Chiral amino-compound fragments widely exist in natural products and active molecules. It has long been a target encouraging the organic synthetic chemists to try to build chiral amino groups with high performance and selectivity. In 1979, Professor Kozikowski at University of Pittsburgh found that the organometallic reagents could selectively catalyze the ring-opening of aziridine compound to synthesize amino-compound (J. Org. Chem., 1979, 44, 788-2790). In recent years, the selective ring-opening of aziridine compound to synthesize amino-compound has been developed prosperously (Org. Lett., 2011, 3, 2349-2351). The synthesis methods of chiral amino compound from natural chiral sources are characterized by their simplicity and customizing the chiral structures or the like, and thus have definite advantages over the methods of chiral induction and chiral resolution.
Sitagliptin phosphate is the first dipeptidyl peptidase-IV (“DPP-IV”) inhibitor for the treatment of type 2 diabetes mellitus which has been approved for marketing by the U.S. Food and Drug Administration (FDA) in 2006. Sitagliptin phosphate shows remarkable hypoglycemic activity whether it is used alone or in combination with metformin or pioglitazone. In addition, it is safe, well-tolerated, and with few adverse effects. Sitagliptin phosphate was developed by Merck & Co., Inc. under the tradename JANUVITA. It was approved by the Ministry of Health in Mexico on Aug. 8, 2006 for the treatment of type 2 diabetes mellitus by once daily medication, and was approved by FDA on Oct. 16, 2006 in US. By now, it has been approved by more than sixty countries around the world. It was reported that the third quarter earnings in 2007 was USD 0.185 billion and the value of sales till 2009 would be up to USD 1 billion. The maximum value of its sales is expected to be USD 1.4 billion after its successfully coming into the market. Therefore, Sitagliptin phosphate, as a hypoglycemic drug, is the latest international “blockbuster” product with extremely high added value. That means the development of this medicine is of great significance. However, by now, there is no enterprise which has the capacity of industrially producing Sitagliptin phosphate in China because of the high technical difficulties in the production. The disclosed synthetic routes of Sitagliptin phosphate are all designed by Merck & Co., Inc., which are reviewed as follows.
(1) U.S. Pat. No. 6,699,871 discloses a synthetic route of Sitagliptin, which is a synthesis method on gram scale suitable for R&D departments. In the method, the chiral source is used to induce a chiral alpha-amino acid compound which is then subjected to a diazotization reaction for forming beta-amino acid compound which can be used to build the required chiral center. The cost of raw materials required in this route is relatively high, and the operation of reaction is relatively complicated. Further, it is hard to control the technical process and the products' quality during the industrialization process. The synthetic route is as described below.

(2) WO 2004087650 discloses the second generation synthetic route of Sitagliptin developed by Merck & Co., Inc. In this method, a chiral phosphorus ruthenium catalyst is applied to the asymmetric catalytic hydrogenation of ketone to afford a chiral secondary alcohol which is then converted into a chiral secondary amine in order to obtain a chiral amine. However, in this route, Rh based catalyst is needed to be used in the key step of the asymmetric catalytic hydrogenation, thus the costs of this step is relatively high. In addition, during the industrialization, it is difficult to control the products' quality due to an apparent scaling effect when the reaction is performed in an amplified scale. The synthetic route is as described below.

(3) WO 2005003135 discloses the third generation synthetic method of Sitagliptin developed by Merck & Co., Inc. In this method S-phenylglycinamide is used as a chiral auxiliary for inducing catalytic hydrogenation to synthesize chiral amine. This route is relatively proper, however, the main problems of this method lie in that catalytic hydrogenations are needed twice and the Pt based catalyst used thereof is relatively expensive. Further, a large amount of Pd(OH)2/C is used to remove the protective group in the final step, thereby rendering high cost. The synthetic route is as described below.

(4) WO 2007050485 discloses the latest synthetic method of Sitagliptin developed by Merck & Co., Inc. In this method, a chiral rhodium catalyst is applied to the asymmetric catalytic hydrogenation of enamine to build a chiral center. Due to fewer steps, this method is relatively simple. However, the expensive catalyst and chiral auxiliary are used in this method as well, and there still exists a scaling effect during the industrialization, which results in products of unstable quality. The synthetic route is as described below.

Owing to the shortcomings existing in the previous synthetic methods of Sitagliptin (i.e., low product yields, high costs, and not eco-friendly), a synthesis method with high yield, low cost and being eco-friendly would have a broad market prospect. Therefore, there is still a need of finding novel intermediates of Sitagliptin to develop new routes to improve the method for synthesizing Sitagliptin.