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 by adding a methylation agent and an organo lithium compound to the compound of formula I 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 methylation agent used with the organo lithium compound is dimethylsulfate.

3. The method according to claim 1 , wherein the organo lithium compound is butyl lithium.

4. The method according to claim 1 , wherein the methylation in the presence of an organo lithium compound takes place at a temperature of 0-10° C. for at least 5 hours.

5. 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).

6. The method according to claim 5 , 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.

7. The method according to claim 6 , wherein the base is 4-methylmorpholine, triethylamine, disopropylethalamine, 1,8-diazabycyclo [5.4.0]undec-7-ene or potassium bicarbonate and the activator of the carboxyl group is an alkyl chloroformate or a carbodiimide.

8. The method according to claim 5 , 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.

9. The method according to claim 8 , wherein step (b) is performed in the absence of pyridine.

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

11. The method according to claim 1 , wherein the N— protecting group is t-butoxycarbonyl (Boc).

12. 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.

13. A method of producing a compound of formula VIII comprising methylating a 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 by adding a methylation agent and an organo lithium compound to the compound of formula VII wherein the compound of formula VIII is obtained in the same configuration as the compound VII and in at least 88% enantiomeric purity.

14. The method of claim 13 , wherein R 1 is H, R 2 is H, R 3 is H and R 4 is an N-protecting group.

15. The method of claim 13 , wherein the compound VII is in the R-configuration.