Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-05-14
2003-02-18
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S198000, C546S205000, C546S206000, C546S236000
Reexamination Certificate
active
06521758
ABSTRACT:
The present application claims the benefit of priority under 35 U.S.C. § 119 from PCT/NL00/00320, filed May 12, 2000, the entire contents of which are incorporated herein by reference.
BACKGROUND OF THE INVENTION
The present invention relates to a tosylate salt of 4-fluorophenyl-3-carbinol piperidine compounds and to the use thereof in purifying 4-fluorophenyl-3-carbinol piperidine compounds against des-fluoro impurities. 4-(p-fluorophenyl)-piperidine 3-carbinols of the general formula (1)
wherein R represents a hydrogen, alkyl, aryl or aralkyl group, are key intermediates in the synthesis of the pharmaceutically active compound paroxetine, represented by the formula (2).
Several industrially applicable synthetic procedures leading to compounds of the formula (1) have been described in the prior art.
U.S. Pat. No. 3,912,743 describes the reduction of 4-aryl-3-piperidinecarboxylic acid esters of the general formula (3) with lithium aluminium hydride,
wherein Ra is an alkyl or aryl group, Ra1 is a lower alkyl group, Y is hydrogen, a halogen atom, a methoxy group or a mercapto group.
EP 223334, corresponding to U.S. Pat. No. 4,902,801, describes reduction of 4-aryl-2,6-dioxo-3-piperidinecarboxylic acid esters of the general formula (4) with lithium aluminium hydride,
wherein Ra is hydrogen, a lower alkyl group or an aralkylgroup, Ra1 is a lower alkyl group, Y is hydrogen, a halogen atom, a lower alkyl group, an aralkylgroup or a trifluoroalkyl group.
EP application 802185 describes the reduction of trans-4-aryl-6-oxopiperidine-3-carbinols of the general formula (5) by hydrides or metal hydrides,
wherein Y is hydrogen, halogen, alkyl group, aryl group, an aralkyl group etc., Ra is hydrogen, lower alkyl group or an aralkyl group, Ra1 is hydrogen, a lower alkyl group, an aryl group or an aralkyl group.
PCT application WO 96/36636 discloses a reduction of the tetrahydropyridine carbinols of the formula (6)
wherein Ra is C2-C5-alkyl, phenyl-C1-C5-alkyl or substituted phenyl-C1-C5-alkyl group, by a metal hydride
There are two centres of optical chirality in the molecule of 4-arylpiperidine-3-carbinols of the above formula (1), and there may exist four optical isomers thereof. As the final pharmaceutically active product paroxetine is a single (−)trans (3S,4R) isomer, it is highly desired that the piperidine-3-carbinols of the formula (1) are produced from a, preferably (3S,4R)trans, stereoisomer with high optical purity.
Accordingly, the starting compounds preferably have trans-configuration on carbons 3 and 4, whereby an additional step of optical resolution is preferably included in all the above-described synthetic processes of the prior art, before or after the reduction. Such resolution processes are known from the prior art.
In the known reduction procedures, an excess of hydride reducing agent is required for a successful and complete reduction of the precursor. The hydride agent however also causes an undesired hydrogenolysis side- reaction resulting in defluorination of the phenyl ring, even under mild reaction conditions, whereby a certain amount of a des-fluorinated impurity of the formula (7),
wherein R has the same meaning as in formula (1), is formed. This side product is more problematically formed when carrying out the processes on an industrial scale, as a result of overloading with the hydride and overheating, since charging with the reducing agent and temperature control is not as efficient as in the laboratory.
The impurity (7) is consequently the source of the most common impurity in the final paroxetine, namely the de-fluorinated, or des-fluoro, paroxetine, as the des-fluoro impurity (7) undergoes the same chemical transformations in the process of paroxetine production. If paroxetine is used as a pharmaceutical substance, the content of the des-fluoro paroxetine therein should be less than 0.1% according to Pharmacopoeia prescriptions (e.g. Paroxetine hydrochloride USP XXIII).
The purification of (1) and subsequent compounds from the corresponding des-fluoro impurities is difficult. The known procedures of optical resolution of racemic (1) into enantiomers by fractional crystallization of salts with optically active acids are not efficient if aimed to remove the des-fluoro impurity. In fact, the amount of undesired desfluoro-impurity in the racemic and resolved product is not substantially decreased by such resolution. The content of the structurally related des-fluoro impurities is also not substantially decreased within the next synthetic steps leading to paroxetine.
Usually, the content of des-fluoro impurity in raw (1) is approx. 0.5-1.5% (w/w) and may be even higher, namely in the industrial scale as explained above. It is apparent that if a reduction method produces compound (1) contaminated with an undesired amount of des-fluoro impurity, some further purification is necessary. Such purification should preferably be made in as early a stage as possible since purification in later synthetic steps is economically less favourable. However, conventional crystallizations are either ineffective or provide low yields, causing losses of the product and making the overall production procedure lengthy and economically undesirable. Thus, it is highly desired to find a process for separating raw 4-arylpiperidine-3-carbinols of the general formula (1) from its corresponding des-fluoro impurity (7) which would allow the industrial producer to minimise the amount of the des-fluoro impurity in (1) to such level that, subsequently, the produced paroxetine will contain less than about 0.1% of the des-fluoro paroxetine.
SUMMARY OF THE INVENTION
The present invention relates to the discovery that 4-arylpiperidine-3-carbinols as defined by the general formula (1) (frequently referred hereinafter as to “compounds (1)”), particularly the trans-racemates thereof, and more particularly the (3S,4R)-trans single optical isomers thereof, can be efficiently purified in respect of the content of the des-fluoro impurity (7), by conversion of the raw compound (1) into a salt thereof with toluene sulfonic acid, preferably p-toluene sulfonic acid and crystallisation of the resulted p-toluene sulfonate salt from a solution in an appropriate solvent.
A first aspect of the present invention relates to a salt compound of the formula (8):
Wherein R is hereinafter defined.
A second aspect of the present invention relates to a process which comprises contacting a compound of formula (1)
or a salt thereof which contains a des-fluoro impurity of formula (7)
wherein R in both compounds (1) and (7) represents a hydrogen atom, a lower alkyl group, an aryl group, an aralkyl group, an alkoxycarbonyl group or an aryloxycarbonyl group, with toluene sulfonic acid in a solvent to form a salt of formula (8).
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a simple, industrially applicable and high-yield purification process which enables a reduction in the amount of des-fluoro impurity in the produced raw compound (1) both in a form of a racemate or as a single enantiomer, so that pharmaceutically acceptable paroxetine can be produced from (1) without a need of specific purification techniques applied in later steps.
By wording “raw compound (1)”, it should be understood a compound (1) as defined above whenever it contains more than 0.2% of the des-fluoro impurity.
Accordingly, an aspect of the invention relates to a process of purification of raw compounds of formula (1) wherein R represents a hydrogen atom, a lower alkyl group, an aryl group, or an aralkyl group, comprising the step of:
contacting a raw compound of formula (1) or salt thereof with toluene sulfonic acid, preferably p-toluene sulfonic acid, under reactive conditions, most preferably in the presence of a solvent.
A further preferred step includes:
isolating the formed p-toluene sulfonate salt of compound of the formula (1), preferably in a solid state by means of crystallisation or precipitation from the solution and, optionally, any of the following steps:
recrystallization of the p-toluene sulfonate sal
Lemmens Jacobus M.
Peters Theodorus H. A.
Slanina Pavel
Covington Raymond
Rotman Alan L.
Synthon BV
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