Process for making duocarmycin prodrugs
Inventors
Huijbregts, Tijl • Elgersma, Ronald Christiaan • Beusker, Patrick Henry • Joosten, Johannes Albertus Frederikus • Coumans, Rudy Gerardus Elisabeth • Spijker, Henri Johannes • MENGE, Wiro • De Groot, Franciscus Marinus Hendrikus
Assignees
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Publication Number
US-9890159-B2
Publication Date
2018-02-13
Expiration Date
Abstract
The present invention relates to a process comprising converting a compound of formula (I) into a compound of formula (II) by reaction with an organolithium reagent, which compound can be further converted into duocarmycin analogs consisting of a DNA-alkylating and a DNA-binding part, and still further into corresponding antibody-drug conjugates.
Core Innovation
The invention describes an improved and scalable synthetic process for duocarmycin prodrugs and duocarmycin analog intermediates, including conversion toward antibody-drug conjugates (ADCs). A compound of formula (I) is converted into a compound of formula (II) by reaction with a monometal organolithium reagent in a suitable solvent, with P and P′ independently protective groups and X as halogen.
The process further includes conversion of the compound of formula (II) into a compound of formula (III) by chlorination, described as one-step or two-step chlorination. The sequence is followed by conversion of the compound of formula (III) into a compound of formula (IV) through deprotection and peptide-bond coupling with a compound of formula (V), and subsequent elimination of an alcohol protective group.
The disclosed synthesis emphasizes the use of a monometal organolithium reagent and explicitly notes avoidance of intermetal cuprate/zincate reagents. Embodiments and example syntheses are provided for preparing specific intermediates and continuing the conversion toward coupled products, including deprotection and hydrogenolysis.
Claims Coverage
The independent claim covers a multistage process for converting a duocarmycin-related compound of formula (I) to a compound of formula (II) using a monometal organolithium reagent under defined substituent and protecting-group constraints, with an explicit halogen option for X. Across the provided dependent claims, additional inventive features narrow the organolithium reagent identity, restrict the halogen identity, and add further conversion stages from formula (II) to (III) and from formula (III) to (IV) including sequential deprotection, coupling, and elimination.
Monometal organolithium conversion from formula (I) to formula (II)
A process comprising converting a compound of formula (I) into a compound of formula (II) by reaction with a monometal organolithium reagent in a suitable solvent, wherein P and P′ are independently protective groups, R1 is CH3, CH2CH3, OCH3, OCH2CH3, CF3, OCF3, Cl or F, R2, R3, and R4 are independently H or C1-6 alkyl or R1 and R2 taken together form a 5- or 6-membered (hetero)cycloalkyl group and X is halogen.
Specific monometal organolithium reagents
The process where the monometal organolithium reagent is selected from n-butyl lithium, tert-butyl lithium, or methyl lithium.
Restricted halogen identity for X
The process where the halogen is bromine or iodine.
Chlorination conversion from formula (II) to formula (III)
A further process converting a compound of formula (II) into a compound of formula (III) via either a one-step or two-step reaction with a chlorinating reagent, where R1, R2, R3, R4, P and P′ are as defined.
Sequential deprotection, coupling, and P′ elimination from formula (III) to formula (IV)
A further process converting a compound of formula (III) into a compound of formula (IV) by removing the P protective group from the compound of formula (III), reacting the unprotected compound of formula (III) with a compound of formula (V) in the presence of a coupling reagent followed by elimination of the P′ protective group, where R1, R2, R3, R4, P and P′ are as defined, P″ is independently a protective group and X1, X2 are X3 are independently C or N.
The claim set provided centers on monometal organolithium conversion of formula (I) to formula (II) with defined protective groups and substituent constraints, then chlorination to formula (III), followed by deprotection and peptide-bond coupling with subsequent elimination to reach formula (IV). Dependent features further narrow the organolithium reagent and the halogen identity, and add the multistage transformation details for the later intermediates.
Stated Advantages
Improved and scalable synthetic process for duocarmycin prodrugs and duocarmycin analog intermediates and conversion toward antibody-drug conjugates (ADCs).
Documented Applications
Conversion toward antibody-drug conjugates (ADCs) using duocarmycin prodrugs and duocarmycin analog intermediates.
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