Author Archives: Viliyana Tsanova

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

VTM012.jpg

VTM010 (0.05 g, 0.12 mmol) was dissolved in degassed toluene (2 mL). Piperidine (0.025 g, 0.29 mmol), NaOtBu (0.016 g, 0.168 mmol), JohnPhos (1.6 mg, 5.4 μmol) and Pd 2 (dba) 2 (0.3 mg, 0.6 μmol) were added to the solution and stirred at 100°C for two weeks. The reaction was quenched with 2M HCl and the organic layer extracted (EtOAc 3x2 mL). The crude was concentrated under reduced pressure and purified via column chromatography (100% EtOAc).

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

VTM011.jpg

VTM010 (0.05 g, 0.12 mmol) was dissolved in degassed toluene (2 mL). Pyrrolidine (0.02 g, 0.288 mmol), NaO t Bu (0.016 g, 0.168 mmol), JohnPhos (1.6 mg, 5.4 μmol) and Pd 2 (dba) 2 (0.3 mg, 0.6 μmol) were mixed in this order and stirred for two weeks at 100°C. The reaction was quenched (2M HCl). The organic layer was extracted (3x2mL EtOAc). The crude was concentrated in vacuo and purified via column chromatography (EtOAc).

VTM011COLUMN.jpg

NMR analysis suggested that a final product was not formed.

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

VTM010.jpg

 

VTM009 (0.738 g, 1.22 mmol) was added to a solution of 3,4-difluorophenyl-1-ol (0.60 g, 4.16 mmol) in dry THF (30 mL). The mixture was cooled down to 0°C and NaH (60%, 0.17 g, 6.93 mmol)was added. The mixture was stirred at room temperature for 2 hours. The reaction was quenched with HCl (30mL) and the organic layer extracted with EtOAc (3x30 mL) and 2M HCl (3x10 mL). The crude was concentrated under reduced pressure

VTM010 CRUDE (2).jpg

and purified via column chromatography (100% EtOAc) to yield the final product (0.50 g, 95%) as a beige solid.

VTM010 PRODUCT (3).jpg

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.

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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.