Preparation of the HIV Attachment Inhibitor BMS-663068. Part 2

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Preparation of the HIV Attachment Inhibitor BMS-663068. Part 2. Strategic Selections in the Transition from an Enabling Route to a Commercial Synthesis Ke Chen, Christina Risatti, James Simpson, Maxime Soumeillant, Michelle Soltani, Michael Bultman, Bin Zheng, Boguslaw Mudryk, Jonathan C. Tripp, Thomas E. La Cruz, Yi Hsiao, David A. Conlon, and Martin D. Eastgate* Chemical & Synthetic Development, Bristol-Myers Squibb, One Squibb Drive, New Brunswick, New Jersey 08903, United States ABSTRACT: During the process of developing a synthesis to a complex molecule, multiple decisions are made regarding the strategies and tactics used to prepare key bonds. In this article, we preface a series of papers describing the development of the commercial synthesis of BMS-663068 (a potential new treatment for HIV), with an in-depth discussion of the important strategic decisions made during the process of designing and demonstrating the proposed commercial synthesis of this complex clinical candidate. We discuss the key strategic disconnections and the key experimental data used to drive our tactical decisions during development. In the remaining articles in this series, we outline the development of these enabling chemical processes into scalable procedures ready to support commercialization of this promising new medicine.

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INTRODUCTION

references regarding this unusual heterocycle, leveraging that insight into help define a new course of action. One of the key elements to the development of the commercial route to BMS-663068 was defining a robust method to generate the 6-azaindole scaffold itself. Not only are there limited methods reported in the literature for the synthesis of such systems, the chemistries reported were not amenable for preparing an azaindole with our desired substitution pattern.4 From a strategic standpoint, avoiding isolation of the parent drug (BMS-626529) had become a necessity; as noted in the previous article, the crystal form of the free acid of BMS-626529 (1) had a long, thin, needle morphologyresulting in extremely poor filtration rates. The issue was so significant that a multiweek filtration of indole 1 was needed on kilo-scale. While a temporary workaround to address this issue was designed and implemented (10.1021/ acs.oprd.7b00134), the modifications made to the synthesis introduced several new complications (Figure 1). While this revised approach was used to prepare over a metric ton of API, some of the new issues were: (a) additional steps being inserted into the linear synthesis, impacting cost, yield, throughput, and cycle time; (b) several new genotoxic compounds (GTIs) were introduced into the sequence, including the chloromethylene compound 5 (which, when tested, was also found to be an extremely potent dermal sensitizer); and (c) several additional practical issues, such as the use of corrosive and hazardous reagents (i.e., chlorine gas), which is not only difficult to handle, but also difficult to charge accurately. The introduction of several GTIs was especially problematic due to the high expected dose of this compound (which at the stage of

As discussed in the prior article (10.1021/acs.oprd.7b00134), BMS-663068 (Figure 1)1 is a potential new medicine for the treatment of human immunodeficiency virus (HIV).2 This compound operates through a new mechanism of action and could offer significant benefits to patients experiencing resistance to current therapies. In this article, we discuss the planning and interrogation phase of route design, review the significant challenges embedded in the existing synthesis, and discuss key decisions made during the invention and proof-ofconcept for the eventual commercial synthesis.3 In the subsequent papers in this series, we discuss the optimization, development, and implementation of the chemical processes outlined in this article (10.1021/acs.oprd.7b00115; 10.1021/ acs.oprd.7b00152; 10.1021/acs.oprd.7b00132; 10.1021/acs.oprd.7b00133; 10.1021/acs.oprd.7b00191; 10.1021/acs.oprd.7b00135; 10.1021/acs.oprd.7b00138). The exploration of this compound leveraged a wide-ranging strategic interrogation of the structureincorporating observations, data, and reactivity trends made across numerous experiments, during research spanning several years and several project teams. The project has been present in our portfolio for some time, with various teams interrogating the chemistry of the chemotype, thus, in confronting such a long-standing challenge, the approach to problem solving was critical. To address the synthetic challenges inherent in the synthesis of this complex structure, we sought to gain an understanding of the reactivity nuances surrounding the azaindole core and apply a first-principles approach. The challenges inherent to this system are caused by the interplay of structure, electronics, and reactivity of the 6-azaindole core and the appended functionality. In setting out to redefine the synthesis of this compound, our initial review covered the data and observations from past approaches, along with prior proposals and literature © XXXX American Chemical Society

Special Issue: From Invention to Commercial Process Definition: The Story of the HIV Attachment Inhibitor BMS-663068 Received: March 27, 2017

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DOI: 10.1021/acs.oprd.7b00121 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

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Figure 1. Challenge no. 1: Pro-drug installation. [−Sar = −S(p-Cl-Ph)].

development was projected to be in the range of 1.2−1.6 g/ day). Thus, as we prioritized the challenges before us, we had two clear goals: (a) invent a new and efficient synthesis of the core 6-azaindole and (b) redesign the phosphonoxymethyl prodrug installationas the current approach propagated several of the other significant issues. More fundamentally, we sought to address the isolation of BMS-626529, which had driven the redesign of the endgame chemistry in the first place. With this in mind, understanding the interplay between the substituents and the azaindole core, product morphology, and material handling was critical to our ability to impact (either by circumventing or mitigating) the issues surrounding installation of the phosphonoxymethyl pro-drug. An additional challenge observed in the existing synthesis of this compound involved the strategy to install the 3-methyl1,2,4-triazole (12). All prior approaches leveraged a two-step

Figure 2. Challenge no. 2: triazole installation. (a) POCl3 (neat, 5 L/ kg), 100 °C, 40 h; (b) triazole 12 (3.0 equiv), 4-Me-2-pentanol, 132 °C, >48 h.

Scheme 1. Initial Synthesis of Intermediate 9a

a (a) AcOH, Ac2O; (b) Br2 (1.8 equiv); (c) HNO3 (1.1 equiv), H2SO4; (d) MeOH, TMSCl (4.0 equiv), NaNO2 (1.5 equiv); (e) DMF, DMA (2.0 equiv); (f) MeONa (7.7 equiv), CuI (0.2 mol %); (g) H2(g) (0.2 MPa), 5 wt % Pd/C (2.5 wt %).

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thermal SNAr to convert the dimethoxy azaindole 9 into the desired intermediate 11 (Figure 2). During our exploration of this chemotype, we found that the reactivity of this electronrich azaindole to direct nucleophilic aromatic substitution was very poor, resulting in SNAr processes that required extremely forcing conditions, generating only modest yield of the desired product. For example, the demethylation/chlorination was performed in neat POCl3 (5 L per kg of input) posing fundamental problems of safety, handling, workup efficiency, waste disposal, and environmental impact. The displacement of the resulting chloride with triazole 12 was similarly problematic, requiring high temperatures (∼140 °C) over the course of several days (∼60 h), generating two key impurities 13 and 14. Despite significant optimization efforts, the use of neat POCl3 in the chlorination could not be avoided, and while this chemistry was used on significant scale, it was considered unviable for the long-term supply of API. The lack of commercial viability becomes clear when placed in the context of manufacturing multimetric ton quantities of BMS-663068, the use of neat POCl3 in step 7 of a 15-step synthesis is especially daunting. In assessing the root cause of this poor reactivity to SNAr, we hypothesized that both issues were related to the early installation of the C4-methoxy, which we presumed electronically deactivates C7 to the addition of nucleophiles. Continuing our initial review, we focused on the issues relating to the length of the synthesis. In this process it became obvious that many of the challenges resulted from the use of a pyridine derivative as the key starting material for the synthesis of the azaindole core. The functionalization of pyridine, especially when forming highly substituted analogues, is a classical problem in organic chemistry.5 The formation of a tetra-ipso system, such as that present in pyridine 19, required both positions meta to the ring nitrogen to be functionalized (the two most challenging positions to modify selectively). To accomplish this via electrophilic chemistry, amino-picoline was used as the starting materialthe presence of the aniline nitrogen increasing the electron density of the ring-system, both improving reactivity toward electrophiles and increasing the regioselectivity of electrophilic additions. Starting from 2amino picoline 15, bromination and nitration were both viable processes, proceeding with good selectivity and quickly forming the tetra-ipso system. However, while this strategy was successful in functionalizing all of the desired carbons, none of the groups introduced on the resulting pyridine 19 were those required in the final molecule. Indeed, to convert intermediate 19 to the desired azaindole 9, multiple challenging functional group interconversions (FGIs) were required, namely, a Sandmeyer methoxylation, Ullmann methoxylation, condensation, and hydrogenation/cyclization (Scheme 1). After this significant effort only the intermediate dimethoxy indole 9 was formed. It was therefore apparent that leveraging pyridine as a starting material resulted in a significant number of functional group manipulations, low ideality,6 high step count, challenging technology, low overall yield, and ultimately higher cost due to the need to overcome the intrinsic reactivity of this system. An alternate approach to this molecule would have to address all of these challenges.

Figure 3. Pyridine strategies and challenges.

Figure 4. “Low-oxidation state” concept.

concepts being worked on during earlier periods of development. Collating and reviewing these concepts, from a strategic standpoint (i.e., assessing the core strategy involved in each proposal), it was clear that the majority of ideas focused on retrosynthetically targeting a pyridine analogue. A wide variety of highly creative options had been suggested, mainly intersecting the prior route through azaindole 11 (Figure 3). Reviewing these synthetic strategies against the challenges noted above, and in the context of a high volume compound with significant pressure on cost-of-goods, it was clear that leveraging a pyridine analogue as the key starting material was not optimal. Many of the suggested reactions proposed highcost processes, precious metals, and challenging transformations, inconsistent with our goals for commercial viability. In considering our design criteria for revising the synthesis, and the goals we needed to achieve, we focused on the following key challenges: (a) obviating all the isolation challenges noted above and reducing the environmental impact of the synthesis; (b) meeting challenging “cost-of-goods” targets for the commercial synthesis; (c) avoiding significant FGIs; (d) limiting the use or formation of genotoxic compounds; (e) leveraging readily available compounds (starting materials, ligands and catalysts); and (f) eliminating significant process hazards. After a thorough review, the retrosynthetic plan which offered the best potential fit against these criteria arose from the inspiration of approaching the synthesis from a lower oxidation state. The genesis of this concept was to electronically disconnect the C4-methoxy from the C7-triazole, the presumed cause of the problematic SNAr transformations. It was hoped that this proposal would enable construction of the azaindole through condensation and installation of the triazole via a new pathway (Figure 4), starting from a simple commercially available pyrrole derivative.

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RESULTS AND DISCUSSION During the time this project was in development; prior to the final route design process, a large number of proposals had been generated by the BMS chemical community, with several C



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Scheme 2. Preparation of Pyrrole Substratesa

a

(a) ClCH2COCl (1.1 equiv), AlCl3 (1.1 equiv), DCM (10 mL/g); (b) (CHO)2NNa (1.5 equiv), THF (10 mL/g).

Scheme 3. Successful Cyclizationsa

a

Conditions: (CH2O)n, (∼0.2 wt/wt), TFA (3.0 equiv), DCM (10 mL/g).

chloride functioned well on a small scale, though we were concerned about the scalability of this transformation, and thus, an alternate pathway to dioxolane 43 was developed; the bromination of pyrrole 25 following literature conditions9 could be followed by metalation under conditions developed by Knochel et al.10 The resulting magnesium complex could then be reacted with the glycine derivative 46, followed by ketalization, to give dioxolane 43 with comparable quality to the Friedel−Crafts approach (Scheme 4). A third, more efficient pathway was later invented, involving Friedel−Crafts acylation with acetyl chloride, followed by chlorination, to enable the multiton production of intermediate 43; this is discussed in Part 3 of the series (10.1021/acs.oprd.7b00115). When the Pictet−Spengler cyclization was conducted on the C4-dioxolane, with formaldehyde, the desired ring structure was generated with in situ deketalization; however, this molecule lacked both the C4-methoxy and functionality at C7 to enable the installation of the triazole (Scheme 3). We were unable to identify cyclization options which preserved functionality at C7, so we decided to investigate aromatization to the azaindole core in the hope of identifying a process to install the triazole. We initially explored methods to oxidize the system while inhibiting aromatization, to allow for approaches for triazole incorporation without the problems of the aromatic system described earlier. Thus, we attempted ideas such as proceeding via a munchnone 51. However, these high risk

In proposing the disconnection outlined in Figure 4, the exact nature of the chemistries of the forward synthesis were purposefully left undefined, focusing our team purely on the strategy of the approachthus maintaining a flexible mindset, focused on innovation and on seeking to understand the options for forming the key ring structure. Following known chemistry, we quickly prepared amino-ketone 27, which could be easily elaborated to several substrates (28−33) to test the desired cyclization (Scheme 2) to the core azaindole skeleton. Initially we hoped to maintain a functional handle at C7 during the condensative cyclization, to enable the smooth installation of the triazole. As discussed in our initial disclosure,3 out of all the conditions explored for the cyclization, only formaldehyde functioned with appropriate reactivity (i.e., a classical Pictet−Spengler cyclization, Scheme 3).7 In a forward sense, the dioxolane 43 was easily prepared; selective C3 acylation of the N-SO2Ph protected the pyrrole to produce the 3-chloroacyl pyrrole,8 displacement of the chloride by the N-formyl tosamide 41, and ketalization/deformylation gave the desired pyrrole 43 in excellent yield (Scheme 4). The installation of the dioxolane was required to gain reactivity in the cyclization, and electronic deactivation at the C3 position of the pyrrole (such as the presence of a ketone) was not tolerated in the Pictet−Spengler cyclization. In considering the viability of this approach, the initial Friedel−Crafts with chloro-acetyl D



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Scheme 4. Assembly of C-3 Pyrrolea

a

(a) ClCH2COCl (1.1 equiv), AlCl3 (1.1 equiv), DCM (10 mL/g); (b) 41 (1.2 equiv), TBABr (0.1 equiv), THF (10 mL/g); (c) ethylene glycol (1.1 equiv), TMOF (2.0 equiv), H2SO4 (20 mol %), MeOH (12 mL/g); (d) Br2 (2.0 equiv), AcOH (10 mL/g); (e) iPrMgCl·LiCl (2.5 equiv 1 M in THF solution), THF (10 mL/g); (f) HOBt (1.0 equiv), EDAc (1.2 equiv), morpholine (1.0 equiv), DMF (10 mL/g).

With one of our main challenges apparently solved (i.e., developing an efficient route to the azaindole core), we focused on addressing the lack of functionality at C7. In this regard, an obvious option was to leverage a modified Reissert reaction.12 Indeed, this transformation had been attempted previously during earlier development, though the initial work indicated that only a 1:1 mixture of the main triazole N-regioisomers (N1 and N2 addition) could be obtained. The apparent lack of regioselectivity resulted in this approach being terminated. In reviewing the data obtained during these initial studies, we felt there were additional levers that could be modified to explore the drivers of regioselectivity, especially in view of the excellent yield (>90%) and the relatively mild reaction conditions required. Thus, we decided to survey a wider variety of conditions and activating agents, and importantly we opted to vary N1-protecting groups on the azaindole (Figure 6). At this stage the focus of this study was solely on understanding the influence of sterics and electronics of the neighboring position on the selectivity of the addition process. We believed that the design of this study was a critical factor in our ability to progress this route. This detailed survey led us to several important findings. First was the discovery that the N1-protecting group on the indole could influence regioselectivity in the triazole addition, albeit only modestly. After optimization we found that a ∼3:1 ratio of desired:undesired regioisomeric products could be

Figure 5. Failed approaches to a C7-substituted azaindole.

concepts were unsurprisingly met with little success, though they were critical to explore at this stage of our interrogation (Figure 5). We therefore developed an unusual redox elimination process of conjugated sulfonamides, which enabled aromatization after the formation of the C4-methyl-enol of the forming azaindole (Scheme 5). This proved to be an interesting reaction to develop and scale. We found that on a small scale the aromatization of methyl-enol 54 required the presence of trace oxygen and, on scale, required the use of a radical initiator to proceed. For this purpose we selected cumyl hydroperoxide (CHP) over reagents such as AIBN, because it is a commodity chemical available in significant quantities due to its use in commercial acetone production, the lack of toxic byproduct formation, and ease of use.11 Scheme 5. Selected Approach to the Azaindole Corea

a

(a) (CH2O)n (0.16 g/g), TFA (3.0 equiv), DCM (10 mL/g); (b) MSA (1.5 equiv), TMOF (5.0 equiv), CHP (0.5 equiv), MeOH (12 mL/g). E



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electronics on the electrophile and wondered if the influence would translate to the triazole partner. Our first attempt in this regard used the commercially available cyano-analogue 57, replacing −Me for −CN. The use of this compound under standard Reissert conditions resulted in a highly regioselective process under basic conditions, with the desired regioselectivity being confirmed by X-ray analysis; with this result in hand, we tested the ester series −CO2R 58 and 59. In contrast to the cyano-analogue (57), basic conditions were not optimal in this case, resulting in low selectivity; conversely, acidic conditions gave the best selectivity in the ester series, with PyBroP as the preferred activator, conditions similar to those reported by Londregan et al.13 The resulting ester 60 was easily converted to the desired methyl analogue 61 via a two-stage reduction. With this result, we had two viable approaches to install the triazole, both representing significant improvements over the existing chemistry, but neither having the “feel” of an optimal process, neither in terms of step count nor the requirement for limited FGI or protecting group exchange. In continuing to explore these PyBroP conditions, we delved into the impurity profile of the reaction mixture; this revealed the production of a small amount of the C7-bromide (Figure 6). This was an extremely important observation with immediate significance; if we could optimize the formation of this side product, this transformation offered a potentially new avenue for installing the triazole through an orthogonal reaction manifold. Simultaneously to this work, we had gathered data that demonstrated that the triazole was a source of several significant challenges in the downstream synthesis. For example, the alkylation of N1 of the azaindole 3 was poorly regioselective (Scheme 6), resulting in a low yielding thiomethylation. While exploring the root-cause of this modest selectivity, we hypothesized that the triazole stabilized configurational isomers of the intermediate metalated indole serving to lower the observed N1/N6 selectivity during alkylation. This appeared to be supported by comparing the alkylation efficiency of triazole 3 to chloride 66, where a significant difference in regiochemical outcomes was observed (Scheme 6).

Figure 6. Introduction of triazole via Reissert. (a) K2CO3 (5 equiv), BnBr (1.2 equiv), MeOH (25 mL/g); (b) MTO (0.2 mol %), H2O2 (2.0 equiv), DCM (20 mL/g); (c) Ms2O (1.2 equiv), triazole 12 (1.5 equiv), THF (20 mL/g); (d) MTO (0.2 mol %), H2O2 (2.0 equiv), DCM (20 mL/g); (e) PyBroP (1.2 equiv), triazole 58 (1.5 equiv), THF (20 mL/g); (f) NaBH4 (1.2 equiv), MeOH (10 mL/g); (g) TsCl (1.5 equiv), TEA (2 equiv), THF (15 mL/g), then LiAlH4 (2 equiv).

formed when the protecting group on N1 was Bn. While this is only modest selectivity, it is comparable to the thermal conditions described previously (vide supra) with obvious advantages in reactivity. The reaction was rapid and occurred at RT (vs >60 h at ∼140 °C in the thermal SNAr process), meaning that this offered a pathway to avoid the problematic two-stage approach (chlorination/displacement). The desired isomer was easily crystallized from the reaction mixture in pure form and good yield ca. 50%. In considering the influence of N1-protecting groups, we noted the subtle influence of

Scheme 6. Selectivity in the Alkylation of C7-Modified Azaindolesa

a

(a) 6 (1.2 equiv), Bu4Nl (0.13 equiv), K2CO3 (1.5 equiv), MeCN, rt; (b) 6 (1.4 equiv), CaCO3 (2.0 equiv), Kl (1.0 equiv), NMP (10 mL/g), rt. F



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Scheme 7. Installation of Intact Side Chaina

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(a) NBS (1.2 equiv), DMF (10 mL/g); (b) 6 (1.7 equiv), Bu4Nl (0.10 equiv), K2CO3 (2.0 equiv), NMP (10 mL/g); (c) ester 70 (1.2 equiv), iPrMgCl.LiCl in THF (2.2 equiv), THF (10 mL/g).

We then turned our attention to optimizing the formation of the C7-bromide 73, formed during the reaction of the azaindole N-oxide 72 with PyBroP. Under low moisture conditions, the simple addition of PyBroP to the N-oxide in the presence of an inorganic base, such as K3PO4, generated the bromide in goodto-excellent yield. The reason for our interest in the C7bromide 73 (vide supra) was the potential for developing a catalytic method to install the triazole 12; bromides are often active to a wider range of metal mediated transformations than the corresponding chlorides, functioning in both palladium and copper mediated processes. We hoped that a ligand mediated transformation would provide a new handle for controlling the regioselectivity of the triazole addition. A wide ranging reactivity screen was therefore conducted on bromo-indole 73, surveying a variety of metals, metal sources, ligands, solvents, and other conditions. To our delight, copper mediated Ullmann−Goldberg−Buchwald15 conditions quickly showed promise, with simple diamine ligands giving the best regioselectivities, favoring our desired isomer (Scheme 8). After the initial screening, trans-dimethylamino cyclohexane was shown to deliver the desired product in high yield and acceptable regioselectivityproviding intermediate 11and demonstrating a critical proof-of-concept for the use of the C7bromide in a metal mediated triazole installation. By combining several of the observations made thus far, there appeared to be three main strategic options for advancing to API (Scheme 9). The three options we considered were: (1) Simply continue from indole 11, and intersect with the previous route. With this approach we had significantly improved both yield and throughput of the azaindole formation, along with eliminating several challenging steps (nitration, chlorination, thermal triazole SNAr); alternatively, (2) Make use of the highly regioselective alkylation prior to triazole installation to alkylate bromide 73 with the chloro-methyl ether 4, moving the triazole installation to a later step in the sequenceoffering several advantages in terms of throughput. Or, (3) Avoid the thio-ether strategy described in Scheme 6 and attempt to advance bromide 73 through the keto-amide installation, and then effect a late-stage coupling with the triazole. However, this would require a return to a direct phosphonoxymethyl prodrug incorporation and isolation of the parent drug, BMS-626529 (1), both problematic steps in the original synthesis. The first option offered little, if any, improvement to the complex pro-drug installation and only impacted the preparation of the core 6-azaindole. The second proposal

Scheme 8. Cu-Mediated Ullmann−Goldberg−Buchwald Installation of Triazole 12a

a (a) MTO (0.2 mol %), H2O2 (2.0 equiv), DCM (20 mL/g), 21 °C; (b) PyBroP (1.2 equiv), K3PO4 (2.0 equiv), TFT (15 mL/g), 21−45 °C, then NaOH (2N, 8 mL/g), IPA (8 mL/g), 21 °C; (c) triazole 12 (1.5 equiv), trans-DMCHDA (1.5 equiv), CuI (15 mol %), KOtBu (2.5 equiv), MeCN (15 mL/g), 80 °C.

In seeking to maximize the impact of the C7-bromination with respect to the current method of pro-drug installation, we investigated new ways to conduct the C3 acylation that would allow us to maximize the regiochemical outcome of the indole alkylation with chloro-methyl thio ether 6 (Scheme 7). Accordingly, 7-chloroazaindole 10 (available from the previous route, not shown)4a was brominated with excellent C3 selectivity. Alkylation of the C3 bromide proceeded in both high yield and chemoselectivityin line with our previous observations. The C3-bromide 69 then offered a functional handle to leverage a more convergent approach for installing the side chain. The selective metalation of the C3 bromide (over the C7 chloride) could be easily accomplished using isopropyl magnesium chloride lithium chloride complex (Turbo Grignard)following the selectivity patterns established by Knochel et al.14 In this manner, the entire side chain of 71 could be installed, with obvious advantages in convergency (Scheme 7). However, this approach was limited by the requirement for thermal addition of the triazole into the C7-chloride, and despite significant effort, the chloro-analogue was not suited to metal mediated processes. While we ultimately obviated the need for this strategy, the reactivity pattern and clear demonstration of the impact of the triazole on N-alkylation regioselectivity were important pieces of data to enable us to identify a viable path forward. G



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Scheme 9. Potential Strategies To Complete the Synthesis

Scheme 11. Late-Stage Ullmann Installation of Triazole 12a

Figure 7. Improved morphology of the Li salt of indole 1.

a

(a) Triazole 12 (1.5 equiv), trans-DMCHDA (1.5 equiv), KOH (45 wt % aq., 2.1 equiv), CuI (20 mol %), MeCN (7 mL/g), 78 °C, 12 h.

the in-process purity was low, and significant optimization would be required. Additionally, Strategy 2 also failed to address the issue of the pro-drug installation [namely, the use of Cl2(g) and generation of GTIs]. Therefore, the final strategy (3) appeared to offer the most advantages in terms of step count and potential to increase yield and to improve throughput. In addition, this final strategy also eliminated the largest number of issues (addressing all the core challenges). However, considering this high-risk, high-impact option meant reconsidering the issues surrounding the morphology and physical characteristics of the parent drug, BMS-626529 (1) (vide supra), and the challenge of installing the phosphonoxymethyl prodrug. In this proposal, an important consideration was that the indole 75 would become our antepenultimate; thus control over quality and the ability to efficiently isolate a stable crystalline form of 1 were critical components to success. To explore this approach we first needed to solve the issues surrounding the morphology of the parent drug substance 1. The morphology of indole 1, the parent drug substance (BMS-626529), had been extensively studied prior to this work. Due to its poor morphology, low solubility, and limited

Figure 8. Potential coordination of 1 to lithium.

Scheme 10. Formation of Amide 75a

a

Conditions: (a) MeO2CCOCl (2.0 equiv), AlCl3 (4.3 equiv), DCM/ MeNO2 then NaOH; (b) CDI (1.1 equiv), 76 (1.0 equiv), MeCN.

improved both regioselectivity and yield in the thio-etherification process, and while the Cu-mediated triazole installation gave high regioselectivity with the thio-ether 74, H



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Figure 9. Process for the salt metathesis of K-1 to Li-1 and relative solubilities in MeCN.

Figure 10. Completed synthesis of BMS-663068. (a) ClCH2COCl (1.1 equiv), AlCl3 (1.1 equiv), DCM (10 mL/g), 21 °C; (b) 41 (1.2 equiv), TBAI (0.1 equiv), THF (10 mL/g), 60 °C; (c) ethylene glycol (1.1 equiv), TMOF (2.0 equiv) H2SO4 (20 mol %), MeOH (10 mL/g), 60 °C; (d) (CH2O)n (0.16 wt %), TFA (3.0 equiv), DCM (10 mL/g), 20 °C; (e) TMOF (5.0 equiv), MSA (1.5 equiv), CHP (0.5 equiv), MeOH (12 mL/g), 30 °C; (f) MTO (0.2 mol %), H2O2 (2.0 equiv), DCM (20 mL/g), 25 °C; (g) PyBroP (1.1 equiv), K3PO4 (5.0 equiv), TFT (∼15 mL/g), 20 °C for 3 h then 50 °C for 2 h, followed by NaOH (2.0 N, 8 mL/g), IPA (8 mL/g), 80 °C; (h) methyl oxalyl chloride (2.0 equiv), AlCl3 (4.3 equiv), DCM (8 mL/g), MeNO2 (2 mL/g), 0 °C; (i) NaOH (10 N, 3.5 equiv), 20 °C; (j) CDI (1.7 equiv), amine 76 (1.3 equiv), DMF (13 mL/g), 25 °C; (k) triazole 12 (1.5 equiv), KOH (45 wt % aq, 2.2 equiv), water (10 equiv), CuI (20 mol %), trans-DMCHDA (1.5 equiv), MeCN (7 mL/g), 78 °C, 12 h then LiBr; (l) K3PO4 (1.0 equiv), chloride 79 (1.3 equiv), TEAI (0.5 equiv), MeCN (6.5 mL/g), 45 °C; (m) AcOH (1.8 mL/g), water (0.9 mL/ g), TRIS (1.0 equiv), 35 °C, acetone.

simple questionwhat about “pharmaceutically unacceptable” options? The first, and most obvious, omission from the previous studies was lithium; thus, this was the first salt investigated. To our delight, the initial experiment yielded a new crystalline form of indole 1. The first microscope image of this new form is shown; while the first test did not result in a pure phase, several interesting features, larger particles, and a new morphology can be clearly seen (Figure 7). Further optimization and development of the new process resulted in an easily filtered and readily isolated compound with a rod morphology. While we

bioavailability, significant effort had been expended interrogating salt forms of 1, without significant improvement in physical characteristics being noted. Within the process chemistry team, we decided to confront this conclusion and conducted an extensive review of the prior art. In taking a fresh look at the data it was apparent that all of the salts and cocrystallizing agents explored with this compound were “pharmaceutically acceptable” options; that is, everything explored was considered safe to be included in the drug substance. As this compound was not the final drug substance (it was an intermediate toward the pro-drug), we asked a I



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have yet to obtain an X-ray crystal structure of the Li-salt, the lithium counterion appears unique in its complexation with indole 1. One explanation for the improved morphology of Li-1 derives from the ability of lithium to complex with the betaketo amide at C3 (Figure 8), rather than being localized on N1. This binding mode could offer a new dimension for crystal growth, resulting in the thicker more cube-like morphology observed. With this potential solution in place for the isolation and purification of indole 1, we focused on gaining a proof-ofconcept for a later-stage Ullmann coupling with triazole 12 and a direct installation of the pro-drug. While not discussed here, this re-evaluation also required ensuring the availability of the reagents needed for the pro-drug synthesis. Several issues for the long-term supply and availability of chloromethyl chlorosulfate (CMCS) were evident and caused by reagent limitations. Hence, new protocols for the preparation of CMCS,16 potassium di-tert-butyl phosphate, and chloromethyl-di-tert-butyl phosphate were discovered, developed, and reported.17 To complete the synthesis, the starting amide 75 was prepared from bromide 73 by Friedel−Crafts acylation, saponification, and amide bond formation (Scheme 10). Screening the Ullmann−Goldberg−Buchwald coupling of indole 75 with triazole 12 leveraged the insight gathered during the initial work on the simpler azaindole 11 (Scheme 11). While the Cu-mediated reaction conditions required significant additional development (see 10.1021/acs.oprd.7b00138),4e high regioselectivities and yields were obtained from the outset. Interestingly, in our initial development the coupling was highly sensitive to base counterion; initially potassium appeared critical to enable a successful transformation. To get to our desired Li-salt form Li-1 to crystallize (Figure 9), we leveraged a metathesis process and were fortunate to find a dramatic difference in solubility between the noncrystalline K-1 salt (generated in situ by the process) and the isolated crystalline Li-1the simple addition of LiBr to the reaction mixture was sufficient to crystallize the product (after a standard aqueous workup) and drive the salt metatheses equilibrium forward. The product salt was isolated as a KBr cocrystal. Further optimization identified dithiocarbamates as efficient copper scavengers18 and LiI as the optimal lithium source, which also precluded the formation of the product as a cocrystal. With the final key bond made, conversion of Li-1 into the API (BMS-663068, 2) closely mirrored the previous procedures, the optimization of which is described in articles 8 and 9 of this series (10.1021/acs.oprd.7b00135; 10.1021/ acs.oprd.7b00138).

Table 1. Selected Metrics for the Routes Utilized To Supply BMS-663068 (2) attribute steps overall yield technical issues sourcing risks GTIs highly potent ints PMI CoG riska

route 1 (initial)

route 2 (thioether)

route 3 (described here)

route 3 (post optimization)

14 4.5% y

15 3.2% y

11 5.6% n

11 11% n

y

y

n

n

2 n

many y

2 n

2 n

y

y

n

n

a

CoG risk corresponds to the use of high cost specialty chemicals, which are critical and cannot be avoided. While compounds such as PyBrOP and ligands are used in the final route described here, we were confident in our ability to remove/reduce all high cost contributors at the time of route selection, as will be shown in later manuscripts in this series.

Table 2. Projected Reduction in Several Key Metrics of Efficiency/Greenness prior route

metric steps overall yield PMI solvents + reactants (kg/kg API) PMI water (kg/kg API) energy use (MJ)8 greenhouse gas, GHG (kg of CO2 equiv)b eutrophication (kg phosphate equiv)8 genotoxic intermediates potent sensitizers

new synthesis

reduction (%)

projected yearly reductiona

15 2.3 1008

10 12.3 676

33 33

2.7 million kg

1241 69000 9600

336 31000 6600

73 54 32

7.2 million kg 300 million MJ 24 million kg

26

12

52

11 000 kg

6 1

2 0

100

a

Estimated reduction at projected peak commercial volume. bACS Green Chemistry Institute Pharmaceutical Roundtable LCA Tool v2, rev 140113.

Table 3. Reagent Reductions during BMS Clinical Development and Projected into Commercialization compound

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POCl3 Br2 Cl2 pClPhSCH2Cl CuI H2SO4 HNO3 total

CONCLUSIONS In reviewing the completion of POC for this new synthesis, it was clear that we had developed an efficient synthetic process, with only 11 linear steps. POC yields were already competitive to the well-established prior route and clearly had significant room for improvementthus, we moved ahead with optimizing this new sequence and preparing it for potential commercialization. This complex compound required a conceptually unusual synthetic plan, approaching the molecule from a low oxidation state. Several parallel workstreams were employed by the project team to gather knowledge on the reactivity of the system and identify additional areas for development. The collation of these data enabled a coherent synthetic strategy to

a b

source reduction (%)

amount avoided in R&Da (kg)

100 100 100 100

130,000 31,000 420 3,400

360,000 87,000 1,200 9,600

75 100 100

2,000 250,000 12,000 429,000

5,500 700,000 33,000 1,196,000

projected yearly reductionb (kg)

Amount avoided during development, by use of this new process. Estimated reduction at projected peak commercial volume.

be quickly defined, with the outline of the synthesis coming together within 6 months. During the course of this work we invented three transformations, along with developing a J



Article

Figure 11. Sources of the main atoms in the commercial synthesis of BMS-663068.

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ACKNOWLEDGMENTS The authors would like to thank Dr. David Kronenthal, Robert Waltermire, Rajendra Deshpande, Michael Randazzo, and Rodney Parsons for supporting this work; Dr. Wendel Doubleday, Chris Sfouggatakis, and Prof. Marty Burke and Phil Baran for useful conversations. We would also like to thank Dr. Charles Pathirana, Mr. Michael Peddicord for structural elucidation, and Dr. Qi Gao for X-ray crystallography.

significant understanding of the chemical reactivity of this system. The chemistries developed are selective, both in terms of chemo and regioselectivity, and the overall synthetic process is free of challenging reaction conditions. The stories of how these enabling procedures were developed into robust chemical procedures, demonstrating several additional important facets of chemical reactivity, are presented in the remaining articles in this series (10.1021/acs.oprd.7b00115; 10.1021/acs.oprd.7b00152; 10.1021/acs.oprd.7b00132; 10.1021/acs.oprd.7b00133; 10.1021/acs.oprd.7b00191; 10.1021/acs.oprd.7b00135; 10.1021/acs.oprd.7b00138). The synthesis described here (Figure 10) compares favorably to the prior process in all respects, a significant improvement with respect to process efficiency and greenness, and was projected to meet all project requirements and cost-of-good projections. A comparison among routes is shown (Tables 1−3). Finally, in considering this new route, it is interesting to ruminate on the source of the atoms present in the molecule (Figure 11). Breaking apart the compound to its sources, it can be seen that each atom is derived from economical, readily available, safe, and easily handled compoundsensuring a robust and secure supply chain for all raw materials and, therefore, the viability of the synthesis long-term.

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EXPERIMENTAL PROCEDURES Detailed procedures are described in the subsequent articles in this series (10.1021/acs.oprd.7b00115; 10.1021/acs.oprd.7b00152; 10.1021/acs.oprd.7b00132; 10.1021/acs.oprd.7b00133; 10.1021/acs.oprd.7b00191; 10.1021/acs.oprd.7b00135; 10.1021/acs.oprd.7b00138).

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REFERENCES

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Bin Zheng: 0000-0002-5466-174X Thomas E. La Cruz: 0000-0002-9745-4580 Martin D. Eastgate: 0000-0002-6487-3121 Notes

The authors declare no competing financial interest. Michelle Soltani’s maiden name is Michelle Mahoney. K



Article

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Preparation of the HIV Attachment Inhibitor BMS-663068. Part 2

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