Process Development of a Copper(II)-Catalyzed Dehydration of an N-Acyl Prolinal Oxime: Cascade Process and Application at an Elevated Lab Scale

Abstract

Chiral N-acyl amino nitriles are important structural motifs in several pharmaceuticals such as Vildagliptin or Saxagliptin. Cyanide-free access to such nitriles is provided by a copper-catalyzed dehydration of oximes, which are readily available by condensation of chiral aldehydes resulting from the chiral pool with hydroxylamine. The application in a cascade process without the need for intermediate purification as well as a demonstrated scalability show the robustness of this methodology.

Key words

aldoximes - cyanide-free nitrile synthesis - dehydration - ­N-acylaminonitriles - cascade process

Publication History

Received: 22 April 2021

Accepted after revision: 13 July 2021

Accepted Manuscript online:
13 July 2021

Article published online:
23 September 2021

• References

• 1 Fleming FF, Yao L, Ravikumar PC, Funk L, Shook BC. J. Med. Chem. 2010; 53: 7902
• 2a Villhauer EB. WO2000034241A1, 2000
• 2b Villhauer EB, Brinkman JA, Naderi GB, Burkey BF, Dunning BE, Prasad K, Mangold BL, Russell ME, Hughes TE. J. Med. Chem. 2003; 46: 2774
• 3a Savage SA, Jones GS, Kolotuchin S, Ramrattan SA, Vu T, Waltermire RE. Org. Process Res. Dev. 2009; 13: 1169
• 3b Vu TC, Brzozowski DB, Fox R, Godfrey JD, Hanson RL, Kolotuchin SV, Mazzullo JA, Patel RN, Wang J, Wong K, Yu J, Zhu J, Magnin DR, Augeri DJ, Hamann LG. WO2004052850A2, 2004
• 4 Gröger H. Chem. Rev. 2003; 103: 2795
• 5 Pellegatti L, Sedelmeier J. Org. Process Res. Dev. 2015; 19: 551
• 6 Denton RM, An J, Lindovska P, Lewis W. Tetrahedron 2012; 68: 2899
• 7 Hendrickson JB, Bair KW, Keehn PM. Tetrahedron Lett. 1976; 603
• 8 Shekharappa Roopesh Kumar L, Srinivasulu C, Sureshbabu VV. Int. J. Pept. Res. Ther. 2020; 46: 8440
• 9 Xu J, Gao Y, Li Z, Liu J, Guo T, Zhang L, Wang H, Zhang Z, Guo K. Eur. J. Org. Chem. 2020; 311
• 10 Ding R, Liu Y, Han M, Jiao W, Li J, Tian H, Sun B. J. Org. Chem. 2018; 83: 12939
• 11 Fang C, Li M, Hu X, Mo W, Hu B, Sun N, Jin L, Shen Z. Adv. Synth. Catal. 2016; 358: 1157
• 12 Zhu J, Lee F, Wu J, Kuo C, Shia K. Synlett 2007; 1317
• 13a Chill ST, Mebane RC. Synth. Commun. 2009; 39: 3601
• 13b Fang W.-Y, Qin H.-L. J. Org. Chem. 2019; 84: 5803
• 13c Augustine JK, Bombrun A, Atta RN. Synlett 2011; 2223
• 14 Attanasi O, Palma P, Serra-Zanetti F. Synthesis 1983; 741
• 15 Tambara K, Pantoş GD. Org. Biomol. Chem. 2013; 11: 2466
• 16 Hyodo K, Kitagawa S, Yamazaki M, Uchida K. Chem. Asian J. 2016; 11: 1348
• 17 Ma X.-Y, He Y, Lu T.-T, Lu M. Tetrahedron 2013; 69: 2560
• 18 Xu Y, Jia X, Ma J, Gao J, Xia F, Li X, Xu J. ACS Sustainable Chem. Eng. 2018; 6: 2888
• 19 Rommelmann P, Betke T, Gröger H. Org. Process Res. Dev. 2017; 21: 1521