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-12252511-B2
Publication Date
2025-03-18
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 concerns a multistep method of preparing a thiol of Formula (XXII), or a pharmaceutically acceptable salt thereof. The method converts a carbamate of Formula (XVI) into an amine of Formula (XVII) under acidic conditions, then reacts the amine with a compound of Formula (VII) to provide a carbamate of Formula (XVIII).
After formation of the carbamate of Formula (XVIII), the method further converts this intermediate into an amine of Formula (XIX) under acidic conditions, and then cyclizes (XIX) to provide (XX). The method culminates in treatment of (XX) with R12-SH to provide the thiol of Formula (XXII).
The disclosure also specifies substituent states in which R1 and R2 are H, R3 and R4 are independently C1-C10 alkyl, and R5 and R6 are arranged as either R5 is H and R6 is C1-C10 alkyl or R5 is C1-C10 alkyl and R6 is H. The described scheme includes carbamate formation and coupling, acid-catalyzed deprotection to amines, cyclization to form (XX), and terminal thiol introduction.
Claims Coverage
The disclosure contains one independent method claim directed to preparing a thiol of Formula (XXII) or a pharmaceutically acceptable salt. The claim coverage centers on a defined multistep transformation sequence and includes explicit substituent constraints on R1-R6 and R12. Dependent claim language specifies acidic reagents, coupling or activation reagents, additives, and bases.
Preparation of thiol of Formula (XXII) via carbamate-to-amine conversion, carbamate coupling, cyclization, and thiol introduction
A method of preparing a thiol of Formula (XXII) or a pharmaceutically acceptable salt, comprising treating the carbamate of Formula (XVI) under acidic conditions to provide the amine of Formula (XVII), reacting the compound of Formula (XVII) with the compound of Formula (VII) to provide the carbamate of Formula (XVIII), treating (XVIII) under acidic conditions to provide the amine of Formula (XIX), cyclization of (XIX) to provide (XX), followed by treatment of (XX) with R12-SH to provide the thiol (XXII).
Substituent constraints for R1-R6 and R12 on the method
The method further defines that R1 and R2 are H, R3 and R4 are independently C1-C10 alkyl, R5 is H and R6 is C1-C10 alkyl or R5 is C1-C10 alkyl and R6 is H, and R12 is H.
Acidic deprotection using trifluoroacetic acid or hydrochloric acid
The conversion of the carbamate of Formula (XVI) to the amine of Formula (XVII) and/or the conversion of the compound of Formula (XVIII) to the amine of Formula (XIX) is carried out by treating with trifluoroacetic acid or hydrochloric acid.
Carbamate formation using selected carbodiimide reagents
The reaction of the amine of Formula (XVII) with the compound of Formula (VII) to provide the carbamate of Formula (XVIII) is carried out in the presence of DCC, DIC, or EDCI, optionally with HOBt or HOAt.
Conversion from (XIX) to (XX) using selected activation and coupling reagents
Conversion of compound (XIX) to compound (XX) is performed by treating (XIX) with specified coupling or activation reagents, optionally in the presence of additional additives including HOSuc, HODhbt, Hot, and HOCt, and substituted HOBt/HOAt reagents.
Bases and reagents for reacting (XX) with R12-SH
The method where (XX) is reacted with R12-SH in the presence of one of the specified bases or reagents, selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, sodium methoxide, potassium tert-butoxide, triethylamine, N,N-diisopropylethylamine, and 1,8-diazabicyclo [5.4.0]undec-7-ene.
Independent claim coverage centers on a multistep transformation sequence converting Formula (XVI) through Formula (XVII), Formula (XVIII), Formula (XIX), and cyclized intermediate (XX) to the target thiol (XXII) by final reaction with R12-SH, while enforcing explicit substituent constraints on R1-R6 and requiring R12 to be H.
Stated Advantages
Reduced waste and improved atom economy over alternative routes.
Recoverable catalysts and recoverable solvents.
Documented Applications
Not explicitly described in patent.
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