Pyrido pyrimidine, preparation

Difficulty was experienced when repetition of this preparation was attempted, but conditions were soon found that enabled the pyrido-pyrimidine to be obtained in good yield. This product, however,... 

Tsuge and Noguchi469 prepared the 3-benzamido-4-oxo-4//-pyrido-[l,2-a]pyrimidine and its methyl substituted derivatives from 2-amino-pyridines and 2-phenyl-4-ethoxymethylene-5-oxazolone in boiling ethanol, without the isolation of the condensation products of type 94. The pyrido-pyrimidine was formed from 2-amino-6-methylpyridine, but in a longer reaction period and in low percentage yield. Condensation product 94 was cyclized in ethanol or polyphosphoric acid or acetic acid. 3-Benzamido-2-methyl-4-oxo-4A/-pyrido[l,2- ]pyrimidine was synthetized from 2-amino-pyridine and the appropriate oxazolone derivative. 

Many of these reactions occur in the course of synthesis of fully or partly unsaturated products after initial ring closure, giving rise to more unsaturated systems, e.g. in the pyrido[2,3-pipemidic acids (Section 2.15.4.1) and their derivatives, e.g. (16a) -> (17) (74JAP(K)7444000). Examples are also found in the pyrido[3,2-[Pg.205]

The preparation of benzo fused pyrido[3,2- i]pyrimidines has furnished the only examples of the classic reaction of this type, the Bischler-Napieralski, involving the cyclization of 5-aryl-4-acylaminopyrimidines to 6-alkylpyrimido[4,5-c]isoquinolines, e.g. (157)->(158) (73YZ330). As often found in this reaction, the presence of activating substituents appears necessary (78CPB245). 

Thioureas give thioxo analogues of a variety of the above syntheses (52JOC542), although these thioxo products are usually prepared from isothiocyanates (Section 2.15.5.2.1). Examples are known in the pyrido-[2,3-[Pg.225]

Amongst the more unusual reactions, 2,3-thiazolo fused pyrido[3,2-d]pyrimidines have been prepared from 3-aminopicolinic acid and 2-bromothiazoles, whilst a similar derivative resulted with allyl isothiocyanate (221 222) <72IJC602). Similar products are also produced in [3 + 3] reactions of 2-aminothiazoles (Section 2.15.5.7.1). 

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 only other pyrimidine-based preparation of pyrido[3,2-d]pyrimidines involves reaction of 5-aminopyrimidine with crotonaldehyde to give (255) (70JHC1219). 

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. 

Formylation of the amino aldehyde, and subsequent treatment of the amide (46) with ammonia enabled Armarego to prepare pyrido[2,3-d]pyrimidine (1). This compound was also obtained by the decomposition of the tosylhydrazino compound (47). ... 

This has been attributed to the self-condensation reactions of these compounds,e.g., acetylacetaldehyde yields s-triacetylbenzene.° Hi. Ethoxymethylene compouTids. Ethoxymethyleneacetoacetates and ethoxymethyleneacetylacetones have been used to prepare pyrido[2,3-d]pyrimidines containing 6-ethoxycarbonyl or 6-acetyl... 

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 preparations of over two hundred tetrahydro- and octahydro-pyrido[4,3-d]pyrimidines from piperidines or from purely aliphatic starting materials are described in the patent literature. Fully aromatic examples of the system have been prepared from pyridines and pyrimidines. 

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... 

All existing syntheses of pyrido[4,3-d]pyrimidines from pyridines build up the pyrimidine ring from a 3-substituted 4-aminopyridine by methods closely similar to those applied for the other systems (routes i and u). The preparation of suitable 4-aminopyridines presents some... 

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... 

Ureido and benzamido derivatives have been prepared, and a 6-amino group in a pyrido[3,2-d]pyrimidine can be diazotized and reduced. ... 

A number of deaza analogs of pteroic acid (182, Ri = R2 = OH) have been prepared and examined by Rydon el al. as antagonists of folic acid in Streptococcus faecalis and Lactobacillus casei. Two of the pyrido[3,2-d]pyrimidines (183, R = OH or OEt, R2 = NH2) showed... 

Methoxy-4//-pyrido[],2-n]pyrimidin-4-one was prepared from 2-chloro-4//-pyrido[],2-n]pyrimidin-4-one with NaOMe in MeOH for 16h, and from n /iyJro-(2-hydroxy-4-oxo-4//-pyrido[l, 2-n]pyridinium)hydroxide with Me2S04 in the presence of NaOMe in MeOH for 3h at room temperature in 93% and 41% yields, respectively (99JCS(P2)1087). 2-(2-Hydroxyethoxy)-4//-pyrido[],2-n]pyrimidin-4-one was prepared from the 2-chloro derivative with HOCH2CH2OH in the presence of K2CO3 at 160 °C for 1 h (00BMC751). 

Risperidone (11) was prepared starting from 3-(2-chloroethyl) 180, via 3-(2-aminoethyl) 181, and 3- 2-[4-(2,4-difluorobenzoyl)piperidino]ethyl 182 derivatives of 4//-pyrido[l, 2-rz]-pyrimidin-4-ones as depicted in Scheme 11 (94MIP8, 95MIP7). 

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... 

Methylthio-4//-pyrido[l,2-u]pyrimidin-4-one was prepared by FVT of 2-methylthio-4-oxo-4//-pyrido[l, 2-u]pyrimidine-3-carboxylic acid at 650 °C at 8 X 10 -nbar for 4h (99JCS(P2)1087). 

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