Pyrido pyrimidine-7-carboxylates

Piromidic acid (PA), 5,8-dihydro-8-ethyl-5-pyrrolidopyrido(2,3-carboxylic acid is a pyrido pyrimidine derivative, a congener of nalidixic acid. PA is widely used for its antibacterial activity against several gram negative pathogens. PA is very slightly water soluble [4, 5]. 

There are few examples of [5 + 1] cyclizations from pyrimidine intermediates. Two of these involve the chloropropionic ester (194), which gives the 5,6,7,8-tetrahydro-7-one (195) with ammonia (59JCS1849), and the cyclization of a 4-ethynylpyrimidine-5-carboxylate with ammonia to give a pyrido[4,3-. In a recent patent, 5-ethoxycarbonylpyrimidin-4-yl-j8 -alanine derivatives are cyclized with ammonia to pipemidic acid analogues (80GEP2903850). One-carbon pyrimidine [5 +1] syntheses are included in Section 2.15.5.5.1 above. 

A final method for the preparation of pyrido[2,3-carboxylic acid chlorides with enamines in the presence of base to give 6,7,8-trisubstituted 5-ones (253 254)... 

Pyrido[2,3-d]pyrimidine-6-carboxylic acid, 5,6,7,8-tetrahydro-5-0x0-synthesis, 3, 221... 

The first recorded pyrido[4,3-d]pyrimidine (133) was synthesized in 1945 by the action of benzamidine on ethyl l-methylpiperid-4-one-3-carboxylate (132). Many more tetrahydro derivatives have been prepared by the similar condensation of various 1,5-substituted... 

It is interesting that somewhat similarly 4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l, 2- ]pyrimidine (A) was transformed into 5,6,7,8-tetrahydro-l,8-naphthyridin-4(lH)-one (B) by action of sec-amines (79H1407). Also in this transformation bond-breaking occurs between the ring nitrogen and the carbon of the carboxyl group. 

An algorithm for an assesment of chromatographic peak purity was proposed. In this study ethyl 8-methyl-4-oxo-4/7-pyrido[l, 2-u]pyrimidine-3-carboxylate was also used (97MI13). Ethyl 7-methyl-4-oxo-4//-pyrido[l,2-u]pyrimidine-3-carboxylate, among other compounds, was applied to show practical mathematical tools for the creation of several figures of merit of nth order instrumentation, namely selectivity, net analyte signal and sensitivity (96ANC1572). 

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). 

Perhydropyrido[l,2-a]pyrimidin-2-one was A -alkylated with 1,4-dibro-mobutane to yield a 1-(4-bromobutyl) derivative (94MIP6). 6-Methyl-4-oxo-4/f-],6,7,8,9,9a-hexahydro-4//-pyrido[],2-a]pyrimidine-3-carboxylate 138 was alkylated with alkyl chlorides 139 to give 1-substituted derivatives 140 (97MIP2). 

Heating 9-ethoxycarbonylmethylene-4-oxo-6,7,8,9-tetrahydro-4//-pyrido-[l,2-n]pyrimidine-3-carboxylate (157) at 250°C yielded 6,7-dihydro derivative 158 (99T10221). Under similar conditions 9-benzylidene-6,7,8,9-tetrahydro derivatives 159 did not gave the respective 9-benzyl-6,7-dihydro isomer. 

The chloro atom of 2-[4-(6-chloronicotinoyl)benzyloxy]-3-methyl-4//-pyrido[l,2-n]pyrimidin-4-one, its 6-methyl derivative and 2-[4-(6-chlo-ronicotinoyl)benzylthio]-3-methyl-4//-pyrido[l,2-n]pyrimidin-4-one was replaced by a 4-piperidinopiperidino and 4-phenylpiperazino group with 4-piperidinopiperidine and 4-phenylpiperazine (96EUP733633). The carboxyl group of 2-[4-(4-carboxybenzoyl)benzyloxy]-3-methyl-4//-pyrido[l,2-n]pyrimidin-4-one, prepared by hydrolysis of methyl ester in DMF with 1 N NaOH, was reacted first with diethyl pyrocarbonate in DMF at room temperature and then with 4-phenylpiperazine and 4-piperidinopiperidine to give the appropriate amide derivatives (96EUP733633). 

The A-substituted derivatives of 4-oxo-4//-pyrido[l,2-n]pyrimidine-3-carboxamides and -3-acetamides and l,6-dimethyl-4-oxo-1,6,7,8-tetrahy-dro-4//-pyrido[l,2-n]pyrimidine-3-carboxamide were prepared by treatment of the appropriate 3-carboxylic acids and acetic acid, first with an alkyl chloroformate in the presence ofNEt3 in CHCI3 below — 10°C, then with an amine (98ACH515). A-Phenethyl and A-[2-(3,4-dimethoxyphenyl)ethyl] derivatives of 6-methyl-6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidine-3-acetamide were obtained in the reaction of 6-methyl-6,7,8,9-tetrahydro-4//-pyrido[l,2-n]pyrimidine-3-acetic acid and phenethylamines in boiling xylene under a H2O separator. Hydrazides of 4-oxo-4//- and 4-oxo-6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidine-3-acetic acid were prepared from the appropriate ester with H2NNH2 H2O in EtOH. Heating 4-oxo-4//- and 6-methyl-4-oxo-6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidine-3-acetic hydrazides in EtOH in the presence of excess Raney Ni afforded fhe appropriafe 4-oxo-6,7,8,9-fefrahydro-4//-pyrido[l,2-n]pyrimidine-3-acefa-mide. In the case of the 4-oxo-4// derivative, in addition to N-N bond... 

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). 

Cyclocondensation of 3-cyano-2-methylthio-4//-pyrido[l, 2-u]pyrimidin-4-ones and ethyl mercaptoacetate in boiling EtOH in the presence of NaOEt afforded 4//-pyrido[l,2-u]thieno[2,3-r/ pyrimidin-4-ones 210 (00HC571). 2-Methylthio-4-oxo-4//-pyrido[l,2-u]pyrimidine-3-carboxylates 211 and mercaptoacetates afforded tricyclic derivatives 212 (93MIP1). Cyclocondensation of 2-methylthio-4-oxo-4//-pyrido[l, 2-u]pyrimidin-3-car-bonitriles 213 with H2NNH2 H2O and with guanidine HCl afforded tricyclic derivatives 214 and 215, respectively (96FES781). 

Fischer indolization of 9-arylhydrazono-6,7,8,9-tetrahydro-4//-pyrido-[l,2-u]pyrimidin-4-ones 289 by heating in 85% phosphoric acid, or in PPA yielded 7,12-dihydropyrimido[l, 2 l,2]pyrido[3,4-Z)]indol-4(6//)-ones 290 (96JHC799, 99MI12, 00MI22). From the 3-ester and 3-carboxylic acid derivatives 289 (R = COOEt, COOH) and decarboxylated products 290 (R = H) were obtained. 

Heating 4-oxo-4//-pyrido[l, 2-n]pyrimidine-3-diazonium tetrafluorobo-rate and its 8-methyl derivative in alcohol at 60-90 °C for 15 min to 5h gave alkyl 1-(2-pyridyl)- and 1-(4-methyl-2-pyridyl)-l//-1,2,3-triazole-4-carboxylates (00H(53)1793). 

Heating diethyl (2-pyridylamino)methylenemalonates 304 (R = COOEt, = Me, OH) in AcOH afforded 4-oxo-4//-pyrido[l, 2-n]pyrimidine-3-carboxylates 305 (R = Me, OH) (96JHC1041). Flash vacuum thermolysis of 2-substituted 3-(2-pyridylamino)acrylates 304 (R = CN, COOEt, R = H) through a packed silica tube (530 °C, 0.01 mmHg) gave 3-substituted 4//-pyrido[l,2-n]pyrimidm-4-ones 306 (R = CN, COOEt) (94AJC1263). Ethyl 7-methyl-4-oxo-l, 4-dihydro-1,8-naphthyridine-3-carboxylate (79%) was... 

Cyclization of A -aryl-2-(ethoxycarbonyl)-3-(2-pyridylamino)acrylamides 307 in AcOH, and in PPA, or in ethylene glycol afforded A-aryl-4-oxo-4//-pyrido[l,2-n]pyrimidine-3-carboxylic amide 308 (94KGS629, 95KFZ(5)39). 

Alkyl 3-(2-pyridylamino)-3-alkoxycarbonylacrylates cyclized into alkyl 4-oxo-4/f-pyrido[l,2-a]pyrimidine-2-carboxylates either spontaneously or by the action of silica gel (00TL5837). 

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). 

Reaction of 2 equiv of 2-aminopyridines with 2-hydropolyfluoroalk-2-anoates 351 in MeCN in the presence of NEts at 90 °C for 50 h afforded a mixture of the isomeric 2-oxo-2H- and 4-oxo-4//-pyrido[l,2-n]pyrimidines 110 and 111. Reaction of 3 equiv of 2-amino-pyridines and 2-hydropoly-fluoroalk-2-enoates 351 in MeCN in the presence K2CO3 could be accelerated by ultrasonic irradiation (125W). 2-Amino-6-methylpyridine yielded only 2-substituted 6-methyl-4//-pyrido[l,2-n]pyrimidin-4-ones 111 (R = 6-Me), whereas 2-amino-5-bromopyridine gave a mixture of 7-bromo-4//-pyrido[l,2-n]pyrimidin-4-one (111, R = 7-Br, R = CF2C1) and 2-(chlor-o,difluoromethyl)-6-bromoimidazo[l, 2-n]pyrimidine-3-carboxylate in 44 and 8% yields, respectively (97JCS(P 1)981). Reactions in the presence of K2CO3 in MeCN at 90°C for 60h afforded only imidazo[l,2-n]pyrimidine-3-carboxylates. 

Reaction of 2-aminopyridine with ethyl 2-cyano-3-ethoxy-3-methyl-, -3-ethyl-, -3-phenylacrylates and ethyl 2-ethoxycarbonyl-3-ethoxy-3-methyl-, -3-phenylacrylates in boiling xylene yielded 2-substituted 4/f-pyrido[l,2-u]pyrimidine-3-carbonitriles and -3-carboxylates (99MI7). Similar reactions of 2-aminopyridine with 2-cyano-3-ethoxyacrylonitrile and its 3-methyl, 3-ethyl, -3-phenyl derivatives in boiling MeCN afforded 4-imino-4//-pyrido[l,2-u]-pyrimidine-3-carbonitrile and its 2-substituted derivatives. 

Cyclocondensation of 2-(nitromethylene)perhydropyrimidine (379) and dimethyl acetylenedicarboxylate yielded a mixture of 9-nitro-l,2,3,4-tetrahydro-6-oxo-6//-pyrido[l,2-n]pyrimidin-8-carboxylate 380 and a pyr-rolo[l,2-n]pyrimidine-7-ylideneacetate 381 (93BCJ2118). Their ratio... 

Reaction of 1,3-propanediamine and 3-cyano-4-methyl-6-methylthio-l-phenyl-2-0X0-],2-dihydropyridine-5-carboxylate 385 yielded 7-cyano-8-methyl-6-oxo-],2,3,4-tetrahydro-6/7-pyrido[],2-a]pyrimidine-9-carboxylate (386) (94JHC393). 

Dipolar cycloadditions of dihydropyrimidine-fused mesomeric betaines 389, 391 and 394 with different dipolarophiles afforded 6-oxo-6H-pyrido[l,2-n]pyrimidine-3-carboxylates 390, 392, 393 and 396 (97JOC3109). 

Reaction of pyridinium-A -(2-pyridyl)amidine (402) and alkyl haloace-tates in the presence of K2CO3 afforded a mixture of 4-oxo-4/f-pyrido[l, 2-u]pyrimidine-2-carboxylates 407 and 2-aminopyridine derivatives 406 through intermediers 403- 05, as depicted in Scheme 15 (00TL5837). Compound 406 could be cyclized on the action of heat or silica gel into 407. The best yield was achieved in the case of ethyl bromoacetate. 

Reaction of 3-amino-2-cyano-4-[(phenylamino)(methylthio)methylene]-2-pentenedioate (408) with a large excess of 1,3-propanediamine afforded ethyl 6-imino-l, 2,3,4-tetrahydro-6//-pyrido[l, 2-n]pyrimidine-9-carboxylate (409) as depicted in Scheme 16 (95JHC477). 

Neurotropic and antistress properties of 2,4-dimethylpyrido[l, 2-u]pyr-imidinium perchlorate were compared with those of piracetam (95MI7). AH-Pyrido[l,2-u]pyrimidin-4-one binds selectively to rat A3 receptors with a A", value of 48/xM. No affinities were observed to rat Ai and A2 receptors (96MI17). 4-Oxo-4//-pyrido[l,2-u]pyrimidine-3-carboxylic acid and -3-carbonitrile did not exhibit significant antibacterial activities (97MI6). 

Dihydro-2//-pyrido[l,2-n]pyrimidin-2-one was used in the synthesis of antiallergic tricyclic triazolobenzazepine derivatives (99MIP3). 8-[2-(4-f-Propyl-2-thienyl)ethenyl]- and 8-[(4-/-propryl-2-thienyl)methoxy]-4-oxo-4//-pyrido[l,2-n]pyrimidine-3-carboxylic acids were patented for the treatment of preventing and/or treating microbial infectious diseases (OlMIPl). 

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