phoenix flow reactor oct 2013
TRANSCRIPT
![Page 1: Phoenix Flow Reactor Oct 2013](https://reader034.vdocuments.mx/reader034/viewer/2022052505/55504ae0b4c905b2788b4fe3/html5/thumbnails/1.jpg)
Phoenix Flow Reactor
Accessing New Molecules or Chemical Space through
applying high pressure and temperature flow chemistry
![Page 2: Phoenix Flow Reactor Oct 2013](https://reader034.vdocuments.mx/reader034/viewer/2022052505/55504ae0b4c905b2788b4fe3/html5/thumbnails/2.jpg)
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
![Page 3: Phoenix Flow Reactor Oct 2013](https://reader034.vdocuments.mx/reader034/viewer/2022052505/55504ae0b4c905b2788b4fe3/html5/thumbnails/3.jpg)
• 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
![Page 4: Phoenix Flow Reactor Oct 2013](https://reader034.vdocuments.mx/reader034/viewer/2022052505/55504ae0b4c905b2788b4fe3/html5/thumbnails/4.jpg)
• 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
![Page 5: Phoenix Flow Reactor Oct 2013](https://reader034.vdocuments.mx/reader034/viewer/2022052505/55504ae0b4c905b2788b4fe3/html5/thumbnails/5.jpg)
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.
5
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
![Page 6: Phoenix Flow Reactor Oct 2013](https://reader034.vdocuments.mx/reader034/viewer/2022052505/55504ae0b4c905b2788b4fe3/html5/thumbnails/6.jpg)
New Scaffold Generation
5 novel bicyclic scaffolds generated-fully characterized. Many more to follow
![Page 7: Phoenix Flow Reactor Oct 2013](https://reader034.vdocuments.mx/reader034/viewer/2022052505/55504ae0b4c905b2788b4fe3/html5/thumbnails/7.jpg)
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
![Page 8: Phoenix Flow Reactor Oct 2013](https://reader034.vdocuments.mx/reader034/viewer/2022052505/55504ae0b4c905b2788b4fe3/html5/thumbnails/8.jpg)
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
![Page 9: Phoenix Flow Reactor Oct 2013](https://reader034.vdocuments.mx/reader034/viewer/2022052505/55504ae0b4c905b2788b4fe3/html5/thumbnails/9.jpg)
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
![Page 10: Phoenix Flow Reactor Oct 2013](https://reader034.vdocuments.mx/reader034/viewer/2022052505/55504ae0b4c905b2788b4fe3/html5/thumbnails/10.jpg)
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
![Page 11: Phoenix Flow Reactor Oct 2013](https://reader034.vdocuments.mx/reader034/viewer/2022052505/55504ae0b4c905b2788b4fe3/html5/thumbnails/11.jpg)
Calculates minimum pressure required for your solvent at selected temperature
![Page 12: Phoenix Flow Reactor Oct 2013](https://reader034.vdocuments.mx/reader034/viewer/2022052505/55504ae0b4c905b2788b4fe3/html5/thumbnails/12.jpg)
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
![Page 13: Phoenix Flow Reactor Oct 2013](https://reader034.vdocuments.mx/reader034/viewer/2022052505/55504ae0b4c905b2788b4fe3/html5/thumbnails/13.jpg)
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
![Page 14: Phoenix Flow Reactor Oct 2013](https://reader034.vdocuments.mx/reader034/viewer/2022052505/55504ae0b4c905b2788b4fe3/html5/thumbnails/14.jpg)
N-Alkylation Application Note
RaNi 70mm 200C, 80bar 0.5ml/min
![Page 15: Phoenix Flow Reactor Oct 2013](https://reader034.vdocuments.mx/reader034/viewer/2022052505/55504ae0b4c905b2788b4fe3/html5/thumbnails/15.jpg)
15
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!
![Page 16: Phoenix Flow Reactor Oct 2013](https://reader034.vdocuments.mx/reader034/viewer/2022052505/55504ae0b4c905b2788b4fe3/html5/thumbnails/16.jpg)
16
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%)
![Page 17: Phoenix Flow Reactor Oct 2013](https://reader034.vdocuments.mx/reader034/viewer/2022052505/55504ae0b4c905b2788b4fe3/html5/thumbnails/17.jpg)
17
Alkylation of 2-methyl-indoline
The total amount of dialkylated products was 18%.
Alkylation coupled with dehydrogenation
![Page 18: Phoenix Flow Reactor Oct 2013](https://reader034.vdocuments.mx/reader034/viewer/2022052505/55504ae0b4c905b2788b4fe3/html5/thumbnails/18.jpg)
18
Ring closuring of 2-methyl-indole with 1,3-butanediol
Ring closure is coupled with hydrogenation of double bond
![Page 19: Phoenix Flow Reactor Oct 2013](https://reader034.vdocuments.mx/reader034/viewer/2022052505/55504ae0b4c905b2788b4fe3/html5/thumbnails/19.jpg)
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).
![Page 20: Phoenix Flow Reactor Oct 2013](https://reader034.vdocuments.mx/reader034/viewer/2022052505/55504ae0b4c905b2788b4fe3/html5/thumbnails/20.jpg)
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
![Page 21: Phoenix Flow Reactor Oct 2013](https://reader034.vdocuments.mx/reader034/viewer/2022052505/55504ae0b4c905b2788b4fe3/html5/thumbnails/21.jpg)
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
![Page 22: Phoenix Flow Reactor Oct 2013](https://reader034.vdocuments.mx/reader034/viewer/2022052505/55504ae0b4c905b2788b4fe3/html5/thumbnails/22.jpg)
THANK YOU FOR YOUR ATTENTION!!
ANY QUESTIONS