- 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 15-17
(2020/10/18)
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- Temozolomide synthesis of intermediates method
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The invention discloses a method for synthesizing intermediate for temozolomide, through 5 - amino imidazole - 4 - carboxamide and a carbamic chloride one-step synthesis to obtain the temozolomide intermediate. The 5 - amino imidazole - 4 - carboxamide and a carbamic chloride is dissolved in organic solvent, cooling to - 5 - 5 °C, dropwise triethylamine, heating to continue stirring 2 - 3 h, filtering, washing, 50 °C ± 5 °C vacuum drying 12 h, temozolomide intermediate is obtained. The method of high safety, to avoid the poisonous reagent methyl isocyanate use, raw material conversion is relatively high, in 95% or more, with a purity of 98.3% above, mild reaction conditions, after treatment is simple, without further purification can be directly feeding the next step reaction.
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Paragraph 0005; 0017-0032
(2019/03/29)
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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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- 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 055; 056
(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; 0012; 0027; 0032-0035
(2019/02/02)
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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 15
(2010/12/29)
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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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Page/Page column 3-4; 5
(2010/03/02)
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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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- Antitumour imidazotetrazines. Part 36. Conversion of 5-aminoimidazole-4-carboxamide to imidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-ones and imidazo[1,5-a][1,3,5]triazin-4(3H)-ones related in structure to the antitumour agents temozolomide and mitozolomide
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Novel 3-substituted imidazo[5,1-d][1,2,3,5]tetrazinones 3 have been prepared by two routes: reaction of 5-diazoimidazole-4-carboxamide 2 and isocyanates, and nitrosative cyclisation of 5-amino-1-carbamoylimidazole-4-carboxamides 7. The latter cyclisations do not proceed efficiently when the 1-carbamoyl group bears an electron-donating alkyl group. 5-Amino-1-carbamoylimidazole-4-carboxamides 7 cyclise with triethyl orthoformate or triethyl orthobenzoate to yield imidazo[1,5-a][1,3,5]triazinones 15. A 1H NMR study of the decomposition of 8-carbamoyl-3-ethylimidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-one 3c in deuteriated phosphate buffer has shown that its ethylating capacity is attenuated by the unproductive generation of ethene. This observation explains why the ethylimidazotetrazine possesses weaker antitumour properties than the clinically-used congener temozolomide 3a.
- Wang, Yongfeng,Wheelhouse, Richard T.,Zhao, Linxiang,Langnel, David A. F.,Stevens, Malcolm F. G.
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p. 1669 - 1675
(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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