Asymmetric Synthesis of Highly Functionalized Tetrahydropyran DPP-4 Inhibitor

Abstract

A practical synthesis of a highly functionalized tetrahydropyran DPP-4 inhibitor is described. The asymmetric synthesis relies on three back-to-back Ru-catalyzed reactions. A Ru-catalyzed dynamic kinetic resolution (DKR) reduction establishes two contiguous stereogenic centers in one operation. A unique dihydropyran ring is efficiently constructed through a preferred Ru-catalyzed cycloisomerization. Hydroboration followed by a Ru-catalyzed oxidation affords the desired functionalized pyranone core scaffold. Finally, stereoselective reductive amination and subsequent acidic deprotection afford the desired, potent DPP-4 inhibitor in 25% overall yield.

Evolution of a Manufacturing Route to Omarigliptin, A Long-Acting DPP-4 Inhibitor for the Treatment of Type 2 Diabetes

“…In addition, as kilogram quantities of the unprotected pyrazole 7 were available for these initial multikilogram deliveries, it was desirable to directly use 7 without the need to reprotect with a Boc group to access 13. Consequently, we set out to develop a regiochemical sulfonation of the known intermediate 3, 5 which could be accessed by diastereoselective reductive amination of pyranone 5 with pyrazole 7 (Scheme 1). 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Our first kilogram delivery began with the reductive amination of pyranone 5 with pyrazole 7 which was modified from the previously reported conditions (Scheme 3).…”

“…1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Our first kilogram delivery began with the reductive amination of pyranone 5 with pyrazole 7 which was modified from the previously reported conditions (Scheme 3). 5 Specifically a switch of solvent from DMAC to DMF was made to suppress formation of the acetylated impurity 17 which was observed to form during the subsequent sulfonation step and was attributed to the presence of low levels of residual DMAC within the isolated 3. Under these modified conditions, the desired 4 was isolated by direct crystallization from the reaction mixture in 80% yield and with 4.5 A% of the undesired diastereomer present.…”

“…5 In 2011, Takasago International Corporation introduced oxo-tethered ruthenium (II) catalyst, (R,R)-Ts-DENEB, 9 as a highly efficient asymmetric transfer hydrogenation catalyst (Scheme 6). We made a switch to this catalyst while maintaining the same reaction conditions and found the performance of this catalyst to be superior in all aspects.…”

“…In the initial development of this telescoped process, we were faced with the question of how to transition from end-of-reaction of mesyl pyrazole TFA salt in TFA (3 vol or 12 equiv) to DMAC (14 vol) solution for reductive amination with Boc ketone (5). Initial attempts involved evaporation of TFA followed by DMAC addition or adding DMAC to the TFA solution followed by concentration.…”

Enantioselective Synthesis of a Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 5 (mGluR5) Receptor via Dynamic Kinetic Resolution of α‐Amino Ketones

“…We evaluated as eries of organometallic catalysts under typical transfer hydrogenation conditions using formic acid as the hydrogen donor and 1,4-diazabicyclo[2.2.2]octane (DABCO) as the base (Table 2). [20] As urvey of several commercial variants of this catalyst revealedt hree that offered high enantioand diastereoselectivities in different solvents( entries 1-7,T able 2). [20] As urvey of several commercial variants of this catalyst revealedt hree that offered high enantioand diastereoselectivities in different solvents( entries 1-7,T able 2).…”