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23rd October 2013 @ 23:58

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)

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23rd October 2013 @ 03:56

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)

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22nd October 2013 @ 03:23

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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15th October 2013 @ 23:38

See MJT-9-2 for first attempt. This time, 2 equiv. of nBuLi used and 2 equiv. bromine.

AEW 88-1 (280 mg, 1.69 mmol) was dissolved in THF (34 mL ~0.05 M) and cooled to -78 °C.  n-BuLi (2.5 M in hexane, 1.36 mL, 3.39 mmol, 2.0 equiv.) was added and stirring continued for 30 minutes. Bromine (0.175 mL, 3.39 mmol, 2.0 equiv.) was added dropwise and the reaction mixture was allowed to reach room temperature whilst stirring for 4 hours. Monitored by TLC over the 4 hours, still SM but faint spot above seems to be growing more intense. Orange solution left to stir at RT overnight.

Data:

TLC (EtOAC) 4 h:

AEW 96-1.jpeg

Hazard and Risk Assessment:

See Repeat synthesis of 6-bromo-N-methylthieno[3,2-d]pyrimidin-4-amine (MJT 9-2)

InChi String:

InChI=1S/C7H7N3S/c1-8-7-6-5(2-3-11-6)9-4-10-7/h2-4H,1H3,(H,8,9,10)

to

InChI=1S/C7H6BrN3S/c1-9-7-6-4(10-3-11-7)2-5(8)12-6/h2-3H,1H3,(H,9,10,11)

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10th October 2013 @ 02:33

AEW 58-1 Scheme

Procedure:

MNR 99-3 (500 mg, 2.93 mmol, 1 equiv.) was dissolved in N,N-dimethylethylenediamine (1.91 mL, 17.7 mmol, 6 equiv.). The reaction mixture effervesced and all SM dissolved. TLC showed presence of SM and the mixture began to ppt out so it was stirred at 100 ˚C according to previous procedure.

After 1 h, no SM present on TLC although product couldn't be clearly seen either. Reaction mixture had turned from yellow solution to white/yellow cloudy mixture. Reaction was stopped and cooled to room temperature then partitioned between EtOAc and water. The aqueous phases were extracted with EtOAc (very cloudy white ppt started to form), then combined org. phases washed with brine, dried (MgSO4), filtered and evaporated to yield an orange oil.

AFter 1 h, no SM present on TLC although product couldn't be clearly seen either. Reaction mixture has turned from orange solution to white/yellow cloudy mixture. Reaction was stopped and cooled to room temperature then partitioned between EtOAc and water. The aqueous phases were extracted with EtOAc (insoluble white oil/solid started to crash out so all layers kept) then combined org. phases washed with brine, dried (MgSO4), filtered and evaporated to yield an orange oil, which slowly crystallised to an orange semi-solid (323 mg, 1.47 mmol, 83% crude yield) and used as crude in AEW 66-1. NMR shows impurity with similar signals to product - used without purification.

Data:

AEW 58-2 (100% EtOAc) just after mix at rt.jpg

Hazard and Risk Assessment:

See Synthesis of N1,N1-dimethyl-N2-(thieno[3,2-d]pyrimidin-4-yl)ethane-1,2-diamine (AEW 58-1)

InChi:

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

and

InChI=1S/C4H12N2/c1-6(2)4-3-5/h3-5H2,1-2H3

to 

InChI=1S/C10H14N4S/c1-14(2)5-4-11-10-9-8(3-6-15-9)12-7-13-10/h3,6-7H,4-5H2,1-2H3,(H,11,12,13)

Attached Files