Improved synthesis of sterically encumbered heteroaromatic biaryls from aromatic β-keto esters

Article abstract of DOI:10.1016/j.tetlet.2020.151855

A protocol for the synthesis of hindered 4-aryl 2-aminopyrimidines from β–keto esters is described. The process employs trifluoroethanol as an essential additive to promote the guanidine condensation reaction, enabling the synthesis of 25 aryl- and heteroaryl substituted aminopyrimidines in good yields and high purities with no column chromatography. The conditions described herein are readily scalable and have been employed in the large-scale synthesis of the clinical A_2a/A_2bR antagonist AB928.

Full text of DOI:10.1016/j.tetlet.2020.151855

Journal Pre-proofs
Improved synthesis of sterically encumbered heteroaromatic biaryls from aro‐
matic β-keto esters
Brandon R. Rosen, Ehesan Ul Sharif, Dillon H. Miles, Nicholas S. Chan,
Manmohan R. Leleti, Jay P. Powers
PII:
S0040-4039(20)30295-1
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.151855
TETL 151855
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
18 February 2020
12 March 2020
16 March 2020
Please cite this article as: Rosen, B.R., Ul Sharif, E., Miles, D.H., Chan, N.S., Leleti, M.R., Powers, J.P.,
Improved synthesis of sterically encumbered heteroaromatic biaryls from aromatic β-keto esters, Tetrahedron
Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.151855
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Improved synthesis of sterically encumbered
heteroaromatic biaryls from aromatic β-keto
esters
Leave this area blank for abstract info.
Brandon R. Rosen,* Ehesan Ul Sharif, Dillon H. Miles, Nicholas S. Chan, Manmohan R. Leleti, Jay P.
Powers
NH2
[25 examples]
[33-76% yield]
O
R
guanidine
TFE, 80 °C
HN
N
R
[Complete selectivity]
[Purification by precipitation]
[No metal catalyst]
R'
O
EtO2C
R'
[poor conversion in EtOH]

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Improved synthesis of sterically encumbered heteroaromatic biaryls from aromatic β-
keto esters
Brandon R. Rosena,* Ehesan Ul Sharif a, Dillon H. Miles a, Nicholas S. Chan a, Manmohan R. Leleti a and
Jay P. Powersa
a Arcus Biosciences, 3928 Point Eden Way, Hayward, CA 94545
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A protocol for the synthesis of hindered 4-aryl 2-aminopyrimidines from β–keto esters is
described. The process employs trifluoroethanol as an essential additive to promote the
guanidine condensation reaction, enabling the synthesis of 25 aryl- and heteroaryl substituted
aminopyrimidines in good yields and high purities with no column chromatography. The
conditions described herein are readily scalable and have been employed in the large-scale
synthesis of the clinical A2a/A2bR antagonist AB928.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Heterocycle
Aminopyrimidine
Guanidine condensation
AB928
Aryl substituted 2-aminopyrimidines represent a broadly adopted pharmacophore in drug discovery.1–6 The inclusion of this motif in
several FDA-approved and investigational medicines underscores its importance, as exemplified by the chemical structures of Xermelo
(1, telotristat ethyl), Momelotinib (2), Braftovi (3, encorafenib), and Gleevec (4, imatinib). The central core of each of these molecules
contains an aryl substituted 2-aminopyrimidine, the synthesis of which is typically straightforward. A common approach is the Suzuki–
Miyaura cross-coupling of an appropriately substituted halopyrimidine and arylboronic acid to forge the Ar–Ar bond.7–10 Alternatively,
these heterocycles can be prepared by condensation of a functionalized guanidine onto a β–keto ester or appropriate surrogate.11–14
O
Me
H
N
NH2
N
N
NHCO2Me
Cl
CF3
N
N
HN
N
O
NH2
CO2Et
N
N
O
O
NC
S
Cl
N
N
N
N
N
Me
H
F
Me
NH
Me
Me
O
Xermelo (Telotristat ethyl, 1)
Tryptophan hydroxylase inhibitor
Momelotinib (2)
JAK1/2 inhibitor
Braftovi (Encorafenib, 3)
BRAF inhibitor
NH2
HO
N
N
N
N
Me
Me
Me
H
H
N
N
N
N
NMe
CN
N
N
N
O
N
Me
Gleevec (Imatinib, 4)
Tyrosine kinase inhibitor
AB928 (5)
A2a/A2bR antagonist
Figure 1. Biologically-active 4-aryl 2-aminopyrimidines.

2
Tetrahedron Letters
(a) Initial Suzuki coupling approach to AB928 synthesis.
NH2
NH2
Me
[Unacceptable selectivity]
[Challenging purification]
[Costly metal catalysis]
[Modest overall yield]
3 mol% [Pd]
N
N
Me
BPin
CN
N
N
CN
1st gen synthesis
28%
Cl
Cl
Cl
6
(b) Second generation approach using trifluoroethanol to accelerate guanidine condensation.
NH2
O
O
Me
[Complete selectivity]
[Purification by precipitation]
[No metal catalyst]
guanidine
HN
N
Me
CN
EtO
CN
TFE, 80 °C
63%
O
[Improved overall yield]
7
[<15% conversion in EtOH]
8
Scheme 1. Approaches to AB928 intermediate using metal-catalyzed cross-coupling or guanidine condensation.
AB928 (5) is a potent and selective dual A2a/A2bR antagonist discovered at Arcus Biosciences currently undergoing clinical trials in
multiple cancer settings.15 As part of ongoing studies focused on the large-scale synthesis of 5, we found that the synthesis of key
intermediate 6 under typical Suzuki cross-coupling conditions was not suitable for the large scale synthesis of AB928 (Scheme 1a).
Scale-up was hampered by poor selectivity for mono- over difunctionalization of the dichloropyrimidine and the resulting challenging
purification. After column chromatography and recrystallization, intermediate 6 was still contaminated with the diaryl substituted
product and 4,6-dichloro-2-aminopyrimidine starting material. Additionally, efforts to employ less than 3 mol% of the palladium
catalyst resulted in inferior conversions, and the costs associated with these higher catalyst loadings on larger scale were deemed
unacceptable.
Thus, we elected to explore an alternative construction of the pyrimidine core employing β-keto ester 7 and guanidine. Following
established protocols for pyrimidine synthesis, prolonged exposure of 7 to guanidine carbonate in refluxing ethanol resulted in trace
formation of product 8, likely due to the ortho-methyl substituent present on the aryl ring. It quickly became clear that our proposed
route to 8 would require the development of novel conditions for this seemingly simple transformation. In this Letter, we report the use
of conditions for the synthesis of sterically hindered 6-aryl 2-aminopyrimidinones from β-keto esters using trifluoroethanol (TFE) as an
accelerant (Scheme 1b).16–18 This scalable approach to pyrimidine synthesis has enabled the preparation of AB928 for further clinical
development with no need to remove hazardous metal contaminants and an improved yield over the previous cross-coupling approach.
The optimized procedure is operationally simple and can be employed in the synthesis of a variety of pyrimidine derivatives containing
sterically hindered aryl and heteroaryl substituents.
NH2
O
O
Me
O
O
Me
guanidine
EtOH, 80 °C
[1:2.6 ratio]
HN
N
Me
+
O
EtO
O
CF3
9
10
11
Scheme 2. Initial pyrimidinone synthesis using trifluoroethyl keto-ester.
Our initial solution to the sluggish reactivity of 7 was to modify the ester in order to increase its electrophilicity. Thus, as shown in
Scheme 2, exposing the related trifluoroethyl keto-ester 9 to guanidine carbonate in refluxing ethanol led to a mixture of desired
pyrimidinone 10 and keto-ester 11 in approximately 1:2.6 ratio, indicating that 9 was a competent coupling partner in the condensation
reaction. Replacing ethanol with TFE solvent to prevent undesired transesterification led to complete conversion of 9 to 10; the
preparation of 9, however, was inadequate for our needs, and we began to contemplate a synthesis of trifluoroethyl keto-ester 9 directly
from 11. Transesterification of 11 in the presence of TFE was sluggish, and efforts to drive the reaction to completion at elevated
temperatures or in the presence of acid additives were unsuccessful. Despite the slow transesterification, we believed we could exploit
the dynamic equilibrium and funnel the trifluoroethyl ester to pyrimidinone 8. Thus, we found that addition of guanidine to a
trifluoroethanolic solution of 11 at reflux resulted in complete consumption of 11 and acceptable isolated yields of pyrimidinone 10
after precipitation. This result could be obtained with as little as 10% v/v TFE/ethanol as solvent, though with slightly prolonged
reaction time. It is noteworthy that the use of other solvents (e.g. HFIP, DMF, NMP) or additives (e.g. AcOH, TsOH) did not improve
conversions, even at temperatures well above the boiling point of TFE. Furthermore, the only detectable byproduct in the reactions was
the corresponding acetophenone derived from decarboxylation of 11; typically, this byproduct was formed in less than 15% yield and
could be washed away from the crude mixture prior to precipitation of the product or separated by column chromatography.19
With these optimized conditions in hand, we elected to explore the scope of the TFE-mediated cyclization. As shown in Scheme 3, a
broad range of ortho-substituted keto-esters were converted to the corresponding aminopyrimidinones. For example, methyl,
trifluoromethyl, chloro, methoxy, and trifluoromethoxy groups were all well-tolerated at the ortho position (10, 12–15). Larger groups
such as cyclopropyl, isopropyl, dimethylamino, methanesulfonyl, benzyl, and even phenyl afforded the corresponding pyrimidinones in
synthetically useful yields (16–21).
Variation of the electronic nature of the benzene ring was also well-tolerated. Both electron deficient and electron rich aryl keto-
esters could be used. Pyrimidinone 8 was prepared in 63% yield, while deuterating the methyl group enabled the synthesis of 22 in a
comparable 65% yield. Replacing the cyano group with a methoxy group resulted in a diminished 50% yield of 23. The electron-
deficient chloro, bromo, trifluoromethyl, and nitro arenes 24–27 were prepared in good yields. The chlorine atom could be incorporated
at other positions of the benzene ring (28 and 29); use of the 2-chloro-6-methylbenzoic acid-derived keto-ester, however, led to a
complex mixture and less than 20% conversion to product. Furthermore, attempts to employ the 2,6-dimethylbenzoic acid-derived keto-

3
ester resulted in substrate decomposition, and no pyrimidinone product was observed. These results suggest that there remains a
limited amount of steric bulk tolerated in the condensation reaction, even under the TFE-accelerated conditions.20
NH2
O
R
guanidine
TFE, 80 °C
HN
N
R
R'
O
EtO2C
R'
Me
CF3
Cl
OMe
OCF3
10
12
57%
13
66%
14
69%
15
55%
62% [2 mmol]
65% [10 mmol]
O
Me
Me
Me
Me
Me
N
O S
16
17
18
19
20
54%
54%
54%
51%
47%
Me
CD3
Me
Me
CN
CN
OMe
Cl
21
8
22
23
24
56%
63%
65%
50%
74%
Me
Me
Me
Br
Me
Me
CF3
NO2
Cl
Cl
25
76%
26
53%
27
73%
28
70%
Me
29
72%
Me
Me
N
Me
Me
N
N
N
N
N
N
Me
30
33%
31
47%
32
57%
33
60%
34
72%
Scheme 3. Scope of TFE-mediated guanidine condensation.
Reaction conditions: keto-ester
substrate (2 mmol), guanidine carbonate (2 mmol), CF3CH2OH (2.5 mL), 80 °C. Yields refer to
isolated yields as an average of two experiments.
Substituted heterocycles also proved to be efficient partners in the condensation reaction, affording nicotinic acid-derived products 30
and 31 as well as isonicotinic acid-derived product 32. Substituted indazole 33 was prepared in 60% yield, while pyrazole 34, which
contains the substitution pattern found in encorafenib 3, was prepared in an efficient 72% yield. It is noteworthy that in all instances,
replacing TFE with ethanol as a solvent for the reaction resulted in dramatically diminished or no conversion after 24 hours.
NH2
NH2
O
Me
guanidine
TFE, 80 °C
POCl3
HN
N
Me
N
N
Me
CN
CN
CN
MeCN, 80 °C
O
Cl
EtO2C
7
8
6
[48 grams isolated]
[64% from keto-ester 7]
NH2
CF3
CF3
N
N
Me
OH
CN
35, Cs2CO3
O
Cl
N
N
dioxane, 80 °C
79%
Cl
N
N
Me
35
36
Me
Scheme 4. Synthesis of chloropyrimidine and conversion to aryl ether.

4
Tetrahedron Letters
The reaction performed quite well on scale-up. For example, pyrimidinone 10 was isolated in 65% yield on 10 mmol (2.06 g) scale
by precipitation. As shown in Scheme 4, these conditions were readily adopted for the multi-gram scale synthesis of 6. Following
precipitation of 8, we were able to convert 8 to chloropyrimidine 6 using POCl3 in 64% yield (two steps, 48 grams isolated),
intercepting the intermediate previously synthesized by Suzuki-Miyaura cross-coupling. This isolated yield compares favorably and
results in a nearly 60% cost reduction for the synthesis of this key intermediate.21 We elected to further functionalize 6 through an SnAr
reaction employing alcohol 35 to give ether 36 in 79% yield, highlighting the utility of these intermediates in the synthesis of bioactive
molecules.
In summary, we have discovered that the synthesis of sterically hindered 2-aminopyrimidines from guanidine and β-keto esters can
be expedited using trifluoroethanol as solvent. Exploiting this underutilized solvent results in a dramatic increase in reaction rate, and
byproducts can be washed away before the product is precipitated in high purity, thereby avoiding chromatographic separation. This
operationally simple route was employed in the large-scale synthesis of a key intermediate for the clinical candidate AB928, replacing a
more costly Suzuki-Miyaura coupling route. The conditions described herein can be used in the synthesis of a variety of substituted
aminopyrimidines with good functional group tolerance on the keto-ester substrate. We expect that this straightforward procedure will
be adopted in other contexts where classical heterocycle synthesis provides a superior alternative to modern cross-coupling.
References and notes
1. Jin, H.; Cianchetta, G.; Devasagayaraj, A.; Gu, K.; Marinelli, B.; Samala, L.; Scott, S.; Stouch, T.; Tunoori, A.; Wang, Y.; Zan, Y.; Zhang, C.;
Kimball, S. D.; Main, A. J.; Ding, Z.-M.; Sun, W.; Yang, Q.; Yu, X.-Q.; Powell, D. R.; Wilson, A.; Lui, Q.; Shi, Z.-C. Substituted 3-(4-(1,3,5-triazin-2-
yl)-phenyl)-2-aminopropanoic acids as novel tryptophan hydroxylase inhibitors. Bioorg. Med. Chem. Lett. 2009, 19, 5229–5232.
2. Burns, C. J.; Bourke, D. G.; Andrau, L.; Bu, X.; Charman, S. A.; Donohue, A. C.; Fantino, E.; Farrugia, M.; Feutrill, J. T.; Joffe, M.; Kling, M. R.;
Kurek, M.; Nero, T. L.; Nguyen, T.; Palmer, J. T.; Phillips, I.; Shackleford, D. M.; Sikanyika, H.; Styles, M.; Su, S.; Treutlein, H.; Zeng, J.; Wilks, A. F.
Phenylaminopyrimidines as inhibitors of Janus kinases (JAKs). Bioorg. Med. Chem. Lett. 2009, 19, 5887–5892.
3. Huang, S.; Jin, X.; Liu, Z.; Poon, D.; Tellow, J.; Wan, Y.; Wang, X.; Xie, Y. Preparation of sulfonamidophenylimidazolylpyrimidine derivatives
and analogs for use as protein kinase inhibitors. World patent WO 2011/025927, March 3, 2009.
4. Gillespie, R. J.; Bamford, S. J.; Clay, A.; Gaur, S.; Haymes, T.; Jackson, P. S.; Jordan, A. M.; Klenke, B.; Leonardi, S.; Liu, J.; Mansell, H. L.; Ng,
S.; Saadi, M.; Simmonite, H.; Stratton, G. C.; Todd, R. S.; Williamson, D. S.; Yule, I. A. Antagonists of the human A2A receptor. Part 6: Further
optimization of pyrimidine-4-carboxamides. Bioorg. Med. Chem. 2009, 17, 6590–6605.
5. Murray, C. W.; Carr, M. G.; Callaghan, O.; Chessari, M.; Cowan, S.; Coyle, J. E.; Downham, R.; Figueroa, E.; Frederickson, M.; Graham, B.;
McMenamin, R.; O’Brien, M. A.; Patel, S.; Phillips, T. R.; Williams, G.; Woodhead, A. J., Woolford, A. J.-A. Fragment-Based Drug Discovery
Applied to Hsp90. Discovery of Two Lead Series with High Ligand Efficiency. J. Med. Chem. 2010, 53, 5942–5955.
6. Medina, J. R.; Becker, C. J.; Blackledge, C. W.; Duquenne, C.; Feng, Y.; Grant, S. W.; Heerding, D.; Li, W.; Miller, W. H.; Romeril, S. P.;
Scherzer, D.; Shu, A.; Bobko, M. A.; Chadderton, A. R.; Dumble, M.; Gardiner, C. M.; Gilbert, S.; Liu, Q.; Rabindran, S. K.; Sudakin, V.; Xiang, H.;
Brady, P. G.; Campobasso, N.; Ward, P.; Axten, J. M. Structure-Based Design of Potent and Selective 3-Phosphoinositide-Dependent Kinase-1 (PDK1)
Inhibitors. J. Med. Chem. 2011, 54, 1871–1895.
7. Benderitter, P.; de Araújo Júnior, J. X.; Schmitt, M.; Bourguignon, J.-J. 2-Amino-6-iodo-4-tosyloxypyrimidine: a versatile key intermediate for
regioselective functionalization of 2-aminopyrimidines in 4- and 6-positions. Tetrahedron 2007, 63, 12645–12470.
8. Harris, J. M.; Neustadt, B. R.; Zhang, H.; Lachowicz, J.; Cohen-Williams, M.; Varty, G.; Hao, J.; Stamford, A. W. Potent and selective adenosine
A2A receptor antagonists: [1,2,4]-triazolo[4,3-c]pyrimidin-3-ones. Bioorg. Med. Chem. Lett. 2011, 21, 2497–2501.
9. Kolman, V.; Kalčic, F.; Jansa, P. Zídek, Z.; Janeba, Z. Influence of the C-5 substitution in polysubstituted pyrimidines on inhibition of
prostaglandin E2 production. Eur. J. Med. Chem. 2018, 156, 295–301.
10. Burgoon, Jr., H. A.; Kanamarlapudi, R. C.; Pickersgill, I. F.; Shi, Z.-C.; Wu, W.; Zhang, H. Process for the preparation of substituted
phenylalanines. US Patent 11,647,517, February 19, 2009.
11. Skulnick, H. I.; Weed, S. D.; Eidson, E. E.; Renis, H. E.; Wierenga, W.; Stringfellow, D. A. Pyrimidinones. 1 2-Amino-5-halo-6-aryl-4(3H)-
pyrimidinones. Inferferon-Inducing Antiviral Agents. J. Med. Chem. 1985, 28, 1864–1869.
12. Shirude, P. S.; Paul, B.; Choudhury, N. R.; Kedari, C.; Bandodkar, B.; Ugarkar, B. G. Quinolinyl Pyrimidines: Potent Inhibitors of NDH-2 as a
Novel Class of Anti-TB Agents. ACS Med. Chem. Lett. 2012, 3, 736–740.
13. Zhu, C.; Xue, X.; Han, G.; Mao, Y.; Xu, J. J. Heterocyclic Chem. 2017, 54, 2902–2905.
14. Hobson, L. A.; Akiti, O.; Deshmukh, S. S.; Harper, S.; Katipally, K.; Lai, C. J.; Livingston, R. C.; Lo, E.; Miller, M. M.; Ramakrishna, S.; Shen,
L.; Spink, J.; Tummala, S.; Wei, C.; Yamamoto, K.; Young, J.; Parson, R. L. Development of a Scaleable Process for the Synthesis of a Next-
Generation Statin. Org. Process Res. Dev. 2010, 14, 441–458.
15. Seitz, L.; Jin, L.; Letelti, M.; Ashok, D.; Jeffrey, J.; Rieger, A.; Tiessen, R. G.; Arold, G.; Tan, J. B. L.; Powers, J. P.; Walters, M. J.; Karakunnel,
J. Safety, tolerability, and pharmacology of AB928, a novel dual adenosine receptor antagonist, in a randomized, phase 1 study in healthy volunteers.
Invest. New Drugs 2019, 37, 711–721.
16. Bégué, J.-P.; Bonnet-Delpon, D.; Crousse, B. Fluorinated Alcohols: A New Medium for Selective and Clean Reaction. Synlett 2004, 1, 18–29.
17. Shuklov, I. A.; Dubrovina, N. V.; Börner, A. Fluorinated Alcohols as Solvents, Cosolvents and Additives in Homogeneous Catalysis. Synthesis
2007, 19, 2925–2943.
18. Fustero, S.; Román, R.; Sanz-Cervera, J. F.; Simón-Fuentes, A.; Cuñat, A. C.; Villanova, S.; Murguía, M. Improved Regioselectivity in Pyrazole
Formation theough the Use of Fluorinated Alcohols as Solvents: Synthesis and Biological Activity of Fluorinated Tebufenpyrad Analogs. J. Org. Chem.
2008, 73, 3523–3529.
19. Addition of water to the reaction medium increased the yield of acetophenone product. For related chemistry, see: Curran, D. P.; Zhang, W.
Microwave Heating Effects Rapid and Selective Decarboxylation of Mono-Alkylated Malonates and β-Ketoesters. Adv. Synth. Catal. 2003, 345, 329–
332.
20. Related hindered pyrimidine derivatives have been prepared by Suzuki-Miyaura cross-coupling of the corresponding boronic acids. See Ref 5.
21. Cost savings based on quotations provided for the synthesis of 24 kg of compound 6.
Supporting Information
The Supporting Information is available free of charge and contains experimental procedures, characterization data, and NMR spectra.
Corresponding Author
* E-mail: brosen@arcusbio.com

5
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.
Notes
The authors declare no competing financial interest.
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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:
Highlights



Aryl substituted 2-aminopyrimidines are important in drug discovery
AB928 is a potent A2a/A2bR antagonist undergoing clinical trials in cancer
Trifluoroethanol promotes reaction between hindered β-keto esters with guanidine