Synfacts 2016; 12(08): 0769
DOI: 10.1055/s-0035-1562377
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of PDE4 Inhibitors

Philip Kocienski
Frutos RP, * Tampone TG, Mulder JA, Rodriguez S, Yee NK, Yang B.-S, Senanayake CH. Boehringer Ingelheim Pharmaceuticals, Ridgefield, USA
Development of a Practical Process for the Synthesis of PDE4 Inhibitors.

Org. Process Res. Dev. 2016;
20: 982-988
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19. Juli 2016 (online)



The target phosphodiesterase type 4 (PDE4) inhibitor J is of interest for the treatment of chronic obstructive pulmonary disease. The multikilogram-scale synthesis depicted features a highly regioselective Dieckmann condensation (A → B) required for the construction of the dihydrothieno[3,2-d]pyrimidine D and the asymmetric sulfoxidation of intermediate G using the conditions of Uemura and co-workers (J. Org. Chem. 1993, 58, 4529).



The transformation EG was accompanied by 15% of the product resulting from displacement of the chlorine at C2. Investigation of alternative bases and solvents failed to improve the regioselectivity; however, the undesired regioisomer was significantly more soluble than H and was completely removed from the product during the isolation by filtration.