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10th July 2014 @ 05:41

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)

Attached Files
9th July 2014 @ 09:27

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)


9th July 2014 @ 02:40

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

Attached Files
3rd July 2014 @ 10:38

 

 

Conditions from Synthesis of 3-(7-aminothiazolo[4,5-d]pyrimidin-2-yl)-4-methyl-benzenesulfonamide (PT-22) were used on a 2x scale, to synthesise OSM-S-106.

 

PT-21-B1 (56.7 mg, 0.2 mmol) was dissolved in isopropyl alcohol (4 mL) and to this was added PT-18-D1 (68 mg, 0.24 mmol, 1.2 eq) followed by potassium carbonate solution (1M, 0.4 mL, 2 equivalents). The solution was degassed with nitrogen for 5 minutes and Pd(dppf)2.CH2Cl2 (32 mg, 40 umol, 20 mol%) was added. The reaction was heated to 90°C for 30 minutes under microwave irradiation in a sealed vessel, then evaporated to dryness. NMR (B1) indicated peaks consistent with a single major product, the title compound, plus misc. impurities (Reference spectrum):

PT-23-B1 1H NMR detail.png

The crude mixture was purified by dry flash column chromatography (gradient: 100% chloroform to 80% chloroform, 18% methanol, 2% sat. aq. ammonia) to give the title compound in two batches: 

C1, pale tan solid, 32.3 mg, 0.105 mmol, 52.8%

C2, tan solid, 23.1 mg, 0.075 mmol, 37.7%

Combined yield: 90.5%


Attached Files
2nd July 2014 @ 19:11

 

 

The procedure was used from Synthesis of 3-(4-(2-(dimethylamino)ethoxy)thieno[3,2-d]pyrimidin-6-yl)benzenesulfonamide (MJT 18-1).

 

PT-21-B1 (28.3 mg, 0.1 mmol) was dissolved in isopropyl alcohol (2 mL) and to this was added PT-20-3-C1 (47 mg, 0.12 mmol, 1.2 eq) followed by potassium carbonate solution (1M, 0.2 mL, 2 equivalents). The solution was degassed with nitrogen for 5 minutes and Pd(dppf)2.CH2Cl2 (16 mg, 20 umol, 20 mol%) was added. The reaction was heated to 90°C for 30 minutes under microwave irradiation in a sealed vessel, then dry-loaded onto silica and purified using dry column vacuum chromatography (0-10% methanol in chloroform, 20 fractions, then 1% sat. aq. ammonia, 9% methanol, 90% chloroform for 5 tubes) to give the title compound as the most beautiful tan solid I've ever seen (16.8 mg, 52 umol, 52%), which was only sparingly soluble in chloroform. 



NMR:

Consistent with desired product. (Note: earlier data was taken when spectrometer was accidentally set to +45°C by a previous user, and is present in the tarball)

1H 13C interpreted.pdf


Mass Spectroscopy (Nominal):

Consistent. [M+H] and [2M+H] visible.

PT-22-C1 ESI Nominal.jpg


Mass Spectroscopy (Accurate):

Main peak consistent to within 2ppm: Observed: 321.0474 Calculated: 321.04801

13C peak consistent to within 4ppm: Observed: 322.0499 Calculated: 322.05137

13C * 2 peak consistent to within 3ppm: Observed: 323.0447 Calculated: 323.04381

PT-22-C1 ESI Accurate.jpg
IMG_20140707_115156.jpg


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Attached Files