Chlorosulfonyl isocyanate → thieno[2,3-d]pyrimidine-2,4-diol

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Reaction Steps

Scheme 6 shows the synthesis of 4-(2-chlorothieno[2,3-d]pyrimidin-4-yl)morpholine 18 starting by cyclization of methyl 2-amino-thiophenecarboxylate 15 (95 g) with chlorosulfonyl isocyanate at low temperature remains (−60° C. to −55° C.) to give thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione 16. Phosphorous oxychloride was added slowly to a cold solution of thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione 16 and N,N-dimethylaniline (0.75 equiv.) in acetonitrile while maintaining the temperature below 25° C. The mixture was then heated to 80-85° C. and stirred for 24 hours to afford dichlorothieno[2,3-d]pyrimidine 17. Morpholine (2.2 equiv.) was added to a solution of 2,4-dichlorothieno[2,3-d]pyrimidine 17 in methanol and stirred at ambient temperature for 1 h to give 18.

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