Process

Details Process Process

2001-05-24

2003-02-11

Rotman, Alan L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S304000, C546S329000, C514S357000

Reexamination Certificate

active

06518432

ABSTRACT:

The present invention relates to an improved process for the preparation of certain medicinal agents.
EP 0 633 879 B 1 discloses compounds said to have NMDA receptor antagonist activity. The compound known as (S)-1-phenyl-2-(2-pyridyl)ethanamine is of particular interest, especially for the treatment of stroke. However, the processes disclosed in EP 0 633 879 B 1 for the preparation of this compound suffer from certain disadvantages, for example, requiring the use of butyl lithium which is not convenient to use on a large scale.
A new process for the preparation of (S)-1-phenyl-2-(2-pyridyl)ethanamine has now been developed which avoids the need to use butyl lithium and is therefore more suitable for commercial use. Since the process of the invention eliminates the need to use butyl lithium it therefore also has the additional advantage that it does not suffer from environmental problems associated with butane emission. Further, it has surprisingly been found that the process of the invention can be carried out with only a catalytic amount of base [with respect to the 2-picoline of formula (II)] rather than a stoichiometric amount of base as used in EP 0 633 879 B 1. Overall the claimed process is therefore more efficient, safer, more environmentally friendly and cheaper than that of EP 0 633 879 B 1.
In a first aspect the invention therefore provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof:
which comprises:
reaction of a compound of formula (II):
 with a compound of formula (III)
 in the presence of a metal hexamethyldisilazide and optionally thereafter resolving the enantiomers of compound (I) and forming a pharmaceutically acceptable salt.
A compound of formula (III) can be prepared from benzaldehyde and a metal hexamethyldisilazide, preferably lithium hexamethyldisilazide (LHMDS). Preferably the compound of formula (III) is prepared at a reduced temperature, that is, below 35° C. and preferably below 25 ° C.
The reaction of compounds (II) and (III) is suitably carried out at elevated temperature, for example, at about 40° C. The reaction can be carried out in an inert solvent, preferably in an ethereal solvent such as t-butyl methyl ether or more preferably tetrahydrofuran. Preferably the metal hexamethyldisilazide is lithium hexamethyldisilazide (LHMDS) and this base is used in a catalytic amount with respect to the 2-picoline (2-methylpyridine) of formula (II), for example, about 10 mol %. Acidic work-up of the reaction mixture gives the required compound of formula (I).
Compounds of the invention can form pharmaceutically acceptable solvates and salts. The compounds of the formula (I) can form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example, malic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, trifluoroacetic and methanesulphonic acids. Preferred salts are the malate and hydrochloride salts.
Particularly preferred salts are those which can be prepared using chiral acids to give salts of a single enantiomer of compound (I) as disclosed in EP 0 691 957 B 1. Preferably the racemic compound of formula (I) is treated with (S)-malic acid to give (S)-1-phenyl-2-(2-pyridyl)ethanamine (S)-malate.
In a further aspect the invention provides (S)-1-phenyl-2-(2-pyridyl)ethanamine and salts thereof, particularly the (S)-malate salt, when prepared using the processes described herein.


REFERENCES:
patent: 5455259 (1995-10-01), Griffith et al.
patent: 5607935 (1997-03-01), Griffith et al.
patent: 0 691 957 (1997-08-01), None
patent: 0 633 879 (1998-11-01), None
patent: 94/22831 (1994-10-01), None

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