3- Amino-5-methylpyridine

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. 

Cyclocondensation of 2-aminopyridines with methyl 3-(A,A-dimethyla-mino)-2-(benzyloxycarbonylamino)acrylate in boiling AcOH for several hours gave 3-(benzyloxycarbonylamino)-4//-pyrido[l, 2-n]pyrimidin-4-ones 370 (99CCC177, 00MI33). 2-Amino-6-methylpyridine afforded only condensation product 371. 

A 1,8-naphthyridine, nalidixic acid (39), shows clinically useful antibacterial activity against Gram-negative bacteria as such, the drug is used in the treatment of infections of the urinary tract. Condensation of ethoxymethylenemalonate with 2-amino-6-methylpyridine (36) proceeds directly to the naphthyri-dine (38) the first step in this transformation probably involves an addition-elimination reaction to afford the intermediate, 37. W-Ethylation with ethyl iodide and base followed by saponification then affords nalidixic acid (39). 

The starting material is prepared by reacting 2-amino-6-methylpyridine with ethoxymethyl-ene-malonic acid diethyl ester and then reacting that product with sodium hydroxide. 

The condensation of 2-amino-6-methylpyridine and EMME was carried out in methyl-phenyl-polysiloxanes at 90-100°C to give high-purity (99%) diethyl A-(6-methyl-2-pyridyl)aminomethylenemalonate in 97% yield (84GEP3308089). 3-Amino-5-(pyridyl)-2-(17/)-pyridones were reacted with dialkyl alkoxymethylenemalonates in boiling ethanol for 6.0-6.5 h to... 

A mixture of 2-amino-6-methylpyridine, ethyl orthoformate, and diethyl malonate was heated at 150°C for 1 hr to give A-(6-methyl-2-pyridyl)-aminomethylenemalonate (262, R = 6-Me, R1 = Et) in 77% yield [74JAP(K)88879],... 

The monoethyl A -(6-methyl-2-pyridyl)aminomethylenemalonate was prepared in 34% yield in the reaction of monoethyl malonate, ethyl orthoformate, and 2-amino-6-methylpyridine in the presence of catalytic amounts of A1C13 at 110-115°C for 45 min (72AF815). 

Amino-6-methylpyridine was reacted with ethyl orthoformate in the presence of acetic acid at 80-110°C for 1.5 hr to give formimidate (305),... 

The reaction between 2-aminopyridine and 2-amino-4-methylpyridine with perfluoro-2-methylpent-2-ene gave pyrido[l,2-a]pyrimidines, but 2-amino-6-methylpyridine gave the naphthyridine (220) (74CC134). 

A range of enantiomerically pure (R)- and (S)-, (E)- or (Z)-oxime ethers of 2,3-dihydro[l,8]naphthyridine have been prepared from 2-amino-6-methylpyridine <2000EJM815>. The selective acetylation of the same compounds in the 1-, 4-, or 1,4-positions has also been reported <1996JHC1185>. 

Amino-6-methylpyridine [1824-81-3] M 108.1, m 44.2 , b 208-209°. Crystd three times from acetone, dried under vacuum at ca 45°. After leaving in contact with NaOH pellets for 3h, with occasional shaking, it was decanted and fractionally distd [Mod, Magne and Skau JPC 60 1651 1956]. Also recrystd from CH2CI2 by addition of pet ether. [Marzilli et al. JACS 108 4830 1986]. 

Oxidation of the metal carbonyl is used in the preparations illustrated by equations (20) to (22),173-175 in the third of which a heteronuciear dimer is formed. No reaction occurred between Cr(CO)6 and 2-amino-6-methylpyridine.176 The binuclear nature of red [Cr PhC(NPh)2 2] has not been established, and an impure sample of [CrMo(mhp)4] has been prepared from [CrMo(02CMe)4].177... 

E. V. Brown105 has described the synthesis of 2-methyl-l,8-naphthyridine, and several new derivatives by the EMME synthesis, starting with 2-amino-6-methylpyridine. 

According to Chuiguk and Oksanich13 the reaction of 2-aminopyridinium perchlorates and /i-chlorovinylaldehydes led exclusively to the 4-substituted products (9) whereas from 2-amino-6-methylpyridine no cyclic product was obtained. With //-chlorovinyl ketones both the 2- and 4-substituted pyrido-[l,2-u]pyrimidinium salts were detected by H NMR.3 2-Amino-6-methyl-pyridine gave rise only to the 2-substituted isomer (10). 

Lappin20,21 studied the reactions of 2-aminopyridine and its monomethyl derivatives with methyl propiolate. In addition to the 2-oxo-2H-pyrido-[l,2-a]pyrimidines (22), the monoadducts (20) and/or the diadducts (21) were isolated. Only the pyrido[l,2-ci]pyrimidine was formed from 2-amino-6-methylpyridine. Lappin came to the conclusion that the addition step of the reaction is not stereospecific and that it leads to both the Z (19) and E (20) acrylates. In the next step the Z stereoisomer (19) readily undergoes cyclization due to its favorable geometric arrangement, thereby forming 22. The E acrylate (20) may react with another molecule of methyl propiolate to give the diadduct (21). Repetition of this work by Wilson and Bottomley22 led, in the case of 2-aminopyridine and 2-amino-5-methylpyridine, to the... 

From 2-amino-6-methylpyridine and ethyl 3-aminocrotonate the expected 2,6-dimethyl-4-oxo-4//-pyrido[l,2-a]pyrimidine was not obtained, but instead a urea derivative is formed.36 Ethyl acetoacetate has also been replaced... 

Kato et al,94 reported that 2-amino-6-methylpyridine and diketene did not yield 4-oxo-4/f-pyrido[l,2-a]pyrimidines but instead yielded 2-acetyl-acetamido-6-methylpyridine and pyridone or pyrone derivatives. 2-Methyl-4-oxo-4H-pyrido[l,2-a]pyrimidine (47) and its 8-methyl derivative have also been prepared from 2-aminopyridine and 2-amino-4-methylpyridine with N,N-dimethyl-3-aminocrotonamide95 or with acetoacetamide45 in yields of 5 and 39°,. respectively. 

From 2-amino-6-methylpyridine and monosubstituted malonates Buu Hoi and Declerq100 obtained 3-substituted 1,8-naphthyridines of type 66, and from 2-aminopyridine they obtained 3-substituted pyrido[l,2- ]pyrimidines of type 63 (R = H). 

Meszaros et al. reacted 2-amino-6-methylpyridine with diethyl malonate in a mixture of phosphoryl chloride and polyphosphoric acid and isolated... 

The expected pyrido[l,2-a]pyrimidines (63) were prepared from carbon suboxide and 2-aminopyridines, including 2-amino-6-methylpyridine at room temperature.121... 

For the product isolated from the reaction of 2-amino-6-methylpyridine and ethoxymethylenemalononitrile, Ceder and Vernmark157 suggested structure 87 (R1 = 6-Me, R2 = H, X = NH). This proved to be incorrect,... 

Flowers et al.164 reacted perfluoro-2-methyl-2-pentene with 2-aminopyri-dine or 2-amino-4-methylpyridine in tetrahydrofuran at room temperature to obtain the pyrido[1.2-u]pyrimidines (95). Reaction with 2-amino-6-methylpyridine yielded the 1,8-naphthyridine (96). 

Lappin20,197 reported that the reaction of 2-aminopyridines with alkyl 3-chloropropionates to give the pyrido[l,2-u]pyrimidines (142) is accompanied by the dehydrohalogenation of the propionates. In the case of 2-amino-6-methylpyridine this side reaction becomes exclusive. From alkyl acrylates and 2-aminopyridine or its 4- and 5-methyl derivatives, Lappin obtained a mixture of the pyrido[l,2- ]pyrimidines (142 R = H, 7-Me, 8-Me) and the 2-pyridylaminopropionates (144). In reactions lasting only 2 to 3 hours the pyrido[l,2-u]pyrimidines were mainly formed, whereas in prolonged reactions (20-100 hours) the propionates were the main products. 2-Amino-3-methylpyridine gave only the pyrido[l,2-a]pyrimidine (142 R = 9-Me), whereas from 2-amino-6-methylpyridine only the propionate (144 R = 6-Me) was obtained. 

Okamoto et al. prepared the pyrido[l,2-c<]pyrimidines (142 R = H, Me) by heating 2-aminopyridines with ethyl 3-chloropropionimidate hydrochloride in ethanol or acetonitrile. In the case of 2-aminopyridine and 2-amino-4-methylpyridine, not only 142 (R = H, 8-Me) but also the 2-imino derivatives were isolated, which on treatment with acid were transformed to 2-oxopyrido[l,2-c<] pyrimidines (142). With 2-amino-6-methylpyridine or... 

From 2-amino-6-methylpyridine only the imidazo [l,2-u]pyridine (162 R = 5-Me) was formed this was interpreted in terms of the steric effect of the 6-methyl group. 

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. 

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