Omarigliptin Synthesis via One-Pot Boc Deprotection

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Solution Overview

Problem

Existing processes for synthesizing omarigliptin, a DPP-4 inhibitor for Type 2 diabetes treatment, face issues with low yield, long reaction times, and poor diastereoselectivity due to the need for isolating BSA salts and the generation of poorly soluble by-products, which complicate the purification process.

Innovation Solution

A novel process that eliminates the isolation of BSA salts and uses trifluoroacetic acid for Boc-deprotection and reductive amination in a one-pot, two-step process, resulting in a homogeneous solution that facilitates crystallization and improves yield and diastereoselectivity, reducing overall cycle time and cost.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If BSA salt isolation is performed as described in WO 2013/003250, then the Boc deprotection can be achieved, but the reaction time increases to up to 72 h and the process complexity increases due to salt isolation steps

Engineering Contradiction:

ImproveBoc deprotection efficiencyVSAvoidreaction time

Core Design Contradiction:

ReliabilityVSLoss of time

Solution Approach 1:

The invention extracts and eliminates the BSA salt isolation step from the synthesis process. By using TFA-based deprotection followed by direct reductive amination, the process removes the intermediate salt isolation operation, reducing both time and complexity while maintaining product quality

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The invention merges the Boc deprotection and reductive amination steps into a continuous one-pot process. The TFA deprotection directly generates the free amine which immediately undergoes reductive amination without isolation, combining two separate operations into one streamlined process

Inventive Principle:

Principle #5Merging (Combining)

2Reliability

If aqueous sulfuric acid in DMAc is used for Boc deprotection as described in WO 2013/003250, then deprotection occurs, but large amounts of poorly soluble ammonium sulfate co-crystallize with the product requiring long filtration and washing times

Engineering Contradiction:

ImproveBoc deprotection efficiencyVSAvoidisolation cycle time

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The invention changes the chemical parameters of the deprotection system from aqueous sulfuric acid in DMAc to trifluoroacetic acid-based system. This parameter change prevents the formation of poorly soluble ammonium sulfate co-crystals, eliminating the need for lengthy filtration and washing operations while maintaining effective deprotection

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention converts the potential harm of acid-mediated deprotection (which could lead to insoluble salt formation) into a benefit by selecting TFA, which produces highly soluble TFA salts. This transforms what could be a purification nightmare into a streamlined process where the by-products remain in solution and do not interfere with product isolation

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

3Manufacturing precision

If the process uses multiple isolation steps including BSA salt isolation, then intermediate purification can be achieved, but the overall process complexity and cost increase

Engineering Contradiction:

Improveintermediate purification qualityVSAvoidprocess complexity

Core Design Contradiction:

Manufacturing precisionVSDevice complexity

Solution Approach 1:

The invention establishes continuous useful action by eliminating interruptive isolation steps. The process flows continuously from deprotection through reductive amination to final product formation, maintaining reaction conditions and avoiding interruptions that would require additional equipment and operational complexity

Inventive Principle:

Principle #20Continuity of useful action

Solution Approach 2:

The TFA-based system serves multiple functions: it acts as the deprotection agent, provides soluble counter-ion formation, and enables direct reductive amination. This multi-functionality eliminates the need for separate purification equipment and operations, reducing overall process complexity while maintaining product quality

Inventive Principle:

Principle #6Universality (Multi-functionality)

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The process achieves high yields (>80% by weight) and improved diastereomeric selectivity (>20:1), simplifying the purification of omarigliptin and reducing the overall reaction time, while avoiding the formation of poorly soluble by-products.

Implementation Method 1

uses trifluoroacetic acid with or without a co-solvent for the transformation of the compound of Formula Ia to omarigliptin

Methodology Applied

Scientific EffectAcid-catalyzed deprotection: Chemical Bonding

Implementation Method 2

reductive amination with Boc-ketone of the compound of structural Formula 7, to produce the compound of structural Formula Ia

Methodology Applied

Scientific EffectReductive amination: Reduction

Implementation Method 3

which facilitates crystallization of the compound of structural Formula Ia

Methodology Applied

Scientific EffectCrystallization: Crystallisation

Data Source

PatentUS10053466B2Process for preparing chiral dipeptidyl peptidase-IV inhibitors

Publication Date: 2018.08.21 MERCK SHARP & DOHME LLC

AI summary

A process for preparing a compound of structural Formula Ia:comprising Boc deprotection with TFA of: andreductive amination of: