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C. Oliver KappeInstitute of Chemistry, University of Graz

and Center for Continuous Flow Synthesis and Processing (CC FLOW) at RCPEHeinrichstrasse 28, A-8010 Graz, Austria

oliver.kappe@uni-graz.atwww.goflow.at

The Use of Continuous Flow Technologyfor the Synthesis of Active Pharmaceutical Ingredients

Flow Chemistry –A Hot Topic in Both Academia an Industry

Thayer, A. M.Chem. Eng. News2014, 92 (21), p. 13-21(May 26 issue)

Baxendale, I. R. et al. J. Pharm. Sci. 2015, 104, 781

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• Very efficient mixing of the reactants (micromixing)

• Rapid heat transfer and temperature control (high surface-to-volume ratio)

• Enhanced mass transfer for multi-phasic reactions (e.g. gas/liquid)

• Control of residence/reaction times

• Multi step reactions in a continuous sequence

• Immobilized catalysts

• Hazardous reagents/conditions

• Easy scale-up of a proven reaction by:

• increase of time

• reactor volume change (smart dimensioning)

• parallel processing (numbering up)

• Automated purification possible by:

• liquid/liquid extraction

• membrane technology

• chromatographic separation

• Integrated analytics and screening (lab-on-a-chip)

Microreactor forFlow Processing

Characteristics and Advantages of Microreactor/Continuous Flow Chemistry

Scale-Up by Parallel Processing

Plutschack, M. B.; Pieber, B.; Gilmore, K.; Seeberger, P. H. Chem. Rev. 2017, DOI: 10.1021/acs.chemrev.7b00183

DSM - NicOx Collaboration

Thayer, A. M. Chem. Eng. News 2009, 87 (March 16 issue), 17Thayer, A. M. Chem. Eng. News 2014, 92 (May 26 issue), 13

Braune, S. et al. (DSM) Chem. Today 2009, 27(1), 26

Naproxcinod (NicOx)

COX-Inhibiting Nitric Oxide-Donator (CINOD) for Relief of Pain and Inflammation - Osteoarthritis

Numbering Up Microreactors (DSM)

• nitration, neutralization and work-up in one flow step• cleaner and higher yields as in batch process• significantly lower waste generation• >100 tons/year production scale (GMP)

Industrial-Scale Use of Microreactors to Produce Pharmaceuticals

96 reactors (Corning) on 2 towersSiC plate reactors

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A. Extreme Process Windows

1. High-Temperature/High-Pressure Operation

2. Very High-Pressure Operation

3. High-Temperature/Low-Pressure Operation (FVP)

B. Hazardous Chemistry

1. Very Fast and/or Exothermic Reactions

2. Hydrogenation

3. Oxidations with Ox species

Air, Oxygen, Singlet Oxygen, Ozone, H2O2, HOX

4. Halogenation Reactions

5. Hazardous Reactions with Nitrogen Compounds

Nitration, Diazo Compounds, Hydrazoic Acid, Azides, XN3, Hydrazine

6. Reactions with Toxic and/or Reactive Low Molecular Weight Compounds

Carbon Monoxide, Cyanide, Isocyanide, Phosgene, Hydrogen Sulfide

Angew. Chem. Int. Ed. 2015, 54, 6688

See also: Ley/Stevens group review: Chem. Soc. Rev. 2016, 45, 4892

General Flow Principles and Safety Aspects

• Temperature management – control of exotherms/extreme-T/p• Time management – control of residence time• Hazardous chemistry – smaller volumes

– inline generation/quenching– headspace issues

Safety Considerations

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Case Studies for Today

Case Study 1: High-speed Exothermic and Mixing Sensitive Chemistry Radical trifluormethylations

Case Study 2: High-temperature/pressure Chemistry (Process Intensification)Cycloadditions, rearrangements, microwave-to-flow paradigm

Case Study 3: Chemical Generators On-site on demand synthesis of hazardous reagentsMembrane separation, connection with downstream chemistry

Case Study 4: Multistep Flow Synthesis – Process IntegrationNitration/hydrogenation/cyclization cascade

Case Study 5: Gases in Flow Aerobic Pd-catalyzed N-demethylations (O2) CO, propyne and H2S

Preparation of APIs or Intermediates in Continuous Flow Format

Case Study 1: Dihydroergotamine (DHE) The First Specific Antimigraine Agent (1946)

• DHE is a semi-synthetic ergotamine (brand names: D.H.E. 45, Migranal)

• approved in the US in 1946 for treatment of migraine

• administered as a nasal spray or by injection

• increasingly replaced by more selective (and more expensive) 5-HT agonists (e.g. sumatriptan)

HN

NH

HNH

O

N

O

O

N

O Ph

HO

CF3-DHE is an active investigational antimigraine agent with reduced activity against receptors responsible for side-effects

HN

NH

HNH

O

N

O

O

N

O Ph

HO

F3C

Dihydroergotamine

CF3-Dihydroergotamine

US20140179707 A1; WO2012177962 A1 (MAP Pharmaceuticals Inc.)

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Minisci-Type C─H-Functionalization(“Innate“ Radical Trifluoromethylation with CF3I)

Mechanism

Minisci, F.; Vismara, E.; Fontana F. J. Org. Chem. 1989, 54, 6224Review: Duncton, M. A. J. Med. Chem. Commun. 2011, 2, 1135

• 6 elementary reaction steps

• fast (close to diffusion controlled) and quite selective

• mild reaction conditions

• suitable for various precursors

• low prize of H2O2 and Fe(II) salts

• no prefunctionalization of substrate

• generally generates isomers

• reaction frequently does not proceed to completion

Minisci Trifluoroalkylations in a Microreactor(Labscale)

C4F9I(equiv)

reactor volume(µL)

flow rates A/B(mL/min)

res. time (s)

conv. (%)

sel. (%)

1.2 tubing (87) 4.75/0.25 1.0 93 941.2 tubing (8) 4.75/0.25 0.1 61 961.2 tubing (4) 4.75/0.25 0.045 51 961.6 UMR (1800) 9.5/0.5 11 94 941.6 CMR (19) 3.8/0.2 0.3 95 93

Uniqsis microreactor (UMR)(1.800 µL internal volume)

Chemtrix microreactor (CMR)(19 µL internal volume)

Y-connector (0.5 mm thruhole, 1.7 µL) and tubing

(PFA, 0.4 mm i.d.)

3-Methylindole (3-MI, Model Substrate)

H2O2 (30%)

DMSO / MeCN (2:1)FeSO4.7H2O (0.4 equiv)

H2SO4 (0.8 equiv)RfI (1.2-1.6 equiv)

Na2S2O3 (1M)

NH

NH

Rf

0 °C

quench

A

B

(1.6 equiv)

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Feed 1• 3-MI in DMSO/MeCN• FeSO4·7H2O (0.25 equiv)• H2SO4 (0.7 equiv)Feed 2• H2O2 (34.4%)Feed 3• CF3I (neat, -25 °C)Feed 4/Feed 5• 10% aq Na2S2O3/EtOAc

in CSTR at 0°C

FlowPlate A6 Reactor• temp: -10 °C• total volume 16.5 mL• reaction volume: 3.1 mL • res time: 19-38 s

1.36 g/min substrate processed // conversion/selectivity similar to labscale runs

Minisci Trifluoromethylations in a Microreactor(Industrial Scale)

Model Substrate (3-MI)

Feed-1 3-MI

Feed 1• DHE mesylate in

DMSO/MeCN (10.5 wt%)• FeSO4·7H2O (0.25 equiv)• H2SO4 (0.7 equiv)Feed 2:• H2O2 (34.5%)Feed 3• CF3I (neat, -25 °C)Feed 4/Feed 5• 10% aq Na2S2O3/EtOAc

in CSTR at 0°C

FlowPlate A6 Reactor• temp: -10 °C• total volume 16.5 mL• reaction volume: 3.1 mL• res time: 12 s600 g of DHE mesylate was processed within 5 h

• product formed with stable conversion of 98%• product selectivity of 85-86%• yield: 87% (19F-NMR assay)• 10.5 kg of the effluent product mixture were

collected for further work-up

Minisci Trifluoroalkylations in a Microreactor(Industrial Scale)

Manufacturing of CF3-Dihydroergotamine

HN

NH

HNH

O

N

O

O

N

O

HO

HN

NH

HNH

O

N

O

O

N

O

HO

F3CH2O2

FeSO4.7H2OH2SO4

in DMSO/MeCN

CF3I

Na2S2O3

CH3SO3H

Monteiro, J. L. et al. Chem. Eur. J. 2017, 23, 176

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3D-Printed Stainless Steel Reactor for Two-Step L/L – G/L Transformation

Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250 (>2500 citations) Kappe, C. O.; Stadler, A. “Microwaves in Organic and Medicinal Chemistry” Wiley-VCH, 2005 (2nd Ed 2012)

Applications in Organic Synthesis

• Transition Metal Catalyzed C-X Bond Formation

• Other Metal-Mediated Processes• Metathesis, CH-Bond Activation• Cycloaddition Reactions• Rearrangements• Enantioselective Reactions• Organocatalysis, Biocatalysis• Radical Reactions• Oxidations, Reductions• Heterocycle Synthesis• Total Synthesis• Solid- /Fluorous Phase Synthesis• Immobilized Reagents, Scavengers and

Catalysts• Solid Phase Peptide Synthesis

Case Study 2: Process Intensification -Translating Microwave to Flow

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k = A e-Ea/RT Ea = 73.4 kJ mol-1

A = 3.1 x 108

Temperature (°C) t >99% conv (HPLC)

CONV 25 9 weeksCONV 60 5 daysCONV 100 5 hMW 130 (2 bar) 30 minMW 160 (4 bar) 10 minMW 200 (9 bar) 3 minMW 270 (29 bar) “1 s“

Why High-T/p Processing?Speeding Up Chemistry (Arrhenius Law)

Batch Microwave 2-Methylbenzimidazol Synthesis

Damm, M. et al. Org. Process Res. Dev. 2010, 14, 215

Batch Microwave Reactor(300 °C, 30 bar)

Convenience (batch) translates to throughput !!

Benzimidazole Synthesis

Damm, M.; Glasnov, T, N.; Kappe, C. O. Org. Process Res. Develop. 2010, 14, 215

Converting Batch Microwave to Continuous Flow Processing

11956-11968

Chem. Eur. J. 2011, 17, 11956

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More High-T/p Flow Chemistry (Lab Scale)

Review on high-T/p flow chemistry: Razzaq, T.; Kappe, C. O. Chem. Asian J. 2010, 5, 1274

Acid-Nitrile Exchange Reaction

cf. Becke, F.; Burger, Liebigs Ann. Chem. 1968, 716, 78(Ag-lined or Ta autoclave, 300 °C)

Cantillo, D. et al. J. Org. Chem. 2013, 78, 10567

90%89%

97%

78%

86%

90%

78%72%

85%

82% 92%

Scope

Accessing “Forbidden” (and “Forgotten”) Chemistries

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Selective Nitro Group Reductionsunder High-T/p Flow Conditions

r.t. 150 ºC 150 ºC, 1-5 min

Selective Reduction of Nitroarenes with Nano-Fe3O4/Hydrazine

• in situ formation of Fe3O4 nanocat (6 nm)

• exothermic reaction

Cantillo, D. et al. Angew. Chem. Int. Ed. 2012, 51, 10190; J. Org. Chem. 2013, 78, 4530cf. supported catalyst in fixed bed reactor: Moghaddam, M. M. et al. ChemSusChem 2014, 7, 3122

One Feed Flow Approach (Colloidal Fe3O4 Nanocatalyst)

Tetrazole Synthesis in Flow underHigh-T/p Conditions

Sartans (Angiotensin II Receptor Antagonists)

Review: Herr, R. J. Bioorg. Med. Chem. 2002, 10, 3379

Two-Feed Continuous Flow Approach (In Situ HN3)

Gutmann, B. et al. Angew. Chem. Int. Ed. 2010, 49, 7101; J. Flow Chem. 2012, 2, 8.Mechanism: Cantilo, D. et al. J. Org. Chem. 2012, 77, 10882; J. Am. Chem. Soc. 2011, 133, 4465

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“On-Site On-Demand“ Generation of Hazardous Chemicals (or Highly Reactive/Unstable Reagents)

Case Study 3:The Chemical Generator Concept

Poechlauer, P. et al. Chim. Oggi/Chem. Today 2012, 30 (4), 51ClCH2OCH3: Singh, A. et al. Nat. Commun. 2016, 7, 10741

• Eliminate need of handling, storage and transportation

• Generation on-site from benign precursors

• Generation, separation, downstream consumption in fully contained fashion

• Classical examples: phosgene, fluorine, ozone, singlet oxygen....

BrCN: Powerful Reagent in Organic Synthesis

• Source of electrophilic cyanide for N, O, S, C and P nucleophiles

• von Braun reaction, thioether cleavage, cyclic guanidines

Case Study 3a:Cyanogen Bromide (BrCN)

Review: V. Kumar, Synlett 2005, 1638

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Properties

• Mp. 50-53°C, bp. 61-62°C (sublimation)

• Storage under dry conditions, 2-8°C

• Solubility: water, alcohol, ether

• Possible exothermic trimerization to cyanuric bromide

Oberhauser, F. Chem. Ber. 1927, 60, 1434

Safety Information

• Volatile at room temperature

• Decomposition by water/acid to HCN and HBr

• Avoid exposure to light and moisture

• Absorption through skin or by inhalation

• Acutely toxic: 92 ppm·10 min (LC50, human, inh.)

BrCN – A “Forbidden Reagent”

Preparation of Cyanogen Bromide

exothermic

Batch

• Formation: aq. Br2 + NaCN or KCN, 0-30°C, 2h, 73-90%

• Purification: distillation from aq. reaction mixture (fraction at 60-62°C)

Development of a Continuous BrCN-Generator

• Formation: aq. Br2 + KCN, 0-5°C

• Purification: liquid/liquid extraction (Zaiput Separator)

• Monitoring: flow-FTIR cell (Mettler Toledo ReactIR)

• Downstream reaction with diamines (cyclic guanidines)

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Optimization of BrCN Generator

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0 5 10 15 20

c (B

rCN

) [m

ol/

L]

Residence time [min]

cBrCN After Extraction

AqueousWaste

1.15 mol L-1 KCN

DCM

P2

P3

0 - 5 °C1 mol L-1 Br2

in 13 % KBr P1

BrCN in DCM

Setup Parameters

• Br2 feed: 1 M Br2 in 13% aq. KBr

• KCN feed: 1.15 M aq. KCN

• Temperature: 0-5°C

• Organic phase: DCM

• Extraction: 250 µL glass static mixer

• Separation: Zaiput; 0.5 µm hydrophobic membrane

Optimization of BrCN Generator

Setup Parameters

• Br2 feed: 1 M Br2 in 13% aq. KBr

• KCN feed: 1.15 M aq. KCN

• Residence time: 5.2 min

• BrCN yield: 72 % AqueousWaste

1.15 mol L-1 KCN

DCM

0.25 mL min-1

0.25 mL min-10.25mL

P2

P3

0 - 5 °C

1 mL4 min

1 mol L-1 Br2

in 13 % KBr

0.25 mL min-1

P1

BrCN in DCM

2.6 mL5.2 min

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Optimization of BrCN Generator

Setup Parameters

• Br2 feed: 1 M Br2 in 13% aq. KBr

• KCN feed: 1.15 M aq. KCN

• Residence time: 5.2 min

• BrCN yield: 72 % AqueousWaste

1.15 mol L-1 KCN

DCM

0.25 mL min-1

0.25 mL min-10.25mL

P2

P3

0 - 5 °C

1 mL4 min

1 mol L-1 Br2

in 13 % KBr

0.25 mL min-1

P1

BrCN in DCM

2.6 mL5.2 min

BrCN Generator Coupled to Cyclic Guanidine Formation

Optimized Setup

Glotz, G.; Lebl, R.; Dallinger, D.; Kappe, C. O. submitted

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Substrate Scope –Cyclic Amidines and Guanidines (50 °C, 25 min)

• 5-membered cyclic guanidines from 1,2-diaminobenzens

• 2-aminobenzoxazoles from 2-aminophenols

• 6-membered guanidines from 1,3-diamines and 2-aminobenzamides

Sequential Combination of Br2 and BrCN Generators with Reactive Product Crystallization

substratein DCM

0.66 mol L-1 NaBrO3

3.34 mol L-1 NaBr

4 mol L-1 HBr

20-30°C1 mL4 min

0.125 mL min-1

P1

P2

AqueousWaste

1

DCM forwash

Waste

1.15 mol L-1 KCN

DCM

FTIR

0.25 mL min-1

0.25 mL min-1

0.25 mL min-10.25 mL

P3

P4

0 - 5°C

1 mL4 min

1 mL4 min

2.6 mL5.2 min

0.125 mL min-1

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The Cyanogen Bromide Generator Concept

Related Generators:

Cl2: Strauss, F. J. et al. React. Chem. Eng. 2016, 1, 472BrN3: Cantillo, D.; Gutmann, B.; Kappe, C. O. Org. Biomol. Chem. 2016, 14, 853

Synthetic applications in flow: ozone, singlet oxygen, phosgene, diazomethane, ….

Glotz, G.; Lebl, R.; Dallinger, D.; Kappe, C. O. submitted

Case Study 3b:Diazomethane Generators

• highly toxic• irritating• explosive• carcinogenic

Precursors

• Diazald®

• N-Methyl-N-nitrosourea (MNU)• Methylnitronitrosoguanidine (MNNG)

•TMSCHN2

Black, T. H. Aldrichim. Acta 1983, 16, 3

Struempel, M. et al. A. Green Chem. 2008, 10, 41; Rossi, E.; et al. Org. Process Res. Dev. 2012, 16, 1146Proctor, L. D.; Warr, A. J. Org. Process Res. Dev. 2002, 6, 884Maurya, R. A.; et al. Angew. Chem. Int. Ed. 2011, 50, 5952; Poechlauer, P. Chim. Oggi 2012, 30, 51

Diazomethane in Flow

NMe

NO

H2N

O

TMS

HC

N2

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Diazomethane Generation in a Tube-in-Tube Reactorfrom Diazald

product

AcOH quench /waste

Mastronardi, F.; Gutmann, B.; Kappe, C. O. Org. Lett. 2013, 15, 5590

A Continuous Generator forAnhydrous Diazomethane

A Continuous Generator forAnhydrous Diazomethane

Diazomethane Generation in a Tube-in-Tube Reactorfrom N-Methylurea

product

AcOH quench /waste

Gabarino, S. et al. J. Flow Chem 2016, 6, 211Review: Dallinger, D.; Kappe, C. O. Aldrichim. Acta 2016, 49, 57

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Synthesis of Chloroketone/EpoxideBuilding Blocks

Arndt Eistert Chemistry (Anhydrous Diazomethane)

Izawa, K.; Onishi, T. Chem. Rev. 2006, 106, 2811

Atazanavir, Sulfate (Reyataz®)

HIV protease inhibitor (BMS)

approved by FDA in 2003

Patent expires in 2017

NH

R

CHN2

O

PGNH

R

OH

O

PGNH

R

OCO2R

O

PGClCO2R CH2N2

NH

R

O

PGHCl

Cl

base

NH

R

OH

PGCl N

H

R

PG

O

Diastereosel.Reduction or

HNN

N

H

PG

N

HN N

NN

OPh

OH

N

O

H

H

OMe

OH

MeO

O

steps R = Ph

Fully Continuous Three-Step Synthesis ofKey HIV Protease Intermediate

Pinho, V. D. et al. J. Org. Chem. 2014, 79, 1555 (Featured Article)cf. biaryl building block: Dalla-Vechia, L. et al., Org. Biomol. Chem. 2013, 11, 6806

HPLC TraceCbzHN

Ph

O

Cl

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The Final Assembly (Options)

NH

HN N

OH

NH

N

O

HN O

O

PhO

O

O

H2N N

OH

NH2

N

Ph

HN

O

OO

OH

+

NH

HN

O

PhO

O

O

HNNH

N

O

HN O

O

NH

HN N

O

NH

N

O

HN O

O

PhO

O

O

HNNH

N

O

HN O

O

NH

HN

O

PhO

O

O

Cl

BocHN N

OH

NH

N

O

HN O

O

PhPh

NH

O

O

O

OH

HNNH

N

O

HN O

O

Ph

+

BocHN

OH

PhCl

or +

BocHNO

Ph

+

HN

NH

OH

Ph

O

O O

HNNHBoc

N

Cl

NH

HN N

OH

NHBoc

N

PhO

O

O

H2N N

OH

NH

N

O

HN O

O

Ph

HNNH

N

O

HN O

O

+

BocHN

OH

PhCl

or

BocHNO

Ph

asymmetric reduction

SiO2, DCM, 64h, 87%.

i. THF/H2O/HCl, 30°, quant. .ii.HOBt,DCC, DMF, DCM, 0°C, 83%.iii.Pd/C, HCOONH4, 40°C, 94%. iv.CH3COCl, DIPEA, 0°C, 49%.

HOBt, WSC, DCM, 95%.

i. TBAB, NaOH, 0-5°C.ii. H2O, 65°C.

H2N N

OH

NHBoc

N

Ph

i. HCl, dioxane.ii. HOBt, EDC, DMF.

.3HClatazanavir A

B

C

D

E

F

LiAl(OtBu)3H, Et2O, 0°C, 4h, 62%.

NaI, NaHCO3, ACN, r.t., 96%.

HOBt, EDAC or DCC or EDC or WSC,DIPEA or TEA, DCM, r.t., 82-95%

i. HCl, H2O, DCM,50°C.ii.HOBt, TEA, SOCl2,15°C. 90% (2 steps)

NH

O

O

O

OH

+

+

NH

O

O

O

OH+

toluene, 80°, 50%.

IPA, reflux, 24h, 25%

BocHN

HN

O

NHBoc

N

Ph

+

i. IPA, 16h, reflux, 69%. ii.THF:HCl, 50°C, quant.

Case Study 4: Process Integration: Nitrations/Hydrogenations

N

O

O

OH

OH

DIBOA

N

O

O

FO

O

Flumioxazin(Sumitomo Chemicals)

500 t/a use in USA

Schulz, M. et al J. Chem. Ecol. 2013, 39, 154

Naturally Occurring Benzoxazinones(Natural Plant Defense)

Synthetic Commercial Analogs (Contact Herbicides)

Steinbrenner, U. et al. WO 2015071087 A1, 2015

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Synthetic Route to Benzoxazinones

ON

F

F F

O

OF

H2N NH

O

F

F ON

F

F F

O

NH2H2N

ON

F

F F

O

NO2O2N

ABO diamino-FPAA

dinitro-FPAAFPAA

HNO3/H2SO4

H3O+

H2

OH

N

F

F F

O

Br+

Nitration: highly exothermic

dinitro-FPAA: explosive

diamino-FPAA: labile

Dochnahl, M. et al. Carbamat-Benzoxazinones, WO 2014/026893 A1, 2014

Fully Integrated Nitration/Hydrogenation/Cyclization Process

Cantillo, D. et al. Org. Process Res. Dev. 2017, 21, 125

Nitration Hydrogenation CyclizationQuench -

Liquid/liquidextraction

Phaseseparation

Gasrelease

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Case Study 6:Flow Chemistry for Synthezising Opioid APIs

Opiates

SemisyntheticOpioids

Analgesic Drugs

Mixed Agonist–Antagonists

Pure Antagonists

Common Opioid N-Demethylation Methods

Chloroformatesvon Braun Reaction (1918)

Mallinckrodt (US20090156818A1)Johnson Matthey (WO2013050748A2)

Polonovski Type Reactions

e.g. Brock University (WO2012149633A1)

• Stoichiometric amounts of reagents(toxic and corrosive)

• stoichiometric quantities of waste

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New Catalytic Methods:Oxidative N-Demethylation with O2 (Hudlicky)

Pd-Catalyzed N-Demethylation/N-Acylation

Machara, A. et al. Adv. Synth. Catal. 2012, 354, 2713

Carroll, R. J. et al. (with Noramco)Adv. Synth. Catal. 2008, 350, 2984

• Pd-catalyzed N-demethylation with O2 as the terminal oxidant• reaction occurred with hydrocodone and diacetyloxymorphone (DAOM)• unsuccessful with other morphine derivatives

Improved Synthesis of Noroxymorphone

A Serendipitious Discovery: Oxidation of14-Hydroxymorphinone to 1,3-Oxazolidine

• increasing scale of reaction decreased reaction rate strongly• reaction on a 500 mg scale in well stirred vessel with 5 mol% Pd(OAc)2 required

reaction time of 2 h at 120 °C for conversion >95%• filtration gave product in excellent purity and 82% yield

0.2 mmol substrate, 2.5 or 5 mol% Pd(OAc)2 and 3 equiv AcOH in 0.6 mL DMA were stirred under an O2 atmosphere (balloon)

Pd(OAc)2 [mol%] oxidant Conv [%]

5.0 O2 98

5.0 air 69

5.0 argon 4

2.5 O2 96

colloidal Pd(0) forms upon heating

Batch Reaction Screening (0.6 mL)

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Possible Mechanism for the Pd(0) Catalyzed Oxidation of 14-Hydroxy Opioids

Pd(0) Cycle without Free Pd(II) Intermediate

• insertion of Pd(0) into the C-H bond adjacent to the nitrogen

• Pd-H oxidized with O2 to Pd-OOH• iminium moiety attacked by 14-

hydroxy group to form oxazolidine

Murahashi, S.-I. Angew. Chem. Int. Ed. 1995, 34, 2443Muzart, J. J. Mol. Catal. A: Chem. 2009, 308, 15

• rarely applied in pharmaceutical manufacturing• often exothermic reactions• formation of flammable/explosive gas-phase

mixtures with organic solvents• generally operation below limiting oxygen

concentration of solvent/reagents required• in 2012 a consortium involving Eli Lilly, Pfizer, Merck

and Universities (MadOx) was formed to promote development and applications of aerobic oxidations

Oxygen Concentration (Vol%) with <5% Probability of Ignition

solvent Temp(°C)

1 bar 20 bar solvent Temp(°C)

1 bar 20 bar

AcOH 200 10.6 9.6 2-Me-THF 100 9.4 9.1

NMP 200 8.1 7.6 MeOH 100 7.6 6.9

DMSO 200 3.9 - MeCN 100 - 11.9

EtOAc 100 9.4 9.9 toluene 100 10.4 9.9

Osterberg, P. M. et al. Org. Process Res. Dev. 2015, 19, 1537

Safety Concerns with Oxygen in Manufacturing

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24

Primary Pump Module(Uniqsis)

Gas Module(ThalesNano)

BPR(Swagelok)

FEP tube reactor (57 mL, 1/8‘‘ o.d. 1/16‘‘ i.d.) in GC oven

Continuous Flow OxidationGas/Liquid/Solid Segmented Flow

scale[mg]

Pd(OAc)2

[mol%]flow rateO2/liquid

temp[°C]

O2

[equiv]res time

[min]p

[bar]conv[%]

oxazolidine[%]

isol[%]

600 1.25 20/2 120 1.3 13 10 91 85 71600 1.5 20/2 120 1.3 13 10 92 85 65

1200 1.5 20/2 120 1.3 15 10 92 82 69600 1.5 10/1 120 1.3 24 7 96 90 -

Three Key Reactor Technologies Used

Plate – FlowPlate®For excellent O2-solvent mixing

saturation of liquid phase

Flow Coil ReactorDemethlylation residence volume

Packed bedPd-catalyzed

hydrogenation

Scale-Up of Flow Route at Lonza (kg)

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Scale-Up: Oxidative N-DemethylationSetup with 100% O2

DAHM

Gutmann, B. et al. ACS Sust. Chem. Eng. 2016, 4, 6048

FlowPlate (Triangle)

Mielke, E.; Roberge, D.; Macchi, A. A. J. Flow Chem. 2016, 6, 279

Combined Three Step Oxidation/Hydrolysis/Hydrogenation Sequence

• from hydroxymorphinone to noroxymorphone by oxidation/hydrolysis/hydrogenation• all steps performed under mild conditions without isolation of intermediates• process consumes only O2 and H2 as stoichiometric reagents and generates

formaldehyde as the sole stoichiometric by-product

It does not get any greener than this !(cf. von Braun, chloroformates, Polonovski)

Gutmann, B. et al. Chem. Eur. J. 2016, 22, 10393 (Hot Paper)Hone, C.; Roberge, D.; Kappe, C. O. ChemSusChem 2017, 10, 32-41 (Concept Article)

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Going Continuous All the Way fromOripavine To Noroxymorphone

Process Integration viaSolvent Switch

Mata, A. et al. Eur. J. Org. Chem. 2017, in press

Final Goal: Integrated Multistep ContinuousFlow Synthesis of Opioid Derived APIs

• Final route selection

• starting materials, solvent

• het or hom Pd catalyst (loading)

• Scale-up

• solids in flow

• catalyst loading and recovery

• API volume

• Business case?

• Patent issues

• Refiling issues

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Further References - Gases in Flow

Diimide Reductions

Reductive Carbonlyations Oxidative Carbonlyations

Benzylic Oxidations

Glotz, G. et al. RSC Adv. 2017, 7, 10469 Chen, Y. et al. OPRD 2017, 21, 1080

Pieber, B. et al. ACIE 2013, 52, 10241Artemisinic acid: Chem. Eur. J. 2015, 21, 4368Thebaine: OPRD 2016, 20, 376

Pieber, B.; Kappe, C. O. Green Chem. 2013, 15, 320cf. Gutmann, B. et al. ACS Catalysis 2013, 3, 2669

Review on Aerobic Oxidations: B. Pieber, C. O. Kappe, Top. Organometal. Chem. 2016, 57, 97

Opportunities for Using Gases in Pharmaceutical Manufacturing

Csjernyik, G. et al. (AstraZeneca) Compounds and Their Use as BACE Inhibitors WO2012087237 (A1) 2012Tayler, B. et al. Org. Process Res. Develop. 2017, in press

Manufacturing Route for AZD3293 (BACE-1 Inhibitor)(Phase III Clinical Trials for Alzheimers Disease )

BrO

OMe

BrO

OMe+

90:10 before, 98.5:1.5 aftercrystallisation from aq. ethanol

OMe

BrNH2

1. 2M NH3, Ti(OiPr)4IPA, 65 °C

2. 6M HCl in IPA

90%

MeN

O

MeNH2

O

S

Br

OMe

NN

Me SH

100%(assumed)

H2S, Et3NTHF, IPA

-70 °C

DiPEACH(OMe)3

IPA

68%

Br

OMe

NN

Me NH2

Me Me

OSO3H

Br

OMe

NN

Me NH2

(Enantiopure)

7N NH3 in MeOHZn(OAc)2, 80 °C

41%(over 2 steps)

nBuOHH2O

OMe

NN

Me NH2N

O3S PtBu2

Hcat. Na2PdCl4

86%AZD3293 Crude

- +

OMe

NN

Me NH2N

IPA, H2O

88%AZD3293 (+)-Camsylate

Me Me

OSO3H

Me Me

OSO3H

Me Me

OSO3H

Cl

(chiral, racemic)

N

B(OH)2

Me

Me

Me

K3PO4, H2O, EtOH, 75 °C

cat.

N Nreflux (110 °C), overnight

BrBrBr

TMS (1.3 equiv)

(0.32 M toluene)

Pd(PPh3)4 (3 mol%), CuI (30 mol%)

Et3N (3 equiv), TBAF (10 mol%)

1. 2.5M n-BuLi in hexanes,

B(OiPr)3, THF/PhMe, 78 °C

2. 3M HCl, rt

5 steps

BrO

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Opportunities for Using Gases in Flowand Pharmaceutical Manufacturing

Propyne Gas for a Pd—Catalyzed Sonogashira Cross-Coupling

Znidar, D. et al. Org. Process Res. Dev. 2017, 21, 878Propyne (bp −23 °C) pre-dissolved in feed

Hydrogen Sulfide Addition to Nitrile

Cantillo, D. et al. J. Flow Chem. 2017, 7, 29

O

CN3 M in THF

NH2

S

OEt3N

in THF

THF

MFC

H2S

rt15 min0°C

1 min

12 bar 96%

Safer, more robust and scalable processes

May open up new chemistries (“designer reagents”)

Allows redesigning of APIs syntheses utilizing “forbidden” chemistries

Cheaper and more sustainable access to APIs and essential medicines(on-site, on-demand)

Conclusions – Flow/Microreactor Chemistry

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29

Acknowledgements – People (goflow.at)

Collaboration Partners

D. Roberge (Lonza), P. Pöchlauer (Patheon)D. Kirschnek (Microinnova), R. Goetz (BASF)O. de Frutos (Eli Lillly), D.P. Cox (Noramco)A. O'Kearney-McMullan, A. Boyd (AZ)

Group

Dr. B. Gutmann Y. Chen F. Strauss G. ScherfDr. D. Cantillo A. Mata M. Köckinger C. Wenzel Dr. D. Dallinger D. Znider G. GlotzDr. C. Hone R. Lebl M. Wernik

T. von Keutz

Center for Continuous Flow Synthesisand Processing (CC FLOW, 2017-2021)

Manufacturing/Plant Design

Pharma

Equipment

3D Printing

Engineering/Simulation

Scientific Partners

Consortium Leader