4-Chlorothieno[3,2-d]pyrimidine

Uses

4-Chlorothieno[3,2-d]pyrimidine serves as a precursor for synthesizing substituted thienopyrimidine derivatives through nucleophilic aromatic substitution with various amines, including substituted anilines and N-methyl-4-methoxyaniline[5].

Synthesis

The general procedure for the synthesis of 4-chlorothieno[3,2-d]pyrimidine using thieno[3,2-d]pyrimidin-4(3H)-one as starting material was as follows: dimethylformamide (15.4 mL, 197.13 mmol) was added to 150 mL of dichloroethane and the reaction system was cooled down to 0 °C. Subsequently, oxalyl chloride (25 mL, 295.70 mmol) was added slowly and dropwise. After the formation of a white gel-like substance was observed, 3H-thieno[3,2-d]pyrimidin-4-one (15 g, 98.57 mmol) was added. The reaction mixture was stirred at 0 °C for 2.5 h and then gradually warmed up to room temperature. Upon completion of the reaction, the reaction was quenched by the addition of water and the organic layer was extracted with dichloromethane (3 x 300 mL), the organic phases were combined and dried over anhydrous magnesium sulfate. The solvent was removed by concentration under reduced pressure and the residue was ground with 200 mL of hexane to afford 4-chlorothieno[3,2-d]pyrimidine (16.7 g, 99% yield) as a dark brown solid. The product was characterized by 1H NMR (400 MHz, DMSO-d6): δ 9.06 (s, 1H), 8.61 (d, J = 5.2 Hz, 1H), 7.78 (d, J = 5.2 Hz, 1H); LC-MS showed the molecular ion peak m/z 173.2 ([MH]+).

References

[1] Patent: US2013/72482,  2013,  A1. Location in patent: Paragraph 0211; 0216; 0217
[2] Patent: WO2005/51304,  2005,  A2. Location in patent: Page/Page column 67-68
[3] Patent: WO2006/10264,  2006,  A1. Location in patent: Page/Page column 51; 67-68
[4] MedChemComm,  2015,  vol. 6,  # 2,  p. 339 - 346
[5] Hopfner, S. M., Lee, B. S., Kalia, N. P., Miller, M. J., Pethe, K., & Moraski, G. C. (2021). Structure guided generation of thieno[3,2- <i>d</i> ]pyrimidin-4-amine <i>Mycobacterium tuberculosis bd</i> oxidase inhibitors. RSC Medicinal Chemistry, 12(1), 73–77. https://doi.org/10.1039/d0md00398k