Development of a Concise Multikilogram Synthesis of LPA-1

Oct 19, 2017 - The process development for the synthesis of BMS-986020 (1) via a palladium catalyzed tandem borylation/Suzuki reaction is described. E...
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Development of a Concise Multi-kilogram Synthesis of LPA-1 Antagonist BMS-986020 via a Tandem Borylation-Suzuki Procedure Michael J. Smith, Michael J. Lawler, Nathaniel Kopp, Douglas D. McLeod, Akin H. Davulcu, Dong Lin, Kishta Reddy Katipally, and Chris Sfouggatakis Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00301 • Publication Date (Web): 19 Oct 2017 Downloaded from http://pubs.acs.org on October 20, 2017

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Development of a Concise Multi-kilogram Synthesis of LPA-1 Antagonist BMS-986020 via a Tandem Borylation-Suzuki Procedure Michael J. Smith*, Michael J. Lawler, Nathaniel Kopp, Douglas D. Mcleod, Akin H. Davulcu, Dong Lin, Kishta Katipally, and Chris Sfouggatakis Chemical and Synthetic Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey 08903, United States [email protected]

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TABLE OF CONTETS GRAPHIC:

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KEYWORDS borylation, palladium catalysis, AtaPhos, Suzuki coupling, tandem reaction ABSTRACT The process development for the synthesis of BMS-986020 (1) via a palladium catalyzed tandem borylation/Suzuki reaction is described. Evaluation of conditions culminated in an efficient borylation procedure using tetrahydroxydiboron followed by a tandem Suzuki reaction employing the same commercially available palladium catalyst for both steps. This methodology addressed shortcomings of early synthetic routes and was ultimately used for the multi-kilogram scale synthesis of the active pharmaceutical ingredient 1. Further evaluation of the borylation reaction showed useful reactivity with a range of substituted aryl bromides and iodides as coupling partners. These findings represent a practical, efficient, mild, and scalable method for borylation.

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INTRODUCTION The lysophosphatidic acid receptor, LPA1, has been implicated as a therapeutic target for fibrotic disorders.1 BMS-986020, (1), a small molecule antagonist of the receptor, is currently undergoing clinical trial as a possible treatment for pulmonary fibrosis. A convergent strategy to make 1 employed a late stage Suzuki coupling2 to generate the biphenyl core, necessitating the synthesis of a boronic acid derivative as a coupling partner. During the initial synthetic route development, a traditional Miyaura borylation3 posed significant processing challenges including incomplete conversion even under high catalyst loadings as well as difficulty in the removal of residual metals arising from the catalyst stoichiometry. An alternative approach that employed a lithium halogen exchange with a subsequent borate quench displayed variability when executed on manufacturing scale. These challenges led to the use of the borylating reagent, tetrahydroxydiboron,4 which has high potential for employment in pharmaceutical development5. The following will describe how the development of a tandem palladium catalyzed borylationSuzuki sequence using the phosphine ligand 4-(di-tert-butylphosphanyl)-N,N-dimethylaniline (AtaPhos)6 obviated the shortcomings of the prior routes to 1. The application of the borylation methodology to generate a variety of known boronic acids from aryl halides will also be described. RESULTS AND DISCUSSION An initial convergent synthesis of 1 began with the two commercially available aryl bromide species 2 and 5 (Scheme 1). A Curtius reaction of the carboxylic acid 5 with diphenylphosphoryl azide and (R)-phenylethanol gave isoxazole carbamate 6. The ethyl ester 3, was made by a high yielding Fischer esterification of carboxylic acid 2. A subsequent Miyaura

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borylation of the bromide 3 using Pd(dppf)Cl2 and bispinacolatodiboron gave boronate ester 4 which was kept in solution, then subjected to a Suzuki reaction with aryl bromide 6. Incomplete conversion, which was often observed during the borylation step of this sequence, necessitated additional catalyst charges of Pd(dppf)Cl2. The high catalyst loading from the multiple charges complicated the removal of both palladium and iron from the biphenyl product 7. In order to isolate the amorphous solid species 7 with appropriately reduced levels of these metals, several laborious solid phase scavenging and chromatography operations were necessary. This multifaceted purification was deemed unsustainable as a long term approach and would need to be addressed in subsequent campaigns. Hydrolysis of the ethyl ester 7 using NaOH in EtOH gave the desired carboxylic acid 1, albeit with significant solvolysis byproducts, the ethyl carbamate 8 and the heteroarylamine 9 (Figure 1). In order to keep the amount of these byproducts under acceptable limits post purification, the reaction was stopped before full conversion of the starting material, decreasing the overall throughput of the sequence. Scheme 1: Early route to 1, BMS-986020a CO2H

CO2Et

CO2Et

CO2Et

CO2H

b

a

B Br

O

Br 3

2

O

Me Me

Me Me

d

e

4 Br

Br

O N

c CO2H

O N

Me 5

H N Me

O N

H N Me

O O

7 Ph

O O

Me

Ph

O N

H N Me

O O

Ph

Me

1 BMS-986020

Me

6

a

Reagents and conditions: (a) EtOH, H2SO4, 78 °C, 95%; (b) bispinacolatodiboron, Pd(dppf)Cl2, (c) DPPA, DIPEA, (R)phenylethanol, MeTHF, 70%; (d) Pd(dppf)Cl2 2.0 mol%, KHCO3, 1,4-dioxane:H2O, 80 °C; (e) NaOH, EtOH, 52% over three steps.

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Figure 1: Solvolysis byproducts in BMS-986020 CO2H

O N

H N Me 8

CO2H

OEt O

NH2

O N

Me 9

To improve the synthesis and purification protocols behest to the project timelines, we focused on simplifying the process using a multi-pronged approach in a second route to 1. To reduce the amount of palladium used in the synthesis and to avoid the stalling issues, the Miyaura borylation reaction that was used to make the boronate ester 4 was replaced with a lithium-halogen exchange and subsequent triisopropyl borate and HCl quench to provide the boronic acid 10 (Scheme 2). This cryogenically controlled reaction performed adequately on laboratory scale (~100g) providing boronic acid 10 in 75% yield. However, variable yield was observed on manufacturing scale with significant undesired protonolysis of the intermediary aryl lithium. Nonetheless, the resulting carboxylic acid moiety was then esterified to provide Suzuki coupling partner 11. By replacing Pd(dppf)Cl2 with (AtaPhos)2PdCl2, a highly reactive catalyst system,6 efficient Suzuki coupling was observed with a catalyst loading as low as 0.2 mol %. This allowed for clean cross-coupling to give biphenyl 7. Residual palladium was reduced to below 20 ppm by using extractive aqueous N-acetylcysteine wash,7 significantly simplifying the purification by avoiding the unsustainable multiple solid phase metal scavenging and chromatography unit operations that were used in the previous route. Finally, to achieve full conversion of the ester and to significantly reduce the amounts of the solvolysis byproducts 8

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and 9, potassium trimethylsilanoate (TMSOK) was used as a mild alternative to NaOH8 for the hydrolysis of ethyl ester 7 to form the carboxylic acid 1. Scheme 2: Second generation route to 1a

a

Reagents and conditions: (a) n-BuLi, -78 °C then B(OiPr)3, 40-70%; (b) triethylorthofomate, H2SO4, EtOH, Toluene, 80 °C, 70% ; (c) H2O, K3PO4, 6, (AtaPhos)2PdCl2 0.2 mol%, 50 °C; (d) TMSOK, THF, 22 °C, 94% yield (2-steps).

Although the second generation route provided more than one hundred kilograms of 1 with acceptable quality in the timeframe of the project needs, the unexpected variable performance of the n-butyllithium mediated borylation during manufacture prompted the identification of more robust borylation conditions. We proposed a new streamlined design based on a tandem borylation/Suzuki coupling sequence to make BMS-986020 (Scheme 3) that would avoid the extraneous esterification and hydrolysis steps executed in the previous routes by performing the sequence on aryl bromide 2. We envisioned that the use tetrahydroxydiboron in a metal catalyzed borylation reaction, a transformation that was initially disclosed by Marccucio4a and popularized by Molander and Dreher,4b would be an appealing alternative to the previously used Miyaura borylation procedure due in part to greater atom economy. However to implement for this process, new conditions that would not only use an inexpensive catalyst system, but also minimize the equivalents of tetrahydroxydiboron needed for clean and complete conversion would need to be identified. The initial evaluations of the borylation of aryl bromide 2 using

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(AtaPhos)2PdCl2 as catalyst showed near quantitative yield of boronic acid 10 with as low as 1.2 equivalents of tetrahydroxydiboron. Additionally, crystalline BMS-986020 was gratifyingly isolated in 90-95% yield over two steps when the reaction stream containing boronic acid 10 was subjected to aryl bromide 6 and an aqueous solution of K3PO4 at 50 °C on a variety of scales ranging from 1 g to 40 kg. This tandem reaction sequence could be executed with as little as 0.2 mol % catalyst in a single bolus for both reactions if the Suzuki reaction was immediately initiated upon completion of the borylation. However, due to the operational hold times encountered during production, adding a second 0.2 mol % catalyst charge for the Suzuki step improved robustness.

Scheme 3. Third generation concise route BMS-986020.a

a

Reagents and conditions: (a) 1) B2OH4, (AtaPhos)2PdCl2 0.2 mol %, DIPEA, MeOH, THF, 50 °C. b) K3PO4, H2O, (AtaPhos)2PdCl2 0.2 mol %, 50 °C.

Due to the success of the borylation reaction employed for the synthesis of 1, we wanted to determine if general applicability of the transformation to other aryl halides existed. A small survey of the reactivity of anisole-based coupling partners using the borylation conditions was executed and is depicted in Figure 2. 4-Bromoanisole and 4-iodoanisole reacted at higher relative rates compared to 4-chloroanisole and the mesylate analog. Although the rates were comparable

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between the bromide and iodide, the slightly faster rate and higher yield for the iodide was reproducible and consistently provided a reduced level of dimeric biaryl impurity. Figure 2. Performance with anisole based coupling partners. 100 90 80 Solution yield (%)

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70 60

X=Cl

50 X=Br 40 X=I

30

X=OMs

20 10 0 0

50

100

150

200

250

300

Time (minutes)

Attention was then placed on evaluating substrate possibilities to probe the scope of the borylation. Table 1 highlights examples of some phenyl-based halides and heterocyclic bromides with the protocol using 1.5 equivalents of B2(OH)4 and 0.2 mol % catalyst at 50-55°C in THF or MeTHF with MeOH as cosolvent. A slow borylation rate was observed for chlorobenzene 12. Selectivity for coupling the carbon-bromine or carbon-iodide bond over a carbon-chlorine bond was demonstrated using both 1-bromo-4-chlorobenzene 13 and 1-chloro-4-iodobenzene 14. In each case (4-chlorophenyl)boronic acid was observed in 78% and 83% yield respectively. The borylation protocol showed compatibility with electron rich and electron poor substrates as observed by the high yields using 4-bromophenol 16 (99%) and 4-bromobenzonitrile 17 (89%). Hindered aryl halides were also competent substrates as shown for both 2-bromo-m-xylene 21 and 3-iodo-2-methylbenzoic acid 20. 1-Bromo-2-fluorobenzene 18 was borylated in low yield (9%) due to high levels of dimerization, while both 1-bromo-4-fluorobenzene 24 and 1-bromo-3-

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fluorobenzene 25 proceeded in 74% and 86% yield respectively. Heterocyclic 5-bromoindole 15 was borylated in high yield, while 3-bromofuran 19 was more challenging and showed variable yield (24-54%) of desired product. Although 3-bromothiophene 23 was also initially low yielding, increasing the stoichiometry of tetrahydroxydiboron to at least 3.0 equivalents resulted in significant yield improvement. The decreased yields of the acetophenone 27 and benzaldehyde 28 derived examples were due to increased dimerization. Even though the borylation of 4-nitrobromobenzene 29 proceeded with poor yield (24%), the starting material was consumed in less than 15 minutes albeit with significant dimerization levels. 4-nitro-iodobenzene 30 was borylated in 50% yield with lower dimerization. This particular aryl iodide was then borylated at ambient temperature increasing the yield to 75% indicating a higher thermal barrier for dimerization versus borylation. Table 1. Aryl and heteroaryl substrates for borylation with B2(OH)4a.

a

1.5 equiv of tetrahydroxy diboron unless noted. HPLC solution yield.

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CONCLUSIONS A streamlined synthetic route that included a single vessel tandem borylation-Suzuki reaction sequence using the commercially available, atmospherically stable catalyst (AtaPhos)2PdCl2 provided the desired biaryl species 1 in excellent isolated yield on multikilogram scale. The demonstration of the procedurally feasible borylation protocol on a variety of aryl bromides, heteroaryl bromides and aryl iodides with a range of electronic and steric properties suggest potential utility for a variety of synthetic applications. EXPERIMENTAL (R)-1-phenylethyl (5-(4-bromophenyl)-3-methylisoxazol-4-yl)carbamate (6): An azeotopic distillation to remove residual water was performed at 500 torr with jacket set to 80-85 °C on a mixture of BMT-052367 (118.0kg, 418.3 mol, 1.0 equiv), and (R)-phenylethanol (153.4 kg, 3.0 equiv) in 2-MeTHF (1279 kg, 12 L/kg). After concentrating to 600 L, the mixture was cooled to 25 °C. Then diisopropylethylamine (109.0 kg, 843.3 mol, 2.0 equiv) was added to the reaction solution which became slightly exothermic (~10 °C). (SAFETY NOTE: The addition of DPPA was accompanied by an exotherm of -181 kJ/mol and Tad of +30 °C. The transfer of the acylazide initiated at 39 °C. The rearrangement initiated at 53 °C and reached a maximum heat rate at 62 °C. In order to safely prevent the acylazide intermediate from accumulating and to ensure that nitrogen off-gassing was controlled by the dosing rate, the reaction was performed at temperatures ≥ 70 °C.) The mixture was heated to 72 ± 2 °C, then diphenylphosphoryl azide (121.0 kg, 443 mol, 1.06 equiv) was added continuously at a rate between 40-60 kg/hr while maintaining the internal temperature between 70-78 °C. A chase wash of MeTHF (5.2 kg) followed. The reaction mixture was then held at 72 ± 2 °C for at least 1 hour followed by cooling to 20 °C. 2-MeTHF (1017 kg) was added and the mixture was

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extracted first with aqueous 10 wt% NaCl (1179 kg), then twice with aqueous 10 wt% KHCO3 (2x 1180 kg) and finally once with aqueous 20 wt% NaCl (1180 kg). The organic layer was treated with active carbon (48 kg) for 3 h then filtered and chase washed with 2-MeTHF (279 kg). The mixture was concentrated to 550 L, heated to 75 °C and then the product was crystallized by the addition of n-heptane (1204 kg). After cooling to 20°C, the product was filtered and washed first with a mixture of 2-MeTHF / n-heptane (1:4 v:v) (2x 422 kg) and then with n-heptane (384.2 kg). The solids were dried under vacuum at 40-50 °C giving the title compound as colorless crystals (124.7 kg, 74.3% yield, HPLC purity = 99.9 %, 99.92:0.08 er). 1

H NMR (500 MHz, DMSO-d6, 25 °C) δ 1.21-1.36 (m, 0.6 H rotamer A), 1.54 (m, 2.4H, rotamer

B), 2.13 (br s, 3H), 5.74 (m, 1H), 7.0-7.5 (m, 5H), 7.57-7.81 (m, 4H), 8.76-8.98 (m, 0.2 H, rotamer A), 9.33 (br s, 0.8 H, rotamer B). 13C NMR (126 MHz, DMSO-d6) δ 160.0, 159.6, 154.2, 142.1, 132.1, 128.4, 127.6, 127.5, 125.6, 125.6, 123.7, 114.2, 72.9, 22.3, 9.1. HRMS (ESI +) Calculated M+H 401.0495, found 401.0491. BMS-986020

(1)

Bis-N,N-dimethyl-4-(di(tert-butyl)-phosphino)aniline

dichloropalladium (II) (0.149 kg, 0.210 mol, 0.23 mol %) was added to a nitrogen sparged solution of 1-(4-bromophenyl)cyclopropane-1-carboxylic acid (2) (24.9 kg, 103.3 mol, 1.2 equiv), tetrahydroxydiboron (11.4 kg, 127.2 mol, 1.4 equiv), diisopropylethylamine (26.9 kg, 208.2 mol, 2.3 equiv) in methanol (68.3 kg, 2.4 L/kg, 2247mol) and 2-MeTHF (200.8 kg, 6.25 L/kg, 2331 mol). The reaction mixture was then heated to 50 ⁰C for 11 h. The reaction mixture was cooled to 20 ⁰C and water (216 kg, 6 L/kg), potassium phosphate tribasic (38.9 kg, 183.2 mol, 2.0 equiv), (R)-1-phenylethyl (5-(4-bromophenyl)-3-methylisoxazol-4-yl)carbamate (6) (36.0 kg, 89.7 mol, 1.0 equiv), 2-MeTHF (190.8kg, 2214 mol) and a second portion of bis N,Ndimethyl-4-(di(tert-butyl)-phosphino)aniline dichloropalladium (II) (0.149 kg, 0.210 mol, 0.23

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mol %) were added. The reaction mixture was heated to 50 ⁰C for 6 h. Upon reaction completion, the biphasic mixture was allowed to separate and the aqueous layer was discarded. N-acetyl-L-cysteine (14.7 kg, 90.1 mol, 1.0 equiv), potassium phosphate tribasic (38.9 kg, 183.2 mol, 2.0 equiv), and water (216.0 kg, 1.2x104 mol) were added to the vessel and the mixture was stirred for 5 h at 50 ⁰C. After cooling, the aqueous layer was discarded. The organic layer was then washed with 1N hydrochloric acid (228.1 kg) before 2-MeTHF (154.8 kg) was added. Water (216.0 kg) was then used to wash the organic layer. After a solvent exchange by distillation to isopropanol, the solution volume was adjusted to 452 L with isopropanol and the product was crystallized by the addition of water (20.6 kg) and seeded with 0.360 kg of product crystals followed by water (534.7 kg). Filtration of solids followed by cake washing three times using 40% isopropanol in water (3x 97.2 kg) and drying under vacuum gave the title compound as a white crystalline powder 41.4 kg (99.3 wt%, 85.3 mol, 95% yield, >99.8 HPLC area percent purity, 99.9:0.1 er). 1H NMR (500 MHz, DMSO-d6) δ 1.19 (dd, J = 6.8, 3.8Hz, 2H ), 1.50 (dd, J = 6.8, 3.8 Hz, 2H), 1.56 (br s, 3H), 2.14 (br s, 3H), 5.78 (br s, 1H), 6.9-7.45 (br, 5H), 7.45 (br d, J = 8.3 Hz, 2H), 7.65 (d, J = 8.3 Hz, 2H), 7.79 (br d, 2H), 7.82 (br d, 2H), 8.87 (br s, 0.8H), 9.29 (s, 0.2H), 12.39 (br s, 1H). 13C NMR (126 MHz, DMSO-d6) δ 9.2, 15.8, 22.4, 28.3, 72.8, 113.8, 125.4, 125.6, 126.2, 126.3, 127.1, 127.7, 128.4, 130.9, 137.4, 140.0, 141.5, 142.2, 154.4, 159.6, 160.8, 175.2. HRMS (ESI +) Calculated M+H 483.19145, found 483.19095. General borylation procedure for aryl and heteroaryl bromides and iodides: Aryl halide (1.0 equiv), tetrahydroxydiboron (1.3 to 4 equiv), and diisopropylethylamine (2.0 equiv) were dissolved in 30-40 v/v % methanol in either THF or 2-MeTHF (10 to 20 mL/g substrate). After sparging with nitrogen, 4-(di(tert-butyl)-phosphino)aniline dichloropalladium(II) (0.2 mol%) was added and the reaction mixture was heated to 50-55 ⁰C until starting material was

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consumed by HPLC. Yields were determined on HPLC by standard curves prepared from commercially available boronic acids. Analytical samples were isolated by column chromatography and compared to the commercially available standards for identity by NMR spectroscopy. ASSOCIATED CONTENT Supporting Information Characterization data are presented for compounds 6 and 1 as well as an evaluation table for catalysts and bases used for borylation of 4-bromoanisole with tetrahydroxyboron. AUTHOR INFORMATION Corresponding Author E-mail: [email protected] Notes The authors declare no competing financial interest ACKNOWLEDGEMENTS The authors would like to thank Carolyn Wei and Yi Xiao for initial catalyst evaluations for the Suzuki reaction as well as Lindsay Hobson and Collin Chan for helpful discussions. Justin Sausker is thanked for preliminary experiments. Jonathan Marshall, Charles Pathirana, Mohan Kanthasamy, Meng Xu, and Xuejun Xu are thanked for help with compound characterization. Francisco Gonzalez-Bobes, Carlos Guerrero, Michael Hay, and Neil Strotman are thanked for review of the manuscript.

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2.

(a) Miyaura, N., Yamada, K., Suzuki, A. Tetrahedron Lett. 1979, 20, 3437-3440; (b) Miyaura, N., Suzuki, A. Chem. Rev. 1995, 95, 2457-2483.

3.

(a) Ishiyama, T.; Murata, M.; Miyaura, N.; J. Org. Chem. 1995, 60, 7508-10; (b) Wei, C. S.; Davies, G. H.; Soltani, O.; Albrecht, J.; Gao, Q.; Pathirana, C.; Hsiao, Y.; Tummala, S.; Eastgate, M. D., Angew. Chem. Int. Ed. 2013, 52 (22), 5822-6.

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(a) Marcuccio, S.; Rodopoulos, M.; Weigold, H. WO Patent 9912940, 1999 (b) Molander, G. A.; Trice, S. L.; Dreher, S. D., J. Am. Chem. Soc. 2010, 132 (50), 17701-3; (c) Molander, G. A.; Trice, S. L.; Kennedy, S. M.; Dreher, S. D.; Tudge, M. T., J. Am. Chem. Soc. 2012, 134 (28), 11667-73.

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(a) Gurung, S. R.; Mithchell, C.; Huang, J.; Jonas, M.; Strawser, J. D.; Daia, E.; Hardy, A.; O’Brien, E.; Hicks, F; Papageorgiou, C. D., Org. Process Res. Dev. 2017, 21, 65-74; (b) Williams, M. J.; Chen, Q.; Codan, L.; Dermenjian, R. K.; Dreher, S.; Gibson, A. W.; He, X.; Jin, Y.; Keen, S. P.; Lee, A. Y.; Lieberman, D. R.; Lin, W.; Liu, G.; McLaughlin, M.; Reibarkh, M.; Scott, J. P.; Strickfuss, S.; Tan, T.; Varsolona, R. J.; Wen, F. Org. Process Res. Dev. 2016, 20, 1227-1238. (c) Hughes, D. Org. Process Res. Dev. 2016, 20, 1404-1415. (d) Scott, R. W.; Vitale, J. P.; Matthews, K. S.; Teresk, M. G.; Formella, A.; Evans, J. W. U.S. Patent 9,056,860, 2015.

6.

(a) Guram, A. S.; King, A. O.; Allen, J. G.; Wang, X.; Schenkel, L. B.; Chan, J.; Bunel, E. E.; Faul, M. M.; Larsen, R. D.; Martinelli, M. J.; Reider, P. J., Org. Lett. 2006, 8 (9), 1787-9. (b) An initial catalyst evaluation for the Suzuki reaction using 4 to make 7 showed that many ligand and palladium combinations including DPEPhos, DCEPhos, 1,1′-Bis(di-tert-butylphosphino)ferrocene, and AtaPhos were nearly equally efficient at the transformation. AtaPhos gave a cleaner reaction profile at lower loadings in the case of making 7 using 11 when compared to DPEPhos.

7.

(a) Garrett, C. E.; Prasad, K., Adv, Synth. Catal. 2004, 346, 889-900. (b) Note: The use of the AtaPhos ligand also removed the use iron in the chemical sequence.

8.

Laganis, E. D.; Chenard, B. L., Tetrahedron Lett. 1984, 25, 5831-5834.

9.

Molander, G. A.; Trice, S. L.J.; Tschaen, B.; Tetrahedron, 2015, 71, 5758-5764.

10.

Tetrahydroxydiboron has been reported to be mutagenic, see Hansen, M. M.; Jolly, R. A.; Linder, R.J. Org. Process Res. Dev. 2015, 19, 1507-1516. To determine the level of tetrahydroxydiboron in the API product 1, an HPLC-MS method was developed

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with a limit of detection of 0.3 ppm and a limit of quantitation = 1 ppm. The level of B2(OH)4 in the final product 1 was found to be ≤ 1 ppm. 11.

Due to the clean conversion and high yield at low loadings for both steps using AtaPhos as ligand, the authors did not wish to evaluate other catalyst systems for this substrate. See the supplemental information for a table evaluating borylation conditions comparing catalyst systems and bases with 4-bromoanisole indicating highest reactivity for the AtaPhos system under various conditions.

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