Pyrido 4-ones

Reaction between 2-chIoronicotinic acid (130) and 2-amino-4-phenyl-thiazole furnishes 3-phenyl-5-H-pyrido[2,3,-d]thiazolo[3.2-fl]pyximidin-5-one (131) (Scheme 86) (293). This reaction was extended to other pyridinyl compounds (294). 

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)... 

The NMR spectra of pyrido[2,3-d]pyridazine Af-oxides reduced derivatives and quaternary salts have also been studied and alkaline deuterium exchange reactions investigated <77BSF919). 

The 3,4-pyridinedicarboxylic phenylhydrazide (337), however, did cyclize in one of the earliest pyrido[3,4-higher temperature (12M(33)393, 66CPBIOIO). 

Few reactions of this type are recorded. The azidopyridazinone ester (349) on reduction with triethyl phosphite, hydrazine or borohydride furnished the pyrido[2,3-c]pyridazin-7-one (350) (79JHC1559), whilst an A-aminopyrido[2,3-c]pyridazine (352) resulted from the... 

Finally, the activated 3-aminopyridazine AT-oxide (381), mimicking 6-aminouracil, cyclizes with /3-ketoesters to give the pyrido[2,3-c]pyridazin-7-one AC-oxide (382). A reduced fused... 

Both the possible non-bridgehead pyridopyrazines, pyrido[2,3-f ]pyrazine (386) and pyrido[3,4-f ]pyrazine (387), are well known, the numbering being as shown. In the older literature they may be known as pyridino-2, 3 -2,3- and -3, 4 -2,3-pyrazines, as 1,4,5- and 1,4,6-triazanaphthalenes, or as 5- and 6-azaquinoxalines respectively. Some derivatives may also be referred to and numbered as deazapteridines, or as deaza derivatives of various natural products (see Section 2.15.16.3). Of the benzo fused systems, representatives of one angular (388) and two linear (389) and (390) derivatives of the [2,3-f ] system are known, but only the linear benzo fused [3,4-6] system (391). 

The tautomerism of some deaza analogues of riboflavin has been studied (77TL2551). The tautomerism of 3-ethoxalylmethyl- and 3-acetonyl-pyrido[2,3-f ]pyrazin-2-ones is fully discussed in (71TH21500 p. 68)... 

An unusual addition of acetoacetic acid to pyrido[2,3-Z>]pyrazin-2(l//)-one (400) to give (eventually) the 3-acetonyl derivative (401) was postulated (71TH21500) to occur via a cyclic transition state, and the similar addition of oxalacetic ester may occur via a related mechanism. 

The nucleophilic substitution reactions in pyrido-[2,3-f>]- and -[3,4-f ]-pyridazines in general follow the usual pattern of polyaza heterocycles. Oxo groups in the 2-, 3- and 6-positions of [2,3-f ]-ones, and in the 2- and 3-positions of [3,4-f ]-ones have been... 

Finally the preformed 2-formyl-3-aminoquinoxaline (448) gave the pyrido[2,3-f ]quin-oxalin-2-one (449) with activated esters/sodium alkoxide (79ZC422). 

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]

H-Pyrido[3,2-c]azepine, 7-methoxy-nucleophilic displacement reactions, 7, 514 Pyridoazepines synthesis, 7, 535, 540 Pyridoazepinones synthesis, 7, 531 Py rido[2,1-a]benzazepin-6-one physiological properties, 7, 546 Py rido[ 1,2-a]benzimidazoles reactions, 6, 1041... 

Pyrido[2,3-b]pyrazin-8-one-7-carboxylic acids H NMR, 3, 249 Pyrido[2,3-b]pyrazinones alkylation, 3, 250... 

One heterocyclic subunit which is an excellent donor group is the 2,6-pyrido-sub-stitutent - ". However, when 4-chloro-2,6-dicarboxypyridine was utilized as precursor to the macrocycle, the product apparently was less stable than was the corresponding nonchlorinated ester The decomposition was apparently initiated by complexation of either Sr or Ba " but the mechanism by which this degeneration occurred was not suggested nor is it obvious to the present authors, especially in the absence of any commentary concerning the products of decomposition. The synthesis of the apparently unstable system is illustrated below. 

Many hydantoins are endowed with significant pharmacological activities as highlighted by 5,5-diphenylhydantoin (Dilantin ), an anticonvulsant and antiepileptic discovered by Parke-Davis in 1940 s. Despite the lapse of more than half a century, Dilantin still plays an important rote in modem medicine. Meanwhile, another anticonvulsant 15 was synthesized from 9,10-dimethoxy-l,3,4,6,7,llb-hexahydro-pyrido[2,l-a]isoquinolin-2-one (14) under the standard Bucherer-Lieb variation in a 2 1 water-ethanol solution (15a 15b = 8 l). ... 

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