Novel macrocyclic inhibitors of hepatitis C virus replication
A technology of cycloalkylated compounds, applied in the field of novel macrocyclic inhibitors of hepatitis C virus replication, which can address the increased risk of hepatocellular carcinoma, among other issues
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[1227] Preparation of NS3 inhibitors
[1228] methodology
[1229] The HCV protease inhibitors in each section can be prepared according to the procedures and schemes shown in each section below. Numbering in the following sections (including general methods or general procedure names) for the preparation of NS3 inhibitors refers only to that specific section and should not be interpreted as the same numbering (if any) in other sections or as in other sections. The same number (if any) is confused.
[1230] Preparation of NS3 Inhibitors: Part I
example 1
[1232] General Synthesis A
[1233] Option I
[1234]
[1235] Macrocycles with general structures I-D and I-E can be synthesized as shown in Scheme I. Isoindoline carbamates 1 can be treated under basic conditions to hydrolyze the isoindoline carbamates, thereby yielding alcohols 2. Heteroaryl chlorides such as 2-chlorobenzothiazole, 2-chloro-6-methylbenzothiazole, 2,6-dichlorobenzothiazole, 6-bromo-2-chloro Benzothiazole, 1-chloroisoquinoline, etc., treatment of alcohol 2 affords compounds with general structure I-A. Compounds of general structure I-A can be treated with an acid in methanol to remove the Boc protecting group and form the methyl ester, thereby giving compounds of general structure I-B. Available in Cu 2+ Treatment of compounds of general structure I-B with optionally substituted arylboronic acids under catalytic conditions affords N-aryl compounds of general structure I-C. Compounds of general structure I-C can be treated under basic conditions to...
example 1-1
[1237] General Procedure A
[1238] Compound 1 (10 g, 15.9 mmol) was dissolved in methanol (100 mL), 5M NaOH solution (95 mL) was added, and after the reaction was completed, the resulting mixture was heated to 50° C. and stirred overnight. The mixture was cooled with ice water, 2M HCl was added to acidify the mixture to pH = 3-4, then the mixture was extracted with EtOAc, the organic layers were combined, washed with brine, dried, and the solvent was removed under reduced pressure, the crude compound 2 (7.5 g) was directly used in in the next step.
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