348620-55-3

Upstream product

• 50-01-1 guanidine hydrochloride 
• 5763-61-1 3,4-dimethoxybenzylamine 
• 243636-63-7 methyl N-crotyl-N-(3',4'-dimethoxybenzyl)malonamide 
• 243637-19-6 ((E)-But-2-enyl)-(3,4-dimethoxy-benzyl)-carbamic acid methyl ester 
• 243636-73-9 ((E)-But-2-enyl)-(3,4-dimethoxy-benzyl)-amine 
• 348620-17-7 methyl N-crotyl-N-(3',4'-dimethoxybenzyl)malonylamide 
• 348620-04-2 methyl N-crotyl-N-(3',4'-dimethoxybenzyl)carbamate 
• 348620-11-1 N-crotyl-(3',4'-dimethoxybenzyl)amine 
• 243636-67-1 methyl N-(3',4'-dimethoxybenzyl)carbamate 
• 113-00-8 guanidine nitrate 

Downstream Products

• 243636-78-4 diethyl N-{4-[2-(2-amino-3,4-dihydro-4-oxo-7-(3',4'-dimethoxybenzyl)pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl}-L-glutamate 
• 146943-43-3 N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]-pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid diethyl ester 

Relevant academic research and scientific papers

A new route to 7-substituted derivatives of N-{4-[2-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl) -ethyl]benzoyl}-L-glutamic acid [ALIMTA (LY231514, MTA)]

Alkylation of various primary amines with crotyl bromide, followed by DMAP-promoted acylation with methyl malonyl chloride to 4 and then manganic triacetate dihydrate/cupric acetate induced radical cyclization, gave 1-substituted-4-vinyl-3-carbomethoxy-2-pyrrolidinones (5). Thiation to the thiolactams 6 and guanidine cyclization then gave a series of 2-amino-3,4-dihydro-4-oxo-5-vinyl-7-substituted pyrrolo[2,3-d]pyrimidines (7). Palladium-catalyzed C-C coupling with diethyl 4-iodobenzoylglutamate led in one step via an unexpected redox reaction to the diethyl esters 9 of a series of 7-substituted derivatives of ALIMTA (LY231514, MTA), from which the target analogues 10 were readily prepared by saponification. Attempted deprotection at position 7 was successful in only one case (9d, R = CH2C6H3(OMe)2 (-3′,4′), which resulted in a known pentultimate precursor (9, R = H) of ALIMTA. The 7-substituted derivatives 10 proved to be inactive in vitro as inhibitors of cell division.

A novel synthetic route to 7-substituted derivatives of the antitumor agent LY231514 (MTA)

This paper describes a further synthesis of the pyrrolo[2,3- d]pyrimidine antitumor agent MTA (LY231514). Manganic triacetate dihydrate- induced radical cyclization of methyl N-crotyl-N-(3',4'- dimethoxybenzyl)malonamide (4d) yielded the 3-carbomethoxy-2-pyrrolidinone 5d that was then thiated with P2S5 to the corresponding thiolactam (6d). Cyclization with guanidine gave the 7-substituted 2-amino-4(3H)-oxo-5,6- dihydro-pyrrolo[2,3-d]pyrimidine (7d). Pd-catalyzed coupling with diethyl 4- iodobenzoylglutamate yielded (in a single step) the diethyl ester 9d. Deprotection with H2SO4/TFA followed by saponification then gave MTA. Several additional 7-substituted derivatives of MTA were prepared by use of this methodology. In contradiction to a published claim, these 7-substituted derivatives proved to be devoid of any significant cell growth inhibitory activity.