Claims:We Claim:
1) An improved process for the preparation of Temozolomide (I) or its pharmaceutically acceptable salts thereof

comprising the steps of
a. reacting 5-amino-1H-imidazole-4-carboxamide or its salt of formula (II)

with 4-nitrophenylchloroformate of formula (III)

in presence of base and a solvent, wherein the solvent used as a ketone solvent to produce in-situ formation of 5-amino-1-[[4-nitrophenyloxyl]carbomyl]imidazole-4-carboxamide of formula (IV)

b. followed by reacting with mono methyl amine to produce 5-amino-1-(N-methylcarbomyl)imidazole-4-carboxamide of formula (V);

c. cyclization of the compound of formula (V) in presence of sodium nitrate and water followed by organic acid to obtained temozolomide;

2) An improved process for the preparation of Temozolomide (I) as claimed in claim 1, wherein step a) the base is organic or inorganic base; the organic base is selected from the group consisting of methylamine, trimethylamine and triethylamine; inorganic base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate.

3) An improved process for the preparation of Temozolomide (I) as claimed in claim 1, wherein step a) the ketone solvent is selected from acetone, methyl ethyl ketone, diethyl ketone.

4) An improved process for the preparation of Temozolomide (I), wherein process for the preparation of 5-amino-1-(N-methylcarbomyl)imidazole-4-carboxamide of formula (V)

comprising the steps of
a. reacting 5-amino-1H-imidazole-4-carboxamide or its salt of formula (II)

with 4-nitrophenylchloroformate of formula (III)

in presence of base and a solvent, wherein the solvent used as a ketone solvent to produce in-situ formation of 5-amino-1-[[4-nitrophenyloxyl]carbomyl]imidazole-4-carboxamide of formula (IV); and

b. followed by reacting with mono methyl amine to produce 5-amino-1-(N-methylcarbomyl)imidazole-4-carboxamide of formula (V).

5) An improved process for the preparation of Temozolomide (I) as claimed in claim 4, wherein step a) the base is organic or inorganic base; the organic base is selected from the group consisting of methylamine, trimethylamine and triethylamine; inorganic base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate.

6) An improved process for the preparation of Temozolomide (I) as claimed in claim 4, wherein step a) the ketone solvent is selected from acetone, methyl ethyl ketone, diethyl ketone.
, Description:FIELD OF THE INVENTION
The present invention provides an improved process for preparation Temozolomide of Formula I and its pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION
Temozolomide is chemically known as 3,4-dihydro-3-methyl-4-oxoimidazo[5,1d]-as-tetrazine-8-carboxamide. Temozolomide is an alkylating drug indicated for the treatment of adult patients with newly diagnosed glioblastoma multiforme (GBM) concomitantly with radiotherapy and then as maintenance treatment (1.1), refractory anaplastic astrocytoma, patients who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine (1.2) and it is approved under the brand name Temodar®.

Temozolomide is a white to light tan/light pink powder with a molecular formula of C6H6N6O2 and a molecular weight of 194.15. The molecule is stable at acidic pH (<5), and labile at pH >7, hence TEMODAR can be administered orally and intravenously. The prodrug, temozolomide, is rapidly hydrolyzed to the active 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC) at neutral and alkaline pH values, with hydrolysis taking place even faster at alkaline pH.

Temozolomide and its pharmaceutically acceptable salts are anticipated in US5260291 together with compounds of broadly similar activity such as higher alkyl analogs at the 3-position. This patent also discloses a process for the preparation of Temozolomide and its derivatives involving condensation of 5-diazo-5H-imidazole-4-carboxamide with an isocyanate. However, the process described very slow, involving reaction times of up to three weeks.

The process for the preparation of Temozolomide schematically represented as below:

Malcolm et.al in J. Med. Chem. 1984, 27, 196-201 describes a process wherein 5-amino-1H-imidazole-4-carboxamide is converted into 5-diazo-1H-imidazole-4-carboxamide, which is then cyclized with methyl isocyanate in dichloromethane. However, the cycloaddition of Methyl isocyanate (MIC) requires a long reaction time i.e. 20 days and also it is essential to limit dichloromethane content in the final API below 600 ppm as per ICH guideline. However, due to one or more drawbacks with respect to this process carrying high level of impurities. Moreover, the unstable 5-diazo-1H-imidazole-4-carboxamide still has to be isolated in the branch of this process that uses it as an intermediate.

Charan et.al in IN 272907 discloses process for the preparation of Temozolomide comprises the diazotization of 5-amino-4-imidazole-carboxamide in presence of sodium nitrate / HCl and water as solvent at 0-5° C to produce 4-carbamoyl-1H-imidazole-5-diazonium chloride is cyclized with methyl isocyanate in presence of suitable solvent at 20-60° C to produce Temozolomide.

Shen et.al in US 6,844,434 describes a process for the preparation of Temozolomide, wherein, the reaction comprises 5-Amino-1H-imidazole-4-carboxamide.HCl is condensed with 4-nitrophenylchloroformate in the presence of triethylamine and dichloromethane as solvent to produce 5-amino-1-[[4-Nitrophenyloxyl]carbomyl]imidazole-4-carboxamide with methyl hydrazine and dimethyl Formamide to produce 4-nitrophenyl 5-amino-4-carbamoyl-1H-imidazole-1-carboxylate, which is cyclized with Bu4NI and mixture of solvents of THF / MeCN at 60° C for 1 hour followed by the addition of H5IO6 to produce Temozolomide as shown in scheme 2.

The above method can be extended to make N-alkyl compounds using other alkyl substituted hydrazines. However, this approach is also more tedious in its operations and suffers in low overall yields. Moreover, the 4-nitrophenyl 5-amino-4-carbamoyl-1H-imidazole-1-carboxylate still has to be isolated in the branch of this process that uses it as an intermediate which carries high level impurity profile. The formation of 4-nitrophenyl 5-amino-4-carbamoyl-1H-imidazole-1-carboxylate involves 4 hours stirring and then left to stand for 18 hours at room temperature, which is time captivating step in the process of temozolamide.

Olga et.al in US 7612202 discloses purification of Temozolomide comprising Temozolomide. hydrochloride is treated with at least one organic acid in organic solvent and the reaction mixture was heated to reflux and stirring was maintained at same temperature for about 10 minutes. The reaction mixture was filtered at elevated temperature and then cooled to 5° C for about half an hour to enable crystallization. The crystals thus obtained were collected and washed with water and cold acetone to produce pure Temozolomide base.

Further review of the available literature regarding Temozolomide discloses various other processes for its preparation. However, due to one or more drawbacks with respect to the production of side products, the use of expensive and toxic cyclizing reagents (methyl isocyanate) and solvent, less than desirable yields, and the need for multiple reaction steps, most of them are not particularly convenient and economical for industrial scale up.
Hence, there is an unmet need to develop improved, cost effective and industrially amenable processes for the preparation of Temozolomide providing higher yield of end product with better purity.

The process of the present invention is a convenient process for the preparation of temozolomide with desired purity and yield by using better preparation techniques, which are ecofriendly, cost-effective, robust and well suited for use on an industrial scale.

Therefore, inventors of the present application provide a simple high yielding process for preparation of highly pure Temozolomide, which overcomes the disadvantages associated with prior disclosed literature methods.

OBJECTIVE OF THE INVENTION
The main objective of the invention is to provide an improved process for the preparation of Temozolomide and its pharmaceutically acceptable salts.

Yet another object of the present invention is to provide an improved process for the preparation of Temozolomide Intermediates.

SUMMARY OF THE INVENTION
The main aspect of the present invention relates to an improved process for the preparation of Temozolomide (I) or its pharmaceutically acceptable salts thereof

comprising the steps of
a. reacting 5-amino-1H-imidazole-4-carboxamide or its salt of formula (II)

with 4-nitrophenylchloroformate of formula (III)


in presence of base and a solvent, wherein the solvent used as a ketone solvent to produce in-situ formation of 5-amino-1-[[4-nitrophenyloxyl]carbomyl]imidazole-4-carboxamide of formula (IV)

b. followed by reacting with mono methyl amine to produce 5-amino-1-(N-methylcarbomyl)imidazole-4-carboxamide of formula (V);

c. cyclization of the compound of formula (V) in presence of sodium nitrate and water followed by organic acid to obtained temozolomide;

Another aspect of the present invention relates to an improved process for the preparation of Temozolomide (I), wherein process for the preparation of 5-amino-1-(N-methylcarbomyl)imidazole-4-carboxamide of formula (V)

comprising the steps of
a. reacting 5-amino-1H-imidazole-4-carboxamide or its salt of formula (II)

with 4-nitrophenylchloroformate of formula (III)


in presence of base and a solvent, wherein the solvent used as a ketone solvent to produce in-situ formation of 5-amino-1-[[4-nitrophenyloxyl]carbomyl]imidazole-4-carboxamide of formula (IV); and

b. followed by reacting with mono methyl amine to produce 5-amino-1-(N-methylcarbomyl)imidazole-4-carboxamide of formula (V).

DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to an improved, commercially viable and industrially –advantageous process for the preparation of Temozolomide and its pharmaceutically acceptable salts thereof.

The present invention relates to an improved process for the preparation of Temozolomide (I) or its pharmaceutically acceptable salts thereof

comprising the steps of
a. reacting 5-amino-1H-imidazole-4-carboxamide or its salt of formula (II)

with 4-nitrophenylchloroformate of formula (III)


in presence of base and a solvent, wherein the solvent used as a ketone solvent to produce in-situ formation of 5-amino-1-[[4-nitrophenyloxyl]carbomyl]imidazole-4-carboxamide of formula (IV)

b. followed by reacting with mono methyl amine to produce 5-amino-1-(N-methylcarbomyl)imidazole-4-carboxamide of formula (V);

c. cyclization of the compound of formula (V) in presence of sodium nitrate and water followed by organic acid to obtained temozolomide;

In one embodiment the present invention relates to a process for the preparation of Temozolomide and its pharmaceutically acceptable salts comprising, reacting 5-Amino-1H-imidazole-4-carboxamide of formula (II) or its salt selected from hydrochloride with 4-nitrophenylchloroformate of formula (III) in presence of base selected from organic base such as methylamine, triethylamine, diisopropylethylamine, t-butylamine, N,N-dimethylaniline, dimethylformamide, pyridine, DBU, DBN, N-methylpiperazine or inorganic base such as sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate, lithium carbonate; wherein solvent is ketone solvent selected from acetone, butanone, 2- pentanone, 3-pentanone, methylbutyl ketone, and methyl isobutyl ketone; at a room temperature for a period of 2 hours to obtain compound of formula (IV). The reaction mixture was allowed to cooled to 0-10 °C and the obtained solid was filtered. The solid was washed with water and suck dried. The obtained product may dried under vacuum to yield 5-amino-1-[[4-Nitrophenyloxyl]carbomyl]imidazole-4-carboxamide of formula (IV).

According to the present invention, the said methods should in particular be more industrially scalable, allow the desired compounds to be obtained with high yields, and use cheaper reagents which are simpler to handle and industrial applicable.

On the other hand, the prior art process does not suggest the use of particular process for the preparation of Temozolomide. Further, the prior art processes involves the use of excess solvents and reagents, further involves time lagging process, which leads in the decomposition of product and lowering the quality of 5-amino-1-[[4-Nitrophenyloxyl]carbomyl]imidazole-4-carboxamide of formula (IV).

To overcome the above disadvantage the inventors of the present invention developed a process, which is industrially liable, viable and environmental friendly. The present inventors now developed a process for the preparation of 5-amino-1-[[4-nitrophenyloxyl] carbomyl] imidazole-4-carboxamide of formula (IV), which yields in highly pure 5-amino-1-[[4-nitrophenyloxyl] carbomyl] imidazole-4-carboxamide of formula (IV), which in parallel leads to the formation of highly pure Temozolomide.

The prior art process involves 18 to 20 hour for completion of the reaction. The present inventors now developed a process for the preparation of 5-amino-1-[[4-nitrophenyloxyl] carbomyl] imidazole-4-carboxamide, which involves the use of ketone solvent, wherein the reaction complete in 2 to 3 hours and yield highly pure 5-amino-1-[[4-nitrophenyloxyl] carbomyl] imidazole-4-carboxamide around 90 -95%, which is commercially and industrially feasible.

The above obtained pure 5-amino-1-[[4-nitrophenyloxyl] carbomyl] imidazole-4-carboxamide of formula (IV) is converted to Temozolomide or its pharmaceutically acceptable salts using any of the prior art processes / process, which are feasible for a person skilled in the art.
The above obtained 5-amino-1-[[4-nitrophenyloxyl] carbomyl] imidazole-4-carboxamide of formula (IV) is reacting with mono methyl amine solution at a temperature ranging from 15 to 35°C for a period of 1 hours to 3 hours to obtain 5-amino-1-(N-methylcarbomyl)imidazole-4-carboxamide solid compound of formula (V). The solid was washed with water and suck dried.

The prior art processes involves the use of excess solvents and reagents, further involves distillation of solvent and purifications, which leads in the formation of additional impurities in the product and also lowers the quantity of yield.

The present process yields in 4-amino-1-(N-methylcarbomyl)imidazole-4-carboxamide, which is highly pure and free of these process related impurities and higher yields compared to prior art processes.
The above obtained 4-amino-1-(N-methylcarbomyl)imidazole-4-carboxamide in water cyclizing with the addition of sodium nitrite at 0-5° C over a period of 30-40 mins and stir the reaction mixture 10-15 mins at same temperature after the reaction mixture is followed by organic acid catalyst; wherein the organic acid catalyst is tartaric acid at the temperature and reaction maintained for 18-20 hours. After completion of the reaction, to obtain solid material of Temozolomide of formula (I) was isolated and purification by the using any of the known techniques.
The obtained pure Temozolomide or its pharmaceutically acceptable salts having purity greater than 99.5% and substantially free from process related impurities:

The process related impurities that appear in the impurity profile of the Temozolomide may be substantially removed by the process of the present invention resulting in the formation of highly pure material. The process of the present invention is as summarized below:

The process related impurities that appear in the impurity profile of the Temozolomide (I) or its pharmaceutically acceptable salts may be substantially removed by the process of the present invention resulting in the formation of Temozolomide (I) or its pharmaceutically acceptable salts of high purity.

In another embodiment the present invention relates to an improved process for the preparation of Temozolomide (I), wherein process for the preparation of 5-amino-1-(N-methylcarbomyl)imidazole-4-carboxamide of formula (V)

comprising the steps of
a. reacting 5-amino-1H-imidazole-4-carboxamide or its salt of formula (II)

with 4-nitrophenylchloroformate of formula (III)

in presence of base and a solvent, wherein the solvent used as a ketone solvent to produce in-situ formation of 5-amino-1-[[4-nitrophenyloxyl]carbomyl]imidazole-4-carboxamide of formula (IV); and

b. followed by reacting with mono methyl amine to produce 5-amino-1-(N-methylcarbomyl)imidazole-4-carboxamide of formula (V).

In one embodiment the present invention relates to a process for the preparation of Temozolomide and its pharmaceutically acceptable salts comprising, reacting 5-Amino-1H-imidazole-4-carboxamide of formula (II) or its salt selected from hydrochloride with 4-nitrophenylchloroformate of formula (III) in presence of base selected from organic base such as methylamine, triethylamine, diisopropylethylamine, t-butylamine, N,N-dimethylaniline, dimethylformamide, pyridine, DBU, DBN, N-methylpiperazine or inorganic base such as sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate, lithium carbonate, wherein solvent is ketone solvent selected from acetone, butanone, 2- pentanone, 3-pentanone, methylbutyl ketone, and methyl isobutyl ketone at a room temperature for a period of 2 hours to obtain compound of formula (IV). The reaction mixture was allowed to cooled to 0-10 °C and the obtained solid was filtered. The solid was washed with water and suck dried. The obtained product may dried under vacuum to obtained 5-amino-1-[[4-Nitrophenyloxyl]carbomyl]imidazole-4-carboxamide of formula (IV).

The merit of the process according to the present invention resides in that product isolated after drying is directly obtained as pure Temozolomide or its pharmaceutically acceptable salts (I). Said material is found devoid of any other crystal lattice and is adequately stable to handle and store for longer time (alteast up to more than 6 months) without any significant or measurable change in its morphology and physicochemical characteristics. Temozolomide or its pharmaceutically acceptable salts (I) obtained according to the process of the present invention results in the final API purity by HPLC of more than 99.5 % w/w, and found to be stable at different ICH conditions.

The prior art process involves 18 to 20 hour for completion of the reaction. The present inventors now developed a process for the preparation of 5-amino-1-[[4-nitrophenyloxyl] carbomyl] imidazole-4-carboxamide, which involves the use of ketone solvent, wherein the reaction complete in 2 to 3 hours and yield highly pure 5-amino-1-[[4-nitrophenyloxyl] carbomyl] imidazole-4-carboxamide around 90-95%, which is commercially and industrially feasible.

In another embodiment, the Temozolomide or its pharmaceutically acceptable salts (I) obtained by the processes of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerine, propylene glycol or liquid paraffin.

The compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLES
Example-1:
Preparation of 5-amino-1-(N-methylcarbomyl) imidazole-4-carboxamide:
5-amino-1H-imidazole-4-carboxamide (250.0 gm), acetone (3750.0 ml) were charged into a round bottom flask at 25-30° C. under stirring Slowly added of triethylamine (301.07 ml) and 4-nitrophenylchlrooformate (466.5 gm) dissolved in acetone (1250.0ml) at 0-10° C under stirring. Raise the temperature to 25-30° C and maintain for 2 hours under stirring. Then added mono methyl amine 40% solution (210.0 ml) at 0-10°C. Raise the temperature to 25-30 °C and maintained for 2 hours under stirring. After completion of the reaction the reaction mixture was allowed to 0-10 °C and filtered the solid. The solid material was slurry washed with purified water (1250.0 ml) and stir for 2-3 hours at 25-30°C under stirring. The solid was filtered and washed with water (250.0 ml) and suck dry for 2-3 hours. Unload the material and dried at 25-30° C to get 218.0 gm of 5-amino-1-(N-methylcarbomyl)imidazole-4-carboxamide.
Yield: 218.0gm
HPLC Purity: 97.18%

Example-2:
Preparation of crude Temozolomide:
5-amino-1-(N-methylcarbomyl)imidazole-4-carboxamide (215 gm), in water (2150 ml) and stir for 10-15 minutes at 25-30° C and then cooled to 0-5° C. Slowly added of sodium nitrite (121.5 gm) dissolved in 243.0 ml in to reaction mixture over the period of 30-40 mins at same temperature and stir for 10-15 mins. 180.0 grams of tartaric acid was added to the reaction mixture over the period of 6-8 hours at 0-5° C under stirring and maintained for 18-20 hours at same temperature. After completion of reaction the solid material was centrifuged and washed with purified water and suck dry for 5 hours. The solid material was charged with sodium hydrosulphite solution and stir for 1-2 hours at 25-30° C. Filtered the solid material and purifying with extraction of acetone solvent ~10 lit (two times) at 55-60°C to obtain crude compound of Temozolomide after solvent recovery.
Yield: 70.0gm
HPLC Purity: 94.57%

Example-3:
Purification of crude Temozolomide
Crude Temozolomide (70.0 gm) dissolved in Acetone: purified water (2100ml: 700ml) at 50-55°C with Tartaric acid (35.0 gm). After dissolution, filtered through celite bed. Filtered ml’s are maintained for 2hr at 0-5°C and filtered the solid compound. Compound dried at 40-45°C under vacuum to get white to off-white solid Temozolomide and unknown impurities are below 0.05%.
Yield: 53.0gm
HPLC Purity: 99.98%