FIELD OF THE INVENTION
The present invention relates to a process for the preparation of bumetanide providing bumetanide essentially free of genotoxic impurities preferably nitrosamine impurities.
BACKGROUND OF THE INVENTION
Bumetanide is a potent loop diuretic of sulphamyl category and chemically known as 3-(butylamino)-4-phenoxy-5-sulfamoylbenzoic acid of formula (I):

Formula I
Bumetanide is indicated for for the treatment of edema associated with congestive heart failure, hepatic and renal disease, including the nephrotic syndrome.
Bumetanide was first disclosed in U.S. Patent No. 3,806,534 as free acid and its sodium salt. The patent discloses a process for the preparation of bumetanide starting from 4-chloro-3-nitro-5-sulfamoyl benzoic acid, which is reacted with phenol in basic conditions to obtain 3-nitro-4-phenoxy-5-sulfamoyl benzoic acid. The nitro compound is further reduced using catalytic hydrogenation process in presence of base to obtain 3-amino-4-phenoxy-5-sulfamoyl benzoic acid, the amino compound so formed is then treated with butanol in the presence of sulphuric acid followed by basification to obtain sodium salt of bumetanide which is treated with hydrochloric acid to obtain bumetanide. The process disclosed as per publication involves use of corrosive sulfuric acid as catalyst for N-alkylation to obtain bumetanide by using complicated dehydration equipment. Also, the reaction time is long which makes the process unsuitable for industrial application.

U.S. Patent No. 3,991,097 discloses process for the preparation of bumetanide involving reaction of alkyl 3-amino-4-phenoxy-5-sulfamoyl benzoate with butyric acid chloride in organic solvent and a base, the amido-ester derivative of bumetanide so obtained is reduced in presence of alkali metal boronates and Lewis acid to obtain bumetanide esters which are subsequently hydrolysed to bumetanide. The disclosed process involves use of diethylene-glycol dimethyl ether for reaction, which is not preferred for use at industrial levels due to its toxic nature.
CN101591276A discloses a method for synthesizing bumetanide by using 3-amino-4-phenoxy-5-sulfonamide benzoic acid and n-butyraldehyde as raw materials in the presence of boron trihalide etherate. However, the reaction process is complicated, and the steps are cumbersome and uses reagents/solvents which are prone to formation of undesirable nitrosamine impurities.
Despite the progress in the manufacturing operations for preparation of bumetanide and various controls applied to make the drugs acceptable for human consumption as per laid down guidelines of drug authorities' world over, the recent alarming situation has gripped the pharmaceutical industry manufacturing to have efficient in-process controls in place for the preparation of active pharmaceutical ingredients essentially free of genotoxic impurities, preferably nitrosamine impurities.
The processes disclosed in the prior art fail to provide the control of undesirable genotoxic nitrosamine impurities. Consequently, there is a need for an improved manufacturing process for the preparation of bumetanide, which is simple, environment friendly, economically viable and industrially feasible for the preparation of bumetanide with essential control on nitrosamine impurity levels.
OBJECT AND SUMMARY OF THE INVENTION
The principal object of the present invention is to overcome or alleviate at least one of the deficiencies of prior art and provide a useful alternative for the preparation of bumetanide suitable for human consumption.

It is another object of the present invention to provide a simple, economic and efficient
process for the preparation of bumetanide essentially free of nitrosamines, wherein
nitrosamine is selected from the group comprising of N-nitrosobumetanide, N-
Nitrosodimethylamine, N-Nitrosodiethylamine, N-Nitrosodiisopropylamine
(NDIPA/DIPNA), N-Nitrosoethylisopropylamine (EIPNA), N-Nitrosomethylethylamine (NMEA), N-Nitrosodipropylamine (NPDA), N-Nitrosodibutylamine (NBDA), N-Nitrosomethyldodecylamine, N-Nitroso-N-methyl-N-tetradecylamine, N-Nitroso-N-methyl-4-fluoroaniline, N-Nitroso-N-methyl-N-(2-phenyl) ethylamine, (4-(methyl) (nitroso) amino) butanoic acid and other nitrosamines.
DESCRIPTION OF THE INVENTION
While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.
Nitrosamines are potent carcinogens in animals and probable carcinogens in humans and nitrosamines and their precursors can be potentially found out throughout a manufacturing process such as in contaminated raw material/intermediates used in the manufacturing process; use of recovered solvents and recovered catalysts which are not subjected to adequate removal of amine contaminants. Importantly, the most probable reason during a manufacturing process is the interaction of secondary amines/tertiary amines with nitrite in acidic conditions. ICH M7 (The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use) recommends that these mutagenic carcinogens should be essentially controlled below the acceptable cancer risk level, by selecting the manufacturing process, which have essential control in minimizing or/and complete removal of undesirable nitrosamine impurities to ensure safety of prepared bumetanide for human consumption.
In light of prior art, the bumetanide having chemical structure of Formula I wherein the structure contains a secondary amine, which is prone to the formation of known nitrosamine impurities and specifically including N-nitrosobumetanide of Formula V,

which is exclusive for bumetanide. The prior art disclosure fails to provide any effective technique to control the formation of undesirable known nitrosamine impurities and N-nitrosobumetanide during preparation of bumetanide. Thus, there is an unmet need in the art for the development of an advantageous process for the preparation of bumetanide providing bumetanide essentially free of nitrosamines, which is provided herein in the present invention.


S02NH2 Formula V The present invention relates to a process for preparing bumetanide of formula I,

S02NH2

Formula I
comprising the steps of:
(a) reacting compound of Formula II with phenol and its salt to obtain compound of Formula III;

COOR
COOR

H2N02S y N02 H2N02S" ^f ^N02
C1 OPh
Formula II Formula III

R = H, alkyl
(b) reducing compound of Formula III to compound of Formula IV in absence of
base; and
COOR
A
H2NO2S'''Y:::NH2
OPh Formula IV
(c) reacting compound of Formula IV with N-butylating agent in absence of base
wherein the bumetanide obtained is having nitrosamines less than 0.01 ppm.
According to the present invention, wherein the solvent used is selected from the group comprising of nitriles, alcohols, ketones, esters, halogenated hydrocarbons, ethers, amides, dialkylsulfoxides, sulfolane, water and mixtures thereof, which are further selected from the group comprising of acetonitrile, propionitrile, butyronitrile, valeronitrile, methanol, ethanol, n-propanol, isopropanol, n-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, dichloromethane (DCM), chloroform, dichloroethane, chlorobenzene, diethyl ether, methyl tert-butyl ether (MTBE), diisopropyl ether, tetrahydrofuran (THF), dioxane, dimethylsulfoxide, diethylsulfoxide, dibutylsulfoxide, pentane, hexane, heptane, octane, cyclohexane, cyclopentane, toluene and xylene, water and mixtures thereof.
According to the present invention, the salt of phenol used is selected from the group comprising of sodium, potassium and the like.
According to the present invention, alkyl is selected from the group comprising of branched and straight chain Ci-Cs alkyl group.
According to present invention, the reducing agent used is selected from the group comprising of palladium-carbon, palladium hydroxide-carbon, platinum oxide, rhodium on

carbon, Raney nickel and the like in presence of hydrogen or hydrogen generating source selected from the group comprising of ammonium formate, hydrazine hydrate and the like; metallic reducing agents selected from the group comprising of iron, zinc, tin and the like in presence of acid. The reductive amination reaction is carried out at a temperature of about 25-70 °C for about 4-8 hours under hydrogen pressure of about 2-8 kg/m2. The compound of formula IV obtained as a result of reduction is optionally used as such without isolation in next step.
According to present invention, the N-butylating agent used is selected from the group comprising of butanol, butyryl chloride, butyraldehyde and the like. The N-butylation reaction is preferably carried out is carried out at a temperature of about 25-70 °C for about 4-8 hours under hydrogen pressure of about 2-8 kg/cm2. The N-butylating agent is used in mole equivalents of 1.0 to 3.0, preferably 1.5-2.0 mole equivalents.
According to the present invention, when R = alkyl, the hydrolysis of amino ester compound IV is performed before or after the reaction with N-butylating agent. The hydrolysis reaction is carried out in presence of acid or base.
According to the present invention, the bumetanide is isolated using one or more work-up processes such as extraction, washing, filtration and the like. The bumetanide obtained is then optionally crystallized from suitable organic solvent to get pure bumetanide. The suitable organic solvent for crystallization is selected from the group comprising of alcohols, esters, ketones, hydrocarbon, halogenated hydrocarbons, water or mixtures thereof; particularly methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, fert-butanol, methyl acetate, ethyl acetate, isopropyl acetate, tertiary butyl acetate, acetone, methyl ethyl ketone, hexane, heptane, toluene, xylene, dichloromethane, water or mixtures thereof.
According to another embodiment, the present invention relates to a process for preparing bumetanide of formula I essentially free of nitrosamines,

S02NH2 Formula I
wherein the process comprises of drying compound of formula I in controlled humidity drying conditions.
According to the present invention, the controlled humidity drying condition is comprised of humidity drying conditions with relative humidity up to about 90%.
According to the present invention, the bumetanide of Formula I is subjected to drying to remove solvent under controlled humidity conditions, wherein the relative humidity during drying is up to about 90%. The drying method used is selected from the group comprising of vacuum drying, fluidized bed drying, freeze drying, rotary vacuum drying convection drying and the like as known in the literature. The relative humidity is controlled by using method selected from the group comprising of use of de-humidifier, desiccant dryer method and the like. The drying is carried out at temperature from about room temperature to 200°C, for 1-50 h. The temperature of dryer is increased optionally in stepwise manner, starting from lower temperature range to higher range, by keeping each range of temperature constant for about 1-20 h.
According to another embodiment of the present invention, the source of nitrite/nitrate and any source of secondary amine is tested and appropriately controlled in raw material/reagents/solvents and upstream process during the preparation of bumetanide.
According to the embodiment of the present invention, bumetanide of Formula I used herein can be prepared according to the processes as disclosed in the prior art and processes of present invention.
According to the present invention, the bumetanide of Formula I obtained by process of the present invention being essentially free of nitrosamines are having nitrosamine

impurities well within the specifications prescribed safe for human consumption, preferably nitrosamine impurity is less than 0.01 ppm, wherein the limit of detection is 0.01 ppm.
According to present invention, bumetanide obtained is essentially free of N-nitrosobumetanide of Formula V, preferably N-nitrosobumetanide is less than 0.01 ppm.

V o
^ N
S02NH2 Formula V
Examples
Example 1: Preparation of 3-nitro-4-phenoxy-5-sulfamoylbenzoic acid:
A mixture of 4-chloro-3-nitro-5-sulfamoylbenzoic acid (50 g, 0.1782 mol), sodium phenoxide (82.74 g, 0.713 mol) and dimethylsulphoxide (100 mL) in toluene (500 mL) was stirred for 3-4 h at 80-85 °C. Then the reaction mass was cooled to room temperature and water (600 mL) was added to it. After stirring for 30 min at room temperature the layers were separated and pH of aqueous layer was adjusted to acidic. The reaction mass was stirred for 2 hours and the precipitated solid was filtered dried under vacuum at 50-60 °C to obtain the title compound (42.5 g) as yellow to yellowish solid. HPLC purity 99.5%
Example 2: Preparation of 3-nitro-4-phenoxy-5-sulfamoylbenzoic acid:
A mixture of 4-chloro-3-nitro-5-sulfamoylbenzoic acid (50 g, 0.1782 mol), sodium phenoxide (82.74 g, 0.713 mol) and dimethylsulphoxide (100 mL) in toluene (500 mL) was stirred for 7-8 h at 60-65°C. Then the reaction mass was cooled to room temperature and water (600 mL) was added to it, continued stirring for 30 minutes and layers were separated. The pH of aqueous layer was adjusted to acidic. The reaction mass was stirred

for 2 hours and the precipitated solid was filtered dried under vacuum at 50-60 °C to obtain the title compound (41.5 g) as yellow to yellowish solid. HPLC purity 99.1%.
Example 3: Preparation of 3-nitro-4-phenoxy-5-sulfamoylbenzoic acid:
A mixture of 4-chloro-3-nitro-5-sulfamoylbenzoic acid (10 g, 0.0365 mol), sodium phenoxide (16.54 g, 0.1425 mol) and sulfolane (20 mL) and toluene (100 mL) was stirred for 3-4 h at 80-90°C. Then the reaction mass was cooled to room temperature and water (100 mL) & was added to it. After stirring for 30 min at room temperature the layers were separated. The pH of aqueous layer was adjusted to acidic. The reaction mass was stirred for 2 hours and the precipitated solid was filtered dried under vacuum at 50-60°C to obtain the title compound (7.8 g) as yellow solid. HPLC purity 99.3%
Example 4: Preparation of 3-amino-4-phenoxy-5-sulfamoylbenzoic acid:
A mixture of 3-nitro-4-phenoxy-5-sulfamylbenzoic acid (3.7 g, 0.011 mol), 10% palladium on carbon (0.5 g) and methanol (100 ml) was stirred in an autoclave for 4-5 hours at a hydrogen pressure of 4-5 kg/cm2 at 40-45 °C. After completion of reaction, the reaction mass was filtered. The desired compound was obtained after distillation of solvent from filtrate under vacuum at 45-50°C. The solid was filtered and recrystallized from isopropanol and water to desired product as white color solid (2.69 g) HPLC purity 99.2%.
Example 5: Preparation of 3-amino-4-phenoxy-5-sulfamoylbenzoic acid:
To a solution of 3-nitro-4-phenoxy-5-sulfamylbenzoic acid (30 g, 0.09 mol) in methanol (300 mL), charged Raney Ni (9.0g) at 25-30°C. Stirred the reaction mass under 4-5 kg/cm2 hydrogen gas pressure at ambient temperature for 6-8 hours. On completion of reaction, the reaction mass was filtered. The solid was obtained by distillation of solvent from filtrate under vacuum at 45-50°C, filtration and crystallization from methanol and water as white color solid (24.9 g). HPLC purity 99.2%.

Example 6: Preparation of bumetanide:
A solution of 3-amino-4-phenoxy-5-sulfamoylbenzoic acid (9 g, 0.029 mol) and butyraldehyde (3,2 g, 0.043 mol) was stirred for 30 minutes at room temperature. The reaction mass was subjected to hydrogenation at a hydrogen pressure of 5-6 kg/cm2 at 40-50 °C in presence of 10% palladium on carbon (0.5 g) for 5-6 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and the reaction mass was filtered through hyflo bed. The residual mass after evaporation of filtrate under vacuum at 50-55°C was crystallized from ethanol and water to obtain the desired bumetanide (8.4 g) as white solid. HPLC purity 99.84%
NMDA: Below detection limit (Detection limit 0.01 ppm) NEDA: Below detection limit (Detection limit 0.01 ppm)
Example 7: Preparation of bumetanide:
A mixture of 3-nitro-4-phenoxy-5-sulfamylbenzoic acid (10 g, 0.0296 mol), 10% palladium on carbon (1.0 g) and methanol (150 ml) was stirred in an autoclave for 4-5 hours at a hydrogen pressure of 5-6 kg/cm2 at 40-45°C. After completion of reaction, the reaction mass was cooled to room temperature and butyraldehyde (3 g, 0.0414 mol) was added. The reaction mixture subjected to hydrogenation at a hydrogen pressure of 5-6 kg/cm2 at 40-50°C for 5-6 hours. After completion of the reaction, the reaction mixture, the reaction mass was filtered. The desired compound was obtained after distillation of solvent from filtrate under vacuum and crystallized from ethanol (40 mL) and water (20 mL) to obtain the desired bumetanide (8 g) as white solid. HPLC purity 99.81%.
NMDA: Below detection limit (Detection limit 0.01 ppm) NEDA: Below detection limit (Detection limit 0.01 ppm)

Example 8: Preparation of bumetanide:
A mixture of 3-nitro-4-phenoxy-5-sulfamylbenzoic acid (10 g, 0.0296 mol), 10% palladium on carbon (1.0 g) and methanol (150 ml) was stirred in an autoclave for 4-5 hours at a hydrogen pressure of 5-6 kg/cm2 at 40-45°C. After completion of reaction, the reaction mass was cooled to room temperature and butyraldehyde (3 g, 0.0414 mol) was added. The reaction mixture subjected to hydrogenation at a hydrogen pressure of 5-6 kg/cm2 at 40-50°C for 5-6 hours. After completion of the reaction, the reaction mixture, the reaction mass was filtered. The desired compound was obtained after distillation of solvent from filtrate under vacuum and crystallized from ethanol (40 mL) and water (20 mL) to obtain the desired bumetanide (8 g) as white solid. The solid was is dried under relative humidity of up to 90% by varying temperature from room temperature to 150°C for about 5-35 h. HPLC purity 99.81%.
NMDA: Below detection limit (Detection limit 0.01 ppm) NEDA: Below detection limit (Detection limit 0.01 ppm)

We claim:

1. A process for preparing bumetanide of formula I,

S02NH2
Formula I
comprising the steps of:
a) reacting compound of Formula II with phenol and its salt to obtain compound of Formula III;

COOR
COOR

H2N02S y N02 CI
Formula II
R = H, alkyl

H2NO2S y NO2
OPh Formula III

b) reducing compound of Formula III to compound of Formula IV in the absence of base; and

COOR
H2NO2S y NH2
OPh
Formula IV

c) reacting compound of Formula IV with N-butylating agent in the absence of base;
wherein bumetanide obtained is having nitrosamines less than 0.01 ppm.

2. The process as claimed in claim 1, wherein when R = alkyl, hydrolysis reaction of ester is performed before or after reaction with N-butylating agent.
3. The process as claimed in claim 2, wherein the process for preparation of bumetanide is comprising the steps of:

(a) reacting 4-chloro-3-nitro-5-sulfamoyl benzoic acid with phenol or its salts to obtain 3-nitro-4-phenoxy-5-sulfamoyl benzoic acid;
(b) reducing 3-nitro-4-phenoxy-5-sulfamoyl benzoic acid to 3-amnio-4-phenoxy-5-sulfamoyl benzoic acid in absence of base;
(c) reacting 3-amnio-4-phenoxy-5-sulfamoyl benzoic acid with N-butylating agent in absence of base to obtain bumetanide;
wherein bumetanide obtained is having nitrosamines less than 0.01 ppm.
4. The process as claimed in preceding claims, wherein N-butylating agent is selected from the group comprising of butanol, butyraldehyde and butyryl chloride.
5. The process as claimed in preceding claims, wherein N-butylating agent is used in 1.0 to 3.0 mole equivalents.
6. A process for preparing bumetanide of formula I,
S02NH2 Formula I wherein the process comprises of drying compound of formula I in controlled humidity drying conditions and bumetanide obtained is having nitrosamines less than 0.01 ppm.

7. The process as claimed in claims 1 to 6, wherein bumetanide obtained is having N-nitrosobumetanide of Formula V less than 0.01 ppm.

SO,NH,
Formula V