Amino-thienopyrimidine Series

 

This experiment uses our newfound Suzuki technology to carry out the synthesis of an important analogue of the thienopyrimidine series hit compound.



Experiment start time: 3 PM, 7/12/2012
4-(6-iodothieno[3,2-d]pyrimidin-4-yl)morpholine (57.4 mg, 0.17 mmol, 1 eq), m-sulfamoylbenzene boronic acid, pinacol ester (65.4 mg, 0.23 mmol, 1.4 eq) and dried potassium acetate (108.4 mg, 1.104 mmol, 6.5 eq) were dissolved in a solution of 1,4-dioxane/H2O (5:1) (7 mL, degassed with argon). To this solution was added PdCl2(dppf) (17.8 mg, 14 mol %). The resultant red solution was heated at reflux with stirring for 72 h. The solution had turned black, and was allowed to cool to rt. To the cooled solution was added ethyl acetate (50 mL). The organic layer was separated, washed with water (2 x 40 mL), brine (40 mL), dried over MgSO4 and concentrated in vacuo to yield a maroon powder. By TLC 6 spots were seen, in the range of rf = 0.5 - 0.8. By ¹H-NMR a mess in the aromatic region was found.

These products would require a complex column, and before attempting this, other reactions were explored (see JRC 32-3).

This experiment is a repeat of JRC 52-1, with 3-chloroaniline used in lieuof 3-bromoaniline.

Conclusion: Desired product synthesised (257 mg)

(note: bromine showed; chlorine used. vide infra)

Experiment start time: 3PM, 7/12/2012

3-chloroaniline (0.12 mL, 1.13 mmol, 1 eq.) was dissolved in benzene (5 mL). To the stirring solution was added phenyl isocyanate (0.12 mL, 1.10 mmol, 0.97 eq.) dropwise. The solution was heated at reflux for 2h. A white prepipitate overcame the solution, and was left under nitrogen for 72 h. This precipitate was washed with hexane and dried in vacuo to yield a white solid (257 mg).

More of this product is needed for Suzuki couplings.

Conclusion: Desired product synthesised in 91% yield. Primary mass loss incurring step is therefore the bromination, unsurprisingly.



6-bromo-4-bromothieno[3,2-d]pyrimidine (250.6 mg, 0.852 mmol, 1 eq) was dissolved in 5 mL NH4OH, eated to 120 °C and stirred for 3 hr. Left to sit overnight. Re-heated for another 4 hr. Extracted into ethyl acetate and water to give 178.3 mg (0.774 mmol, 91%) product as an orange solid which, by TLC, contained three new products and no starting material (which is highly unusual). Contains the desired product by ¹H-NMR analysis.

This experimenta aims to generate a material needed to synthesise an analogue of the thienopyrimidine series hit compound.



Experiment start time: 2:30 pm, 6/12/2012

3-bromoaniline (0.12 mL) was dissolved in benzene (5 mL). To the stirring solution was added phenyl isocyanate (0.14 mL) dropwise. The solution was heated at reflux for 2 h. A cream coloured gel formed. The gel was allowed to cool to rt before it was filtered and washed with a little chilled benzene/petrol. The resultant white solid was concentrated in vacuo to yield a flaky white solid (423.3 mg).

NEED TLC, HNMR.

The previous entry in this series, it turned out, did not generate the desired product. Or at least, this product was not sufficiently characterised. Since this product represents an interesting compound for screening, it needs to be made.



Experiment start timne: 5:17 pm, 5/12/2012
Methyl 3-(2,2,2-trifluoroacetamido)thiophene-2-carboxylate (489 mg, 1.93 mmol, 1 eq) and ammonium formate (265.5 mg, 4.31 mmol, 2.2 eq) were dissolved in formamide (10 mL). The resultant brown solution was heated to 140 °C and stirred for 24 h. Aqueous extraction with ethyl acetate, water, brine, MgSO4 to yield a white powder (189 mg). ¹H-NMR analysis indicates that this is thieno[3,2-d]pyrimid-4-one.

Need to re-examine aqueous layer, given low mass recovery.