Improved Synthesis and Impurity Identification of (R)-Lacosamide

Abstract

An improved synthesis of Lacosamide 1 with high purity has been developed. Critical parameters of each step were identified as well as the impurities generated. Moreover, a creative method to improve chiral purity and stability of the key intermediate (R)-2-amino-N-benzyl-3-methoxypropionamide 10 by forming salt with an achiral acid (phosphoric acid) was discovered to ensure the chiral purity of (R)-Lacosamide. Phosphoric acid was further developed for the deprotection of the Boc group.

A Short Review of Synthetic Routes for the Antiepileptic Drug (R)-Lacosamide

“…Initial strategies for the synthesis of this drug used the non-natural amino acid d -serine (( R )- 2 ) as the starting material. The conversion of ( R )- 2 into ( R )- 1 involves N-acylation and O-methylation steps with the introduction and manipulation of protecting groups used in different orders . O-Methylation was the problematic step because of partial racemization of the amino acid during the step. − To overcome this partial racemization, Choi et al utilized neutral methylation conditions involving MeI and Ag 2 O to synthesize ( R )- 1 in the three steps starting from ( R )- 2 in 30% overall yield (Scheme ).…”

“…The medicinal importance of ( R )-lacosamide has attracted the attention of researchers around the world, and several asymmetric, chiral pool, and enzymatic syntheses have been reported in the literature. − ,− Chemically, ( R )-lacosamide, or ( R )-2-acetamido- N -benzyl-3-methoxypropionamide, can be considered as a functionalized derivative of the amino acid d -serine.…”

Large-Scale Amidations in Process Chemistry: Practical Considerations for Reagent Selection and Reaction Execution

“… General remarks: There are numerous references on the application of IBCF in process chemistry for amide bond formation. ,,,, This reagent is available in bulk quantities and inexpensive. IBCF displays lower toxicity than ECF and gives much better regioselectivity during amide coupling because of the larger steric bulk of the isobutyl group, thus minimizing urethane formation.…”

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

“…13u Zang’s group in 2019 reported the synthesis of 7 from Boc-protected d -serine in four steps in 65% overall yield over 4 steps. 13v Stecko employed modified Overmann rearrangement for the synthesis of lacosamide in which the expensive chemical trichloroacetyl isocyanate is used. 14a Recently, Mondal et al established the synthesis of 7 from a rare chiral synthon glycine enolate equivalent of 4-benzyl- N -glycinyloxazolidinone in 4 steps in 36% overall yield.…”