Continuous Flow Chemistry and Crystallization Development ... · Green Chemistry & Engineering: Launch Accelerate Breakthrough Flow Chemistry For Greener, More Efficient Processes

Green Chemistry & Engineering: Launch Accelerate Breakthrough

Flow Chemistry For Greener, More Efficient Processes

Michel Journet, Merck Process Chemistry

Continuous Flow Chemistry and Crystallization Development Symposium

September 26th, 2012

+ =

Flow Chemistry Green Chemistry Natural Evolution (?)


versus

Flow Chemistry Batch Chemistry



What is Flow Chemistry?

In a flask

A + B C

HE

HE

A

B

C

Flow reactor

Extra tubing

In flow

Reaction time : aging the reaction mixture. Temperature : cooling or heating the flask (time cycle). Add A and B, age and produce C. Production mode : multiple batches required.

Residence time : flow rate (additional tubing after flow reactor). Temperature : heat transfer highly efficient (small reactor). A and B are pumped continuously to produce C (steady state). Production mode : 24/7 (high productivity).

→

→ →

Louis Pasteur (1822-1895)

Still using batch or semibatch mode in 21st century. Round bottom flasks, stirrers, condensers … are the same as in the 19th century. Of all sciences, organic chemistry has not moved into the 21st century. Change of mindset necessary (cultural, change is hard). Change is made possible by new equipment availability.


Advantages of Flow Chemistry

Flow chemistry is not the answer to all chemical reactions BUT, it offers many advantages over batch chemistry:

Scalability: scaling up is simply numbering up (e.g. 5 channels reactor → 50 channels reactor …). Fast reactions (obvious choice). Slow reactions (in batch) can be much faster in flow :

↑ pressure/temperature greener process (superheated e.g. ethanol at high pressure can replace high boiling point solvents).

Safety : low build-up of unstable intermediates. hazardous reactions (explosive reactions, azide (HN3), etc…). No head-space. enclosed (but not closed). efficient heat transfer: allows to operate near exotherm.

Productivity : used for decades in petrochemistry (24/7). continuous processing necessary to keep manufacturing costs down (PGM).

Energy efficiency (small reaction volume= efficient heat transfer).

Caveat : slurry is usually a no/no on small scale (clogging).


versus

Clogging (Flow Chemistry) Ka-boom !!! (Batch Chemistry)



Waste generated when starting up (dummy run), and shutting down the system, but still very low compared to batch. C.I.P (Cleaning In Process not taken into account for PMI calculations) – Alfa Laval has a 200

Kg/h unit that has not been opened in 2 years.

Batch

(huge reactor)

Flow

(small reactor)

If used effectively, flow can greatly streamline chemical synthesis. Several reactors assembled in series : multi-step through process. Flow chemistry linked to continuous processing : possibility to recycle solvents

(known examples).

Space saved in the plant compared to batch (flexibilty : interchangeable skids).

Alfa Laval PR49 (Production) >200 Kg/h

FLOW

Solvent

ContinuousProcessing

A

B

C

Recycle

A

B

C

FD

E

G



Equipment Availability High Temperature/Pressure


Vapourtec R series +130 ºC, τ= 20 min(BPR 8 bar)

+

Heck SynthesisEtOH

Ley, S. V. et al. Org. Proc. Res. Dev. 2007, 11, 458.

I

CO2EtCO2Et

(88% yield)

High Temperature/Pressure Flow Reactions

Mimic MicroWave conditions BUT scalable. Advantages over batch chemistry :

Shortening reaction times. Improving yield. Cleaner reaction profile. Green solvents (superheated).

200 ºC, τ= 3 min(BPR 75 bar)

AcOH/IPA

Fischer Indole Synthesis

NHNH2

+

O

NH

(96% yield)Kappe, C. O. et al. Eur. J. Org. Chem. 2009, 1321.


Low Temperature Flow Chemistry : The Reactor

Koflo Static mixer 3/16-21 (1.1 mL)

Microchip Reactor

FFMR (gas-liquid)

MDAT (in-house) 0.3 mL


Synthetron™, Spinning Disc Reactor

FUMI “in action”

Formation of thin flowing films of reagents, and Forced Uniform Molecular Interdiffusion (FUMI).


CHO

OMe

+ CH3MgCl τ ~ 5 s

OMe

H3C OH

(RPM~7000)

Br+20 ºC

τ ~ 12 s

+ n-BuLi

+ DMF

CHO

(RPM~7000)

+35 ºC

Synthetron™ : Spinning Disc Reactor

1 Disc Reactor 2 Disc Reactors

>98.5 A%

+20 ºC, τ~ 12 s (8 s + 4 s) “Diffusion-controlled” reaction

>95 A%


O

CO2H CO2H

HO Het(1.5 equiv)

3.5 equiv BF3-Et2O3.5 equiv n-BuLi

THF, -78 ºC, 2 h80% AY (10 g)

R RHet.+

O

CO2H

2 equiv)

; Het

(THF solution)

R

BATCH

Quench

FLOW

3 equiv BF3-Et2O

“mixing”

τ<10 s, -30 ºC

τ= 30 s, -30 ºC n-BuLi 2.5 equiv

84% AY

CO2H

HO Het

R

→ →

10 g scale (-78 ºC, 2 h): 80% yield. Mixing issue arised upon scale-up leading to >20% yield drop.

No scale up issue. Higher temperature (-30 ºC vs -78 ºC).

Case Study : Lithiated Heterocycle Addition To a Ketoacid


+

HO Het

BuLi, BF3-Et2O THF

MeO2C

O

MeO2C

-40 CHO Het

OHet

HO Het1 2 3 4

R R R R

Het. Het

HetHO

+ +

Batch: BuLi : “too hot” – Unstable lithiated heterocycle even at low temperature. Turbo Grignard (iPrMgCl/LiCl) : Low Yield (ca. 40%), 10% over-addition = Chromatography.

Flow: n-BuLi at -40 ºC : clean (80/20 enol equilibrium). Add 1 equiv BF3 : suppress ketone enolization. Fully optimized with MDAT (g scale) – 90% yield, 5% over-addition = Crystallization.

Case Study : Lithiated Heterocycle Addition To a Ketoester

4

2

3,1


Flow:

“High productivity”: 25 mL reactor needed. Question: how to fit 8 Kg into a 25 mL reactor???

Flow Chemistry – From the g Scale to the Kg Scale

→

Is it magic???

… the magic of “flow chemistry”.

Reactor (static mixers) designed for a flow rate of 120 mL/min, τ of 15 seconds, -40 ºC: ⇒ 8 Kg prepared in 85% yield! Conditions: V= 25 mL, 120 mL/min, τ= 15 s (5 + 10) 0.5M ketoester/BF3 in THF, 0.5M Heterocycle (1.5 equiv) in THF, 2.5M BuLi/Hex (1.05 equiv).

Batch: Unscalable. 8 Kg of intermediate needed : FLOW.


BocN

O

OEtHN

OEt

O

BocR

1M NaHMDS/THF

Cl R

DMF

Ser-OEtHCl

2 steps

N-Alkylation

Decreasing yieldson scale up-15 ºC

N-Alkylation was found to be not scalable on batch modes: long addition times led to lower yields.

Unstable sodium anion even at -15 ºC : yield lower upon scale-up (time cycle): 1, 10, 40 g rxns afforded 70, 60 and 50% respectively.

Flow (short τ = stability ↑) BUT reaction (not very) fast in batch. Can we speed up the reaction by ↑ temperature? But then stability ↓ (rob Peter to pay Paul?)

Case Study : N-Alkylation


NaHMDS

CO2EtBocHN

CO2EtNNa

Boc

Cl R

CO2EtNBoc

R

At -15 ºC (τ = 2 min) : No reaction at all!!! At +20 ºC (τ = 2 min) : 4% product (clean, no decomposition).


Temp. τ (min) Conv. AY

-15 ºC 2 No Reaction N/A

+ 20 ºC 2 4% n.d.


NaHMDS (1M/THF, 1.1 eq)

CO2EtBocHN

CO2EtNNa

Boc

Cl R

CO2EtNBoc

R(0.5M/DMF)

(0.5M/DMF) 1.6 equiv


rt 2 4% n.d.

rt 4 30% n.d.

rt 8 50% n.d.

rt 15 70% n.d.

rt 30 88% 70%



rt 2 4% n.d.

rt 4 30% n.d.

rt 8 50% n.d.

rt 15 70% n.d.

rt 30 88% 70%

+50 ºC 15 90% 77%

+50 ºC 5 95% 86%

+70 ºC 2 95% 91%

+70 ºC 1 77% 76%

0.25 min

1.75 min

+70 ºC


Case Study : An Isoindoline Synthesis

CN

Br

n-BuLi, DIPA

THF, -78 ºC

CN

BrLi

(Unstable)"benzyne"

1) HCO2Et

-78 ºC

Br

NH

2) Quench

O

OH

"Red."

Br

NH

CN

BrLi Br

NH

O

OH

BATCH

FLOW

10 g scale : 90% yield. 100 g scale : 80% yield. Unstable aryllithium (time cycle!).

90% yield. No issue even at -40 ºC (short residence time).

Quench

τ<10 s, -40 ºC

τ= 30 s, -40 ºC

τ= 30 s, -40 ºC

→ →

→

DIPA

n-BuLi

LDA

HCO2Et

CN

Br

CN

BrCHO


Equiv. Grignard

Conversion Hemiketal Aldol

1.2 96.50% 2.0 A% 1.5 A%

1.5 >99.90% 1.8 A% 0.4 A%

2.0 >99.95% 1.2 A% 0.20 A%

E-2

E-3

MeMgCl (3M/THF)

Acetophenone (2M/THF)

Syringe pump

V-1

V-3

THF(purge)

E-4

P-1

3PSI

E-6

P-3

Koflo 3/16-21, 1.1 mL

P-17

E-17

P-20

V-9

P-21

P-22

P-27

2.2 mL loop E-19

E-20

20% aq. H3PO4P-31P-32

P-33

COLLECT

T

Koflo 3/16-21, 1.1 mL

R1

O

R2 R1 R2

OH

MeMgCl

THF, +30 ºC+

R2

O OH

R2

R1

R1

+

"Hemiketal" (1.2 A%) "Aldol" (0.2 A%)>99.9% conv.

R2

OH

O

R2

R1

R1

τ < 30 s

Case Study - Grignard Addition

Static mixer


Mettler-Toledo FlowIR (NTRLC) – OnLine Monitoring

0.8, 1.0, 1.2, 1.4, 1.6, 1.8, 2.0 equiv MeMgCl Monitoring reaction with FlowIR HPLC profile of different samples align with the experimental data from the IR

R1

O

R2 R1 R2

OH

MeMgCl

THF, +30 ºC+

R2

O OH

R2

R1

R1

+

"Hemiketal" (1.2 A%) "Aldol" (0.2 A%)>99.9% conv.

R2

OH

O

R2

R1

R1

τ < 30 s


BATCH

Reaction optimized : Solvents, temp., res. time. 93% assay yield.

“one-pot” BuLi/Borate at -70 ºC : 82% isolated yield (Pilot Plant)

MK-0859 (CETP) : Synthesis of the Boronic Acid (API SM)

FLOW (greener, more productive … more efficient!)

τ<10 s, -50 ºC

→ n-BuLi

Aq. H3PO4

R2

R3

R1

Br

R2

R3

R1

Li

R2

R3

R1

(PrOi)2B

R2

R3

R1

(HO)2B

B(OiPr)3 τ=20 s, -50 ºC

→ →

Toluene

1) 1.35 eq B(OiPr)3, 1.25 eq n-BuLi THF/Toluene, -70 ºC, 2 hR2

R3

R1

Br

R2

R3

R1

(HO)2B2) Quench / Workup

Case Study : Aryl Boronic Acid


Boronic Acid Solvent Effect

solvent, -50 ºC

R1

Br

R2

R3

R1

(HO)2B

R2

R3

R1

H

R2

R3

1.3 equiv BuLi5 eq B(OiPr)3 + +

R1

Br

R2

R3

+

Ar-Br (1) Boronic ac. (2) Des-Br (3) Ar-Br (1) Biaryl (4)

R1

B

R2

R3HO

Ar

R1

B

R2

R3OiPr

OiPrB

Hydolysis

4R1

Li

R2

R3

R1

R2R3

OiPrR2R1

R3 BR1

R2R3

HO

R2R1

R3

solvent, -50 ºC

R1

Br

R2

R3

R1

(HO)2B

R2

R3

R1

H

R2

R3

1.3 equiv BuLi5 eq B(OiPr)3 + +R1

Br

R2

R3

+


R1

B

R2

R3HO

Arsolvent, -50 ºC

R1

Br

R2

R3

R1

(HO)2B

R2

R3

R1

H

R2

R3


Br

R2

R3

+


R1

B

R2

R3HO

Arsolvent, -50 ºC

R1

Br

R2

R3

R1

(HO)2B

R2

R3

R1

H

R2

R3


Br

R2

R3

+


R1

B

R2

R3HO

Ar

Heptane OR Toluene: Very clean but 1/1 Boronic/ Biaryl


Boronic Acid Additive effect

Toluene would be a good solvent for the process:

Generally accepted as good manufacturing solvent (THF undesirable) Clean reaction (HPLC baseline) Caveat: generates high level of biaryl impurity

During solvent screen: Additive (e.g. TMEDA) minimizes formation of the biaryl impurity

Toluene, -50 ºCadditive

MeO

Br

F MeO

(HO)2B

F MeO

H

F1.3 equiv BuLi5 eq B(OiPr)3 + +MeO

Br

F+


MeO

B

F

HO

Ar


TMEDA (2 equiv) minimizes Biaryl in the BuLi Flow Process! Colder is better to minimize biaryl

-50 ºC : 2% biaryl -20 ºC : 5% biaryl 0 ºC : 9% biaryl (still very clean)

Boronic Acid Additive effect

A picture is worth a thousand words!


Flow Chemistry : How to?

Documents

Continuous Flow Chemistry and Crystallization Development ... · Green Chemistry & Engineering: Launch Accelerate Breakthrough Flow Chemistry For Greener, More Efficient Processes