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Synthesis of temozolomide and analogs

Inactive Publication Date: 2005-06-16
SCHERING CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0016] Step (b) is preferably carried out by hydrolysis with a strong mineral acid such as concentrated HCl or HBr, or HClO4, CF3SO3H, or MeSO3H, or especially concentrated sulfuric acid, at a moderate temperature such as −20 to 50° C. In a particularly preferred embodiment, the readily-removable protecting group is a 1,1-dimethylethyl group (a t-butyl group), together with a hydrogen atom. Its bulk also helps to promote the correct direction of cyclization.

Problems solved by technology

However, this process requires isolation of the unstable and potentially dangerous 5-diazo-1H-imidazole-4-carboxamide (B).
Moreover, methylisocyanate is a difficult reagent to handle and ship, especially on the industrial scale, and indeed is better avoided in industrial manufacture.
Moreover, the unstable 5-diazo-1H-imidazole-4-carboxamide (B) still has to be isolated in the branch of this process that uses it as an intermediate.

Method used

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  • Synthesis of temozolomide and analogs
  • Synthesis of temozolomide and analogs
  • Synthesis of temozolomide and analogs

Examples

Experimental program
Comparison scheme
Effect test

example 1

3-Methyl-8-aminocarbonvl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (Temozolomide)

[0059] Step A: Preparation of 2-cvano-N-(1,1-dimethylethyl)-2-[(diphenylmethylene)amino]-acetamide

[0060] The imine 3 (700 g, 3.178 mol) and CH2Cl2 (7 L) were placed into a 22 L three-necked flask equipped with a nitrogen inlet, a gas outlet tube, reflux condenser, thermometer, mechanical stirrer, and maintained under a positive pressure of nitrogen. 1,1-Dimethylethyl-isocyanate (442 mL, 3.870 mol) was added to this stirred mixture at 0° C., and after stirring for 10 min a solution of potassium t-butoxide in THF (1.0 M in THF, 3.88 L, 3.88 mol) (as supplied by Aldrich) was added slowly (1 hour). The solution was stirred at 0° C. for 4 hours, when the reaction mixture had become a very thick paste with a deep brown color, and thin layer chromatography (EtOAc / hexanes=¼) indicated that no more starting material was present. The resulting mixture was quenched with saturated NH4Cl solution (5 L), and the o...

example 2

Preparation of Intermediates and Reagents

[0073] Part A: 2-Cyano-N(1,1-dimethylethyl)-2-(hydroxyimino)acetamide 13

[0074] Amide 11 (3.11 g, 22.18 mmol) (Bhawal, B. M.; Khanapure, S. P.; Biehl, E. R.; Syn. Commun., 1990, 20, 3235) dissolved in CH2Cl2 (100 mL) was placed into a 500 mL 3-necked round-bottom flask equipped with a stirring bar. The solution was cooled to 0° C. (ice bath) and NOCl (Fluka) was bubbled through until the reaction mixture turned a brick-red color. The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 18 hours. The precipitate was collected and washed with CH2Cl2 (25 mL) to afford the product as a white solid (2.88 g, 17.0 mmol).

[0075]1H NMR (400 MHz, DMSO-d6, δ): 7.70 (s, 1H), 3.32 (s, 1H), 1.32 (s, 9H); mp: 218-219° C.

Part B: 2-Amino-2-cyano-N-(1,1-dimethylethyl)acetamide 13

[0076] Oxime 13 (2.5 g, 14.78 mmol), Al amalgam (0.81 g) and distilled H2O (100 mL) were placed into a 250 mL round-bottom flask equipped with a stirr...

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Abstract

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.

Description

REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Ser. No. 10 / 050,488 filed on Jan. 16, 2002, which claims the benefit of U.S. Provisional Application Ser. No. 60 / 262,465 filed Jan. 18, 2001.FIELD OF THE INVENTION [0002] 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. BACKGROUND OF THE INVENTION [0003] Temozolomide, 3-methyl-8-aminocarbonyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one, is a known antitumor drug; see for example Stevens et al., J. Med. Chem. 1984, 27,196-201, and Wang et al., J. Chem. Soc., Chem. Commun., 1994, 1687-1688. It has the formula: [0004] It is described in U.S. Pat. No. 5,260,291 (Lunt et al.) together with compounds of broadly similar activity such as higher alkyl analogs at the 3-position. [0005] The synthesis of I by the process described in J. Med. Chem. 1984, 27,196-201 can be simply depicted as follows, eve...

Claims

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Application Information

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IPC IPC(8): A61K31/4188A61P35/00C07B51/00C07C255/28C07D233/88C07D233/90C07D487/04
CPCC07C255/28C07D487/04C07D233/90Y02P20/55A61P35/00
Inventor KUO, SHEN-CHUNMAS, JANET L.HOU, DONALD
Owner SCHERING CORP
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