An Alternative Formal Synthesis of (S)-(+)-Vigabatrin

Abstract

An improved synthesis of chirally pure advanced pyrrolidone intermediate of the (S)-(+)-vigabatrin, an antiseizure active pharmaceutical ingredient (API) is reported. The synthesis is developed using commercially available, cheaper amino acid (R)-methionine. Meldrum’s acid served as a two-carbon homologation unit to access the pyrrolidone intermediate in a short synthetic sequence. The sequence to pyrrolidone intermediate is scalable and eludes the use of organometallic pyrophoric reagents on a large scale.

Key words

GABA - vigabatrin - decarboxylative cyclization - Meldrum’s acid - seizure - API

Publication History

Received: 17 March 2023

Accepted after revision: 07 June 2023

Article published online:
03 July 2023

• References

• 1a Gale K. Epilepsia 1989; 30: S1
• 1b Gram L, Larsson O, Johnsen A, Schousboe A. Br. J. Clin. Pharmacol. 1989; 27: 13S
• 2a Grant SM, Heely RC. Drugs 1991; 41: 889
• 2b Ben-Menachem E. Acta Neurol. Scand. Suppl. 2011; 124: 5
• 2c Tolman JA, Faulkner MA. Expert Opin. Pharmacother. 2009; 10: 3077
• 2d Press Announcements - FDA approves first generic version of Sabril to help treat seizures in adults and pediatric patients with epilepsy; www.fda.gov
• 3a Wei ZY, Knaus EE. Tetrahedron 1994; 50: 5569
• 3b Wei ZY, Knaus EE. J. Org. Chem. 1993; 58: 1586
• 3c Frieben W, Gerhart F. Patnet UK 2133002, 1984
• 3d Kwon TW, Keusenkothen PF, Smith MB. J. Org. Chem. 1992; 57: 6169
• 3e Trost BM, Lemoine RC. Tetrahedron Lett. 1996; 37: 9161
• 3f Alcon M, Poch M, Moyano A, Pericas MA, Riera A. Tetrahedron: Asymmetry 1997; 8: 2967
• 3g Wei ZY, Knaus EE. Synlett 1993; 295
• 3h Jachak GR, Reddy DS. Eur. J. Org. Chem. 2019; 1257
• 4 Takacs JM, Helle MA, Seely FL. Tetrahedron Lett. 1986; 27: 1257
• 5a Youn IK, Yon GH, Pak CS. Tetrahedron Lett. 1986; 27: 2409
• 5b Hudlický T, Sinai-Zingde G, Natchus MG. Tetrahedron Lett. 1987; 28: 5287
• 6a Karumanchi K, Natarajan SK, Gadde S, Vanchanagiri K. Chem. Pap. 2020; 74: 2035
• 6b Karumanchi K, Natarajan SK, Gadde S, Chavakula R, Korupolu RB, Bonige KB. Synth. Commun. 2019; 49: 359
• 7a Smrcina M, Majer P, Majerova E, Guerassina T, Eissenstat MA. Tetrahedron 1997; 53: 12867
• 7b Kerr MS, de Alaniz JR, Rovis T. J. Org. Chem. 2005; 70: 5725
• 7c Zeng P, Gondo CA, Bode JW. Chem. Asian. J. 2011; 6: 614
• 7d Medha BH, Gunaratna J, Zhang M, Weerasekara S, Seiwald SN, Nguyen VT, Meier A, Hua DH. J. Am. Chem. Soc. 2016; 138: 16839
• 7e King AM, Salome C, Dinsmore J, Salome-Grosjean E, De Ryck M, Kaminski R, Valade A, Kphn H. J. Med. Chem. 2011; 54: 4815
• 8a Hoye AT, Wipf P. Org. Lett. 2011; 13: 2634
• 8b Badrinarayana V, Lovely CJ. Tetrahedron 2007; 48: 2607
• 8c Snider B, Ahn Y, O’hare SM. Org. Lett. 2001; 3: 4217
• 9 Gurjar MK, Tripathy NK, Mahale RD, Pramanik CM, Chaskar SP, Shimpi AS. Indian Patent Application No. 201821014755, 2018 , pending.