An Efficient and Telescopic Process for Synthesis of Saxagliptin Hydrochloride PRABHAKAR

An efficient and telescopic process for the preparation of saxagliptin hydrochloride (1) is described using T3P as a reagent for condensation and dehydration steps.

Saxagliptin 1 is a dipeptidyl peptidase-4 inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus and it is approved by United States of Food and Drug Administration (USFDA) in the form of 2.5 and 5 mg base film-coated tablets under the brand name of Onglyza®.
. Finally, compound 6 was treated with hydrochloric acid to afford 1.In addition the first reported 3 procedure an alternative process for dehydration of 4 using imidazole & phosphorous oxy chloride (POCl 3 ) in presence of pyridine was reported.
Despite the proven potential of reported procedures for the synthesis of 1, there are certain disadvantages associated with the repor ted procedures including (i) usage of hazardous chemicals such as TFAA, POCl 3 , and pyridine.(ii) Use of numerous reagents, which are needed purifications or acid base treatments for removal such as HOBt, TFAA.(iii) requirement of stringent water content for the moisture sensitive reagents such as EDC.HCl, (iv) multiple steps and (v) purifications including column chromatography for the removal of impurities generated during the reaction or carried from the raw materials and for the reagents that are used in the reaction.
We have developed a process using propylphosphonic anhydride (T3P) 4 as a reagent for condensation and dehydration steps and finally Boc deprotection of 6 and simultaneous HCl salt formation leads to saxagliptin hydrochloride.
The obtained compound 4 was confirmed by spectral data (Mass & NMR) Solvent always plays pivotal role on yield and quality of the end product.In view of this, to check the impact of T3P reagent in various solvents including polar aprotic solvents (DMF), ether solvents (THF), acetate solvents (EtOAc) and chlorinated solvents (DCM) were examined.Optimal results were obtained in DCM when compared with other solvents as depicted in Table 2 entry-6.
Having developed an efficient process for 4, our attention was turned towards the dehydration of 4. The reported processes involved the usage of TFAA & pyridine, combination of imidazole, POCl 3 & pyridine as dehydrating agents for the conversion of 4 to 6. Dehydration of 4 by using TFAA as dehydrating agent proceed through the ester compound 5 as an intermediate, which is an additional step and hydrolysis of ester compound 5 needed a strong base.To avoid the usage of a noxious carcinogen base (pyridine) and highly toxic reagents such as POCl 3 and TFAA and to circumvent the disadvantageous associated with the reporting procedures, screened the various dehydrating reagents such as cyanuric chloride 13 , triethylammonium sulphate (TEA.SO 3 ) 14 , DECP 15 , 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) , (Chloromethylene)dimethyliminium chloride (Vilsmeier Reagent) 16 and T3P.Experimental results revealed that T3P and TFAA offer better yield and purity when compared with the other reagents as shown in Table 3. Safety, handling and process efficiency point of view T3P found to be better reagent when compared to TFAA.
To further improve the efficiency of process, as per our strategy different solvents including DMF, THF, EtOAc, and DCM were examined.DCM as a solvent furnished the product in highest yield and purity as shown in Table 4 entries 5 and 6.
This modification was eliminated the laborious work up process and allowed us to develop an one pot synthesis for the penultimate intermediate 6 in single solvent system without isolation of amide compound of 4. Absence of acid proton at δ 12.4 of 2 and amine proton at δ 2.5 of 3 indicating the peptide bond formation, further absence of amide protons of 3 at δ 4.6 and presence of peak at δ 119.3 in 13 C NMR of 6 indicating the cyano carbon and confirms the formation of 6.The obtained compound 6 was further substantiated by 1 H-1 H correlation (gDQ-COSY, Figure 3) and 1 H- 13 C correlation (gHSQC, Figure 4).
Telescoped the process by the direct conversion of 2 and 3 to 6 using T3P and DIPEA alone it self for both the stages and observed incompletion of reaction during dehydration step and performed the reaction at elevated temperature in order to completion of the reaction and ended up with impurities formation.
Finally the obtained compound 6 from the above process was subjected to Boc deprotection with aq.HCl followed by HCl salt formation as per the literature process 2 leads to saxagliptin HCl.Absence of Boc protons at δ 1.14 in 1 H NMR and δ 155.8 in 13 C NMR indicating the formation of 1 and the obtained results are congruence with reported values of 1.

EXPERIMENTAL
Solvents and reagents were obtained from commercial sources and used without further purification.The 1 H and 13 C spectra were measured in DMSO-d 6, CD 3 OD and CDCl 3 using 400 and 100 MHz on a Varian Gemini and Varian Mercury plus 2000 FT NMR spectrometer, g-DQ-COSY and gHSQC experiments were performed to identify the 1 H-1 H correlation and 1 H- 13 C correlation, the chemical shifts were reported in δ ppm.IR spectra were recorded in the solid state as KBr dispersion using Perkin-Elmer 1650 FT IR spectrometer.The mass spectrum (70 eV) was recorded on an HP 5989 A LC-MS spectrometer.The solvents and reagents were used without further purification.Given the current socioeconomic and environmental concerns, commercial synthetic approach to an active pharmaceutical ingredient (API) needs to be safer, greener, simple, cost effective and less energy intensive.Therefore, in order to develop business driven commercial route as early as possible in the lifecycle of a compound, where even modest cost improvements can result in large savings in the cost of manufacturing a drug substance, a meticulous scientific approach is required.

CONCLUSIONS
We have developed simple, cost effective, robust, high yielding and safer process for the synthesis of saxagliptin hydrochloride 1 that has following advantages over the repor ted processes; (i) usage of hazardous reagents such as trifluoroacetic anhydride (TFAA), phosphorous oxy chloride (POCl 3 ), pyridine etc. are replaced Scheme 1: Precedented synthetic approach Scheme 2: Improved synthetic approach with non-toxic, non-allergenic and commercially available propylphosphonic anhydride (T3P) (ii) usage of numerous reagents, which are needed purifications or acid base treatments for removal such as HOBt, TFAA are avoided (iii) column chromatography purifications for the removal of the related compounds/impurities are avoided and (iv) one pot synthesis was developed for the penultimate intermediate of saxagliptin hydrochloride 1.

Table 1 : Condensation of 2 and 3 with different coupling agents Entry Reagent Base Solvent Reagent equiv. c Purity (%)
a N-Methylmorpholine, b N,N-Diisopropylethylamine, c Isolated crude compound purity.

Table 2 : Condensation of 2 and 3 with different T3P solutions Entry a
a T3P reagent available in 50% solution , b Isolated crude compound purity

Table 3 : Dehydration of 4 with different regents Entry Reagent
Solvent Temp (°C) Yield (%) Time (h) a Purity (%)a Isolated crude compound purity