Synthesis scheme for lacosamide

1. A method of producing (R)-2-acetamido-N-benzyl-3-methoxypropionamide (lacosamide) comprising methylating a compound of formula I

to produce a compound of formula II

wherein Rx is an N-protecting group,

wherein the methylation is carried out in a one-step reaction as a phase transfer catalysis and wherein the compound of formula II is obtained as an R-enantiomer of at least 88% enantiomeric purity.

2. The method according to claim 1 , wherein the method comprises adding a methylation agent to a phase transfer reaction system comprising the compound of formula I, an aqueous phase, an organic phase and a phase transfer catalyst.

3. The method according to claim 2 , wherein the phase transfer catalyst is a pyridinium, phosphonium, ammonium or sulfonium salt.

4. The method according to claim 2 , wherein the phase transfer catalyst is chosen from compounds of

(a) general formula IV

(b) general formula V

or

(c) general formula VI

wherein R, R′, R″ and R′″, if present, are independently selected from alkyl, aryl and aralkyl groups;

Q, in compounds of formula IV, is a nitrogen or phosphorus; and

X is a halide, acetate, p-toluenesulfonate, trifluoromethanesulfonate, hexafluoroantimonate, hydroxide, perchlorate, hydrogensulfate, thiocyanate or tetrafluoroborate group.

5. The method according to claim 2 , wherein the phase transfer catalyst is tetrabutylammonium bromide.

6. The method according to claim 2 , wherein the methylating agent used in the phase transfer catalysis is selected from the group consisting of dimethyl sulphate, trimethyl phosphate and methyl iodide.

7. The method according to claim 2 , wherein the aqueous phase is aqueous sodium hydroxide, aqueous lithium hydroxide, aqueous potassium hydroxide, aqueous sodium carbonate or aqueous potassium carbonate.

8. The method according to claim 2 , wherein the organic phase is toluene, hexane, methylene chloride or methyl t-butyl ether.

9. The method according to claim 1 , wherein the phase transfer catalysis is performed at 0-10° C. for at least 30 minutes.

10. The method according to claim 1 , further comprising reacting the compound II with benzylamine to produce a compound of formula III,

and replacing the protecting group Rx with methyl carbonyl to produce (R)-2-acetamido-N-benzyl-3-methoxypropionamide (lacosamide).

11. The method according to claim 10 , wherein the reaction of the compound of formula II with benzylamine takes place in the presence of an activator of the carboxyl group and a base.

12. The method according to claim 11 , wherein the base is 4-methylmorpholine, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene or potassium bicarbonate and the activator of the carboxyl group is an alkyl chloroformate or a carbodiimide.

13. The method according to claim 10 , wherein the N-protecting group Rx is replaced by methyl carbonyl by successively

(a) cleaving off the protecting group Rx from the compound of formula III by the addition of (i) a mineralic acid or (ii) H 2 /Pd—C to yield (R)-2-amino-N-benzyl-3-methoxypropionamide and then

(b) adding the methyl carbonyl group to (R)-2-amino-N-benzyl-3-methoxypropionamide by the reaction of (R)-2-amino-N-benzyl-3-methoxypropionamide with acetic anhydride.

14. The method according to claim 13 , wherein step (b) is performed in the absence of pyridine.

15. The method according to claim 1 , wherein lacosamide is isolated from the final reaction mix by crystallization.

16. The method according to claim 1 , wherein the N-protecting group is t-butyoxycarbonyl (Boc).

17. A method of producing a pharmaceutical formulation comprising lacosamide by the subsequent steps of

(a) producing lacosamide by the method of claim 1 ; and

(b) mixing the lacosamide with pharmaceutically acceptable excipients.

18. A method of producing a compound of formula VIII comprising methylating compound of formula VII,

to produce a compound of formula VIII,

wherein R 4 is H, an N-protecting group or/and a group having 0-30 C atoms, and

wherein R 1 , R 2 and R 3 are independently selected from H and groups having 0-30 C atoms,

wherein the methylation is carried out in a one-step reaction as a phase transfer catalysis and wherein the compound of formula VIII is obtained in the same configuration as the compound VII and in at least 88% enantiomeric purity.

19. The method of claim 18 , wherein R 1 is H, R 2 is H, R 3 is H and R 4 is an N-protecting group.

20. The method of claim 18 , wherein the compound VII is in the R-configuration.