ian r. baxendale - cmac · synthesis of grossamide dmf loading step thf grossamide h 2 o 2–urea...
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Ian R. Baxendale
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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
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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%
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3+2 Cycloaddition Reactions
60 min, 60-100 oC
MeCN
SiO2
Synlett, 2010, 5, 749
30 min, 80 oC
Heterocycles, 2011, 82, 1297
or
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Fluorination using DAST
SynLett. 2008, 2111.
DAST
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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
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Azides: Preparation in Flow
10 min
60 oC
MeCN
TMS-N3
Back
pressure
regulator
Org. Biomol. Chem. 2011, 9, 1927
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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.
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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.
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60 oC
Triazole Synthesis in Flow
Org. Biomol. Chem. 2011, 9, 1938
MeCN
TMS-N3
MeCN Cartridge recycled
Cartridge consumed
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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
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Curtius-Rearrangements in Flow Using Azide Monoliths
150 mm
15 mm
15-18 mmol N3
Org. Biomol. Chem. 2008, 6, 1587.
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Stauginger Aza Wittig Reaction Azides
Aldehydes
NH3/MeOH
65-99% isolated yield, >95% purity
MeOH
Org. Biomol. Chem. 2011, 9, 1927
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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
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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
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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
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Casein Kinase I-ε/δ Inhibitors
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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
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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
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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
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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
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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
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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
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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
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Route B: Claisen Rearrangement
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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
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Route B: Claisen Rearrangement
3
1
2
Chem. Euro. J. 2012, 32, 9901-9910
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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
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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
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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
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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.
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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.
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Adamantane Amino acid Synthesis
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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
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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
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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
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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
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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.
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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 !!!
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5-8 min
KOH
(1.2 equiv.) (1 equiv.)
MeOH
H2O
+
KMnO4 Nef Oxidation in Flow
Exothermic
Org. Lett. 2010, 12, 3618.
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Heterogeneous flow mixtures
Coflore ACR (Agitated Cell reactor) flow reactor
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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
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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
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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
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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
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Department of Chemistry
E-mail: [email protected]
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