Pyrimidines, 2,4-dimethoxy

The recorded use of metallo derivatives in the pyrimidine and quinazoline series is minimal. The best described pyrimidinyllithium compounds are those derived from 5-bromopyrimidines. Their reactions are illustrated in the following examples. Pyrimidin-5-yllithium (474 R = H) reacts with solid carbon dioxide under ether to give pyrimidine-5-carboxylic acid (475 R = H) in good yield (65ACS1741) 4,6-dimethoxy- (474 R = OMe),... 

The pyrimidine compounds are known to undergo a rearrangement of the 0-alkyl derivatives to the iV-alkyl ones. The methoxy derivatives of 1,3,5-triazine display a similar behavior. On applying methyl iodide to 2,4-dimethoxy-l,3,5-triazine one of the methyl groups is shifted giving rise to l-methyl-4-methoxy-derivative (22). This compound was also obtained by methylation of 4-methoxy-2-oxo-1,2-dihydro-1,3,5-triazine (18) with diazomethane. At higher temperature (100°C) in presence of methyl iodide a shift of both methyl groups takes place and methiodide is formed simultaneously (23). Similarly,... 

Methyl and 6-methyl-5-n-propyl substituted 2,4-dimethoxy-pyrimidines react with methyl iodide, as does the simple dimethoxy compound, to give methoxypyrimidones, but the 6-chloro-2,4-dimethoxy derivative (47) is affected only at 100°, when it gives 4-chloro-1,3-dimethyluracil (48). ... 

It was elaimed that eyelization of ethyl 2-ehloro-5-eyelopropyl-6- [(A-(4,5-dimethoxy-2-nitrophenyl)methoxy)earbonyl]-A-(2-fluoro-3-hydroxy-l-oxo-2-propen-l-yl)amino nieotinate (321) in boiling aqueous dioxane in the presenee of K2CO3 overnight yielded l- [(4,5-dimethoxy-2-nitrophe-nyl)methoxy]earbonyl -9-eyelopropyl-3-fluoro-2-oxo-2,6-dihydropyrido[l, 2-n]pyrimidine-7-earboxylate (160) (95MIP1, 96MIP4, 96USP5580872). 

Hydrolysis of 3-[(2,6-dimethoxy-4-pyrimidinyl)hydroxymethyl]perhydro-pyrido[l,2-c]pyrimidin-l-iminium salts 174-177 in boiling cone. HCl afforded the appropriate 3-[(2-hydroxy-6-oxo-l,6-dihydropyrimidin-4-yl) hydroxymethyl] derivative (98TL7021, 00JA5017). 

There is thus obtained 0.51 gram of 4-sulfanilamido-5,6-dimethoxy-pyrimidine of MP 190° to 194°C, from 50% ethanol. 

Reaction of 2-cyanomethylpyridine with iV-(l-aryl-l-chloro-2,2,2-trifluoroethyl)-iV -(4-methylphenyl)carbodiimides, and with (1,1,2,2,2-pentachloro- and l,l-dichloro-2,2,2-trifluoroethyl)isocyanates or A-methoxycarbonyl-l,2,2,2-tetrachloro-, — l-chloro-2,2-trifluoroacetaldehyde imines afforded 3-aryl-4-cyano-l-(4-methylphenyl)imino-3-trifluoromethyl-2,3-dihydro-17/-pyrido[l,2-f]pyrimidines and 4-cyano-3-trichloro-, 4-cyano-3-trifluoro-17/-pyrido[l,2-4pyrimidin-l-ones, respectively <2004CHE47>. Refluxing 2-cyanomethylpyridine and iV-(l-aryl-l-chloro-2,2,2-trifluoroethyl)isocyanates in benzene furnished l-aryl-4-cyano-l-trifluoromethyl-l,2-dihydro-3//-pyrido[l,2-4pyrimidin-3-ones. However, when the solution of the isocyanate was added dropwise to the solution of 2-cyanomethylpyridine, and the reaction mixture was then treated with NEt at room temperature, the isomeric 3-aryl-4-cyano-3-trifluoromethyl-2,3-dihydro-l//-pyr-ido[l,2-dpyrimidin-l-ones were obtained. Reaction of l-(acetyl- and benzoylmethylene)-6,7-dimethoxy-l,2,3,4-tetra-hydroisoquinolines with PhCONCS yielded 1-acetyl-, 1 -benzoyl-9,10-dime thoxy-3-pheny 1-6,7-dihydro-2//-pyrimido[6,l- ]isoquinoline-2-thiones <2003SL2369>. 

Photolytic cleavage (at 320nm) of the substituent at position 1 of 9-cyclopropyl-l-[(4,5-dimethoxy-2-nitrophenyl)-methoxycarbonyl-3-fluoro-2,6-dioxo-l,2-dihydro-6//-pyrido[l,2-tf]pyrimidine-7-carboxylate gave 9-cyclopropyl-3-fluoro-2-hydroxy-6-oxo-6//-pyrido[ 1,2-tf]pyrimidin-7-carboxylate <1995WO95/010519, 1996WO96/039407,... 

T3 M 75.1% after 15 days 4-(6-Imino-2, 4-dimethoxy pyrimidin-l-yl) aniline additional metabolites were preliminary assigned but not confirmed [22]... 

A nucleophilic attack of morpholine on the pyrimidine ring in l,2,3-triazolo[l,5- ]pyrimidinium salts 1203 leads to unstable intermediates 1204. Spontaneous opening of the pyrimidine ring results in formation of 1,2,3-triazole derivatives 1205 that are isolated in 80-85% yield. A similar nucleophilic attack of the hydroxide anion (from aq. K2CO3) on dimethoxy derivative 1203 provides transition species 1206 that opens to intermediate 1207, and finally tautomerizes to ester 1208, isolated in 87% yield (Scheme 200) <2003T4297>. 

It is mentioned in an early paper on the effect of water on Heck vinylations [62] that 2,4-dimethoxy-5-iodopyrimidine reacted with 1-(ethoxyethenyl)-tri-n-butylstannane to afford an acylated pyrimidine derivative in 83 % yield (via in situ hydrolysis of the intermediate enol ether) (Scheme 6.28). 

An alternative synthesis of pyrimidine boronic acids, which avoids lithiation chemistry altogether, has been developed <2001SL266>. Thus, reaction of 2,4-dimethoxy-5-iodopyrimidine 352 with cedrane-8,9-diolborane 351 using catalytic amounts of Pd(PPh3)4 and Cul gave the intermediate boronate 353 which could be converted to the free boronic acid 354 in 83% yield by transesterification with diethanolamine, followed by treatment with acid (Scheme 3) <2001SL266>. 

Similarly, chlorination of 2,4,8-trioxopyrido[3,2-t/ pyrimidine 189 afforded the trichloro derivative 190, which upon treatment with sodium methoxide gave 2,4-dimethoxy derivative 191 where the chlorine atom at position 8 was not displaced (Scheme 5) <1993JME3103, 1995JME2615>. 

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