A new synthesis of sitagliptin (MK-0431), a DPP-IV inhibitor and potential new treatment for type II diabetes, suitable for the preparation of multi-kilogram quantities is presented. The triazolopyrazine fragment of sitagliptin was prepared in 26% yield over four chemical steps using a synthetic strategy similar to the medicinal chemistry synthesis. Key process developments were made in the first step of this sequence, the addition of hydrazine to chloropyrazine, to ensure its safe operation on a large scale. The beta-amino acid fragment of sitagliptin was prepared by asymmetric reduction of the corresponding beta-ketoester followed by a two-step elaboration to an N-benzyloxy beta-lactam. Hydrolysis of the lactam followed by direct coupling to the triazolopiperazine afforded sitagliptin after cleavage of the N-benzyloxy group and salt formation. The overall yield was 52% over eight steps.

Asymmetric reductive amination of beta-keto amides catalyzed by the chiral catalyst Ru(OAc)(2)((R)-dm-segphos) produces unprotected beta-amino amides with high yields and high enantioselectivities (94.7-99.5% ee). This "one-pot" methodology is general in substrate scope and has been successfully employed to produce sitagliptin with 99.5% ee and 91% assay yield. The excellent reaction efficiency is attributed to the remarkable tolerance to high concentrations of ammonium ion, the high chemoselectivity, and the high enantioselectivity (99.5% ee) of the Ru catalyst system.

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The discovery of 1,3,8-triazaspiro[4.5]decane-2,4-diones (spirohydantoins) as a structural class of pan-inhibitors of the prolyl hydroxylase (PHD) family of enzymes for the treatment of anemia is described. The initial hit class, spirooxindoles, was identified through affinity selection mass spectrometry (AS-MS) and optimized for PHD2 inhibition and optimal PK/PD profile (short-acting PHDi inhibitors). 1,3,8-Triazaspiro[4.5]decane-2,4-diones (spirohydantoins) were optimized as an advanced lead class derived from the original spiroindole hit. A new set of general conditions for C-N coupling, developed using a high-throughput experimentation (HTE) technique, enabled a full SAR analysis of the spirohydantoins. This rapid and directed SAR exploration has resulted in the first reported examples of hydantoin derivatives with good PK in preclinical species. Potassium channel off-target activity (hERG) was successfully eliminated through the systematic introduction of acidic functionality to the molecular structure. Undesired upregulation of alanine aminotransferese (ALT) liver enzymes was mitigated and a robust on-/off-target margin was achieved. Spirohydantoins represent a class of highly efficacious, short-acting PHD1-3 inhibitors causing a robust erythropoietin (EPO) upregulation in vivo in multiple preclinical species. This profile deems spirohydantoins as attractive short-acting PHDi inhibitors with the potential for treatment of anemia.

Process research and development of a synthetic route towards a novel renin inhibitor (1) is described. The highly convergent synthetic route provided 1 in 15% yield on multikilogram scale with a longest linear sequence of 11 steps. The use of catalytic hydrogenation features prominently in our design. The proper choice of N-methylpyridone surrogate was also important, and we describe a method for the easy conversion of 2-methoxypyridines to N-methylpyridones using cheap and readily available reagents.