Process for the preparation of amino acid derivatives
AssigneeUCB Pharma S.A.
InventorsDidier Bouvy, Alain Merschaert, Véronique Pinilla, Joerg Hamann, Ralf Kanzler, Antoine Thomas
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Abstract
The present patent application relates to an alternative process for the preparation of amino derivatives. In particular, the present application relates to an improved process for the manufacture of Lacosamide (LCM), (R)-2-acetamido-N-benzyl-3-methoxypropion-amide, which is useful as an anticonvulsive drug. In a particular aspect, the present invention relates to a process of manufacture of optically enriched (R)-2-acetamido-N-benzyl-3-methoxypropion-amide (I) comprising resolution of 2-acetamido-N-benzyl-3-methoxypropion-amide (II).
Claims24
A process for the manufacture of substantially optically pure (R)-2-acetamido-N-benzyl-3-methoxypropion-amide (I) consisting essentially of:
- (a) resolving 2-acetamido-N-benzyl-3-methoxypropion-amide (II) into (R)-2-acetamido-N-benzyl-3-methoxypropion-amide (I) and (S)-2-acetamido-N-benzyl-3-methoxypropionamide (III);
- (b) racemizing (S)-2-acetamido-N-benzyl-3-methoxypropion-amide (III) thereby obtained;
- (c) further resolving the resulting 2-acetamido-N-benzyl-3-methoxypropion-amide (II);
- and
- (d) combining the (R)-2-acetamido-N-benzyl-3-methoxypropion-amide (I) of (a) and (c).
A process of manufacture of substantially optically pure (R)-2-acetamido-N-benzyl-3-methoxypropion-amide (I) comprising:
- (i) reacting 2,3-dibromo ethyl propionate (VIIa) or 2,3-dibromo methyl propionate (VIIb)
- with sodium methoxide in methanol in the presence of an alkylchloroformiate followed by benzylamine to afford 2-bromo-N-benzyl-3-methoxypropion-amide (Va)
- (ii) reacting 2-bromo-N-benzyl-3-methoxypropion-amide (Va) with aqueous ammonia to afford 2-amino-N-benzyl-3-methoxypropion-amide (IV)
- (iii) acetylating 2-amino-N-benzyl-3-methoxypropion-amide (IV) with acetic anhydride in a solvent to afford 2-acetamido-N-benzyl-3-methoxypropion-amide (II)
- (iv) isolating compound of formula (II);
- (v) resolving isolated 2-acetamido-N-benzyl-3-methoxypropion-amide (II) into (R)-2-acetamido-N-benzyl-3-methoxypropion-amide (I) and (S)-2-acetamido-N-benzyl-3-methoxypropion-amide (III)
- (vi) racemizing (S)-2-acetamido-N-benzyl-3-methoxypropion-amide (III) thereby obtained;
- and
- (vii) further resolving resulting 2-acetamido-N-benzyl-3-methoxypropion-amide (II)
- (viii) combining the (R)-2-acetamido-N-benzyl-3-methoxypropion-amide (I) of (v) and (vii).
Dependencies are inferred from the claim text.