Pyrimidine-5-carboxylates, 4-hydroxy

The methods outlined, of course, are readily applicable to a wide variety of substituted heterocycles like the carboxyl, hydroxy and mercapto derivatives of pyridines, pyridine 1-oxides, pyrroles, etc. The application to amines and to diaza compounds such as pyrimidine, where the two centers are basic, is obvious except that now 23 takes the role of the neutral compound, 21 and 22 the roles of the tautomeric first conjugate bases, and 20 the role of the second conjugate base. Extensions to molecules with more than two acidic or basic centers, such as aminonicotinic acid, pyrimidinecarboxylic acids, etc., are obvious although they tend to become algebraically cumbersome, involving (for three centers) three measurable Kg s, four Ay s, and fifteen ideal dissociation constants (A ), a total of twenty-two constants of which seven are independent. 

The relative stereostructure of 9-acetyl-7-hydroxy-l,2-dimethyl-7-meth-oxycarbonyl-4-phenyl-6-oxo-l, 4,7,8-tetrahydro-6/7-pyrido[l, 2-u]pyri-midine-3-carboxylate 122 was justified by an X-ray diffraction analysis (97JOC3109). The stereochemistry and solid state structure of racemic trans-6,9-//-l, 6-dimethyl-9 z-ethoxy-9-hydroxy-4-oxo-l,6,7,8,9,9 z-hexahydro-4//-pyrido[l,2- z]pyrimidine-3-carboxylate (123), adopting a cw-fused conformation, were determined by X-ray investigations (97H(45)2175). 

Acidic and basic hydrolysis of ethyl 4-oxo-4//-pyrido[l, 2-u]pyrimidin-3-carboxylates gave 3-carboxylic acid derivatives (OlMIPl). Stirring rerr-butyl ( )-3-(2-hydroxy-8-[2-(4-isopropyl-l, 3-thiazol-2-yl)-l-ethenyl]-4-oxo-4//-pyrido[l,2-u]pyrimidin-3-yl)-2-propenoate in CF3CO2H at room temperature yielded ( )-3-substituted 2-propenoic acid. 

Fluorophenyl)-3-fluoro-2-hydroxy-6-oxo-6/7-pyrido[],2-n]pyrimidine-7-carboxylic acid (197, R = 4-FPh, R = H) was obtained from the 2-(4-methyl-]-piperazinyl)-7-ester derivative by the treatment with 1 N NaOH in an 1 1 mixture of H2O and THF at room temperature for 6h (95MIP1, 96JMC3070, 96MIP4, 96USP5580872). 

Cyclopropyl-3-fluoro-2-hydroxy-6-oxo-6//-pyrido[l,2-n]pyrimidine-7-carboxylates 340 were obtained in the reaction of 2-cyclopropyl-2-(5-fluoro-4-hydroxy-2-pyrimidinyl)acetaldehyde (339) and ethyl, rerr-butyl and dibenzyl malonates in the presence of piperidine and AcOH (95MIP1, 96JMC3070, 96MIP4, 96USP5580872). 

Hydroxy-L-prolin is converted into a 2-methoxypyrrolidine. This can be used as a valuable chiral building block to prepare optically active 2-substituted pyrrolidines (2-allyl, 2-cyano, 2-phosphono) with different nucleophiles and employing TiQ as Lewis acid (Eq. 21) [286]. Using these latent A -acylimmonium cations (Eq. 22) [287] (Table 9, No. 31), 2-(pyrimidin-l-yl)-2-amino acids [288], and 5-fluorouracil derivatives [289] have been prepared. For the synthesis of p-lactams a 4-acetoxyazetidinone, prepared by non-Kolbe electrolysis of the corresponding 4-carboxy derivative (Eq. 23) [290], proved to be a valuable intermediate. 0-Benzoylated a-hydroxyacetic acids are decarboxylated in methanol to mixed acylals [291]. By reaction of the intermediate cation, with the carboxylic acid used as precursor, esters are obtained in acetonitrile (Eq. 24) [292] and surprisingly also in methanol as solvent (Table 9, No. 32). Hydroxy compounds are formed by decarboxylation in water or in dimethyl sulfoxide (Table 9, Nos. 34, 35). 

Reduction of 3-benzyl-8-chloro-4-oxo-4//-pyrido[l,2- ]pyrimidine-2-carboxylate <2004W004/064741> and 2-methyl-4-oxo-4//-pyrido[l,2-tf]pyrimidine-3-carboxylate <2003T4123> with DIBAL-H afforded 2- and 3-formyl derivatives, respectively. Reduction of /V-(4-fluorobenzyl)-3-hydroxy-8-[methoxy(methyl)amino]-4-oxo-6,7,8,9-tetra-hydro-4//-pyrido[l,2- ]pyrimidine-2-carboxamide with Zn-dust in aqueous AcOH afforded the 8-methylamino derivative, which was acylated with AcOH in the presence of Hiinig s base, HOBt, and l-(3-dimethylaminopro-pyl)-3-ethylcarbodiimide-HCl <2004W004/058756>. 3-(Perhydropyrido[l,2- ]pyrimidin-2-yl)propylamine was obtained by catalytic hydrogenation of 2-(perhydropyrido[l,2- ]pyrimidin-2-yl)propionitrile over a Pt02 catalyst <2003FRP1275647>. 

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,... 

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