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21st May 2013 @ 04:41

Orange semi-solid (323 mg, 1.47 mmol, 83% crude yield)

AEW 58-1 Scheme

Procedure:

MNR 99-3 (300 mg, 1.76 mmol, 1 equiv.) was dissolved in N,N-dimethylethylenediamine (1.15 mL, 10.6 mmol, 6 equiv.) and stirred at 100 ˚C. 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 58-1 crude 1H.pdf
AEW 58-1 13 C.pdf

1H NMR (300 MHz, CDCl3) δ: 8.44 (1H, s), 7.62 (1H, d, J 5.7), 7.29 (1H, d, J 5.7), 3.83 (2H, t, J 6.7), 3.39 (3H, s), 2.84 (2H, t, J 6.7), 2.40 (3H, s), 2.19 (1H, s); 13C NMR (125 MHz, CDCl3) δ: 160.6, 158.3, 154.1, 131.4, 124.7, 114.0, 50.5, 49.6, 37.7, 36.3.

Hazard and Risk Assessment:

HIRAC AEW 58-1.pdf

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)

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21st May 2013 @ 04:37

AEW 57-1 Scheme

Procedure:

MNR 99-3 (300 mg, 1.76 mmol, 1 equiv.) was stirred in ethanolamine (10% in water, 10.6 mL, 17.6 mmol, 10 equiv.) at 100 ˚C for 1 h.

AFter 1 h, no SM present on TLC although product couldn't be clearly seen either. Reaction mixture remains orange solution. Reaction was stopped and cooled to room temperature then partitioned between EtOAc and water. The aqueous phases were extracted with EtOAc then combined org. phases washed with brine, dried (MgSO4), filtered and evaporated to yield 

Data:

Hazard and Risk Assessment:

HIRAC AEW 57-1.pdf

InChi:

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

and

InChI=1S/C2H7NO/c3-1-2-4/h4H,1-3H2

to

InChI=1S/C8H9N3OS/c12-3-2-9-8-7-6(1-4-13-7)10-5-11-8/h1,4-5,12H,2-3H2,(H,9,10,11)

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20th May 2013 @ 05:09

Reaction returned SM - mono-methyl derivative will be synthesised from MNR 99-3 and methyl amine prior to bromination

Starting material from Amination of chlorobromothienopyrimidine (AT-6-5)

Procedure:

A solution of acetic anhydride (49 microL, 0.52 mmol, 1.2 equiv.) in dry CH2Cl2 (0.5 mL) was added dropwise over 15 min to a  stirred solution of AT 6-5 (100 mg, 0.43 mmol, 1.0 equiv.) and triethylamine (73 microL, 0.52 mmol, 1.2 equiv.) in dry CH2Cl2 (6.5 mL). After 15 minutes and then 1 h TLC analysis seemed to suggest no reaction but the SM and reaction mixture contained a streak to the main spot that is not present in the product spot. Decided to leave stirring o/n will check in the morning.

Volatiles removed in vacuo and the off white powder was sonicated and water and the cream solid filtered off to give 67 mg of SM.

Expected more product so: The aqueous layer was extracted with ethyl acetate, washed with water, brine, dried (MgSO4), filtered and evaporated to give starting material (20 mg). 

Decided on alternative method for synthesis of mono-methylated analog.

 

Hazard and Risk Assessment:

HIRAC AEW 56-1.pdf

Literature Ref:

http://intramural.nimh.nih.gov/mib/radio/pubs/radiopub2009-16.pdf

InChi

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

to

InChI=1S/C8H6BrN3OS/c1-4(13)12-8-7-5(10-3-11-8)2-6(9)14-7/h2-3H,1H3,(H,10,11,12,13)

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17th May 2013 @ 10:19

Repeat of Nucleophilic Displacement of MNR99 with 1-Methylpiperazine to give MNR125-1 but with 1.5 equiv of amine rather than 2.


AEW 55-1 Scheme

Procedure:

To MNR 99-3 (1.0 g, 5.86 mmol, 1 equiv)) in THF (7 mL) (ethanol (5 mL added to get the starting material into solution) was added 1-methylpiperazine (0.98 mL, 8.79 mmol, 1.5 equiv) at 0 ˚C and the reaction mixture was stirred overnight at room temperature. Volatiles removed in vacuo (~4 mL remains) and then dissolved in EtOAc, washed with a saturated aqueous solution of sodium hydrogen carbonate, water, brine, dried (MgSO4), filtered and evaporated to give a

Data:

TLC 20 h 100% EtOAc

AEW 54 and 55 100% EtOAc.jpg

Hazard and Risk Assessment:

See Nucleophilic Displacement of MNR99 with 1-Methylpiperazine to give MNR125-1 and links within.

 

 
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17th May 2013 @ 10:07

Starting material from commercially purchased 4-chloroethieno[3,2-d]pyrimidine

Repeat of Nucleophilic Displacement of MNR99 with ethyl 1-piperazinecarboxylate to give MNR126-1 but with 1.5 equiv of amine rather than 2.

 

Scheme AEW 54-1

Procedure

To 4-chloroethieno[3,2-d]pyrimidine (1.0 g, 5.86 mmol, 1 equiv) in THF (7 mL) (ethanol (5 mL added to get the starting material into solution) was added ethyl 1-piperazinecarboxylate (1.29 mL, 8.79 mmol, 1.5 equiv) at 0 ˚C.  The reaction was stirred at room temperature overnight. Still some SM 20 h later. Stirred for the rest of the weekend. On Monday still SM but volatiles removed in vacuo (~4 mL remains) and then dissolved in EtOAc, washed with a saturated aqueous solution of sodium hydrogen carbonate, water, brine, dried (MgSO4), filtered and evaporated to give a cream solid (1.93g) containing ~1:<0.1 product:SM. Decided to column rather than use crude to avoid purification problems in the next step.

Hazard and Risk Assessment:

See Nucleophilic Displacement of MNR99 with ethyl 1-piperazinecarboxylate to give MNR126-1 and links contained within.

Data:

AEW 54 and 55 100% EtOAc.jpg

Crude 1H NMR

AEW54-1-crude.pdf
AEW 54-1.zip

InChi

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

and

InChI=1S/C7H14N2O2/c1-2-11-7(10)9-5-3-8-4-6-9/h8H,2-6H2,1H3

to give

InChI=1S/C13H16N4O2S/c1-2-19-13(18)17-6-4-16(5-7-17)12-11-10(3-8-20-11)14-9-15-12/h3,8-9H,2,4-7H2,1H3

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