4-Alkyl-2-aminopyridines

Directed metallation continues to be developed as a convenient method for regiospecific substitution of pyridines. A mild and general procedure for the preparation of structurally diverse 4-alkyl-2-aminopyridines 37 involves the lithiation/alkylation of aminopyridine derivative 36 <96JOC(61)4810>. 

The amidine rearrangement of N-alkyl-2-iminopyridines into 2-alkyl-aminopyridines (Scheme 1.9). In this rearrangement bond breakage occurs... 

Thiophenealdehyde has been used in the reductive alkylation of 2-aminopyridine and 2-aminopyrimidine. 2-Arylamino-4- (2-thienyl )thiazoles have been prepared by the reaction of 2-acetylthio-phene with A-arylthioureas in the presence of iodine, ... 

This method is not applicable if the spectra of the potentially tautomeric compound and both alkylated derivatives are very similar, e.g., it is not suited to an investigation of the tautomerism of 4-aminopyridine 1-oxide (Fig. 3). A further limitation is that often only qualitative conclusions can be drawn because no contribution from the spectrum of the minor constituent can be found in the spectrum of the tautomeric compound. It should also be noted that, un-... 

Comparison by Gardner and Katritzky of the pKa values of the cations formed by 2- and 4-aminopyridine 1-oxide and the alkylated derivatives of both forms showed that in aqueous solution the amino form predominates for 2- and 4-aminopyridine 1-oxide (cf. 241 242) and the methylamino form for 2- and 4-methylaminopyridine 1-oxide by factors of ca. 10 and >10 in the 2- and 4-series, respectively. The ultraviolet spectra of the 4-isomer and its alkylated derivatives... 

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. 

Substitution of a 2-pyridyl residue for the phenyl attached rectly to nitrogen affords a series of potent antihistamines, eparation of these compounds, too, is accomplished by a series alkylation reactions. It is further probable that the order the reaction can be readily interchanged. Thus, alkylation 2-aminopyridine with the chloroethyldimethylamine side chain ads to the diamine, 59. Alkylation with benzyl chloride af-rds tripelenamine (60) reaction with p-methoxybenzyl chloride ads to pyrilamine (61), °... 

In a variation on this approach, p-chlorobenzaldehyde is rst condensed with 2-aminopyridine. Reduction of the resulting iff base (62) affords the corresponding secondary amine. Alkyl-ion with the usual side chain affords the antihistamine, chlor-ramine (64). ... 

Resorting to alkylation chemistry again, 2-aminopyridine is condensed with the usual side chain halide to give diamine, 74. Alkylation of this with 2-chloromethylthiophene gives methapyrilene (75). Reaction with 2-chloromethyl-5-chlorothiophene affords the potent antihistamine chlorothen (76). ... 

In the uncatalyzed condensations of 2-aminopyridines, alkyl orthoformate, and dialkyl malonate at 110°C, 2-pyridylaminomethylenemalona-mates (263, R = H, Me R1 = Me, Et) were obtained in 20-25% yields. When isoamyl orthoformate was applied, a 5.2 4.8 mixture of ethyl and isoamyl N-(6-methyl-2-pyridyl)aminomethylenemalonamates (263, = Me, R1 = Et and isoamyl) was isolated in 90% yield (87SC549). 

The benzotriazole derivatives 101 (R1 = alkyl) formed from aliphatic aldehydes, ben-zotriazole and primary aromatic amines are reduced by lithium aluminium hydride or sodium borohydride to secondary amines 102, while Grignard reagents yield compounds of type 103116. The reaction has been used for the side-chain alkylation of 2-aminopyridine (equation 42) (direct alkylation occurs predominantly at the ring nitrogen atom). 

BOC-protected 2-aminopyridines undergo o/t, ti-alkylation with a,o -dihaloalkanes followed by an in situ cyclization to give bicyclic adducts in excellent yield (Scheme 24) <2004TL1721>. 

Condensation of a 2-aminopyridine with an a-haloketone provides an alternative method for budding the imidazopyiridine. For example, reaction of 2-aminopicoline (9-1) with para-methylphenacyl bromide (9-2) leads directly to the imidazopyridine (9-4). The overall transformation can be rationalized by assuming an initial alkylation on ring nitrogen (9-3) imine formation followed by bond reorganization then forms... 

A group from Spain patented a similar synthesis of risperidone (1) using similar synthetic transformations but in a different sequence (Scheme 2). Reaction of 2-aminopyridine with 2-acetylbutyrolactone in polyphosphoric acid at 160 °C afforded alcohol 15, which was hydrogenated to 16 and then converted to chloride 10 with thionyl chloride. Benzoyl piperidine 19 was prepared in a similar manner as in Scheme 1. In contrast to Scheme 1, 19 was alkylated with 10 prior to conversion to the 1,2-... 

An improved procedure using 2-methoxyethyl 2-chloroacetate in place of methyl 2-chloroacetate for the alkylation of sodium saccharin has been described. The resulting 2-methoxyethyl saccharin-2-acetate is treated with sodium 2-methoxyethoxide in dimethyl sulfoxide, then acidified to give 2-methoxyethyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide, which is N-alkylated with methyl iodide in acetone-aqueous sodium hydroxide. The resulting 2-methoxyethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide is heated with 2-aminopyridine in xylene to give piroxicam. 

---