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31st October 2013 @ 23:52

According to Althea's method AT-6-4. Spoke to Althea who confirmed the use of sealed tube, not Q-tube. Failed reaction AEW 100-2 may have been a result of a perished seal. 

Procedure:

AT-5 (200 mg, 0.8 mmol, 1.0 equiv.), isopropanol (4 mL) and ammonia (8 mL) were stired in a sealed tube and then heated to 120 ˚C [blast shield in place] for 6 hours (according to AT-6-4). 

Asked colleague to switch the reaction off but unfortunately they forgot and reaction remained stirring for 20 h extra. 

Reaction stopped and solvents removed in vacuo. Crude 1H NMR showed the desired product and also the de-brominated product AEW 100-3-B.

Data:

AEW 100-3 crude proton.pdf
AEW 100-3.zip

Hazard and Risk Assessment:

See: Amination of bromochlorothienopyrimidine (AT-6-4) 

InChi:

InChI=1S/C6H2BrClN2S/c7-4-1-3-5(11-4)6(8)10-2-9-3/h1-2H

to 

InChI=1S/C6H4BrN3S/c7-4-1-3-5(11-4)6(8)10-2-9-3/h1-2H,(H2,8,9,10)

Attached Files
31st October 2013 @ 02:01

Reaction did not work

According to Althea's method AT-6-4

Procedure:

AT-5 (200 mg, 0.8 mmol, 1.0 equiv.), isopropanol (4 mL) and ammonia (8 mL) were stired in a sealed tube and then heated to 120 ˚C [blast shield in place] for 6 hours (according to AT-6-4). Some of the reaction mixture seeped through the seal..not sure why. Reaction mixture was evaporated but some water remained and so extraction into EtOAc (30 mL) was performed and the organic layers were washed with brine before being dried in vacuo. NMR showed SM and impurities from previous reaction (prior to bromination.

Need to ask Althea if the reaction was performed in the Q-tube or if the reaction just didn't work because of the leaking seal.

Data:

AEW 100-2 crude reaction - SM.pdf
AEW 100-2 crude reaction - SM.mnova
AEW 100-2.zip

Hazard and Risk Assessment:

See: Amination of bromochlorothienopyrimidine (AT-6-4) 

InChi:

InChI=1S/C6H2BrClN2S/c7-4-1-3-5(11-4)6(8)10-2-9-3/h1-2H

to 

InChI=1S/C6H4BrN3S/c7-4-1-3-5(11-4)6(8)10-2-9-3/h1-2H,(H2,8,9,10)

Attached Files
24th October 2013 @ 00:58

Attempt at synthesis of AT 6 without high pressure tube - more amenable to scale.

Didn't work - could try with isopropanol or stick to Althea's high pressure method.

NBProton of AT 6 recorded in MeOD, but in CDClooking for: 1H NMR (400 MHz, CDCl3): δ 7.40 (1H, s), 8.33 (1H, s).

Procedure:

Ammonia (28% w/v in H2O, 3 mL) was added to AT 5 (100 mg, 0.4 mmol), insoluble. The mixture was stirred at 100 ˚C for 48 h. Extracted into EtOAc, washed with water, brine, dried over MgSO4, filtered and evaporated to give a crude yellow solid - SM.

Data:

 

AEW 100-1 crude.pdf
AEW 100-1 crude.mnova
AEW 100-1.zip

Hazard and Risk Assessment:

See: Amination of bromochlorothienopyrimidine (AT-6-4) but without sealed tube or isopropanol.

InChi:

InChI=1S/C6H2BrClN2S/c7-4-1-3-5(11-4)6(8)10-2-9-3/h1-2H

to 

InChI=1S/C6H4BrN3S/c7-4-1-3-5(11-4)6(8)10-2-9-3/h1-2H,(H2,8,9,10)

Attached Files
23rd October 2013 @ 04:56

To MNR 99-3 (2.10 g, 12.3 mmol, 1.0 equiv.) in THF (120 mL) at -78 C was added n-BuLi (7.38 mL, 18.5 mmol, 1.5 equiv.) dropwise and the reaction mixture stirred at -78 C for 30 minutes. Bromine (1.26 mL, 24.6 mmol, 2.0 equiv.) was added dropwise and the reaction mixture warmed to rt and stirred for 1 h. Some SM but also product on TLC plate. The reaction mixture was diluted with an aqueous solution of sodium thiosulfate (150 mL) and extracted into ethyl acetate (3 x 100 mL). The combined organic extracts were dried (MgSO4), concentrated under reduced pressure and the residue purified by flash column chromatography (7:1 hexanes:ethyl acetate) to give the desired product as a pale yellow solid (1.73 g, 6.93 mmol, 56% yield) and a second fraction containing SM.

Data:

Crude NMR

AEW 99-1.cdxml
AEW 99-1 crude proton.pdf

After column

AEW 99-1 first spot.pdf
AEW 99-1 first spot.mnova
AEW 99-1 col frac A.zip

Hazard and Risk Assessment:

See Bromination of chlorothienopyrimidine (AT-5-1)

InChi:

InChI=1S/C6H3ClN2S/c7-6-5-4(1-2-10-5)8-3-9-6/h1-3H

to

InChI=1S/C6H2BrClN2S/c7-4-1-3-5(11-4)6(8)10-2-9-3/h1-2H

 

See Also:

Bromination of chlorothienopyrimidine (AT-5-1)

Bromination of chlorothienopyrimidine (AT-5-2)

Bromination of chlorothienopyrimidine (AT-5-3)

Bromination of chlorothienopyrimidine (AT-5-5)

Bromination of chlorothienopyrimidine (AT-5-6)

Linked Entries
Attached Files
22nd October 2013 @ 04:23

Methylamine (24% w/v in H2O, 5 mL) was added to MNR 99-3 (175 mg, 0.7 mmol),. The mixture was stirred at 85 ˚C overnight.

Reaction mixture was cooled to room temperature and then water (20 mL) was added and the product was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to give a yellow solid. 1H NMR showed desired product along with some impurities.

Data:

AEW 98-1 crude proton.pdf
fid

Hazard and Risk Assessment:

See Bromination of chlorothienopyrimidine (AT-5-5)

InChi:

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