Tag Archives: Malaria

Repeated SnAr Reaction

NH1-007

SNAr reaction 

Mechanism

 
week 3.jpg


Reagent Equivalent Molecular Weight mMol Quantity
4-flurophenylethan-1-ol 2 140.00 7.10 0.9mL
Sodium Hydride 2 24.00 14.06 540.00mg
Triazolopyrazine 1 309.55 3.55 1100.00mg
THF - - - 30.00mL

Procedure

THF (30.00mL) was added to Triazolopyrazine (1100.00mg, 3.5mmol) and the mixture was stirred under a nitrogen atmosphere. 4-flurophenylethan-1-ol (0.9mL, 7.10mmol) was added and the mixture was cooled in ice. NaH (540.00mg, 14.06mmol) was added and the dark brown mixture was stirred and left under a nitrogen atmosphere for 2 hours (RMTP).  

 
nitrogen atmosphere.jpg

TLC analysis (Petroleum ether/EtOAc 25:75) confirmed that the reaction had worked.

HCl (2M) and EtOAc (60.00mL) were added to separate the solution, the sample was filtered. The solution was dried over MgSO4 which was filtered off and rinsed with EtOAc. The solution was evaporated in vacuo. 

The crude was purified via flash column chromatography (100% Ethyl acetate). TLC analysis (100% ethyl acetate) showed that test tubes 19-57 contained the product.

repeat 1-15.jpg
repeat 17-32.jpg
repeat 33-47.jpg
repeat final 57.jpg

The product was collected and dried in vacuo. This formed golden crystals.

1H NMR of the product NH-1-007 was taken in chloroform. The NMR showed the desired structure.

The product was weighed and dissolved in CDCl3 to ensure that no product was left in the round bottom flask. This was left to dry. The product was re-weighed (360.00mg, 0.87mol, 24%)

Analysis of product NH-1-004

δH(400 MHz, CDCl3: 9.01 (3H, s, CHAr), 7.61 (4H, d, CHAr), 6.91 (2H, d, CHAr), 6.78 (2H, d, CHAr) 4.42 (6H, s, CHAr) and 2.94 (6H, s, CHAr).

 

Further Analysis of NH1-005-3

NH1-005-3= NH1-006

Further Analysis of NH1-006

Mechanism

mechanism final step.jpg

 

Procedure

TLC was carried out in three different solvents which is shown below. The first plate was carried out in 100% EtOAc, the second plate was carried out in 5% MeOH/ 95% DCM and the third plate was carried out in 50% EtOAC/ 50% Pet.Ether.

TLC 3 different solvents.jpg

NH1-006 was purified via flash column chromatography (2% MeOH/ 98% DCM) on a small scale.

small scale FCC.jpg

The TLC concluded a potential product in vials 3-6.  These vials were collected and dried in vacuo.

TLC NH-006 fluoro.jpg

1H NMR and 19F NMR of the product NH-1-006 was taken in chloroform.

Analysis of product NH-1-006

δH(400 MHz, CDCl3: 9.95 (1H, s, CHAr), 7.52 (4H, d, CHAr), 6.80 (5H, q, CHAr), 6.60 (5H, q, CHAr) 4.37 (2H, d, CHAr), 3.36 (4H, s, CHAr), 2.97 (2H, d, CHAr) and 2.05 (5H, s, CHAr).

δF(370Mhz), CDCl3: -115.4 (1F)

The reaction showed a potential product. However, as this reaction was carried out using such a small scale it is difficult to confirm that the reaction had worked to completion. Therefore this reaction needs to be repeated on a larger scale.

Biological Data from Dundee – Oct 2017 Compounds

A set of 26 Series 4 Triazolopyrazine compounds were sent to have their efficacy evaluated against Plasmodium flaciparum in-vitro at Dundee (GitHub issue #8)

The data has been posted here

Strings:

MMV Number SMILES InChI InChI Key
MMV1576784 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC/C4=C/BBBBBBBBBB4)N32 InChI=1S/C16H22B10F2N4O2/c27-16(28)34-12-3-1-10(2-4-12)15-31-30-13-8-29-9-14(32(13)15)33-6-5-11-7-17-19-21-23-25-26-24-22-20-18-11/h1-4,7-9,16-26H,5-6H2/b11-7- AGPVLTOPROUGPQ-XFFZJAGNSA-N
MMV1576785 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(N4CCOCC4)C5=CC=CC=C5)N32 InChI=1S/C24H23F2N5O3/c25-24(26)34-19-8-6-18(7-9-19)23-29-28-21-14-27-15-22(31(21)23)33-16-20(17-4-2-1-3-5-17)30-10-12-32-13-11-30/h1-9,14-15,20,24H,10-13,16H2 NLNZVWQRJHUCOA-UHFFFAOYSA-N
MMV1576786 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCCN4CC5(COC5)C4)N32 InChI=1S/C19H19F2N5O3/c20-18(21)29-14-3-1-13(2-4-14)17-24-23-15-7-22-8-16(26(15)17)28-6-5-25-9-19(10-25)11-27-12-19/h1-4,7-8,18H,5-6,9-12H2 CWOUGAWUCYKRFC-UHFFFAOYSA-N
MMV1576787 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC4=CC=C(CO)C=C4)N32 InChI=1S/C20H16F2N4O3/c21-20(22)29-16-7-5-15(6-8-16)19-25-24-17-9-23-10-18(26(17)19)28-12-14-3-1-13(11-27)2-4-14/h1-10,20,27H,11-12H2 VIQWBWLDUDXSBJ-UHFFFAOYSA-N
MMV1576788 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCCC4COC4)N32 InChI=1S/C17H16F2N4O3/c18-17(19)26-13-3-1-12(2-4-13)16-22-21-14-7-20-8-15(23(14)16)25-6-5-11-9-24-10-11/h1-4,7-8,11,17H,5-6,9-10H2 VMXSRABLXQMXLK-UHFFFAOYSA-N
MMV1576789 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC4(OCCO4)C5=CC(F)=C(F)C=C5)N32 InChI=1S/C22H16F4N4O4/c23-16-6-3-14(9-17(16)24)22(32-7-8-33-22)12-31-19-11-27-10-18-28-29-20(30(18)19)13-1-4-15(5-2-13)34-21(25)26/h1-6,9-11,21H,7-8,12H2 UAZNIGDYRZOARG-UHFFFAOYSA-N
MMV1576790 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC/C4=C/BBBBB[BH]5[BH]([H]5)BB4)N32.[Cs+] InChI=1S/C16H22B9F2N4O2.Cs/c26-16(27)33-12-3-1-10(2-4-12)15-30-29-13-8-28-9-14(31(13)15)32-6-5-11-7-17-19-20-21-23-25-24(34-25)22-18-11;/h1-4,7-9,16-25H,5-6H2;/q;+1/b11-7-; GZUNPULXOLJYSG-AJULUCINSA-N
MMV1576791 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(N(CC)CC)C4=CC(F)=C(F)C=C4)N32 InChI=1S/C24H23F4N5O2/c1-3-32(4-2)20(16-7-10-18(25)19(26)11-16)14-34-22-13-29-12-21-30-31-23(33(21)22)15-5-8-17(9-6-15)35-24(27)28/h5-13,20,24H,3-4,14H2,1-2H3 FFKUJTSUMDVIQH-UHFFFAOYSA-N
MMV1576792 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(N(CC)C)C4=CC(F)=C(F)C=C4)N32 InChI=1S/C23H21F4N5O2/c1-3-31(2)19(15-6-9-17(24)18(25)10-15)13-33-21-12-28-11-20-29-30-22(32(20)21)14-4-7-16(8-5-14)34-23(26)27/h4-12,19,23H,3,13H2,1-2H3 XPBTWBXREHLVRP-UHFFFAOYSA-N
MMV1576793 FC1=CC(CCOC2=CN=CC3=NN=C(C4=CC=C(C(N)=O)C=C4)N32)=CC=C1F InChI=1S/C20H15F2N5O2/c21-15-6-1-12(9-16(15)22)7-8-29-18-11-24-10-17-25-26-20(27(17)18)14-4-2-13(3-5-14)19(23)28/h1-6,9-11H,7-8H2,(H2,23,28) INLVQLIAJLYDGP-UHFFFAOYSA-N
MMV1576794 FC1=CC(CCOC2=CN=CC3=NN=C(C4=CC(C(N)=O)=CC=C4)N32)=CC=C1F InChI=1S/C20H15F2N5O2/c21-15-5-4-12(8-16(15)22)6-7-29-18-11-24-10-17-25-26-20(27(17)18)14-3-1-2-13(9-14)19(23)28/h1-5,8-11H,6-7H2,(H2,23,28) SUVZMBHYRLCWQO-UHFFFAOYSA-N
MMV1576795 FC1=CC(CCOC2=CN=CC3=NN=C(C4=CC=C(C(N(C)C)=O)C=C4)N32)=CC=C1F InChI=1S/C22H19F2N5O2/c1-28(2)22(30)16-6-4-15(5-7-16)21-27-26-19-12-25-13-20(29(19)21)31-10-9-14-3-8-17(23)18(24)11-14/h3-8,11-13H,9-10H2,1-2H3 VILLYIKHHVUPAT-UHFFFAOYSA-N
MMV1576796 BrC1=NN=C2C=NC=C(OCCC3=CC(F)=C(F)C=C3)N21 InChI=1S/C13H9BrF2N4O/c14-13-19-18-11-6-17-7-12(20(11)13)21-4-3-8-1-2-9(15)10(16)5-8/h1-2,5-7H,3-4H2 MNOZFILPXCZGRJ-UHFFFAOYSA-N

Crude NMR Data for SGS 17-3-1, SGS 17-4-1 and SGS 17-5-1

 

 

 

  

SGS 17-3-1

SGS17-3-1proton.png
SGS17-3-1proton.jcamp
SGS17-3-1proton.mnova

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

SGS17-4-1.png
SGS17-4-1.jcamp
SGS17-4-1.mnova

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

SGS17-5-1.png
SGS17-5-1.jcamp
SGS17-5-1.mnova

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+

Crude NMR Data for SGS 17-3-1, SGS 17-4-1 and SGS 17-5-1

 

 

 

  

SGS 17-3-1

SGS17-3-1proton.png
SGS17-3-1proton.jcamp
SGS17-3-1proton.mnova

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

SGS17-4-1.png
SGS17-4-1.jcamp
SGS17-4-1.mnova

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

SGS17-5-1.png
SGS17-5-1.jcamp
SGS17-5-1.mnova

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+

Synthesis of 6-ethyl-5-(4-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine (SGS17-8-1)

This reaction is the second attempt at preparing an analogue of pyrimethamine, following the method used for SGS 16-4.

Synthesis of SGS17-8-1

Deep purple crude 3-isobutoxy-2-(4-(trifluoromethyl)phenyl)pent-2-enenitrile (SGS17-5-1, ~1.7 g, 5.6 mmol, mixture of E and Z isomers) was dissolved in 20 mL DMSO.  Guanidine hydrochloride (1.173 g, 12.28 mmol) was added to the solution along with sodium methoxide (1.530g, 28.32 mmol), and then the mixure was heated at 80 oC for 40 h. After this time the reaction mixture turned a dark red. 

Reaction was worked up with addition of 30 mL of water, and then extracted with DCM (2 x 40 mL). Intense colour of reaction mixture made extraction difficult. 

TLC of SGS17-8-1 against SGS17-5-1 in isobutanol

TLC of CP SGS17-8-1 Against SM SGS17-5-1 in Isobutanol 

In the reaction mixture, the spot at Rf = 0.9 is orange in colour, and the spot at R= 0.6 appears colourless. In the starting material the spot 0.6 appears orange coloured and