The First Kilogram Synthesis of Beclabuvir, an HCV NS5B Polymerase

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Cite This: Org. Process Res. Dev. 2018, 22, 1393−1408

The First Kilogram Synthesis of Beclabuvir, an HCV NS5B Polymerase Inhibitor Jeffrey Bien, Akin Davulcu, Albert J. DelMonte,* Kenneth J. Fraunhoffer, Zhinong Gao, Chao Hang, Yi Hsiao, Wenhao Hu, Kishta Katipally, Adam Littke, Aghogho Pedro, Yuping Qiu, Maria Sandoval, Richard Schild, Michelle Soltani, Anthony Tedesco, Dale Vanyo, Purushotham Vemishetti, and Robert E. Waltermire

Org. Process Res. Dev. 2018.22:1393-1408. Downloaded from pubs.acs.org by UNIV OF SUNDERLAND on 11/02/18. For personal use only.

Chemical and Synthetic Development, Bristol-Myers Squibb Company, One Squibb Drive, P.O. Box 191, New Brunswick, New Jersey 08903, United States ABSTRACT: The process development and kilogram-scale synthesis of beclabuvir (BMS-791325, 1) is described. The convergent synthesis features the use of asymmetric catalysis to generate a chiral cyclopropane fragment and coupling with an indole fragment via an alkylation. Subsequent palladium-catalyzed intramolecular direct arylation efficiently builds the central seven-membered ring. The target was prepared in 12 linear steps with five isolations in an overall yield of 8%. KEYWORDS: asymmetric, cyclopropanation, direct arylation, palladium, rhodium, catalysis

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INTRODUCTION The hepatitis C virus (HCV) is transmitted through infected blood and currently affects an estimated 2−3% of the world’s population. 1 Infection with hepatitis C is frequently asymptomatic but left untreated often leads to cirrhosis of the liver, liver failure, hepatocellular cancer, and even death. In the not too distant past, most infections were treated with PEGylated interferon-α and ribavirin. Treatment typically lasted 24−48 weeks and was physically demanding, as patients often experience flu-like side effects. Fortunately, for those afflicted with HCV, there have been a number of modern treatments that offer reduced side effects and shortened treatment duration.2,3 In addition, many patients are treated with combinations of these drugs and experience even greater cure rates. The HCV NS5B RNA polymerase is an attractive target for drug inhibition because it is required for HCV replication. The potential for a very selective inhibitor exists, as there is no analogous enzyme in human cells. It was for this purpose that beclabuvir (BMS-791325, 1) was selected as a potential drug candidate for the inhibition of HCV NS5B RNA polymerase.4 This paper details the development of a convergent chemical route and production of multikilogram quantities of 1, which were required to meet initial toxicological and clinical supply material demands.

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(9) utilized in the synthesis of 10, as we believed that it would require extensive development to understand and control potential polymerization challenges. New Route Strategy. Although a number of potential synthetic approaches were considered, we concentrated our efforts on the identification of a convergent route. As shown in the retrosynthetic analysis (Figure 1), a disconnection strategy leading back to an achiral indole fragment (16) and a chiral cyclopropane fragment (17) was envisioned. When considering the variety of options within this strategy, we leveraged existing knowledge. Work by our Discovery colleagues suggested that a final coupling of intermediate 13 with bridged piperazine 14 was preferable, as they found that this approach afforded 1 in higher purity than alternative endgames. An added benefit is that the relatively expensive bridged piperazine 14 is introduced in the final step. Published work by Kosikowski and Ma6 (Scheme 2) also suggested that if the indole and cyclopropyl fragments were already coupled through the carbon−nitrogen bond (as shown in intermediate 15), an intramolecular palladium-catalyzed direct arylation was possible to form the seven-membered ring and produce compound 13. This was an important precedent, as the direct arylation strategy would significantly streamline the route by avoiding unnecessary steps to install a bromide on the indole and a boronic ester on the aryl group.7 The alcohol moiety of the cyclopropyl fragment had to be activated to function as an alkylating agent, and the preparation of cyclopropyl tosylate 17 not only served in this role but also imparted a high level of crystallinity, which was viewed to be advantageous at the time. Another approach to improve the convergent nature of the synthesis was to couple the indole and cyclopropyl fragments with the N,N-dimethylsulfamide moiety already installed on

RESULTS AND DISCUSSION

In order to support the clinical development, a short and efficient route was desired that addressed the challenges of the Discovery route (Scheme 1). Although this approach adequately met initial material requirements, a more convergent approach that would be amenable to rapid scaleup was desired. One aspiration for a scalable synthesis was to eliminate the late-stage achiral cyclopropanation and preparatory HPLC chiral separation, as this would greatly impact the yield and throughput. There was also concern regarding the use of the reagent methyl 2-(dimethoxyphosphoryl)acrylate © 2018 American Chemical Society

Received: July 2, 2018 Published: August 16, 2018 1393

DOI: 10.1021/acs.oprd.8b00214 Org. Process Res. Dev. 2018, 22, 1393−1408

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Scheme 1. Discovery Synthesis of 1a

a

Reagents and conditions: (a) THF, Et3SiH, cyclohexanone (77%); (b) Br2, HOAc (76%); (c) NaOH, THF, MeOH (99%); (d) CDI, THF; (e) N,N-dimethylsulfamide, DBU, THF (74%); (f) Pd(PPh3)4, LiCl, Na2CO3, EtOH, toluene (88%); arylboronic acid aldehyde 7 was synthesized in four steps;5 (g) Cs2CO3, DMF (71%); (h) trimethylsulfoxonium iodide, NaH, DMSO (83%); (i) Chiracel-OJ chromatography, 44% recovery (50% theoretical); (j) NaOH, THF, MeOH, H2O (86%); (k) TBTU, DIPEA, DMF; (l) chromatography, MeOH, CH2Cl2 (70%).

modified to iteratively evolve the synthesis into a commercially viable route without having to modify the overall strategy. Synthesis of Indole Fragment 16. Scheme 3 reveals our synthesis of indole fragment 16. We adopted a reductive alkylation and hydrolysis approach to prepare indole 18. A telescoped multistep process was utilized to install the N,Ndimethylsulfamide to afford 16. The literature method for the reductive alkylation8 afforded only a 36% yield of 3 when the reaction was conducted with Scheme 3. Synthesis of Indole 16

Figure 1. Revised retrosynthetic analysis of 1.

Scheme 2. Precedent of Direct Indole Arylation To Form a Seven-Membered Ring

the indole 16, obviating the need for ester hydrolysis and sulfamide coupling in the endgame of the synthesis. There are several practical advantages to this synthetic approach: (1) the convergent nature leads to a more efficient synthesis; (2) the earlier introduction of the chiral cyclopropane results in higher throughput even if a resolution is required; (3) the syntheses of the individual fragments can be 1394

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control feature from a safety perspective. Boc protection of 19 effectively led to the formation of intermediate 20, which upon treatment with N,N-dimethylsulfamide and 1,8diazabicyclo[5.4.0]undec-7-ene (DBU) afforded intermediate 21. DBU was found to perform better than triethylamine (TEA), diisopropylethylamine (DIPEA), Cs2CO3, pyridine, and 1,4-diazabicyclo[2.2.2]octane (DABCO). Although acidic conditions were effective at removing the Boc protecting group, the associated CO2 offgassing was a concern, as it was not easily controlled. However, basic conditions at an elevated temperature (65 °C) were effective at removing the Boc group from 21 and allowed for addition-controlled evolution of CO2 during the subsequent neutralization with HCl. A number of solvents were screened for this reaction sequence, with dichloromethane (DCM), acetonitrile (ACN), tetrahydrofuran (THF), dimethylformamide (DMF), and dimethylacetamide (DMAc) all demonstrated to be viable. Ultimately, DCM was chosen because it allowed for a facile distillative swap to IPA for the basic hydrolysis of the Boc group. By means of this approach, 38 kg of indole 16 was produced with 98.9−99.3 HPLC area percent purity in 65.6−76.6% yield in two batches. These results were also duplicated in a subsequent campaign in which 254 kg of 16 was prepared with 99.4−99.7 HPLC area percent purity in an improved yield of 76.3−77.4% in four batches. Overall, the synthesis of indole fragment 16 was conducted in six chemical transformations, but only three isolations, in 53% overall yield. Synthesis of the Chiral Cyclopropane. Multiple potential approaches to the cyclopropane fragment were considered. During our investigations, acid alcohol cyclopropane 23 (Scheme 4) emerged as a key intermediate in the

cyclohexanone. The original conditions were optimized for order of addition, acid, temperature, stoichiometry, solvents, and crystallization conditions. The modified process involved the controlled addition of trifluoroacetic acid (TFA) to a cold (0 °C) toluene mixture of 2, Et3SiH (3 equiv), and cyclohexanone (2 equiv) while the temperature was maintained at ≤20 °C. The reaction mixture was slowly warmed to 20−25 °C and monitored for reaction conversion. Upon reaction completion, the addition of petroleum ether produced a suspension. Filtration followed by washing and drying of the cake directly afforded the crystalline material. This process was demonstrated on pilot scale and afforded 89 kg of 3 in 64.7− 69.9% yield with >99.6 HPLC area percent purity over two batches. These procedures were repeated in a subsequent campaign and afforded 374 kg of 3 in 74.5−75.3% yield9 with >99.3 HPLC area percent purity over four batches.10 The hydrolysis conditions for the conversion of 3 to 18 were optimized for concentration of base, temperature, solvents, and crystallization conditions. The optimized conditions required the treatment of 3 in 2 N NaOH solution (6 L/kg)11 and isopropyl alcohol (IPA) (6 L/kg) at 75 °C. Increased concentrations of NaOH led to transesterification with IPA. Upon reaction completion, the mixture was cooled to 50 °C and neutralized with 2.5 N HCl to pH ≤ 1, resulting in a white suspension. Cooling to 25 °C and filtration afforded the desired product 16. This process was demonstrated on scale and afforded 39.9 kg in 95.2−96.5% yield with 99.8−99.9 HPLC area percent purity over two batches. These results were also duplicated in a subsequent campaign that afforded 342 kg in 96.2−97.2% yield with 99.6−99.7 HPLC area percent purity over four batches. The coupling of 18 with sulfonamide proved more challenging than initially anticipated. Although the desired product 16 was obtained when indole 18 was subjected to 1,1′carbonyldiimidazole (CDI)-mediated coupling conditions analogous to those used successfully for the 2-bromo analogue 5, unexpectedly high levels of impurity 22 (Figure 2) were also

Scheme 4. Synthesis of Cyclopropane Fragment 17

synthesis of tosylate 17. Intermediate 23 was not only highly crystalline but also formed a highly crystalline intermediate with (R)-α-methylbenzylamine ((R)-AMBA) to afford 23·(R)AMBA. These crystalline properties provided flexibility to the synthetic approach to either leverage chiral salt formation as a way to conduct a resolution of racemic 23 or as a tool to upgrade 23 of moderate enantiomeric excess (ee). 23·(R)AMBA could then be converted to tosylate 17 via an esterification and subsequent tosylation reaction (vide infra). We envisioned that cyclopropane 23 could be produced by functional group transformation of vinylcyclopropane 24, as shown retrosynthetically in Figure 3. The seminal work by Davies13 was clear precedent for the synthesis of trisubstituted cyclopropane 24 with good enantioselectivity from the tetrakis[1-[[4-alkyl(C 1 1 −C 1 3 )phenyl]sulfonyl]-(2S)pyrrolidinecarboxylate]dirhodium (Rh2(S-DOSP)4)-catalyzed reaction between vinyldiazoacetate 25 and styrene 26.

Figure 2. Indole coupling impurity 22.

produced by competitive nucleophilic attack by the indole nitrogen on activated intermediate 19.12 Although impurity 22 showed some promise of being converted to the desired indole 16 under relatively harsh conditions (prolonged heating in the presence of excess N,N-dimethylsulfonamide), we believed that a more attractive approach would be to circumvent the formation of impurity 22 entirely via in situ protection of the indole nitrogen. During the development of this chemistry, we found that the optimal sequence involved generation of acyl imidazole 19 with CDI followed by Boc protection. When catalytic 4dimethylaminopyridine (DMAP) (0.2 equiv) was introduced during the formation of 19, there was no initiation period, and the offgassing was addition-controlled, which is an important 1395

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filtered off before the solution was introduced to the cyclopropanation reaction. The potency of the n-heptane solution of 25 would slowly decrease over time, but the purity of the reagent solution was always maintained.15 Styrene substrate 26 was generated in a two-step sequence (Scheme 6). In the first step, commercially available 3Scheme 6. Synthesis of Styrene 26

Figure 3. Retrosynthetic analysis of cyclopropane 23.

The synthesis of vinyl diazoester 25 involved the reaction of 27 with 4-acetamidobenzenesulfonyl azide (4-ABSA) and DBU in ACN (Scheme 5). The crude reaction mixture was Scheme 5. Synthesis of Vinyldiazoacetate 25

methoxybenzaldehye (29) was brominated in glacial AcOH at 30−35 °C. Addition of water led to direct precipitation of the crude product, 2-bromo-5-methoxybenzaldehyde (30). The resulting wet cake was reslurried with a dilute sodium bicarbonate solution to remove any residual acid, affording the desired pure 30 in 83−90% isolated yield.16 Selection of the appropriate solvent, AcOH, was critical to minimize overbromination. Aldehyde 30 was then subjected to a Wittig olefination in THF. n-Heptane was added, followed by an aqueous workup. Optimization of the reaction and workup conditions led to facile crystallization of the triphenylphosphine oxide reaction byproduct. However, the cyclopropanation reaction proved to be highly sensitive even to residual levels of triphenylphosphine oxide, so the mixture was passed through a basic alumina plug. Surprisingly, we still observed variable catalyst performance. Careful evaluation of the mixture revealed the culprit to be very low levels of triphenylphosphine (200−400 ppm). To address the trace levels of this highly impactful impurity, an oxidative wash with sodium percarbonate and hydrogen peroxide was implemented during the aqueous workup. This converted any residual triphenylphosphine to triphenylphosphine oxide, which was readily removed via the original removal strategy (crystallization and passage through a basic alumina plug). After distillative solvent reduction, pure styrene 26 was obtained as a solution in nheptane.17 Two batches were prepared on kilogram scale. The first batch was produced as a 31.2 wt % n-heptane solution in 64.7% yield, and the second batch was prepared as a 21.5 wt % n-heptane solution in 54.8% yield from aldehyde 30. With access to n-heptane streams of styrene 26 as well as vinyl diazoester 25, the cyclopropanation chemistry was investigated (Scheme 7). The reactor was charged with 1.1 equiv of 26 relative to diazoester 25 (the limiting reagent). The Rh2(S-DOSP)4 catalyst was charged, and diazoester 25 was added over approximately 1 h at room temperature. Lab experiments demonstrated that a catalyst loading of 0.2 mol % could afford a 90% solution yield with 85−86% ee. Upon scaleup, the enantioselectivity ranged between 80.6 and 83.2% ee. Upon reaction completion, n-heptane was removed via distillation, and methylene chloride was charged.

diluted with methyl tert-butyl ether (MTBE), and an aqueous workup effectively removed the DBU byproducts and ACN. This also induced crystallization of the sulfonamide byproduct, which was removed via filtration. The mixture was solventswapped to n-heptane, affording a 6−9 wt % solution of diazoester 25 in n-heptane in 75−80% yield. The removal of ACN was found to be a critical operation, as residual levels were detrimental to catalyst performance in the cyclopropanation. Controlling the ACN level to ≤0.5% (relative to the n-heptane solvent) ensured a high-quality product in the subsequent step. Before scale-up it was important to understand any stability or safety issues associated with this specific vinyl diazoester 25. Fortuitously, different from most diazo compounds, decomposition of 25 did not lead to nitrogen offgassing. The inherent reactivity of 25 instead resulted in electrocylization to form pyrazole 28 (Figure 4). In the solid state, this electrocyclization

Figure 4. Electrocyclization of 25 to afford pyrazole 28.

event had an onset temperature of 42 °C and a heat of reaction of 872 J/g. However, it was shown that in solution this reaction was solvent- and concentration-dependent.14 Calorimetry studies revealed that solutions of 25 in n-heptane with concentrations of ≤10 wt % were suitable for processing, wherein the rate of the decomposition to 28 was approximately 3−5% per day. One additional advantage of this electrocyclization decomposition mode was that the resulting pyrazole 28 was not soluble in n-heptane and could easily be 1396

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the excess 0.1 equiv of styrene 26, respectively, were produced (Figure 5). Solvent exchange to MeOH/THF and subsequent

Scheme 7. Rhodium-Catalyzed Asymmetric Cyclopropanation of Styrene 26

Figure 5. Alcohol impurities generated after ozonolysis and reduction.

introduction of an aqueous LiOH solution effected ester hydrolysis to afford a solution of lithium carboxylate 23·Li. Extraction of the reaction mixture with MTBE served to conveniently remove the two benzylic alcohols 32 and 33 along with other organic impurities, affording a relatively pure aqueous solution of 23·Li. The aqueous lithium carboxylate stream was then acidified, and the corresponding acid was extracted into dichloromethane. While the free acid is crystalline (mp >140 °C), we found that isolation from a variety of solvents failed to improve the optical purity. The dichloromethane solution was solventexchanged to IPA/water, and the resulting solution was warmed to 60 °C and treated with (R)-AMBA, resulting in the crystallization of 23·(R)-AMBA. This process performed well in the lab, furnishing an approximately 65% isolated yield of optically enriched 23·(R)-AMBA. At pilot scale, this telescoped sequence afforded 61 kg in 53% isolated yield with high chemical and optical purity (>99.0 HPLC area percent purity, >98% ee). To our knowledge, this was the first use of the Davies catalyst system on a multikilogram scale. It was ideal from a fitfor-purpose perspective, as it identified a key intermediate to control the quality and facilitate isolation of 23·(R)-AMBA, was developed very quickly, and successfully enabled the delivery of early clinical supplies. The overall route to 23·(R)AMBA was seven linear steps, but only two isolations, affording high-quality product in an overall yield of 26% (Scheme 9). It was recognized that there would be a number of challenges in the implementation of this first-generation cyclopropanation chemistry in the commercial environment. The issues identified to be addressed or mitigated with the next-generation approach19 included (1) the cost of the chiral catalyst, (2) the stability of the diazo compound and safety concerns, (3) the sensitivity of the catalyst to impurities in the substrates or reagents that could result in lower than desired ee’s or conversions, (4) the difficulty of directly isolating material in high yield and ee from a reaction stream with only 82−86% ee, and (5) the need for specialized equipment and facilities to accommodate the diazo chemistry as well as the ozonolysis chemistry. Conversion of the Chiral Cyclopropane to an Alkylating Agent. As mentioned previously, 23·(R)-AMBA was targeted because it could be readily converted to the desired cyclopropyl tosylate 17 through simple functional group conversions (Scheme 4). In our initial investigations, we freebased the salt and removed the (R)-AMBA, but we quickly

The crude reaction stream, which contained cyclopropane 24 and residual styrene 26 in an approximately 10:1 ratio, was then subjected to several telescoped functional group transformations to afford crystalline 23·(R)-AMBA (Scheme 8). This approach was necessary because of both the lack of crystalline intermediates and the desire to avoid diminishing the ee during isolations. Scheme 8. Telescoped Functional Group Transformations of Vinylcyclopropane 24

The DCM solution of cyclopropane 24 was first cooled to −60 °C and exposed to a stream of ozonized air while the internal temperature was maintained at or below −40 °C. Upon complete consumption of 24, a methanolic solution of sodium borohydride was introduced to reduce the ozonide to the corresponding alcohol 31.18 The mixture was quenched with an aqueous HCl solution, and an extractive workup afforded a DCM solution of 31. Along with the desired product 31, the expected benzyl alcohol byproduct 32 and alcohol 33, resulting from ozonolysis and reduction of 24 and 1397

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It was determined that a 4 L/kg solution of 17 in toluene could be held for several days, even at temperatures above the conditions required for the alkylation chemistry to occur. More importantly, if uncontrolled decomposition were to occur, the toluene stream would not pose a safety risk (−30 J/g, Tadiabatic = 17 °C). The inherent stability liability of isolated 17 required us to rapidly adjust our strategy and develop a telescoped process that did not require isolation, storage, and handling of 17 as a solid. Alkylation of Indole 16. With access to indole 16 and cyclopropyl tosylate 17, we set out to develop the alkylation chemistry to couple the two fragments. Identifying the optimal reaction conditions proved to be challenging. A solvent and strong base system that could generate the relatively insoluble indole dianion and facilitate the alkylation chemistry was required. Sodium hexamethyldisilazide (NaHMDS) in DMF was selected after initial screening. While the alkylation product 15 could then be formed in good in-process yields, the crystallization also proved to be highly challenging. It was found that while pure 15 could be crystallized from THF/IPA, the crystallization was simply not robust, as it was highly sensitive to impurities (including unreacted starting materials 16 and 17), which resulted in low isolated yields and product purity. The most significant challenge with the alkylation chemistry was the sensitivity to the reagent and base stoichiometry, especially given the lack of a robust crystallization. It was critical to maintain a slight excess of indole 16 relative to cyclopropyl tosylate 17. Development work identified a narrow range of 1.05−1.10 equiv of indole 16 relative to 17 under which high conversion could be obtained with minimal remaining indole 16. In addition, it was also critical to utilize slightly less than 2.0 equiv of base relative to indole 16, with the desired range identified as 1.90−1.95 equiv. When the base was undercharged, lower in-process yields were observed and much lower isolated yields were obtained. When the base was overcharged, epimerization of the cyclopropane to compound 34 was observed (Figure 6). Even low levels of 34 resulted in dramatic losses of product to the mother liquor during the isolation.

Scheme 9. First-Generation Synthesis of Chiral Cyclopropane 23

found that this extra step was not required. Esterification could be done directly via in situ generation of anhydrous HCl with trimethylsilyl chloride (TMSCl) in EtOH. One of the challenges with the esterification is related to the fact that 23 has an alcohol functionality and can self-esterify. Although this dimerization did not impact the quality, as the ester is ultimately hydrolyzed, high levels would correspond to decreased yields, so two control points (concentration and temperature) were identified. The concentration of 9 L/kg was a good balance between minimizing the dimer formation observed under high-concentration reaction conditions and managing volumes for efficiency, throughput, and cost. Upon reaction completion, the bulk of the ethanol was removed via distillation, again to control volumes. Operating under vacuum allowed the temperature to be maintained at ≤40 °C, thus minimizing further dimerization. After an aqueous workup that served to remove the 1 equiv of (R)-AMBA, the final toluene solution was azeotropically distilled. Development of the tosylation reaction quickly identified DABCO and tosyl chloride (TsCl) as the ideal reagents. DABCO not only served as a base but also activated the TsCl and promoted fast reactions (1−2 h).20 The toluene stream was treated with DABCO and TsCl to generate the desired tosylate 17 in high in-process yield (>90%). The levels of the dimer were typically at 0.6−1.1 HPLC area percent. After an aqueous extraction, the mixture was azeotropically distilled under vacuum, and the product was crystallized by charging heptane, resulting in good purging of the dimer (99.6 HPLC area percent purity and 99.97 HPLC area percent purity and >99.9% ee in four batches. A

Scheme 14. EDAC/HOBt Coupling of 13·K and 14 To Produce BMS-791325·HCl (1·HCl)

MeTHF did not perform well; specifically, the reaction proceeded at a lower rate compared with the reactions in acetonitrile and THF, presumably because of diminished solubility of the reaction components in 2-MeTHF. As discussed above, our initial development work and scale-up to produce intermediate 13 would inevitably contain high levels of water and EtOH (∼10% by weight). In the API step, EtOH was shown to generate the ethyl ester impurity, and excess water caused reaction stalling. As a result, the API step required modification to contend with these contaminants. Azeotropic removal of EtOH and water was found to be an effective solution, and in this regard, acetonitrile proved to be far superior to THF in its ability to purge EtOH and water via azeotropic distillation. Thus, acetonitrile was selected as the reaction solvent. The primary impurities of concern in the amidation chemistry are N-acylureas 43 and 44 (Figure 9), which form

Figure 9. Observed N-acylurea impurities 43 and 44.

via isomerization of the primary O-acylurea.23 These compounds are dead ends on the reaction pathway. They form in approximately a 2:1 ratio favoring isomer 44. Implementation of HOBt at loadings of >0.5 equiv minimized the formation of impurities 43 and 44. From the perspective of overall reaction purity/impurity profile and reaction rate (our targeted time to reaction completion was ≤10 h), 1.15 equiv of HOBt was found to be an optimal loading. The other components in this reaction (EDAC, DIPEA, and bridged piperazine 34) were not subjected to extensive rangefinding studies at the time of initial scale-up. The loadings of EDAC and 14 were simply adjusted to match the HOBt 1401

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Scheme 15. Complete Linear Synthesis of BMS-791325·HCl (1·HCl)

subsequent delivery afforded 68.9 kg in 78.5% average yield27 with >99.6 HPLC area percent purity and >99.9% ee in three batches. One of the challenges with the crystallization of BMS791325·HCl is the fact that up to 16% of the product often remained in the mother liquors postcrystallization despite all efforts to optimize the antisolvent ratio and temperature of the crystallization. This was identified as something that would have to be addressed in subsequent development work.

from vendors were used as received, unless otherwise noted. NMR spectra were recorded on a Bruker DRX-400 or AVANCE III 600 MHz instrument and are referenced to residual undeuterated solvents. The following abbreviations are used to denote multiplicities: br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. High-resolution mass spectrometry (HRMS) was performed on an Agilent 6230B TOF instrument. Preparation of Methyl 3-Cyclohexyl-1H-indole-6carboxylate (3). To a reactor were charged methyl indole6-carboxylate (2) (85.0 kg, 485.2 mol, 1.0 equiv) and toluene (206.0 kg). The resulting slurry was stirred for 15 min at 20 °C. To this mixture was charged cyclohexanone (94.0 kg, 957.7 mol, 2.0 equiv) while the temperature was maintained at 20 °C. To the solution was charged Et3SiH (172.0 L, 1479.2 mol, 3.0 equiv) in three portions. The mixture was cooled to 0 °C. Trifluoroacetic acid (172.0 kg, 1508.5 mol, 3.1 equiv) was charged over 90 min, while the temperature was kept below 30 °C (note: this addition was exothermic and required active cooling). After the addition was complete, the reaction mixture was maintained at 20 °C and monitored for reaction completion (starting material < 3.0%). To the mixture was charged petroleum ether (155 kg). The mixture was then cooled to 0−5 °C and held for 1 h. The slurry was filtered, and the cake was washed two times with petroleum ether (78.0 kg each wash) at 0 °C. The wet cake was dried under vacuum (