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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
28th April 2014 @ 07:57

scheme

TM 17-1 (106 mg, 0.25 mmol) was combined with Chloramine T (85 mg, 0.3 mmol, 1.2 eq) in 2-methyl THF (5 mL; more dilute than previously), and the solution stirred at 60 oC for 4.5 hours. The reaction mixture was diluted with 2-Me THF (10 mL), then washed with 10 % sodium sulphite solution (10 mL) and 1M NaOH (2 x 10 mL). The organic layer was evaporated under vacuum to give 60 mg of crude TM 19-1 as a brown powder.

The crude product was purified by automatic column chromatography, using our new Biotage:

TM 19-1_arch.pdf

The second major peak (in green) was thought to be the product, and on evaporation gave 80 mg of yellow product. However, proton NMR (DMSO, 400 MHz) showed that this was in fact beautifully pure starting material, Synthesis of (Z)-N-(3-chloro-2-fluorophenyl)-6-(2-(4-(difluoromethoxy)benzylidene)hydrazinyl)pyrazine-2-carboxamide (TM 17-1).

19-1 1H DMSO 400 MHz.pdf

TM 19-1 purified DMSO.zip

Oxidative cyclisation will be attempted again.

 

InChI:

InChI=1S/C19H13ClF3N5O2/c20-13-2-1-3-14(17(13)21)27-18(29)15-9-24-10-16(26-15)28-25-8-11-4-6-12(7-5-11)30-19(22)23/h1-10,19H,(H,26,28)(H,27,29)/b25-8-

to

InChI=1S/C19H11ClF3N5O2/c20-12-2-1-3-13(16(12)21)25-18(29)14-8-24-9-15-26-27-17(28(14)15)10-4-6-11(7-5-10)30-19(22)23/h1-9,19H,(H,25,29)

HIRAC:

HIRAC.pdf
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Attached Files
28th April 2014 @ 02:00

scheme

TM 16-1 (Synthesis of (Z)-N-(3-chloro-2-fluorophenyl)-6-(2-(4-cyanobenzylidene)hydrazinyl)pyrazine-2-carboxamide (TM 16-1), 98 mg, 0.25 mmol) was combined with Chloramine T (85 mg, 0.3 mmol, 1.2 eq) in 2-methyl THF (5 mL; more dilute than previously), and the solution stirred at 60 oC for 4.5 hours. TLC showed some product, together with much starting material, but as the reaction had already been on for longer than usual workup was attempted. The reaction mixture was diluted with 2-MeTHF (10 mL), then washed with 10 % sodium sulphite solution (10 mL), followed by 1 M NaOH (2 x 10 mL). The organic layer was evaporated to give crude TM 18-1, 81 mg.

 

HIRAC:

HIRAC.pdf
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Attached Files
25th April 2014 @ 02:25

scheme

Crude TM 15-1 (90 mg, 0.32 mmol, see Synthesis of N-(3-chloro-2-fluorophenyl)-6-hydrazinylpyrazine-2-carboxamide (TM 15-1)) was combined with 4-difluoromethoxybenzaldehdye (55 mg, 43 uL, 0.32 mmol, 1 eq) in MeCN (1.5 mL), and AcOH (30 uL, catalytic) added. The reaction was stirred at room temperature for 3.5 hours, when it appeared complete by TLC.

TLC.jpg


Volatiles were removed under vacuum, leaving 156 mg of crude product.

NMR:

1H,DMSO, 400 MHz:

Sample still quite wet. Appears to contain desired product, along with unknown byproduct based on difluoromethoxy benzaldehyde.

TM 17-1 1H DMSO 400 MHz.pdf

InChIs:

InChI=1S/C11H9ClFN5O/c12-6-2-1-3-7(10(6)13)17-11(19)8-4-15-5-9(16-8)18-14/h1-5H,14H2,(H,16,18)(H,17,19)

InChI=1S/C8H6F2O2/c9-8(10)12-7-3-1-6(5-11)2-4-7/h1-5,8H

to

InChI=1S/C19H13ClF3N5O2/c20-13-2-1-3-14(17(13)21)27-18(29)15-9-24-10-16(26-15)28-25-8-11-4-6-12(7-5-11)30-19(22)23/h1-10,19H,(H,26,28)(H,27,29)/b25-8-

HIRAC:

17-1 hirac.pdf

 

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Attached Files
25th April 2014 @ 01:52

scheme

 

Crude TM 15-1 (90 mg, 0.32 mmol, see Synthesis of N-(3-chloro-2-fluorophenyl)-6-hydrazinylpyrazine-2-carboxamide (TM 15-1)) was combined with 4-formylbenzonitrile (42 mg, 0.32 mmol, 1 eq) in MeCN (1.5 mL), and AcOH (30 uL, catalytic) added. The reaction was stirred at room temperature for 4.5 hours, after which volatiles were removed to give 136 mg of crude product.

 

HIRAC:

16-1 hirac.pdf
Linked Posts
Attached Files