Ian R. Baxendale

Synthesis of Grossamide

DMF

loading step

THF

Grossamide

H2O2–urea complex

Acetone / H2O (10:1)

En

zym

e

Second input stream

Synlett 2006, 427.

Heater/Cooler module a reactor chip -40-150 oC

Two HPLC pumps 100-10,000 µL/min 35 bar system pressure

2 reagent loading channels from liquid handling unit

UV/diode array detection

Split stream real-time MS analysis for optimisation

In-line reverse phase preparative purification – Mass directed

Fully software controlled via UNIPOINT + DoE software

35 Oxazoles structures prepared

Synthesis of Oxazoles and Thiazoles in Flow

Org. Lett. 2006, 8, 5231.

J. Comb. Chem. 2008, 10, 851.

, some on 10-25g scale.

R= NO2 90%

2-OMe 89%

4-OMe 96%

3-F 68%

4-Cl 48%

4-Br 53%

90%

88%

89%

85% 85%

50-96%

25-55 oC

MeCN

12:5 89% 4:5 94%

2:1 86% 5:4 87%

3+2 Cycloaddition Reactions

60 min, 60-100 oC

MeCN

SiO2

Synlett, 2010, 5, 749

30 min, 80 oC

Heterocycles, 2011, 82, 1297

or

Fluorination using DAST

SynLett. 2008, 2111.

DAST

QP-TU

Purities greater than 95%

96%

98%

93%

91%

90%

94%

88%

95%

89%

82%

91%

88%

89%

87% 85%

93%

81%

85% 70%

Org. Biomol. Chem. 2007, 5, 1559.

Azide coupling in Flow

Azides: Preparation in Flow

10 min

60 oC

MeCN

TMS-N3

Back

pressure

regulator

Org. Biomol. Chem. 2011, 9, 1927

QP-SA QP-DMA

30 min

100 oC

QP-BZA

70 oC Evaporate

Preparation of Alkynes in Flow : Seyferth-Gilbert

Angew. Chem. Int. Ed., 2009, 48, 4017.

Seyferth-Gilbert: Extended Sequence

t-BuOK

in MeOH

(2 equiv.)

(1 equiv.)

(1.5 equiv.)

(2 equiv.)

MeCN

60 oC

30 min

100 oC

QP-TU

QP-SA QP-DMA QP-BZA

70 oC

Scavenge

Sequester Cu

Couple and

Oxidation

Angew. Chem. Int. Ed., 2009, 48, 4017.

60 oC

Triazole Synthesis in Flow

Org. Biomol. Chem. 2011, 9, 1938

MeCN

TMS-N3

MeCN Cartridge recycled

Cartridge consumed

Polymeric Monoliths

Mono DVB Porogen Solvent AIBN Temp.

35% 20% 40% 5% v/v 1 mol% 80 oC

Waste

Heat 80-100 oC

Substrates

Product

Curtius-Rearrangements in Flow Using Azide Monoliths

150 mm

15 mm

15-18 mmol N3

Org. Biomol. Chem. 2008, 6, 1587.

Stauginger Aza Wittig Reaction Azides

Aldehydes

NH3/MeOH

65-99% isolated yield, >95% purity

MeOH

Org. Biomol. Chem. 2011, 9, 1927

Casein Kinase I-ε/δ Inhibitors

• Targeting Kinases: A typical medicinal chemistry project

• Potential regulators of circadian rhythm: sleep disorders/mood disorders

• Target oriented application of flow technologies: challenging steps, solubility issues Imidazo [1,2-b]pyridazine/Sanofi-Aventis

Org. Biomol. Chem., 2010, 8, 1798.

Organometallic reagents

(moisture, oxygen, precipitation, stability)

Reactivity/Chemoselectivity

Mono vs multi addition

Chemoselectivity

Solubility of product

High temperature

Purification of final product

Casein Kinase I-ε/δ Inhibitors

Org. Biomol. Chem., 2010, 8, 1798.

• 50.0 mmol reaction scale - 100 mmol of BuLi (× 2 eq.) was handled safely

Note: no more than 4.0 mmol at a time

• Continuous throughput of 6.0 mmol/hour (1.3 g/h)

Employing organometallic reagents in flow:

Imidazo [1,2-b]pyridazine/Sanofi-Aventis

Casein Kinase I-ε/δ Inhibitors Org. Biomol. Chem., 2010, 8, 1798.

0.3 ml/min MeOH quantitative

0.2 M in EtOH

K2CO3

Pure product precipitated

upon addition of water.

40%

0.1 M in EtOH

BPR

0.05 M in EtOH

2.0 M in EtOH

Vapourtec V-10

0.1 ml/min

0.1 ml/min

52% CH2Cl2

Casein Kinase I-ε/δ Inhibitors

Synthesis of Gleevec

DCM

DCM

0.4 mL/min

RT

Chem. Commun., 2010, 46, 2450.

SiO2

25 min 80 oC

K2CO3

50 °C

N2 in

Exhaust

0.15 mL/min DBU

2:1 Dioxane/tBuOH

30 min

150 oC

30 min

Convergent synthesis

Prepared from Ynone

32% isolated yield

After chromatography

0.15 mL/min

H2O 0.1 mL/min

Catalyst system

40 min, 100 oC

Pd(OAc)2 (1 mol%)

(iPr)2NEt (1.2 equiv.)

Ynone Synthesis – numbering out

DCM

1:1 EtOH/H2O

NaOH (1.1 equiv.)

Water Aqueous

output

MgSO4

Catch and

Release

30 min, 100-130 oC

OR H2N-NHR’’

NH3 in

MeOH/DCM

QP-TU

Chem. Eur. J., 2010, 16, 89-94

Stream Splitting in Flow

30 min, 100 oC

QP-TU

CaCO3

Pd(OAc)2 (1 mol%)

(iPr)2NEt (1.2 equiv.)

DCM

Input 1

Input 2

Input 3

Input 4

Product 1

Product 2

Product 3

Product 4

60% yield

20 min

100 oC

87% yield

30 min

100 oC

88% yield

20 min

120 oC

71% yield

20 min

100 oC Chem. Eur. J., 2010, 16, 89-94

Chem. Eur. J. , 2010, 16, 12342.

d-Opioid Receptor Agonist

40 min, RT

THF

0.125 ml/min

0.125 ml/min

10 min, 60 oC

React IR

Flow cell

0.5 ml/min

0.25 ml/min

20 min, RT

SiO2

RT

60 oC

NH3/MeOH

Catch and release

To waste

35% overall yield

Potent 5HT1B Antagonist

SynLett 2010, 505-508

99%

10 min, 135 oC

EtOH

0.5 ml/min

0.5 ml/min

0.5 M

0.5 M

H-Cube 10% Pd/C

70 oC

Full H2 mode

10 min, 130 oC

0.4 ml/min 0.24 M

0.4 ml/min

K2CO3

0.20 M in PhMe

250 oC

250 psi

14 min

1:1 mixture; 0.5 M

0.1 ml/min, DMF

0.24 M in DMF

0.1 ml/min

rt, 50 min

Catch and release purification

NH3/MeOH release.

18%, 95% purity

PNAS, 2012, doi:10.1073/pnas.1115623109

Duff Reaction

15-22%

• Cheap starting materials/reagents

• Scaleable via the same route

• Highly reproducible

• Automated synthesis

• Avoid work-up/purification

Synthesis of an IRE-1 binding probe

Selective inhibition of unconventional

mRNA splicing by an IRE1-binding small molecule

Route A: N-oxide Derived Synthesis

1 h, 125 oC

DCM/EtOH

2:1

83 ml/min

83 ml/min

91%

83 ml/min

DCM/EtOH

1 h, 120 oC

83 ml/min

93%

1 h, 0 oC

83 ml/min

DCM

82%

83 ml/min

DCM

166 ml/min

1 M HCl

overall yield 46%

66%

rt

1 h

Isolated by filtration

Chem. Euro. J. 2012, 32, 9901-9910

Route B: Claisen Rearrangement

Loading stream

A B

1

Route B: Claisen Rearrangement

Breakthrough

Detection at 330 nm

NMP solvent

Wash stream

10 cartridges loaded sequentially

in a fully automated procedure

~ 2 M of substrate

Route B: Claisen Rearrangement

3

1

2

Chem. Euro. J. 2012, 32, 9901-9910

4

51% overall yield

Route B: Claisen Rearrangement

Fluid flow

Gas flow

Fluid flow

Gas flow

Gas feed

Liquid substrate feed

Taken using UV light profiling

T-piece connector

Gas flow

0.02 mm id

tubing

4 mm id

tubing

Neurotensin physiologically roles in a variety of biological processes,

Merclinertant and SR 142948A

• temperature control

• pain sensation,

• modulation of appetite

• pituitary hormone secretion

• disruption of NT’s binding proposed as a possible treatment of schizophrenia and Parkinson’s disease

• up-regulation of NT receptor (NTR) expression is linked with cancer

3 Neurotensin receptors.

NTR 1 and NTR 2 are both seven-transmembrane G-coupled protein receptors

NTR3 (showing 100% identity with Sortilin) possess a single transmembrane domain

Neurotensin has poor stability in vivo and is degraded by several endopeptidases and metalloproteases.

Its size prevents passage across the blood brain barrier resulting in poor bioavailability (injection CNS).

Offers NTR agonism, however, study of these receptors require access to antagonists of NTR receptor function.

Meclinertant SR 48692 SR 142948A Levocabastine - Novartis

NTR1 antagonist (Ki = 2.6 ±0.2 nM)

NTR2 (Ki = 418±82.2 nM) and NTR3 (IC50 = 238±46 nM) Binds NTR1 and NTR2

but much more selective for NTR2.

Selectively binds to NTR2

Sanofi-Aventis

Continuous Microwave Synthesis

Processing times for Bucherer-Lieb synthesis.

STEP 1 Heating

times

Reaction

time

Cooling

times

Wash

and prep

times

Total

cycle

time

Cycles

required

Total

processing

time

Voyager 14.5 min 90 min 20 min 11.5 min 130 min 24 54 hours

Vials 4 min 90 min 6 min 1 min 102 min 60 101 hours

STEP 2

Voyager 20 min* 180 min 24 min 12 min 236 min 10 39.3 hours

Vials 9 min* 180 min 7 min 2 min 198 min 25 82.5 hours

*Needed to be heated at reduced power to prevent overpressure.

Meclinertant SR 48692

1.2 L; 0.25 M 0.5 L; 0.5 M

81-84% 2 steps

Bucherer-Berg strategy

Amino acid preparation issue

Microanalysis (Observed C = 36-48%, Desired 67.7%).

Full conversion of the hydantoin and extent of inorganic

impurities could be determined by 1H NMR (D2SO4)

analysis of samples of material doped with known

concentration of p-Anisidine

(result: approx 30% of material by mass). Preparations following other known literature

methods gave identical or worse purities

of the hydantoin.

Meclinertant SR 48692 SR 142948A

Required development of a new synthetic route !

Poor subsequent conversion in derivatization reactions - needed 3-4 equivalents to prepare adducts in expected yields.

Adamantane Amino acid Synthesis

0.5 M in THF

0.18 mL/min

14 mL

40 oC

0.5 M in THF

0.2 mL/min

3 M in H2O

0.18 mL/min

NH4Cl

Ultra sonication

37 min

AcOH/Ac2O/H2SO4

88% isolated

Grignard addition

91% isolated

AcOH/MeCN 1:1

KOH 3 M in H2O

14 mL

RT

1 mL/min

7 min

2:1:1

1 mL/min

0.65 M

3 mL/min

Ritter reaction

5-endo-exo-dig

cyclisation

0.2 mL/min

KOH 0.8 M

H2O/EtOH 4:1

0.1 mL/min

0.1 M

125 oC

47 min 91% isolated

0.5 M in DCM

8 mL/min

O3 1 bar

500 mL/min

99% isolated

ozonolysis

92% 92% 97%

Overall yield 72%

Overall yield 68%

94%

Hydrolysis

HCl/H2O/AcOH

9:2:1

Org. Process Res. Dev. 2012, 16, 798-810.

Adamantane Amino acid Synthesis

Scale-up Synthesis in Flow

Aqueous

Organic

30 L 47.19 moles

Conc: 1.57 M

30 L 51.91 moles

1.1 equiv. Conc: 1.73 M

60 L 56.63 moles

1.2 equiv. Conc: 0.94 M

waste

NaS2O3/NaOH 1.5 M

Exotherm

Regulated <55 oC Ambient

temperature

75 oC

Ambient

temperature

SR 142948A (Sanofi-Aventis) Generate~12 kg

Scale-out Synthesis in Flow

30 L 47.19 moles

Conc: 1.57 M

30 L 51.91 moles

1.1 equiv. Conc: 1.73 M

60 L 56.63 moles

1.2 equiv. Conc: 0.94 M

Aqueous

Organic

waste

NaS2O3/NaOH 1M

12 mL/min flow rate

3 mL/min per channel

2 mL/min per channel

3 channels

Max 2.5 mL/min

1.5 mL/min

12 ways split

Increase residence time

6.9 days processing

120 L of reaction solution

11.5 kg 95%

Exotherm

Regulated <55 oC

75 oC

SR 142948A

Scale-up Synthesis in Flow

35 min

20 bar

90 oC

Pressure regulator

EtOH

Et3N (3 equiv.)

Pd(dppf)Cl2

(3.5-5 mol%)

Gas bubble Liquid

7 bar CO

(+ Additive)

SR 142948A

5 cm

5 cm

EtOH

Gas vent

QP-SA

QP

-TU

1.8 kg; 92% purity

Sediment tank

Liquid Pd nanoparticles

HPLC pump

Scale-up Synthesis in Flow

1 h 15 min

105 oC

Pd(PPh3)2Cl2 (0.01 mol%)

PPh3, MeOH

TMG, EtOH,

CuI (0.02 mol%)

SR 142948A

QP-SA

QP

-TU

Mixing Chip 2 mL

>95% conversion

RuO2 0.25 mol%

KIO4 2.2 equiv.

Na2CO3/H2O 3 M

NaOH (2.5 M)

40 oC, 3.5 h

>94% conversion >99% conversion

80 oC

72% isolated yield

3.5 h

0.1 mL/min

tBuONO

0.3 M in MeCN

0.3 M in MeCN

0.45 M in MeCN

BF3.Et2O

0.4 mL/min

0.4 mL/min

0.4 mL/min

2 mL volume

Hydrazine Formation in Flow

L-ascorbic acid

0.4 M in MeCN

H2O

0.4 mL/min

100 min run

4.25 g

98% yield

tBuONO

0.2 M in MeCN

0.2 M in MeCN

0.5 mL/min

0.5 mL/min

2 mL volume

L-ascorbic acid

0.4 M in H2O

0.5 mL/min

RT, 5 min 60 oC, 20 min

µW 120 oC

2 h

72%

Tetrahedron 2011, 67, 10296-10303.

Meclinertant SR 48692 SR 142948A

Scale-up Synthesis in Flow

60 oC, 16 min

1.1 M NaOEt

EtOH

0.5 mL/min 0.25 M

1.0 mL/min

0.375 M

1.0 mL/min

> 95%

conversion

2-Me-THF

2-Me-THF 2 M aq. HCl

Precipitation !!!

5-8 min

KOH

(1.2 equiv.) (1 equiv.)

MeOH

H2O

+

KMnO4 Nef Oxidation in Flow

Exothermic

Org. Lett. 2010, 12, 3618.

Heterogeneous flow mixtures

Coflore ACR (Agitated Cell reactor) flow reactor

Heterogeneous flow mixtures

I2

4 mL/min

8 mL/min

0.3 M in hexane

0.15 M in DCM

12 mL/min, 0.1 M

94% isolated yield

Org. Process Res. Dev., 2011, 15, 693–697

Meclinertant SR 48692 (Sanofi-Aventis) SR 142948A (Sanofi-Aventis)

Scale-up Synthesis in Flow

60 oC, 16 min

1.1 M NaOEt

EtOH

0.5 mL/min 0.25 M

1.0 mL/min

0.375 M

1.0 mL/min

> 95%

conversion

2 M aq. HCl

2-Me-THF

2-Me-THF

Precipitation !!!

Isolated by filtration

2',6'-Dimethoxyacetophenone

~ £6.50 per gram

78% isolated

Scale-up Synthesis in Flow

35 oC, 10 min 0.5 M

0.5 mL/min

2-MeTHF

Mixing Chip 2mL

15 oC

0.55 M

Iodine 0.6 M

1.0 mL/min

2-MeTHF

0.5 mL/min

90 oC, 2 h

KOH/H2O

90 oC, 1 h

KOH/H2O

185 oC, 1 h

Scale-up Synthesis in Flow

35 oC, 10 min 0.5 M

0.5 mL/min

2-MeTHF

Mixing Chip 2mL

15 oC

0.55 M

Iodine 0.6 M

1.0 mL/min

2-MeTHF

0.5 mL/min

120 oC, 2 h

2.5 M NaOH

120 oC, 1.15 h

5 M HCl

35 oC, 7 min

0.5 M

0.3 mL/min

0.3 mL/min

MeOH/2-MeTHF

MeOH

NIS 2.2 equiv.

(MeO)3CH 3 equiv. Pd(PPh3)2Cl2 (0.01 mol%)

PPh3, MeOH

Et3N, MeOH,

CuI (0.02 mol%)

QP-TU

100 oC, 35 min

Department of Chemistry

E-mail: i.r.baxendale@durham.ac.uk

Special thanks to the following organisations

for their generosity and friendship

Advion, AM Technologies, EPSRC, Syngenta,

The Royal Society, Unilever, Uniqsis.

Past Members of the ITC

Dr Francesco Tozzi

Dr Lucia Tamborini

Dr Heiko Lange

Dr Laetitia Martin

Dr Matt Kitching

Dr Jorg Sedelmeir

Dr Chris Smith

Dr Christian Hornung

Dr Jane Jin

Dr Catherine Smith

Dr Rainer Martin

Dr Marcus Baumann

Current Members

Dr Lucie Guetzoyan

Dr Nikzad Nikbin

Kim Roper

Sean Newton

Ben Deadman

Sam Bourne

Ben Bhawal

Richard Ingham

Dr Steve Lanners

Dr Tash Polyzos

Celeste Iannuzzi Maria

Dr Malte Brasholz

Dr Francesco Venturoni

Dr John Hayward

Trine Petersen

Antti Kataja

Dr Jens Wegner

Dr Mark Hopkin

Dr Keiji Nakayama

Dr Ulrike Gross

Dr Jason Tierney

Dr Peter Koos

Dr Victoria Rojo

Dr Catherine Carter

Dr Elena Riva

Olivia Dixon

Dr Sam Qian

Dr Tobias Brodmann

Claudio Battilocchio