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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 a saturated aqueous solution of  (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 cream solid (5.39 g, 99.6% crude yield) NMR shows that DMF is still present in crude sample but used in next reaction.

 

300 MHz NMR Data:

Crude

AEW 301-1 crude 300 MHz.png
AEW 301-1 crude 300.jcamp
AEW 301-1.mnova
AEW 301-1 crude.zip

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
AEW 301-1.png
AEW 301-1.cdxml
AEW 301-1 crude 300 MHz.png
AEW 301-1 crude 300.jcamp
AEW 301-1.mnova
AEW 301-1 crude.zip