反应详情

Scheme I-19 depicts the preparation of isothiazolobenzene or isothiazolopyridine glyoxylic acid derivatives which may be employed to prepare compounds of formula I. 3-methyl isothiazolopyridines can be prepared as depicted in step a by using methodology as described in Taurins, A.; Khouw, V. T. Can. J. Chem. 1973, 51(11), 1741-1748. For example Isothiazolo[3,4-b]pyridine was synthesized from 2-aminonicotinonitrile in three steps: by the reaction with NH3 and H2S to produce 2-aminothionicotinamide; oxidative cyclization with H2O2 to give 3-amino-isothiazolo[3,4-b]pyridine, followed by diazotization and reduction with hypophosphorous acid. 3-Aminoisothiazolo[4,3-b]pyridine was prepared in a similar way from 3-aminopicolinonitrile via 3-aminothiopicolinamide. Isothiazolo[5,4-b]pyridine was synthesized from 2-chloronicotinonitrile in three steps: reduction with HCO2H in the presence of Raney Nickel to obtain 2-chloronicotinaldehyde; transformation of the latter into 2-thiocyanonicotinaldehyde; and cyclization with NH3 to obtain isothiazolo[5,4-b]pyridine. 3-Methylizothiazolo[5,4-c]pyridine was prepared by cyclization of 4-acetyl-3-thiocyanopyridine with NH3. Alternatively, the 3-methylisothiazolopyridines may be prepared as described in Chimichi, S.; Giomi, D.; Tedeschi, P. Synth. Commun. 1993, 23(1), 73-78 in a single step procedure by treating a cyanomercaptopyridine with methyllithium in an appropriate solvent such as tetrahydrofuran to provide the 3-methylisothiazolopyridine derivative. As described previously for Scheme I-18 the methyl group may be converted to the bromide with N-bromosuccinimide as shown in step b. Bromide displacement with cyanide, as shown in step c, followed by hydrolysis and esterification, as shown in step d, provides the methyl ester. Oxidation of the methyl ester to the oxalate can then be carried out as depicted in step e. The oxidation can be carried out in one step with selenium dioxide to provide the oxalate. Alternatively, the methyl ester can be treated with a strong base such as lithium bistrimethylsilyl amide in tetrahydrofuran at reduced temperature followed by camphorsulfonyl oxaziridine to provide the corresponding α-hydroxy ester which may be oxidized with the Dess-Martin reagent in order to obtain the oxalate. The oxalate may then be hydrolyzed under standard conditions as depicted by step f to provide the oxalic acid derivative. The oxalic acid derivative may then be coupled to an appropriate piperazine derivative to provide a compound of Formula I.

1. customto prepare compounds of formula I