Indian Patents. 272907:"IMPROVED PROCESSES FOR THE PREPARATION OF TEMOZOLOMIDE"

Title of Invention	"IMPROVED PROCESSES FOR THE PREPARATION OF TEMOZOLOMIDE"
Abstract	NEW POLYMORPH OF TEMZOLAMIDE AND PROCESSES FOR THE PREPARATION THEREOF The present invention relates to an improved process for the preparation of Temozolomide. The present invention also relates to novel crystalline form X of crude Temozolomide. The crystalline form X of crude Temozolomide is a solvated form of Temozolomide, and preferably a DMSO solvate.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & The Patent Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule 13) TITLE OF THE INVENTION "NEW POLYMORPH OF TEMZOLAMIDE AND PROCESSES FOR THE PREPARATION THEREOF" We, CADILA HEALTHCARE LIMITED, of Zydus Tower, Satellite Cross Road, Ahmedabad -380 015, Gujarat, India. The following specification particularly describes the invention and the manner in which it is to be performed: FIELD OF THE INVENTION The present invention relates to an improved process for the preparation of Temozolomide. The present invention also relates to novel crystalline form X of crude Temozolomide. The crystalline form X of crude Temozolomide is a solvated form of Temozolomide, and preferably a DMSO solvate. BACKGROUNG OF THE ART Temozolomide (also known as 3,4-dihydro-3-methyl-4-oxoimidazo[5,l-d]-l,2,3,5- tetrazine-8-carboxamide; 8-carbamoyl-3-methyiimidazo[5,1 -d]-1,2,3,5-tetrazin-4(3H)-one; methazolastone; M & B 39831 ; CCRG-81045; NSC-362856; Temodal; Temodar) is a well known anti-neoplastic agent that acts as an alkylating agent. Its primary application is in the treatment of brain cancer (e.g., glioma). Temozolomide is indicated in the treatment of refractory anaplastic astrocytoma, a form of brain tumour, glioblastoma multiforme and metastatic melanoma. Temozolomide is a prodrug, being cleaved in a multi-step pathway firstly to liberate an unstable monomethyl triazeno Imidazole carboxamide (MTIC), which then suffers proteolytic fragmentation to generate a highly-reactive methylating agent (methanediazonium ion) and 5-aminoimidazole-4-carboxamide (see, e.g., Arrowsmith et al, 2002, J. Med. Chem. Vol. 45, pp. 5458-5470). TMZ is the abbreviation commonly used for a compound having the chemical name 3,4-dihydro-3- methyl-4-oxoimidazo[5,l-d]-l,2,3,5-tetrazine-8-carboxamide or 3-methyl-8-amino carbonyl-imidazo [5,l-d]-l,2,3,5-tetrazin-4(3H)-one. It has the following structure. Formula (I) It is described in US 5260291 together with compounds of broadly similar activity such as higher alkyl analogs at the 3-position. Also described therein is a process for the preparation of Temozolomide and its derivatives involving condensation of 5-diazo-5H-imidazole-4 carboxamide (and related compounds) with an isocyanate. However, the process described is very slow, involving reaction times of up to 3 weeks. J. Med. Chem. 1984, 27, 196-201 describes a process wherein 5-amino-lH-imidazole-4-carboxamide is converted into 5-diazo-lH-imidazole-4-carboxamide, which is then cyclised with methyl isocyanate in dichloromethane. However, the cycloaddition of Methyl isocyanate (MIC) requires a long reaction time i.e. 20 days and also it is essential to limit dichloromethane content in the final API below 600 ppm as per ICH guideline. US 2002/0133006 discloses a process for the preparation of compound of formula (I) using methyl hydrazine which is a toxic and flammable liquid, hence not feasible on industrial scale and the final isolation involves tedious workup including column chromatography. J. Org. Chem. 1997, 62, 7288-7294 describes a process wherein the final step of diazotization provides equal-formation of aza-hypoxanthine and Temozolomide, resulting in low yield. This literature does not provide the experimental procedure for work up. US 2005/0131227 describe a process involving the use of a bulky protecting group on nitrogen of the primary amide for cyclisation in presence of LiCl to minimize the undesired cyclisation product. After cyclisation the protecting group has to be removed which makes the process more laborious with more number of steps. US 2007/0225496 describes a process for the preparation of Temozolomide comprising pyrrolysing N'-methyl-N,N-diphenyl urea to form Methyl isocyanate (MIC) vapour and slowly condensing the Methyl isocyanate (MIC) vapour into a reservoir of a solution of 5-diazo-5H-imidazoIe-4-carboxamide in dimethyl sulphoxide. A yield of crude Temozolomide of 68.6% is reported. During filtration of the crude Temozolomide produced in this process, excess Methyl isocyanate (MIC) vapors may be released to the atmosphere. US 2480088 discloses a process for the preparation of Methyl isocyanate (MIC) comprising the conversion of N-methyl carbamoyl chloride (NMCC) by using toluene in the presence of pyridine. However, US4082787 also disclosed the process for the preparation of Methyl isocyanate (MIC) but a drawback associated with this process is that it is not possible to charge whole of the raw material in one slot and the process also required column for final distillation. It has now surprisingly been found that the compounds described in US5260291 can be prepared by a new process developed under the present invention that avoids many of the problems encountered in the prior art. The process of the present invention is a convenient process for the preparation of Temozolomide with desired purity and yield by using better preparation techniques, which are eco-friendly, cost-effective, robust and well suited for use on an industrial scale. The US 2007/0225496 patent describes the process for the preparation of Temozolomide comprises of pyrrolysing N'-Methyl-N,N-diphenyl urea to form Methyl isocyanate (MIC) vapour which slowly condenses the Methyl isocyanate (MIC) vapour into a reservoir of a solution of 5-diazo-lH-imidazole-4-carboxamide in dimethyl sulphoxide whereby they have employed 300 °C temperature for pyrolysis. The inventors of the present invention have come out with a unique process whereby MIC is prepared by using N-methyl carbamoyl chloride (NMCC) and does not employ that much of higher temperature as mentioned in prior art. The present process is thus found to be more industrially feasible as compared to the conventional processes for the preparation of Temozolomide. It is well known that pharmaceutical solids can exist in different physical forms. Polymorphism is often characterized as the ability of a drug substance to exist as two or more crystalline forms that have different arrangements and/or conformations of the molecules in the crystalline lattice. These polymorphs differ in internal solid state structure, and, therefore, possess different chemical and physical properties, including packing, thermodynamic, spectroscopic, kinetic, interfacial, and mechanical properties. These properties can have a direct impact on drug product quality/performance, including stability, dissolution, therapeutic efficacy and bioavailability. Some of these forms may or may not be suitable therapeutically, but may have important benefits as being suitable as intermediates to obtain the therapeutically active form in better yield, purity etc. Therefore, such alternate forms have their utility as intermediates and are therefore are attractive commercially. We herein disclose such alternate forms having one or more of the above advantages, in addition/alternate to the known utility of the base and salt. The most stable polymorphic form of a drug substance is often used in a formulation because it has the lowest potential for conversion, from one polymorphic form to another. On the other hand, metastable and even amorphous forms may be chosen to enhance the bioavailability of the drug product. An amorphous form, being a disorganized solid mass, does not need to lose crystal structure before dissolution in the gastric juices, and, thus, often has greater bioavailability than a crystalline form. Further, such forms can be used for obtaining the stable form/marketed form. The preparation of new crystalline form of active pharmaceutical ingredients provides opportunities to improve the performance characteristics of a pharmaceutical product. Such preparation enlarge the repertoire of materials that formulation scientist have available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic and so the present invention provides new crystalline form Temozolomide. US 5260291 disclose different crystalline forms of Temozolomide. The solvent used for getting specific crystalline form, its M.P. and IR mentioned in below table; Example No. Solvent M.P IR cm-1 Example 1 MethanoI+ diethyl ether 160-210 °C Example 4(1) Acetone :Water (3:1) 210° C 3410,3205, 1758, 1730,1678 Example 4 (II) Acetone :water (1:3) 210° C ' 3430,3200, 1740, 1675 Example 4 (III) Hot water 215°C 3450, 3380, 3200, 1742, 1688, 1640 Example 9 Acetonitrile About 200°C ** US 7615632 B2 discloses nine crystalline forms of Temozolomide. Form I has a powder XRD (PXRD) pattern with peaks at 10.8, 11.3, 19.1, 17.7, 29.0 ±0.2 degree theta. Form II has a powder XRD (PXRD) pattern with peaks at 29.0, 10.8, 11.3, 14.5, 16.0, 17.9, 19.1, 17.7 ±0.2 degree theta. Form III has a powder XRD (PXRD) pattern with peaks at 10.8, 13.2, 14.7, 16.2, 16.8, 18.0,19.1,19.6, 21.5, 26.6, 23.8, 28.8, 29.8 ±0.2 degree theta. Form IV has a powder XRD (PXRD) pattern with peaks at 4.2, 12.6,14.8,16.7 ±0.2 degree theta. Form V has a powder XRD (PXRD) pattern with peaks at 11.4, 13.2, 21.5, 26.5, 26.8, 30.9 ±0.2 degree theta. Form VI has a powder XRD (PXRD) pattern with peaks at 8.4, 14.4, 25.1±0.2 degree theta. Form VII has a powder XRD (PXRD) pattern with peaks at 14.1, 28.2, 22.2, 23.0, 23.9 ±0.2 degree theta. Form VIII has a powder XRD (PXRD) pattern with peaks at 9.3, 10.8, 11.8, 14.7, 26.6, 28.2, 28.8, 19.7 ±0.2 degree theta. Form IX has a powder XRD (PXRD) pattern with peaks at 13.7, 16.1, 23.2, 30.1, 26.4,17.5,19.9 ±0.2 degree theta. Chinese Journal of pharmaceuticals- (2003), 34(4), 178-180 disclosed three polymorph of Temozolomide as mentioned in below table; Preparation of polymorph Solvent M.P XRD-2-theta (IA) Acetone: Water (3:1) 203-205° C 10.61, 14.50, 16.40, 17.79, 18.99,26.28,28.55,29.74 (IB) Acetone :water (1:3) 208-210° C 10.71, 14.52, 16.02, 17.79, 19.01,26.34,28.52,29.77 (IC) Hot water 213- 21.75,24.28,26.91 214°C The procedure for obtaining the crystalline form of Temozolomide in J. Med. Chem, 1992, 35(18), 3377-3382 is not disclosed and the IR data given for Temozolomide is: 1755, 1725,1675 cm"1 The inventors of the present invention have come out with a unique crystalline form of crude Temozolomide as a DMSO solvate. SUMMARY OF THE INVENTION The present invention relates to a process for the preparation of Temozolomide of Formula I with high yield and purity. In one aspect, the present invention provides a process for the preparation of Temozolomide of Formula I, comprising the steps of, 1) reacting the compound of formula (II) with sodium nitrite in a suitable solvent(s) and at suitable temperature to get compound of the formula (III); 2) reacting N-methyl carbamoyl chloride (NMCC) with pyridine in a suitable solvent(s) and at suitable temperature to obtain Methyl isocyanate (MIC); 3) cyclizing the compound of formula (III) by using Methyl isocyanate (MIC) in a suitable solvent and subsequently by adding suitable antisolvent to get crude comp 4) purifying the compound of formula (I) obtained above to get pure compound of formula (I). Optionally, the step-(3) is performed in-situ after the completion of step-(2). In one aspect, the present invention provides a process for the preparation of Temozolomide of Formula (I), comprising formation of Methyl isocyanate (MIC) from N-methyl carbamoyl chloride (NMCC), and reacting formed Methyl isocyanate (MIC) with 4-carbamoyl-lH-imidazole-5-diazoniumchloride. Another embodiment of the invention provides a process for preparing Temozolomide, comprising formation of Methyl isocyanate (MIC) from N-methyl carbamoyl chloride (NMCC), and reacting formed Methyl isocyanate (MIC) with a solution comprising 4-carbamoyl-lH-imidazole-5-diazoniumchloride in dimethyl sulfoxide, dioxane, ethyl acetate N,N-dimethylformamide, N,N-dimethylacetamide or mixture thereof as a solvent. In an another embodiment, the present invention provides a crystalline form X of crude Temozolomide, which can be characterized by its powder X-ray diffraction pattern as depiceted in Fig. 4; thermo gravimetric analysis (TGA) as depicted in Fig. 5 and an IR spectrum as depicted in Fig. 6 and process for preparation thereof. BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS FIG. 1 is an X-ray powder diffraction pattern of Temozolomide prepared according to present invention. FIG.2 is a Differential scanning calorimetry of Temozolomide prepared according to present invention. FIG.3 is an Infrared absorption spectrum of Temozolomide prepared according to present invention. FIG. 4 is an X-ray powder diffraction pattern of the crystalline form X of crude Temozolomide according to present invention. FIG.5 is thermal gravimetric analysis (TGA) of the crystalline form X of crude Temozolomide according to present invention. FIG.6 is an Infrared absorption spectrum (IR) of the crystalline of crystalline form X of crude Temozolomide according to present invention. DETAILED DESCRIPTION As used herein, the term "TMZ" refers to Temozolomide. As used herein, the term "MIC" refers to Methyl isocyanate. As used herein, the term "NMCC" refers to N-methyl carbamoyl chloride. As used herein, the term "reflux temperature" refers to the boiling point of the solvent. As used herein, the term "DMSO" refers to dimethyl sulfoxide. As used herein, the term "IPA" refers to isopropyl alcohol. As used herein, the term "RT" refers to room temperature. As used herein, the term "RM" refers to reaction mass As used herein, the term "DMF" refers to dimethylformamide As used herein, the term "MDC" refers to Dichloromethane As used herein, the term "THF" refers to Tetrahydrofuran As used herein, the term "DIPE" refers to Diisopropyl ether As used herein, the term "MTBE" refers to methyl tert.butyl ether The present invention provides an improved process for the preparation of Temozolomide as depicted in Scheme 1. Scheme 1: Accordingly, the invention provides a process for the preparation of Temozolomide comprising the steps of, 1) reacting the compound of formula (II) with sodium nitrite and HC1 in a suitable solvent(s) and at suitable temperature to get compound of the formula (III). 2) reacting N-methyi carbamoyl chloride (NMCC) with pyridine in a suitable solvent(s) and at suitable temperature to obtain Methyl isocyanate (MIC). 3) cyclizing the compound of formula (III) by using Methyl isocyanate (MIC) in a suitable solvent and optionally isolated by suitable antisolvents. Further step-(3) could also be performed in-situ after the completion of step-(2). 4) purifying compound of formula (I) as obtain in above step to get pure compound of formula (I)- The suitable solvent used in step (1) is water and the reaction mixture in step (1) is maintained at -5°C to 5°C. Preferably, the temperature is at 0 to 5°C. The suitable solvents used in step (2) are selected from but not limited to suitable esters like ethyl acetate and isopropyl acetate, chlorinated solvents like chloroform, dichloromethane, nitriles like acetonitrile, hydrocarbons like toluene, xylene, chlorobenzene, ketones like acetone, methyl ethyl ketone, ethers like diethyl ether, 1,4-dioxane, DIPE, MTBE, THF and their suitable mixtures. The quantity of N-methyl carbamoyl chloride (NMCC) used to produce Methyl isocyanate (MIC) that is sufficient for complete reaction ranges from about 0.7 to about 5 times the weight of the compound of formula (III). Methyl isocyanate (MIC) is produced and directly reacted with the compound of formula (III). The reaction mixture in step (2) is maintained at 30 to 150°C. Preferably, the temperature is at 50 to 130 °C. The suitable solvent used in step (3) is selected from suitable esters like ethyl acetate and isopropyl acetate, chlorinated solvents like chloroform, dichloromethane, nitriles like acetonitrile, hydrocarbons like toluene, xylene, chlorobenzene, ketones like acetone, methyl ethyl ketone, ethers like diethyl ether, 1,4-dioxane, DIPE, MTBE, THF, aprotic polar solvents such as DMF, DMSO, DMA and their suitable mixtures. The preferred solvent used in step-3 are dimethyl sulfoxide, dioxane, ethyl acetate N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane or mixture thereof. The reaction mixture in step (3) is maintained at 20 to 60°C. Preferably the temperature is maintained at 25 to 35°C. After the completion of the reaction the Temozolomide may be isolated by diluting the reaction mixture with suitable solvent or by adding suitable anti-solvent; and isolating the Temozolomide by removing the solvents. Removing the solvents may be performed by various techniques which may include, for example, one or more of filtration, filtration under vacuum, evaporation, decantation, and centrifugation. The suitable antisolvents used in step (3) may be selected from suitable alcohols like methanol, ethanol, isopropanol, butanol, 1,2-dimethoxy ethanol, 2-methoxy ethanol, 2-ethoxy ethanol and ethylene glycol; esters like ethyl acetate and isopropyl acetate;chlorinated solvents like chloroform, dichloromethane; nitriles like acetonitrile; hydrocarbons like toluene, xylene, chlorobenzene; ketones like acetone, methyl ethyl ketone; ethers like diethyl ether, 1,4-dioxane, DIPE, MTBE, THF; aprotic polar solvents such as DMF, DMSO, DMA, water, or their suitable mixtures. In an embodiment, the present invention provides a crystalline form X of crude Temozolomide. In an embodiment this crystalline form may be present either in partially crystalline form or may exist either in hydrated, solvated as well as non-solvated forms. The present invention disclosed crystalline form X of crude Temozolomide characterized by an XPRD peaks at about 7.34, 8.66, 10.94, 12.86, 14.99, 17.37, 19.04, 21.97, 22.38, 23.87, 26.17, 26.80, 30.06 and 30.29° ±0.2 degrees 29; and an XPRD pattern substantially in accordance with the pattern in Fig. 4. The crystalline form X of crude Temozolomide can be further characterized by an XPRD peaks at about 7.34, 8.66, 10.94,-12.86, 14.99, 17.37, 19.04, 21.97, 22.38, 23.87, 26.17, 26.80, 30.06 and 30.29° +_0.2 degrees 26; and a weight loss of about 27.45 % at a temperature up to 155 °C, due to loss of dimethyl sulfoxide, as measured by TGA. The crystalline form X of crude Temozolomide can be further characterized by TGA substantially in accordance with Fig. 5. The crystalline form X of crude Temozolomide is a solvated form of Temozolomide, and preferably a DMSO solvate. The crystalline form X of crude Temozolomide is further also characterized by IR absorption spectrum having characteristic peaks value at 3419.90, 3379.40, 3115.14, 1734.06, 1681.98, 1458.23, 1357.93, 1265.35, 1028.09, 713.69 ± 4 cm"1; and an IR absorption spectrum substantially in accordance with the Fig. 6. The crystalline form X of crude Temozolomide has better stability and also it is non hygroscopic. In another embodiment, the invention provides a process for the synthesis of crystalline form X of crude Temozolomide by reacting 4-Carbamoyl-lH-imidazole-5-diazoniumchloride with methyl isocyanate (MIC) in DMSO and isolation by addition of suitable antisolvents. Preferred temperature for the synthesis of crystalline form X of crude Temozolomide is 20 to 60°C and preferably the temperature is about 25 to 35 °C. The suitable antisolvents used for the preparation of crystalline form X of crude Temozolomide may be selected from suitable esters such as ethyl acetate, isopropyl acetate and the like or suitable mixtures thereof. The suitable solvent used in step (4) is selected from suitable alcohols like methanol, ethanol,isopropanol, butanol, 1,2-dimethoxy ethanol, 2-methoxy ethanol, 2-ethoxy ethanol and ethylene glycol; esters like ethyl acetate and isopropyl acetate; chlorinated solvents like chloroform, dichloromethane; nitriles like acetonitrile; hydrocarbons like toluene, xylene, chlorobenzene; ketones like acetone, methyl ethyl ketone; ethers like diethyl ether, 1,4-dioxane, DIPE, MTBE, THF; aprotic polar solvents such as DMF, DMSO, DMA, water and their suitable mixtures. Suitable solvent that can be used and more preferred is acetone and water in ratio from about 1: 1 to about 1:5; and more preferred ratio is about 3:1 or 1:3 by volume. The reaction mixture in step (4) is maintained at 55 to 60°C. A polymorphic form of Temozolomide obtained according to the process of the present invention is characterized by an XPRD pattern substantially in accordance with the pattern in Fig. 1; an XPRD peaks at 20 about 10.76, 13.17, 14.61, 16.11, 16.74, 17.93, 19.02, 19.53,20.61, 21.39, 23.14, 23.72, 25.14, 26.43, 27.17, 27.74, 28.73, 29.76 and 30.25° ±02 degrees 26; a DSC thermogram comprising onset at about 199.06 ° C ± 2 ° C and peak set about 202.87 ° C ± 2 ° C; an IR absorption spectrum having characteristic peaks value at 3421.83, 3389.04, 3190.37, 3115.14, 1759.14, 1734.06, 1678.13, 734.90, 709.83 ± 4 cm-1; and combination thereof. Analytical method: i) The complete x-ray powder spectrum was recorded with a Rigaku D/Max 2200 VPC X-ray powder diffractometer mode! using copper radiation. The X-ray diffraction pattern was recorded by keeping the instrument parameters as below: X-ray: Cu/40kv/30mA, Diverging slit: 1°, Scattering slit: 1°, Receiving slit: 0.15 mm, Monochromator RS : 0.8 mm, Counter: Scintillation counter, Scan mode: Continuous, Scan speed: 3.000°/min.', Sampling width: 0.020°, Scan axes: 2 theta vs CPS, Scan range: 2° to 40.0', Theta offset: 0.000 ii) Differential scanning calorimetric analysis was carried out in a DSC-60 model from Shimadzu (S/W: TA-60WS Aquisition version 2.1.0.0) by keeping following parameters, Sample Size: Approx. l-2mg, Sample Pans: Hermetic/Crimping Pans, Start Temperature: 50°C, End Temperature: 300°C, Rate of Heating: 10 °C/min., Purge Gas: Nitrogen, Flowrate: 20 ml/min iii) The infrared (IR) spectrum has been recorded on a Shimadzu FTIR-8400 model spectrophotometer, between 400 cm"1 and 4000 cm"1, with a resolution of 4 cm'1 in a KBr pellet. The process is further described by the following non-limiting examples, which provides the preferred mode of carrying out the process of the present invention. It is to be appreciated that several alterations, modifications, optimizations of the processes described herein are well within the scope of a person skilled in the art and such alterations, modifications, optimizations etc. should be construed to be within the scope of the present inventive concept as is disclosed anywhere in the specification. Exam pie-1 Preparation of 4-carbamovl-lH-imidazole-5-diazonium chloride In a suitable vessel charged 180 ml water and 7.2 gm (104.35 mmol) sodium nitrite under stirring and cooled to 0-5°C. Subsequently, 5-amino-4-imidazole-carboxamide.HCl solution (AIC.HC1 solution was prepared by dissolving 15 gm of 5-aminoimidazole-4-carboxamide in a mixture of 12 ml of 36 % HC1 and 108 ml water) was added slowly in 30 minutes time interval at 0-5 °C. After the addition was completed, the reaction mixture was stirred for 45 minutes at 0-5°C and filtered. The solid obtained was washed with cold water and suck dried for 15 minutes. The solid was again washed with THF and suck dried for 15 minutes. Finally the solid was dried at 50°C for 6 hrs under vacuum to obtain 13 gm of title compound. Yield = 91.66% Purity = 97.63 % by HPLC. Example-2 Preparation of Methyl isocvanate (MIC) In a suitable vessel charged 147 ml toluene and 21 gm N-methyl carbamoyl chloride (NMCC) at 25-30°C. The RM was cooled at 5-10°C and 19.9 ml pyridine was added slowly. After addition cooling was removed and heating applied for the distillation of Methyl isocyanate (MIC). Collected distilled MIC at vapor temperature between 30-50°C. Weight of MIC = 11.78 gm Yield = 92 % Example-3 Preparation of 3-methYl-4-oxo-3,4-dihydroimidazo[5,l-dlfl,2,3,51 tetrazine-£-carboxamide In a suitable vessel Methyl isocyanate (MIC) (9.91 gm, 176.62 mmol), 60 ml dimethylsulfoxide and 4-carbamoyl-lH-imidazole-5-diazoniumchIoride (12 gm, 87.52 mmol) were charged. The reaction mixture was stirred at 25-30°C for 16 hrs and subsequently, ethyl acetate was added and reaction mixture was cooled at 0-5°C for 1H and filtered the crystalline form of crude Temzolamide, designated as Form X. The compound was dried under vacuum at 50°C for 6 hrs. Yield = 19.34 gm, Purity = 99.40 %. Crystalline form of crude Temzolamide (Form X), a PXRD substantially in accordance with Fig. 4; a TGA thermogram substantially in accordance with Fig. 5; and IR absorption spectrum substantially in accordance with Fig. 6. Example-4 Preparation of 3-methvl-4-oxo-3,4-dihvdroimidazo[5,l-dlfl,2,3,51 tetrazine-8-carboxamide In a suitable vessel Methyl isocyanate (MIC) (1.66 gm, 29.17 mmol), 10 ml dimethylsulfoxide and 4-carbamoyl-lH-imidazoIe-5-diazoniumchloride (2 gm, 14.58 mmol) were charged. The reaction mixture was stirred at 25-30°C for 16 hrs and subsequently, ethyl acetate was added and cooled reaction mixture at 0-5°C for 1H and filtered the crystalline form of crude Temzolamide, designated as Form X. The compound was dried under vacuum at 50°C for 6 hrs. Yield = 2.77 gm (98.05%), Purity - 100 %. Example-5 Preparation of 3-methvl-4-oxo-3,4-dihvdroimidazo[5,1-d] 11,23.51 tetrazine-8-carboxamide In a suitable vessel Methyl isocyanate (MIC) (0.21 gm, 3.65 mmol) 0.8 ml dimethylsulfoxide: dioxane (1:1) and 4-carbamoyl-lH-imidazole-5-diazoniumchloride (0.25 gm, 1.823 mmol) were charged. The reaction mixture was stirred at 25-30°C for 16 hrs and subsequently ethyl acetate was added and cooled reaction mixture at 0-5 °C for 1H and filtered. The compound was dried under vacuum at 50 °C for 6 hrs. Yield = 0.2 gm (74.57%), Purity = 85.88%. Example-6 Preparation of 3-methvl-4-oxo-3,4-dihvdroiinidazo[5,l-dl [1,23,51 tetrazine-8-carboxamide In a suitable vessel Methyl isocyanate (MIC) (0.21 gm, 3.65 mmol), 1.25 ml dimethylsulfoxide: dioxane (7:3) and 4-carbamoyl-lH-imidazole-5-diazoniumchloride (0.25 gm, 1.823 mmol) was charged. The reaction mixture was stirred at 25-30°C for 16 hrs and subsequently ethyl acetate was added and cooled the reaction mixture at 0-5°C for 1H and filtered. The compound was dried under vacuum at 50°C for 6 hrs. Yield = 0.2 gm (74.57%), Purity = 87.88%. Exampie-7 Preparation of 3-methyI-4-oxo-3,4-dihydroimidazo[5,1-d] [1,2,3,51 tetrazine-8-carboxamide In a suitable vessel Methyl isocyanate (MIC) (0.42 gm, 7.29 mmol), 2.5 ml dimethylsulfoxide: dioxane (8:2) and 4-carbamoyl-lH-imidazole-5-diazoniumchloride (0.5 gm, 3.65 mmol) was charged. The reaction mixture was stirred at 25-30°C for 16 hrs and subsequently, ethyl acetate was added and cooled reaction mixture at 0-5 °C for 1H and filtered. The compound was dried under vacuum at 50°C for 6 hrs. Yield = 0.575 gm (81.21%) Purity = 100%. Example-8 Preparation of 3-methyl-4-oxo-3,4-dihvdroimidazo[5,1-d][l,2,3,51 tetrazine-8-carboxamide In a suitable vessel Methyl isocyanate (MIC) (0.21 gm, 3.65 mmol), 1.25 ml dimethylsulfoxide: dioxane (9:1) and 4-carbamoyl-lH-imidazole-5-diazoniumchloride (0.25 gm, 1.823 mmol) were charged. The reaction mixture was stirred at 25-30°C for 16hrs and subsequently, ethyl acetate was added and cooled reaction mixture at 0-5°C for 1H and filtered. The compound was dried under vacuum at 50°C for 6 hrs. Yield: 0.245 gm (69.2%) Purity = 100 %. Example-9 Preparation of 3-methvI-4-oxo-3,4-dihydroimidazo[5,l-dl [1,23,51 tetrazine-8-carboxamide In a suitable vessel Methyl isocyanate (MIC) (2.55 gm, 44.67 mmol), 7.3 ml ethyl acetate and 4-carbamoyl-lH-imidazole-5-diazohiumchloride (0.5 gm, 3.65 mmol) were charged. The reaction mixture was stirred at 25-30°C for 21 days. The solid was filtered and washed with diethyl ether. The compound was dried under line vacuum for 15 minute. Yield: 0.605 gm (85.45%) Purity = 99.61 %. Example-10 Purification of 3-methvl-4-oxo-3,4-dihydroimidazo[5,l-dl [1,2,3,5] tetrazine-8-carboxamide In a suitable vessel lgm 3-methyl-4-oxo-3,4-dihydroimidazo[5,l-d][ 1,2,3,5] tetrazine-8-carboxamide and 30 ml Acetone: water (3:1) mixture was charged and heated to 55-60°C to get clear solution. Activated carbon (0.05 gm) was added to the reaction mixture and maintained 55-60°C for 30 min and filtered the reaction mixture over hyflo-bed. Cooled filtrate to 0-5°C for 1H. Filtered solid and dried under vacuum at 50°C for 6 hrs. Yield = 0.705 gm (70.5%). Purity = 100 %. Exam ple-11 Purification of 3-methYl-4-oxo-3,4-dihvdroimidazo[5,l-dl [1,23.51 tetrazine-8-carboxamide In a suitable vessel 1 gm 3-methyI-4-oxo-3,4-dihydroimidazo[5,l-d][l,2,3,5] tetrazine-8-carboxamide and 27 ml Acetone: water (1:3) mixture was charged and heated to 55-60°C to get clear solution. Activated carbon (0.05 gm) was added to the reaction mixture and maintained 55-60°C for 30 min and filtered the reaction mixture over hyflo-bed. Cooled filtrate to 0-5°C for 1H. Filtered solid and dried under vacuum at 50°C for 6 hrs. Yield = 0.664 gm (66.4 %). Purity = 99.24 %. Exam ple-12 Purification of 3-methvl-4-oxo-3,4-dihvdroimidazo[5 ,1-d][l,2,3,51 tetrazine-8-carboxamide In a suitable vessel 16 gm 3-methyl-4-oxo-3,4-dihydroimidazo[5,l-d][l,2,3,5] tetrazine-8-carboxamide and 480 ml Acetone: water (3:1) mixture was charged and heated to 55-60°C to get clear solution. Activated carbon (0.8 gm) was added to the reaction mixture and maintained 55-60°C for 30 min and filtered the reaction mixture over hyflo-bed. Cooled filtrate to 0-5oC for 1H. Filtered solid and dried under vacuum at 50°C for 6 hrs. Yield = 10.45 gm (65.3 %). Purity = 100 %. Assay = 99.48% We claim: 1. A process for the preparation of Temozolomide comprising i) reacting the compound of formula (II) with sodium nitrite and HC1 in water at 0-5 °C to obtain compound of the formula (III); ii) cyclisation of the compound of formula (III) by using Methyl isocyanate (MIC) in a suitable solvent to obtain crude temzolamide; iii) purification of crude Temzolamide to obtain Temzolamide. 2. The process as claimed in claim 1 in step (ii), wherein suitable solvent used is selected from suitable hydrocarbons; halogenated hydrocarbons; alcohols; ketones; ester; aprotic polar solvents or mixtures thereof. 3. The process as claimed in claim 2 wherein the solvents are selected from dimethylsulfoxide, dioxane, ethyl acetate N,N-dimethylforrnamide, N,N-dimethylacetamide, dichloromethane or mixture thereof 4. The process as claimed in claim I in step (iii), wherein suitable solvent used is selected from alcohols; esters; chlorinated solvents; nitriles; hydrocarbons ketones; ethers; aprotic polar solvents or any mixtures thereof. 5. The process for the preparation of Methyl isocyanate (MIC) as claimed in claim 1 wherein N-methyl carbamoyl chloride (NMCC) is reacted with pyridine in suitable solvents) and at suitable temperature. 6. The process as claimed in claim 5, wherein said suitable solvent used is selected from suitable hydrocarbons; chlorinated solvents; esters; nitriles; ethers; ketones; aprotic polar solvents or suitable mixtures thereof 7. The process as claimed in claims 6 wherein the solvent is a hydrocarbon solvent. 8. The process as claimed in claim 5, wherein suitable temperature is in the range of from 30 to 150°C. 9. The process for preparing Temozolomide, comprising preparing Methyl isocyanate (MIC) from N-methyl carbamoyl chloride (NMCC), and reacting the formed Methyl isocyanate (MIC) with 4-carbamoyl-lH-imidazole-5-diazoniumchloride. 10. The process as claimed in claim 9, wherein the vapor of Methyl isocyanate (MIC) is condensed into a solution containing 4-carbamoyl-lH-imidazole-5-diazoniumchloride. 11. The process as claimed in claim 9, wherein 4-carbamoyl- lH-imidazole-5-diazoniumchloride is in made into a solution with solvents selected from suitable hydrocarbons; halogenated hydrocarbons; alcohols; ketones; ester; aprotic polar solvents or suitable mixtures thereof. 12. The process as claimed in claim 11, wherein the preferred solvent is selected from dimethyl sulfoxide, dioxane, ethyl acetate N,N-dimethyl formamide, N,N-dimethyl acetamide, dichloromethane or mixture thereof. 13. The process as claimed in claim 9, wherein methyl isocyanate (MIC) is prepared at temperatures between about 50 °C to about 130 °C. 14. The process as claimed in claim 9, wherein the weight of N-methyl carbamoyl chloride (NMCC) used is about 0.7 to about 5 times the weight of 4-carbamoyl- lH-imidazole-5-diazoniumchloride. 15. The crystalline form X of crude Temozolomide having characteristic powder X-ray diffraction pattern having peaks expressed as 29 at about 7.34, 8.66, 10.94, 12.86, 14.99, 17.37, 19.04, 21.97, 22.38, 23.87, 26.17, 26.80, 30.06 and 30.29° ±0.2 degrees 2G. 16. The crystalline form X of crude Temozolomide as claimed in claim 15, characterized by a PXRD pattern as depicted in Figure 4. 17. The crystalline form X of crude Temozolomide as claimed in claim 15, further characterized by a weight loss of about 27.45 % at a temperature up to 155 °C, as measured by TGA. 18. The crystalline form X of crude Temozolomide as claimed in claim 15, characterized by a TGA as depicted in Figure 5. 19. A process for preparing the crystalline form X of crude Temozolomide as claimed in claim 15 to 18 comprising reaction of 4-carbamoyl-lH-imidazole-5-diazoniumchloride with methyl isocyanate (MIC) in DMSO and isolation done by adding suitable antisolvent. 20. The process as claimed in claim 19, wherein the suitable antisolvent used is selected from suitable ester or suitable mixtures thereof. 21. The process as claimed in claim 19, wherein the suitable solvent used is selected from suitable hydrocarbons; halogenated hydrocarbons; alcohols; ketones; ester; aprotic polar solvents and mixtures thereof. 22. The suitable solvent as claimed in claim 21 is selected from dimethylsulfoxide, dioxane, ethyl acetate N,N-dimethyl formamide, N,N-dimethyl acetanride, dichloromethane or suitable mixtures thereof.

Full Text

FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
& The Patent Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
"NEW POLYMORPH OF TEMZOLAMIDE AND PROCESSES FOR THE PREPARATION THEREOF"
We, CADILA HEALTHCARE LIMITED, of Zydus Tower, Satellite Cross Road, Ahmedabad -380 015, Gujarat, India.
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Temozolomide. The present invention also relates to novel crystalline form X of crude Temozolomide. The crystalline form X of crude Temozolomide is a solvated form of Temozolomide, and preferably a DMSO solvate. BACKGROUNG OF THE ART
Temozolomide (also known as 3,4-dihydro-3-methyl-4-oxoimidazo[5,l-d]-l,2,3,5-
tetrazine-8-carboxamide; 8-carbamoyl-3-methyiimidazo[5,1 -d]-1,2,3,5-tetrazin-4(3H)-one;
methazolastone; M & B 39831 ; CCRG-81045; NSC-362856; Temodal; Temodar) is a well known anti-neoplastic agent that acts as an alkylating agent. Its primary application is in the treatment of brain cancer (e.g., glioma). Temozolomide is indicated in the treatment of refractory anaplastic astrocytoma, a form of brain tumour, glioblastoma multiforme and metastatic melanoma.
Temozolomide is a prodrug, being cleaved in a multi-step pathway firstly to liberate an unstable monomethyl triazeno Imidazole carboxamide (MTIC), which then suffers proteolytic fragmentation to generate a highly-reactive methylating agent (methanediazonium ion) and 5-aminoimidazole-4-carboxamide (see, e.g., Arrowsmith et al, 2002, J. Med. Chem. Vol. 45, pp. 5458-5470).
TMZ is the abbreviation commonly used for a compound having the chemical name 3,4-dihydro-3- methyl-4-oxoimidazo[5,l-d]-l,2,3,5-tetrazine-8-carboxamide or 3-methyl-8-amino carbonyl-imidazo [5,l-d]-l,2,3,5-tetrazin-4(3H)-one. It has the following structure.

Formula (I)
It is described in US 5260291 together with compounds of broadly similar activity such as higher alkyl analogs at the 3-position. Also described therein is a process for the preparation of Temozolomide and its derivatives involving condensation of 5-diazo-5H-imidazole-4 carboxamide (and related compounds) with an isocyanate. However, the process described is very slow, involving reaction times of up to 3 weeks.
J. Med. Chem. 1984, 27, 196-201 describes a process wherein 5-amino-lH-imidazole-4-carboxamide is converted into 5-diazo-lH-imidazole-4-carboxamide, which is then cyclised with methyl isocyanate in dichloromethane. However, the cycloaddition of Methyl isocyanate (MIC)

requires a long reaction time i.e. 20 days and also it is essential to limit dichloromethane content in the final API below 600 ppm as per ICH guideline.
US 2002/0133006 discloses a process for the preparation of compound of formula (I) using methyl hydrazine which is a toxic and flammable liquid, hence not feasible on industrial scale and the final isolation involves tedious workup including column chromatography. J. Org. Chem. 1997, 62, 7288-7294 describes a process wherein the final step of diazotization provides equal-formation of aza-hypoxanthine and Temozolomide, resulting in low yield. This literature does not provide the experimental procedure for work up.
US 2005/0131227 describe a process involving the use of a bulky protecting group on nitrogen of the primary amide for cyclisation in presence of LiCl to minimize the undesired cyclisation product. After cyclisation the protecting group has to be removed which makes the process more laborious with more number of steps.
US 2007/0225496 describes a process for the preparation of Temozolomide comprising pyrrolysing N'-methyl-N,N-diphenyl urea to form Methyl isocyanate (MIC) vapour and slowly condensing the Methyl isocyanate (MIC) vapour into a reservoir of a solution of 5-diazo-5H-imidazoIe-4-carboxamide in dimethyl sulphoxide. A yield of crude Temozolomide of 68.6% is reported. During filtration of the crude Temozolomide produced in this process, excess Methyl isocyanate (MIC) vapors may be released to the atmosphere.
US 2480088 discloses a process for the preparation of Methyl isocyanate (MIC) comprising the conversion of N-methyl carbamoyl chloride (NMCC) by using toluene in the presence of pyridine.
However, US4082787 also disclosed the process for the preparation of Methyl isocyanate (MIC) but a drawback associated with this process is that it is not possible to charge whole of the raw material in one slot and the process also required column for final distillation.
It has now surprisingly been found that the compounds described in US5260291 can be prepared by a new process developed under the present invention that avoids many of the problems encountered in the prior art.
The process of the present invention is a convenient process for the preparation of Temozolomide with desired purity and yield by using better preparation techniques, which are eco-friendly, cost-effective, robust and well suited for use on an industrial scale. The US 2007/0225496 patent describes the process for the preparation of Temozolomide comprises of pyrrolysing N'-Methyl-N,N-diphenyl urea to form Methyl isocyanate (MIC) vapour which slowly condenses the Methyl isocyanate (MIC) vapour into a reservoir of a solution of 5-diazo-lH-imidazole-4-carboxamide in dimethyl sulphoxide whereby they have employed 300 °C temperature for pyrolysis.

The inventors of the present invention have come out with a unique process whereby MIC is prepared by using N-methyl carbamoyl chloride (NMCC) and does not employ that much of higher temperature as mentioned in prior art. The present process is thus found to be more industrially feasible as compared to the conventional processes for the preparation of Temozolomide.
It is well known that pharmaceutical solids can exist in different physical forms. Polymorphism is often characterized as the ability of a drug substance to exist as two or more crystalline forms that have different arrangements and/or conformations of the molecules in the crystalline lattice.
These polymorphs differ in internal solid state structure, and, therefore, possess different chemical and physical properties, including packing, thermodynamic, spectroscopic, kinetic, interfacial, and mechanical properties. These properties can have a direct impact on drug product quality/performance, including stability, dissolution, therapeutic efficacy and bioavailability. Some of these forms may or may not be suitable therapeutically, but may have important benefits as being suitable as intermediates to obtain the therapeutically active form in better yield, purity etc. Therefore, such alternate forms have their utility as intermediates and are therefore are attractive commercially. We herein disclose such alternate forms having one or more of the above advantages, in addition/alternate to the known utility of the base and salt.
The most stable polymorphic form of a drug substance is often used in a formulation because it has the lowest potential for conversion, from one polymorphic form to another. On the other hand, metastable and even amorphous forms may be chosen to enhance the bioavailability of the drug product. An amorphous form, being a disorganized solid mass, does not need to lose crystal structure before dissolution in the gastric juices, and, thus, often has greater bioavailability than a crystalline form. Further, such forms can be used for obtaining the stable form/marketed form.
The preparation of new crystalline form of active pharmaceutical ingredients provides opportunities to improve the performance characteristics of a pharmaceutical product. Such preparation enlarge the repertoire of materials that formulation scientist have available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic and so the present invention provides new crystalline form Temozolomide.
US 5260291 disclose different crystalline forms of Temozolomide. The solvent used for getting specific crystalline form, its M.P. and IR mentioned in below table;

Example No. Solvent M.P IR cm-1
Example 1 MethanoI+ diethyl ether 160-210 °C
Example 4(1) Acetone :Water (3:1) 210° C 3410,3205, 1758, 1730,1678
Example 4 (II) Acetone :water (1:3) 210° C ' 3430,3200, 1740, 1675
Example 4 (III) Hot water 215°C 3450, 3380, 3200, 1742, 1688, 1640
Example 9 Acetonitrile About 200°C **
US 7615632 B2 discloses nine crystalline forms of Temozolomide. Form I has a powder XRD (PXRD) pattern with peaks at 10.8, 11.3, 19.1, 17.7, 29.0 ±0.2 degree theta. Form II has a powder XRD (PXRD) pattern with peaks at 29.0, 10.8, 11.3, 14.5, 16.0, 17.9, 19.1, 17.7 ±0.2 degree theta. Form III has a powder XRD (PXRD) pattern with peaks at 10.8, 13.2, 14.7, 16.2, 16.8, 18.0,19.1,19.6, 21.5, 26.6, 23.8, 28.8, 29.8 ±0.2 degree theta. Form IV has a powder XRD (PXRD) pattern with peaks at 4.2, 12.6,14.8,16.7 ±0.2 degree theta. Form V has a powder XRD (PXRD) pattern with peaks at 11.4, 13.2, 21.5, 26.5, 26.8, 30.9 ±0.2 degree theta. Form VI has a powder XRD (PXRD) pattern with peaks at 8.4, 14.4, 25.1±0.2 degree theta. Form VII has a powder XRD (PXRD) pattern with peaks at 14.1, 28.2, 22.2, 23.0, 23.9 ±0.2 degree theta. Form VIII has a powder XRD (PXRD) pattern with peaks at 9.3, 10.8, 11.8, 14.7, 26.6, 28.2, 28.8, 19.7 ±0.2 degree theta. Form IX has a powder XRD (PXRD) pattern with peaks at 13.7, 16.1, 23.2, 30.1, 26.4,17.5,19.9 ±0.2 degree theta.
Chinese Journal of pharmaceuticals- (2003), 34(4), 178-180 disclosed three polymorph of Temozolomide as mentioned in below table;

Preparation of polymorph Solvent M.P XRD-2-theta
(IA) Acetone: Water (3:1) 203-205° C 10.61, 14.50, 16.40, 17.79, 18.99,26.28,28.55,29.74
(IB) Acetone :water (1:3) 208-210° C 10.71, 14.52, 16.02, 17.79, 19.01,26.34,28.52,29.77
(IC) Hot water 213- 21.75,24.28,26.91

214°C
The procedure for obtaining the crystalline form of Temozolomide in J. Med. Chem, 1992, 35(18), 3377-3382 is not disclosed and the IR data given for Temozolomide is: 1755, 1725,1675 cm"1
The inventors of the present invention have come out with a unique crystalline form of crude Temozolomide as a DMSO solvate. SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of Temozolomide of Formula I with high yield and purity.
In one aspect, the present invention provides a process for the preparation of Temozolomide of Formula I, comprising the steps of,
1) reacting the compound of formula (II) with sodium nitrite in a suitable solvent(s) and at suitable temperature to get compound of the formula (III);
2) reacting N-methyl carbamoyl chloride (NMCC) with pyridine in a suitable solvent(s) and at suitable temperature to obtain Methyl isocyanate (MIC);

3) cyclizing the compound of formula (III) by using Methyl isocyanate (MIC) in a suitable solvent and subsequently by adding suitable antisolvent to get crude comp
4) purifying the compound of formula (I) obtained above to get pure compound of formula (I). Optionally, the step-(3) is performed in-situ after the completion of step-(2).
In one aspect, the present invention provides a process for the preparation of Temozolomide of Formula (I), comprising formation of Methyl isocyanate (MIC) from N-methyl carbamoyl chloride (NMCC), and reacting formed Methyl isocyanate (MIC) with 4-carbamoyl-lH-imidazole-5-diazoniumchloride.
Another embodiment of the invention provides a process for preparing Temozolomide, comprising formation of Methyl isocyanate (MIC) from N-methyl carbamoyl chloride (NMCC), and reacting formed Methyl isocyanate (MIC) with a solution comprising 4-carbamoyl-lH-imidazole-5-diazoniumchloride in dimethyl sulfoxide, dioxane, ethyl acetate N,N-dimethylformamide, N,N-dimethylacetamide or mixture thereof as a solvent.
In an another embodiment, the present invention provides a crystalline form X of crude Temozolomide, which can be characterized by its powder X-ray diffraction pattern as depiceted in Fig. 4; thermo gravimetric analysis (TGA) as depicted in Fig. 5 and an IR spectrum as depicted in Fig. 6 and process for preparation thereof.

BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS
FIG. 1 is an X-ray powder diffraction pattern of Temozolomide prepared according to present
invention.
FIG.2 is a Differential scanning calorimetry of Temozolomide prepared according to present
invention.
FIG.3 is an Infrared absorption spectrum of Temozolomide prepared according to present
invention.
FIG. 4 is an X-ray powder diffraction pattern of the crystalline form X of crude Temozolomide
according to present invention.
FIG.5 is thermal gravimetric analysis (TGA) of the crystalline form X of crude Temozolomide
according to present invention.
FIG.6 is an Infrared absorption spectrum (IR) of the crystalline of crystalline form X of crude
Temozolomide according to present invention.
DETAILED DESCRIPTION
As used herein, the term "TMZ" refers to Temozolomide.
As used herein, the term "MIC" refers to Methyl isocyanate.
As used herein, the term "NMCC" refers to N-methyl carbamoyl chloride.
As used herein, the term "reflux temperature" refers to the boiling point of the solvent.
As used herein, the term "DMSO" refers to dimethyl sulfoxide.
As used herein, the term "IPA" refers to isopropyl alcohol.
As used herein, the term "RT" refers to room temperature.
As used herein, the term "RM" refers to reaction mass
As used herein, the term "DMF" refers to dimethylformamide
As used herein, the term "MDC" refers to Dichloromethane
As used herein, the term "THF" refers to Tetrahydrofuran
As used herein, the term "DIPE" refers to Diisopropyl ether
As used herein, the term "MTBE" refers to methyl tert.butyl ether
The present invention provides an improved process for the preparation of Temozolomide as depicted in Scheme 1. Scheme 1:

Accordingly, the invention provides a process for the preparation of Temozolomide comprising the steps of,
1) reacting the compound of formula (II) with sodium nitrite and HC1 in a suitable solvent(s) and
at suitable temperature to get compound of the formula (III).
2) reacting N-methyi carbamoyl chloride (NMCC) with pyridine in a suitable solvent(s) and at
suitable temperature to obtain Methyl isocyanate (MIC).
3) cyclizing the compound of formula (III) by using Methyl isocyanate (MIC) in a suitable solvent and optionally isolated by suitable antisolvents. Further step-(3) could also be performed in-situ after the completion of step-(2).
4) purifying compound of formula (I) as obtain in above step to get pure compound of formula
(I)-
The suitable solvent used in step (1) is water and the reaction mixture in step (1) is maintained at -5°C to 5°C. Preferably, the temperature is at 0 to 5°C.
The suitable solvents used in step (2) are selected from but not limited to suitable esters like ethyl acetate and isopropyl acetate, chlorinated solvents like chloroform, dichloromethane, nitriles like acetonitrile, hydrocarbons like toluene, xylene, chlorobenzene, ketones like acetone,

methyl ethyl ketone, ethers like diethyl ether, 1,4-dioxane, DIPE, MTBE, THF and their suitable mixtures.
The quantity of N-methyl carbamoyl chloride (NMCC) used to produce Methyl isocyanate (MIC) that is sufficient for complete reaction ranges from about 0.7 to about 5 times the weight of the compound of formula (III). Methyl isocyanate (MIC) is produced and directly reacted with the compound of formula (III).
The reaction mixture in step (2) is maintained at 30 to 150°C. Preferably, the temperature is at 50 to 130 °C.
The suitable solvent used in step (3) is selected from suitable esters like ethyl acetate and isopropyl acetate, chlorinated solvents like chloroform, dichloromethane, nitriles like acetonitrile, hydrocarbons like toluene, xylene, chlorobenzene, ketones like acetone, methyl ethyl ketone, ethers like diethyl ether, 1,4-dioxane, DIPE, MTBE, THF, aprotic polar solvents such as DMF, DMSO, DMA and their suitable mixtures.
The preferred solvent used in step-3 are dimethyl sulfoxide, dioxane, ethyl acetate N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane or mixture thereof. The reaction mixture in step (3) is maintained at 20 to 60°C. Preferably the temperature is maintained at 25 to 35°C.
After the completion of the reaction the Temozolomide may be isolated by diluting the reaction mixture with suitable solvent or by adding suitable anti-solvent; and isolating the Temozolomide by removing the solvents.
Removing the solvents may be performed by various techniques which may include, for example, one or more of filtration, filtration under vacuum, evaporation, decantation, and centrifugation.
The suitable antisolvents used in step (3) may be selected from suitable alcohols like methanol, ethanol, isopropanol, butanol, 1,2-dimethoxy ethanol, 2-methoxy ethanol, 2-ethoxy ethanol and ethylene glycol; esters like ethyl acetate and isopropyl acetate;chlorinated solvents like chloroform, dichloromethane; nitriles like acetonitrile; hydrocarbons like toluene, xylene, chlorobenzene; ketones like acetone, methyl ethyl ketone; ethers like diethyl ether, 1,4-dioxane, DIPE, MTBE, THF; aprotic polar solvents such as DMF, DMSO, DMA, water, or their suitable mixtures.
In an embodiment, the present invention provides a crystalline form X of crude Temozolomide. In an embodiment this crystalline form may be present either in partially crystalline form or may exist either in hydrated, solvated as well as non-solvated forms. The present invention disclosed crystalline form X of crude Temozolomide characterized by an XPRD peaks at about 7.34, 8.66, 10.94, 12.86, 14.99, 17.37, 19.04, 21.97, 22.38, 23.87, 26.17,

26.80, 30.06 and 30.29° ±0.2 degrees 29; and an XPRD pattern substantially in accordance with the pattern in Fig. 4.
The crystalline form X of crude Temozolomide can be further characterized by an XPRD peaks at about 7.34, 8.66, 10.94,-12.86, 14.99, 17.37, 19.04, 21.97, 22.38, 23.87, 26.17, 26.80, 30.06 and 30.29° +_0.2 degrees 26; and a weight loss of about 27.45 % at a temperature up to 155 °C, due to loss of dimethyl sulfoxide, as measured by TGA. The crystalline form X of crude Temozolomide can be further characterized by TGA substantially in accordance with Fig. 5.
The crystalline form X of crude Temozolomide is a solvated form of Temozolomide, and preferably a DMSO solvate. The crystalline form X of crude Temozolomide is further also characterized by IR absorption spectrum having characteristic peaks value at 3419.90, 3379.40, 3115.14, 1734.06, 1681.98, 1458.23, 1357.93, 1265.35, 1028.09, 713.69 ± 4 cm"1; and an IR absorption spectrum substantially in accordance with the Fig. 6. The crystalline form X of crude Temozolomide has better stability and also it is non hygroscopic.
In another embodiment, the invention provides a process for the synthesis of crystalline form X of crude Temozolomide by reacting 4-Carbamoyl-lH-imidazole-5-diazoniumchloride with methyl isocyanate (MIC) in DMSO and isolation by addition of suitable antisolvents. Preferred temperature for the synthesis of crystalline form X of crude Temozolomide is 20 to 60°C and preferably the temperature is about 25 to 35 °C. The suitable antisolvents used for the preparation of crystalline form X of crude Temozolomide may be selected from suitable esters such as ethyl acetate, isopropyl acetate and the like or suitable mixtures thereof.
The suitable solvent used in step (4) is selected from suitable alcohols like methanol, ethanol,isopropanol, butanol, 1,2-dimethoxy ethanol, 2-methoxy ethanol, 2-ethoxy ethanol and ethylene glycol; esters like ethyl acetate and isopropyl acetate; chlorinated solvents like chloroform, dichloromethane; nitriles like acetonitrile; hydrocarbons like toluene, xylene, chlorobenzene; ketones like acetone, methyl ethyl ketone; ethers like diethyl ether, 1,4-dioxane, DIPE, MTBE, THF; aprotic polar solvents such as DMF, DMSO, DMA, water and their suitable mixtures.
Suitable solvent that can be used and more preferred is acetone and water in ratio from about 1: 1 to about 1:5; and more preferred ratio is about 3:1 or 1:3 by volume. The reaction mixture in step (4) is maintained at 55 to 60°C.
A polymorphic form of Temozolomide obtained according to the process of the present invention is characterized by an XPRD pattern substantially in accordance with the pattern in Fig. 1; an XPRD peaks at 20 about 10.76, 13.17, 14.61, 16.11, 16.74, 17.93, 19.02, 19.53,20.61, 21.39, 23.14, 23.72, 25.14, 26.43, 27.17, 27.74, 28.73, 29.76 and 30.25° ±02 degrees 26; a DSC thermogram comprising onset at about 199.06 ° C ± 2 ° C and peak set about 202.87 ° C ±

2 ° C; an IR absorption spectrum having characteristic peaks value at 3421.83, 3389.04,
3190.37, 3115.14, 1759.14, 1734.06, 1678.13, 734.90, 709.83 ± 4 cm-1; and combination
thereof.
Analytical method:
i) The complete x-ray powder spectrum was recorded with a Rigaku D/Max 2200 VPC X-ray
powder diffractometer mode! using copper radiation. The X-ray diffraction pattern was recorded
by keeping the instrument parameters as below:
X-ray: Cu/40kv/30mA, Diverging slit: 1°, Scattering slit: 1°, Receiving slit: 0.15 mm, Monochromator RS : 0.8 mm, Counter: Scintillation counter,
Scan mode: Continuous, Scan speed: 3.000°/min.', Sampling width: 0.020°, Scan axes: 2 theta
vs CPS, Scan range: 2° to 40.0', Theta offset: 0.000
ii) Differential scanning calorimetric analysis was carried out in a DSC-60 model from
Shimadzu (S/W: TA-60WS Aquisition version 2.1.0.0) by keeping following parameters,
Sample Size: Approx. l-2mg, Sample Pans: Hermetic/Crimping Pans,
Start Temperature: 50°C, End Temperature: 300°C, Rate of Heating: 10 °C/min., Purge Gas:
Nitrogen, Flowrate: 20 ml/min
iii) The infrared (IR) spectrum has been recorded on a Shimadzu FTIR-8400 model
spectrophotometer, between 400 cm"1 and 4000 cm"1, with a resolution of 4 cm'1 in a KBr pellet.
The process is further described by the following non-limiting examples, which provides the preferred mode of carrying out the process of the present invention. It is to be appreciated that several alterations, modifications, optimizations of the processes described herein are well within the scope of a person skilled in the art and such alterations, modifications, optimizations etc. should be construed to be within the scope of the present inventive concept as is disclosed anywhere in the specification. Exam pie-1 Preparation of 4-carbamovl-lH-imidazole-5-diazonium chloride
In a suitable vessel charged 180 ml water and 7.2 gm (104.35 mmol) sodium nitrite under stirring and cooled to 0-5°C. Subsequently, 5-amino-4-imidazole-carboxamide.HCl solution (AIC.HC1 solution was prepared by dissolving 15 gm of 5-aminoimidazole-4-carboxamide in a mixture of 12 ml of 36 % HC1 and 108 ml water) was added slowly in 30 minutes time interval at 0-5 °C.
After the addition was completed, the reaction mixture was stirred for 45 minutes at 0-5°C and filtered. The solid obtained was washed with cold water and suck dried for 15 minutes. The solid was again washed with THF and suck dried for 15 minutes. Finally the solid was dried at 50°C for 6 hrs under vacuum to obtain 13 gm of title compound.

Yield = 91.66% Purity = 97.63 % by HPLC.
Example-2
Preparation of Methyl isocvanate (MIC)
In a suitable vessel charged 147 ml toluene and 21 gm N-methyl carbamoyl chloride (NMCC) at 25-30°C. The RM was cooled at 5-10°C and 19.9 ml pyridine was added slowly. After addition cooling was removed and heating applied for the distillation of Methyl isocyanate (MIC). Collected distilled MIC at vapor temperature between 30-50°C. Weight of MIC = 11.78 gm Yield = 92 % Example-3 Preparation of 3-methYl-4-oxo-3,4-dihydroimidazo[5,l-dlfl,2,3,51 tetrazine-£-carboxamide
In a suitable vessel Methyl isocyanate (MIC) (9.91 gm, 176.62 mmol), 60 ml dimethylsulfoxide and 4-carbamoyl-lH-imidazole-5-diazoniumchIoride (12 gm, 87.52 mmol) were charged. The reaction mixture was stirred at 25-30°C for 16 hrs and subsequently, ethyl acetate was added and reaction mixture was cooled at 0-5°C for 1H and filtered the crystalline form of crude Temzolamide, designated as Form X. The compound was dried under vacuum at 50°C for 6 hrs. Yield = 19.34 gm, Purity = 99.40 %. Crystalline form of crude Temzolamide (Form X), a PXRD substantially in accordance with Fig. 4; a TGA thermogram substantially in accordance with Fig. 5; and IR absorption spectrum substantially in accordance with Fig. 6. Example-4 Preparation of 3-methvl-4-oxo-3,4-dihvdroimidazo[5,l-dlfl,2,3,51 tetrazine-8-carboxamide
In a suitable vessel Methyl isocyanate (MIC) (1.66 gm, 29.17 mmol), 10 ml dimethylsulfoxide and 4-carbamoyl-lH-imidazoIe-5-diazoniumchloride (2 gm, 14.58 mmol) were charged. The reaction mixture was stirred at 25-30°C for 16 hrs and subsequently, ethyl acetate was added and cooled reaction mixture at 0-5°C for 1H and filtered the crystalline form of crude Temzolamide, designated as Form X. The compound was dried under vacuum at 50°C for 6 hrs. Yield = 2.77 gm (98.05%), Purity - 100 %. Example-5 Preparation of 3-methvl-4-oxo-3,4-dihvdroimidazo[5,1-d] 11,23.51 tetrazine-8-carboxamide
In a suitable vessel Methyl isocyanate (MIC) (0.21 gm, 3.65 mmol) 0.8 ml dimethylsulfoxide: dioxane (1:1) and 4-carbamoyl-lH-imidazole-5-diazoniumchloride (0.25 gm, 1.823 mmol) were charged. The reaction mixture was stirred at 25-30°C for 16 hrs and subsequently ethyl acetate was added and cooled reaction mixture at 0-5 °C for 1H and filtered. The compound was dried under vacuum at 50 °C for 6 hrs. Yield = 0.2 gm (74.57%), Purity = 85.88%.

Example-6
Preparation of 3-methvl-4-oxo-3,4-dihvdroiinidazo[5,l-dl [1,23,51 tetrazine-8-carboxamide
In a suitable vessel Methyl isocyanate (MIC) (0.21 gm, 3.65 mmol), 1.25 ml dimethylsulfoxide: dioxane (7:3) and 4-carbamoyl-lH-imidazole-5-diazoniumchloride (0.25 gm, 1.823 mmol) was charged. The reaction mixture was stirred at 25-30°C for 16 hrs and subsequently ethyl acetate was added and cooled the reaction mixture at 0-5°C for 1H and filtered. The compound was dried under vacuum at 50°C for 6 hrs. Yield = 0.2 gm (74.57%), Purity = 87.88%. Exampie-7 Preparation of 3-methyI-4-oxo-3,4-dihydroimidazo[5,1-d] [1,2,3,51 tetrazine-8-carboxamide
In a suitable vessel Methyl isocyanate (MIC) (0.42 gm, 7.29 mmol), 2.5 ml dimethylsulfoxide: dioxane (8:2) and 4-carbamoyl-lH-imidazole-5-diazoniumchloride (0.5 gm, 3.65 mmol) was charged. The reaction mixture was stirred at 25-30°C for 16 hrs and subsequently, ethyl acetate was added and cooled reaction mixture at 0-5 °C for 1H and filtered. The compound was dried under vacuum at 50°C for 6 hrs. Yield = 0.575 gm (81.21%) Purity = 100%. Example-8 Preparation of 3-methyl-4-oxo-3,4-dihvdroimidazo[5,1-d][l,2,3,51 tetrazine-8-carboxamide
In a suitable vessel Methyl isocyanate (MIC) (0.21 gm, 3.65 mmol), 1.25 ml dimethylsulfoxide: dioxane (9:1) and 4-carbamoyl-lH-imidazole-5-diazoniumchloride (0.25 gm, 1.823 mmol) were charged. The reaction mixture was stirred at 25-30°C for 16hrs and subsequently, ethyl acetate was added and cooled reaction mixture at 0-5°C for 1H and filtered. The compound was dried under vacuum at 50°C for 6 hrs. Yield: 0.245 gm (69.2%) Purity = 100 %.
Example-9 Preparation of 3-methvI-4-oxo-3,4-dihydroimidazo[5,l-dl [1,23,51 tetrazine-8-carboxamide
In a suitable vessel Methyl isocyanate (MIC) (2.55 gm, 44.67 mmol), 7.3 ml ethyl acetate and 4-carbamoyl-lH-imidazole-5-diazohiumchloride (0.5 gm, 3.65 mmol) were charged. The reaction mixture was stirred at 25-30°C for 21 days. The solid was filtered and washed with diethyl ether. The compound was dried under line vacuum for 15 minute. Yield: 0.605 gm (85.45%) Purity = 99.61 %. Example-10 Purification of 3-methvl-4-oxo-3,4-dihydroimidazo[5,l-dl [1,2,3,5] tetrazine-8-carboxamide
In a suitable vessel lgm 3-methyl-4-oxo-3,4-dihydroimidazo[5,l-d][ 1,2,3,5] tetrazine-8-carboxamide and 30 ml Acetone: water (3:1) mixture was charged and heated to 55-60°C to get

clear solution. Activated carbon (0.05 gm) was added to the reaction mixture and maintained 55-60°C for 30 min and filtered the reaction mixture over hyflo-bed. Cooled filtrate to 0-5°C for 1H. Filtered solid and dried under vacuum at 50°C for 6 hrs. Yield = 0.705 gm (70.5%). Purity = 100 %. Exam ple-11
Purification of 3-methYl-4-oxo-3,4-dihvdroimidazo[5,l-dl [1,23.51 tetrazine-8-carboxamide In a suitable vessel 1 gm 3-methyI-4-oxo-3,4-dihydroimidazo[5,l-d][l,2,3,5] tetrazine-8-carboxamide and 27 ml Acetone: water (1:3) mixture was charged and heated to 55-60°C to get clear solution. Activated carbon (0.05 gm) was added to the reaction mixture and maintained 55-60°C for 30 min and filtered the reaction mixture over hyflo-bed. Cooled filtrate to 0-5°C for 1H. Filtered solid and dried under vacuum at 50°C for 6 hrs. Yield = 0.664 gm (66.4 %). Purity = 99.24 %. Exam ple-12
Purification of 3-methvl-4-oxo-3,4-dihvdroimidazo[5 ,1-d][l,2,3,51 tetrazine-8-carboxamide In a suitable vessel 16 gm 3-methyl-4-oxo-3,4-dihydroimidazo[5,l-d][l,2,3,5] tetrazine-8-carboxamide and 480 ml Acetone: water (3:1) mixture was charged and heated to 55-60°C to get clear solution. Activated carbon (0.8 gm) was added to the reaction mixture and maintained 55-60°C for 30 min and filtered the reaction mixture over hyflo-bed. Cooled filtrate to 0-5oC for 1H. Filtered solid and dried under vacuum at 50°C for 6 hrs. Yield = 10.45 gm (65.3 %). Purity = 100 %. Assay = 99.48%

We claim:
1. A process for the preparation of Temozolomide comprising
i) reacting the compound of formula (II) with sodium nitrite and HC1 in water at 0-5 °C to obtain compound of the formula (III);

ii) cyclisation of the compound of formula (III) by using Methyl isocyanate (MIC) in a suitable solvent to obtain crude temzolamide;

iii) purification of crude Temzolamide to obtain Temzolamide.
2. The process as claimed in claim 1 in step (ii), wherein suitable solvent used is selected from suitable hydrocarbons; halogenated hydrocarbons; alcohols; ketones; ester; aprotic polar solvents or mixtures thereof.
3. The process as claimed in claim 2 wherein the solvents are selected from dimethylsulfoxide, dioxane, ethyl acetate N,N-dimethylforrnamide, N,N-dimethylacetamide, dichloromethane or mixture thereof
4. The process as claimed in claim I in step (iii), wherein suitable solvent used is selected from alcohols; esters; chlorinated solvents; nitriles; hydrocarbons ketones; ethers; aprotic polar solvents or any mixtures thereof.
5. The process for the preparation of Methyl isocyanate (MIC) as claimed in claim 1 wherein N-methyl carbamoyl chloride (NMCC) is reacted with pyridine in suitable solvents) and at suitable temperature.
6. The process as claimed in claim 5, wherein said suitable solvent used is selected from suitable hydrocarbons; chlorinated solvents; esters; nitriles; ethers; ketones; aprotic polar solvents or suitable mixtures thereof
7. The process as claimed in claims 6 wherein the solvent is a hydrocarbon solvent.

8. The process as claimed in claim 5, wherein suitable temperature is in the range of from 30 to 150°C.
9. The process for preparing Temozolomide, comprising preparing Methyl isocyanate (MIC) from N-methyl carbamoyl chloride (NMCC), and reacting the formed Methyl isocyanate (MIC) with 4-carbamoyl-lH-imidazole-5-diazoniumchloride.
10. The process as claimed in claim 9, wherein the vapor of Methyl isocyanate (MIC) is condensed into a solution containing 4-carbamoyl-lH-imidazole-5-diazoniumchloride.
11. The process as claimed in claim 9, wherein 4-carbamoyl- lH-imidazole-5-diazoniumchloride is in made into a solution with solvents selected from suitable hydrocarbons; halogenated hydrocarbons; alcohols; ketones; ester; aprotic polar solvents or suitable mixtures thereof.
12. The process as claimed in claim 11, wherein the preferred solvent is selected from dimethyl sulfoxide, dioxane, ethyl acetate N,N-dimethyl formamide, N,N-dimethyl acetamide, dichloromethane or mixture thereof.
13. The process as claimed in claim 9, wherein methyl isocyanate (MIC) is prepared at temperatures between about 50 °C to about 130 °C.
14. The process as claimed in claim 9, wherein the weight of N-methyl carbamoyl chloride (NMCC) used is about 0.7 to about 5 times the weight of 4-carbamoyl- lH-imidazole-5-diazoniumchloride.
15. The crystalline form X of crude Temozolomide having characteristic powder X-ray diffraction pattern having peaks expressed as 29 at about 7.34, 8.66, 10.94, 12.86, 14.99, 17.37, 19.04, 21.97, 22.38, 23.87, 26.17, 26.80, 30.06 and 30.29° ±0.2 degrees 2G.
16. The crystalline form X of crude Temozolomide as claimed in claim 15, characterized by a PXRD pattern as depicted in Figure 4.

17. The crystalline form X of crude Temozolomide as claimed in claim 15, further characterized by a weight loss of about 27.45 % at a temperature up to 155 °C, as measured by TGA.
18. The crystalline form X of crude Temozolomide as claimed in claim 15, characterized by a TGA as depicted in Figure 5.
19. A process for preparing the crystalline form X of crude Temozolomide as claimed in claim 15 to 18 comprising reaction of 4-carbamoyl-lH-imidazole-5-diazoniumchloride with methyl isocyanate (MIC) in DMSO and isolation done by adding suitable antisolvent.
20. The process as claimed in claim 19, wherein the suitable antisolvent used is selected from
suitable ester or suitable mixtures thereof.

21. The process as claimed in claim 19, wherein the suitable solvent used is selected from
suitable hydrocarbons; halogenated hydrocarbons; alcohols; ketones; ester; aprotic polar
solvents and mixtures thereof.
22. The suitable solvent as claimed in claim 21 is selected from dimethylsulfoxide, dioxane,
ethyl acetate N,N-dimethyl formamide, N,N-dimethyl acetanride, dichloromethane or
suitable mixtures thereof.

Documents:

http://ipindiaonline.gov.in/patentsearch/GrantedSearch/viewdoc.aspx?id=5U3WzQFyq7sLRga5ipHvDw==&loc=vsnutRQWHdTHa1EUofPtPQ==

« Previous Patent

Next Patent »

Patent Number

272907

Indian Patent Application Number

162/MUM/2012

PG Journal Number

19/2016

Publication Date

06-May-2016

Grant Date

02-May-2016

Date of Filing

18-Jan-2012

Name of Patentee

CADILA HEALTHCARE LIMITED

Applicant Address

ZYDUS TOWER, SATELLITE CROSS ROAD, AHMEDABAD-380 015, GUJARAT, INDIA

Inventors:

#	Inventor's Name	Inventor's Address
1	SINGH, KUMAR, KAMLESH, LAXMI	CADILA HEALTHCARE LIMITED, ZYDUS TOWER, SATELLITE CROSS ROAD, AHMEDABAD-380 015, GUJARAT, INDIA
2	NARODE, SUNIL, DNYANESHWAR	CADILA HEALTHCARE LIMITED, ZYDUS TOWER, SATELLITE CROSS ROAD, AHMEDABAD-380 015, GUJARAT, INDIA
3	THAKER, TIRTH, HARIKRISHNA	CADILA HEALTHCARE LIMITED, ZYDUS TOWER, SATELLITE CROSS ROAD, AHMEDABAD-380 015, GUJARAT, INDIA
4	CHARAN, GANPAT, DAN, SHIMBHU	CADILA HEALTHCARE LIMITED, ZYDUS TOWER, SATELLITE CROSS ROAD, AHMEDABAD-380 015, GUJARAT, INDIA

PCT International Classification Number

C07D 487/04

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA