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30th April 2014 @ 04:50

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See also: Synthesis of (6-chloropyrazin-2-yl)(4-fluoroisoindolin-2-yl)methanone (AEW 126-1)

Procedure:

4-Bromoisoindoline hydrochloride (606 mg, 2.59 mmol) grey solid was suspended in EtOAc (30 mL) in a separating funnel and then an aqueous solution of sodium hydroxide (20 mL, 2 M) was added and the mixture was shaken until all of the salt had dissolved and the organic layer turned from clear and colourless to pale brown. The aqueous layer was re-extracted with EtOAc (30 mL) and then combined organic layers were washed with brine (20 mL), dried (MgSO4), filtered and evaporated to give a brown semi-solid (~xx mg).

6-Chloropyrazine-2-carboxylic acid (410 mg, 2.59 mmol, 1 equiv.), 4-bromoisoindoline (~xxmg, ~1.51 mmol, 1 equiv.) and DIPEA (0.90 mL, 5.17 mmol, 2 equiv.) were stirred in DMF (3 mL) at 0 ˚C. T3P (50% by wt in EtOAc, 1.5 equiv.) was added dropwise at 0 ˚C. The reaction mixture turned instantly solid on addition of some T3P and so DMF (12 mL) was added and the mixture cooled to 0˚C before resuming addition.

The reaction mixture was stirred for 15 min at this temperature and then allowed to reach room temperature, whilst stirring overnight. After 18 hours, new spot and faint spot on baseline - thought to be complete so work-up.

The reaction mixture was diluted by the addition of EtOAc, washed with water (x 3), brine, dried (MgSO4), filtered and evaporated to give a pale purple solid. NMR showed product and both SM.

Solid was resubmitted to the reaction conditions (15 mL DMF) and stirred for 20 hours. Following work-up NMR showed product and amine SM. Solid was dissolved in acetone and filtered to give 560 mg of an off-white solid. NMR shows clean mixture of product and amine SM.

Column:

Data:

 

Hazard and Risk Assessment:

See Synthesis of 6-chloro-N-(2-chloro-5-fluorobenzyl)pyrazine-2-carboxamide (AEW 121-1)

and Synthesis of N-(3,5-bis(trifluoromethyl)phenyl)-3-(4-(difluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine-5-carboxamide (AEW 120-1)

InChi:

InChI=1S/C13H9BrClN3O/c14-10-3-1-2-8-6-18(7-9(8)10)13(19)11-4-16-5-12(15)17-11/h1-5H,6-7H2

Attached Files
AEW 143-1.cdxml
AEW 143-1.png