Preparation of a Tricyclopropylamino Acid Derivative via Simmons

Publication Date (Web): November 22, 2016. Copyright © 2016 American Chemical Society. *E-mail: [email protected]. Cite this:Org. Process Res. Dev...
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Preparation of a Tricyclopropylamino Acid Derivative via Simmons− Smith Cyclopropanation with Downstream Intramolecular Aminoacetoxylation for Impurity Control Ian S. Young,* Yuping Qiu, Michael J. Smith, Michael B. Hay, and Wendel W. Doubleday Chemical and Synthetic Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey 08903, United States S Supporting Information *

ABSTRACT: A tricyclopropylamino acid derivative was prepared via Simmons−Smith cyclopropanation of the corresponding alkene. This transformation was plagued by inconsistent conversions, and the opportunity for the removal of the structurally similar alkene contaminant at this stage and downstream via crystallization was limited. These factors combined to make control of the alkene impurity level in the active pharmaceutical ingredient (API) difficult. A removal strategy was developed that utilized downstream, in-process aminoacetoxylation to convert the alkene impurity to structurally dissimilar compounds that purged during crystallization. Using this protocol, the alkene contaminant in the subsequent intermediates, and thus the API, could be controlled to less than 0.1 area percent.



INTRODUCTION Compound 1 contains the functionalized proline substructure found within a series of molecules that were previously evaluated for the treatment of hepatitis C (Scheme 1).1 This

propanation of an alkene derivative and the N-cyclopropylsulfonyl amide installed via an “amide-type” coupling. Arriving at compound 5 as a potential starting material led to the question of in what order these two transformations should be performed. Generating the N-cyclopropylsulfonyl amide first was attractive with respect to step count (vide infra), although it was thought that it might complicate process development by introducing another acidic hydrogen during the cyclopropanation step. For the preparation of compounds utilized in the initial biological evaluation, Discovery Chemistry synthesized intermediate 6 via the palladium catalyzed cyclopropanation of 5 with diazomethane (Scheme 2). Subsequent ester hydrolysis, N-cyclopropylsulfonyl amide installation through coupling with 7, and removal of the Boc-group produced target compound 4. Although the cyclopropanation was high-yielding (92%), safety concerns regarding the use of diazomethane on kilogram scale

Scheme 1. Retrosynthesis of Active Pharmaceutical Ingredient (1)

Scheme 2. Discovery Chemistry Route to Tricyclopropylamino Acid 4

disease affects more than 180 million people worldwide2 and is typically chronic and life threatening due to serious impact on liver function. Retrosynthetically, compound 1 can be dissected via two peptide bond scissions, with the preparation of tricyclopropylamino acid derivative 4 representing the greatest synthetic challenge. It was reasoned that the peripheral cyclopropane motif of 4 could be prepared through cyclo© XXXX American Chemical Society

Received: October 8, 2016

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DOI: 10.1021/acs.oprd.6b00334 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

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was determined that the stoichiometry range tolerated for the cyclopropanation of 12 was narrow, with slightly greater than three equivalents (3.20 equiv of both dichloroacetic acid6 and diiodomethane and 3.39 equiv of diethyl zinc7) of preformed reagent being required to obtain >98% conversion to 13 (Scheme 4). A larger excess of Simmons−Smith reagent led to

and vendor lead times associated with outsourcing this transformation required the evaluation of alternative routes toward 4. Our objective was to develop a synthesis of 4 that would allow for rapid delivery of two 1−2 kg batches of API (1) to fund initial toxicology and First in Human studies. Strategy 1: Cyclopropanation Prior to N-Sulfonyl Amide Installation. Initially, alternative routes toward 4 were based on performing the cyclopropanation prior to Ncyclopropylsulfonyl amide formation. bis-Boc protection of amine 5 and dibromocarbene insertion into the alkene formed the requisite cyclopropane of 9 in good yield (95%, Scheme 3).

Scheme 4. Simmons−Smith Cyclopropanation of 12 and Two-Drop Isolation Utilized To Produce 13 for the Toxicology Delivery

Scheme 3. Routes to 4 Utilizing 5 as a Starting Material

ethylated impurities, so an increase in reagent stoichiometry to further enhance reaction conversion resulted in diminished yields of 13. Under the acidic reaction conditions, concomitant Boc-removal occurred which complicated isolation due to the water solubility of 4. As the reaction progressed, a thick slurry composed of Zn complex 13 and inorganic zinc salts formed. We decided to take advantage of the Zn-complex formation, and two isolation procedures were developed to recover Zn complexes of 4 from the reaction mixture. For the campaign to prepare material for toxicological studies, the solid material that precipitated during the reaction was collected by filtration (Scheme 4). The undesired inorganic zinc salts that coprecipitated were selectively solubilized by the addition of this solid mixture to aqueous EDTA. Careful control of the Zn:EDTA stoichiometry was required, as an excess of EDTA decomplexed zinc from insoluble 13 to produce water-soluble 4. Undercharging EDTA led to product 13 being contaminated with residual inorganic zinc salts. To ensure an isolated product free of inorganic zinc salts, we utilized a slight overcharge of EDTA (2.55 equiv EDTA vs 3.39 equiv Et2Zn) and incurred slight product loss (5−10%, typical yields of 13 = 70−80%, Scheme 4). The actual structure of complex 13 was not established, as X-ray analysis of a single crystal grown from DMSO/H2O indicated that reorganization to dimeric Zn-complexed 15 occurred (see Scheme 5). This was determined by the differences in the PXRD pattern of these single crystals and the material (13) isolated from the EDTA procedure. Although this procedure was a viable strategy for the isolation of a Zn-complexed compound 4 equivalent, several drawbacks were apparent with this process: (1) multiple filtrations; (2) sensitivity to EDTA stoichiometry; (3) residual

Subsequent removal of the bromines with tributyltin hydride/ AIBN and mono-Boc removal/hydrolysis proceeded in excellent yield (92% and 95%, respectively). To obtain 4 from 10, a strategy similar to that used by Discovery Chemistry (Scheme 2) was required. Although the key transformations proceeded in high yields, detractors from this strategy are the required five steps to arrive at 4 from 5 and the use of toxic tributyltin hydride and AIBN.3 The use of Simmons−Smith cyclopropanation4 offered an alternative that eliminated the necessity of potentially hazardous diazomethane and tin/AIBN. Subjection of 5 to the Shi modified5 Simmons−Smith produced intermediate 11, which had the Boc group removed, in 86% yield (Scheme 3). Bocremoval was undesired, and to arrive at 4 multiple protections/ deprotections would be required to install the N-cyclopropylsulfonyl amide. Both of the CHBr3/Bu3SnH and Simmons−Smith cyclopropanation procedures that utilized intermediate 5 required five steps, and implementation would be challenging to ensure on-time delivery of intermediate 4. As a result, the potentially risky but direct strategy toward 4 that formed the N-cyclopropylsulfonyl amide prior to cyclopropanation was examined. Strategy 2: Cyclopropanation of the N-Sulfonyl Amide Containing Substrate. Significant quantities (∼4.0 kg) of 12 were available from an alternative compound in our portfolio, and direct conversion of this compound to 4 could be envisioned via Simmons−Smith cyclopropanation and Boc removal. The presence of the N-cyclopropylsulfonyl amide introduced an additional acidic hydrogen, requiring an increase in Simmons−Smith reagent when compared to compound 5. It

Scheme 5. Single Isolation Process Used to Produce ZnComplexed Dimer 15 for First in Human Campaign

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DOI: 10.1021/acs.oprd.6b00334 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

precipitation of Zn-complexed 15 (Scheme 5). In addition to producing a product form of a defined structure, this modified isolation protocol was substantially easier to perform; only one isolation was necessary to produce product free of inorganic Zn salts, and difficulties associated with using EDTA were eliminated. Although a substantial improvement with regards to processing, we were disappointed to find that this solventswap isolation offered no reduction of the alkene impurity 17 that resulted from incomplete cyclopropanation. Fate and Tolerance of the Alkene Impurity en Route to the API. Due to the new form (15) of Zn-complexed 4 offering little to no rejection of the alkene impurity, we focused our attention on increasing reaction conversion. It was found that charging additional preformed Simmons−Smith reagent once the reaction had stalled had no effect on starting alkene consumption. The inconsistencies in the conversion to 13 are thought to result from uncontrolled Boc removal that occurs during the 4−6 h required for reaction. Once the Boc group was removed, whether pre- or post-cyclopropanation, the material would precipitate as the insoluble Zn complex 13/14 preventing further cyclopropanation. Alternative reaction solvents8 and additives9 were found to inhibit premature precipitation, but at a great cost to conversion. With the constraints imposed by the delivery timelines, it appeared that we might not be able to develop a control strategy to reduce the alkene contaminant at this stage. Approximately 1.2 kg of substrate 12 remained in inventory after preparation of the toxicology material, which allowed us to run three cyclopropanation batches of ∼400 g. To meet our clinical API delivery requirements in terms of quantity (1.5 kg) and quality (