Processes and intermediates for preparing tirzepatide
Inventors
KOPACH, MICHAEL EUGENE • RICHEY, Rachel Nicole • BERGLUND, Mark Richard • Seibert, Kevin Dale • MURZINSKI, Emily Suzanne
Assignees
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Publication Number
US-12304938-B2
Publication Date
2025-05-20
Expiration Date
Abstract
The present invention provides new intermediates and processes useful in the manufacture of tirzepatide, or a pharmaceutically acceptable salt thereof.
Core Innovation
The disclosed invention is a process for preparing a compound of formula (I), wherein PG is a protecting group. The process comprises contacting a compound of formula (Ia) with diisopropylethylamine, contacting the product with 2-(5-norbornene-2,3-dicarboximido)-1,1,3,3-tetramethyluronium tetrafluoroborates in DMF, and adding a compound of formula (Ib) to the resulting mixture.
The protected intermediates used in the coupling include compounds of formula (Ia) and (Ib) carrying protecting groups, and the document enumerates protecting group options including Fmoc and Boc, as well as tert-butyl and trityl. The overall coupling sequence is described as a three-step process starting with contacting formula (Ia) with diisopropylethylamine, followed by activation and condensation in DMF using the norbornene-based uronium tetrafluoroborate, and then addition of the protected compound of formula (Ib).
The document further provides embodiments for implementation in continuous flow and/or in a flow reactor. It also describes improved tirzepatide manufacturing via peptide-coupling followed by deprotection, including formation of an intermediate peptide by coupling peptide components followed by deprotecting to obtain tirzepatide or salts, with optional isolation and/or washing of the coupled intermediate.
Claims Coverage
The independent claim content centers on a three-step process for preparing a compound of formula (I), with dependent claim refinements specifying protecting-group selections and implementation in continuous flow or a flow reactor. The inventive features can be grouped into the coupling sequence and the optional refinement of the process mode and protecting group.
Three-step coupling to form compound of formula (I)
A process comprising contacting a compound of formula (Ia) and diisopropylethylamine, contacting the product with 2-(5-norbornene-2,3-dicarboximido)-1,1,3,3-tetramethyluronium tetrafluoroborates in DMF, and adding a compound of formula (Ib) to the mixture, wherein PG is a protecting group.
Protecting group options for compound of formula (I)
The process further refines that PG is either Boc or Fmoc, and includes an embodiment in which the protecting group is Fmoc.
Continuous flow process execution
The process of any one of the claims is conducted using continuous flow.
Flow reactor implementation
The process is performed in a flow reactor.
Claim coverage is anchored by a three-step, DMF-based coupling sequence using diisopropylethylamine and 2-(5-norbornene-2,3-dicarboximido)-1,1,3,3-tetramethyluronium tetrafluoroborates, followed by addition of a protected compound of formula (Ib). Dependent claims refine the protecting group selection and narrow execution to continuous flow and/or a flow reactor.
Stated Advantages
Improved tirzepatide manufacturing via peptide-coupling followed by deprotection.
Optional isolation and/or washing of the coupled intermediate.
Documented Applications
Preparation of a compound of formula (I).
Improved tirzepatide manufacturing.
Obtaining tirzepatide or salts.
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