small-scale synthesis campaigns in two-stage flow systems · specification of product 66763: purity...

Small-Scale Synthesis Campaignsin

Two-Stage Flow Systems

By Gregor Wille

[email protected]

CPAC Satellite Meeting, Rome

March 23, 2010

Switzerland

www.sigmaaldrich.com/mrt Small-Scale Synthesis Campaigns in Two-Stage Flow Systems

2

Micro-reactor(MR)

0.2 - 2 mL

reagent 1product

reagent 2

Supervision Unit

p

Basics

� Focus on liquid/liquid synthesis

� Reaction mixture must stay in solution

� Reaction should complete within < 30 min

� Classical product analysis

Typical parameters

� Pressure 0.2 – 4 bar

� Temperature accuracy +/- 2 K (in MR)

� Flow rates 1 – 15 (max. 90) mL/min/line

� Target output 3.8 mmole/min � 1 kg/18h (MW 250 g/mole)

10 mL/min (75 % yield, 0.5 M sln.)

p

PressureMonitor

ResidenceTime

Unit (RTU)

to 200 mL

TemperatureMonitor

Concept of MicroReaction Technology


3

MR systems @ Sigma-Aldrich MRT centre (Switzerland)

inlet A

inlet B

Stainless MicroreactorType CYTOS Channel width ca. 0.2 mmActive temperature control

CYTOS Lab System

Glass MacroreactorType XXLChannel width 2 mm15 mL RTU

inlet A product inlet B

15 c

m

Glass microreactorType S01/S02 Channel width 0.5 mm

inlet A&B

product

12 c

m

� Glass & metal MRs for multi-purpose use

� Standard pump type: Rotary piston


4

Technology pushes innovation

� Production of 40 catalogue products

� Several SAFC CS projects

� Launch Microreactor Explorer Kit, 19979

� Tech transfer to manufacturing & SAFC

...

today

2004

� Purchase of integrated MRT-system as enabling technology forproblematic batch synthesis (exothermic, side product formation)

� Corporate production of retinol (Vitamin A alcohol, sales 180 k$)

� Further technology development (glass reactors)

kit 19979


5

� All-in-one solution*

� Built from commercially available elements

� Microreactor type S02 & rotary piston pumps

� Suitable for kg-campaigns

� Low prices for reagent touching parts permits

dedicated set-up

*) Thermobath not included

Microreactor Explorer Kit

reagent 1

product

Micro-

reactorreagent 2

Supervision Unit

Thermobath

TemperatureMonitor

p

PressureMonitor

p


6

�Product sensitive to air, temperature, light

� MR process permits instant quench by shock cooling (0°C)

R OHR O

O

KOH

acetate vitamin A derivative

Batch process Microreactor process

Reactor type 20 lt Vessel Microreactor (1.5 ml + RTU)

Reaction conditions KOH, MeOH/water

Feed 1: 1 M Acetate in THF

Feed 2: 2 M KOH

Reaction time 16 h 39 min

Operation time 16 h 15 h

Reliability low high

Upscale no unrestricted

Yield 40% 68%

Comparrison for 500 g campaigns

T=60°C

Generation I: Product stabilisation, ester cleavage


7

Generation I: Product stabilisation, epoxidation

Micro-reactor

T=0°Cτ<3 min

NC

NC CN

CN

H2O2

35% in water

1.2 M in AcCN

NC

NC CN

CN

O

87121

� Yield 47% (batch 23%)

� Reaction is exothermic

� Temperature in batch controlled by dosing rate

� Product decomposes on extended reagent contact

� Instant work-up required

� Colour change in reaction zone (photo right)

� White material collected from MR (batch product is yellow)

instant quench on ice-water


8

No accumulation of product � Safety

No accumulation of un-

reacted reagents � Safety

Enhanced safety

Time and solvent savingin manufacturing

Enhanced safety

Instant removal of material from the reaction zone

Elimination of dosing time

Minimal hold-up volume

Pressurising the system Working above solvent boiling point

Time- and scale independent mixture composition

Easy to clean, spilling solution reaches all contaminated volumes

Continuous Synthesis

Side reaction suppression.Clean product profile

Expanding temperature range

Handling of instable batch-processes

Performance Benefits Chemistry Benefits

Side reaction suppression.Clean product profile

Continuous Synthesis in Microstructured Systems

Efficient mixing

High surface to volume ratio

Precise temperature control

Discrimination between competing reactions

Side reaction suppression. Clean product profile

Enhanced safety

Minimising heating/ cooling costs

Constant output quality

Microreaction technology benefits


9

Product stabilisation: Methylene cyclopentane

Crucial points

�Product 66763 isomerises on extended contact time product/catalyst

� Instant catalyst quench essential

�Specification of product 66763: Purity > 99%

�By-product has very similar b.p. (distillation not possible)

� Raw material must be pure

�Catalyst requires min. 55°C � close to reagent b.p. � pressure valve

Synthesis using neat materials � output > 4 kg/24h

66763

(By-) product 66540

quenchmodule

water

Micro-reactor

T=55°C

ResidenceTime Unit

τ=7 min

catalyst, phenylacetylene

DIBAH 20% in toluene


10

aq. phase

org. phase

691321

water(3 % Na2S2O3)

NEt3, DCM

Microreactor2

T=20°Cτ=2 min

waste

Bromine1 M, DCM

� Complete conversion

� Yield ca. 50%, output 350 g/24h

� DSC analysis intermediate 691321 (1:1 DCM mixture): 641 J/g, left limit 88°C

� Elimination time with aq. KOH aq. is > 20 min

� NEt3 x HCl critical for precipitation

� HCl salt extraction in XXL MR very fast

Safety control: Critical reagents, bromine

pMicroreactor1

T=0°Cτ=1.5 min

O

1 M, DCM

Br

Br

O

Br

O

pp


11

aq. phase

org. phase

691321

water(3 % Na2S2O3)

NEt3 in DCM

Microreactor2

T=20°Cτ=2 min

waste

Bromine1 M, DCM

� Pulsation found (piston pumps)

� No negative effect to reaction

Safety control: Critical reagents, bromine

pMicroreactor1

T=0°Cτ=1.5 min

O

1 M, DCM

Br

Br

O

Br

O

pp


12

Safety control: Critical reagents, diazoester

Micro-reactor

T=15°C

00833

N

Boc

O

N2

O

OEt

Et2O-BF3

MTBE

N

O

Boc

O

OEt

N

O

Boc

� Reaction scale is limited in batch mode (diazo ester)

� Full reagent consumption important to prevent purification difficulties

� Fouling in narrow channel MR

� Reliable overnight operation in 2 mm channel MR

� Nitrogen liberation effected residence time

� Residence time not well defined (extra tubing)

Zhang, X. et al. Org. Process Res. Dev. 2004, 8, 455.

p

p

and

acetone


13

Safety control: Intermediate interception, azides I

� Output > 1 kg/24h (yield 60 %)

� Critical mixture (2), DSC onset 114°C

� Raw diazide 2 has potential of 3’800 J/g

� Direct interception permits safe handling

� Critical amount is always < 10 g

� Scale-up by extended running time,

cell dimensions left unchanged. DSC analysis diazide (2) raw product

p

p Microreactor2

T=50°Cτ<8 min

1

2

CH2Cl

CH2Cl

CH2N3

CH2N3 CH2NH2

CH2NH2

2 HCl

711462

NaN3

1 M, water

Microreactor1

T=90°Cτ=10 min

triphenyl-phosphine2 M, toluene


14

aq. phase

org. phase

p

PTFE tube

T=100°Cτ=20 min

NHNH2

O

NHNH2

O

NH2

NH2

2 HCl

726184

NaNO2

1 M, water

toluene

Microreactor1

T=20°Cτ=11 min

waste

N3

O

N3

O2

dropped into HCl (32 % )

10.8 M, water

�Yield ca. 60% � Output 300 g/24h

� DSC analysis of intermediate 2 (1 M raw sln.): Potential 364 J/g, onset 58°C

� Critical amount < 5 g in each element (MR 1 and phase separator)

�Material from MR synthesis is easier to purify

�Enabling technology

Safety control: Intermediate interception, azides II

2 HCl

R1 – R3

R1 – R3

R1 – R3

p


15

Intermediate stabilisation: Li-R interception

Micro-reactor

1

T=0°Cτ<1 min

p

p

n-BuLi

X

Br

R1-R3

� Yield 55%, output > 3 kg/24h

� Campaign in a Corning G1 3-stage system

� Impurity profile improved

� Elimination of dosing time suppresses side reactions

� Batch yields changing

� Mixture from MR comes in constant quality

� Li-intermediate unstable at T > -30°C � safe handling at +30°C in MR

� Short contact time prevents degradation

X

Li

R1-R3

N

R1-R3

R1-R3R1-R3

N

X

Li

Micro-reactor

2

T=30°Cτ<5 min

R1-R3R1-R3

N

X

PG

12

3

4

5

p

Micro-reactor

3

T=0°Cτ<1 min

ProtectiveGroupreagent


16

Concept of MicroReaction Technology

� Residence time ττττ stands for reaction time

Reaction volume

Total flow rateττττ =

+ Outputττττ =

+ Output

Reaction volume

Total flow rate

Micro-reactor

Reagent 1Product

Reagent 2

RTU

� Enhanced reaction volume need more volume to reach steady-state

� Mismatches with parameter screening


17

Perspective: Multi-kg to ton scale (pilot study)

� Parameter screening in glass MR S02 (vol. 2.5 mL)

� Reaction time reduced from hours to < 1 min (MR)

� Output 1.1 kg / 24 h (low flow rates)

� Parameter transfer to Alfa Laval type 37 plate reactor

� Volume enhancement permitted high range flow rates

� Envisaged productivity: 200-300 kg/24 h

� Higher purity of raw mixture facilitated product isolation

N CN MgCl

+

N

O

quenchstep 1

EtOH

Micro-reactor

T = 40°C

ResidenceTime Unitτ < 1 min

PhMgCl, 2M

PyCN, 3.4M

Raw mixture(full conversion)

quenchstep 2

aq. HCl


18

Conclusions

� Operation in multiple stage systems expand MRT capabilities

� Individual adaptations are needed frequently

� Work-up should be part of the process

� Extra time needed for setting-up the instrument

� Good results achieved with “simple” equipment (robust processes preferred)

� Fine tuned equipment needed for delicate processes

(example 1,4-dibromo benzene Li-halide exchange)

small-scale synthesis campaigns in two-stage flow systems · specification of product 66763: purity...

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