Related Experiment Video
Updated: Jun 22, 2026
08:36
Scaled-Up Preparation of an Intermediate of Upatinib, ACT051-3
Published on: April 7, 2023
Highly efficient asymmetric synthesis of sitagliptin
Karl B Hansen1, Yi Hsiao, Feng Xu
1Department of Process Research, Merck Research Laboratory, Rahway, New Jersey 07065, USA.
Journal of the American Chemical Society
|June 11, 2009
Summary
A new, green synthesis for sitagliptin, a type 2 diabetes drug, has been developed. This efficient process yields high-purity sitagliptin phosphate salt while reducing waste and cost.
Area of Science:
- Medicinal Chemistry
- Process Chemistry
- Green Chemistry
Background:
- Sitagliptin is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor.
- It is a key therapeutic agent for managing type 2 diabetes mellitus (T2DM).
- Existing synthesis routes present challenges in efficiency and environmental impact.
Purpose of the Study:
- To develop a highly efficient and environmentally friendly synthesis of sitagliptin.
- To optimize the preparation of the dehydrositagliptin intermediate.
- To achieve high enantioselectivity in the final hydrogenation step.
Main Methods:
- A one-pot, three-step synthesis for the dehydrositagliptin intermediate.
- Highly enantioselective hydrogenation using a low loading of a Rh(I)/(t)Bu JOSIPHOS catalyst.
- Isolation of sitagliptin as its phosphate salt.
Main Results:
- The dehydrositagliptin intermediate was prepared in 82% yield and >99.6 wt % purity.
- Sitagliptin was obtained with nearly perfect optical and chemical purity.
- The 'green' synthesis significantly reduces waste and eliminates aqueous waste streams.
- Overall isolated yield reached up to 65%.
Conclusions:
- A cost-effective, scalable, and environmentally sustainable synthesis for sitagliptin has been established.
- This optimized process offers substantial improvements over previous methods.
- The developed route is suitable for manufacturing and contributes to greener pharmaceutical production.
More Related Videos
Related Concept Videos
01:23Dipeptidyl Peptidase 4 Inhibitors
Dipeptidyl peptidase 4 (DPP-4) is a serine protease widely distributed in the body. It's involved in the inactivation of GLP-1 and GIP hormones, which are crucial for insulin regulation. DPP-4 inhibitors, such as sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), alogliptin (Nesina), and vildagliptin (Galvus), help increase the proportion of active GLP-1, enhancing insulin secretion. These inhibitors work by competitively binding to DPP-4. This binding causes a significant...
02:57Sharpless Epoxidation
The conversion of allylic alcohols into epoxides using the chiral catalyst was discovered by K. Barry Sharpless and is known as Sharpless epoxidation. The use of a chiral catalyst enables the formation of one enantiomer of the product in excess. This chiral catalyst is mainly a chiral complex of titanium tetraisopropoxide and tartrate ester (specific stereoisomer). The stereoisomer used in the chiral catalyst dictates the formation of the enantiomer of the product. In other words, the use of...
02:17Reduction of Alkenes: Asymmetric Catalytic Hydrogenation
Catalytic hydrogenation of alkenes is a transition-metal catalyzed reduction of the double bond using molecular hydrogen to give alkanes. The mode of hydrogen addition follows syn stereochemistry.
The metal catalyst used can be either heterogeneous or homogeneous. When hydrogenation of an alkene generates a chiral center, a pair of enantiomeric products is expected to form. However, an enantiomeric excess of one of the products can be facilitated using an enantioselective reaction or an...
The metal catalyst used can be either heterogeneous or homogeneous. When hydrogenation of an alkene generates a chiral center, a pair of enantiomeric products is expected to form. However, an enantiomeric excess of one of the products can be facilitated using an enantioselective reaction or an...
01:06Oral Hypoglycemic Agents: Glinides
Repaglinide (Prandin) and Nateglinide (Starlix), known as glinides, are oral insulin secretagogues that stimulate insulin release from pancreatic β cells by closing the ATP-sensitive potassium channels (KATP channel). Repaglinide controls insulin release from pancreatic β cells by managing potassium efflux. It shares two binding sites with sulfonylureas and also has a unique site, indicating overlapping mechanisms of action. With a rapid onset and a 4-7 hour duration, it effectively manages...
01:30Production of Pharmaceuticals
Industrial insulin production uses genetically engineered E. coli expressing a proinsulin gene controlled by a tryptophan promoter and containing a methionine linker for later cleavage. The cells also carry ampicillin resistance for selective growth. Seed cultures are stored at −80 °C and production begins by thawing a small amount to inoculate starter cultures, which are progressively scaled to a 50,000-L bioreactor. In the bioreactor, E. coli grow in nutrient-rich media under sterile, tightly...
02:23SN2 Reaction: Stereochemistry
In an SN2 reaction, the nucleophilic attack on the substrate and departure of the leaving group occurs simultaneously through a transition state. As the nucleophile approaches the substrate from the back-side, the configuration of the substrate carbon changes from tetrahedral to trigonal bipyramidal and then back to tetrahedral, leading to an inversion in the configuration of the product.
If the substrate is an achiral molecule at the α-carbon, the inversion of configuration is not observed.
If the substrate is an achiral molecule at the α-carbon, the inversion of configuration is not observed.