PAT application in rapid development of multi-step chemical syntheses of active compounds

252nd American

Chemical Society

National Meeting

August 24th, 2016

Dom Hebrault, Ph.D.

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Agenda 2

1 The Importance of Real Time Analytical Spectroscopy for Kinetics

2 Mid-Infrared Spectroscopy in Chemical Development

3 Kinetics Investigations using RPKA

4 Application to the Synthesis of a Chiral Dipeptide Drug Intermediate

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What is Reaction Progress Monitoring?

When does it start?

When do these reagents react?

When does it stop?

Did I make what I thought I did?

Is there an intermediate?

What do the kinetics look like?

Typically would take samples and analyze offline to construct trends to determine these events

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Traditional Lab Techniques

Gaps in Understanding Lead to Unpredictable Results

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Scientist must be present to sample

Reactors are

poorly controlled

Process parameters

are not recorded

Gaps or delays in

results

start isolate

Results: Offline Analysis

Info

rma

tio

n

Time

No data

collected Sample 2

Sample 1

Sample 3

The Lab of Today

Make Informed Decisions, Faster

Reactors are

precisely controlled

and run overnight

Parameters are automatically

recorded with PAT

Unattended,

Representative Analytics

start isolate

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Results: Real-Time Data Capture

Info

rma

tio

n

°C In Situ Analytics

mL

Time

Knowledge and Control Lead to Innovative Development

Fundamental bond vibrations

Invasive but non-destructive

Specific

Sensitive

The Lab of Today 6

From real time data capture with PAT to mid-IR spectroscopy

Practical to implement and use

Bach and flow processes, liquid and gas

Affordable (?)

The Lab of Today 7

From real time data capture with PAT to mid-IR spectroscopy

Understand the Chemistry with In-Situ Spectroscopy

ReactIR 15, 45m, 45p

real time mid-infrared

24/7 unattended

Software-enabled

real time full data

interpretation

For gas, liquid, batch or

continuous process

From mL to plant scale

Example of full process

crystallization workstation

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ReactIR™ is a real time process analytical technology based on ATR-FTIR. It is

suitable for a wide range of chemistries, tracks reaction progression – providing

specific information about reaction initiation, conversion, intermediates, endpoint.

Mid-IR Spectroscopy for Reaction Monitoring 9

Ar-NHOH

Ar-N=O

Ar-NH2

Ar-NO2

Time

Concentration

Start stirring

LeBlond, J. Wang, R. Larsen, C.J. Orella, Y.K. Sun, “A Combined Approach to Characterization of Catalytic Reactions using in

situ Kinetic Probes,” Topics in Catalysis, 1998, 5, 149-158

Spectroscopy at Different Development Stages 10

A new type of laboratory is required to

innovate and optimize at each step.

y is required to innovate and optimize at each step.

Invent the

Molecule

Develop a

Reaction

Create the

Process

Bring to

Manufacturing

Identify New

Compounds

Optimize

Safety &

Cycle Time

Establish

Scalable

Parameters

Eliminate Upsets

& Improve

Quality

Maintain

Steady-State

Evaluate

Critical

Parameters

Set up in hood with pH and ReactIR probe

Overhead

Stirrer ReactIR 45m

EasyMax Touchpad

9.5mm ReactIR

DiComp

Probe

25 mL Syringe Pump

2 positions

100 mL Reactor

Teflon Cover

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Set up in standard hood with ReactIR and pressure

Pressure Reactor

Mag-coupled

overhead stirrer

Gas Uptake

Reservoir

Touchscreen

UCB for Gas Uptake

9.5 mm DiComp

Probe

Ambient Pressure

Glassware

ReactIR 15

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Standard and Custom ReactIR gas cells 13

ReactIR 45m

Gas cell

Advanced PFR Setup with Inline Analysis 14

Advanced-Flow™ and ReactIR™ 45m

ReactIR™ 45p for Classified Areas 15

ReactIR 45p

25m3 manufacturing reactor

Roche – Clarecastle

Ireland

Integrated Strategic Solution 16

Reactor

Platforms

Probes and

Analytics

Data Analysis

and Storage

Reaction Progress Kinetic Analysis (RPKA)

Blackmond, D. G.

Angew. Chemie Int. Ed. 2005, 44, 4302

Blackmond, D. G. et al.,

J. Org. Chem. 2006, 71, 4711

Leverages the extensive data available from accurate in situ monitoring with PAT

Provides a full kinetic analysis from a minimum of two reaction progress experiments

Involves straightforward manipulation of the data to extract kinetic information

Blackmond, D. G. “Reaction Progress Kinetic Analysis”, Webinars, Part 1 (April 2010) and 2 (October 2010) available at www.mt.com

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Convergent, Concise Synthesis of Chiral Dipeptide

Interest in developing small molecule inhibitors of HCV NS3 protease

Faldaprevir possesses required in vivo potency, safety, and bioavailability

Highly convergent route developed

HOBT-based peptide coupling used by Discovery, unsafe for scale-up, replaced

by TsCl / NMM

PAT instrumental in process development and scale-up

N. Haddad*, D. Hebrault, et .al. Org. Process Res. Dev., 2015, 19, 132-138

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Experimental setup with ReactIR15 and EasyMax

EasyMax with 2-piece

vessel and overhead

stirrer

Window and light

to see the

reaction mixture

ReactIR 15 with

fiber optic probe

Real time data logging

on laptop

EasyMax touchpad for more

faster and efficient reaction

control

2.5 days experiments

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Kinetic visualization

and modeling

software

Kinetic Approach in the Synthesis of Faldaprevir

"Perpendicular" methods confirmation (IR, heat)

Improve process robustness and define design

space

Sensitivity of reaction rate to reactants

concentration, i.e. driving force analysis

Impact of temperature on the coupling rate

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IR data from in situ monitoring

throughout the sequence of preparing dipeptide

Oxazolone

Leucine

derivative

(B)

L-4-Hydroxyproline methyl ester

*

*

Kinetic investigation

Kinetic Approach in the Synthesis of Faldaprevir 21

IR data from in situ monitoring

throughout the sequence of preparing dipeptide

Add NMM

Add TsCl

Add hydroxyproline

Ester cleavage

Leucine

derivative

(B)

L-4-Hydroxyproline methyl ester

*

*

(A)

Two reactions at different “excess” values are used to define the orders in two

substrate involved in a synthetic reaction

Neither substrate concentration is held constant: [Leu deriv.] and [HO-Pro-OMe]

decrease simultaneously over the course of these reactions

iC Kinetics instantly choose (x,y) to obtain straight lines and overlay (3 kinetic

trends)

Power law rate equation shows non-integer orders (A = HO-Pro-OMe; B = Leu deriv.)

22 "Different Excess" Protocol

Oxazolone concentration versus time in

Different Excess (DE) experiments A = [HO-Pro-OMe]

x

Ra

te/[

Le

u d

eri

v.]y

What do we mean with elementary reaction?

“An elementary reaction is a chemical reaction in which one or more of the chemical

species react directly to form products in a single reaction step and with a single

transition state”

Organocatalytic reaction

Steady-state reaction rate law more

complex than for an elementary

reaction

Blackmond, D. G. “Reaction Progress Kinetic Analysis”, Webinars, Part 1 (April 2010) and 2 (October 2010) available at www.mt.com

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What do we mean with elementary reaction?

IC Kinetics provides the power law form without the need to describe each individual

elementary reaction

No need to know or describe reaction mechanism

(k’, x, y) → driving force analysis

approximates

this form

Power law form Steady-state rate law

non-integer x and y

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25 "Different Excess" Protocol

Empirical model for oxazolone reaction with hydroxyproline

Development of a power law-based kinetic model

400 simulated conditions used to find optimum conditions out of only ≥ 2

experiments

Model tested on central point

2-D kinetic profiles available for each datapoint. Point and click action.

Time hh:mm:ss

HO-Pro-OMe 9.9mM,

Boc-L-t-Leu 15.4mM (1.5 eq)

10˚C, ACN

Model testing on a central point

[HO-Pro-OMe]

26 Temperature analysis - Arrhenius plot

Temperature-dependent model (Arrhenius) across -10 °C →+30 °C range

[HO-Pro-OMe]

Time

Ea = 32 kJ/mol (typically 10-50 kJ/mol)

Reaction rate x1.5 per 10K increase

Summary and Conclusions

• Extensive utilization of real-time in situ mid-IR reaction monitoring of the

oxazolone concentration, confirmed by EasyMax calorimetry

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• Development of a full kinetic model (concentration and temperature

dependencies -10ºC → +30ºC) with only a few carefully selected

experiments (7, RPKA).

• Providing sufficient process knowledge to complete all three steps in

one operation in less than 10 h, following a robust, safe, and reliable

process.

• 3-D visualization of 400 simulated experimental conditions and rates to

quickly find optimum process operating conditions (cycle time,

robustness, yield, cost, safety)

Acknowledgements

Boehringer-Ingelheim Pharmaceuticals, Chemical Development, Inc.; 900 Ridgebury Rd.,

Ridgefield, CT 06877

- Nizar Haddad*

- Chris H. Senanayake

- Bo Qu

- Heewon Lee

- Jon Lorenz

- Rich Varsolona

- Suresh Kapadia

- Max Sarvestani

- XuWu Feng

- Carl A. Busacca,

Mettler Toledo AutoChem Inc., 7075 Samuel Morse Drive, Columbia, MD 21046

- Simon Rea

- Leen Schellekens

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