Processes for the preparation of aryl hydrocarbon receptor ligands
Inventors
Strack, Martin Benedict • Kaiser, Jasper • Mkrtchyan, Gnel • Zhang, Wen-Chun
Assignees
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Publication Number
US-11136318-B2
Publication Date
2021-10-05
Expiration Date
Abstract
The present disclosure relates to the preparation of methyl 2-(1H-indole-3-carbonyl)thiazole-4-carboxylate (ITE) and related compounds with high yield, purity, and scalability. The processes apply the use of a Weinreb amide intermediate as a scaffold for the preparation of ITE and structural analogs.
Core Innovation
The disclosure describes a synthetic strategy for preparing a compound of Formula I and related analogs, including the aryl hydrocarbon receptor (AhR) ligand methyl 2-(1H-indole-3-carbonyl)thiazole-4-carboxylate (ITE). The process is centered on building the indole-thiazole carbonyl linkage through compounds (II) to (VI), with selections for heteroatoms and substituents used throughout the structures.
A core sequence forms a protected intermediate by contacting a compound of formula (II) with a protecting group in the presence of a nucleophile to prepare a compound of formula (III). The document then contacts formula (III) with a halogenating agent followed by an amine to prepare a compound of formula (IV), and proceeds by contacting formula (IV) with a compound of formula (V) using a base and a solvent to prepare formula (VI).
Finally, the document contacts the compound of formula (VI) with an acid to prepare the compound of Formula I. The embodiments also describe compound (III), compound (IV), compound (V), compound (VI), and report regioisomer formation evidence during the thiazole metalation/Weinreb/esterification steps, attributing regioisomer formation to directed ortho metalation by the thiazole-4-carboxylic acid moiety.
Claims Coverage
The document provides one independent claim directed to a multi-step synthetic process to prepare a compound of Formula I, with the main inventive content implemented across the sequence from compound (II) to compound (III), then to compound (IV), then to compound (VI), and finally to Formula I by contacting with an acid. The claim also defines the structural scope of Formula I through W/X/Y/Z and R substituent selections, including R1–R8 and R9.
Process for preparing a compound of Formula I
The process comprises contacting a compound of formula (II) with a protecting group in the presence of a nucleophile to prepare a compound of formula (III), contacting the compound of formula (III) with a halogenating agent followed by an amine to prepare a compound of formula (IV), contacting the compound of formula (IV) with a compound of formula (V) in the presence of a base and a solvent to prepare a compound of formula (VI), and contacting the compound of formula (VI) with an acid to prepare the compound of Formula I.
Formula I substituent limitations
The compound of Formula I is defined with W, X, Y, and Z independently selected from O, S, and NH, and with R1–R8 independently selected from the listed substituent group. R9 is defined as directly connected to S and selected from the listed group.
Overall, the claim coverage centers on a multi-step process that uses protecting-group and nucleophile chemistry to form intermediate (III), halogenating followed by an amine to reach (IV), base and solvent conditions to transform (IV) with (V) into (VI), and acid treatment to yield the Formula I compound, with Formula I constrained by the enumerated heteroatom and substituent selections.
Stated Advantages
Not explicitly described in patent.
Documented Applications
The disclosure identifies methyl 2-(1H-indole-3-carbonyl)thiazole-4-carboxylate (ITE) as an aryl hydrocarbon receptor (AhR) ligand.
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