David Ford, Ph.D.

Mettler Toledo Autochem Symposium – June 21, 2017Cambridge, MA

Snapdragon Chemistry

Snapdragon Chemistry was created to deliver complete flow chemistry

solutions to clients. Using advanced continuous manufacturing

technology, we are helping our clients to…

Improve access to existing molecules

Reduce safety and environmental risks

Enable new chemistries for manufacture

Discover new molecules

2

Flow Chemistry

CRO

Process Development

Custom Building Blocks

Product Delivery

Technical Consulting

Batch vs. Flow Chemistry

Flexible – lots of installed capacity

Difficult to scale from lab to plant

Difficult to model computationally

Significant safety risks

Poor control over process parameters

Limited range of temp & pressure

Fixed output

3

Purpose-built inexpensive (disposable

reactor) for given reaction

Easy to scale from lab to plant

Can be modeled computationally

Inherently safer

Exquisite control over process

parameters

Broader range of temp & pressure

Flexible output with same reactor

Is “flow chemistry” new?

4

Chemical engineers have been running

continuous processes since the dawn of

time!

Flow chemistry is a new and exciting way

to think about developing reactions!

Always affords incremental

efficiency gains compared to an

analogous batch process

Save time on start-up and

shutdown

Less material “at risk”

Limited inventory of hazardous

chemicals or reaction mixtures

Compact apparatus

Opportunity for excellent process

control

Flow chemistry is chemistry that is only

practical as a continuous process

We use detailed knowledge of the

chemical process to produce results

that would be difficult to impossible

to replicate in batch

Mixing sensitivity

Precise timing

Extreme pressures and

temperatures

Very hazardous conditions

The equipment of continuous

production allows us to access new

chemical space (i.e. flow chemistry)!

Continuous vs. flow chemistry

5

Continuous production Flow chemistry

Snapdragon works on projects in both categories!

Evolution from Simple to Complex Molecules

6

24’x8’x8’

3’x2’x6’

Acrylic acid production

• Decades old process

• Simple, 3 carbon

molecule

• Prepared in one step

from propylene feed

• >5 million tons per year

Novartis-MIT Redline Project

• Reported in 2013

• One drug product

• Integrated synthesis and

formulation

• 3 chemical steps, isolations

and formulation

• Angew. Chem. Int. Ed.

2013, 52, 12359

Darpa-MIT POD

• Reported in 2016

• Seven drug products

• Integrated synthesis and

formulation

• Multiple chemical steps,

isolations and formulation

• Science, 2016, 6281, 61-

67

Evolution of flow chemistry toward general

platforms

7

Engineering investment

Ch

emis

try

inve

stm

ent

Commoditychemical

manufacturing

Pharma continuous manufacturing process (GMP)Opportunity: rapid

development with tools that are

broadly applicable

Minimal engineering

investment to adapt to a new process

Snapdragon areas of expertise

Ultrafast reactions

8

High temperature/High pressure reactions

Gas/liquid reactions Flow Photochemistry (1O2, photoredox etc)

Electrochemistry Fixed bed catalysis

50

500

5000

50000

0.1 1 10 100 1000

Static Mixer CharacterizationMixing time vs Total Flow Rate

Flow rate (mL/min)

mix

ingcompletiontim

e(m

s)

1/8" mixer(100 g/h)

1/4" mixer(1-5 kg/h)

3/8" mixer(>5 kg/h)

Operating range (≤ 200 ms)

• Temp > 200 ∘C• Pressure > 1000 psi

Fast reactions

Prototypical reactions are lithiations

Batch processes often are often run at cryogenic

temperatures. Why? Two major drivers:

Mixing sensitivity

Heat transfer

Continuous processes can offer scalable mixing

and heat transfer

Added benefit: all of the other advantages of

continuous processing!

9

Heat transfer

Q = U × A × ΔT

10

As we scale up in a batch reactor, volume scales as r3,

but area only scales as r2 – decreasing surface area

per unit volume for heat transfer

In a tubular reactor, area and volume can scale together

by using longer tubes or by using parallel tubes

If we can’t remove the heat quickly enough, we need

to cool the reactor down to prevent the temperature

from getting too high

Temp. diff. across jacket

Surface areaHeat transfer coeff (materials of construction)

Mixing sensitivity in batch

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SM Product ImpurityRLi RLi

SM in soln

RLi dosing

High [SM]

High [RLi]

Impurity formation

Mixing rate needs to be faster than reaction rate!

Solution: slow down the chemistry or speed up the mixing. We cool the reaction to buy ourselves time to mix.

Mixing sensitivity in flow

12

SM Product ImpurityRLi RLi

SM in soln

RLi dosing

Trouble!

SmoothFast mixing

(static mixer)

Unsteady stoichiometry

(pulsation)

SmoothSlow mixing

(laminar flow)

13

Where and how do we use FlowIR?

• How: Peel FlowIR multi-layer information

- Chemometrics analysis of solvent composition

- Quantification of starting material and product (IC Quant.)

- Programmed FlowIR titration

• Where: pretty much everywhere- Reagent stock solution stability- Gas dissolution in flow- Reactive intermediate stability and

tracking- Tracking flow reaction steady state- Product process optimization and

characterization

productintermediateStarting materials

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Real-time reaction monitoring

Need on-line PAT to gain reaction insight

Low-maintenance and robust

- No need for liquid nitrogen cooling: rarely turned off

- No N2 purge, no alignment

- Small footprint

Small sample size

- 20 or 50 µL flow cell

- Auxiliary flow cell heater and temp controlled

- Microscale reaction in flow cell (sealed reactor)

- stability studies

- rapid reaction screening

- reaction kinetics studies at variable temp

FlowIR Data Provides Diagnosis of Issues

Inconsistent results from aliquot

sample and bulk collected sample

Lower conversion found in bulk

collected material

FlowIR data shown repeated spiking

pattern

Chemometrics analysis enhanced the

resolution

Glitch in Pump A delivery of n-BuLi

explains observation of un-converted

ArBr

15

≠

2.5 min intervals

Chemometrics data processing

16

Pump Performance Evaluation using Pressure Monitoring

0

5

10

15

20

25

30

0 5 10 15 20

difference drop (PSI)

Pressure Monitoring with Pump A

Pre

ssu

re(P

SI)

2 mL/min

4 mL/min

6 mL/min

8 mL/min

0

5

10

15

20

25

30

0 5 10 15 20

difference drop (PSI)

Pressure Monitoring with Pump X

Pre

ssu

re(P

SI)

2 mL/min

4 mL/min

6 mL/min

8 mL/min

Pump A: reciprocating syringe pump with motor-driven switching valve

Pump X: piston pump

Smooth flow needs to be verified in the lab for mixing-sensitive reactions!

Switching to pump X resolved the issue

Case Study: A Practical Asymmetric

Propargylation

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Original Chemistry:

• Scale up of med chem process in batch failed

• Chiral epoxide synthesis required multiple steps, challenging chemistry

• TMS acetylene expensive raw material driving up cost of intermediate

Snapdragon Proposal:

Project Goals:

• Ligand controlled propargylation using allene as starting material

• Scalable asymmetric process delivering better than 10:1 diastereoselectivity

HN

Me

O

Boc BocHNO

MeTMSLi

Me2AlCl HN

Me

OH

Boc

TMS

OMe

Hui Li, Jill Sheeran, Andy Clausen, Eric Fang, Matt Bio, Scott BaderAngew. Chem. Int. Ed. – doi: 10.1002/anie.201704882

18

Using FlowIR to Determine Gas Concentration in Pressurized Flow Reactor

Allene saturated in THF at 1 atm RT

>2.5M solution in flow at 40 psi

Stability of Lithium Allene?

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y = -0.1449x - 1.7216R² = 0.9799

-5

-4.5

-4

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

0 5 10 15 20

Organolithium Decay Kinetics

TTime (min)

Ln [

rel.

Li-R

]

• Decomposition follows 1st order kinetics

• k = 0.145 min-1, t1/2 = 4.8 min @ 22 °C

Study of Lithiation Stoichiometry in Flow

2020

Precipitation risk beyond 0.7

equiv. HexLiEfficient formation of

lithioallene

Importance of Mixing on Lithiation

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3D printed static mixer Laminating mixer

• Static mixer was stable

for short periods of time

but failed due to

precipitation of

dilithioallene during

extended operation

• Laminating mixers

rapidly clogged

• Dynamic mixer gave

stable performance

without clogging for

extended reaction times

Allenylzinc Screening and Optimization

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OH

N

N

L1, cinchonine

OH

N

N

L2, cinchonidine

OH

Ph

NH2

Ph

L3

OH

Ph

N

Me

L4 L5

OH

Ph

NMe

Ph

F3C OH

A1

OHMe

MeMe

A2

O2N

OH

A3

Ph OH

A4

OH

A5

MeOH

A6

Chiral Ligands

Achiral Additives

1-S,S 1-R,S

Optimized conditions delivered 32:1 diastereoselectivity with 85% yield

HN

Me

O

BocHN

Me

OH

Boc

HN

Me

OH

Boc+C Li

ZnEt2,R2N OHC Zn

O

R2NTHF

H

H

H H

H

H

Li, H.; Sheeran, J.; Clausen, A. M.; Fang, Y.-Q..; Bio, M. M.; Bader, S. J. Angew. Chem. Int. Ed. 2017, in press

1864 cm-1

1905 cm-1

Optimized Propargylation Reactor Train

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Li Zn CSTR Tube Reactor

12.3 minutes

THF

FlowIR 20 psi

waste

HexLi

Zn*

Tube reactor

MFC

alle

ne

-10 oC bath

OH

FlowIR

CSTR

Me

BocHN

BocHN

Me

CHO

1/8” OD tubing

30 mmol/hr = 15 grams/hr

Optimized Propargylation Reactor Train

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Li Zn CSTR Tube Reactor

12.3 minutes

Case study: lithiation scale-up

Challenge: lithiation reaction

performed in batch with

consistency issues, requires

cryogenic conditions

Evaluation in flow revealed

that complete mixing in ~200

ms was required for

acceptable product quality.

Understanding the mixing

allowed us to design and

build a flow skid capable of

performing the

transformation at 1-2 kg/hour

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Static mixers

Static mixers provide efficient mixing without moving parts

Characterized by Snapdragon using Bourne reactions and

colorimetric readout of acid-base chemistry (publication

forthcoming)

Static mixers are critical for developing scalable

processes with mixing-sensitive reactions!

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Case Study: Rapid Scale-up by DesignLab to Plant by Calculation

27

50

500

5000

50000

0.1 1 10 100 1000

Static Mixer CharacterizationMixing time vs Total Flow Rate

Flow rate (mL/min)

mix

ingcompletiontim

e(m

s)

1/8" mixer(100 g/h)

1/4" mixer(1-5 kg/h)

3/8" mixer(>5 kg/h)

Operating range (≤ 200 ms)

Special opportunities afforded by fast

reactions

When we develop a process for a very fast reaction, the

reactor can reach steady-state in just a few minutes

It is practical to establish PAR and validate the process at

full-scale using a modest amount of material

In our case, ~15 minutes to establish stoichiometry PAR,

and another ~15 minutes at the target conditions

We can perform experiments using the unaltered >10

kg/day production process using only a few hundred

grams of starting material!

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Conclusions

Continuous reactors afford us an exceptional degree of

control over chemical processes, even in the most

challenging cases

Flow chemistry gives us the tools to reliably and safely

perform chemistry that would be challenging or

impossible in batch – this allows chemists to think

more creatively about new ways to assemble

molecules

PAT goes hand-in-hand with continuous: monitoring

these processes gives valuable insights and in-process

control

Scale-up can be enabled through careful characterization

of the reactor using model systems29

Where do we go from here?

Organic chemistry has lagged behind other fields in

taking up new advances in data science

One major challenge: we can’t control batch processes

well enough to collect good data!

Continuous processes allow us the ability to precisely

describe the conditions and collect high quality data

Can we use this data combined with a deep

understanding of our reactors to predictably and quickly

scale up, scale down, and tech transfer?

Can we leverage modern data science tools to develop

chemical processes more rapidly? To lead us to better

solutions?

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Acknowledgements

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Matthew Bio

Andrew Clausen

Eric Fang

Hui Li

Jillian Sheeran

www.snapdragonchemistry.com

Jade Nelson

Scott Bader

Adam Brown