WO2010140168A1

WO2010140168A1 - Improved process for preparing temozolomide

Info

Publication number: WO2010140168A1
Application number: PCT/IN2010/000365
Authority: WO
Inventors: Shekhar Bhaskar Bhirud; Gurdeep Singh Sarin; Neeraj Gupta; Parveen Kumar Tiwari; Venkateswaran Srinivasan Chidambaram; Lalit Wadhwa
Original assignee: Ind-Swift Laboratories Limited
Priority date: 2009-06-03
Filing date: 2010-06-02
Publication date: 2010-12-09

Abstract

A process for preparing temozolomide by employing mild reaction and easy isolation of temozolomide is provided.

Description

IMPROVED PROCESS FOR PREPARING TEMOZOLOMIDE

FIELD OF THE INVENTION

The present invention relates to an improved and industrially applicable process for the preparation of temozolomide of formula I,

Formula I

BACKGROUND OF THE INVENTION

Temozolomide of formula I, is an antitumor drag and is chemically known as 3-methyl-8- aminocarbonyl-imidazole[5,l-d]-l,2,3,5-tetrazin-4(3H)-one.

Formula I

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 said 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. Melting point of temozolomide reported in above patent is 200 ⁰C (recrystallized from acetonitrile); 21O⁰C with effervescence (recrystallized from acetone and water), and 215⁰C with effervescence and darkening (recrystallized from hot water). Major drawback of process is the longer reaction duration of three to four weeks for completion of reaction. Further, the process described in the patent involves use of low boiling and extremely toxic, methyl isocyanate, which is very difficult to handle, especially on industrial scale, as its use should be avoided in the industrial synthesis. Further, cycloaddition reaction requires a very long period of 21 to 28 days, which makes the process unattractive for industrial scale. US patent 5,003,099 discloses a process for 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 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 intermediate and process needs extraction of the above mentioned intermediate from filtrate.

US patent 6,844,434 describes synthesis of temozolomide by cyclization of 5-amino-l-(N-rnethyl- hydrazinocarbonyl)-lH-imidazole-4-carboxylic acid in the presence of tetrabutyl nickel and periodic acid to form a reaction mixture which is concentrated under reduce pressure and resulting residue was treated with acetonitrile and filtered. The filtrate was concentrated and chromatographed on a column of silica gel to give temozolomide. Use of time consuming and cumbersome technique i.e. column chromatography for isolation of product makes the process not suitable to employ at industrial level. US patent 7,087,751 discloses a process for the preparation of temozolomide from protected imidazole intermediate. The process involves reaction of l-methyl-3-carbamoyliminomethyl-urea with JV- protected aminocyanoacetamide in the presence of acetic acid in a suitable solvent to form an JV- protected imidazole intermediate which is then cyclized in the presence of lithium chloride to minimize 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 JV-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 inteπnediate 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. These additional purification further takes away around 20 % yield of the inteπnediate thus yield of the pure intermediate, which is suitable for the further reaction, remains around 53 % which is very low from commercial point of view.

The patent also describes 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 above two processes, this adds further four additional steps to the synthesis of temozolomide. The process of preparation of temozolomide is described by the following scheme:

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 reaction for isolating 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 cyclization of imidazole intermediate using aqueous solution of sodium nitrite and tartaric acid to give temozolomide in 45 % yield in solution. Above publication is silent for the isolation of temozolomide from the solution. It is found that relatively elevated temperature used in the reaction increases the content of decomposition products.

US patent publication 2007/0225496 exemplified a process for preparation of temozolomide by pyrolising N'-methyl-N,N-diphenyl urea to form vapor of methyl isocyanate which is then reacted with 5-diazo-5H-imidazole-4-carboxylic acid amide to form temozolomide. The above described process involves use of methyl isocyanate, which is highly flammable and makes the process unsuitable for industrial synthesis, hi addition to this, isolation of temozolomide from the reaction mixture requires addition of large amount of ethyl acetate followed by addition of hexane and again ethyl acetate to isolate compound.

US patent publication 2009/0326028 describes a process for preparation of temozolomide by diazotization of imidazole intermediate in the presence of at least one metal halide, a source of nitrous acid and an acid to form acidic solution of temozolomide, wherein temozolomide forms a salt with acid. The desired product i.e. temozolomide is then isolated from the acidic solution by extraction with a solvent. The process 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 cyclization. Patent application also describes two methods for the extraction of temozolomide. In first method, temozolomide is extracted from the reaction mixture by counter current extraction using continuous liquid-liquid extractor. Although the use of counter-counter extraction reduces the usage of solvent during extraction (approx. 40 times solvent used) but isolation requires a specific apparatus. The use of tedious step of counter current extraction and need of the specific apparatus (continuous liquid-liquid extractor) makes the process unsuitable from the industrial point of view. In the second method, temozolomide is extracted using conventional techniques which requires large volumes of solvent such as 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. The process is not industrially viable and product can not be extracted effectively due to handling problem of huge volumes of solvent. Further cost of the raw material and solvent plays an important role in 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, hi addition to this dichloromethane is a low boiling solvent, so recovery losses are very high which add cost to the process. US patent publication 2010/0036121 discloses a process for the preparation of temozolomide by reaction of 5-aminoimidazole-4-carboxamide with N-succinimidyl-N'-methylcarbamate to form carbamoyl 5~aminoimidazole-4-carboxamide which is then reacted with alkali or alkaline earth nitrile to give reaction mass containing temozolomide. The resulting mass is treated with 5% HCl to make acidic and then eluted through a column. The fraction containing temozolomide is evaporated to give temozolomide which is then recrystallized from a mixture of acetone and water. The process involves purification of temozolomide by means of column chromatography on adsorbent polymeric resin, which is considered to be tedious and time consuming process and hence industrially not applicable. Moreover since temozolomide is an anticancer compound, its handling in solid as well as solution requires special care and needs isolated area for working, hi addition to this, during commercial synthesis of the API, size of equipment and space has to be taken in to account, because use of such large reactors (as required for the distillation) and specific apparatus for the extraction like liquid-liquid extractor, as reported in prior art, adds to the cost of the final API so makes process unsuitable. Most of the references, discloses the isolation of temozolomide either using extraction technique with huge volume of solvent or require specific apparatus to isolate temozolomide from the reaction mass. In the view of above, we have not found any reference wherein solid temozolomide is isolated from reaction mass, obtained after diazotization and cyclisation. Therefore, there is an urgent need to develop an alternative and improved process for the recovery of temozolomide which will prove effective with respect to cost, industrial applicability and operational efficiency. The process of present invention overcome disadvantages of prior art by avoiding use of hazardous reagent such as methyl isocyanate and also involving easy isolation of temozolomide either by filtration or by using less amount of the solvent . Thus, present invention fulfills the need of the art and provides an improved and industrially applicable process for preparation of temozolomide, which provides temozolomide and the intermediates useful for its synthesis in high overall yield and purity. OBJECTIVE OF THE INVENTION

The principal objective of the present invention is to provide an efficient and industrially advantageous process for preparation of temozolomide under mild reaction conditions.

Another objective of the invention is to provide a process for preparation of temozolomide under mild reaction conditions avoiding the use of excess amount of acid and easy workup for isolation of the intermediate.

Another objective of the invention is to provide an efficient, improved and industrially advantageous process for preparation of temozolomide which is conveniently applicable to industrial scale and involves use of less amount of the solvent. Another objective of the present invention is to provide a process for isolation of solid temozolomide from reaction mass by filtration or centrifugation.

Still another objective of the present invention is to provide a process for the preparation of temozolomide avoiding use of huge volumes of solvent during extraction.

Yet another objective of the present invention is to provide temozolomide having plate shape morphology.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides an improved process for the preparation of temozolomide of formula I,

Formula I which proves to be efficient and industrially advantageous.

The process comprises the step of: a), condensing compound of formula II,

Formula II with compound of formula III,

CH₃ H CH₃ Formula III in the presence of an acid in an alcoholic solvent to form a compound of formula IV;

Formula IV b). isolating the compound of formula IV from the reaction mixture by filtration; c). diazotizing and cyclizing 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. Accordingly, the present invention provides an improved process for the preparation of temozolomide of formula I, process comprises the steps of: a), diazotizing and cyclizing the compound of formula IV in the presence of a source of nitrous acid and a suitable acid; b). optionally, cooling the reaction mixture; c). isolating precipitate of temozolomide from the reaction mixture; and d). purifying temozolomide of formula I with a suitable solvent. BRIEF DESCMPTION OF DRAWINGS Figure 1 Shows morphology of crystals of temozolomide Figure 2 Shows morphology of crystals of temozolomide in enlarged view Figure 3 shows powdered X-ray diffraction spectrum of temozolomide. Figure 4 shows an Infra red spectrum of temozolomide.

Figure 5 Shows a differential scanning calorimetry (DSC) thermogram of temozolomide DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an improved and efficient process for the preparation of temozolomide of formula I.

According to one aspect of the invention, the present invention provides an industrially advantageous process for preparation of temozolomide starting from compound of formula II.

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 O ⁰C 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 Ci_-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 filtration. 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 using a source of nitric acid in the presence of a suitable acid to undergo subsequent diazotization followed by in situ cyclization and easy isolation of the final product avoiding use of large volume of solvent.

Generally, the reaction involves 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 ⁰C. 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 optionally stirred for few minutes to few hours and desired compound of formula I can be isolated from the reaction mixture. According to another embodiment, present invention provides two ways of easy isolation of the resulting product from the reaction mixture to avoid the use of large volume of the solvent. In one embodiment, temozolomide can be extracted from the reaction mixture using 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, ΛζiV-dimethylformamide 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 -1O⁰C.

In other embodiment, temozolomide can be isolated from the reaction mixture by filtration or centrifugation. The complete precipitation of temozolomide can be induced by reducing the temperature of the reaction mixture. Preferably, reaction mixture is cooled to -15 to 5° C. Temozolomide, thus precipitated, can be isolated from the reaction mixture by employing filtration or centrifugation.

Above isolation method is highly advantageous as it avoids the use of huge volume of solvent for extraction of desired compound.

Temozolomide, thus obtained by the process of present invention, can be optionally, purified by employing suitable purification method to enhance the purity as well as to minimize the amount of impurities present in the final product. Specifically, temozolomide can be dissolved in a suitable solvent at a temperature of 10 to 8O⁰C for few minutes to few hours, preferably till the complete dissolution. It is optional to add activated charcoal along with solvent to reaction mixture to improve the colour of material. The reaction mixture is then filtered to remove activated charcoal and other undissolved materials. Suitable solvents for purification include allcyl nitriles such as acetonitrile, propionitrile; ketones such as acetone, diethyl ketone; ethers such as tetrahydrofuran, 1,2- dimethoxyethane, 1,2-diethoxyethane; water; polar aprotic solvent such as dimethylsulfoxide, N,N- dimethylformamide and the like or mixture thereof. Crystallization is initiated either by cooling or concentration of the reaction mixture followed by cooling of the remaining solution. Specifically, the reaction mixture can be cooled to a temperature of -15 ⁰C to ambient temperature to initiate precipitation. The precipitation can be optionally initiated with seeding of a particular polymorph to give the corresponding polymorph of the final product. The crystallized product is then isolated from the mixture by suitable techniques such as filtration, centrifugation and the like.

Optionally, the wet product obtained after filtration is slunied 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 0-5⁰C, or at ambient temperature. Thereafter the reaction mixture is cooled followed by stirring at 0-5° C or at ambient temperature. The product can be isolated from the mixture by a suitable methods such as filtration or centrifugation and then dried. Temozolomide, thus obtained, by the process of present invention can optionally be crushed.

The purification process can be repeated with same or different solvent till the temozolomide of desired purity is obtained. Temozolomide obtained from the present invention is highly pure and free from undesired impurities. Temozolomide, thus obtained displays purity of more than 98%, preferably more than 99%, more preferably 99.9%.

In another alternate way, present invention provides a process for recovery of temozolomide from the filtrate. Thus, temozolomide can be extracted from the filtrate obtained after the filtration of temozolomide from the reaction mixture to increase the total yield of the final product. It is highly advantageous to recover temozolomide from the filtrate using less amount of solvent as the recovered material enhances the final yield of the API. The process of recoveiy of the temozolomide from the filtrate involves the extraction using a suitable solvent or solvent mixture thereof. 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, ΛζiV-dimethylacetamide, N₁N- dimethylformamide and the like or mixture thereof. Preferably, product is extracted with dichloromethane, dimethylsulfoxide, benzyl alcohol or mixture thereof in any suitable proportion. The volume of solvent employed for the extraction can be from 2 to 100 times, more preferably 10 to 60 v/w with respect to compound of formula IV. Preferably, 25 to 60 times solvent is used for the extraction purposes.

It is highly advantageous to use a mixture of solvents for extraction of temozolomide from the filtrate, as it circumvents the need of large amount of solvent for the purpose of extraction of the desired compound.

It is observed that size as well as structure of the temozolomide crystals, obtained after crystallization, depends upon several factors such as the cooling profile, time etc. During crystallization, when reaction mixture is allowed to cool at temperature 15 to ambient temperature or allowed to stand (without any stirring) then crystals are obtained in large size and seems to be needle shape through naked eye. But when crystallization reaction mixture is allowed to cooled at low temperature such as -5 to 5 ⁰C or stirred continuously, then crystals obtained seems to be micro crystals through naked eye. Thus rate of cooling and stirring effects the morphology of crystals obtained.

Scanning electron microscope study of temozolomide crystals shows plate shaped morphology as shown in Figures 1 and 2.

Crystalline nature of temozolomide is characterized powder X-Ray diffraction (PXRD). 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 Figure 3.

Similarly, due to change in crystallization conditions change in IR spectrum of the final product i.e. temozolomide is observed, it can be attributed due to differing population of the H-bonded modification of the molecule. 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 absoiption bands expressed in reciprocal centimeter. The crystalline temozolomide as synthesized by the process of present invention displays infrared spectrum substantially in as shown in Figure 4.

Another variation that can be seen is in the melting point of the temozolomide, that may be due to hydrogen bonding interaction between them. Differential scanning calorimetry (DSC) studies of temozolomide shows an exothermic peak at around 210 ⁰C as shown in Figure 5. The exothermic peak in DSC thermogram can be attributed to decomposition of the compound. It is also supported from the melting range of temozolomide that varies between 199-210 ⁰C. It is known that molecule of temozolomide usually melts at around 199-201⁰C and shows effervesce or melts completely around

209 to 211 ⁰C (with decomposition).

The starting materials, compound of formula II and compound of fornmla III can be prepared by methods already known in the art or by the method as described herein for reference.

The compound of formula II can be prepared by the ammoniation of compound of formula V,

NH₂ Formula V wherein R is selected from Ci^allcyl 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 ⁰C for 5 minutes to 12 hours preferably till completion of reaction. Ammonia employed for reaction may be gaseous ammonia or a solution of ammonia in a suitable solvent that includes C_1-6 alcohols such as methanol, ethanol or propanol and the like or mixture thereof. Suitable solvents for 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 reaction is soluble in aqueous solutions which results in loss of yield. Therefore by employing gaseous ammonia in the present invention, the compound of formula II is obtained in higher yields in comparison to prior art processes. 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 starting material is very important in 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 putity. Specifically, the compound of formula II is dissolved in a suitable solvent at a temperature of 25 to 100 ⁰C 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 C_1-6 alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol, butanol; C_2-5 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 stalling compound of formula ill 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 ⁰C to 200⁰C for few minutes to few hours. Preferably the reaction mixture is refluxed at a temperature of 140 to 170 ⁰C 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; C_4-8 aliphatic ethers such as diethyl ether, isopropyl ether, methyl tertiarybutyl ether; C_2-4 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 acid for isolation of imidazole intermediate, since intermediate precipitates in the reaction mixture itself. The present invention also avoids excessive heating of the intermediate to prevent the decomposition, thus providing mild reaction condition. Another 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. Still another advantage, but not the last, is that it involves easy isolation of temozolomide from the reaction mixture by employing filtration or centrifugation and avoiding the need of extraction with huge volume of solvent or liquid-liquid extractor or column chromatography, therefore making the process cost effective and industrially advantageous..

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 S-Aøiino-N'-methyl-lH-imidazole-ljΦdicarboxamide (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 20-25⁰C 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 20-25⁰C, filtered, suck dried and dried under vacuum at

2O⁰C for 18 hours to obtain 11.2 g of title compound as greyish solid.

EXAMPLES

Example 1: Preparation of hydroxylirainocyano 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 0-5⁰C over a period of one hour.

Temperature was slowly raised to 23-27⁰C 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 (5 x 1.5 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-

45⁰C. The resulting solid was stirred with cyclohexane (3.0 L) for 30 minutes at 25-30⁰C, filtered and dried at 40-45⁰C 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 amimøcyanoacetamide

The solution of aminocyanoacetic acid ethyl ester (as prepared above) in methanol was cooled to 0-5

⁰C 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 0-5⁰C and stirred for 1 hour. The precipitated solid was filtered, washed with chilled methanol (200 ml) and dried at 35-40⁰C 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 (25g) 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 0-5⁰C and stirred for 45 minutes. The resulting solid was filtered, washed with chilled methanol (250 ml) and dried at 40-45⁰C under vacuum to obtain 425g (53.6%) of pure title compound having purity 99.46% by HPLC. Example 4: Preparation of l-methyl-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 150-160⁰C for 12 hours. The reaction mixture was cooled to 5-10⁰C, 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 45-5O⁰C to yield 1.08 kg (67.9%) of title compound having purity 93.82% by HPLC.

Exainple-5: Preparation of S-amino-N^methyl-lH-imidazole-l^-dicarboxamide Acetic acid (200 ml, 3.53 mol) was added to a suspension of aminocyanoacetamide (40Og, 4.04 mol) and l-methyl-3-methylcarbamoyliminomethyl urea (76Og, 4.8 mol) in methanol (2.0 L) at 20-25⁰C and the mixture was stirred at 20-25⁰C for 18 hours till completion of the reaction (monitored by HPLC). The reaction mixture was cooled to 0-5⁰C, stirred for 1 hour and the resulting solid was filtered, washed with chilled methanol (450 ml), suck dried and finally dried under vacuum at 30-35⁰C 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 S-amino-N^methyl-lH-imidazole-l^- dicarboxamide (500g, 2.73mol) and sodium nitrite (25Og, 3.62mol) in water (5.0 L) at -5 to 0⁰C 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- 30⁰C 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 4O⁰C and residual dimethylsulfoxide layer was degassed completely. The dimethylsulfoxide layer was cooled to 0 to - 10⁰C and stirred for 1 hour. The resulting solid was filtered, washed with ethyl acetate (25OmL), and suck dried for 2 hours to afford 32Og 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-ammo-N¹ -methyl- lH-imidazole- 1,4- dicarboxamide (1Og, 0.054mol) and sodium nitrite (5g, 0.072mol) in water (100ml) at -5 to 0⁰C at a rate so that temperature does not rise above 0-5⁰C. The reaction mixture was stirred at 0-5⁰C 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 (25Og) in water (5.0 L) at -5 to O⁰C at a rate so that temperature does not rise above 0-5⁰C. The reaction mixture was stirred at 0-5⁰C 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 40⁰C and residue at 35- 40⁰C 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: Preparation of temozolomide

Acetic acid (90 g) was slowly added to a mixture of N-methyl-5-aminoimidazole-l,4-dicarboxamide (100 g) and sodium nitrite (50 g) in water (1000 ml) at -5 to 0 ⁰C. The reaction mixture was stirred at 0-5 ⁰C for 1.5 hours. After completion of reaction, ice bath was removed and powdered calcium chloride (250 g) was added to the reaction mixture and wanned to 25-30 ⁰C. The reaction mixture was stirred at 25-30 ⁰C for 3 hours and cooled to -5 to 0 ⁰C. The reaction mixture was further stirred for 1 hour, filtered and suck dried to give 92 g of crude temozolomide. Example 10: Preparation of temozolomide

Acetic acid (90 g) was added to a suspension of N-methyl-5-aminoimidazole-l,4-dicarboxamide (100 g) and sodium nitrite (50 g) in water (1000 ml) at -5 to 0⁰C. The reaction mixture was stirred at 0-5 ⁰C for 1.5 hours. After the completion of reaction, calcium chloride (250 g) was added to the reaction mass and heated to 25-30 ⁰C. The reaction mixture was stirred at 25-30 ⁰C for 3 hours and cooled to -5 to 0 ⁰C. The reaction mixture was stirred for 1 hour, resulting solid was filtered and suck dried to give 70 g of wet temozolomide. The filtrate was extracted twice with a mixture of dichloromethane and dimethylsulfoxide (9:1, 500 ml). The resulting organic layer was combined with wet compound (as obtained above) and solvent was distilled off under reduced pressure. Dimethylsulfoxide (450 ml) was added to the resulting reaction mass and heated to 60-70 ⁰C. Charcoal (5 g) was added to the resulting solution and reaction mixture was stirred at 60-70 ⁰C for 10 minutes. The reaction mass was filtered through hyflo bed, filtrate was cooled to 5-10 ⁰C and stirred for 60 minutes. Solid thus precipitated was filtered and suck diied to 78 g of temozolomide.

Purification of temozolomide: Temozolomide (75 g) was dissolved in a mixture of acetone (1125 ml) and water (375 ml) at 40-45 ⁰C, activated charcoal (7.5 g) was added to it and the solution was stirred for 10 minutes. The reaction mixture was filtered while hot through hyflo bed. The reaction mixture was slowly cooled to 0-5 ⁰C, stilted for 1 hour, filtered and suck dried for 30 minutes. The resulting product was stirred in acetone and water (1:1, 300ml) at 25-30 ⁰C for 1 hour and cooled to 5-10⁰C. The reaction mixture was further stirred for 30 minutes and filtered. The resulting solid was stirred with acetone (150 ml) for 60 minutes at 25-30 ⁰C, filtered and dried under vacuum at 55-6O⁰C for 15 hours to give 28 g of temozolomide having purity 99.97% by HPLC. Example 11: Preparation of temozolomide

Acetic acid (450 ml) was slowly added to a suspension of S-amino-N^methyl-lH-imidazole-l, 4- dicarboxamide (500 g) and sodium nitrite (250 g) in water (5.0 L) at -5 to 0 ⁰C. The reaction mixture was stirred at 0-5 ⁰C for 1 hour. After the completion of the reaction (monitored by HPLC), powdered calcium chloride (1250 g) was added in small lots to the reaction mass and stirred at 25-30 ⁰C for 2 hours. The reaction mixture was cooled to -5 to 0 ⁰C and stirred for 1 hour. The resulting solid was filtered and suck dried to give 430 g of crude temozolomide. Example 12: Purification of temozolomide

Method A: Crude temozolomide (90 g) was dissolved in a mixture of acetone (1125 ml) and water (375 ml) at 40-45 ⁰C. Activated charcoal (7.5 g) was added to the reaction mixture and was stirred for 10 minutes and filtered hot through hyflo bed. The reaction mixture was slowly cooled to 0-5 ⁰C and stirred for 1 hour. The resulting solid was filtered and suck dried for 30 minutes. The resulting residue was stirred with 1:1 mixture of acetone and water (300 ml) at 25-30 ⁰C for 1 hour. The reaction mixture was cooled to 5-10 ⁰C, stirred for 30 minutes and filtered. The resulting wet solid was stirred with acetone (150 ml) for 60 minutes at 25-30 ⁰C, filtered and dried under vacuum at 55-60 ⁰C- for 15 hours to give 34.66 g of the title compound having purity 99.97% by HPLC.

Method B: Crude temozolomide (90 g) was dissolved in a mixture of acetone and water (3000 ml, 1:1) at 40-45 ⁰C. Activated charcoal (10 g) was added to the resulting mixture and the was stirred for 10 minutes at 40-45 ⁰C. The reaction mixture was filtered while hot through hyflo bed. Thereafter, reaction mixture was slowly cooled to 5-10 ⁰C and stirred for 1 hour. The resulting solid was filtered and suck dried for 30 minutes which was stirred with mixture of acetone: water (500 ml, 1:1) at 25-30 ⁰C for 1 hour, cooled to 5-10 ⁰C. The reaction mixture was further stirred for 30 minutes, filtered and suck dried for 30 minutes to give 52.34 g of the title compound having purity 98.80% by HPLC. Method C: Crude temozolomide (52 g) was dissolved in dimethylsulfoxide (270 ml) at 60-70⁰C. Activated charcoal was added and stirred for 30 minutes at 60-70⁰C. The resulting solution was filtered through hyflo bed and washed with hot dimethylsulfoxide (30 ml). The resulting filtrate was cooled to 5-10 ⁰C and stirred for 30 minutes at 5-10 ⁰C. The solid thus formed was filtered, washed with acetone and suck dried for 2 hours to give 56 g of wet compound, which was stirred with acetone: water (1:1, 560 ml) for 60 minutes at 25-30 ⁰C, filtered, and dried under vacuum at 55-6O⁰C for 15 hours to give 50 g of the title compound having purity 99.97% by HPLC.

Method D: Crude temozolomide (215 g) was dissolved in dimethylsulfoxide (1125 ml) at 70-75 ⁰C and stirred for 30 minutes. The reaction mixture was filtered through hyflow bed and bed was with hot dimethylsulfoxide (125 ml). The resulting filtrate was cooled up to 0-5 ⁰C and stirred for 30 minutes. The resulting solid was filtered and suck dried to give 170 g of compound, which was dissolved in acetone: water (3:1, 3400 ml) at 50-55 ⁰C. Activated charcoal was added to the solution and stirred for 30 minutes. The solution was filtered through hyflo, filtrate was cooled to 0-5 ⁰C and stirred for 30 minutes. The solid, thus formed, was filtered and washed with chilled acetone to give 65 g of the tile compound having purity 99.91% by HPLC.

Method E: Crude temozolomide (210 g) was dissolved in acetone: water (3:1, 4200 ml) and stirred till complete dissolution. Activated charcoal (12 g) was added to the reaction mixture and stirred for 20 minutes. The resulting solution was filtered hot through hyflow bed and bed was washed with hot solution of acetone: water (3:1, 210 ml). The resulting filtrate was cooled up to 0-5⁰C and stirred for 30 minutes. The solid thus formed was filtered, washed with acetone and sucked dried to give 120 g of the wet title compound which was dissolved in dimethylsulfoxide (450 ml) at 70 ⁰C. The solution was filtered hot through hyflow bed after charcoal treatment and the bed was washed with hot dimethylsulfoxide (50 ml). The filtrate was cooled to 0-5 ⁰C and stirred for 30 minutes, The resulting product was filtered and suck dried for 2 hours. The resulting solid was slurried in mixture of acetone and water (1:1, 300 ml) at 25-30 ⁰C and suck dried to give title compound which stirred in acetone (150 ml) for 30 minutes at 25-30 ⁰C. The mixture was filtered and suck dried to give 66.6 g of temozolomide. having purity 99.88 % by HPLC.

Method F: Crude temozolomide (25 g) was dissolved in acetone: water (3:1, 500 ml) at 40-45⁰C. Activated charcoal (2.5 g) was added to the reaction mixture and stirred for 10 minutes. The resulting solution was filtered hot through hyflow bed. The resulting filtrate was cooled up to 25-30 ⁰C and stirred for 30 minutes. The reaction mixture was seeded with temozolomide crystal and reaction mixture was further cooled to -10 to -5 ⁰C. The solid thus formed was filtered and dried to give 15 g of temozolomide having purity 99.82 % by HPLC, melting point: 208-210 ⁰C.

Method G: Crude temozolomide (350 g) was dissolved in acetone: water (3:1, 7 L) at 40-45⁰C. Activated charcoal (50 g) was added to the reaction mixture and stirred for 10 minutes. The resulting solution was filtered hot through hyflow bed. The resulting filtrate was cooled up to -10 to -5 ⁰C and stirred for 60 minutes. The solid thus precipitated was filtered and dried under vacuum at 55-60 ⁰C for 15 hours to give title compound. The crystals thus obtained was crushed to give 142 g of title compound having purity 99.89 % by HPLC, melting point: 208-210 ⁰C.

Method H: Crude temozolomide (225 g) was dissolved in acetone: water (3:1, 11.25 L) at 40-45⁰C. The reaction mixture was slowly cooled to 15-20⁰C and allowed to stand for 12 hours. The solid thus precipitated was filtered and dried under vacuum at 55-60 ⁰C for 15 hours to give 80 g of the title compound having purity 99.89 % by HPLC, melting point: 208-210 ⁰C.

Method I: Temozolomide (25g) was dissolved in a mixture of acetone and water (1.5L) in the ratio of 3:1 at 45-50⁰C, 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 -5⁰C 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 50-60⁰C 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. 210⁰C (with effervescence) Method J: Temozolomide (25g) was dissolved in a mixture of acetone and water (750 ml) in the ratio of 1: 1 at 40-45⁰C. 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 5-1O⁰C, 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 25-3O⁰C for 1 hour, filtered, washed with chilled acetone (40 ml), suck dried at 25-3O⁰C for 30 minutes and finally dried under vacuum at 50-60⁰C for 20 hours to obtain 11.6 g of title compound having purity 99.93% by HPLC. M.P. 210⁰C (with effervescence)

Method K: Temozolomide (24Og) was stirred in a mixture of acetone and water (2.4L) in the ratio of 1:1 at 45-5O⁰C, 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 25-3O⁰C and cooled to 0 to 5 ⁰C. the reaction mixture was further stirred for 60 minutes, filtered and finally dried under vacuum at 50-60⁰C for 15 hours to obtain 174 g of title compound having purity 99.92 % by HPLC. M.P. 210⁰C (with effervescence)

Claims

WE CLAIM:

1). A process for the preparation of temozolomide of formula I,

Formula I comprising the steps of: a), condensing compound of formula II,

H₂N NH₂ Formula II with compound of formula III,

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

Formula IV b). isolating the compound of formula IV from the reaction mixture by filtration; c). diazotizing and cyclizing 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 C_1-6 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 in step d) isolation of temozolomide is carried out either by extraction with a suitable solvent followed by solvent removal or by inducing precipitation of temozolomide in the reaction mixture. 6). The process according to claim 1, wherein in step d) isolation of temozolomide is carried out either by extraction with a suitable solvent followed by solvent removal. 7). The process according to claim 6, wherein suitable solvent includes 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. 8). The process according to claim 1, wherein in step d) isolation of temozolomide is carried out by inducing precipitation of temozolomide in the reaction mixture. 9). The process according to claim 8, wherein in precipitate of temozolomide is isolated by filtration or centrifugation. 10).The process according to claim 1, wherein the process for the preparation of compound of formula

II comprising the steps of: a), ammoniation of compound of formula V,

Formula V wherein R is selected from C_/.g allcyl 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. ll).The process according to claim 10, wherein in step a) ammonia used in the reaction is either gaseous or a solution of ammonia in a suitable solvent that includes Ci_-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. 12).The process according to claim 10, wherein step b) suitable solvents include Ci_-6 alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol, butanol; C_2-5 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.

13). A process for the preparation of compound of formula IV, comprising the steps of: a), condensing compound of formula II with compound of formula III in the presence of an acid in an alcoholic solvent; and b). isolating the compound of formula IV from the reaction mixture by filtration.

14).The process according to claim 13, 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 Ci_-6 alcoholic solvents such as methanol, ethanol, n- propanol, isopropanol, n-butanol, isobutanol and the like or mixture thereof in any suitable proportion.

15). A process for the preparation of temozolomide of formula I, comprising the steps of: a), diazotizing and cyclizing the compound of formula IV in the presence of source of nitrous acid and a suitable acid; b). optionally, cooling the reaction mixture; c). isolating precipitates of temozolomide from the reaction mixture; and cl). purifying temozolomide of formula I with a suitable solvent.

16).The process according to claim 15, wherein in step a) 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.

17).The process according to claim 15, wherein in step a) an acid is selected from organic acid which include carboxylic acid, preferably lower alkanoic acid such as foπnic acid, acetic acid, propionic acid, tartaric acid, oxalic acid and the like; or inorganic acid which include hydrochloric acid, hydrobromic acid, sulfuric acid and the like or combination thereof.

18).The process according to claim 15, wherein in step b) reaction mixture is cooled at a temperature of -15 to 5 ⁰C.

19).The process according to claim 15, wherein in step c) precipitate of temozolomide is isolated by filtration or centrifugation. 20).The process according to claim 15, wherein in step d) solvent includes alkyl nitriles such as acetonitrile, propionitrile; ketones such as acetone, diethyl ketone; ethers such as tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane; water, aprotic solvent such as dimethylsulfoxide, N,N- dimethylformamide; and the like or mixture thereof.

21).The process according to claim 15, wherein solvent is preferably selected from dimethylsulfoxide or mixture of acetone and water.

22).Temozolomide having plate shape morphology.