Yi Hsiao

Highly Efficient Asymmetric Synthesis of Sitagliptin

A highly efficient synthesis of sitagliptin, a potent and selective DPP-4 inhibitor for the treatment of type 2 diabetes mellitus (T2DM), has been developed. The key dehydrositagliptin intermediate 9 is prepared in three steps in one pot and directly isolated in 82% yield and >99.6 wt % purity. Highly enantioselective hydrogenation of dehydrositagliptin 9, with as low as 0.15 mol % of Rh(I)/(t)Bu JOSIPHOS, affords sitagliptin, which is finally isolated as its phosphate salt with nearly perfect optical and chemical purity. This environmentally friendly, green synthesis significantly reduces the total waste generated per kilogram of sitagliptin produced in comparison with the first-generation route and completely eliminates aqueous waste streams. The efficiency of this cost-effective process, which has been implemented on manufacturing scale, results in up to 65% overall isolated yield.

HIGHLY EFFICIENT SYNTHESIS OF 2-AMINO-3-PYRIDINECARBOXALDEHYDE

2-Amino-3-pyridinecarboxaldehyde is synthesized in a highly efficient process via ortho-lithiation of 2-(pivaloylamino)pyridine and reaction with DMF, followed by acid hydrolysis. Major impurities were identified and were cleanly eliminated through careful choice of base and solvent.

Preparation of crystalline P-nitrobenzyl 2-formyl carbapenems by oxidative cleavage

Crystalline 1beta-methyl-2-formyl carbapenem pNB esters were prepared by osmium-mediated oxidative cleavage of the corresponding 2-vinyl derivatives. Reduction of the 2-formyl compounds gave the corresponding 2-hydroxymethyl derivatives, which are key intermediates for the anti-MRS carbapenem candidate (1).

Gas chromatographic analysis of the thermally unstable dimethyl methylphosphonate carbanion via trimethylsilyl derivatization.

A sensitive gas chromatographic method was developed to monitor the reaction of lithium diisopropylamide (LDA) with dimethyl methylphosphonate (DMMP) to generate the phosphonate carbanion (DMMPA). Analysis of the DMMPA was complicated due to its thermal instability and lack of a chromophore. To overcome these problems, samples were derivatized with trimethylsilylchloride (TMSCI) to form DMMPA-TMS which was sufficiently volatile and thermally stable for GC analysis. Work-up of the derivatized solution with 10 vol.% 2-propanol in hexanes was necessary to quench residual TMSCI prior to GC analysis. The presence of DMMPA-TMS and other sample components was confirmed by GC-MS analysis. This method was utilized to profile the synthesis of DMMPA as DMMP was added to LDA and then aged at -78 degrees C. Method precision for DMMPA-TMS of less than 0.2% RSD was achieved for repeat injections after normalization of the response with n-dodecane contained in the sample. Due to the thermal instability of the DMMPA, subambient derivatization temperatures were essential to the stability, and consequently, accurate quantification. Under optimized conditions, this derivatization was successfully utilized as a process monitoring tool.