Synthesis of (S)-1-(2-chloroacetyl)pyrrolidine- 2-carbonitrile: A key intermediate for dipeptidyl peptidase IV inhibitors

• Santosh K. Singh,
• Narendra Manne and
• Manojit Pal

Beilstein J. Org. Chem. 2008, 4, No. 20, doi:10.3762/bjoc.4.20

• inhibitor Vildagliptin. Keywords: amides; DPP-IV inhibitors; L-proline; N-acylation; 2(S)-cyanopyrrolidine; Background One of the emerging and mechanism based approaches for the treatment of type-II diabetes is dipeptidyl peptidase IV (DPP-IV; CD26; E.C. 3.4.14.5) inhibition with the help of small

• -cells [1]. Because of its key role in DPP-IV inhibition the 2(S)-cyanopyrrolidine moiety has been found to be an integral part of many DPP-IV inhibitors (Figure 1). Apart from behaving as a proline mimic, the presence of the nitrile on the five-membered ring provides (i) reversible and nanomolar

• inhibition of DPP-IV and (ii) chemical stability adequate for oral administration [6] (Figure 2). Chemically, incorporation of a 2(S)-cyanopyrrolidine moiety into a molecule can be carried out by using (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile (6) as a reactant. Thus, compound 6 has become a widely