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Synthesis of 2-(3,5-bis(trifluormethyl)phenyl)-3-isobutoxypent-2-enenitrile (SGS17-7-1)

Reaction for SGS17-7-1

Crude 2-(3,5-bis(trifluoromethyl)phenyl)-3-oxopentanenitrile (SGS17-4-1) (approx. 5 g, 0.02 mol max. depending on purity) was dissolved in a mixture of toluene (75 mL) and 2-mthylpropan-1-ol (7 mL, 0.08 mol). 15 drops of 18 M sulfuric acid was added to the mixture, which was then refluxed for 7 h, left at room temperature over the weekend and refluxed for a further 7 h.

At the end of the reflux the reaction mixture was orange.  4 mL of triethylamine was added to neutralise the sulfuric acid, and the mixture turned red immediately.  Chromatography silica (10 g) was added to the mixture and stirred overnight.  An initial TLC in DCM was done showing the presence of a number of different compounds.

TLC of SGS17-7-1 against starting material (SGS17-4-1)

TLC of SGS17-7-1 against starting material (SGS17-4-1)

The mixture was left to evaporate, and a red oil was produced.  A sample was sent to the Univerisity of Sydney for NMR.

Reaction performed by: James Arnall, Kieran Connor, Alex Crawford, Duncan Currie, Oliver Hervir, Hugo McCahon-Boersma, Harry Thawley, Erin Sheridan 

Synthesis of 6-ethyl-5-(3-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine (SGS17-6-1)

This reaction is the first attempt at preparing an analogue of pyrimethamine.

Synthesis of SGS17-6-1

Crude 3-isobutoxy-2-(3-(trifluoromethyl)phenyl)pent-2-enenitrile (SGS17-2-1, ~1.5 g, 0.0050 mol, mixture of E and Z isomers) was dissolved in 40 mL DMSO.  Guanidine carbonate (1.16 g, 0.13 mol) was added to the solution and then the mixure was heated to 80 oC for 20 h.

TLC at 13 h

TLC at 13 h in DCM 

The reaction mix was poured into 20 mL of water and extracted with dichloromethane (3 x 25 mL).  The combined organic layers were left to evaporate over three days, and a small amount of red precipitate was formed, along with a red oil.

TLC of SGS17-6-1 in isobutanol against starting material (SGS17-2-1)

TLC of the (unwashed) precipitate in isobutanol showed a number of spots, including two more polar spots (R= 0.5 and 0.33 respectively) which corresponds with those seen in the synthesis of pyrimethamine. A sample was sent of to the University of Sydney for analysis. 

Reaction performed by: James Arnall, Kieran Connor, Alex Crawford, Duncan Currie, Oliver Hervir, Hugo McCahon-Boersma, Harry Thawley, Erin Sheridan 

Synthesis of E-2-(2-(4-bromobenzylidene)hydrazineyl)-6-chloropyrazine

VTM008

23/10/2017

VTM008.jpg

4-bromobenzaldehyde (3.13 g, 16.92 mmol) was added to a solution of 2-chloro-6-hydrazineylpyrazine (2.94 g, 20.30 mmol) in EtOH (70 mL) and stirred at room temperature for 12 hours.The mixture was filtered and washed with EtOH (20 mL) to afford the product (5.21 g, 98 %)  as a light beige solid.

VTM008 P1.jpg
VTM008 P2.jpg

Synthesis of 5-(3,4-difluorophenethoxy)-3-(4-(pyrrolidin-1-yl)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine

VTM007

23/10/2017

VTM007.jpg

 

VTM004 (0.03 g, 0.07 mmol) was dissolved in toluene (2 mL). Pyrrolidine (0.006 g, 0.084 mmol), NaO t Bu (9 mg, 98 µmol), JohnPhos (0.9 mg, 3 µmol) and Pd 2 (dpa) 3 (0.3 mg, 0.35 µmol) were added in this order to the solution and the mixture was heated at 80 °C for 16 hours. TLC analysis showed the presence of large quantities of the starting material.

VTM007 TLC.jpg

The temperature was increased to 100 °C and the reaction left to stir for two weeks.

Synthesis of 5-(3,4-difluorophenethoxy)-3-(4-(pyrrolidin-1-yl)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine

VTM007

23/10/2017

VTM007.jpg

 

VTM004 (0.03 g, 0.07 mmol) was dissolved in toluene (2 mL). Pyrrolidine (0.006 g, 0.084 mmol), NaO t Bu (9 mg, 98 µmol), JohnPhos (0.9 mg, 3 µmol) and Pd 2 (dpa) 3 (0.3 mg, 0.35 µmol) were added in this order to the solution and the mixture was heated at 80 °C for 16 hours. TLC analysis showed the presence of large quantities of the starting material.

VTM007 TLC.jpg

The temperature was increased to 100 °C and the reaction left to stir for two weeks.

Synthesis of 5-(3,4-difluorophenethoxy)-3-(4-(pyrrolidin-1-yl)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine

VTM006

23/10/2017

VTM006.jpg

 

VTM004 (0.063 g, 0.146 mmol) was dissolved in toluene (2 mL). Pyrrolidine (0.012 g, 0.175 mmol), CsCO3 (0.066 g, 0.204 mmol), BINAP (4 mg, 6.6 µmol) and Pd (OAc) 2 (0.98 mg, 4.4 µmol) were added in this order to the solution and the mixture was heated at 80 °C for 16 hours. The temperature was increased to 100 °C and the reaction left to stir for two weeks.

Synthesis of 5-(3,4-difluorophenethoxy)-3-(4-(pyrrolidin-1-yl)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine

VTM006

23/10/2017

VTM006.jpg

 

VTM004 (0.063 g, 0.146 mmol) was dissolved in toluene (2 mL). Pyrrolidine (0.012 g, 0.175 mmol), CsCO3 (0.066 g, 0.204 mmol), BINAP (4 mg, 6.6 µmol) and Pd (OAc) 2 (0.98 mg, 4.4 µmol) were added in this order to the solution and the mixture was heated at 80 °C for 16 hours. The temperature was increased to 100 °C and the reaction left to stir for two weeks.

Synthesis of 5-(3,4-difluorophenethoxy)-3-(4-(pyrrolidin-1-yl)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine

VTM005

23/10/2017

VTM005.jpg

VTM004 (0.037 g, 0.08 mmol) was dissolved in toluene (2 mL). Pyrrolidine (0.007 g, 0.96 mmol), NaO t Bu (0.011 g, 0.11 mmol), BINAP (0.37 mg, 0.6 µmol) and Pd 2 (dpa) 3 (0.7 mg, 0.8 µmol) were added in this order to the solution and the mixture was heated at 80 °C for 16 hours. TLC analysis showed the presence of large quantities of the starting material.

VTM005 TLC 16hours.jpg

The temperature was increased to 100 °C and the reaction left to stir for two weeks.

Synthesis of 3-(4-bromophenyl)-5-(3,4-difluorophenethyl) – [1,2,3]triazolo[4,3-a]pyrazine

VTM004

17/10/2017

VTM004.jpg

 

VTM001 (0.31 g, 2.15 mmol) was dissolved in dry THF (10 mL) and mixed with VTM003 (0.40 g, 1.29 mmol). 60 % NaH (0.08 g, 2.15 mmol) was added and the mixture was stirred at room temperature for 3 hours. The reaction was quenched with 2M HCl (~ 30 mL). The organic layer was extracted (2M HCl 2x20 mL and EtOAc 3x20 mL), dried (MgSO4) and concentrated under reduced pressure. The crude was purified via column chromatography (50% - 80 % EtOAc in petroleum ether) to afford the final product (0.250 g, 45 %) as a yellow solid.

1HNMR VTM004.jpg

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