FIELD OF THE INVENTION
The present invention relates to an improved and industrially applicable process for preparing temozolomide of formula I,
(Formula Removed)
BACKGROUND OF THE INVENTION
Temozolomide of formula I, is an antitumor drug and is chemically known as 3-methyl-8-aminocarbonyl-imidazole[5,l-d]-l,2,3,5-tetrazin-4(3H)-one.
(Formula Removed)
It is indicated for treating patients with malignant glioma such as cancer, breast cancer, refractory anaplastic, astrocytoma, i.e. patient at first relapse who have experienced disease progression in malignant glioma, glioblastoma multiform and anaplastic astrocytoma, on a drug containing a nitrosourea and procarbazine. It is sold in the US market as hard capsules containing 5 mg, 20 mg, 100 mg or 250 mg as temodar® by Schering corporation.
Temozolomide and compounds having similar activity (higher alkyl analogues at the 3-position) were first disclosed in US patent 5,260,291. According to 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
the above patent is 200 °C (recrystallized from acetonitrile); 210°C with effervescence (recrystallized from acetone and water), and 215°C with effervescence and darkening (recrystallized from hot water). Major drawbacks of the process is the longer reaction duration of three to four weeks for completion of reaction. Further, the process described in the patent involves the use of low boiling and extremely toxic, methyl isocyanate, which is very difficult to handle, especially on the industrial scale, so its use should be avoided in the industrial synthesis. Further, the cycloaddition reaction requires a very long period of 21 to 28 days and makes the process unattractive on the industrial scale.
US patent 6,844,434 describes the synthesis of temozolomide by the cyclization of 5-amino-l-(N-methyl-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 the isolation of product makes the process not suitable to employ at industrial level.
US patent 7,087,751 disclose a process for the preparation of N-methyl-5-amino imidazole-1,4-dicarboxamide, a key intermediate of temozolomide, by the reaction sequence as described below:
(Formula Removed)
Above patent does not disclose conversion of intermediate of formula IV to temozolomide but discloses the synthesis of temozolomide by the cyclisation of N-
protected intermediate of formula IV followed by deprotection. The process disclosed in the patent involves more number of steps thus not amenable at industrial scale.
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 of formula IV,
(Formula Removed)
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.
US patent publication 2007/0225496 exemplified a process for the 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. In 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 the preparation of temozolomide by the diazotization of the imidazole intermediate of formula IV at least in the presence of metal halide, a source of nitrous acid and an acid to form
acidic solution of temozolomide, where temozolomide forms a salt with acid. The desired product i.e. temozolomide is then isolated from the acidic solution by extraction with a solvent. Patent application describes two methods for the extraction of temozolomide. In first method, temozolomide is extracted from the reaction mixture by the counter current extraction using continuous liquid-liquid extraction. 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. 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. In 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 the 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 mixture is treated with 5% HC1 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. In 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 from the commercial point of view.
In view of the above, most of the references use extraction technique to isolate temozolomide from the reaction mass obtained after diazotization and cyclisation. We have not found any reference wherein solid temozolomide is isolated from reaction mass. 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. Thus, present invention fulfills the need of the art and provides an improved and industrially applicable process for preparation of temozolomide.
OBJECTIVE OF THE INVENTION
The principal objective of the present invention is to provide an improved and industrially applicable process for the preparation of temozolomide.
Another objective of the present invention is to provide a process for isolation of solid temozolomide from reaction mass by filtration or centrifugation.
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.
Still 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 Removed)
which proves to be efficient and industrially advantageous. The process comprises the steps of:
a), diazotizing and cyclizing the compound of formula IV,
(Formula Removed)
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 DESCRIPTION OF DRAWINGS
Figure 1: Shows morphology of the crystals of temozolomide
Figure 2: Shows morphology of the crystals of temozolomide in enlarged view
Figure 3: Shows a differential scanning calorimetry (DSC) thermogram of temozolomide
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved and industrially applicable process for the preparation of temozolomide of formula I wherein isolation of temozolomide from reaction mixture is carried out by filtration and thus avoiding extraction with huge volumes of solvents. .
According to one aspect of the invention, the present invention provides a process for the preparation of temozolomide by reaction of compound of formula IV with 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 °C. The reaction can be conducted in a suitable solvent that include water; or alcohols such as methanol, ethanol; aliphatic ketones such as acetone, diethyl ketone; ethers such as tetrahydrofuran, 1,2-dimethoxy ethane, 1,2-diethoxy ethane, 1,4-dioxane; alkyl nitrile such as acetonitrile, propionitrile and the like or mixture thereof. Source of nitrous acid employed in the reaction includes alkali metal salt of nitrous acid like sodium nitrite, potassium nitrite which can be used as such or in solution with a solvent that includes water; aliphatic alcohols such as methanol, ethanol; aliphatic ketones such as acetone, diethyl ketone; water miscible ethers such as tetrahydrofuran, 1,2-dimethoxy ethane, 1,2-diethoxy ethane, 1,4-dioxane; alkyl nitrile such as acetonitrile, propionitrile and the like or mixture thereof. Suitable acid can be organic or inorganic acid. Organic acids include carboxylic acid preferably lower alkanoic acid such as formic acid, acetic acid, propionic acid, tartaric acid, oxalic acid and the like or mixture thereof; and inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid and the like or combination thereof. The reaction mixture is stirred for 30 minutes to 8 hours, preferably till the completion of the reaction. The completion of the reaction is monitored by a suitable chromatographic techniques such as HPLC
or TLC till the absence of compound of formula IV in the reaction mixture. After completion of reaction, it is optional and advantageous to add solid calcium chloride or sodium chloride to the reaction mixture. Thereafter, reaction mixture is stirred for few minutes to few hours at ambient temperature. Optionally, the reaction mixture is cooled to -15 to 5° C. Temozolomide thus precipitated can be isolated from the reaction mixture by employing the filtration or centrifugation.
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 80°C 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 alkyl 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 °C 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 slurried with a suitable solvent that includes aliphatic ketones such as acetone, diethyl ketone and the like or mixture thereof or mixture thereof with water in any suitable proportions at 0-5°C, or at ambient temperature. Thereafter the 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 recovery 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, N,N-dimethylacetamide, N,N-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 mixture of solvents for the extraction of temozolomide from the filtrate, as it circumvents the need of large amount of the 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 °C 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.
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.
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 °C as shown in Figure 3. 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 °C. It is known that molecule of temozolomide usually melts at around 199-201°C and shows effervesce or melts completely around 210 °C (with decomposition).
The starting material of compound of formula IV can be prepared by the methods already known in the art or by the condensation of compound of formula II with compound of formula III by the method as described in our co-pending application.
The major advantage of the present invention lies in high yield and purity of the final API, temozolomide. Secondly, the present invention 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..
Having described the invention with reference to certain preferred aspects, other aspects will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail by the preparation of the compounds of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
EXAMPLES
Example 1: Preparation of temozolomide
Acetic acid (90 g) was slowly added toa mixture of N-methyl-5-aminoimidazole-l,4-dicarboxamide (100 g) and sodium nitrite (50 g) in water (1000 ml) at -5 to 0 °C. The reaction mixture was stirred at 0-5 °C 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 warmed to 25-30 °C. The reaction mixture was stirred at 25-30 °C for 3 hours and cooled to -5 to 0 °C. The reaction mixture was further stirred for 1 hour, filtered and suck dried to give 92 g of crude temozolomide.
Example 2: 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 °C. 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 °C 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 °C for 1 hour. The reaction mixture was cooled to 5-10 °C, stirred for 30 minutes and filtered. The resulting wet solid was stirred with acetone (150 ml) for 60 minutes at 25-30 °C, filtered and dried under vacuum at 55-60 °C 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 °C. Activated charcoal (10 g) was added to the resulting mixture and the was stirred for 10 minutes at 40-45 °C. The reaction mixture was filtered while hot through hyflo bed. Thereafter, reaction mixture was slowly cooled to 5-10 °C 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 °C for 1 hour, cooled to 5-10 °C. 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 60-70°C. Activated charcoal was added and stirred for 30 minutes at 60-70°C. The resulting solution was filtered through hyflo bed and washed with hot dimethylsulfoxide (30 ml). The resulting filtrate was cooled to 5-10 °C and stirred for 30 minutes at 5-10 °C. 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 °C, filtered, and dried under vacuum at 55-60°C for 15 hours to give 50 g of the title compound having purity 99.97% by HPLC.
Example 3: 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 0 °C. The reaction mixture was stirred at 0-5 °C for 1.5 hours. After the completion of reaction, calcium chloride (250 g) was added to the reaction mass and heated to 25-30 °C. The reaction mixture was stirred at 25-30 °C for 3 hours and cooled to -5 to 0 °C. 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 °C. Charcoal (5 g) was added to the resulting solution and reaction mixture was stirred at 60-70 °C for 10 minutes. The reaction mass was filtered through hyflo bed, filtrate was cooled to 5-10 °C and stirred for 60 minutes. Solid thus precipitated was filtered and suck dried 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 °C, 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 °C, stirred 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 °C for 1 hour and cooled to 5-10 °C. 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 °C, filtered and dried under vacuum at 55-60°C for 15 hours to give 28 g of temozolomide having purity 99.97% by HPLC.
Example 4: Preparation of temozolomide
Acetic acid (450 ml) was slowly added to a suspension of 5-amino- N1-methyl-1H-imidazole-1, 4-dicarboxamide (500 g) and sodium nitrite (250 g) in water (5.0 L) at -5 to 0 °C. The reaction mixture was stirred at 0-5 °C 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 °C for 2 hours. The reaction mixture was cooled to -5 to 0 °C and stirred for 1 hour. The resulting solid was filtered and suck dried to give 430 g of crude temozolomide.
Example 5: Purification of temozolomide
Method A: Crude temozolomide (215 g) was dissolved in dimethylsulfoxide (1125 ml) at 70-75 °C 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 °C 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 °C. Activated charcoal was added to the solution and stirred for 30 minutes. The solution was filtered through hyflo, filtrate was cooled to 0-5 °C 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 B: 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 0-5 °C 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 °C. 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 °C 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 °C and suck dried to give title compound which stirred in acetone (150 ml) for 30 minutes at 25-30 °C. The mixture was filtered and suck dried to give 66.6 g of temozolomide. having purity 99.88 % by HPLC.
Method C: Crude temozolomide (25 g) was dissolved in acetone: water (3:1, 500 ml) at 40-45°C. 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 °C and stirred for 30 minutes. The reaction mixture was seeded with temozolomide crystal and reaction mixture was further cooled to -10 to -5 °C. The solid thus formed was filtered and dried to give 15 g of temozolomide having purity 99.82 % by HPLC, melting point: 208-210 °C.
Method D: Crude temozolomide (350 g) was dissolved in acetone: water (3:1, 7 L) at 40-45°C. 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 °C and stirred for 60 minutes. The solid thus precipitated was filtered and dried under vacuum at 55-60 °C 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 °C.
Method E: Crude temozolomide (225 g) was dissolved in acetone: water (3:1, 11.25 L) at 40-45°C. The reaction mixture was slowly cooled to 15-20°C and allowed to stand for 12 hours. The solid thus precipitated was filtered and dried under vacuum at 55-60 °C for 15 hours to give 80 g of the title compound having purity 99.89 % by HPLC, melting point: 208-210 °C.

WE CLAIM:
1). A process for the preparation of temozolomide of formula I,
(Formula Removed)
comprising the steps of:
a), diazotizing and cyclizing the compound of formula IV,
(Formula Removed)
in the presence of 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.
2). The process according to claim 1, wherein in step a) source of nitrous acid include alkali metal salt of nitrous acid or solution thereof with a solvent.
3). The process according to claim 2, wherein in alkali metal salt of nitrous acid is sodium nitrite.
4). The process according to claim 2, wherein solvent includes water; alcohols such as methanol, ethanol; aliphatic ketones such as acetone, diethyl ketone; ethers such as tetrahydrofuran, 1,2-dimethoxy ethane, 1,2-diefhoxy ethane, 1,4-dioxane; alkyl nitriles such as acetonitrile, propionitrile and the like or mixture thereof.
5). The process according to claim 1, wherein in step a) an acid is selected from organic acid which include carboxylic acid, preferably lower alkanoic acid such as
formic 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.
6). The process according to claim 1, wherein in step b) reaction mixture is cooled at a temperature of-15 to 5 °C.
7). The process according to claim 1, wherein in step c) precipitate of temozolomide is isolated by filtration or centrifugation.
8). The process according to claim 1, 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.
9). The process according to claim 8, wherein solvent is preferably selected from dimethylsulfoxide or mixture of acetone and water.
10). Temozolomide having plate shape morphology.