Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-09-06
1997-10-28
Chang, Ceila
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
546240, C07D21122, C07D21140
Patent
active
056819625
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP94/00194 filed Mar. 8, 1994.
The present invention relates to a novel process for preparing aryl-piperidine carbinols.
U.S. Pat. No. 4,007,196 describes certain compounds which are described as possessing anti-depressant activity.
An intermediate in the preparation of the above mentioned compounds is a compound of formula (A): ##STR2## wherein R.sup.1 represents hydrogen, trifluoro (C.sub.1-4 ) alkyl, alkyl or alkynyl, and X represents hydrogen, alkyl having 1-4 carbon atoms, alkoxy, trifluoroalkyl, hydroxy, halogen, methylthio, or aralkyloxy.
The compounds of formula (A) are disclosed as having pharmacological properties that make them useful as anti-depressants.
One particular compound of formula (A) has been found to be especially effective as an anti-depressant. This compound is known as paroxetine and has the following formula: ##STR3##
U.S. Pat. No. 4,902,801 describes the preparation of compounds of formula (B): ##STR4## wherein Ar represents an aryl or substituted aryl group and R represents hydrogen, an alkyl or aralkyl group; by reduction of a compound of formula (C): ##STR5## wherein Ar and R are as defined for formula (B), and R.sup.a is an alkyl group.
Such a process is described as being suitable for preparing the precursor compounds of formula (B) to paroxetine.
The only specially disclosed reducing agents for carrying out the process described in U.S. Pat. No. 4,902,801 are lithium aluminium hydride or aluminium hydride. These reducing agents are expensive, difficult to handle and are associated with a large exotherm which creates process control problems when carrying out the reaction on a large scale.
The present invention surprisingly overcomes or alleviates the above problems by the use of diborane as the reducing agent. It also gives a better yield and is more economical.
Accordingly, the present invention provides a process for the preparation of compound of formula (I): ##STR6## in which R.sub.3 is hydrogen, C.sub.1-6 alkyl or C.sub.1-6 alkylaryl, by reduction using diborane, of a compound of formula (II): ##STR7## in which R.sub.3 is as defined in relation to formula (I) and R.sub.4 is C.sub.1-6 alkyl.
Preferably R.sub.3 is methyl.
Preferably R.sub.4 is ethyl or methyl or a mixture of ethyl/methyl.
The reaction is suitably carried out in an inert solvent such as tetrahydrofuran or dimethoxyethane (DME).
The diborane is suitably generated in situ by the addition of boron trifluoride etherate to sodium borohydride in the presence of the compound of formula (II), at reduced temperature such as -10.degree.to 20.degree. C., preferably at 0.degree.to 5.degree. C. Alternatively, and more preferably for safety and handling reasons diborane is generated by the addition of hydrogen chloride gas (which can suitably be dissolved in an inert solvent such as DME) to sodium borohydride in the presence of the compound of formula (II), at reduced temperature such as -10.degree. C. to 20.degree. C., preferably at 0.degree.to 5.degree. C.
Once the addition of the boron trifluoride etherate or the hydrogen chloride gas is complete, the reaction is suitably allowed to warm to ambient or elevated temperature for example 20.degree.to 60.degree. C. more preferably 20.degree.to 40.degree. C.
The reaction may then be terminated or "quenched" by the addition of the reaction mixture to a mineral acid such as aqueous hydrochloric acid or by the addition of a mineral acid such as aqueous hydrochloric acid to the reaction mixture. Any resulting solid may then be filtered off and the product compound of formula (I) may be isolated by distilling off the reaction solvent, replacing it with a suitable solvent from which the product may be precipitated from, such as toluene, and precipitating the product by the addition of a suitable precipitating solvent such as n-heptane suitably after concentration of the solution of the product.
The present invention also provides a process for the preparation of paroxetine or a pharmaceutically acceptable salt thereof, especially the hydrochlori
REFERENCES:
patent: 4007196 (1977-02-01), Christensen et al.
patent: 5258517 (1993-11-01), Zepp et al.
Campaigne et al. "Reduction of 1-methyl-3methoxy-5-arylpyrrole carboxylic ester with selected reducing agents." J. Heterocycl. Chem. v. 12, pp. 317-319, 1975.
Chemical Abstracts, vol. 91, No. 25, 17 Dec. 79, Columbus, Ohio Abstract No. 211258g.
Chang Ceila
Kinzig Charles M.
Lentz Edward T.
SmithKline Beecham Plc
Venetianer Stephen
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