Synthesis of Bempedoic Acid through Electrochemical Decarboxylation of Dialkylated Malonic Acid

Abstract

Bempedoic acid is a small-molecule inhibitor of adenosine triphosphate-citrate lyase (ACL) that is effective in the treatment of hypercholesterolemia and hypertension. In this paper, a new, six-step synthesis of bempedoic acid with 42% overall yield is reported. Ketone formation by electrochemical decarboxylation of dialkylated malonic acid is introduced as the key step of this process. This method uses mild conditions and its high efficiency makes it potentially suitable for industrial production.

Key words

bempedoic acid - electrochemical synthesis - decarboxylation - malonic acid - high efficiency

Publication History

Received: 28 January 2021

Accepted after revision: 15 April 2021

Accepted Manuscript online:
15 April 2021

Article published online:
06 May 2021

• References

• 1 Stroes ES, Thompson PD, Corsini A, Vladutiu GD, Raal FJ, Ray KK, Roden M, Stein E, Tokgözoğlu L, Nordestgaard BG, Bruckert E, Backer GD, Krauss RM, Laufs U, Santos RD, Hegele RA, Hovingh GK, Leiter LA, Mach F, März W, Newman CB, Wiklund O, Jacobson TA, Catapano AL, Chapman MJ, Ginsberg HN, Stroes E, Thompson PD, Corsini A, Vladutiu GD, Raal FJ, Ray KK, Roden M, Stein E, Tokgözoğlu L, Nordestgaard BG, Bruckert E, Krauss RM, Laufs U, Santos RD, März W, Newman CB, Chapman MJ, Ginsberg HN, Chapman MJ, Ginsberg HN, Backer G. d, Catapano AL, Hegele RA, Hovingh GK, Jacobson TA, Leiter L, Mach F, Wiklund O. Eur. Heart J. 2015; 36: 1012
• 2 Sirtori CR, Yamashita S, Greco MF, Corsini A, Watts GF, Ruscica M. Eur. J. Prev. Cardiol. 2020; 27: 1576
• 3 Pinkosky SL, Newton RS, Day EA, Ford RJ, Lhotak S, Austin RC, Birch CM, Smith BK, Filippov S, Groot PH, Steinberg GR, Lalwani ND. Nat. Commun. 2016; 7: 13457
• 4 Dasseux JH, Oniciu DC. PCT Int. Appl WO 2004067489, 2004
• 5a Yan M, Kawamata Y, Baran PS. Chem. Rev. 2017; 117: 13230
• 5b Yang Q.-L, Fang P, Mei T.-S. Chin. J. Chem. 2018; 36: 338
• 5c Möhle S, Zirbes M, Rodrigo E, Gieshoff T, Wiebe A, Waldvogel SR. Angew. Chem. Int. Ed. 2018; 57: 6018
• 5d Lin D.-Z, Huang J.-M. Org. Lett. 2018; 20: 2112
• 5e Zhao Y, Xia W. Chem. Soc. Rev. 2018; 47: 2591
• 5f Kärkäs MD. Chem. Soc. Rev. 2018; 47: 5786
• 5g Yoshida J.-i, Shimizu A, Hayashi R. Chem. Rev. 2018; 118: 4702
• 5h Jiang Y, Xu K, Zeng C. Chem. Rev. 2018; 118: 4485
• 5i Yuan Y, Lei A. Acc. Chem. Res. 2019; 52: 3309
• 5j Xiong P, Xu H.-C. Acc. Chem. Res. 2019; 52: 3339
• 5k Ackermann L. Acc. Chem. Res. 2020; 53: 84
• 5l Leech MC, Lam K. Acc. Chem. Res. 2020; 53: 121
• 5m Zheng Y, Shao X, Ramadoss V, Tian L, Wang Y. Synthesis 2020; 52: 1357
• 5n Shao X, Zheng Y, Ramadoss V, Tian L, Wang Y. Org. Biomol. Chem. 2020; 18: 5994
• 5o Ramadoss V, Zheng Y, Shao X, Tian L, Wang Y. Chem. Eur. J. 2021; 27: 3213
• 5p Gale-Day ZJ. Synthesis 2021; 53: 879
• 6a Ma X, Luo X, Dochain S, Mathot C, Markò IE. Org. Lett. 2015; 17: 4690
• 6b Ma X, Dewez DF, Du L, Luo X, Markò IE, Lam K. J. Org. Chem. 2018; 83: 12044
• 7 Tufariello JJ, Kissel WJ. Tetrahedron Lett. 1966; 7: 6145
• 8 Alcaraz L, Bailey A, Bull RJ, Johnson T, Kindon ND, Lister AS, Robbins AJ, Stocks MJ, Teobald BJ. PCT Int. Appl WO 2009098448, 2009
• 9a Shao X, Zheng Y, Tian L, Martín-Torres I, Echavarren AM, Wang Y. Org. Lett. 2019; 21: 9262
• 9b Xiang J, Shang M, Kawamata Y, Lundberg H, Reisberg S, Chen M, Mykhailiuk P, Beutner G, Collins M, Davies A, Bel MD, Gallego G, Spangler J, Starr JT, Yang S, Blackmond D, Baran PS. Nature 2019; 573: 398
• 10a Schafer HJ. Top. Curr. Chem. 1990; 152: 91
• 10b Klocke E, Matzeit A, Gockeln M, Schafer HJ. Chem. Ber. 1993; 126: 1623