Methyl Isocyanate → Temozolomide

HRID 16933

Reaction equation

HRID 16933 reaction equation
NC1NC(C(N)=O)=NC=1.[N+:10](=[C:12]1[NH:16][CH2:15][N:14]=[C:13]1[C:17]([NH2:19])=[O:18])=[N-:11].[CH3:20][N:21]=[C:22]=[O:23]>ClCCl>[CH3:20][N:21]1[N:11]=[N:10][C:12]2[N:16]([CH:15]=[N:14][C:13]=2[C:17]([NH2:19])=[O:18])[C:22]1=[O:23]

Participants

5

Reactant 3

HCID 12228Methyl IsocyanateHCID 219832884-amino-1H-imidazole-2-carboxamideHCID 1363774465-diazo-1H-imidazole-4-carboxamide

Product 1

HCID 5394Temozolomide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

In this process, 5-amino-1H-imidazole-carboxamide (A) is converted into 5-diazo-1H-imidazole-4-carboxamide (B), which is then cyclized with methylisocyanate in dichloromethane to provide a high yield of clinical-grade Temozolomide. 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. Furthermore, the cycloaddition of methylisocyanate requires a very long reaction time: Table I in J. Med. Chem. 1984, 27, 196-201, suggests 20 days.

Sources & evidence

ORD record
ord-d39ed1e4e8d04f3592ef23528a553348
Source dataset
uspto-grants-2010_06
Patent number
US07737284B2

Linked notes

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