A Non-infringing Route for Enantioselective Synthesis of Antiepileptic Agent Lacosamide

Abstract

A non-infringing route for enantioselective synthesis of lacosamide has been developed. The synthesis started from commercially available acrylic acid and was completed in eight steps using Sharpless asymmetric dihydroxylation as a key step with an overall yield of 29%. All the reactions were very clean with good yields.

Organocatalytic Approach to the Enantioselective Total Synthesis of (+)-Serinolamides A and B and (+)-Lacosamide

“…[𝜶] 𝟐𝟎 𝑫 = +16.1 (c = 1.2, MeOH), [Lit. : [𝜶] 𝟐𝟎 𝑫 = +16.2 (c = 1, MeOH), 22 [𝜶] 𝟐𝟎 𝑫 = +16.4 (c = 1, MeOH), 13c [𝜶] 𝟐𝟎 𝑫 = +16.1 (c =1,MeOH) 13q ]. 1 H NMR (400 MHz, CDCl3) 13,14,5H),6.78 (br s,1H),6.48 (br s,1H),1H),4.50 (d,J = 4.5 Hz,2H),3.83 (dd,J = 9.4,3.4 Hz,1H),3.45 (t,J = 9.7,8.0 Hz,1H),3.40 (s,3H),2.05 (s,3H).…”

“…The crude product was purified by column chromatography (silica gel, DCM/MeOH 95:05) to afford ( R )-lacosamide ( 7 ) as a white solid; yield: 0.38 g (80%); mp 143–144 °C; [α] D 20 +16.1 ( c 1.2, MeOH) {Lit. [α] D 20 +16.2 ( c 1, MeOH), 22 [α] D 20 +16.4 ( c 1, MeOH), 13c [α] D 20 +16.1 ( c 1, MeOH) 13q }.…”

“…1 H NMR (400 MHz, CDCl 3 ): 13 14 22 δ = 7.26–7.38 (m, 5 H), 6.78 (br s, 1 H), 6.48 (br s, 1 H), 4.52–4.58 (m, 1 H), 4.50 (d, J = 4.5 Hz, 2H), 3.83 (dd, J = 9.4, 3.4 Hz, 1 H), 3.45 (t, J = 9.7, 8.0 Hz, 1 H), 3.40 (s, 3 H), 2.05 (s, 3 H).…”

“…13 C NMR (101 MHz, CDCl 3 ): 13 14 22 δ = 170.7, 170.0, 137.7, 128.6, 127.4, 71.8, 59.1, 52.6, 43.6, 23.2.…”

Concise Synthesis of Lacosamide with High Chiral Purity

“…In the past decades, many routes have been developed to synthesize lacosamide. − However, its commercial routes were based on the synthetic route reported by UCB Pharma, involving the O -methylation of an N -Boc- d -serine, benzylamide formation, N -deprotection, and N -acetylation . However, the main problem of the present synthetic routes (Scheme ) is the partial racemization .…”