Development of a Scalable Synthesis of BMS-978587 Featuring a

Article Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Development of a Scalable Synthesis of BMS-978587 Featuring a Stereospecific Suzuki Coupling of a Cyclopropane Carboxylic Acid Prantik Maity,† V. V. Ramana Reddy,† Jayaraj Mohan,† Satish Korapati,† Harishkumar Narayana,† Nagesh Cherupally,† Sathishkumar Chandrasekaran,† Ravikumar Ramachandran,† Chris Sfouggatakis,‡ Martin D. Eastgate,‡ Eric M. Simmons,‡ and Rajappa Vaidyanathan*,† †

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Chemical Development and API Supply, Biocon Bristol-Myers Squibb Research and Development Center, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore-560099, India ‡ Chemical and Synthetic Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, New Jersey 08903, United States ABSTRACT: A modified synthetic route to BMS-978587 was developed featuring a chemoselective nitro reduction and a stereospecific Suzuki coupling as the key bond formation steps. A systematic evaluation of the reaction conditions led to the identification of a robust catalyst/ligand/base combination to reproducibly effect the Suzuki reaction on large scale. The modified route avoided several challenges with the original synthesis and furnished the API in high overall yield and purity without recourse to chromatography. KEYWORDS: Metal-free nitro reduction, chemoselective sodium dithionite reduction, stereospecific Suzuki coupling, 2-iodocyclopropane carboxylic acid

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INTRODUCTION Indoleamine-2,3-dioxygenase (IDO) is an enzyme that degrades the essential amino acid tryptophan into kynurenine. The depletion of tryptophan in the microenvironment of cells is believed to be one mechanism by which tumor cells escape detection and become “invisible” to the immune system.1 Overexpression of IDO has been implicated in a wide range of human cancers, while its inhibition has been shown to reinvigorate the natural immune response to cancer cells, thus fueling the quest for a potent IDO inhibitor.2,3 BMS-978587 (1) was discovered and developed within Bristol-Myers Squibb as a potent small molecule IDO inhibitor.4 To support the early development of this potential drug candidate, we needed a rapid, safe, and robust synthesis that would allow for its large-scale production. This report discloses the development of a scalable approach to BMS978587 featuring a Pd-catalyzed, stereospecific Suzuki coupling5 of an aryl boronate with an enantiomerically pure 3-iodocyclopropane carboxylic acid (6) in the key step.

corresponding boronate) with the appropriate chiral cyclopropane carboxylic acid derivative (5 or 6). While these key bond formations may be intuitively obvious, the exact sequence of executing these transformations was critical to the successful delivery of kilogram quantities of 1. The Discovery route to 1 is depicted in Scheme 2.4c Nucleophilic displacement of the fluoro group in 2-fluoro-5bromonitrobenzene 2 with i-Bu2NH via an SNAr reaction afforded 7 in excellent yields. Treatment of 7 with B2neop2 8 under Miyaura coupling conditions,7 followed by stereospecific Suzuki reaction of the resulting boronate 9 with ester 5, led to the coupled product 10. Reduction of the nitro group over Pd/ C gave aniline 11, which upon treatment with p-tolyl isocyanate 4 furnished urea 12.8 Saponification of the ester in 12 led to 1 in an overall yield of 33% over six steps from 2. While this approach worked well to provide material for early preclinical evaluation, there were a few limitations from a process perspective that prompted further investigation: (a) The nitro group was carried through three steps in the synthetic sequence (2 → 7 → 9 → 10). While designing our approach, we were cognizant of the thermochemical profile and potential genotoxicity of nitro compounds and wished to “reduce” this risk as early as possible in the synthetic sequence. (b) Enantiomerically pure (1S, 2S)-ethyl 2-iodocyclopropanecarboxylate 5 was a fairly expensive material. Introduction of this moiety early in the sequence in a low-yielding transformation was not ideal. (c) Intermediates 9, 10, and 11 were viscous oils that required chromatographic purificationan option that is generally not favored on large scale. And (d) the early installation of the cyclopropane motif before a Pd/C mediated hydrogenation (10 → 11, Scheme 2) generates

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RESULTS AND DISCUSSION Retrosynthetically, 1 can be accessed from 2-fluoro-5bromonitrobenzene 2 in three key disconnections (Scheme 1): (a) SNAr to introduce the di-isobutylamine moiety,6 (b) reduction of the nitro group followed by installation of the urea side chain by reaction with isocyanate 4, and (c) stereospecific C−C bond formation reaction of the aryl halide (via the © XXXX American Chemical Society

Received: May 24, 2018

A

DOI: 10.1021/acs.oprd.8b00171 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

Scheme 1

Scheme 2

Scheme 3

difficult-to-remove degradants resulting from the reductive opening of the cyclopropane. To overcome these challenges, we proposed a modified synthetic sequence installing the urea much earlier in the sequence (Scheme 3). It was envisioned that introduction of the urea moiety early in the route would impart crystallinity to subsequent intermediates and facilitate their isolation and purification, analogous to urea 12. Adoption of this strategy would

necessitate reduction of the nitro group early in the sequence (Step 2) and consequently address the safety concerns associated with carrying nitro compounds through multiple steps in the synthesis. However, this would require reducing the nitro group selectively in the presence of the aryl bromide. Enantiomerically pure carboxylic acid 6 was proposed as the iodo coupling partner in the key stereospecific Suzuki step instead of the corresponding ester 5. This choice has two B



Article

solvent in the presence of sodium carbonate (entry 7, Table 1). The dehalogenated impurity 16 was never observed in the sodium dithionite conditions; however, a new peak appeared in the in-process chromatograms. This was identified as the intermediate sulfamic acid 17, which converted to the desired product 13 upon workup. This protocol proved extremely scalable, leading to complete reduction within 1 h on a multikilogram scale to furnish 13 in 84% yield as a viscous oil (Scheme 5).11 The next step in the sequence was the formation of urea 14 via the coupling of 13 with p-tolyl isocyanate 4 (Scheme 6). While this reaction proceeded well in multiple solvents (MTBE, THF, n-heptane), n-heptane was chosen for scaleup for two reasons: (a) The homo urea byproduct 18 was formed in low levels in MTBE and THF (up to 1%) and was difficult to purge, both in this step and in the downstream sequence; in n-heptane, this impurity was not detected. (b) The product 14 crystallized out directly from the reaction mixture in n-heptane (which was not the case with other solvents) and was isolated in high yield and purity by a simple filtration of the reaction mixture. With pure, crystalline 14 in hand, the next step was the Miyaura coupling to provide the precursor boronate or boronic acid for the final stereospecific Suzuki reaction. While the original Discovery conditions utilized B2neop2 as the borylating agent (vide supra), we envisioned that the less expensive B2Pin2 would be a better alternative.12 Several solvents, palladium sources, and bases were evaluated for this transformation, and representative results are captured in Table 2. The best conversions were observed in 1,2-dimethoxyethane (DME) and DMAc (entries 2, 5, and 7, Table 2). As is most often the case with metal-mediated cross-couplings featuring aryl halides, the debrominated impurity 19 was formed under a majority of the conditions evaluated; however, this was suppressed by subsurface sparging of nitrogen into the reaction mixture for about 1 h before the addition of 9 (for more information, please see Experimental Section). Ultimately, the best in-process results (92% 15; 0.5% 19) were obtained by carrying out the reaction using Pd(dppf)Cl2·CH2Cl2 in the presence of KOAc in DME (entry 7, Table 2). The reaction mixture was then treated sequentially with activated charcoal and Silia MetS-Thiol to remove color, insoluble inorganics, and

major advantages: (a) The known commercial synthesis of 5 involves esterification of acid 6. The use of 6 in the synthesis will effectively remove two steps, i.e. esterification of 6 and saponification of the coupled product 12, resulting in a shorter process. (b) Ester 5 is an oil, whereas acid 6 is a solid that is easier to handle on scale. This sequence was appealing from a process chemistry perspective in that it provided a convergent approach with late-stage introduction of the most expensive fragment, i.e. the cyclopropane moiety. The modified second-generation route started with an SNAr reaction of 2 with i-Bu2NH 3 to provide 7 as crystalline reddish brown solid (Scheme 4). While the first-generation route Scheme 4

(Scheme 2) involved the use of a large excess of i-Bu2NH 3 under neat conditions, the second-generation route utilized only ∼2.3 equiv of i-Bu2NH 3 (without any external base) in 2propanol. Addition of water to the reaction mixture led to precipitation of 7, which was isolated in 97% yield. Reduction of the nitro group in 7 to the corresponding amine was challenging due to the presence of the reducible bromo functionality in the molecule. Several metal-catalyzed hydrogenation conditions as well as a myriad of other reducing conditions9 were screened in an attempt to effect clean, selective reduction of 7 to 13, and a few representative examples are provided in Table 1. Metal-mediated reductions with a variety of reducing agents including hydrogen and polymethylhydrosiloxane (PMHS) required several hours to reach completion (entries 1−3, Table 1) and/or produced significant quantities of the dehalogenated impurity 16, which was difficult to remove during isolation of intermediate 13. While reduction using sodium dithionite according to the literature protocol (CH2Cl2/H2O) led to poor conversion (entry 4, Table 1),10 it was found that the use of THF or methanol as the solvent led to much improved conversions (entries 5 and 6, Table 1). The best rates and reactivities were achieved using a MeOH/THF/H2O (3:1:1) system as the Table 1. Summary of Reduction Conditions

in-process results (area %)a entry

reduction conditions

solvent

temp (°C)

base

time (h)

7

13

16

17

1 2 3 4 5 6 7

H2, Pd/C (28 psig) Fe(acac)3/PMHS Zn-dust/NH4Cl Na2S2O4 (5 equiv) Na2S2O4 (5 equiv) Na2S2O4 (5 equiv) Na2S2O4 (5 equiv)

EtOAc THF THF DCM/H2O THF/H2O DCM/H2O/MeOH THF/H2O/MeOH

rt 60 0−5 rt rt rt rt

− − − Na2CO3 Na2CO3 Na2CO3 Na2CO3

18 40 21 6 6 6 1

ND 19 ND 87 0.5 1 ND

78 79 71 7 60 69 72

12 0.3 13 ND ND ND ND

NA NA NA 0.2 34 17 22

a

NA: Not Applicable. ND: Not Detected. C



Article

Scheme 5

Scheme 6

Table 2. Summary of Miyaura Coupling Conditions

in-process results (area %) entry

Pd source

base

solvent

14

15

19

1 2 3 4 5 6 7

Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd(dppf)Cl2·CH2Cl2 Pd(dppf)Cl2·CH2Cl2 Pd(dppf)Cl2·CH2Cl2 Pd(dppf)Cl2·CH2Cl2

KOAc KOAc Me4NOAc KOAc KOAc Me4NOAc KOAc

DMSO DME DMSO DMSO DMAc DME DME

6 0 0 11 3 0 0

70 80 75 73 87 76 92

7 4 6 10 8 7 0.5

residual Pd to furnish 15 in 83% yield and 99.3 area % purity after crystallization from n-heptane. The stereospecific Suzuki coupling between boronate ester 15 and cyclopropane carboxylic acid 6 was the key step in the synthesis (Figure 1). Given the fact that this was the last bond formation step in this sequence, it was imperative to design this reaction in such a way that the highest purities and yields were achieved. To this end, we embarked on a quick first-pass

screening of ligands and solvents for this critical transformation using Pd(OAc)2 as the Pd source and K3PO4 as the base. This screen revealed that both CXPOMetB and DtBPF provided excellent and acceptable conversions, regardless of the solvent used. P(o-tol)3 came a distant third in the screen, while most of the other ligands provided little to no conversion (Figure 1). With these initial two hits from the ligand screen (CXPOMetB and DtBPF), we carried out a limited solvent D



Article

Figure 1. First-pass ligand screen for the stereospecific Suzuki reaction.

these cases, affirming the high level of stereocontrol in this transformation. In general, the conversions mirrored the trend observed with CXPOMetB and DtBPF (Figure 2): DMAc and acetonitrile provided very low conversions, while ethereal solvents (DME, dioxane, and THF) led to substantially higher levels of product formation. The best conditions identified from the ligand/solvent/base screen (P(o-tol)3/THF/NaOH) were utilized to produce over 6 kg of 1 via coupling of 15 with 6. The majority of dimer 20 and desborylated impurity 19 were removed via an aqueous ethanol−n-heptane phase separation under basic conditions. An extractive workup with MTBE−aqueous acid followed by treatment with activated charcoal and Silia MetS-Thiol helped remove color, insoluble inorganics, and residual Pd from the product-containing layer. A crystallization from the aqueous ethanol−n-heptane solvent mixture provided the product 1 in 60% yield (42% overall yield from 2) and in >99% purity (Scheme 7).

and base screen (K3PO4 and NaOH) to quickly identify the best conditions that would allow for rapid delivery of the API for early preclinical evaluation and First-in-Human studies. In this screen, the best results were obtained in ethereal solvents (THF, dioxane, and DME). Interestingly, it was found that aqueous NaOH provided superior conversion to K3PO4 in most cases (except when using DtBPF/2-PrOH and CXPOMetB/DMAc), and in general, CXPOMetB provided higher conversions (Figure 2). However, despite these encouraging results, the lack of commercial availability of CXPOMetB and DtBPF in bulk quantities within the required timeline to meet our needs removed these as viable options. We therefore continued the search for additional options to effect this transformation. As we analyzed the results from the first-pass ligand screen, we were intrigued by the tangible yet suboptimal conversions with P(o-tol)3 in the presence of K3PO4 (Figure 1). In light of the improved conversions using aqueous NaOH as the base (Figure 2), we hypothesized that a switch to NaOH could lead to acceptable conversions using P(o-tol)3, a relatively inexpensive ligand that is commercially available in bulk quantities. A solvent screen was then carried out using a combination of Pd(OAc)2, P(o-tol)3, and NaOH, and the results are depicted in Figure 3. In addition to monitoring just the conversion of 15 to 1, we also tracked the formation of impurities in this screen. It was observed that desborylated impurity 19, dimer 20, and phenol 21 formed to varying degrees depending upon the solvent. Most importantly, diastereomer 22 was detected at levels below 0.5% in all of

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SUMMARY In summary, we have developed a streamlined process for the large-scale synthesis of BMS-978587. This approach relies on an early introduction of the urea moiety to impart crystallinity to the intermediates in the synthetic sequence and to obviate the need to carry the energetic nitro functionality through multiple steps. The nitro group was chemoselectively reduced in the presence of an aryl bromide group using sodium dithionite. A systematic, phase-appropriate screening of bases, ligands, and solvents led to the identification of robust E



Article

Figure 2. Base and solvent screen using CXPOMetB (A) and DtBPF (B).

was stirred at 70−75 °C for 15 h. Upon reaction completion, the reaction mass was cooled to 45−50 °C, and purified water (17 L) was added over a period of 45 min. The mixture was cooled to 20−25 °C over an hour and stirred for 30 min. The resulting slurry was filtered, and the wet cake was washed with water (10.5 L). The wet solid was dried under vacuum at 45 °C for 16 h to afford 4-bromo-N,N-di-isobutyl-2-nitroaniline 7 as a reddish-brown solid (2.1 kg, 99.71 HPLC area % purity, 99.2% potency, 97% yield). 1H NMR (300 MHz, DMSO-d6) 7.90 (d, 1H, J = 2.7 Hz), 7.59−7.62 (q, 1H, J = 2.4, 6.6, and 2.4 Hz), 7.31−7.33 (d, 1H, J = 9.0 Hz), 2.88−2.90 (d, 4H, J = 7.2 Hz), 1.77−1.86 (m, 2H), 0.76−0.79 (d, 12H, J = 6.6 Hz); 13 C NMR (75 MHz, DMSO-d6) 144.1, 141.9, 136.1, 128.2, 124.3, 109.5, 60.2, 26.8, 20.3. HRMS (ESI) m/z calcd for C14H22BrN2O2 [M + H]+ 329.0865, found 329.0835. 4-Bromo-N′,N′-di-isobutylbenzene-1,2-diamine (13). To a solution of sodium carbonate (2.7 kg, 25.3 mol, 6.4 equiv) in water (18.8 L) and methanol (6.3 L) in a glass reactor, sodium dithionite dihydrate (4.4 kg, 25.3 mol, 6.4 equiv) was charged at ambient temperature. A solution of 4-bromo-N,N-diisobutyl-2-nitroaniline 7 (1.3 kg, 1 equiv, 4.0 mol) in tetrahydrofuran (6.3 L) was charged into the same reactor over a period of 30 min maintaining the reaction mass temperature below 30 °C. The reaction mass was stirred at ambient temperature for 1 h. Upon reaction completion, purified water (18.8 L) and MTBE (12.5 L) were added to the

conditions for the key stereospecific Suzuki coupling step and resulted in a process that delivered the API in high quality (>99% purity) and 42% overall yield over five steps.

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EXPERIMENTAL SECTION All anhydrous solvents were commercially obtained and used. All other reagents and solvents were purchased and used without purification. NMR spectra were recorded on a Bruker 400 MHz instrument. Chemical shifts (δ) are reported in parts per million (ppm) referenced to TMS at 0.00 or CDCl3 at 7.27 for 1H, and TMS at 0.00 or CDCl3 at 77.23 for 13C. Coupling constants (J) are reported in hertz (Hz). Mass spectra data were acquired on a JEOL LCMate, double-focusing mass spectrometer, in either APCI positive or negative mode. For high-resolution mass spectra, the resolving power was set at 3000. Optical rotations were determined on a PerkinElmer model 241 polarimeter. Analytical HPLC was conducted on an Agilent 1100 using a 250 mm × 4.6 mm octadecylsilane (ODS), 100 Å column at a flow rate of 1.0 mL/min, and the data were processed with Chemstation software. Peaks were monitored at 254 or 215 nm. Experimental Procedure. 4-Bromo-N,N-di-isobutyl-2nitroaniline (7). To a solution of N,N-di-isobutylamine 3 (2.1 kg, 16.0 mol, 2.4 equiv) in 2-propanol (15 L) in a glass reactor, 4-bromo-1-fluoro-2-nitrobenzene 2 (1.5 kg, 6.7 mol, 1 equiv) was charged at ambient temperature. The reaction mass F



Article

Figure 3. Solvent screen for the Suzuki coupling reaction using aqueous NaOH as the base, Pd(OAc)2 as the Pd source, and P(o-tol)3 as the ligand.

mixture and stirred at 20−30 °C for 10 min. The mixture was filtered through Celite, and the filtrate was subjected to an extractive workup. After phase separation, the aqueous layer was extracted using MTBE (1 × 12.5 L). The combined organic layers were washed with water (4 × 12.5 L) and saturated brine solution (1 × 12.5 L). The organic phase was distilled to minimum volume under vacuum at 50 °C, and the resultant viscous oil was dissolved in MTBE (12.5 L) and charged into a clean reactor. Neutral alumina (1.25 kg) was added, and the slurry was stirred at 20−30 °C for 2 h and filtered through Celite. The filter cake was then washed with MTBE (6.3 L). The combined filtrate was distilled under reduced pressure at 50 °C to afford 4-bromo-N′,N′-diisobutylbenzene-1,2-diamine 13 as a pale brown viscous oil (1.0 kg, 99.14 HPLC area % purity, 98.0% potency, 84% yield); 1H NMR (300 MHz, DMSO-d6) 6.91−6.94 (d, 1H, J = 8.4 Hz), 6.82 (d, 1H, J = 2.4 Hz), 6.62−6.66 (q, 1H, J = 2.4, 6.0, and 2.4 Hz), 5.04 (s, 2H), 2.50−2.55 (m, 4H,), 1.58−1.72 (m, 2H), 0.83−0.85 (d, 12H, J = 6.6 Hz); 13C NMR (75 MHz, DMSO-d6) 145.9, 136.3, 124.3, 118.5, 116.7, 116.3, 61.5, 25.7,

20.6. HRMS (ESI) m/z calcd for C14H24BrN2 [M + H]+ 299.1123, found 299.1087. 1-[5-Bromo-2-(di-isobutylamino)phenyl]-3-(p-tolyl)urea (14). To a solution of 4-bromo-N′,N′-di-isobutylbenzene-1,2diamine 13 (1.1 kg, 3.7 mol, 1 equiv) in n-heptane (16 L) in a glass reactor, 1-isocyanato-4-methylbenzene 4 (530 g, 3.7 mol, 1 equiv) was charged at ambient temperature. The reaction mass was stirred at 20−30 °C for 12−16 h, and the resulting slurry was filtered. The wet cake was then washed with nheptane (5.5 L). The wet solid was deliquored at 20−25 °C under line vacuum for 3 h to afford 1-[5-bromo-2-(diisobutylamino)phenyl]-3-(p-tolyl)urea 14 as an off-white solid (1.42 kg, 99.47 HPLC area % purity, 98.4% potency, 99% yield); 1H NMR (300 MHz, DMSO-d6) 9.47 (s, 1H), 8.21−8.22 (d, 1H, J = 2.4 Hz), 7.96 (s, 1H), 7.35−7.37 (d, 2H, J = 8.4 Hz), 7.08−7.19 (m, 4H), 2.67−2.70 (d, 4H, J = 6.9 Hz), 2.25 (s, 3H), 1.59−1.68 (m, 2H), 0.82−0.84 (d, 12H, J = 6.6 Hz); 13C NMR (75 MHz, DMSO-d6) 152.3, 139.2, 137.0, 136.9, 131.0, 129.1, 124.8, 124.2, 121.8, 118.9, 116.2, 62.6, G



Article

Scheme 7

HRMS (ESI) m/z calcd for C28H43BN3O3 [M + H]+ 480.3397, found 480.3350. (1R,2S)-2-[4-(Di-isobutylamino)-3-(3-(p-tolyl)ureido)phenyl] Cyclopropanecarboxylic Acid (1). A solution of sodium hydroxide (260 g, 3.5 equiv, 6.6 mol) in purified water (4 L) was charged into a glass reactor at 20−25 °C and sparged with N2 for 1 h. THF (12 L) was added, and the sparging operation was continued for another 30 min. Pd(OAc)2 (21.2 g, 0.05 equiv, 0.09 mol) and tri-otolylphosphine (63.3 g, 0.11 equiv, 0.21 mol) were added to the reactor under a N2 atmosphere. The reaction mixture was heated to 50 °C and stirred for 1 h at the same temperature. (1S,2S)-2-Iodocyclopropanecarboxylic acid 6 (400 g, 1 equiv, 1.89 mol) and 1-(2-(di-isobutylamino)-5-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)phenyl)-3-(p-tolyl)urea (15) (910 g, 1 equiv, 1.89 mol) were added sequentially into same the reactor. The reaction mass was heated to 55 °C and stirred for 14 h. After completion of the reaction, the mass was cooled to 20−30 °C. Ethanol (12 L) and 5% sodium hydroxide solution in water (4 L) were added, and the mixture was washed with nheptane twice (22 and 4 L, respectively). The n-heptane layer was then discarded. The basic layer was saturated with sodium chloride (1.2 kg) and extracted using MTBE (24 L). The MTBE phase was washed with 1.5 N HCl (1 × 2 L), followed by water (4 × 4 L) and a saturated brine solution (1 × 4 L). The organic layer was distilled under reduced pressure, and the resultant brown viscous liquid was dissolved in MTBE (8 L). Activated charcoal (40 g), silica gel (300 g), and Silia MetSThiol (300 g) were added into this solution and stirred at 20− 30 °C for 18 h. The slurry was filtered through Celite (800 g), and the Celite bed was washed with MTBE (2 L). The combined filtrate was distilled under vacuum at 50−55 °C to a low volume, and the oily residue was dissolved in a mixture of ethanol (8 L) and n-heptane (8 L) at 20−25 °C. Water (8 L) was added slowly into the mixture over about 30 min, and the mixture was stirred for 16 h to afford a white solid, which was filtered, deliquored for 2 h, and dried under vacuum at 75 °C for 2 days to afford 1 as a white solid (510 g, 99.05 HPLC area % purity, 96.0% potency, 60% yield; Pd content:

Development of a Scalable Synthesis of BMS-978587 Featuring a

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