- Alternative syntheses of the antitumour drug temozolomide avoiding the use of methyl isocyanate
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Ethyl (8-carbamoyl-3,4-dihydro-4-oxoimidazo[5,1-d] -1,2,3,5-tetrazin-3-yl)acetate 5 can be prepared by two routes starting from 5-aminoimidazole-4-carboxamide 2; hydrolysis of 5 to the corresponding carboxylic acid 6 followed by Barton radical decarboxylation gives the antitumour imidazotetrazinone temozolomide 1.
- Wang,Stevens,Thomson
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Read Online
- Identification and physicochemical characteristics of temozolomide process-related impurities
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In this article the crystal structures of the starting material TZ-5 and the key intermediate TZ-6 of temozolomide (TZ-7), an anticancer therapeutic agent, are presented, together with their spectroscopic and thermal characteristics. Both compounds crystallize in the triclinic P-1 space group. X-ray crystallography studies proved that the compound TZ-6 exists as a monohydrate. A complete structural assignment was obtained for the signals in the 1H-, 13C- and 15N-nuclear magnetic resonance spectra and the structures were confirmed by Fourier-Transform infrared and Raman spectroscopy. The article describes the importance of the high purity of TZ-6 during the small-scale plant production of TZ-7 in a desired polymorphic form III with the purity higher than 99.50%, according to an HPLC method.
- Laszcz, Marta,Kubiszewski, Marek,Jedynak, Lukasz,Kaczmarska, Monika,Kaczmarek, Lukasz,Luniewski, Wojciech,Gabarski, Krzysztof,Witkowska, Anna,Kuziak, Krzysztof,Malinska, Maura
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Read Online
- Temozolomide intermediate compound VII
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The invention belongs to the field of pharmaceutical and chemical engineering, and particularly relates to a novel intermediate VII VII used for synthesizing temozolomide by using an imidazole azo intermediate compound as a raw material, and a novel method for synthesizing temozolomide by using the intermediate. The method is economical, environment-friendly, high in yield and suitable for industrial production.
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Paragraph 0092-00100
(2021/10/13)
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- Temozolomide intermediate compound IV
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The invention belongs to the field of pharmaceutical chemical engineering, and particularly relates to a IV novel method for synthesizing temozolomide by reacting a nitroimidazole type substrate with methylhydrazine, and the method IV avoids the use of dangerous chemical reagents, and the synthesized intermediate does not generate new impurities. The method is economical, environment-friendly, high in yield and suitable for industrial production.
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Paragraph 0026; 0090-0098
(2021/10/13)
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- Preparation method of temozolomide
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The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of temozolomide, which comprises the following steps: reacting a nitrosoimidazole compound with methylhydrazine to generate an azo compound IV, further hydrolyzing the compound IV to obtain an intermediate V, and further performing nucleophilic substitution on the compound V and p-nitrophenyl chloroformate to obtain a new intermediate VII; and carrying out intermediate VIIcyclization to obtain temozolomide. According to the method, the use of methyl isocyanate with high toxicity and the process of instable diazo compound intermediates are avoided, the synthesized intermediates do not generate dimerization impurities, a green catalyst is used for replacing a traditional catalyst, the reaction is milder, the method is economical and environmentally friendly, the yield is high, and the method is suitable for industrial production.
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Paragraph 0092-0100
(2021/10/13)
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- PROCESS FOR PREPARING HIGHLY PURE TEMOZOLOMIDE
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The present invention provides a commercially viable process for preparation of highly pure Temozolomide (VI), which is useful in the treatment of cancer. The invention also provides an economically viable process for an intermediate compound of formula III useful in the process for preparing Temozolomide.
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Page/Page column 17
(2020/10/18)
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- Preparation method of temozolomide
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The invention discloses a preparation method of temozolomide, which comprises the following steps: carrying out formylation reaction on N-methylurea and a formylation reagent to obtain N-methyl-N'-formyl urea, and carrying out cyclization reaction on the N-methyl-N'-formyl urea and 2-amino-2-ethyl cyanoacetate in an acid and solvent system to obtain 1-(methylaminoformyl)-5-aminoimidazole-4-ethyl formate; with temozolomide as a raw material, performing diazotization and cyclization synergistic reaction to obtain 3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-1,2,3,5-tetrazine-8-ethyl formate, and performing amidation reaction with an amidation reagent solution under the condition to obtain temozolomide. According to the method, ideal yield and purity can be obtained under mild reaction conditions, side reactions are reduced, post-treatment is simple, adopted reagent raw materials are cheaper and easier to obtain, and the method is safe, environmentally friendly and suitable for industrial large-scale production.
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Paragraph 0070; 0071; 0079-0080; 0089-0090; 0091; 0099-0100
(2020/06/20)
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- ORAL SUSPENSION OF TEMOZOLOMIDE
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The present invention concerns a pharmaceutical composition, advantageously a liquid suspension, comprising: a. temozolomide or a salt thereof;b. at least one agent controlling the solid state of temozolomide in suspension;c. a pharmaceutically acceptable liquid vehicle, advantageously water;d. optionally at least one acid in a quantity so that the pH of the composition is below 5; or a powder blend for reconstituting said suspension.
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- Synthesis and growth-inhibitory activities of imidazo?5,1-d]-1,2,3,5-tetrazine-8-carboxamides related to the anti-tumour drug temozolomide, with appended silicon, benzyl and heteromethyl groups at the 3-position
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A series of 3-(benzyl-substituted)-imidazo?5,1-d]-1,2,3,5-tetrazines (13) and related derivatives with 3-heteromethyl groups has been synthesised and screened for growth-inhibitory activity in vitro against two pairs of glioma cell lines with temozolomide-sensitive and -resistant phenotypes dependent on the absence/presence of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). In general the compounds had low inhibitory activity with GI50 values >50 μM against both sets of cell lines. Two silicon-containing derivatives, the TMS-methylimidazotetrazine (9) and the SEM-analogue (10), showed interesting differences: compound (9) had a profile very similar to that of temozolomide with the MGMT+ cell lines being 5 to 10-fold more resistant than MGMT- isogenic partners; the SEM-substituted compound (10) showed potency across all cell lines irrespective of their MGMT status.
- Cousin, David,Hummersone, Marc G.,Bradshaw, Tracey D.,Zhang, Jihong,Moody, Christopher J.,Foreiter, Magdalena B.,Summers, Helen S.,Lewis, William,Wheelhouse, Richard T.,Stevens, Malcolm F.G.
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p. 545 - 553
(2018/03/28)
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- PROCESS FOR PREPARING TEMOZOLOMIDE AND AN INTERMEDIARY
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The present invention relates to an efficient and industrially advantageous process for preparing temozolomide and the carbamoyl-AICA intermediate through the use of N-methyl carbamoylimidazole in a good overall yield and high purity.
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Paragraph 057
(2018/07/29)
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- TEMOZOLOMIDE PROCESS
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The present invention relates to improved process for the preparation of Temozolomide Formula I. Said Temozolomide (I) is useful in the treatment of cancer.
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Page/Page column 12
(2018/07/29)
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- A tiemoazoleamine and method for synthesizing intermediate
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The invention discloses a modified optimized synthetic method for temozolomide and an intermediate thereof. The synthetic method is characterized in that a new oxidation ring-closing reagent is introduced for a reaction with lithium chloride and sodium nitrite in an aqueous solution, and the synthetic method helps to improve the yield of the reaction, increase the controllability on the reaction and avoid usage of methyl isocyanate with relatively high toxicity.
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Paragraph 0006; 0016; 0027; 0036-0040
(2019/02/02)
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- An efficient and practical radiosynthesis of [11C]temozolomide
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Temozolomide (TMZ) is a prodrug for an alkylating agent used for the treatment of malignant brain tumors. A positron emitting version, [ 11C]TMZ, has been utilized to help elucidate the mechanism and biodistribution of TMZ. Challenges in [11C]TMZ synthesis and reformulation make it difficult for routine production. A highly reproducible one-pot radiosynthesis of [11C]TMZ with a radiochemical yield of 17 ± 5% and ≥97% radiochemical purity is reported.
- Moseley, Christian K.,Carlin, Stephen M.,Neelamegam, Ramesh,Hooker, Jacob M.
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p. 5872 - 5875
(2013/02/23)
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- PROCESS FOR PREPARING TEMOZOLOMIDE
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This present invention provides an improved process for preparing Temozolomide (TMZ) stable at room temperature for at least 18 months. This present invention also relates to Temozolomide stable at room temperature for at least 18 months.
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Page/Page column 4
(2012/05/07)
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- METHODS AND INTERMEDIATES FOR THE SYNTHESIS OF 4-OXO-3,4-DIHYDRO-IMIDAZO[5,1-D][1,2,3,5]TETRAZINES
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The present invention provides a compound of general formula (II), or a salt or solvate thereof wherein A is independently -A1, -A2, -A3, -A4, -A5, -A6, or -A7, wherein: -A1 is independently C5-12heteroaryl, and is optionally substituted; -A2 is independently thioamido or substituted thioamido; -A3 is independently imidamido, substituted imidamido, N-hydroxyimidamido, or substituted N-hydroxyimidamido; -A4 is independently hydroxamic acid or hydroxamate; -A5 is independently carboxamide or substituted carboxamide; -A6 is independently aliphatic C2-6alkenyl, and is optionally substituted; and -A7 is independently carboxy or C1-4alkyl-carboxylate; and its use in the synthesis of temozolomide and analogues thereof.
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(2011/10/03)
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- IMPROVED PROCESS FOR PREPARING TEMOZOLOMIDE
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A process for preparing temozolomide by employing mild reaction and easy isolation of temozolomide is provided.
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Page/Page column 16-17
(2010/12/29)
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- PROCESS FOR THE PREPARATION OF TETRAZINE DERIVATIVES
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The present invention provides a process for the preparation of a tetrazine derivative of formula (I), or a pharmaceutically acceptable salt thereof wherein R1 represents a hydrogen atom, a straight or branched C1-C6 alkyl group, C2-C6 alkenyl group or C2-C6 alkynyl group, which C1-C6 alkyl group, C2-C6 alkenyl group and C2-C6 alkynyl group is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen atoms, straight or branched C1-C4 alkoxy groups, C1-C4 alkylthio groups, C1-C4 alkylsulphinyl groups, C1-C4 alkylsulphonyl groups and phenyl groups, which phenyl groups are unsubstituted or substituted with one or more substituents selected from C1-C4 alkyl groups, C1-C4 alkoxy groups and nitro groups; or R1 represents a C3-C8 cycloalkyl group; and R2 represents a group of formula -(C=O)NR3R4, wherein R3 and R4 are independently selected from hydrogen atoms, C1-C4 alkyl groups, C2-C4 alkenyl groups and C3-C8 cycloalkyl groups, which process comprises: i) providing a compound of formula (III), wherein R1 is as defined; R1-N=C=O ii) absorbing the compound of formula (III) into a solvent to obtain a solution of the compound of formula (III); iii) adding to the thus obtained solution a compound of formula (II), to obtain a compound of formula (I), as defined above, wherein R2 is as defined above; iv) decomposing any excess compound of formula (III) remaining by addition of water; and v) optionally salifying the thus obtained compound with a pharmaceutically acceptable acid, or base.
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(2010/07/10)
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- Synthesis and antitumor activity of 3-Methyl-4-oxo-3,4-dihydroimidazo [5,1-d][1,2,3,5]tetrazine-8-carboxylates and -carboxamides
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Seventeen novel 3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine- 8-carboxylate and -carboxamide derivatives were synthesized and evaluated for their growth inhibition in seven human solid tumor and a human leukemia HL-60 cell lines. Compound IVa showed more activity than the other compounds and the positive control temozolomide. In the presence of 40 μg/mL of IVa, the survival rate of all tested tumor cells was less than 10%. Esters displayed more potent antitumour activity than amides and temozolomide against HL-60 cells. These compounds also exhibited considerably enhanced water-solubility.
- Liu, Dan,Yang, Jian-Guo,Cheng, Jie,Zhao, Lin-Xiang
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scheme or table
p. 9427 - 9436
(2011/03/22)
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- Process for preparing temozolomide
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Described is a new process for producing temozolomide, comprising the reaction between 5-aminoimidazole-4-carboxamide and N-succinimidyl-N′-methyl carbamate and the subsequent reaction of the thus obtained carbamoyl 5-aminoimidazole-4-carboxamide with sodium nitrite. Temozolomide is then purified by chromatography on adsorbent polymeric resin and subsequent crystallization from water and acetone.
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(2010/03/02)
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- 3-SUBSTITUTED-4-OXO-3,4-DIHYDRO-IMIDAZO-[5,1-D][1,2,3,5-TETRAZINE-8-CARBOXYLIC ACID AMIDES AND THEIR USE
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The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain 3-substituted-4-oxo-3,4-dihydro-imidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid amide (collectively referred to herein as 3TM compounds). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit cell proliferation, and in the treatment of proliferative disorders such as cancer, etc., and methods of preparing such compounds.
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- AN IMPROVED PROCESS FOR THE PREPARATION OF TEMOZOLOMIDE AND ANALOGS
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A process for the preparation of compounds of formula (IA), where R=CH3 (i.e. temozolomide) comprising diazotizing a compound of the formula (IIA) where in R is as defined above in the presence of at least one metal halide, an acid and a source of nitrous acid, followed by conversion of acidic solution containing temozolomide. The conversion can be carried out by a liquid-liquid extraction technique in a water immiscible solvent. The temozolomide may be further purified in an acetone-water mixture.
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(2008/06/13)
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- PROCESS FOR PREPARING TEMOZOLOMIDE
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The present invention relates to a process for preparing temozolomide.
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Page/Page column 4-5
(2008/06/13)
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- Process for preparing temozolomide
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The present invention provides a process for preparing highly pure Temozolomide base which includes recovery from the purification mother liquors by using an anionic exchange resin. By treating Temozolomide hydrochloride with a mixture of an organic acid, a water miscible organic solvent, and water, Temozolomide free base is obtained in an acidic medium. Due to the high sensitivity of Temozolomide to basic pH values the recovery-including process is especially advantageous because it enables obtaining high yields of highly pure Temozolomide base in acidic conditions. The process for producing Temozolomide base includes hydrolysis of the starting material 8-cyano-3-methyl-[3H]-imidazo[5,1-d]-tetrazin-4-one in acidic medium to obtain highly pure Temozolomide hydrochloride in high yield.
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(2008/06/13)
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- Antitumor imidazotetrazines. 40.1 Radiosyntheses of [4-11c-carbonyl]- and [3-n-11c-methyl]-8-carbamoyl-3-methylimidazo[5,1-d]-1,2, 3,5-tetrazin-4(3h)-one (temozolomide) for positron emission tomography (PET) studies
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8-Carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (temozolomide, 1) is an anti-cancer prodrug. As part of investigations to probe its postulated mode of action using PET we have developed two rapid radiosynthetic routes for the preparation of temozolomide labeled with the short-lived positron emitter, carbon-11 (t1/2 = 20.4 min). Reaction of 5-diazoimidazole-4-carboxamide (7) with the novel labeling agent [11C-methyl] methyl isocyanate (8) gave [3-N- 11C-methyl]temozolomide (9) in 14-20% radiochemical yield from [11C-methyl] methyl isocyanate (8) (decay corrected). The position of radiolabeling in the 3-N-methyl group was confirmed by [11/13C]colabeling and subsequent carbon-13 NMR spectroscopy. Similarly, the reaction of 5-diazoimidazole-4-carboxamide (7) with [11C-carbonyl]methyl isocyanate (10) gave [4-11C-carbonyl]temozolomide (11) in 10-15% radiochemical yield from [11C-carbonyl]methyl isocyanate (10) (decay corrected). Apyrogenic samples of [3-N-11C-methyl]temozolomide (9) and [4-11C-carbonyl]temozolomide (11), with good chemical and radiochemical purities, have been prepared and used in human PET studies.
- Brown, Gavin D.,Luthra, Sajinder K.,Brock, Cathryn S.,Stevens, Malcolm F. G.,Price, Patricia M.,Brady, Frank
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p. 5448 - 5457
(2007/10/03)
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- Synthesis of temozolomide and analogs
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This invention relates to a novel process for the synthesis of temozolomide, an antitumor compound, and to intermediates useful in this novel process.
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- Synthesis of temozolomide and analogs
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This invention relates to a novel process for the synthesis of Temozolomide, an antitumor compound, and analogs, and to intermediates useful in this novel process.
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- A new synthesis of temozolomide
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An efficient condensation reaction for the synthesis of phenyloxycarbonyl substituted triazenylimidazoles was described. The condensation reaction made use of nitrosoimidazoles and phenyl methylcarbazate as the reacting products. The exposure of the triazenes to diffuse daylight induced the isomerization of the triazene-nitrogen bonds, resulting in a high yield of temozolomide.
- Wanner, Martin J.,Koomen, Gerrit-Jan
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p. 1877 - 1880
(2007/10/03)
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- Antitumor Imidazotetrazines. 35. New Synthetic Routes to the Antitumor Drug Temozolomide
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Three new pathways to the antitumor drug temozolomide (4) have been explored via intermediates 3, 6, and 7. The key intermediate 5-amino-1-(N-methylcarbamoyl)imidazole-4-carboxamide (6) has been successfully converted to 4 in 45% yield by employing sodium nitrite in aqueous tartaric acid at 0-5°C. Compound 6 is prepared from nitrophenyl carbamate 14a and methylamine or directly from 5-aminoimidazole-4-carboxamide (13) and either methyl isocyanate or N-methylcarbamoyl chloride. Temozolomide (4) is also prepared from 8-cyano-3-methylimidazo[5,1-d]-l,2,3,5-tetrazin4(3H)-One (7) by hydrolysis to the hydrochloride salt of 4 in 10 M hydrochloric acid. Compound 7 is prepared from either 5-diazoimidazole-4-carbonitrile (28) and methyl isocyanate or by diazotization of 5-amino-1-(N-methylcarbamoyl)imidazole-4-carbonitrile (25). Attempts to cyclize 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (3) with phosgene or phosgene equivalents were unsuccessful: only 2-azahypoxanthine (11) was isolated.
- Wang, Yongfeng,Stevens, Malcolm F. G.,Chan, Tze-Ming,DiBenedetto, Donald,Ding, Zhe-Xing,Gala, Dinesh,Hou, Donald,Kugelman, Max,Leong, William,Kuo, Shen-Chun,Mas, Janet L.,Schumacher, Doris P.,Shutts, Bruce P.,Smith, Lyman,Zhan, Zheng-Yun J.,Thomson, William T.
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p. 7288 - 7294
(2007/10/03)
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- A new route to the antitumour drug temozolomide, but not thiotemozolomide
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Interaction of 5-aminoimidazole-4-carboxamide with alkyl isocyanates yields N-substituted 1-carbamoylimidazoles which can be cyclised to imidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-ones, including temozolomide 3a, on nitrosation; a similar reaction with methyl isothiocyanate, followed by nitrosation, affords the nitrosomethylamino derivative 11 of a new ring-system, imidazo[l,5-b][1,2,4]thiadiazole.
- Wang, Yongfeng,Lowe, Philip R.,Thomson, William T.,Clark, Jonathan,Stevens, Malcolm F. G.
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p. 363 - 364
(2007/10/03)
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- Synthetic studies of 8-carbamoylimidazo-[5,1-D]-1,2,3,5-tetrazin-4(3H)-one: A key derivative of antitumor drug temozolomide
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5-Diazoimidazole-4-carboxamide 4 reacted with trimethylsilyl isocyanate in acetonitrile to afford 8-carbamoylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one 1, which was undergoing a methylation to give antitumour drug temozolomide 2; while 1,5-dicarbamoyl aminoimidazole 6 failed in an azo-cyclization to give 1 but accomplished a carbon-cyclization to produce 8-carbamoylimidazo[1,5-a] s-triazin-4(3H)-one 7.
- Wang,Stevens
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p. 185 - 188
(2007/10/03)
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- Antitumour imidazotetrazines. Part 33. New synthesis of the antitumour drug temozolomide using 'masked' methyl isocyanates
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Ethyl 8-carbamoyl-4-oxo-3,4-dihydroimidazo-1,2,3,5-tetrazin-3-ylacetate 6a can be prepared by treating 5-diazoimidazole-4-carboxamide 3 with ethyl isocyanatoacetate or by diazotisation of N-(5-amino-4-carbamoylimidazol-1-ylcarbonyl)glycine ethyl ester 5.Barton radical decarboxylation of the tetrazin-3-ylacetic acid 6b affords temozolomide 1 (26percent) whereas deprotection of the 3-trimethylsilylmethylimidazotetrazine 6g with TBAF in acetonitrile-acetic acid yields 1 in 78percent yield. 3-Benzylimidazotetrazinones 10a-c are stable to hydrogenolytic or oxidative debenzylation reactions.
- Wang, Yongfeng,Stevens, Malcolm F. G.,Thomson, William T.,Shutts, Bruce P.
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p. 2783 - 2789
(2007/10/02)
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- TETRAZINE DERIVATIVES
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[3H]-Imidazo[5,1-d] -1,2,3,5-tetrazin-4-one derivatives of the formula:wherein R1represents hydrogen, or an alkyl, alkenyl or alkynyl group containing up to 6 carbon atoms, each such group being unsubstituted or substituted by from one to three substituents selected from halogen atoms, alkoxy, alkylthio, alkylsulphinyl and alkylsulphonyl groups containing up to 4 carbon atoms, and optionally substituted phenyl groups, or R1represents a cycloalkyl group containing from 3 to 8 carbon atoms, and R2 represents a carbamoyl group optionally N-substituted by one or two groups selected ftom alkyl and alkenyl groups containing up to 4 carbon atoms, and cycloalkyl groups containing 3 to 8 carbon atoms, are new therapeutically useful compounds possessing antineoplastic and immunomodulatory activity
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- Antitumor Imidazotetrazines. 1. Synthesis and Chemistry of 8-Carbamoyl-3-(2-chloroethyl)imidazo-1,2,3,5-tetrazin-4(3H)-one, a Novel Broad-Spectrum Antitumor Agent
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Interaction of 5-diazoimidazole-4-carboxamide and alkyl and aryl isocyanates in the dark affords 8-carbamoyl-3-substituted-imidazo-1,2,3,5-tetrazin-4(3H)-ones.In cold methanol or ethanol, the 3-(2-chloroethyl) derivative 7a decomposes to afford 2-azahypoxanthine (14) and methyl and ethyl N-(2-chloroethyl)carbamates, respectively.Compound 7a has curative activity against L-1210 and P388 leukemia and may act as a prodrug modification of the acyclic triazene 5-imidazole-4-carboxamide (MCTIC), since it ring opens to form the triazene in aqueous sodium carbonate.
- Stevens, Malcolm F. G.,Hickman, John A.,Stone, Robert,Gibson, Neil W.,Baig, Ghouse Unissa,et al.
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p. 196 - 201
(2007/10/02)
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