Process for the preparation of cyclic depsipeptides
Inventors
Piscopio, Anthony D. • Fu, Xiaoyong • Shi, Feng • Liu, Huayan • Li, Zhifeng
Assignees
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Publication Number
US-11739123-B2
Publication Date
2023-08-29
Expiration Date
Abstract
Processes for preparing compounds of Formula (1) and Formula (2) are described, wherein X, Y, Z, R1-R7, L and n are defined herein. Intermediates useful in the preparation of the compounds of Formula (1) and Formula (2) are also described.
Core Innovation
The disclosed subject matter includes substituted cyclic depsipeptides as histone deacetylase (HDAC) inhibitors, and also describes alkyl chloride compounds of Formula (XX) and pharmaceutically acceptable salts thereof. The compounds are defined by specific selections for substituent variables, including broad independently selected H, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, halo, hydroxyl, and carbonyl-containing or amino-containing substituent classes, with preferred heteroaryl selected from thiazole and oxazole and substitution patterns such as methyl and isopropyl.
The patent disclosure further describes preparation of cyclic depsipeptides through defined intermediates, including converting an alcohol intermediate with a chiral auxiliary TDx to a protected carbamate, coupling with a protected amino acid, forming amides, selectively removing protecting groups, performing ring closure, and reacting with an R12/SH reagent to form the final cyclic depsipeptide. Related intermediates and macrocyclic carbamate/ester-bearing intermediates are also described as being converted through activation, acid-mediated hydrolysis/deprotection, intramolecular macrolactamization, and conversion to thioate-linked products using thioate nucleophiles generated from thiol-acid precursors and bases.
The overall disclosure provides a defined chemical space of substituted alkyl chloride compounds and related derivatized macrocyclic and thioate-linked products, including S-thioate and amino-thioate derivatives. It also includes synthetic pathways that use ruthenium carbene-catalyzed cross olefin metathesis and oxidation steps, and it states synthetic advantages over Horner-Wadsworth-Emmons-type routes involving reduced waste streams and recoverable, recyclable components.
Claims Coverage
The independent claim coverage includes an alkyl chloride compound of Formula (XX) or a pharmaceutically acceptable salt thereof, together with a method claim defined by treatment of the alkyl chloride with a specified compound followed by deprotection. Across the provided material, the inventive coverage is refined by narrowing substituent selections and specifying particular salt forms, while the method coverage requires a preparation sequence from Formula (XX) through Formula (XXIV) to Formula (XXV).
Alkyl chloride compound of formula (xx) with defined substituent selections
An alkyl chloride compound of Formula (XX) or a pharmaceutically acceptable salt thereof, with broadly defined independently selected H, C1-C10 alkyl, C3-C7 cycloalkyl, and C3-C7 heterocycloalkyl substituent patterns, optionally substituted by the listed substituents.
R1-r6 restricted to H or C1-C10 alkyl
In the alkyl chloride compound of Formula (XX), R1 through R6 are each independently H or a C1-C10 alkyl group.
Specific substituent identities for r3-r4 and r5-r6
In the alkyl chloride compound of Formula (XX), R1 and R2 are H, R3 and R4 are CH3, and R5 and R6 are either H and isopropyl or isopropyl and H.
Preparation sequence from an alkyl chloride to a deprotected formula (xxv) compound
A method of preparing a compound of Formula (XXV) or a pharmaceutically acceptable salt thereof by treating an alkyl chloride compound of Formula (XX) with a compound of Formula (XXIII) to form a compound of Formula (XXIV), and then deprotecting the Formula (XXIV) compound to yield the Formula (XXV) compound or salt.
Hydrochloride salt specification
The method uses a pharmaceutically acceptable salt in which the salt is a hydrochloride salt.
Benzenesulfonate salt specification
The method uses a pharmaceutically acceptable salt in which the salt is a benzenesulfonate salt.
Overall, the claim set covers a family of alkyl chloride compounds defined by Formula (XX) with position-specific substituent-selection rules, narrows the substituent scope in dependent claims, and includes a method claim defined by treatment of the alkyl chloride with a specified Formula (XXIII) compound followed by deprotection to a Formula (XXV) compound; the method further specifies hydrochloride and benzenesulfonate salt forms.
Stated Advantages
Reduced waste streams compared with Horner-Wadsworth-Emmons-type routes.
Recoverable catalysts and solvents.
Recycling of starting materials, catalysts, and manganese oxides compared with Horner-Wadsworth-Emmons-type routes.
Documented Applications
Substituted cyclic depsipeptides are described as histone deacetylase (HDAC) inhibitors.
Related intermediates are described as useful for preparing Largazole and Largazole analogs.
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