Development of a Concise Multikilogram Synthesis of LPA-1 Antagonist BMS-986020 via a Tandem Borylation-Suzuki Procedure

Article abstract of DOI:10.1021/acs.oprd.7b00301

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 multikilogram 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.

Full text of DOI:10.1021/acs.oprd.7b00301

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Full Paper
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 Multiꢀkilogram Synthesis
of LPAꢀ1 Antagonist BMSꢀ986020 via a Tandem
BorylationꢀSuzuki Procedure
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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, BristolꢀMyers Squibb Company, One Squibb Drive, New
Brunswick, New Jersey 08903, United States
michael.smith2@bms.com
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KEYWORDS borylation, palladium catalysis, AtaPhos, Suzuki coupling, tandem reaction
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ABSTRACT The process development for the synthesis of BMSꢀ986020 (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
multiꢀkilogram 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
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The lysophosphatidic acid receptor, LPA1, has been implicated as a therapeutic target for
fibrotic disorders.1 BMSꢀ986020, (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 borylationꢀ
Suzuki sequence using the phosphine ligand 4ꢀ(diꢀtertꢀbutylphosphanyl)ꢀN,Nꢀdimethylaniline
(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.
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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.
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Scheme 1: Early route to 1, BMSꢀ986020a
CO2Et
CO2H
CO2Et
CO2Et
CO2H
b
a
B
Br
O
O
Br
Me
Me
3
2
d
e
Me
Me
4
Br
Br
H
N
H
N
O
N
O
N
O
O
Ph
Ph
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O
c
Me
Me
Me
Me
H
1
N
7
CO2H
O
O
O
BMS-986020
Ph
N
N
O
Me
Me
Me
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6
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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, 1,4ꢀdioxane:H2O, 80 °C; (e) NaOH, EtOH, 52% over three steps.
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Figure 1: Solvolysis byproducts in BMSꢀ986020
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CO2H
CO2H
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H
N
NH2
Me
O
O
OEt
N
N
O
Me
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To improve the synthesis and purification protocols behest to the project timelines, we
focused on simplifying the process using a multiꢀpronged 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
lithiumꢀhalogen 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 crossꢀcoupling to give biphenyl 7. Residual palladium was reduced to
below 20 ppm by using extractive aqueous Nꢀacetylcysteine 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.
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Scheme 2: Second generation route to 1a
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a
Reagents and conditions: (a) nꢀBuLi, ꢀ78 °C then B(OiPr)3, 40ꢀ70%; (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 (2ꢀsteps).
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 nꢀbutyllithium 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 BMSꢀ986020 (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 BMSꢀ986020 was gratifyingly
isolated in 90ꢀ95% 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.
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Scheme 3. Third generation concise route BMSꢀ986020.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 anisoleꢀbased coupling partners using the borylation conditions was
executed and is depicted in Figure 2. 4ꢀBromoanisole and 4ꢀiodoanisole reacted at higher relative
rates compared to 4ꢀchloroanisole 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.
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Figure 2. Performance with anisole based coupling partners.
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X=Cl
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Time (minutes)
Attention was then placed on evaluating substrate possibilities to probe the scope of the
borylation. Table 1 highlights examples of some phenylꢀbased halides and heterocyclic bromides
with the protocol using 1.5 equivalents of B2(OH)4 and 0.2 mol % catalyst at 50ꢀ55°C in THF or
MeTHF with MeOH as cosolvent. A slow borylation rate was observed for chlorobenzene 12.
Selectivity for coupling the carbonꢀbromine or carbonꢀiodide bond over a carbonꢀchlorine bond
was demonstrated using both 1ꢀbromoꢀ4ꢀchlorobenzene 13 and 1ꢀchloroꢀ4ꢀiodobenzene 14. In
each case (4ꢀchlorophenyl)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 4ꢀbromophenol 16 (99%) and 4ꢀbromobenzonitrile 17 (89%).
Hindered aryl halides were also competent substrates as shown for both 2ꢀbromoꢀmꢀxylene 21
and 3ꢀiodoꢀ2ꢀmethylbenzoic acid 20. 1ꢀBromoꢀ2ꢀfluorobenzene 18 was borylated in low yield
(9%) due to high levels of dimerization, while both 1ꢀbromoꢀ4ꢀfluorobenzene 24 and 1ꢀbromoꢀ3ꢀ
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fluorobenzene 25 proceeded in 74% and 86% yield respectively. Heterocyclic 5ꢀbromoindole 15
was borylated in high yield, while 3ꢀbromofuran 19 was more challenging and showed variable
yield (24ꢀ54%) of desired product. Although 3ꢀbromothiophene 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 4ꢀnitroꢀ
bromobenzene 29 proceeded with poor yield (24%), the starting material was consumed in less
than 15 minutes albeit with significant dimerization levels. 4ꢀnitroꢀiodobenzene 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.
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Table 1. Aryl and heteroaryl substrates for borylation with B2(OH)4 .
a
1.5 equiv of tetrahydroxy diboron unless noted. HPLC solution yield.
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CONCLUSIONS
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A streamlined synthetic route that included a single vessel tandem borylationꢀSuzuki
reaction sequence using the commercially available, atmospherically stable catalyst
(AtaPhos)2PdCl2 provided the desired biaryl species 1 in excellent isolated yield on multiꢀ
kilogram 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.
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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
80ꢀ85 °C on a mixture of BMTꢀ052367 (118.0kg, 418.3 mol, 1.0 equiv), and (R)ꢀphenylethanol
(153.4 kg, 3.0 equiv) in 2ꢀMeTHF (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 offꢀgassing 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 40ꢀ60 kg/hr while maintaining the internal temperature between 70ꢀ78 °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. 2ꢀMeTHF (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 2ꢀMeTHF (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 2ꢀMeTHF / nꢀheptane (1:4 v:v) (2x 422 kg) and then
with nꢀheptane (384.2 kg). The solids were dried under vacuum at 40ꢀ50 °C giving the title
compound as colorless crystals (124.7 kg, 74.3% yield, HPLC purity = 99.9 %, 99.92:0.08 er).
1H NMR (500 MHz, DMSOꢀd6, 25 °C) δ 1.21ꢀ1.36 (m, 0.6 H rotamer A), 1.54 (m, 2.4H, rotamer
B), 2.13 (br s, 3H), 5.74 (m, 1H), 7.0ꢀ7.5 (m, 5H), 7.57ꢀ7.81 (m, 4H), 8.76ꢀ8.98 (m, 0.2 H,
rotamer A), 9.33 (br s, 0.8 H, rotamer B). 13C NMR (126 MHz, DMSOꢀd6) 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.
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BMS-986020
(1)
BisꢀN,Nꢀdimethylꢀ4ꢀ(di(tertꢀbutyl)ꢀphosphino)aniline
dichloropalladium (II) (0.149 kg, 0.210 mol, 0.23 mol %) was added to a nitrogen sparged
solution of 1ꢀ(4ꢀbromophenyl)cyclopropaneꢀ1ꢀcarboxylic 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 2ꢀMeTHF (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)ꢀ1ꢀphenylethyl (5ꢀ(4ꢀbromophenyl)ꢀ3ꢀmethylisoxazolꢀ4ꢀyl)carbamate (6)
(36.0 kg, 89.7 mol, 1.0 equiv), 2ꢀMeTHF (190.8kg, 2214 mol) and a second portion of bis N,Nꢀ
dimethylꢀ4ꢀ(di(tertꢀbutyl)ꢀ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.
NꢀacetylꢀLꢀcysteine (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 2ꢀMeTHF (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, DMSOꢀd6) 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), 6.9ꢀ7.45 (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
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(s, 0.2H), 12.39 (br s, 1H). C NMR (126 MHz, DMSOꢀd6) 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 30ꢀ40 v/v % methanol in either THF or 2ꢀMeTHF (10 to 20 mL/g substrate).
After sparging with nitrogen, 4ꢀ(di(tertꢀbutyl)ꢀphosphino)aniline dichloropalladium(II) (0.2
mol%) was added and the reaction mixture was heated to 50ꢀ55 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.
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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 4ꢀbromoanisole with tetrahydroxyboron.
AUTHOR INFORMATION
Corresponding Author
Eꢀmail: michael.smith2@bms.com
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 GonzalezꢀBobes, Carlos Guerrero, Michael Hay, and Neil Strotman
are thanked for review of the manuscript.
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REFERENCES
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1.
Tager, A. M., LaCamera, P., Shea, B. S., Campanella, G. S., Selman, M., Zhao, Z.,
Polosukin, V., Wain, J., KarimiꢀShah, B. A., Kim, N. D., Hart, W. K., Pardo, A.,
Blackwell, T. S., Xu, Y., Chun, J., Luster, A. D. Nature Medicine¸ 2008, 14, 45ꢀ54.
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(a) Miyaura, N., Yamada, K., Suzuki, A. Tetrahedron Lett. 1979, 20, 3437ꢀ3440; (b)
Miyaura, N., Suzuki, A. Chem. Rev. 1995, 95, 2457ꢀ2483.
(a) Ishiyama, T.; Murata, M.; Miyaura, N.; J. Org. Chem. 1995, 60, 7508ꢀ10; (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), 5822ꢀ6.
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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),
17701ꢀ3; (c) Molander, G. A.; Trice, S. L.; Kennedy, S. M.; Dreher, S. D.; Tudge, M.
T., J. Am. Chem. Soc. 2012, 134 (28), 11667ꢀ73.
(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, 65ꢀ74; (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, 1227ꢀ1238. (c) Hughes,
D. Org. Process Res. Dev. 2016, 20, 1404ꢀ1415. (d) Scott, R. W.; Vitale, J. P.;
Matthews, K. S.; Teresk, M. G.; Formella, A.; Evans, J. W. U.S. Patent 9,056,860,
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6.
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(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), 1787ꢀ9. (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(diꢀtertꢀbutylphosphino)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.
(a) Garrett, C. E.; Prasad, K., Adv, Synth. Catal. 2004, 346, 889ꢀ900. (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, 5831ꢀ5834.
9.
Molander, G. A.; Trice, S. L.J.; Tschaen, B.; Tetrahedron, 2015, 71, 5758ꢀ5764.
10.
Tetrahydroxydiboron has been reported to be mutagenic, see Hansen, M. M.; Jolly, R.
A.; Linder, R.J. Org. Process Res. Dev. 2015, 19, 1507ꢀ1516. To determine the level
of tetrahydroxydiboron in the API product 1, an HPLCꢀMS 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.
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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 4ꢀbromoanisole indicating
highest reactivity for the AtaPhos system under various conditions.
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