2//-Pyrido pyrimidine-2-ones

The final chapter by Istvan Hermecz (Chinoin, Ltd., Budapest, Hungary) deals with bicyclic systems containing one ring junction nitrogen and one heteroatom and their benzologs, i.e. pyrido-oxazines, pyrido-thiazines, pyrido-pyridazines, pyrido-pyrazines, pyrido-pyrimidines and their analogs. Much of this material has not been reviewed for forty years, during which time immense advances have occurred. 

Zimmerman and coworkers studied the dimer formed from ureido pyrido-pyrimidine 6 and its tautomer (Scheme 10.2d) [21]. They pointed out that prototropy can be detrimental to hydrogen-bonded complex formation. Therefore, heterocycle 6 was designed to contain only one self-complementary hydrogen-bonding array (DDAA) eliminating others. They measured the self-association constant by employing H NMR dilution studies in chloroform, which was estimated to be more than 10 IVT. ... 

Enzymic oxidations at the 7-position of pyrido[2,3-oxygenated derivatives and of the 8-N-oxide have been observed in the metabolism of the pyrido[2,3-e/]pyrimidine analogues of the antiepileptic drug methaqualone (75MI21502, 74MI21500). 

Appropriate pyrido[2,3-d]pyrimidin-5-ones with formyl groups in the 6-position have been oxiized to piromidic (68) and pipemidic (69) acids, or to intermediates for these, using moist silver oxide, chromium trioxide (potassium dichromate), potassium permanganate or, alternatively, sodium chlorite/hydroxylamine-O-sulfonic acid. 6-Acetyl groups have been similarly oxidized using sodium hypobromite in aqueous dioxane, whilst 2-acetyl groups give dimethylaminomethylene derivatives en route to 2-pyrazolylpyrido[2,3-d]pyrimidines. 

A rare type of reaction involves the photocyclization of the 5-(unsaturated acyl)aminopyrimidines (168) to reduced 7-methylpyrido[3,2-Similar reactions are known involving related 4-aminopyrimidine derivatives, leading to pyrido[2,3-[Pg.221]

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. 

The pyrido[2,3-[Pg.227]

An unusual reaction involving s-triazine (247) and ethyl acetoacetate with sodium ethoxide leads eventually to the pyrido[4,3-ring opening and Dimroth-type rearrangement of the intermediate (248) (80JHC389>. 

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)... 

H,4H-Oxazolo[5,4,3-y]pyrido[3,2-g]quinolin-4-one, 8-hydroxymethyl-6-methyl — see Nybomyein 5H-Oxazolo[2,3-[Pg.731]

Only one cyclic hydroxamic acid which contains the pyrido[2,3-d]-pyrimidine ring system has been reported.This is 2-methyl-3-hydroxypyrido[2,3-d]pyrimidin-4(3i/)-one (21) which was prepared by the action of acetic anhydride on 2-aminonieotinhydroxamic acid (20) or from ethyl 2-aeetamidonicotinate (22) and hydroxylamine. In view of the known antibacterial activity of certain cyclic hydroxamic acids further work on these compounds would be of interest. 

Amino esters (26) have also been shown to yield pyrido[2,3- Z]-pyrimidin-4(3I/)-ones (25, 27) when treated with isocyanates and isothiocyanates. The reactions proceed via intermediate ureido and thioureido derivatives. 

The reaction involves an electrophilic attack into the 5-position of the pyrimidine ring and thus only those pyrimidines that are activated toward electrophilic substitution by the presence of electron-donating substituents at the 2- and 4-positions undergo cyclization. 2,4,6-Triaminopyrimidine, 6-aminouracil, 6-amino-2-thiouracil, 4-amino-2,4 dimercaptopyrimidine, 2,4-diaminopyrimidin-6(l/I)-one, and various 4-amino-vV-alkyl and aryl pyriinidones have all been converted into pyrido[2,3-[Pg.160]

V. Acyl acetates. j8-Keto esters have proved useful for the preparation of pyrido[2,3-d]pyrimidin-7(8H)-ones bearing alkyl and aryl... 

The 6-methyl derivative (98, R = Me) was an important intermediate in the synthesis of analogs (e.g., 183) of folic acid. Korte has shown that 2-aminopyrido[3,2-guanidine carbonate with 3-aminopicolinic acid and that treatment of the same acid with ammonium thiocyanate or potassium cyanate yields the thioureido and ureido derivatives (100, X = S and X = 0). In contrast to the pyrido[2,3-d]pyrimidine system bsoth of these compounds could be cyclized by heat and the latter (100, X = O) is a likely intermediate in the synthesis of the dione (98) by the fusion with urea. 

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... 

Pyrido[4,3-rf]pyrimidin-4(3/7)-oiie (138) was prepared from either ethyl 4-aminonicotinate or from 4-aminomcotinamide by fusion with formamide. A parallel to the pyrido[3,2-d]pyrimidines (cf. Section II,B, la) was demonstrated in the conversion of 2-methyl-pyrido[4,3-d][l,3]oxa7in-4-ones (139, Ri = Me) into the corresponding pyrido[4,3-d]pyrimidin-4(377)-ones (142) on treatment with a number of amines.There were certain limitations to the method in this series, however, and the intermediate diamides (140) were more conveniently prepared from the appropriate 4-amidonicotinate (141) and. .Ri... 

Mason has determined the infrared spectrum of pyrido[3,2-d]-pyrimidin-4(3ff)-one (149, N in position 5) in chloroform solution and as a KBr disc and has suggested that the low frequency of th e NH band (3389 cm ) and high frequency of the C=0 band (1745 cm i) in the solution spectra are indicative of a quasi o-quinonoid form. The infrared spectra of the four pyridopyrimidin-4(377)-ones (149), the four 2,4(ljff,3//)-diones (150), and a number of substituted derivatives, have been determined, as Nujol mulls, in these laboratories. ... 

Scheme 1. Fragmentation pattern of pyrido[3,2-c ]pyrimidin-4(3H)-one, (t. Spiteller, Advan. Heterocyclic Chem. 7, 301 (1966).

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