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  • P Benzoxaborole substituted macrocyclic compounds based on I

    2021-09-18

    P4-Benzoxaborole-substituted macrocyclic compounds based on ITMN-191 scaffold were prepared using a general scheme as shown in . ITMN-191 was prepared by following a patent procedure. The P4 BOC group was removed by treatment with TFA in dichloromethane to give amine . The coupling of the amine to 6-aminobenzoxaboroles (, and ) providing urea compounds (, and ) was accomplished via an isocyanide intermediate, which was prepared by treatment of compound with triphosgene in the presence of triethylamine at low temperature. The intermediate was not isolated, 6-aminobenzoxaboroles were added in situ. This reaction sequence provided urea compounds in modest 30% isolated yield. The carbamate-linked P4-benzoxaborole-substituted macrocyclic compounds ( and ) were generated going through the same isocyanate intermediate reacting with hydroxybenzoxaboroles instead ( and ). The synthesis of urea compound involves conversion of 6-aminomethylbenzoxaborole to its -nitrophenyl carbamate , followed by reaction of it with macrocyclic amine in somewhat higher (50%) yield. The amide was prepared in 50% by coupling of 6-benzoxaborole carboxylic fatty acid amide hydrolase with macrocyclic amine in the presence of HATU, DIEA in DMF at room temperature. The functionalized benzoxaborole compounds necessary for the preparation of benzoxaborole-substituted macrocyclic HCV inhibitors were prepared as follows. The 6-aminobenzoxaborole (RNH, RRH) was prepared according to a published procedure. Both 5- and 6-hydroxybenzoxaboroles ( and ) were prepared in the same fashion starting from separate starting material 5 or 4-methoxysalicylaldehyde, as illustrated for 6-hydroxybenzoxaborole in . 4-Methoxysalicylaldehyde was converted to its triflate by treatment with triflic anhydride in the presence of pyridine at low temperature. Boronation was accomplished by pinacol diborate in the presence of a palladium catalyst to provide boronobenzaldehyde . Reduction with sodium borohydride and acidic work up gave 6-methoxybenzoxaborole . Cleavage of the methoxy group by BBr provided 6-hydroxybenzoxaborole . 6-Amino-5-fluorobenzoxaboroles and were prepared as shown in from 2-bromo-5-fluorobenzaldehyde . Reduction with sodium borohydride or addition of methyl magnesium bromide to produced benzyl alcohol or in high yield. Halogen-metal exchange reaction and deprotonation were accomplished using two equivalents of -butyllithium, the resulting dianion was reacted with triisopropyl borate and acidic work-up providing benzoxaboroles and . Nitration of both compounds with fuming nitric acid produced 6-nitro derivatives and with high regio-selectivity and yield. Raney nickel reduction of the two nitro compounds provided 6-amino-7-fluorobenzoxaboroles and . 6-Aminomethylbenzoxaboroles and benzoxaborole-6-carboxylic acid were prepared as shown in . 2-Bromo-4-cyanobenzaldehyde was converted to 6-cyanobenzoxaborole by following the same sequence of reactions as shown in for preparation of benzoxoborole and . The aminomethylbenzoxaborole was obtained from reduction of compound using lithium aluminium hydride, while compound was obtained from hydrolysis of compound with concn HCl. Inhibitors with P2∗ groups other than isoindoline (ITMN-191 scaffold) were prepared as described in through heteroaryl displacement reactions. Prerequisite chloro-isoquinoline and chloro-quinoline were prepared by following the published procedures. The other coupling partner hydroxymacrocycle was also prepared according to a published reference procedure. Heteroaryl displacement reaction of compound with either or was achieved in good yield by treatment of with slightly more than two equivalents of potassium -butoxide in DMF at room temperature. Both products and were treated with HCl in dioxane to produce aminomacrocycles and . Linking of either or with both 6-aminobenzoxaborole and 6-aminomethylbenzoxaborole was accomplished by the same reaction sequence as described in . Compounds and are products of amine coupled to 6-aminobenzoxaborole and aminomethylbezoxaborole ; while and are products of amines coupled with the same benzoxaboroles.