Pyrimidine-5-carboxylate

The aminolysis of esters of pyrimidine occurs normally to yield amides. The reagent is commonly alcoholic ammonia or alcoholic amine, usually at room temperature for 20-24 hours, but occasionally under refiux aqueous amine or even undiluted amine are used sometimes. The process is exemplified in the conversion of methyl pyrimidine-5-carboxylate (193 R = Me) or its 4-isomer by methanolic ammonia at 25 °C into the amide (196) or pyrimidine-4-carboxamide, respectively (60MI21300), and in the butylaminolysis of butyl ttracil-6-carboxylate (butyl orotate) by ethanolic butylamine to give A-butyluracil-5-carboxamide (187) (60JOC1950). Hydrazides are made similarly from esters with ethanolic hydrazine hydrate. 

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),... 

In fact, most pyrimidinecarboxylic acids are made by hydrolysis of the corresponding esters, nitriles or sometimes amides, many of which can be made more easily by primary synthesis than can the acids themselves. Thus, pyrimidine-5-carboxylic acid may be made by alkaline hydrolysis of its ethyl ester (62JOC2264) and pyrimidin-5-ylacetic acid (789 ... 

Pyrimidine-5-carboxylic acid, 4-amino-2-methyl-ethyl ester synthesis, 3, 111... 

Enolates can also function as masked aldehydes or ketones and a new synthesis of 2-substituted pyrimidine-5-carboxylic esters 652 used a doubly masked dialdehyde 651, where one aldehyde was protected as an acetal and the other was used in the form of its sodium enolate <2002S720>. 

In what may be the simplest reaction in this section, a series of pyrimidine-5-carboxylic acids 325 were heated with thionyl chloride to produce 326 (Equation 117) in which a yield is reported only for 326f <1994APH55>. 

The potassium salt of 7-methyl-3-phenyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[2,3- pyrimidine-5-carboxylate 153 was condensed with l-bromo-3-chloropropane or 1,4-dibromobutane in anhydrous DMF at room temperature to afford the A-l-alkyl derivatives 154 and 155, respectively <1994FA499>. The corresponding A-l-piperazinylalkyl derivatives of 153 were also prepared in more than 40% yield. Debenzylation of 6-benzyl-3-methylpyrido[4,3-,7 pyrimidine 156 by Pd/C-catalyzed hydrogenolysis in AcOH gave the analogue 157 <1994JHC1569>. 

Ring transformation of ethyl 2,4-dioxo-l,2,3,4-tetrahydropyrido[2,3- pyrimidine-5-carboxylates 317 with 80% hydrazine hydrate in boiling ethanol gave a mixture of 5-methyl/allyl/benzylamino-l,2,3,4-tetrahydro-l,4-dioxopyr-ido[3,4-i/ pyridazines 318, pyrido[2,3,4-< <7]pyridazino[3,4-/ [l,2,4]triazepines 319, and a low yield of 2,3,4,6,7-penta-azaphenalene 320. The reaction of 317 with hydrazine hydrate was also performed without a solvent in an oil bath at 125 °C for 1 h to give the same products, but higher yields of 318 and lower yield of 319 as well as traces of 320 were obtained (Equation 25) <1997FA657>. 

A variety of methods for the preparation of pyrimido[4,5-,7]pyridazines are discussed in CHEC(1984) < 1984CHEC(3)329> and CHEC-II(1996) <1996CHEC-II(7)737>, and most of the work that has appeared since describes adaptations of the earlier methods. Notable examples include the use of imide hydrazinolysis in a two-step construction of the ring system (Scheme 23) < 1996H(43)1597, 2002JHC571>. In addition, the reaction of 4-(halomethyl)pyrimidine-5-carboxylates with... 

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