Daraprim Synthesis

 

This reaction was performed by Heath, Ronan, Francis, Nathan, Jonah, Oliver, Daniel, Stuart, Jacky and Erin.

3-(Trifluoromethyl)phenylacetonitrile (11.4g, 0.0617 mol) was added to ethyl propanoate (5.35 g, 0.0524 mol) and THF (100 mL). Potassium tert-butoxide (17.0 g, 0.152 mol) was added with stirring. The reaction mixture immediately turned red and warmed. The reaction was then placed in a water bath and the temperature maintained at 40°C with stirring for 7 h. The potassium tert-butoxide dissolved after 30 min of stirring.

HCl (80 mL, 1 M) was added to stop the reaction, then DCM (60 mL) was added. The intense red organic layer was collected, and the aqueous layer extracted with DCM (30 mL x 2). The organic layer was dried over sodium sulfate and then filtered.

A TLC was run in 25:75 EtOAc:hex, and showed that the crude mixture contains some starting material and two coloured spots. This is consistent with the expected keto and enol tautomers.

 

Reaction performed by Heath, Jonah, Ronan, Francis, Stuart, Daniel, Oliver, Jacky, Nathan and Erin!

4-(trifluoromethyl)phenylacetonitrile (10 g, 0.054 mol) was added to ethyl propanoate (5.52 g, 0.055 mol) and THF (100 mL), and stirred until dissolved. Potassium tert-butoxide (12.5 g, 0.112 mol) was added with stirring.  The reaction immediately turned red and warmed to ~40 ^oC.  The reaction was kept at this temperature and stirred for 7 h.

HCl (80 mL, 1 M) was added to stop the reaction, then DCM (40 mL) was added. The intense red organic layer was collected, and the aqueous layer extracted with DCM (20 mL x 2). The organic layer was dried over sodium sulfate and then filtered.

TLCs were run in 10:90 EtOAc:hex and 25:75 EtOAc:hex, and both showed that the crude mixture contains some starting material and two coloured spots.  This is consistent with the expected keto and enol tautomers. 

Reaction performed by Stuart, Heath and Francis (contributions by Jonah, Ronan, Nathan, Jacky, Daniel, Oliver and Erin) 

This is a repeat of SGS 10-2 to verify synthesis and yield of Daraprim.

 (4-chloropenyl)acetonitrile (11.426 g, 75 mmol) was added to ethyl propanoate (7.698 g, 75 mmol) and THF (50 mL). Potassium tert-butoxide (24 g, 214 mmol) was added with stirring. The reaction mixture immediately turned red and warmed. The reaction was then placed in a water bath and the temperature maintained at 40°C with stirring for 7 h. The potassium tert-butoxide dissolved after 30 min of stirring.

HCl (80 mL, 1 M) was added to stop the reaction, then DCM (60 mL) was added. The intense red organic layer was collected, and the aqueous layer extracted with DCM (30 mL x 2). The organic layer was dried over sodium sulfate and then filtered.

TLCs were run in 10:90 EtOAc:hex and 25:75 EtOAc:hex, and both showed that the crude mixture contains some starting material and two coloured spots.  This is consistent with the expected keto and enol tautomers. 

 

TLC 10:90 EtOAc:hex. R_f values of major spots are 0.1 and 0.52 (of darker and lighter respectively).

TLC 25:75 EtOAc:hex. R_f values of the largest spots are 0.3 and 0.74 (darker and lighter respectively).

 

 

 

SGS 17-5-1

N#C/C(C1=CC=C(C(F)(F)F)C=C1)=C(OCC(C)C)/CC

InChI=1S/C16H18F3NO/c1-4-15(21-10-11(2)3)14(9-20)12-5-7-13(8-6-12)16(17,18)19/h5-8,11H,4,10H2,1-3H3/b15-14+

  

SGS 17-6-1

NC1=C(C(CC)=NC(N)=N1)C2=CC(C(F)(F)F)=CC=C2

InChI=1S/C13H13F3N4/c1-2-9-10(11(17)20-12(18)19-9)7-4-3-5-8(6-7)13(14,15)16/h3-6H,2H2,1H3,(H4,17,18,19,20)

 

SGS 17-7-1

N#C/C(C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1)=C(OCC(C)C)/CC

InChI=1S/C17H17F6NO/c1-4-15(25-9-10(2)3)14(8-24)11-5-12(16(18,19)20)7-13(6-11)17(21,22)23/h5-7,10H,4,9H2,1-3H3/b15-14+

SGS 17-8-1

NC1=C(C(CC)=NC(N)=N1)C2=CC=C(C(F)(F)F)C=C2

InChI=1S/C13H13F3N4/c1-2-9-10(11(17)20-12(18)19-9)7-3-5-8(6-4-7)13(14,15)16/h3-6H,2H2,1H3,(H4,17,18,19,20)

 

 

 

  

SGS 17-3-1

O=C(CC)C(C#N)C1=CC=C(C(F)(F)F)C=C1

InChI=1S/C12H10F3NO/c1-2-11(17)10(7-16)8-3-5-9(6-4-8)12(13,14)15/h3-6,10H,2H2,1H3

SGS 17-4-1

O=C(CC)C(C#N)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1

InChI=1S/C13H9F6NO/c1-2-11(21)10(6-20)7-3-8(12(14,15)16)5-9(4-7)13(17,18)19/h3-5,10H,2H2,1H3

SGS 17-5-1

N#C/C(C1=CC=C(C(F)(F)F)C=C1)=C(OCC(C)C)/CC

InChI=1S/C16H18F3NO/c1-4-15(21-10-11(2)3)14(9-20)12-5-7-13(8-6-12)16(17,18)19/h5-8,11H,4,10H2,1-3H3/b15-14+