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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