FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of temozolomide of formula I,
(Formula removed)

BACKGROUND OF THE INVENTION
Temozolomide of formula I, is an antitumor drug and is chemically known as 3-methyl-8-aminocarbonyl-imidazole[5,l-d]-l,2,3,5-tetrazin-4(3H)-one.
(Formula removed)

It is indicated for treating patients with malignant glioma such as cancer, breast cancer, refractory anaplastic, astrocytoma, i.e. patient at first relapse who have experienced disease progression in malignant glioma, glioblastoma multiform and anaplastic astrocytoma, on a drug containing a nitrosourea and procarbazine. It is sold in the US market as hard capsules containing 5 mg, 20 mg, 100 mg or 250 mg as temodar® by Schering corporation.
Temozolomide and compounds having similar activity (higher alkyl analogues at the 3-position) were first disclosed in US patent 5,260,291. According to the patent, temozolomide is prepared by the reaction of 5-diazoimidazole-4-carboxamide with methyl isocyanate in the presence of N-methylpyrrolid-2-one in dichloromethane at room temperature for three to four weeks. The melting point of the temozolomide reported in the patent is 200 °C (recrystallized from acetonitrile); 210°C with effervescence (recrystallized from acetone and water), and 215°C with effervescence and darkening (recrystallized from hot water). Major drawbacks of the process is the longer reaction duration of three to four weeks for completion of reaction., Further, the process described in the patent involves the use of low boiling and extremely toxic, methyl isocyanate, which is very difficult to handle, especially on the industrial scale, so its use should be avoided in the industrial synthesis. Further, the cycloaddition reaction requires a very long period of 21 to 28 days and makes the process unattractive on the industrial scale.
US patent 5,003,099 discloses a process for the preparation of aminocyanoacetamide, a key intermediate for the synthesis of temozolomide. According to the patent, aminocyanoacetamide is synthesized in two steps by the reaction of cyanoacetic acid alkyl ester using sodium nitrite in the presence of glacial acetic acid to form a hydroxyimino intermediate, which is then reduced in the presence of platinum on carbon to yield aminocyanoacetic acid alkyl ester, which is unstable. The alkyl ester intermediate is then in situ reacted with aqueous ammonia to give the desired product. The main drawback of the above mentioned process is the use of aqueous ammonia, since aminocyanoacetamide, generated in the reaction, is soluble in aqueous solution and hence difficult to extract from the reaction mass which results in lower yields. The patent is silent about the purity of the intermediate and the process needs extraction of the above mentioned intermediate from the filtrate.
US patent 7,087,751 discloses a process for the preparation of temozolomide from protected imidazole intermediate. The process involves the reaction of l-methyl-3-carbamoyliminomethyl-urea with N-protected aminocyanoacetamide in the presence of acetic acid in a suitable solvent to form an iV-protected imidazole intermediate which is then cyclised in the presence of lithium chloride to minimize the undesired cyclisation product. After cyclisation, the protected group has to be removed which makes the process more laborious with more number of steps.
As exemplified in example 1 of the above patent, yield of the TV-protected imidazole intermediate obtained is very low, almost half of the product goes in the filtrate which further needs extraction from the filtrate. After extraction of the intermediate from the filtrate, the combined yield is only 67 %. The intermediate obtained is only 93 to 94% pure and requires additional purifications, crystallization using ethyl acetate and slurry wash with mixture of methyl tertiary butyl ether and isopropanol. This additional purification takes away around 20 % yield of the intermediate thus yield of the pure intermediate, which is suitable for the further reaction, remains around 53 % which is very low from the commercial point of view.
The patent also describes the condensation of l-methyl-3-carbamoyliminomethyl-urea with unprotected aminocyanoacetamide in presence of acetic acid to give an imidazole intermediate. This patent fails to disclose the process of conversion of above imidazole intermediate to temozolomide, but only up to hydrolysis to prepare 5-amino-lH-imidazole-4-carboxamide hydrochloride is reported. Another US patent no. 6,844,434 of same applicant (Schering) discloses a process for the conversion of 5-amino-lH-imidazole-4-carboxamide hydrochloride, which is prepared by the hydrolysis of above imidazole intermediate, to temozolomide. By combining the two processes, this adds further four additional steps to the synthesis of temozolomide. The process of the preparation of temozolomide is described by the following scheme:
(Formula removed)

It has been observed that for the preparation of unprotected imidazole intermediate as exemplified in US 7,087,751, use of excess amount of the acetic acid (around 21 times with respect to aminocyanoacetamide) is reported. Thereafter acetic acid is removed by distillation.
The inventors of the present invention have repeated example 2 as described in US 7,087,751 for the preparation of unprotected imidazole intermediate. As per the process, after the completion of the reaction, acetic acid has to be removed from the reaction mixture. It is noticed that removal of acetic acid is a very tedious move so as on commercial scale and leads to decomposition. The decomposition of the imidazole
intermediate can be ascertained from the grey color of the intermediate which requires additional slurry wash with water and re-crystallization from mixture of acetonitrile and water. The workup of the reaction for isolating the intermediate is very difficult. Even after complicated workup, intermediate thus obtained, is found to contain decomposed product and have low yields.
In a publication namely, Journal of Organic Chemistry, volume 62, no. 21, 7288-7294, a process is disclosed for the preparation of temozolomide by the hydrolysis of 8-cyano-3-methyl-[3H]-imidazole-[5,l-d]-tetrazin-4-one in the presence of hydrochloric acid to give hydrochloride salt of temozolomide, which has to be neutralized to obtain temozolomide. In the same Journal, another process for the preparation of temozolomide is also described. Temozolomide is prepared by the nitrosative cyclisation of imidazole intermediate using aqueous solution of sodium nitrite and tartaric acid to give temozolomide in 45 % yield in solution. The process for the isolation of temozolomide is not disclosed in the publication. It is found that relatively elevated temperature used in the reaction increases the content of decomposition products.
PCT publication WO 2008/038031 describes the process for the preparation of temozolomide by the diazotization of the imidazole intermediate at least in the presence of metal halide, a source of nitrous acid and an acid to form acidic solution of temozolomide which require further conversion to temozolomide free base by the counter current extraction using continuous liquid liquid extraction.
The process is quite effective but requires very strict reaction parameters including the addition of metal halide during diazotization as well as addition of pre-cooled reaction mixture to sodium nitrite solution to achieve desired level of selective cyclisation. Also the isolation of the final product i.e temozolomide requires a tedious step of counter current extraction which makes the process not suitable from the industrial point of view. In the absence of counter current extraction methodology,
the reaction workup, using conventional techniques, requires extraction of the desired product with huge amount of dichloromethane (1000 times) with respect to the starting imidazole intermediate to obtain reasonable amount of crude temozolomide which needs further two or three times crystallization to achieve desired purity. Cost of the raw material and solvent plays an important role in the commercial and cost effective synthesis of the final API, temozolomide. In this view, use of large amount of dichloromethane makes the process costly and non competitive. Dichloromethane is a low boiling solvent, so recovery losses are very high which add cost to the process and extraction of temozolomide using counter current mechanism makes the process not feasible on the commercial scale.
In view of the above problems, there is an urgent need to develop an alternative and improved process for synthesis of temozolomide which will prove effective with respect to the cost, industrial applicability and also involves use of less amount of the solvent. Thus, present invention fulfills the need of the art and also provides temozolomide and the intermediates useful for its synthesis in high overall yield and purity.
OBJECT OF THE INVENTION
The principal object of the present invention is to provide an efficient and industrially advantageous process for the preparation of temozolomide under mild reaction conditions.
Another object of the invention is to provide a process for the preparation of temozolomide under mild reaction conditions avoiding the use of excess amount of acid and easy workup for the isolation of the intermediate.
Still another object of the invention is to provide an efficient, improved and industrially advantageous process for the preparation of temozolomide which is conveniently applicable to industrial scale and involves the use of less amount of the solvent.
SUMMARY OF THE INVENTION
Accordingly, The present invention provides an improved process for the preparation of temozolomide of formula I,
(Formula removed)

which proves to be efficient and industrially advantageous.
The process comprises the step of:
a), condensing compound of formula II,
(Formula removed)

with compound of formula III,
(Formula removed)

in the presence of an acid in an alcoholic solvent to form a compound of formula IV;
(Formula removed)

b). isolating the compound of formula IV from the reaction mixture by filtration;
c). diazotizing the compound of formula IV in the presence of source of nitrous acid and a suitable acid;
d). isolating temozolomide therefrom;
e). and optionally purifying temozolomide of formula I.
BRIEF DESCRIPTION OF DRAWINGS
Figure 1 shows powdered X-ray diffraction spectrum of temozolomide.
Figure 2 shows an Infra red spectrum of temozolomide.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved and efficient process for the preparation of temozolomide.
According to one aspect of the invention, the present invention provides an industrially advantageous process for the preparation of temozolomide starting from compound of formula II.
(Formula removed)

The compound of formula II is reacted with compound of formula III to form compound of formula IV.
Generally, the reaction involves the condensation of compound of formula II with compound of formula III in the presence of catalytic amount of suitable acid in an alcoholic solvent at 0 °C to reflux temperature of the solvent. Suitable acids include organic acids such as carboxylic acids. Preferably, carboxylic acids are lower alkanoic acids such as acetic acid, formic acid, tartaric acid, lactic acid and the like. Alcoholic solvents include, but are not limited to C1-6 alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and the like or mixture thereof in any suitable proportion. The reaction mixture is stirred for 1 to 48 hours, preferably for 12 hours, more preferably till the completion of the reaction. The reaction completion is monitored by a suitable chromatographic techniques such as high pressure liquid chromatography (HPLC) or thin layer chromatography (TLC). The compound of formula IV can be isolated from the reaction mixture by suitable techniques such as filtration or centrifugation and the like to yield the desired compound in high yield and purity. Particularly, compound of formula II is reacted with compound of formula IV in the presence of acetic acid in methanol at ambient temperature. After completion of reaction the reaction mixture is cooled to 0-5°Cand stirred at this temperature to induce precipitation. The solid, thus obtained is collected by Alteration. The present invention is advantageous as it circumvents the need of removal of acetic acid, during the preparation of compound of formula IV, which in addition to longer and tedious removal, also cause the degradation of the desired compound. The resulting product obtained as per the repeated process of US patent
7,087,751 further needs triple purification. The compound of formula IV prepared according to present invention avoids the need of further purification and isolated as off white to cream colored solid from the reaction mixture itself in high yield and high purity. The compound of formula IV obtained by the present invention have purity more than 95%, preferably more than 97%, more preferably greater than 99 %.
The compound of formula IV is then converted to temozolomide of formula I and its pharmaceutically acceptable salts by the subsequent diazotization followed by in situ cyclisation.
Typically, the reaction involves the addition of a suitable acid to a solution of compound of formula IV and a source of nitrous acid at a temperature -5 to 5 °C. The reaction can be conducted in a suitable solvent that include water; or alcohols such as methanol, ethanol; aliphatic ketones such as acetone, diethyl ketone; ethers such as tetrahydrofuran, 1,2-dimethoxy ethane, 1,2-diethoxy ethane, 1,4-dioxane; alkyl nitrile such as acetonitrile, propionitrile and the like or mixture thereof. Source of nitrous acid employed in the reaction includes alkali metal salt of nitrous acid like sodium nitrite, potassium nitrite which can be used as such or in solution with a solvent that includes water; aliphatic alcohols such as methanol, ethanol; aliphatic ketones such as acetone, diethyl ketone; water miscible ethers such as tetrahydrofuran, 1,2-dimethoxy ethane, 1,2-diethoxy ethane, 1,4-dioxane; alkyl nitrile such as acetonitrile, propionitrile and the like or mixture thereof. Suitable acid can be organic or inorganic acid. Organic acids include carboxylic acid preferably lower alkanoic acid such as formic acid, acetic acid, propionic acid, tartaric acid, oxalic acid and the like or mixture thereof; and inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid and the like or combination thereof. The reaction mixture is stirred for 30 minutes to 8 hours, preferably till the completion of the reaction. The completion of the reaction is monitored by a suitable chromatographic techniques such as HPLC or TLC till the absence of compound of formula IV in the reaction mixture. After the
completion of the reaction, it is optional and advantageous to add a saturating agent to reaction mixture to saturate the reaction mixture, to make the extraction of the product from the reaction mixture easy and convenient. Saturating agent includes solid calcium chloride, sodium chloride and the like. After the addition of saturating agent, the reaction mixture is stirred and extracted with a suitable solvent, suitable solvent includes halogenated solvent such as dichloromethane, chloroform, 1,2-dichloroethane; ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, methyl tertiary butyl ether, isopropyl ether, dibutyl ether; aromatic hydrocarbon solvents such as toluene, 1,2-xylene, 1,4-xylene; ketones such as acetone, diethyl ketone; high boiling alcohols such as benzyl alcohol, butanol, furfuryl alcohol, ethylene glycol, 1,3-propanediol, glycerol; aprotic solvent such as dimethyl sulfoxide, N,N-dimethylacetamide, N,N-dimethylformarnide and the like or mixture thereof. Preferably, product is extracted with dichloromethane, dimethylsulfoxide, benzyl alcohol or mixture thereof in any suitable proportion. Most preferably the product is extracted using a mixture of dimethylsulfoxide and dichloromethane. The final product is then isolated from the reaction mixture by a suitable technique such as filtration, centrifugation and the like.
It is highly advantageous to use mixture of dimethylsulfoxide and dichloromethane for the extraction of temozolomide from the reaction mixture, as it circumvents the need of use of large amount of the solvent for the purpose of extraction of the desired compound. Preferably, 100 to 500 times solvent is used for the extraction purposes. The ratio of the solvent used can be 1: 10 to 1: 50, preferably 1:19 to 1: 40. After the recovery of dichloromethane, the product along with the impurity remain in residual dimethylsulfoxide. The product along with the impurities at the level of 1.0 to 30% can be crystallized from the dimethylsulfoxide at 0 to -10°C.
Temozolomide, thus obtained is optionally, purified with a suitable solvent to enhance the purity of the product. Specifically, temozolomide is dissolved in a
suitable solvent at a temperature of 10 to 80°C for few minutes to few hours, preferably till the complete dissolution. It is optional to add activated charcoal along with solvent to the reaction mixture. The hot reaction mixture is then filtered to remove activated charcoal and other undissolved materials. Suitable solvents for purification include alkyl nitriles such as acetonitrile, propionitrile; ketones such as acetone, diethyl ketone; ethers such as tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane; water; and the like or mixture thereof. The crystallization is initiated either by cooling or concentration followed by cooling of the remaining solution. The crystallized product is isolated from the mixture by suitable techniques such as filtration, centrifugation and the like. Optionally, the wet product obtained after filtration is slurried with a suitable solvent that includes aliphatic ketones such as acetone, diethyl ketone and the like or mixture thereof or mixture thereof with water in any suitable proportions at 0-5°C, or at ambient temperature. Thereafter the mixture is cooled followed by stirring at 0-5°C or at ambient temperature. The product is thus isolated from the mixture by a suitable methods such as filtration or centrifugation and dried.
Temozolomide obtained from the present invention is highly pure and free from the undesired impurities. Temozolomide, thus displays purity of more than 98%, preferably more than 99%, more preferably 99.9%.
Temozolomide, so formed by the process of the present invention, is crystalline and characterized by at least one of the following methods such as powder X-Ray diffraction (PXRD), Infra-red spectroscopy (IR) or differential scanning calorimetry (DSC).
The X-ray diffraction patterns of temozolomide are measured on a PANalytical X'Pert Pro diffractometer with Cu radiation and expressed in terms of two-theta, d-spacings and relative intensities. One ordinarily skilled in the art understands that experimental differences may arise due to differences in instrumentation, sample
preparation or other factors. Temozolomide as synthesized by the process of present invention displays the X-ray diffraction pattern as given in figures 1.
The infrared (IR) absorption spectrum of temozolomide has been recorded on a Perkin Elmer System Spectrum 100 spectrometer between 450 cm"1 and 4000 cm"1 using potassium bromide pellets having the characteristic absorption bands expressed in reciprocal centimeter. The crystalline temozolomide as synthesized by the process of present invention displays the infrared spectrum substantially in as shown in figures 2.
Crystalline temozolomide of the present invention melts at 209°C to 211°C with effervescence.
The starting material of compound of formula II and compound of formula III can be prepared by the methods already known in the art or by the method as described here for reference.
The compound of formula II can be prepared by the ammoniation of compound of formula V,
RO
(Formula removed)

wherein R is selected from C1-6 alkyl group; preferably methyl or ethyl and the like
Specifically, the process involves reacting the compound of formula V in a suitable solvent with ammonia at a temperature -10 to 50 °C for 5 minutes to 12 hours preferably till completion of the reaction. Ammonia employed for the reaction may be gaseous ammonia or a solution of ammonia in a suitable solvent that includes C1-6
alcohols such as methanol, ethanol or propanol and the like or mixture thereof. Suitable solvents for the reaction include aliphatic alcoholic solvent such as methanol, ethanol, propanol; alkyl nitrile such as acetonitrile, propionitrile and the like or mixture thereof. It is preferable to use gaseous ammonia, as the product of the reaction is soluble in aqueous solutions which results in loss of yield. Therefore by employing gaseous ammonia in the present invention, yield the compound of formula II is obtained in higher yields in comparison to the prior art. After completion of the reaction, the mixture is concentrated by suitable techniques and then cooled to precipitate the compound. The precipitated compound of formula II can be isolated from the mixture by suitable techniques such as filtration or centrifugation and the like.
The purity of the starting material is very important in the synthesis of a compounds capable of acting as medicines. Therefore, the compound of formula II, if desired, can be purified with a suitable solvent to enhance the purity of the compound. Specifically, the compound of formula II is dissolved in a suitable solvent at a temperature of 25 to 100 °C for few minutes to few hours, preferably till the complete dissolution. It is optional to add activated charcoal along with solvent to the reaction mixture. The hot reaction mixture is then filtered to remove activated charcoal. Suitable solvents includes C1-6 alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol, butanol; C2-5 alkyl nitriles such as acetonitrile, propionitrile; ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane; aromatic solvents such as toluene, 1,2 or 1,4-xylene and the like or mixture thereof. The crystallization is initiated either by cooling or concentration followed by cooling of the remaining solution. The crystallized product is isolated from the mixture by suitable techniques such as filtration, centrifugation and the like.
The starting compound of formula III can be prepared by methods already known in the art.
Specifically, the compound of formula III can be prepared by the condensation of monomethyl urea with triethyl orthoformate at a temperature of 70 °C to 200°C for few minutes to few hours. Preferably the reaction mixture is refluxed at a temperature of 140 to 170 °C for 12 hours, more preferably till completion of the reaction. The resulting product is optionally purified by slurry wash in a suitable solvent to enhance the purity of the compound. Suitable solvents for washing include alkyl esters such as methyl acetate, ethyl acetate, n-propyl acetate; C4-8 aliphatic ethers such as diethyl ether, isopropyl ether, methyl tertiarybutyl ether; C2-4 alkyl nitriles such as acetonitrile, propionitrile and the like or mixture thereof.
The major advantage of the present invention lies in high yield and purity of the intermediates as well as of final API, temozolomide. Secondly, the present invention involves the use of catalytic amount of acid during the condensation of compound of formula II and III; and avoids the need of tedious removal of acetic for the isolation of imidazole intermediate, since intermediate precipitates in the reaction mixture itself. The present invention also avoids the excessive heating of the intermediate to avoid the decomposition, thus providing mild reaction condition. Another but not the last advantage, is that present invention circumvents the use of large amount of solvent for the extraction purpose, therefore making the process cost effective on a commercial scale.
Having described the invention with reference to certain preferred aspects, other aspects will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail by the preparation of the compounds of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
REFERENCE EXAMPLE:
Preparation of 5-Amino-N'-methyl-lH-imidazole-l,4-dicarboxamide (US
7,087,751)
2-Amino-2-cyanoacetamide (10 g), l-methyl-3-methylcarbamoyliminomethyl urea (19 g) and acetic acid (120 ml) were stirred together at ambient temperature under the positive pressure of nitrogen for 2 hours. Excess acetic acid was removed under reduced pressure and methyl tertiary butyl ether (25 ml) was added to the concentrated reaction mass, cooled to obtained crude solid. The mixture was stirred for 30 minutes and the precipitate was collected by vacuum filtration. The solid was dried under vacuum at 20-25°C for 18 hours to obtain 13 g of title compound as grayish solid. The crude product was stirred with water (66 ml) for 1 hour at 20-25°C, filtered, suck dried and dried under vacuum at 20°C for 18 hours to obtain 11.2 g of title compound as greyish solid.
EXAMPLES
Example 1: Preparation of hydroxyliminocyano acetic acid ethyl ester
To a suspension of ethyl cyanoacetate (1.0 Kg, 8.84 mol) and sodium nitrite (0.735 kg, 10.65 mol) in water (0.80 L), acetic acid (0.70 kg, 11.66 mol) was added at 0-5°C over a period of one hour. Temperature was slowly raised to 23-27°C and the reaction mixture was stirred for one hour at that temperature. After the complete consumption of ethyl cyanoacetate (monitored by TLC/GC), the reaction mixture was extracted with ethyl acetate (5x1.5 L). The combined organic layer was successively washed with 10% sodium bicarbonate (2 x 1.25 L) and brine solution (1.25 L), dried over sodium sulfate and filtered through hyflow bed. Solvent was removed under reduced pressure at 40-45°C. The resulting solid was stirred with cyclohexane (3.0 L) for 30 minutes at 25-30°C, filtered and dried at 40-45°C under vacuum to afford 1.14 kg (91.2 %) of title compound having purity 99.82% by HPLC.
Example 2: Preparation of aminocyanoacetic acid ethyl ester
To a solution hydroxyliminocyano acetic acid ethyl ester (1.14 Kg, 8.02 mol) in methanol (11.4 L) was added 5% platinum on carbon (91.2 g, 50 % wet) and the mixture was hydrogenated at hydrogen gas pressure of 6.2-6.4 kg/cm2 over a period of 12 hours and the completion of reaction was checked by TLC. The reaction mixture was filtered under nitrogen atmosphere to recover the catalyst. The filtrate was used as such for the next stage.
Example 3: Preparation of aminocyanoacetamide
The solution of aminocyanoacetic acid ethyl ester (as prepared above) in methanol was cooled to 0-5 °C and ammonia gas was purged into it approximately for 1 hour. After the completion of the reaction (monitored by TLC), the reaction mass was concentrated to 2.5-3.0 L under reduced pressure at 40-45°C, cooled to 0-5°C and stirred for 1 hour. The precipitated solid was filtered, washed with chilled methanol (200 ml) and dried at 35-40°C under vacuum for 6 hours to obtain 572 g of title compound.
The resulting product was added to methanol (4.57 L) and heated to reflux till the solution become clear. Activated charcoal (25 g) was added to the reaction mixture and refluxed for 15 minutes. The solution was filtered through hyflow bed, the bed was washed with methanol (500 ml) and the filtrate was concentrated to half of its original volume (approx 2.0 L). The mixture was cooled to 0-5°C and stirred for 45 minutes. The resulting solid was filtered, washed with chilled methanol (250 ml) and dried at 40-45°C under vacuum to obtain 425g (53.6%) of pure title compound having purity 99.46% by HPLC.
Example 4: Preparation of l-methyI-3-methylcarbamoyliminomethyl urea
A suspension of monomethyl urea (1.5 kg, 20.27 mol) in triethyl orthoformate (4.5 L, 30.40 mol) was heated to reflux at 150-160°C for 12 hours. The reaction mixture was cooled to 5-10°C, and stirred for 1 hour to ensure complete precipitation of the product. The resulting solid was filtered, washed with ethyl acetate (350ml) and dried
under vacuum at 45-50°C to yield 1.08 kg (67.9%) of title compound having purity 93.82% by HPLC.
Example-5: Preparation of S-amino-N1methyl-lH-imidazole-1,4-dicarboxamide
Acetic acid (200 ml, 3.53 mol) was added to a suspension of aminocyanoacetamide (400g, 4.04 mol) and l-methyl-3-methylcarbamoyliminomethyl urea (760g, 4.8 mol) in methanol (2.0 L) at 20-25°C and the mixture was stirred at 20-25°C for 18 hours till completion of the reaction (monitored by HPLC). The reaction mixture was cooled to 0-5°C, stirred for 1 hour and the resulting solid was filtered, washed with chilled methanol (450 ml), suck dried and finally dried under vacuum at 30-35°C to afford 648 g (88.04%) of title compound as an off white colored solid having purity 99.21% by HPLC.
Example 6: Preparation of temozolomide
Acetic acid (450 ml, 7.95 mol) was added to a suspension of 5-amino-Nl-methyl-lH-imidazole-l,4-dicarboxamide (500g, 2.73mol) and sodium nitrite (250g, 3.62mol) in water (5.0 L) at -5 to 0°C at such a rate so that temperature does not rise above 5°C. The reaction mixture was stirred at 0 to 5°C for one hour and absence of starting material was checked by HPLC analysis. Ice bath was removed and powdered calcium chloride (1.25Kg) was added in small lots to the reaction mass and stirred at 25-30°C for 2 hours. The reaction mass was extracted with a 2.5% solution of dimethylsulfoxide in dichloromethane (5 X 50 L). Combined organic layer was dried over sodium sulfate and filtered through a hyflow bed. Solvent was removed under reduced pressure below 40°C and residual dimethylsulfoxide layer was degassed completely. The dimethylsulfoxide layer was cooled to 0 to -10°C and stirred for 1 hour. The resulting solid was filtered, washed with ethyl acetate (250mL), and suck dried for 2 hours to afford 320g of the title compound having purity 78.5% by HPLC.
Example 7: Preparation of temozolomide
Acetic acid (9ml, 0.159mol) was added to a suspension of 5-amino-N'-methyl-lH-
imidazole-1,4-dicarboxamide (lOg, 0.054mol) and sodium nitrite (5g, 0.072mol) in water (100ml) at -5 to 0°C at a rate so that temperature does not rise above 0-5°C. The reaction mixture was stirred at 0-5°C for one and half hour. Brine (30g) was added to the reaction mixture and stirred at room temperature for two hours to saturate the reaction mixture. The reaction mass was extracted with a 2.5% solution of dimethylsulfoxide in dichloromethane (5 X 1 L). Combined organic layer was dried over sodium sulfate and filtered through a hyflow bed. Solvent was removed under reduced pressure and residual dimethylsulfoxide layer was degassed completely. The dimethylsulfoxide layer was cooled to 0 to -5°C and stirred for 1 hour. The resulting solid was filtered, washed with ethyl acetate (2x 5 ml), and suck dried for 2 hours to afford 5.0 g of the title compound having purity 81.6% by HPLC.
Example 8: Preparation of temozolomide
Acetic acid (450ml) was added to a suspension of 5-amino-N1-methyl-lH-imidazole-1,4-dicarboxamide (500g) and sodium nitrite (250g) in water (5.0 L) at -5 to 0°C at a rate so that temperature does not rise above 0-5°C. The reaction mixture was stirred at 0-5°C for one and half hour and the absence of starting material was checked by HPLC analysis. Ice bath was removed and powdered calcium chloride (1.25 kg) was added to the reaction mixture and stirred at room temperature for two hours. The reaction mass was extracted with a 2.5% solution of dimethylsulfoxide in dichloromethane (5 X 50 L). Combined organic layer was dried over sodium sulfate and filtered through a hyflo bed. Solvent was removed under reduced pressure at below 40°C and residue at 35-40°C was filtered through a candle filter to remove suspended particles and the filtrate was then degassed completely. The residual dimethylsulfoxide layer was cooled to 0±2°C and stirred for one hours. The resulting solid was filtered and sucked dried. The solid was then washed with ethyl acetate (2x 250 ml), and suck dried for 1 hours to afford 240 g of the title compound.
Example 9: Purification of temozolomide
Temozolomide (25g) was dissolved in a mixture of acetone and water (1.5L) in the ratio of 3:1 at 45-50°C, activated charcoal (1.25g) was added to the solution. The reaction mixture was stirred for 10 minutes and filtered while hot through hyflo bed. The solution was cooled to -5°C and stirred for one hour. The resulting solid was filtered, washed with chilled acetone (50 ml), suck dried for 30 minutes and finally dried under vacuum at 50-60°C for 18 hours to obtain 10.8 g of title compound as a off white crystalline powder having purity 99.98 % by HPLC. M.P. 210°C (with effervescence)
Example 10: Purification of temozolomide
Temozolomide (25g) was dissolved in a mixture of acetone and water (750 ml) in the ratio of 1:1 at 40-45°C. Activated charcoal (1.25g) was added to the solution, stirred the solution for 10 minutes and filtered while hot through hyflo bed. The hyflo bed was washed with warm acetone (100ml). The solution is cooled to 5-10°C, stirred for 3 hours. The resulting solid was filtered and suck dried for 30 minutes. The product was stirred with acetone: water mixture (1:1, 100ml) at 25-30°C for 1 hour, filtered, washed with chilled acetone (40 ml), suck dried at 25-30°C for 30 minutes and finally dried under vacuum at 50-60°C for 20 hours to obtain 11.6 g of title compound having purity 99.93% by HPLC. M.P. 210°C (with effervescence)
Example 11: Purification of temozolomide
Temozolomide (240g) was stirred in a mixture of acetone and water (2.4L) in the ratio of 1:1 at 45-50°C, for 30 minutes. The reaction mixture was cooled to 0 to 5°C and stirred for two hour. The resulting solid was filtered, suck dried for 30 minutes. The resulting solid was stirred with acetone (1.25 L) for 60 minutes at 25-30°C and cooled to 0 to 5 °C. the reaction mixture was further stirred for 60 minutes, filtered and finally dried under vacuum at 50-60°C for 15 hours to obtain 174 g of title compound having purity 99.92 % by HPLC. M.P. 210°C (with effervescence)

WE CLAIM:
1). A process for the preparation of temozolomide of formula I,
(Formula removed)

comprising the steps of:
a. condensing compound of formula II,
(Formula removed)

with compound of formula III,
(Formula removed)

in the presence of an acid in an alcoholic solvent to form compound of formula IV;
(Formula removed)

b. isolating the compound of formula IV from the reaction mixture by filtration;
c. diazotizing the compound of formula IV in the presence of source of nitrous
acid and a suitable acid;
d. isolating temozolomide therefrom; and
e. optionally, purifying temozolomide of formula I.
2). The process according to claim 1, wherein in step a) acids include organic acid like carboxylic acids selected from lower alkanoic acid such as acetic acid, formic acid, tartaric acid, lactic acid and the like; and alcoholic solvents includes C1-6 alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and the like or mixture thereof in any suitable proportion.
3). The process according to claim 1, wherein step c) source of nitrous acid include alkali metal salt of nitrous acid such as sodium nitrite or solution thereof with a solvent that includes water; alcohols such as methanol, ethanol; aliphatic ketones such as acetone, diethyl ketone; ethers such as tetrahydrofuran, 1,2-dimethoxy ethane, 1,2-diethoxy ethane, 1,4-dioxane; alkyl nitriles such as acetonitrile, propionitrile and the like or mixture thereof.
4). The process according to claim 1, wherein step c) an acid includes organic acid like carboxylic acid, preferably lower alkanoic acid such as formic acid, acetic acid, propionic acid, tartaric acid, oxalic acid and the like or inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like or combination thereof.
5). The process according to claim 1, wherein temozolomide is extracted from the reaction mixture using high boiling alcoholic solvent such as high boiling alcohols such as benzyl alcohol, butanol, furfuryl alcohol, ethylene glycol, 1,3-propanediol, glycerol; aprotic solvent such as dimethylsulfoxide, halogenated solvents such as dichloromethane or mixture thereof and preferably a mixture of dimethylsulfoxide and dichloromethane.
6). The process according to claim 1, wherein the process for the preparation of compound of formula II comprises:
a), ammoniation of compound of formula V,
(Formula removed)

wherein R is selected from C1-6 alkyl group; preferably methyl or ethyl and the like
using ammonia in a suitable solvent; and
b). optionally, purifying the compound of formula II with suitable solvent or solvent mixture.
7). The process according to claim 6, wherein in step a) ammonia used in the reaction is either gaseous or a solution of ammonia in a suitable solvent that includes C1-6 alcohol such as methanol, ethanol or propanol and the like or mixture thereof; and suitable solvents include alcoholic solvents such as methanol, ethanol, propanol; nitriles such as acetonitrile and the like or mixture thereof.
8). The process according to claim 6, wherein step b) suitable solvents include C1-6 alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol, butanol; C2-5 alkyl nitrile such as acetonitrile, propionitrile; ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4 dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane; aromatic solvent such as toluene, 1,2 or 1,4-xylene and the like or mixture thereof.
9). A process for the preparation of compound of formula IV,
(Formula removed)

comprising the step of:
a), condensing compound of formula II,
(Formula removed)

with compound of formula III,
(Formula removed)

in the presence of an acid in an alcoholic solvent to form compound of formula IV;
b). isolating the compound of formula IV from the reaction mixture by filtration;
10). The process according to claim 9, wherein in step a) acids include organic acid, like carboxylic acids selected from lower alkanoic acids such as acetic acid, formic acid, tartaric acid, lactic acid and the like; and alcoholic solvents include C1-6 alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and the like or mixture thereof in any suitable proportion.