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9th December 2016 @ 19:30

O=C(C1=NC(Cl)=CN=C1)C(F)(F)F

 

Reference

Holsinger, L.J., Compounds that Inhibit Protease Cathepsins and HCV Replication. U.S. Patent 2008080785, April 30, 2009.

 UNSUCCESSFUL
 

Substance

Amount

Mol. wt.

mmols

Equiv.

Starting Material

1 g

172.57

5.79

1

trimethylsilyltrifluoro-methane

0.70 g

142.2

4.92

0.85

caesium fluoride

0.880

151.9

5.79

1

tetra-butylammoniun fluoride (1M in THF)

7.25 mL

261.46

7.25

1.25

Concentrated Acetic Acid (17.4 M)

2.8 mL

 

49.2

8.5

Product

 

1-(6-chloropyrazin-2-yl)-2,2,2-trifluoroethan-1-one

1.033 g (Theoretical)

 

0.1127 mg

(Actual)

209.98

4.92 (Theoretical)

 

0.54

(Actual)

0.85 (Theoretical)

 

11% Yield

(Actual)

 

Procedure:

(11/30/16)

 
  1. Dissolved starting material in dimethoxy ethane (15 mL).

  2. Dried CsF (0.88g) under vacuum while heating with a heat gun.

  3. Add trimethylsilyltrifluoro-methane (0.82 g) and CsF (0.880 g) to the starting material solution.

  4. Stirred at 4 degrees celsius for 36 hours.
    (12/2/16)

  5. A TLC was taken to see if the reaction was complete.

  6. The reaction was then concentrated at room temperature in high vac to a brown oil.



    (12/7/16)

  7. The concentrated product was then dissolved in 10 mL of THF, 2.8 mL acetic acid, and treated with 7.25 mL of tetrabutylammonium fluoride.

  8. Reaction was aged for 3 hours and then stopped by diluting the reaction with ethyl acetate (20 mL). A TLC was taken after 3 hours but no change was observed between the starting material before the workup and the product after the workup.

  9. The product was then gravity filtered to remove excess CsF.

  10. Product was washed three times with dilute aqueous sodium bicarbonate solution (0.25M, 100 mL portions).

  11. Washed with brine (100 mL).

  12. Dried over anhydrous magnesium sulfate, then filtered.

  13. Concentrated in vacuo.

1;1 Ethyl Acetate : Hexanes; S → Starting Material, C→ Co-Spot, P → Product
(12/8/16)

  1. Triturated brown oil product in a minimal amount of dichloromethane and hexanes to yield a brown solid.

    1. Yield: 0.1127 g (11%)

 

Analysis: In order to determine the identity of the product, GCMS and NMR were run.

 

GCMS:

 
[Untitled].pdf

The Peak at 207 m/z is the same that was observed last attempt. The mass of the expected product is 209, thus this data suggests that the synthesis was not successful.

 

NMR:

Carbon:
VRBP_TheBurnsFinal_CARBON_cdcl3_01.pdf
 
Proton
VRBP_TheBurnsFinal_PROTON_cdcl3_01.pdf

Both Carbon and PRoton NMR do not match any the expected spectra for the desired product, which further suggests that the synthesis was not successful.

 

Conclusions:

 

Decreasing the temperature of the reaction and decreasing the molar equivalents of the reactants did not improve the outcome of the reaction. Looking back at the previous group that worked on this project, their data suggests that they too were not successful in making this compound. We would suggest that future attempts to synthesize “The Burns” take another synthesis route. One possible synthesis is proposed below:

 

other thing.jpg

 

The reference for this reaction didn’t perform this reaction exactly; however, it might still work. Another option is to come up with a complete new total synthesis for “The Burns” compound.

 
Attached Files
1st December 2016 @ 18:25

O=C(C1=NC(Cl)=CN=C1)C(F)(F)F

 

Reference

Holsinger, L.J., Compounds that Inhibit Protease Cathepsins and HCV Replication. U.S. Patent 2008080785, April 30, 2009.

 
 

Substance

Amount

Mol. wt.

mmols

Equiv.

Starting Material

1 g

172.57

5.79

1

trimethylsilyltrifluoro-methane

1 g

142.2

7.032

1.35

caesium fluoride

0.880

151.9

5.79

1

tetra-butylammoniun fluoride

1.514 g

261.46

5.79

1

Product

 

1-(6-chloropyrazin-2-yl)-2,2,2-trifluoroethan-1-one

1.216 g (Theoretical)

 
 

(Actual)

209.98

5.90 (Theoretical)

 
 

(Actual)

1 (Theoretical)

 
 

(Actual)

 

Procedure:

(11/16/16)

  1. Dissolved starting material in dimethoxy ethane (15 mL).

  2. Dried CsF (1.435g) under vacuum while heating with a heat gun.

  3. Add trimethylsilyltrifluoro-methane (1 g) and CsF (0.880 g) to the starting material solution.

  4. Stirred at room temperature overnight.
    (11/17/16)

  5. The reaction was then concentrated under reduced pressure at room temperature.
    (11/19/16)

  6. The concentrated product was then dissolved in 7.2 mL of THF, 3 mL acetic acid, and treated with 1.514 g of tetrabutylammonium fluoride.

  7. Reaction was aged for 3 hours, while progress was monitored with TLC, and then stopped by diluting the reaction with ethyl acetate (20 mL).

  8. Washed three times with dilute aqueous sodium bicarbonate solution (0.25M, 100 mL portions).

  9. Washed with brine (100 mL).

  10. Dried over anhydrous magnesium sulfate, then filtered.

  11. Concentrated in vacuo.
    (11/21/16)

  12. Attempted to triturated in dichloromethane and hexanes, but it was not successful. TLC was taken showing that product contained significant impurities.
    IMAG0104.jpg
    50% hexanes in EtOAc solvent system, silica gel plate, UV visualization.
    Bottom is starting material, middle is a co-spot and the top is the product.

    (11/21/16)

  13. Attempted to separate the different spots observed in the TLC on the biotage. Several fractions collected containing mixtures of different products.

  14. All the fractions were spotted with TLC and those containing only one product were separated. Fraction 20 which may contain the starting material was separated and concentrated in vacuo. Fractions 23, 24, and 25, which may contain the product, were concentrated. And fractions 12-16 were also concentrated which contain an unknown byproduct. Fractions 21 and 22, which contained a mixture of two products were concentrated together for further separation.
    Notes: Some other oil seemed to have made its way into the fraction 20 concentrate, so it may need further purification.


 

(11/28/16)

  1. Prepared fraction 23-25 and fraction 20 for NMR. Both samples were readily dissolved in chloroform.

  2. The fractions were dissolved in acetonitrile and analyzed via Gas Chromatography.

    Fractions 23 - 25:


    Fraction 20:

 
 
  1. Fractions 23-25 and 20 were dissolved in chloroform and analyzed via NMR

Fraction 23-25  Carbon NMR

VRBPBurns2325CarbonNMRchloroform.JPG

Fraction 23-25 Proton NMR

VRBPBurns2325ProtonNMRchloroform.JPG

 
 
 
 
 

Fraction 20 Carbon NMR

VRBPBurns20CarbonNMRchloroform.JPG

Fraction 20 Proton NMR

VRBPBurns20ProtonNMRchloroform.JPG

 
 

Though it was predicted  Fraction 23-25 would be the location of our main product, NMR results suggest product is actually present in Fraction 20. There are many unidentifiable peaks present in both NMR spectra of Fraction 23-25 compared to those of Fraction 20. Proton NMR of Fraction 20 shows all anticipated peaks, though the strong peak at 4 ppm remains to be identified. Carbon NMR also came out as expected for desired product except for small unidentifiable peaks at approximately 50 ppm and 165 ppm. These impurities suggests that a synthesis of 1-(6-chloropyrazin-2-yl)-2,2,2-trifluoroethane-1-one should be attempted again, at a lower temperature and lower equivalence of trimethylsilyltrifluoro-methane.

5th November 2016 @ 16:00



2nd November 2016 @ 17:30

Purpose: In order to work out the issues seen in the reductive amination step (see Lab Notebook), more precursor needs to be prepared.

10-31-16 step 1 reaction.JPG

Image courtesy of Eliana von  Krusenstiern and Claudia Nguyen. Values on table represent both what we did and the yeild values that Claudia and Eliana produced when they ran this reaction.

Procedure:

(10/31)

  1. Malononitrile (0.887 g, 13.42 mmol) was dissolved in 85 mL of dry THF under argon.

  2. NaH in mineral oil suspension (0.45g, 60% NaH by mass) was added slowly to the mixture prepared above and the solution was allowed to age for 30 mins.

  3. 2,6-dichloropyrazine (1g, 6.71mmol) was dissolved in dry THF (25 mL). Some white solid impurity remained undissolved, which was also reported by Eliana and Claudia in their lab notebook. The solution was added dropwise to the aged solution under argon.

  4. (11/2/16)
    The mixture was green-yellow and was placed in Reflux at 60 ℃ for 5 hours. The solution dried out and another 25 mL of dry THF was added and the solution refluxed for another 5 hours. The reactions was losing solvent to a hole in the glassware.

  5. (11/3/16)
    To acidify the solution, 20 mL of 1M HCL was added to the mixture. The solution turned deep red.

  6. Ethyl acetate (50 mL) was added to improve separation between the organic and aqueous layers, and the organic layer was separated from the aqueous layer.

  7. (11/4/16)
    The organic phase was separated and volatiles removed in vacuo.

  8. The residue was partitioned between H2O (150 mL) and Et2O (150 mL) to wash away inorganic salts and excess malononitrile. The organic layer was then washed with H2O and brine and then dried. The solution was a deep red/orange color.

  9. Significant product was lost during the extraction due to accidental disposal. A brown solid contaminant was observed in the organic layer.

  10. (11/7/16)
    The brown solid observed above was removed via vacuum filtration and the solution was concentrated in vacuo. Our final product was a dark brown liquid. Water vapor around the neck of the r.b. was seen in vacuo, which indicates the presence of some water contamination in the final product (0.13g).

Observation and Analysis:

TLC:

After Reflux:

10% methanol in EtOAc solvent system, silica gel plate, UV visualization

Left = After 10 horus reflux, Right = After 5 hours reflux

Rf(SM) = 0.75, Rf(Prod)= 0.3

The TLC suggests that the reflex reaction was successful and product was formed.

After Extractions:

20161107_150253.jpg

10% methanol in EtOAc solvent system, silica gel plate, UV visualization

Conclusions:


The sysnthesis was unsuccessful. TLC analysis shows that whatever was isolated is neither our starting material or our product. The product was likely lost due to error during the extraction step as noted above. We found a commercially available source to purchase a further intermediate, so we will continue with that.