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  • br Chemistry Scheme shows the synthesis of

    2021-06-09


    Chemistry Scheme 1 shows the synthesis of compounds 15-1–15-33 from commercially available 2-(4-aminophenyl)acetonitrile (8a). Protection of the starting material 8a with di-t-butyl dicarbonate afforded 9. The reaction of 9 with methyl 1-chloroisoquinoline-4-carboxylate in the presence of sodium hexamethyldisilazane, followed by oxidative decyanation under oxygen atmosphere produced 10 in 58% yields. The carboxylic Busulfan 11, prepared by the basic hydrolysis of 10, was converted to the corresponding acid chloride, and was treated with trimethylsilyldiazomethane to afford the diazoketone intermediate. Wolff rearrangement of the diazoketone intermediate followed by methylation of the resulting carboxylic acid moiety with trimethylsilyldiazomethane provided 12a in 50% yield from 11. Deprotection of the t-butoxycarbonyl group in 12a under an acidic condition (TFA), and the subsequent acylation of the resulting aniline intermediate 13 with a variety of acid chlorides gave 14-1–14-33. Finally, hydrolysis of the ester moiety afforded the target isoquinoline derivatives 15-1–15-33 in 27%-quant yields. Compound 15-1 was obtained by the treatment of 14-1 with acetic anhydride and the subsequent basic hydrolysis, and compound 15-33 was obtained by the treatment of 14-33 with 1,2-dichloro-4-isocyanatobenzene followed by basic hydrolysis. Scheme 2 summarizes the synthesis of compounds 15-34–15-44. Compound 15-34 was prepared by selective N-methylation of the amide of 15-20. The common intermediate 13 was reacted with phenylcarbonochloridate. The addition of (3,4-dichlorophenyl)methanol followed by hydrolysis of the resulting ester moiety generated 15-35. With regard to the synthesis of compounds 15-36, 13 was treated with 3,4-dichlorobenzylbromide in the presence of potassium carbonate, and the ester moiety was hydrolyzed by sodium hydroxide. Compound 15-37 was synthesized by the reaction of the aniline intermediate 13 with 3,4-dichlorobenzene-1-sulfonyl chloride in the presence of pyridine followed by basic hydrolysis of the ester moiety. Intermediate 12b was prepared from methyl 1-chloroisoquinoline-4-carboxylate and t-butyl 4-(cyanomethyl)benzoate, in a manner similar to the synthesis of 12a as described in Scheme 1. Using 12b, compounds 15-38–15-41 were prepared as follows: (1) acidic removal of the ester moiety (TFA); (2) conversion to acyl chloride (oxalyl chloride); (3) condensation of the acyl chloride with 3,4-dichloroaniline; and (4) hydrolysis of the ester moiety. 15-42–15-44 were achieved by demethylation of 12c by boron tribromide, which was derived from methyl 1-chloroisoquinoline-4-carboxylate and 2-(4-methoxyphenyl)acetonitrile in a procedure similar to the synthesis of 12a (Scheme 1), and the subsequent etherification of the resulting phenol followed by hydrolysis. Compounds 15-45 and 15-46, in which the acetic acid moiety at the 4-position of the isoquinoline core was modified, were synthesized as shown in Scheme 3, Scheme 4. Geminal dimethylation of 12b by sodium hydride and iodomethane resulted in 16 with a 72% yield. Deprotection of the t-butyl ester moiety using TFA, followed by the condensation reaction of 17 with 4-chlorophenethylamine (WSC·HCl, HOBT·H2O), gave 18 in a 44% yield. Finally, hydrolysis of the ester moiety afforded the target derivative 15-45. Compound 15-46 was synthesized from commercially available 4-bromo-1-chloroisoquinoline (19), which was reacted with methyl 4-(cyanomethyl)benzoate in the presence of sodium hexamethyldisilazane. Subsequent oxidative decyanation afforded 20. Compound 20 was converted to 22 using the boronic acid ester 21 by the following two-step reaction method: (1) treatment with bis(pinacolato)diboron in the presence of PdCl2(dppf) and potassium acetate; and (2) oxidation of 21 using oxone. Transformation of 22 into the target compound 15-46 was accomplished using the following conventional method: (1) alkylation of the hydroxyl moiety in 22 with t-butyl 2-bromoacetate in the presence of potassium carbonate; (2) basic hydrolysis of the methyl ester (NaOH); (3) condensation of the acid with 4-chlorophenethylamine (WSC–HCl and HOBT–H2O); and (4) hydrolysis of the t-butyl ester moiety.