut-2-en-2-yl ethyl oxalate of formula VI according to claim 6, wherein the suitable organic solvent is selected from a group consisting of alcohols such as methanol, ethanol, isopropyl alcohol, n-butanol and the like; ketone solvents such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, t-butyl acetate and the like; or mixtures thereof.