Amino-thienopyrimidine Series

Resynthesised for hERG evaluation

AEW 100-6 (29 mg, 0.1 mmol) was dissolved in isopropyl alcohol (2 mL) and to this was added MNR 103 (34 mg, 0.12 mmol, 1.2 eq) followed by potassium carbonate solution (1M, 0.2 mL, 2 equivalents). The solution was degassed with Ar for 10 minutes and Pd(dppf)2.CH2Cl2 (16 mg, 20 umol, 20 mol%) was added and the red/pink reaction mixture was placed in the microwave reactor and heated to 85 ˚C. Originally, 200 W was applied as per optimised conditions but the temperature was unsteady. Found to be steady at 60 W and so heated to 85 ˚C at 60 W for 30 minutes. 

InChi:

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

and

InChI=1S/C12H18BNO4S/c1-11(2)12(3,4)18-13(17-11)9-6-5-7-10(8-9)19(14,15)16/h5-8H,1-4H3,(H2,14,15,16)

to

InChI=1S/C12H10N4O2S2/c13-12-11-9(15-6-16-12)5-10(19-11)7-2-1-3-8(4-7)20(14,17)18/h1-6H,(H2,13,15,16)(H2,14,17,18)

Reaction scheme:

Procedure: Perfomed on 2 x 200 mg scale

AEW 99-1 (0.200 g, 0.80 mmol), isopropanol (4.5 mL) and ammonia (aq, 28% (w/w), 9 mL) were added to a sealed tube, stirred and heated at 120 °C for 2 hours. The reaction mixture was allowed to cool to room temperature and the solvent was removed under vacuum.

2 batches of CT 3 were made (total 0.400 g starting material). CT 3-6 and CT 3-7 were purified together by column chromatography over silica (99:1 DCM:MeOH to 97:3 DCM:MeOH to 96.5:3.5:0.5 DCM:MeOH:NH3).

Data:

InChI strings:

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)

See also AT 1-1

To MNR89-1 (1.50 g, 9.87 mmol, 1.0 equiv.) under argon was added phosphorus(V) oxychloride (15.1 g, 9.15 mL, 98.7 mmol, 10.0 equiv.) dropwise with stirring. The reaction mixture was heated to reflux and stirred for x h, before cooling to rt.

Ice (approx. 20 mL), an aqueous solution of NaHCO₃ (approx. 600 mL) and solid NaHCO₃ (approx. 5 g) were added sequentially until effervesence ceased and the reaction mixture was extracted with ethyl acetate (6 x 100 mL). The organic phases were combined, dried (MgSO₄) and concentrated under reduced pressure to give the product as a yellow solid (xx%).  

HIRAC

See AT 1-1

InChi:

InChI=1S/C6H4N2OS/c9-6-5-4(1-2-10-5)7-3-8-6/h1-3H,(H,7,8,9)

to

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

Posted in wrong place, moved to Triazolopyrazine Blog: http://malaria.ourexperiment.org/uri/647

GitHub Tag: Issue #

AEW 103-5 (500 mg, 2.48 mmol, 1 equiv.) was dissolved in DMF (3 mL) under Ar. Imidazole (220 mg, 6.18 mmol, 2.5 equiv.) was added and the reaction mixture was stirred at room temperature for 10 minutes. TBS-Cl (484 mg, 3.42 mmol, 1.3 equiv.) was then added and the reaction stirred at room temperature overnight. 

Data:

Hazard and Risk Assessment:

InChi

InChI=1S/C9H8F2O3/c1-14-9(13)8(12)5-2-3-6(10)7(11)4-5/h2-4,8,12H,1H3

to

InChI=1S/C15H22F2O3Si/c1-15(2,3)21(5,6)20-13(14(18)19-4)10-7-8-11(16)12(17)9-10/h7-9,13H,1-6H3

Postponed until tomorrow as microwave not accessible today

A solution of AEW 98-1 (29 mg, 0.12 mmol, 1 equiv.), MNR 103-  (40 mg,  0.14 mmol, 1.2 equiv.) and PdCl₂dppf (17 mg, 0.02 mmol, 0.20 equiv.) in isopropanol (2.4 mL) and K₂CO₃ (1 M, 0.24 mL, 0.22 mmol, 2.0 equiv.) was degassed with argon for 10 minutes.

The reaction mixture was heated at 90 ^oC for 30 minutes in a microwave reactor (200 W).

Hazard and Risk Assessment:

See http://malaria.ourexperiment.org/uri/3da and links within

InChi:

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

and

InChI=1S/C12H18BNO4S/c1-11(2)12(3,4)18-13(17-11)9-6-5-7-10(8-9)19(14,15)16/h5-8H,1-4H3,(H2,14,15,16)

to

InChI=1S/C13H12N4O2S2/c1-15-13-12-10(16-7-17-13)6-11(20-12)8-3-2-4-9(5-8)21(14,18)19/h2-7H,1H3,(H2,14,18,19)(H,15,16,17)