phoenix flow reactor oct 2013
TRANSCRIPT
Phoenix Flow Reactor
Accessing New Molecules or Chemical Space through
applying high pressure and temperature flow chemistry
Heterocyclic rings of the future, J. Med. Chem., 2009, 52 (9), pp 2952–2963.
• 3000 potential bicyclic systems unmade • Many potential drug like scaffolds Why? • Chemists lack the tools to expand into new chemistry space to access these new compounds. • Time • Knowledge
The quest for novel heterocycles
• Standard benzannulation reaction • Good source of:
• Quinolines • Pyridopyrimidones • Naphthyridines
→ Important structural drug motifs
Disadvantages: • Harsh conditions • High b.p. solvents • Selectivity • Solubility
W. A. Jacobs, J. Am. Chem. Soc.; 1939; 61(10); 2890-2895
High T Chemistries – in Batch
• Replacement of diphenyl ether (b.p: 259°C) with THF (b.p.: 66 °C)
Cyclization conditions: a: 360 °C, 130 bar, 1.1 min b: 300 °C, 100 bar, 1.5 min c: 350 °C, 100 bar, 0.75 min
Pyridopyrimidinone Quinoline
No THF polymerization!
Batch conditions: 2 hours
Gould-Jacobs Reaction – in Flow
The nature of the substituents is critical because they increase or decrease the nucleophilicity of the ring: Electron donating groups increase yields, Electron withdrawing groups decrease yields.
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Process exploration
• Meldrum’s acidic route to pyridopyrimidones and to hydroxyquinolines
Cyclization conditions: a: 300 °C, 160 bar, 0.6 min b: 300 °C, 100 bar, 0.6 min c: 360 °C, 100 bar, 1 min d: 350 °C, 130 bar, 4 min e: 300 °C, 100 bar, 1.5 min
Lengyel L., Nagy T. Zs., Sipos G., Jones R., Dormán Gy., Ürge L., Darvas F., Tetrahedron Lett., 2012; 53; 738-743
New Scaffold Generation
5 novel bicyclic scaffolds generated-fully characterized. Many more to follow
Phoenix Flow Reactor: High temperature synthesis
Powerful: Up to 450°C
Versatile: Heterogeneous and homogeneous capabilities.
Fast: Reactions in seconds or minutes.
Innovative: Validated procedure to generate novel bicyclic compounds
Simple: 3 button stand-alone control or via simple touch screen control on H-Cube Pro™.
Safe: Emergency backpressure release valve and cooling by nitrogen gas
Phoenix loop-reactor possibilities
• Materials - sizes § Stainless steel (1 – 16 mL) –
up to 450oC and 100bar • Coil (1/16” 4-16 ml) • Short coil (1/16” 1-4ml) • Static mixer (3/8”, 32ml)
§ PTFE coil (4 – 16 ml) – up to 150oC or 20bar
§ Hastelloy (4 – 16 ml) – up to 450oC and 100bar
• Easy to recoil • Versatile
Phoenix packed bad reactor possibilities
• CatCart (30, 70 mm) – up to 250°C and 100 bar • MidiCart – up to 150°C and 100bar • Special high temperature cartridge – up to 450°C and 100bar
90 × 9.5 mm
Cartridge Volumes and Packing Type Volume Max. T/p (100 bar
un6l it is indicated otherwise)
Comment
H-‐Cube Pro Type CatCarts 30 mm 0.38 mL 250°C Packed by
ThalesNano 70 mm 0.76 mL 250°C Packed by
ThalesNano Phoenix Metal-‐Metal Sealing High T CatCarts
125 mm (1/4 SS id 3 mm) 0.9 mL 450 °C User can fill 125 mm (1/4 SS id 3.8 mm) 1.3 mL 450 °C User can fill 125 mm (1/2 SS id 9.4mm) 9 mL 450 °C User can fill, filters
are needed 250 mm (1/4 SS id 3mm) 1.8 mL 450 °C User can fill, filters
are needed 250 mm (1/4 SS id 3.8 mm) 2.6 mL 450 °C User can fill, filters
are needed 250 mm (1/2 SS id 9.4mm) 18 mL 450 °C User can fill, filters
are needed H-‐Cube Midi Type MidiCarts
MidiCart 7.6 mL 150 °C Packed by ThalesNano
Calculates minimum pressure required for your solvent at selected temperature
Versatile Catalysis Platform
Add H-Cube Pro and Gas Module
• Reactions from 10-450C and 1-100bar (1450 psi) • Up to 13 different reagent gases • Heterogeneous or homogeneous catalysis
Fully Automated system now available
Ring closure on aryl NH : key step • Mitsunobu reaction or traditional heating with T3P did not
furnish the bicyclic heterocycle. • Reaction proceeded smoothly in Phoenix reactor at 300oC with
65% yield despite requirement for the cis amide conformer in transition state.
Mitsunobu Reaction Application Note
N-Alkylation Application Note
RaNi 70mm 200C, 80bar 0.5ml/min
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Reaction pathway using Raney-Ni catalyst
Advantages of Raney-Nickel: • Cheaper than Pd, Pt containing catalysts • Differently preactivated Raney-Ni catalyst can give more
flexibility – selectivity issues
But: Pyrophoric!
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Optimizing the reaction conditions:
• 0.1M Indole solution in ethanol, RaNi 4200 Catalyst, GC-MS results
Reach higher selectivity: Protect the N-atom with TMS-Cl Result: 90% conversion with 80%
selectivity (300 °C, 100 bar, 0.5 mL/min,
isolated yield: 76.5%)
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Alkylation of 2-methyl-indoline
The total amount of dialkylated products was 18%.
Alkylation coupled with dehydrogenation
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Ring closuring of 2-methyl-indole with 1,3-butanediol
Ring closure is coupled with hydrogenation of double bond
Diels Alder
• Diels-Alder reactions usually require long reaction times.
• This reaction time could be reduced to 5 minutes at 250°C using toluene.
• .Product isolated in near quantitative yield.
• Reaction also possible using lower boiling solvents (MeCN, THF, DME) with same result using higher pressures (200 bar).
Fischer-Indole Synthesis: Scale Out
cf. MW reaction: Bagley, M. C.; et al. J. Org. Chem. 2005, 70 , 7003
In AcOH/2-propanol (3:1) (0.5M) 150 °C, 60 bars,
1.0 mL min-1 (4 min res. time) 88% isolated yield
Continuous Flow Results (4 mL or 16 mL Coil) Scale-up
200 °C, 75 bars, 5.0 mL min-1 (~3 min res. time)
96% isolated yield
25 g indole/hour
High temperature reactions
Conditions: p = 70 bar T = 270°C v = 0.4 mL/min c = 0.04 M (NMP) Result: 82% yield
Kappe, O. C. et al. Eur. J. Org. Chem., 2009, 9, 1321-1325.
X-Cube FlashTM – Kolbe Synthesis Conditions: p = 60 bar T = 180°C v = 4 mL/min Residence time: 440 s c = 0.49 M (H2O) Best result: 51% conversion
Kappe, O. et al. Chem. Eng. Technol. 2009, 32(11), 1-16.
X-Cube FlashTM – SNAr reaction
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