Preparation of selegiline

Details Preparation of selegiline Preparation of selegiline

1997-02-27

1998-12-08

Lambkin, Deborah C.

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

Organic compounds

Amino nitrogen containing

C07C21100

Patent

active

058472169

DESCRIPTION:

BRIEF SUMMARY
This application is a 571 of PCT/EP95/03460 filed Feb. 9, 1995.
The present invention relates to a novel process for preparing selegiline.
Selegiline is the (R)-(-)-isomer of deprenyl (.dbd.N,.alpha.-dimethyl-N-2-propynylphenethylamine), which has the formul a I. racemic product and the optical isomers for the synthesis of deprenyl or its antipodes, are known. The starting material used is racemic or --CH.sub.2 --CH (CH.sub.3)--NH--CH.sub.3 (.dbd.II)!.
CH Patent 393,306 describes, inter alia, the preparation of racemic deprenyl starting from II with the aid of a metalating agent such as lithium amide or phenylsodium and subsequent alkylation for ten hours in boiling toluene with 3-bromo-1-propyne. Reactions of this type can hardly be carried out on an industrial scale.
According to another chemical process (NL-OS 6,605,956), II can be reacted with propargylaldehyde and the resulting intermediate can be reduced with aluminum amalgam. The disadvantages of this process are the strong tendency of the propargylaldehyde to polymerize under the reaction conditions, and for it to cause severe skin irritation. In addition, mercury and its salts are severe (environmental pollutants, which can only be disposed of at great cost.
The preparation of deprenyl by reaction of .alpha.-methylphenylethyl chloride by means of N-methylpropynylamine in a closed tube at 80.degree. C. described in DE-AS 1,227,447 cannot be realized on an industrial scale in practice because of the poor yield and the high costs of the N-methylpropynylamine. The high costs of the reagents employed make the process economically inefficient.
According to DE-AS 1,227,447, II is allowed to react with 1,3-dibromopropene at 100.degree. C. for 7 hours. Unreacted starting material is converted by reaction with benzoyl chloride into N,.alpha.-dimethyl-N-benzoylphenethylamine, which is separated from the desired final product. Hydrogen bromide has to be eliminated from the resulting N,.alpha.-dimethyl-N-3-bromo-2-propenylphenethylamine under the action of alcoholic/aqueous potassium hydroxide solution in order to obtain the desired propynyl compound. This process is laborious, time-consuming and unsuitable for production on an industrial scale.
Finally, DE-AS 1,227,447 (cf. Example 5) describes the reaction of propargyl bromide with twice the molar amount of N-(1-phenylisopropyl)-methylamino in the absence of a solvent at 100.degree. C. This process does give a relatively good yield, but is not suitable for an industrial-scale synthesis because isolation and purification of the end product are extremely elaborate.
The same goes for the reaction, cited in Acta Pharm. Hung. 1992, 62, 201 (page 204), of N-(1-phenylisopropyl)-methylamine with acetylene in the presence of paraformaldehyde and CuCl.sub.2 (AT 252,901). The selegiline has to be purified by distillation in this reaction.
An elaborate purification procedure is also necessary for the selegiline produced in accordance with H. Cabelled Compds. Rodiopharm 1988, 25, 1 (page 7).
EP Patent 99,302 describes the alkylation of (R)-II with 3-bromo-1-propyne in a two-phase binary system of benzene and aqueous alkali at a starting temperature of 60.degree. C. Working at elevated temperature and the use of aqueous sodium hydroxide solution, however, cause problems due to the presence of 3-bromo-1-propyne, eg. ready and increased formation of polymeric products.
According to a further method (EP-OS 344,675), alkylation with 3-bromo-1-propyne is carried out in halogen-containing aliphatic hydrocarbons using potassium carbonate. The alkylating agent and the auxiliary base are used in an excess of at least 10%. The total amount of 3-bromo-1-propyne is added in a single portion or in a time interval of only 5 minutes. The excess and addition of a single portion are unnecessary for the course of the alkylation, since the yields of selegiline hydrochloride are only barely over 50%. Additionally, the use of halogen-containing hydrocarbons, such as chloroform in particular, is not safe from the occupational and environmental

REFERENCES:
patent: 3429922 (1969-02-01), Beregi et al.
patent: 3485874 (1969-12-01), Ecsery et al.
patent: 4156017 (1979-05-01), Kruger et al.
patent: 4564706 (1986-01-01), Ecsery et al.
patent: 5589513 (1996-12-01), Magyar et al.
Chemical Abstracts, vol. 105, No. 13, (1986).
MacGregor et al., Journal of Labelled Compounds and Radiopharmaceuticals, vol. 25, No. 1, pp. 1-9 (1988).
Acta Pharm. vol. 62, pp. 201-211 (1992).

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