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Evolution of a Manufacturing Route to Omarigliptin, A Long-Acting DPP‑4 Inhibitor for the Treatment of Type 2 Diabetes John Y. L. Chung,*,† Jeremy P. Scott,*,‡ Camille Anderson,§ Brian Bishop,‡ Nadine Bremeyer,‡ Yang Cao,† Qinghao Chen,† Robert Dunn,† Amude Kassim,† David Lieberman,‡ Aaron J. Moment,§ Faye Sheen,‡ and Michael Zacuto† Department of Process Chemistry, §Department of Chemical Process Development & Commercialization, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States ‡ Department of Process Chemistry, Merck Sharp and Dohme Ltd, Hertford Road, Hoddesdon, EN11 9BU, United Kingdom Downloaded via 80.82.77.83 on June 17, 2018 at 07:09:44 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
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ABSTRACT: Development of a convergent synthesis of omarigliptin (MK-3102) suitable for commercial manufacture is described. The target molecule is assembled through a diastereoselective reductive amination of a highly functionalized pyranone with a mesylated pyrazole followed by deprotection of a Boc group. The synthesis of the pyranone relies on three Ru-catalyzed reactions: (1) a DKR reduction of a rac-α-aminoketone to set the two contiguous stereogenic centers, (2) a cycloisomerization of a bis-homopropargylic alcohol to a dihydropyran, and, finally, (3) a Ru-catalyzed oxidation of a pyranol to the desired pyranone. The regioselective synthesis of a N-Boc-1-mesyl pyrazole fragment was achieved via base-promoted mesyl group isomerization to afford 30:1 selectivity. A highlight of the endgame process development is telescoping a Boc deprotection and reductive amination followed by direct crystallization of the penultimate from the reaction mixture. This avoids handling of an unstable, mutagenic 1-mesylpyrazole BSA salt used in the earlier multikilogram deliveries and improves the overall diastereoselectivity and efficiency of the route.
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INTRODUCTION
RESULTS AND DISCUSSION Initial Multikilogram Deliveries of Omarigliptin (1). A critical evaluation of the endgame of the discovery chemistry route indicated that the most salient issue to be addressed was the lack of regiochemical control over the N-sulfonation of the pyrazole moiety embedded within 1 (Scheme 2). An approximately 1:1 mixture of the two N-sulfonated regiochemical isomers, 14 and 15, was typically obtained when using NaH and MsCl to sulfonate 13, requiring chromatographic purification,6 an operation that becomes prohibitive as the scale of operation increases. 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 known intermediate 3,5 which could be accessed by the diastereoselective reductive amination of pyranone 5 with pyrazole 7 (Scheme 1). 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 acetylated impurity 17 that 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
Type 2 diabetes mellitus is a growing worldwide epidemic affecting more than 366 million people globally, including nearly 26 million people in the United States.1 Commercial proof of concept for dipeptidyl peptidase-4 (DPP-4) inhibitors has been established with Merck’s sitagliptin,2 which was the first once-daily DPP-4 inhibitor approved by the FDA in October 2006. Subsequently, additional DPP-4 inhibitors have entered the marketplace.3 Given the clinical success of DPP-4 inhibitors, there has been interest in generating structurally diverse potent drug candidates with longer half-lives that are amenable to once-weekly dosing. Merck Research Laboratories recently discovered 1 (omarigliptin, MK-3102) (Scheme 1), a highly functionalized and structurally differentiated long-acting DPP-4 inhibitor,4 that recently received marketing authorization in Japan for the once-weekly treatment of type 2 diabetes. The scalable, first-generation synthesis of a forerunner of 1, namely, 2, which differs only by a mesyl group, was recently reported.5 We adopted similar chemistry for the initial kilogram deliveries of 1 by mesylation of 3 followed by Boc deprotection. Although the process was productive and capable of supporting the program through development, this was not a process that met our standards for commercial manufacture. Significant improvements were made to the first-generation synthesis of Boc-ketone 5 to improve the robustness and reduce both process mass intensity and cost of goods. Herein, we report the evolution and development of an efficient process for multikilogram scale synthesis of omarigliptin amenable to manufacturing scale. © 2015 American Chemical Society
Received: August 18, 2015 Published: October 1, 2015 1760
DOI: 10.1021/acs.oprd.5b00267 Org. Process Res. Dev. 2015, 19, 1760−1768
Organic Process Research & Development
Article
Scheme 1. Retrosynthetic Analysis of Omarigliptin (1)
Scheme 2. Discovery Chemistry Pyrazole N-Sulfonation
Scheme 3. First Multikilogram Delivery of Omarigliptin (1)
diastereomer present. The diastereoselectvity of the reduction was 16:1. With intermediate 3 in hand, screening of the mesylation indicated that amine bases such as Et3N and pyridine when used in combination with mesyl chloride favored undesired regioisomer 16 with as high as 9:1 selectivity. Moving to stronger K and Na metal bases provided more encouraging results, with selectivities as high as 1:8 favoring desired isomer 4 under certain conditions. A key observation was made when using NaHMDS, namely, that the selectivity of the reaction improved as long as there remained some 3 present within the reaction mixture (or more specifically the Na anion of 3, vide inf ra). Once all of 3 had been consumed to 4 and 16, no further change in the ratio of 4:16 occurred on extended aging. Application of DOE to one set of reagents (NaHDMS as base, MsCl as mesylating agent in DMF) indicated that the regioselectivity was not directly dependent on concentration,
temperature, or reagent equivalents. In addition, the regioselectivity was not dependent on the age time when preforming the anion prior to MsCl addition. A slow addition of MsCl resulted in high regioselectivity for the desired 4 (up to 1:68 in favor of 4 in the reaction mixture). Our mechanistic hypothesis for these observations is that undesired 16 can serve as a mesylating agent under the reaction conditions and undergoes turnover to the more thermodynamically stable isomer 4. Optimized conditions required a balance between the amount of unconverted 3 left over at the end of reaction and achieving a high regioselectivity for the penultimate intermediate, 4. Ultimately, for this first kilogram delivery, conditions of 2.0 equiv of NaHMDS and 1.75 equiv of MsCl in DMF were used, with the addition of MsCl occurring over 4−6 h. The desired 4 crystallized toward the end of addition, and following addition of water as antisolvent, it could be 1761
DOI: 10.1021/acs.oprd.5b00267 Org. Process Res. Dev. 2015, 19, 1760−1768
Organic Process Research & Development
Article
Scheme 4. Evolution of the Synthesis of Boc Pyrazole 13
DMF·DMA, eliminated the silica gel chromatography, and utilized mild dehydration conditions to retain the Boc group. In addtion, the levels of mutagenic impurities (such as hydrazine, methyl tosylate) in the downstream steps were estimated through purge factor calculations8 and/or confirmed by analysis to be significantly below threshold of toxicological concern (TTC) levels. Building on the discovery of the regioselective sulfonation of intermediate 3, whereby an initially formed mixture of regioisomers was converged to the desired isomer 4, we sought to develop a related process for the sulfonation of Boc-pyrazole 13 (Scheme 5). While application of our previously developed
isolated in 74% yield (96 A% purity) with regioisomer 16 present at just 0.1 A%. Deprotection of the Boc group within 4 proved to be challenging. This was due to competitive cleavage of the mesyl group to form undesired byproduct 2. From a screen of acid and solvent combinations, benzenesulfonic acid (BSA) in dichloromethane as solvent emerged as the most promising, with levels of 2 suppressed to around 3.0 A% in the reaction mixture. Extended aging led to an increase in the level of 2, and as such, the reaction was typically quenched with around less than 2.0 A% of 4 remaining. A further impurity that proved to be problematic was the formation of N-benzenesulfonated 18, which occurred during basification in the workup and is speculated to occur by besylation with the mixed anhydride formed from benzenesulfonic acid and the mesyl portion cleaved from 4. The final level of 18 was ultimately controlled through recrystallization, and application of the deprotection conditions afforded crude omarigliptin (1) in 78% yield (1.7 A % 18), followed by recrystallization from EtOAc to give pure 1 in 72% yield with 1.0 A% of 18 present. In a subsequent kilogram campaign, the addition of water (0.2 wt %) was found to suppress the formation of 18, and omarigliptin could be isolated in an improved 73% yield without the need for recrystallization (vs 56% for the previous campaign). Process Development for Manufacturing Scale. While significant progress to solving the N-sulfonation regiochemical problem was made during the first kilogram campaign to 1, specifically on fully elaborated intermediate 3, it was considered desirable to move back to the more convergent approach, wherein mesylated pyrazole 8 is coupled with pyranone 5, followed by a final Boc deprotection to form omarigliptin (Scheme 1). In so doing, we expected to be able to utilize our knowledge gained in the sulfonation of 3 to pyrazole 13 and turnover any of the undesired regioisomer 15 that might form to 14. In addition, focused process development on other steps on the routes to pyrazole 8 and pyranone 5 was pursued to reduce cost, improve processability and scalability, and address safe handling as well as other aspects associated with readiness for manufacturing scale operations. Process Development of Boc-mesyl-pyrazole 8 for Manufacturing Scale. Before embarking on the development of the selective mesylation of 13, we needed a scalable synthesis of this intermediate. The discovery chemistry route to 13 (Scheme 4, route A) employed high temperatures, excess N,Ndimethylformamide dimethylacetal (DMF·DMA),7 silica gel chromatography, and a Boc reprotection, which were all undesirable. We undertook process development to address these issues, and the revised process to 13 (Scheme 4, route B) used lower reaction temperatures and fewer equivalents of
Scheme 5. Regioselective Pyrazole N-Sulfonylation
NaHMDS/MsCl conditions was studied first, unacceptably high levels of starting material 13 were typically present, and only a 63% yield of 14 was obtained with a 9:1 regioselectivity. Following screening, a telescoped process was developed whereby a kinetic mesylation with MsCl/Et3N was carried out in 2-MeTHF to afford a quantitative combined yield of 14 and regioisomer 15 that favored 15 in a 5:1 ratio. Following an aqueous workup to remove triethylamine salts and azeotropic drying, addition of 7 mol % of solid t-BuOK to the mixture afforded turnover to a 30:1 mixture that favored the desired 14. Following a recrystallization of the isolated solids, 14 was obtained in 84% yield from 13 and with
