Scaling Up Microwave Scaling Up Microwave ReactionsReactions

An Overview of the Biotage AdvancerAn Overview of the Biotage Advancer

Presented by Joe Pawluczyk, Merck Research LaboratoriesPresented by Joe Pawluczyk, Merck Research Laboratories

Microwave Synthesis Users Group MeetingMicrowave Synthesis Users Group MeetingMarriott Philadelphia West, West Conshohocken PAMarriott Philadelphia West, West Conshohocken PA

October 13, 2005October 13, 2005

TopicsTopics

Introduction to SST groupIntroduction to SST group

Overview of Advancer hardware and softwareOverview of Advancer hardware and software

ChemistryChemistry

SummarySummary

Synthetic Services Team (SST)Synthetic Services Team (SST)

Where: Department of Medicinal Chemistry MRL West Point PaWhere: Department of Medicinal Chemistry MRL West Point Pa

Synthetic Services Team (SST)Synthetic Services Team (SST)

Where: Department of Medicinal Chemistry MRL West Point PaWhere: Department of Medicinal Chemistry MRL West Point Pa

Who: Group of 8 chemistsWho: Group of 8 chemists

Synthetic Services Team (SST)Synthetic Services Team (SST)

Where: Department of Medicinal Chemistry MRL West Point PaWhere: Department of Medicinal Chemistry MRL West Point Pa

Who: Group of 8 chemistsWho: Group of 8 chemists

What: Support ongoing research projects by providing multigraWhat: Support ongoing research projects by providing multigram m quantities of synthetic intermediates quantities of synthetic intermediates

Synthetic Services Team (SST)Synthetic Services Team (SST)

Where: Department of Medicinal Chemistry MRL West Point PaWhere: Department of Medicinal Chemistry MRL West Point Pa

Who: Group of 8 chemistsWho: Group of 8 chemists

What: Support ongoing research projects by providing multigraWhat: Support ongoing research projects by providing multigram m quantities of synthetic intermediates quantities of synthetic intermediates

Why the Advancer? To position our group to handle scaleWhy the Advancer? To position our group to handle scale--up up requests that incorporate microwave assisted reactions requests that incorporate microwave assisted reactions

Advancer 350Advancer 350

Advancer 350Advancer 350

-- Batch FormatBatch Format-- 50 50 –– 300 ml300 ml-- 60 60 –– 250 degrees C250 degrees C-- 1 1 –– 20 bar20 bar-- 1200 W magnetron1200 W magnetron-- Mechanical StirringMechanical Stirring-- Flash CoolingFlash Cooling

Reactor CabinetReactor Cabinet

Reactor LidReactor Lid

Mechanical StirrerMechanical StirrerPressure SensorPressure SensorRupture DiskRupture DiskValve for N2 flowValve for N2 flowValve for SampleValve for SampleFiber optic temperature Fiber optic temperature probeprobe

2 Extra entry ports2 Extra entry ports

Reactor LidReactor Lid

Reaction VesselsReaction Vessels

Reactor CavityReactor Cavity

Advancer CoolingAdvancer Cooling

Flash CoolingFlash Cooling

Gas CoolingGas Cooling

Passive CoolingPassive Cooling

Safety TiersSafety Tiers

Crash CoolingCrash Cooling

Rupture Disk Rupture Disk (> 30 bar)(> 30 bar)

Spring loaded reaction Spring loaded reaction vessel lidvessel lid (35(35--55 bar)55 bar)

Venting floorVenting floor

Graphic User InterfaceGraphic User Interface

Preparation TabPreparation Tab

Process TabProcess Tab

Report TabReport Tab

ChemistryChemistry

Since May 2004, 1.65 kgSince May 2004, 1.65 kgof material have been of material have been processed in the processed in the Advancer.Advancer.

Largest run 60g Largest run 60g Smallest run .625gSmallest run .625gAverage run 8 Average run 8 –– 9g9g

Amide bondAmide bondSuzukiSuzukiCopper cross couplingCopper cross coupling1,5 naphthyridine1,5 naphthyridineReductive aminationReductive aminationOlefin metathesisOlefin metathesisBeckmann Beckmann RearrangementRearrangementChlorinationChlorinationDiaryl ethers via SDiaryl ethers via SNNArAr

PathfinderPathfinderO

HN

O

NaN3

HOAcconc H2SO460o C 2hrs

J Med Chem., 1967, 10: 944-945

Problem:

Reaction was to be run on 200g. Concerns over exotherm upon addition of conc. sulfuric acid and heating the azide on scale.

Solution:

Beckmann Rearrangement and Pathfinder.

HN

O NO

OH

NH2OH HCl Pyridine

Eaton'sReagent

10 min @ 140oC 15 min @ 125oC

HIV Integrase InhibitorHIV Integrase Inhibitor

N

N

HN

N O

O N

OHO

F - Preclinical Proof of Concept for HIV therapy

Daria J. Hazuda, Steven D. Young et al. Science 23 July 2004, Volume 305, pp 528-532

HIV Integrase Inhibitor HIV Integrase Inhibitor

N

N

HN

N O

O N

OHO

F - Preclinical Proof of Concept for HIV therapy

Daria J. Hazuda, Steven D. Young et al. Science 23 July 2004, Volume 305, pp 528-532

HIV Integrase Inhibitor HIV Integrase Inhibitor

N

N

HN

N O

O N

OHO

F - Preclinical Proof of Concept for HIV therapy

Daria J. Hazuda, Steven D. Young et al. Science 23 July 2004, Volume 305, pp 528-532

Amide Bond FormationAmide Bond Formation

N

N

HN

Br

OHO

FN

N

NH2

Br

OHO

F

HO+

AB

- Original conditions : A + B(OMe) heat in THF for 4 days Complications: Limited solubility of B(OMe)

- A + B + EDC + HOBT very dilute Complications: not practicle on scale

- Make methyl ester of B under standard conditions Complications: B(OMe) + bromine displacement

- Microwave assisted reaction: A + B + EDC + NMM in MeCN 20 min @ 1500 C Results: On a 50g reaction, 15g of B was recovered and rest was C. Currently work in ongoing to improve conditions such that 1.7 kgs of material can be processed Unfortunately pushing the reaction to completion yielded displacement of bromine by the amine.

C

HIV Integrase Inhibitor HIV Integrase Inhibitor

N

N

HN

N O

O N

OHO

F - Preclinical Proof of Concept for HIV therapy

Daria J. Hazuda, Steven D. Young et al. Science 23 July 2004, Volume 305, pp 528-532

Bromide DisplacementBromide Displacement

N

N

HN

O

F

Br

OH

N

N

HN

O

F

NH

OH

A or B

Conditions:

A: MeNH2 in THF, DIEA, DMSO, sealed vessel 140o C, 72 h 78% projected 120g/run

B: MeNH2 in THF, DIEA, DMSO, microwave 170o C, 1 h 68% 35g/run

The Challenge:

Process approximately 1200g of bromide.

The Winner: MICROWAVES!

Microwaves: about 35 hours reaction time versus 30 days for conventional method.

SummarySummary

Offers an increased working volume (50 Offers an increased working volume (50 –– 300mls): 300mls): Batch ProcessingBatch Processing

SummarySummary

Offers an increased working volume (50 Offers an increased working volume (50 –– 300mls): 300mls): Batch ProcessingBatch ProcessingHeating and pressure profiles are similar to other Heating and pressure profiles are similar to other microwave instruments: Scalable!microwave instruments: Scalable!

SummarySummary

Offers an increased working volume (50 Offers an increased working volume (50 –– 300mls): 300mls): Batch ProcessingBatch ProcessingHeating and pressure profiles are similar to other Heating and pressure profiles are similar to other microwave instruments: Scalable!microwave instruments: Scalable!GUI is user friendlyGUI is user friendly

SummarySummary

Offers an increased working volume (50 Offers an increased working volume (50 –– 300mls): 300mls): Batch ProcessingBatch ProcessingHeating and pressure profiles are similar to other Heating and pressure profiles are similar to other microwave instruments: Scalable!microwave instruments: Scalable!GUI is user friendlyGUI is user friendlyMultilayered and independent safety featuresMultilayered and independent safety features

SummarySummary

Offers an increased working volume (50 Offers an increased working volume (50 –– 300mls): 300mls): Batch ProcessingBatch ProcessingHeating and pressure profiles are similar to other Heating and pressure profiles are similar to other microwave instruments: Scalable!microwave instruments: Scalable!GUI is user friendlyGUI is user friendlyMultilayered and independent safety featuresMultilayered and independent safety features

An instrument that thus far has permitted safe and An instrument that thus far has permitted safe and reproducible microwave reproducible microwave –– assisted reactionsassisted reactions

AcknowledgementsAcknowledgements

James P. Guare James P. Guare SST group Merck West PointSST group Merck West Point

Susan Alderfer Susan Alderfer Merck Visual CommunicationsMerck Visual Communications

BiotageBiotage