Benzamide → Methyl 4-methyl-1H-pyrrole-3-carboxylate
Reaction equation
N1[C:6]2=[CH:7][CH:8]=[N:9][C:5]2=C(C(N)=O)N=N1.[C:13](N)(=O)C1C=CC=CC=1.[C:22]([O:27][CH3:28])(=[O:26])/C=C/C.S(C[N+]#[C-])(C1C=CC(C)=CC=1)(=O)=O>>[CH3:28][O:27][C:22]([C:7]1[C:6]([CH3:13])=[CH:5][NH:9][CH:8]=1)=[O:26]Participants
Procedure
WO 00/71129 describes the preparation of 1,4-dihydro-5-alkyl-4-oxo-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylates, key intermediates in the synthesis of pyrrolotriazine carboxamide and benzamide compounds of formula I, by reacting a Michael acceptor such as methyl crotonate with an anion of tosylmethyl isocyanide (TosMIC) to give 4-methylpyrrole-3-carboxylic acid methyl ester. The resulting 4-methylpyrrole-3-carboxylic acid methyl ester is acylated with trichloroacetyl chloride in the presence of aluminum chloride to afford 2-trichloroacetyl-3-methylpyrrole-4-carboxylic acid methyl ester. Treatment of 2-trichloroacetyl-3-methylpyrrole-4-carboxylic acid methyl ester with sodium methoxide produces 3-methylpyrrole-2,4-dicarboxylic acid methyl ester. N-amination of 3-methylpyrrole-2,4-dicarboxylic acid methyl ester using an aminating reagent such as diphenyl phosphoryl hydroxylamine affords 1-amino-3-methylpyrrole-2,4-dicarboxylic acid methyl ester. Finally, reaction of 1-amino-3-methylpyrrole-2,4-dicarboxylic acid methyl ester with formamide at elevated temperature gives 1,4-dihydro-5-methyl-4-oxo-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester (Hunt, J. T.; Bhide, R. S.; Borzilleri, R. M.; Qian, L. WO 00/71129, Nov. 30, 2000). Although a number of 1,4-dihydro-5-substitued-4-oxo-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylates can be prepared by this method, this process is limited due to its lengthy chemical transformations, the use of hazardous aminating reagents and expensive chromatographic separation of products. WO 02/40486 describes an improved synthesis of 3-methylpyrrole-2,4-dicarboxylates by condensing ethaldehyde and isocyanoacetates in the presence of DBU. The synthesis is shorter, however, generation of the side-product, cyanide, is a safety concern. Preparation of 6-ethyl-1,2,4-triazin-5-one by Raney nickel mediated desulfurization of 6-ethyl-1,2,4-triazin-5-one-3-thione has been reported (Taft, W. E.; Shepherd, R. G. J. Med. Chem. (1967), 10, at 883).
Sources & evidence
- ORD record
- ord-2302c05d8110458ead099c2f1da8d8c1
- Source dataset
- uspto-grants-2006_04
- Patent number
- US07034151B2
Reaction notes
Loading…