Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-07-28
2002-09-03
Chang, Celia (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S216000, C546S240000
Reexamination Certificate
active
06444822
ABSTRACT:
FIELD OF INVENTION
The present invention concerns a process for the preparation of 3-substituted 4-phenyl-piperidine derivatives of formula (I) given below, in particular for the preparation of paroxetine.
STATE OF THE ART
Paroxetine, i.e. the 3-[(1,
3
-benzodioxol-5-yloxi)methyl]-4-(p-fluoro-phenyl)piperidine, is a compound capable of acting as an inhibitor of serotonin's recaptation at the synaptic junctions and, due to its pharmacological properties, has been used for a long time as an effective antidepressant.
The paroxetine molecule has two chiral centres at positions 3 and 4 of the piperidine ring, and therefore possesses various enantiomeric forms: the (−) trans isomer having the absolute configurations (3S,4R) is pharmacologically the most active one for paroxetine.
Therefore numerous preparation procedures for paroxetine and its precursors have been developed up to present, and separation processes of the racemic mixtures obtained have been studied, so as to isolate the pharmacologically most active isomer.
The U.S. Pat. No. 4,007,196 (Ferrosan AS) concerns, for example, 3-substituted 4-phenyl-piperidine derivatives of formula (A)
among which the paroxetine is also included, when X=p-fluoro and R
1
=H. Moreover, the preparation procedure of such compounds is described starting from the corresponding carbinols prepared, in their turn, by reduction of the formula B) compounds
with a metallic complex hydride, for example lithium aluminum hydride. The formula (B) compounds are prepared starting from methyl arecoline (1,2,5,6-tetrahydro-3-pyridincarboxylate) or suitable homologues thereof, by reaction with X-phenyl-magnesium bromide; such compounds (B) are obtained as a cis/trans mixture in which each isomer has, in its turn, two enantiomeric forms.
The procedure according to the U.S. Pat. No. 4,007,196 therefore provides that resolution methods of the racemic mixtures are used to obtain the pharmacologically most active optic isomer, i.e. the (−)trans isomer, having the absolute configuration (3S,4R).
Such a preparation process involves considerable drawbacks, such as the lack of stereoselectivity and the use as the starting compound of arecoline, a highly toxic and expensive reagent.
The European Patent EP 223334 (Beecham Group PLC) describes a process for the preparation of 4-(4′-fluorophenyl)-3-hydroxymethyl-1-methyl-piperidine by reduction of formula a) compounds
in which Z is alkyl and R is H, alkyl or arylalkyl.
According to EP 223334 the compounds of formula a) are prepared by the reaction of alkyl amido-malonates with suitable cinnamic acid esters, e.g. alkyl or aryl esters. From this reaction an enantiomeric mixture is thus obtained; to gain a pharmaceutically useful end product, it is therefore necessary to perform the resolution of the mixture and isolate the pharmacologically most active enantiomer.
The European Patent Application EP 812827 (Sumika Fine Chemicals Co.) describes a process for the preparation of 4-(4′-fluorophenyl)-3-hydroxymethylpiperidine in the (−) trans isomer form by reduction of (−)trans-2-keto-4-(4′-fluorophenyl)-5-carboxy-piperidine, obtained by the resolution of the corresponding racemic mixture, or by reduction of 2-keto-4-(4-fluorophenyl)-5-carboxyalkyl-piperidine in the racemic form, and the subsequent resolution of 3-hydroxymethyl-piperidine thus obtained.
It is apparent how the above described processes involve a considerable number of steps which is automatically reflected in a low overall yield of the synthesis. It is therefore felt necessary to set up a preparation process of 3-substituted 4-phenyl-piperidine derivatives, and in particular of paroxetine, that does not present the drawbacks experienced with the known processes as described above.
SUMMARY OF THE INVENTION
Now the Applicant has surprisingly found that it is possible to obtain the 3-substituted 4-phenyl-piperidine derivatives of formula (I) reported below, in particular paroxetine, starting from commercially available raw materials and by few synthetic steps of easy industrial scalability.
Therefore the subject of the present invention is a process for the preparation of formula (I) 3-substituted 4-phenyl-piperidine derivatives
in which X is selected from H and F, and R is selected from the group consisting of H, C1-C6 alkyl, C3-C6 alkenyl, and benzyl, comprising the following steps:
a) Michael addition between the formula (II) cinnamic aldehyde and the amide of formula (III) in which R
1
is selected from the group consisting of C1-C6 alkyl, C3-C6 alkenyl, and benzyl, to obtain the formula (IV) 2-keto-3-carboxyalkyl-4-phenyl-6-hydroxy-piperidine, optionally enriched in the (3S,4R) isomer by using a suitable chiral catalyst:
b) reduction of the formula (IV) 2-keto-3-carboxyalkyl-4-phenyl-6-hydroxy-piperidine coming from step a) to obtain the 3-hydroxymethyl4-phenyl-piperidine of formula (V):
c) reaction of 3-hydroxymethyl-4-phenyl-piperidine of formula (V) coming from step b) with sesamol (VI) to obtain the formula (I) 3-[(1,3-benzodioxol-5-yloxi)methyl-]4-phenyl-piperidine:
The intermediate of formula (IV) reported above represents a further subject of the invention.
The characteristics and advantages of the process according to the present invention will be illustrated in detail in the following description.
REFERENCES:
patent: 4007196 (1977-02-01), Andres
patent: 5258517 (1993-11-01), Zepp et al.
patent: 6051712 (2000-04-01), Binggeli et al.
patent: 0190496 (1986-08-01), None
patent: 0223334 (1987-05-01), None
patent: 374674 (1990-06-01), None
patent: 374675 (1990-06-01), None
patent: WO 9636636 (1996-11-01), None
patent: WO98/01424 (1998-01-01), None
patent: WO98/53824 (1998-12-01), None
Surrey “Name reactions in Organic Chemistry” Aca. Press. pp. 173-174 (1961).*
Waldmann et al. “Amino acid esters as chiral auxiliaries in asymmetric cycloadditions” CA 115:159693 (1991).*
Aparicio et al. “N-amino-2-pyridones from acetohydrazide derivatives” J. Chem. Soc. Perkin. Trans. I, pp. 1975-1979 (1989).
Cignarella Giorgio
De Ferra Lorenzo
Massardo Pietro
Piccolo Oreste
Chang Celia
Chemi S.p.A.
Hedman & Costigan ,P.C.
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