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27th July 2016 @ 02:44

requires HRMS, IR and 19F NMR 

Crude AEW 102-11 was dissolved in MeOH (20 mL) and a few drops of H2SO4 was added and the reaction mixture stirred at 80 ˚C for 16 hours.

 Poured over water (40 mL) and extracted into EtOAc (30 mL x3). Combined organic layers were dried over MgSO4, filtered and evaporated to give a yellow oil. Crude material was filtered by flash column chromatography over silica (10% EtOAc in Petrol to EtOAc) to give a yellow oil (x g, x mmol, x% yield over three steps).

 

Data:

TLC (30% EtOAc in hexane)

 

Ref NMR from CRO:

Methyl ESTER NMR.pdf

 

Hazard and Risk Assessment:

HIRAC AEW 103-1.pdf

 

InChi:

InChI=1S/C8H6F2O3/c9-5-2-1-4(3-6(5)10)7(11)8(12)13/h1-3,7,11H,(H,12,13)

to

InChI=1S/C9H8F2O3/c1-14-9(13)8(12)5-2-3-6(10)7(11)4-5/h2-4,8,12H,1H3

Literature:

Possible useful paper for chiral HPLC of enantioenriched compounds: JACS, 2002, 124, 2870 (http://pubs.acs.org/doi/abs/10.1021/ja0255047?source=chemport)


27th July 2016 @ 02:32

Scaled up for the synthesis of left-hand side chain of some 'Frontrunner Molecules"

GitHub Issue #400

Outcome

Rationale

Attempt to couple 3-chloro-4-fluoroaniline to carboxylic acid for resynthesis.

Procedure

6-chloropyrazine-2-carboxylic acid (3.00 g, 18.9 mmol, 1 equiv.), 3-chloro-4-fluoroaniline (2.75 g, 18.9 mmol, 1 equiv.) and DIPEA (6.59 mL, 4.89 g, 37.9 mmol, 2 equiv.) were dissolved in DMF (30 mL) and cooled to 0 ˚ C. T3P (50% in EtOAc, 16.9 mL, 28.4 mmol, 1.5 equiv.) was added dropwise with stirring, and the reaction mixture was kept at 0 oC for 15 min, then stirred at rt overnight.

 

The reaction mixture was diluted with EtOAc (60 mL), washed with an aqueous solution of HCl (1M, 3 x 40 mL) to remove excess amine. The combined aqueous layers was extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with water (2 x 20 mL), then brine (20 mL) and concentrated under reduced pressure to give the crude product as a pale brown tar.

TLC analysis showed the amine had been removed (top spot on TLC) but that a large quantity of acid remained which had not been visible in reaction mixture TLC - should have left for longer.

The crude product was purified by automated flash chromatography on silica (100 g column, ethyl acetate in hexanes) to give three fractions.

 

200 MHz NMR Data:

Crude

Hazard and Risk Assessment:

HIRAC AEW 297-1.doc

Strings:

InChI=1S/C5H3ClN2O2/c6-4-2-7-1-3(8-4)5(9)10/h1-2H,(H,9,10)

to

InChI=1S/C11H6ClF3N4O/c12-9-5-16-4-7(19-9)10(20)18-6-1-2-17-8(3-6)11(13,14)15/h1-5H,(H,17,18,20)

 

ClC1=CN=CC(C(O)=O)=N1

to

ClC1=CN=CC(C(NC2=CC=NC(C(F)(F)F)=C2)=O)=N1


Attached Files
27th July 2016 @ 01:26

Synthesised for PfATP4  'Frontrunner Molecules"

GitHub Issue #400

 

Procedure:

Crude AEW 299-1 (~2.01 mmol, 1 equiv.) was suspended in CH2Cl2 (20 mL) and PhI(OAc)2 (647 mg, 2.01 mmol, 1 equiv.) was added. The reaction mixture was stirred at rt.

 

Data:

TLC

AEW 300-1 EtOAc.JPG
6 hours EtoAc


Hazard and Risk Assessment:


Strings:

InChI=1S/C19H13F5N6O2/c20-18(21)32-13-3-1-11(2-4-13)8-27-30-16-10-25-9-14(29-16)17(31)28-12-5-6-26-15(7-12)19(22,23)24/h1-10,18H,(H,29,30)(H,26,28,31)/b27-8+

to

InChI=1S/C19H11F5N6O2/c20-18(21)32-12-3-1-10(2-4-12)16-29-28-15-9-25-8-13(30(15)16)17(31)27-11-5-6-26-14(7-11)19(22,23)24/h1-9,18H,(H,26,27,31)

O=C(NC1=CC=NC(C(F)(F)F)=C1)C2=NC(N/N=C/C3=CC=C(OC(F)F)C=C3)=CN=C2

to

FC(F)OC(C=C1)=CC=C1C2=NN=C3N2C(C(NC4=CC=NC(C(F)(F)F)=C4)=O)=CN=C3

 

Linked Entries
Attached Files
26th July 2016 @ 08:31

Synthesised for PfATP4  'Frontrunner Molecules"

GitHub Issue #400


 

Crude AEW 298-1 (600 mg, 2.01 mmol, 1 equiv.) was suspended in EtOH (20 mL) and  4-(difluoromethoxy)benzaldehyde (0.27 mL, 2.01 mmol, 1 equiv.) was added to the reaction mixture. The reaction was stirred at rt overnight. A bright yellow suspension was formed, solvent was removed in vacuo and the crude yellow product dried further at the high vac (quantitive yield). Used directly as crude in next step: Synthesis of 3-(4-(difluoromethoxy)phenyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyrazine-5-carboxamide (AEW 300-1).


Data:

 

Hazard and Risk Assessment:


Strings:

InChI=1S/C11H9F3N6O/c12-11(13,14)8-3-6(1-2-17-8)18-10(21)7-4-16-5-9(19-7)20-15/h1-5H,15H2,(H,19,20)(H,17,18,21)

to

InChI=1S/C19H13F5N6O2/c20-18(21)32-13-3-1-11(2-4-13)8-27-30-16-10-25-9-14(29-16)17(31)28-12-5-6-26-15(7-12)19(22,23)24/h1-10,18H,(H,29,30)(H,26,28,31)/b27-8+

O=C(NC1=CC=NC(C(F)(F)F)=C1)C2=NC(NN)=CN=C2

to

O=C(NC1=CC=NC(C(F)(F)F)=C1)C2=NC(N/N=C/C3=CC=C(OC(F)F)C=C3)=CN=C2

 

Attached Files
26th July 2016 @ 06:39

Procedure:

Reaction started at 4:00pm 26th Jul

5-Chloro-[1,2,4]triazolo[4,3-a]pyrazine (100mg,0.65mmol, 1 equiv.) and NBS (104mg, 0.58mmol, 0.9euqiv.) was combined in a flask.  DMF (5ml) was added to the flask. Reaction mixture was stirred at room temperature

HIRAC

HM3-4.docx

Log

27th Jul 2016

TLC showed no reaction happenned. Another 0.9 equiv of NBS was added.

Attached Files