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