Significant rate enhancement via potassium pivalate in a Miyaura borylation approach to verinurad

Article abstract of DOI:10.1016/j.tetlet.2019.151589

We describe herein the significant rate-enhancing effect of employing potassium pivalate as a base in a Miyaura borylation. The manufacturing route to verinurad currently employs a Suzuki-Miyaura cross-coupling, requiring cryogenic conditions to generate the boronic acid coupling partner. This process has manufacturability challenges including those associated with low temperature operations and thus an alternative Miyaura borylation approach is described. High throughput screening was employed to investigate the effects of various carboxylate bases and their corresponding counterions on reactivity. Our results highlight potassium pivalate as producing exceptional rate acceleration. To the best of our knowledge this base has not previously been reported for use in Miyaura borylations. Diethanolamine transesterification is also reported as a facile and robust boronate isolation protocol. Successful application of this diethanolamine boronate ester in downstream cross-coupling chemistry has demonstrated the potential for this new route in commercial manufacture of verinurad.

Full text of DOI:10.1016/j.tetlet.2019.151589

Journal Pre-proofs
Significant rate enhancement via potassium pivalate in a Miyaura borylation
approach to verinurad
Oliver T. Ring, Andrew D. Campbell, Barry R. Hayter, Lyn Powell
PII:
S0040-4039(19)31388-7
DOI:
https://doi.org/10.1016/j.tetlet.2019.151589
TETL 151589
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
15 November 2019
20 December 2019
29 December 2019
Please cite this article as: Ring, O.T., Campbell, A.D., Hayter, B.R., Powell, L., Significant rate enhancement via
potassium pivalate in a Miyaura borylation approach to verinurad, Tetrahedron Letters (2019), doi: https://doi.org/
1
0.1016/j.tetlet.2019.151589
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Graphical Abstract:
Commented [RO1]: Graphical abstract updated to
percentage conversion.
Title:
Significant rate enhancement via potassium pivalate in a Miyaura borylation approach to verinurad
Authors:
Oliver T. Ring*, Andrew D. Campbell, Barry R. Hayter, Lyn Powell.
Corresponding Author details:
Oliver Thomas Ring
oliver.ring@astrazeneca.com
+
44016256397.
Address:
Chemical Development, Pharmaceutical Technology and Development, AstraZeneca, Macclesfield, SK10 2NA, UK.
Key Words:
Miyaura borylation, Suzuki, kinetics, route design.

Abstract:
We describe herein the significant rate-enhancing effect of employing potassium pivalate as a base in a
Miyaura borylation. The manufacturing route to verinurad currently employs a Suzuki-Miyaura cross-coupling, requiring
cryogenic conditions to generate the boronic acid coupling partner. This process has manufacturability challenges
including those associated with low temperature operations and thus an alternative Miyaura borylation approach is
described. Combining hHigh throughput screening and rational designwas employed to investigate the effects of
various carboxylate bases and their corresponding counterions on reactivity. were investigated. Our results highlight
potassium pivalate as producing exceptional rate accelerationOur results highlighted potassium pivalate as producing
exceptional rate accelerating properties.. To the best of our knowledge this base has not previously been reported for
use in Miyaura borylations. Diethanolamine transesterification is also reported as a facile and robust boronate isolation
protocol. Successful application of this diethanolamine boronate ester in downstream cross-coupling chemistry has
demonstrated the potential for this new route in commercial manufacture of verinurad.
Introduction:
Studies have shown that hyperuricaemia and gout are intricately linked with hypertension and chronic kidney
disease.(1) A number of studies also suggest hyperuricaemia and gout are independent risk factors for the development
of cardiovascular disease. (1) Verinurad 1 is a highly potent URAT1 inhibitor with a greater than 100-fold potency
increase compared to other uric acid transporters. (2) Studies investigating a combination therapy of 1 and xanthine
oxidase inhibitors suggest that 1 is highly selective and reduces serum uric acid levels in the body. (2, 3) These promising
clinical results have prompted a re-evaluation of the current route with the aim of developing a long-term manufacturing
route to 1.
Palladium catalysed coupling reactions are now a central tool for the synthesis of biologically active
compounds in the pharmaceutical industry. (4) Verinurad 1 is currently manufactured using a convergent synthetic route
with a Suzuki-Miyaura cross-coupling of building blocks 2 and 3 in the penultimate stage (Scheme 1). (5, 6) This current
route involves the formation of
2 by lithium/bromine exchange followed by a tri-iso-propyl borate quench.
Lithium/bromine exchange requires cryogenic conditions to inhibit uncontrolled nucleophilic attack on the sensitive
nitrile group. These conditions are unfavourable from a manufacturability perspective due to limited reactor availability,
the high costs associated with long operation times and the high energy cost of cooling reactors. (7, 8) Unfavourable
physical properties displayed by 2 led to slow filtration with concomitant impurity formation. Concerns were raised in-

house due to the propensity of 2 to readily form oligomers such as boroxines, which could lead to artificially high purity
assay readings and therefore the potential to jeopardise accurate charging in the following stage. (9) The resulting
development work aimed to alleviate the described issues through the investigation of alternative, plant-feasible routes,
the removal of cryogenics and the isolation of intermediates as stable single species, facilitating the delivery of 1 for
further clinical studies.
Commented [RO2]: Minor formatting change made to
scheme 1 to adjust bond angles of compound 6.
Scheme 1: Current verinurad manufacturing route. Reagents and conditions: a i) KSAc; water; 35 ℃; ii) NaOH (aq); 20 ℃; b
K
2
CO
3
; iPrAc; acetone; 40 ℃; c i) SOCl
2
; toluene; DMF; 60 ℃; ii) SO(NH
2 2 3
) ; sulfolane; 120 ℃; d i) B(OiPr) ; THF, n-hexLi; -80 ℃, ii)
HCl (aq); e Pd
2
(dba) ; [(t-Bu) PH]BF ; Na
3
3
4
2
3
CO ; NaOH; n-BuOH; water; 75 ℃; f NaOH (aq); MeOH; 27 ℃.

Results and Analysis:
To explore alternatives to the Suzuki-Miyaura cross-coupling approach, organomagnesium and organozinc
derivatives of both 3 and 8 were generated for use in Kumada (10) and Negishi (11) transformations. Poor organometallic
intermediate stability, low starting material conversions and difficulties in the purification of 9 led to alternative
approaches being sought. Direct iridium catalysed oxidative borylation via C-H activation of cyanonaphthalene was
explored initially in silico. Combinations of calculated pK
a
values (12), NMR shifts (13), bond dissociation energies (14) and
transition state modelling as described by Green and co-workerset. al. (15) were explored. These computational results
consistently failed to identify strong selectivity towards the desired regioisomer. This was verified experimentally in the
laboratory with multiple by-products observed, resulting in this approach being abandoned. Initial scouting of a Miyaura
borylation (16) approach (Scheme 2) was more fruitful and led to optimisation studies via high throughput screening,
rational design and reaction
profilingmonitoring.
Scheme 2: Miyaura borylation and Suzuki-Miyaura cross
coupling route. Reagents and cConditions: a i) B(OiPr)
n-hexLi; -80 ℃, ii) HCl (aq); Pin
diethanolamine, iPrOH; d i) Pd (dba)
3
; THF,
b
B
2
2
2
; Pd-cat; base; solvent; c
3
; [(t-Bu)
3
PH]BF
4
; Na
2
CO
3
;
NaOH; n-BuOH; water; 75 ℃; ii) NaOH (aq); MeOH; 27 ℃.
The Miyaura borylation was initially investigated using a 96 well screening plate (screen 1) in which
combinations of 8 catalysts, 6 acetate bases and 2 solvents were explored. Conditions were selected based on
literature precedent and in-house knowledge. (16-19) Results from screen 1 indicated combinations of Pd(PPh
KOAc, CsOAc and NMe OAc, afforded the highest conversion and were further investigated to assess their scalability.
Although complete consumption of 8 was achieved when scaling Pd(PPh Cl and KOAc in 2-MeTHF to 43 mmol
10 g), isolation of 10 by crystallisation proved difficult due to its high solubility, with consistently poor isolated yields
3 2 2
) Cl ,
4
3
)
2
2
(
and purity obtained. A facile boronate ester isolation process can be achieved through transesterification to a
diethanolamine (DEA) boronate ester as illustrated in Scheme 2. Due to the characteristic low solubility of such
boronate esters in non-polar organic solvents, isolation by crystallisation has been reported in high yields. (9, 20, 21)

To aid in the development of a transesterification isolation process, solubility studies were performed on 10
and 11. This data was considered alongside the results from screen 1 to design a second borylation screen (Table 1)
in which Miyaura borylation reactivity in six transesterification-appropriate solvents was assessed.
2
hHours
24 hours
CsOAc
93.0
KOAc
95.0
28.5
8.2
CsOAc
72.5
NMe
4
OAc
KOAc
96.2
94.6
87.2
86.0
92.4
78.1
4
NMe OAc
2
-MeTHF
85.3
36.2
88.0
89.2
94.1
58.6
90.3
77.2
89.6
88.5
91.0
71.5
THF
65.3
94.6
chlorobenzene
toluene
31.7
48.0
8.6
51.8
91.7
anisole
10.8
5.0
53.3
93.9
cyclohexanone
86.2
90.0
Table 1: Borylation screen 2: Aryl bromide 2 (4.3 mmol); B
2
Pin
2
(1.1 eq); base (3.0 eq); Pd(PPh
3
)
2
Cl
2
(1.0 mol %),
60 - 80 ℃. Percentage area product by HPLC. Conversion: low (red) → high (green).
Complete conversion of 8 was achieved after 2 hours when employing KOAc in 2-MeTHF with the lowest
levels of the expected homo-dimer and protodehalogenation by-product formation. A visual increase in base solubility
(
KOAc < CsOAc < Me
4
NOAc) was observed across the six solvents suggesting counterion size had an impact on
NOAc
solubility. No clear trend could be drawn between counterion size and the rate of conversion. CsOAc and Me
4
were observed to be highly hygroscopic upon weighing, resulting in the development of a process using these bases
becoming more difficult.
Considering conversion to 8, hygroscopicity, cost of goods, ease of work-up and solvent miscibility with free
DEA, conditions utilising KOAc in 2-MeTHF were selected for scale up. Upon scaling to 216 mmol (50 g), reaction
stalling was observedthe reaction was observed to stall at 70 % conversion, which was initially attributed to poor
agitation. Repeating the reaction with improved agitation failed to prevent the reaction stalling. Increasing the KOAc
charge from 3 to 5 equivalents was shown to force the reaction to complete conversion, however this “quick fix” was
considered risky in terms of robustness upon further scale-up. Reaction stalling could be attributed to a number of
factors in the solid-liquid heterogeneous system linked to reactor design, base particle size distribution or impeller type.
(22)
It was hypothesised that the precipitation of KBr could also have partially coated the KOAc particles, inhibiting
dissolution and hence availability of the base. (22) It was envisaged that increasing base solubility, and hence base
availability, could be a means of overcoming this issue and therefore this led to us revisiting the base selection.
As previously demonstrated in screens 1 and 2, cation modification of the acetate base had a positive impact
on solubility but was linked to increased hygroscopicity and indirectly to by-product formation. Further investigation into
cation modification was therefore not pursued. Consideration of the reaction mechanism suggested two critical
properties of acetate bases could be key to their use in Miyaura borylations. In contrast to stronger bases such as
carbonates which can promote homo coupling, acetates are weak Brønsted bases. (17) Acetates can also be considered

hard Lewis bases. Following oxidative addition, this latter property allows for ligand exchange with the
arylpalladiumhalide complex, forming an arylpalladiumacetate species. (16) This complex has high reactivity towards
bispinacolatodiboron based on two factors: high oxophilicity of the boron centres and a weak palladium-oxygen
bond. (19) Any modification to the base with the aim of increasing solubility would therefore also have to ensure the
following criteria were met: low hygroscopicity, low Brønsted basicity and “hard” Lewis base character.
potassium bases
acetate
pK
a
(H
2
O)
LogP
-0.170
0.604
1.240
1 hour
55.4
24 hours
96.2
4.76
4.87
5.03
propionate
pivalate
51.2
94.2
95.2
95.4
Table 2. Borylation screen 3: pK
octanol/water) calculated values. Aryl bromide
3.0 eq); Pd(PPh Cl (1.0 mol %), 80 ℃. Percentage area product by HPLC.
a
(23, 24) and Maestro (12) LogP (corresponding acid -
(4.3 mmol); Pin (1.1 eq); base
2
B
2
2
(
3
)
2
2
Conversion: low (red) → high (green).
As indicated in Table 2 alongside meeting the discussed criteria above, potassium propionate and pivalate
KOPiv) were selected for investigation due to their increased lipophilicity and likely increased solubility in 2-MeTHF.
(
C-H activation cross-coupling reactions employing pivalates have also previously been reported. (25-27) Base solubility
was visually observed to increase with lipophilicity (acetate < propionate <<< pivalate). Small scale reactions (4.30
mmol 1 g) showed significant rate enhancement with the visually more soluble KOPiv by comparison to acetate or
propionate (Table 2). Complete conversion to 10 was observed with KOPiv in less than 1 hour. To investigate
robustness on a larger scale (43 mmol 10 g), a comparison between KOAc (5.0 eq) and KOPiv (1.1, 1.5 and 3.0 eq)
was performed and conversion to 10 monitored. (Fig. 1Figure 1).
Figure 1: KOPiv vs KOAc Miyaura borylation: Percentage
conversion to product area 10 by HPLC.
Replacement of KOAc (5.0 eq) with KOPiv (3.0 eq) resulted in a 12-fold increase in borylation rate. It is
postulated this increase could result from a combination of solubility and steric factors. Increased base solubility and
hence availability could increase the rate of arylpalladiumhalide ligand exchange. Improved base availability could also
increase the degree of bispinacolatodiboron activation, in turn increasing theat rate of transmetalation. The presence
of the bulky tert-butyl group of the arylpalladiumpivalate complex could also lead to steric congestion around the
catalytic centre, resulting in elongation and weakening of the palladium-oxygen bond, again promoting transmetalation.

(16-19)
Further investigation would will be required to explain the observed differences in reaction the observed reaction
progression (Fig. 1Figure 1) between acetate and pivalate in order to generate a full understanding of the reaction
mechanism.
Aqueous work-up, followed by transesterification with DEA led to the isolation of 11 in 84 % yield and in
excellent purity. The viability of replacing 2 with 11 in the Suzuki-Miyaura cross-coupling transformation was then
assessed. The reaction was observed to reach completion within 4 hours with the same impurity profile compared to
the corresponding reaction with 2. This is expected due to the reaction proceeding by rapid hydrolysis of 11 to 2 in
situ. (6) Subsequent telescoped ester hydrolysis led to the isolation of 1 in 63% yield and in excellent purity.
Conclusion:
A Miyaura borylation approach was identified as a viable alternative route to a boronate precursor of 1. Multiple
rounds of screening were employed to explore the impact of solvents, catalyst and base on reactivity. These results,
together with thoughts as to the desired properties of the base led to the choice of potassium pivalate as a novel,
significantly rate accelerating base for the reaction. Implementation of a DEA transesterification protocol allowed the
facile isolation of 11 in high yield and purity. This new boronate ester was successfully employed in the subsequent
Suzuki-Miyaura cross-coupling transformation, affording 1 after hydrolysis in high yield and purity. This alternative route
removed boroxine linked analytical complications, unfavourable physical properties displayed by 2 and the need for
cryogenic reaction conditions.
Acknowledgements:
The authors would like to thank Adam J. Leahy and Stephen W. Holman for analytical support, David Buttar for
computational support, David W. C. Jones for work on the Suzuki stage and Holly L. Carter for performing solubility
screening. The authors would like to especially thank Lucie Miller-Potucka, Phillip A. Inglesby, Malcolm A. Y. Gall and
Martin F. Jones for their continued support throughout this project.
Commented [RO3]: Minor change to acknowledgements

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Commented [RO4]: Additional C-H activation articles.
Declaration of interests
☒
The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐
The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests:
na

Highlights:



Potassium pivalate was identified as producing exceptional rate accelerating properties.
Diethanolamine transesterification is reported as a facile boronate isolation protocol.
The diethanolamine boronate was shown to perform excellently in the following Suzuki reaction.