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PROCESS FOR THE PREPARATION OF AN N-(PHENYLMETHYL)PROPANAMIDE DERIVATIVE

IP.com Disclosure Number: IPCOM000200591D
Publication Date: 2010-Oct-20
Document File: 16 page(s) / 90K

Publishing Venue

The IP.com Prior Art Database

Abstract

Improved process for the preparation of an N-(phenylmethyl)propanamide derivative from substantially enantiomerically pure D-Serine derivative compounds.

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PROCESS FOR THE PREPARATION OF AN N-(phenylmethyl)propanamide DERIVATIVE

BACKGROUND OF THE INVENTION

[0001]               Lacosamide (Compound I) is the international commonly accepted name for (2R)-2-(acetylamino)-3-methoxy-N-(phenylmethyl)propanamide (which is also known as (R)-N-benzyl-2-acetamido-3-methoxypropionamide), and has an empirical formula of C13H18N2O3 and a molecular weight of 250.30.

(I)

[0002]               Lacosamide is an active substance indicated for adjunctive treatment of partial‑onset seizures and diabetic neuropathic pain.  In the

United States

, lacosamide is marketed under the name VIMPATTM for the treatment of epilepsy.

[0003]               U.S. Patent No. 6,048,899 (“the ‘899 patent”) discloses the preparation of lacosamide by means of two alternative synthetic routes.

[0004]               Scheme 1 of the ‘899 patent discloses the preparation of lacosamide from d-serine (compound II) comprising O-methylating an N-protected d -serine prior to benzylamide formation, followed by N-deprotection of the resulting intermediate and final N-acetylation.  Scheme 1 of the ‘899 patent is summarized herein at Scheme 1 (“the Scheme 1 synthetic route”).

[0005]               The Scheme 1 synthetic route suffers a number of deficiencies which make it non suitable for industrial purposes. For example, the O-methylation reaction of N-protected serine using silver (I) oxide and methyliodide is impractical and expensive, since not only these conditions result in partial racemisation of about 15% [see Example 1(b) of this reference], but also the removal of the non desired (S)-enantiomer during the production is extremely difficult and requires chromatographic purification. Further, the O-methylation reaction leads to the esterification of the free carboxylic group, which then requires an additional step of hydrolyzing the methyl ester group.

Scheme 1

[0006]               Scheme 2 of the ‘899 patent discloses the preparation of lacosamide from d-serine (compound II) mainly comprising benzylamide formation of an N-protected d -serine prior to O-methylating the resulting compound, followed by N-deprotection of the resulting intermediate and final N-acetylation.  Scheme 2 of the ‘899 patent is summarized herein at Scheme 2 (“the Scheme 2 synthetic route”).

[0007]               The Scheme 2 synthetic route results in various impurities both in the benzylamide formation and in the later O-methylation step which hence must be removed by chromatography. Thus, the Scheme 2 synthetic route is impractical on an industrial scale. Further, no information about the racemization of the intermediate compounds is described in the ‘899 patent with respect to the Scheme 2 synthetic route.

Scheme 2

[0008]               U.S. Patent Publication No. 2008/0027137 (“the ‘137 publication”) attempts to address the problem of providing an improved process for preparing lacosamide which may be efficient and suitable for industrial scale. The ‘137 publication discloses that the process of Scheme 1 of U.S. Patent No. 6,048,899 is a more pr...