Process

Details Process Process

1998-05-29

2002-12-03

Seaman, D. Margaret (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S356000, C514S355000, C514S273000, C546S298000, C546S301000, C546S302000, C546S315000, C546S318000, C546S322000, C546S339000

Reexamination Certificate

active

06489347

ABSTRACT:

The present invention relates to a new process for preparing pharmaceutically active compounds and intermediates therefor.
Pharmaceutical products with antidepressant and anti-Parkinson properties are described in U.S. Pat. Nos. 3,912,743 and 4,007,196. An especially important compound among those disclosed is paroxetine, the (−) trans isomer of 4-(4′-fluorophenyl)-3-(3′,4′-methylenedioxy-phenoxymethyl)-piperidine. This compound is used in therapy as the hydrochloride salt to treat inter alia depression, obsessive compulsive disorder (OCD) and panic.
This invention aims to overcome disadvantages in the existing processes for preparation of such compounds and so to provide alternative processes for their manufacture.
This invention has been developed on the basis that compounds of structure (1) below are either valuable chemical intermediates useful for the manufacture of important medicinal products, for example paroxetine hydrochloride, or are themselves active compounds, such as disclosed in U.S. Pat. Nos. 3,912,743 and 4,007,196.
By reference to Example 4 of U.S. Pat. No. 4,007,196, paroxetine may be prepared from a compound of structure (1) below in which R is methyl, and Z is hydrogen, that is 4-(4′-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine, by reaction with 3,4-methylenedioxyphenol followed by demethylation. In the same Example, 4-(4′-fluorophenyl)-3-hydroxymethyl-1-methyl piperidine is prepared by reduction of 4-(4′-fluorophenyl)-3-hydroxymethyl-1-methyl-1,2,3,6-tetra-hydropyridine (II), which is in turn prepared from 4-(4′-fluorophenyl)-1-methyl-1,2,3,6-tetrahydropyridine (III), by reaction with formaldehyde.
Alternative processes for the preparation of 4-(4′-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine are given in EP-A-0223334, by reduction of compounds of structure (A)
in which Z is alkyl and R is H, alkyl or aralkyl.
The above described processes produce compounds of structure (1) as a mixture of enantiomers. Therefore conversion of compounds of structure (1) to useful pharmaceuticals, such as paroxetine i.e. the (−) trans isomer of 4-(4′-fluorophenyl)-3-(3′,4′-methylenedioxy-phenoxymethyl)-piperidine, will normally require a resolution stage, as described in EP-A-0223334.
This invention provides a process for the preparation of 4-aryl-piperidines of structure (1)
in which R is hydrogen or an alkyl, aralkyl, aryl, acyl, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl group, and Z′ is a 3,4-methylendioxyphenyl group, which comprises reduction of a compound of structure (2a) or (2b)
in which
Y is oxygen or sulphur, and
R and X are as defined above and Z is hydrogen or an alkyl, aralkyl or aryl group, and where Z is other than a 3,4-methylenedioxyphenyl group thereafter converting Z to 3,4-methylenedioxyphenyl.
This invention also provides a process for the preparation of 4-aryl-piperidines of structure (1)
 in which R is hydrogen or an alkyl, aralkyl, aryl, acyl, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl group, and Z is hydrogen or an alkyl, aralkyl or aryl group, most suitably where Z is a hydrogen atom or a 3,4-methylenedioxyphenyl group,
which comprises reduction of a compound of structure (2a) or (2b)
 in which
Y is oxygen or sulphur, and
R, X, and Z are as defined above.
When Z incorporates an aryl group, the aryl group, for example phenyl, may be optionally substituted by one or more groups such as halogen or alkyl or alkoxy, or by two substituents linked to form a fused ring. For example, an especially suitable substituent Z is 3,4-methylenedioxyphenyl, as found in paroxetine. Alkyl groups, including alkyl groups that are part of other moieties such as alkoxy or acyl, are typically C
1-6
, especially C
1-4
groups.
Compounds of structure (2a) and (2b) are believed to be novel and form part of this invention, especially compounds in which X is H, Z is H or 3,4-methylenedioxyphenyl and R is H or C
1-4
alkyl, especially methyl.
In a first aspect of the process of this invention compounds of structure (2a) or (2b) are reduced to give compounds of structure (1) in which Z is H, that is 3-hydroxymethyl-4-aryl piperidines. Reduction may be accomplished by hydrogenation at atmospheric or above atmospheric pressure using a variety of known catalysts, or using hydride reagents such as lithium aluminium hydride and sodium borohydride, or by a combination of known methods. A particularly useful aspect of this invention is the transformation of 4-aryl-3-carboxyalkyl-1-(optionally substituted)-piperidines to 4-aryl-3-hydroxymethyl-1-(optionally substituted)-piperidines.
It will be appreciated that reduction of esters or carboxylic acids of structure (2) may be carried out stepwise and an intermediate may be isolated, for example a carboxaldehyde, and the reduction of these intermediate compounds to a compound of structure (1) is also included in the scope of this invention.
Intermediate carboxaldehydes are believed to be novel and form part of this invention. A particularly valuable intermediate is 4-(4-fluorophenyl)-5-oxopiperidine-3-carboxaldehyde.
In a second aspect of the process of this invention compounds of structure (2a) and (2b), where Z is not H, are reduced to ethers of structure (1). This may be accomplished by the use of known selective reagents such as diborane and DIBAL, or by Raney nickel desulphurization of a thionoester intermediate. A particularly advantageous ether for the manufacture of paroxetine is the 3,4-methylenedioxyphenyl ether.
Following the reduction to give an ether of structure (1), either or both the groups Z and R may be subsequently converted to a different group Z or R by conventional means, in order to produce the desired pharmaceutical agent. For example, in the preparation of paroxetine, it may be appropriate to convert Z=H to Z=3,4-methylenedioxyphenyl and/or R=C
1-4
alkyl to R=H. This aspect is also included in the scope of this invention.
One advantageous aspect of this process is that a single enantiomer of the intermediate (2) may be prepared either by enantioselective synthesis or from a chiral precursor, in which case the resolution noted above may be avoided entirely or transferred to an early stage in the overall process.
Starting materials of structure (2a), where Y is oxygen, may be prepared conveniently by carboxyalkylation of a 4-aryl-piperidine-2-one precursor, which may in turn be obtained from the reaction of an activated alkyl 3-aryl-5-hydroxyvalerate with an amine. In a particularly advantageous embodiment of this invention the alkyl 3-aryl-5-hydroxyvalerate is prepared as a single enantiomer by selective reduction of a 3-arylglutarate mono-ester obtained by enzymatic hydrolysis of the pro-chiral dialkyl 3-arylglutarate, for example using pig liver esterase to obtain S-enantiomers and -chymotrypsin to obtain R-enantiomers.
Suitable dialkyl 3-arylglutarates may be obtained by, for example, reaction of 4-fluorobenzaldehyde with methyl acetoacetate.
The ester group at the 3-position or a group convertible to an ester group may already be present in the starting material or may be introduced for example by reaction of a 2-piperidone of structure (3) firstly with a strong base, such as sodium hydride or lithium hexamethyldisilazide followed by a carboxylating agent, such as a chloroformic ester or thiono chloroformic ester.
Compounds with structure (2b) where Y is oxygen may be prepared by, for example, reductive cyclisation of 2-cyano-3-(4′-fluorophenyl)-glutarate esters. A similar preparation has been described for the preparation of 3-ethoxycarbonyl-4-(3′-methoxyphenyl)-2-piperidone (Journal of Organic Chemistry (1977) volume 42, pages 1485-1495), but this procedure had been found to be unsuitable for the preparation of compounds with structure (2b) and results in a complex mixture of products. A new and efficient process has now been discovered in which 2-cyano-3-(4′-fluorophenyl)glutarate esters, especially diethyl 2-cyano-3-(4′-fluorophenyl)g

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