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-10100089-B2
Publication Date
2018-10-16
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 invention relates to methods for preparing compounds of Formula (1) and Formula (2) or pharmaceutically acceptable salts thereof, including substituted cyclic depsipeptides and largazole analogs. The compounds are defined by variable structural features including X, Y and Z, R1 to R19, ring-related constraints such as n being 2 or 3, and selected substituent patterns for R5/R6 and R12.
A defined stepwise synthetic sequence converts alcohol (VI-A) to carbamate (VIII-A), reacts carbamate (VIII-A) with heterocyclic compound (IX) to provide compound (X-A), selectively removes the carbamate protecting group to provide amine (XVII-A), and reacts the amine with protected amino acid (VII-A) to provide amide (XVIII-A). Further steps include deprotecting amide (XVIII-A) to provide compound (XIX-A), ring closure to compound (XX-A), and reacting (XX-A) with R12—SH to provide a compound of Formula (1).
In the alternative route, carbamate (VIII) reacts with heterocyclic compound (XXVI) to form compound (XXVII), the carbamate protecting group is removed to provide amine (XXVIII), ring closure provides amide (XXIX), and (XXIX) reacts with (XXI) to yield a compound of Formula (2). The disclosed approach includes selective removal of carbamate protecting groups, ring closure, and final coupling to the sulfur reagent or related coupling partner.
Claims Coverage
The document includes two independent method claims. Each independent claim covers a multi-step synthetic sequence with specified structural classes for the target compounds and a final coupling step for Formula (1) or Formula (2).
Method for preparing a compound of Formula (1)
A method for preparing a compound of Formula (1) or a pharmaceutically acceptable salt thereof, with X, Y, Z and substituent variables defined within specified classes, comprising conversion of alcohol (VI-A) to carbamate (VIII-A), reaction of carbamate (VIII-A) with heterocyclic compound (IX) to provide compound (X-A), selective removal of the carbamate protecting group to provide amine (XVII-A), reaction with protected amino acid (VII-A) to provide amide (XVIII-A), deprotection to provide compound (XIX-A), ring closure to compound (XX-A), and reaction with R12—SH to provide Formula (1).
Method for preparing a compound of Formula (2)
A method for preparing a compound of Formula (2) or a pharmaceutically acceptable salt thereof, with X, Y, Z and substituent variables defined within specified classes, comprising reaction of carbamate (VIII) with heterocyclic compound (XXVI) to provide compound (XXVII), removal of the carbamate protecting group to provide amine (XXVIII), ring closure to provide amide (XXIX), and reaction with (XXI) to provide Formula (2).
Overall claim coverage centers on two independent synthetic method sequences that construct Formula (1) and Formula (2) from defined intermediates, with the key distinction being coupling of the ring-closed intermediate to R12—SH for Formula (1) versus coupling with (XXI) for Formula (2).
Stated Advantages
Comparative rationale is provided for ruthenium carbene-catalyzed cross olefin metathesis versus traditional Horner-Wadsworth-Emmons-type routes.
The metathesis route is asserted to provide waste reduction and is associated with recyclable catalysts/reagents.
Downstream use of intermediates without purification is mentioned.
Documented Applications
Preparation of compounds of Formula (1) and pharmaceutically acceptable salts thereof.
Preparation of compounds of Formula (2) and pharmaceutically acceptable salts thereof.
Preparation of largazole and largazole analogs.
The disclosed substituted cyclic depsipeptides are histone deacetylase (HDAC) inhibitors.
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