Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-02-04
2004-08-17
Chang, Celia (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C514S321000
Reexamination Certificate
active
06777554
ABSTRACT:
FIELD OF THE INVENTION
The field of the invention is synthesis of paroxetine and like compounds, more specifically the preparation of an intermediate in the synthesis of paroxetine.
BACKGROUND OF THE INVENTION
Paroxetine, trans (−)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl) piperidine, is a serotonin re-uptake inhibitor, and has the following molecular formula:
Paroxetine is an orally administered antidepressant for the treatment of depression, social anxiety disorders, obsessive compulsive disorder, panic disorder, social anxiety disorder, generalized anxiety disorder and posttraumatic stress disorder. Paroxetine is marketed as Paxil® by GlaxoSmithKline.
Paxil® is prescribed as oral dosage tablets containing 10 mg, 20 mg, 30 mg and 40 mg of the base equivalent of paroxetine hydrochloride. Paxil® tablets include dibasic calcium phosphate dihydrate, hydroxypropyl methylcellulose, magnesium stearate, polyethylene glycols, polysorbate 80, sodium starch glycolate, titanium dioxide and one or more of the following: D&C Red No. 30, D&C Yellow No. 10, FD&C Blue No. 2, FD&C Yellow No. 6.
Paxil® is also available as an oral suspension with a dosage of 10 mg of the base equivalent of paroxetine hydrochloride in a 5 mL suspension containing polacrilin potassium, microcrystalline cellulose, propylene glycol, glycerin, sorbitol, methyl paraben, propyl paraben, sodium citrate dihydrate, citric acid anhydrate, sodium saccharin, flavorings, FD&C Yellow No. 6 and simethicone emulsion, USP.
Paroxetine may be produced by synthesizing an intermediate, N-methylparoxetine, wherein the methyl group is attached to the amine of the piperidine group. In paroxetine, the amine is a secondary amine, while in the intermediate, the amine is a tertiary amine.
U.S. Pat. Nos. 4,007,196, 5,258,517 and 4,585,777, incorporated herein by reference, disclose the conversion of N-methylparoxetine to paroxetine. The methyl group is removed by reaction with phenyl chloroformate followed by deacylation with a base such as KOH to obtain paroxetine.
N-methylparoxetine has the following structure (II):
The '196 patent discloses obtaining N-methylparoxetine by reacting 4-(4-fluorophenyl)-3-chloromethyl-N-methyl-piperidine, also named CIPMA of structure (III):
with 3,4-methylenedioxyphenol (“sesamol”) of structure (IV):
to obtain N-methylparoxetine. U.S. Pat. No. 4,007,196 reacts CIPMA with sesamol in a solution of sodium in methanol, giving N-methylparoxetine with a yield of about 25%.
U.S. Pat. No. 4,585,777, is directed to the composition 4-(4-fluorophenyl)-3-((4-methoxyphenoxy)-methyl)-piperidine, which has the structure of:
To obtain the product, the '777 patent first prepares an N-methyl intermediate by reacting in examples 5 and 8 the sulfonate esters of the enantiomers of cis-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine with p-methoxyphenol. The '777 patent does not give a yield for example 5. For example 8, 38.5 grams of the ester were used to obtain 1.8 grams of the product as a free base, giving a yield of about 5%.
Much of the prior art is directed to synthesis of CIPMA, related compounds and their precursors, rather than synthesis of N-methylparoxetine from CIPMA. For example, U.S. Pat. No. 6,326,496, incorporated herein by reference, teaches obtaining CIPMA by reducing a precursor through the use of a metal hydride. These patents provide little insight on how to synthesize N-methylproxetine after obtaining CIPMA, or how to increase the yield of such synthesis.
The low yield of N-methylparoxetine produced results in lower yields of paroxetine. The low yield increases the cost of the process and requires additional purification.
A need exists in the art to produce N-methylparoxetine and related compounds with a reaction that produces a high yield.
SUMMARY OF THE INVENTION
The present invention provides a process for preparing compound (VII) comprising reacting compound (V) with compound (VI) in an organic solvent:
wherein:
X is selected from the group consisting of halogen and —OSO2R
3
;
Ar is phenyl optionally substituted by halogen, alkoxy or other inert group;
R
1
is selected from the group consisting of hydrogen, alkyl, aralkyl, alkaryl, alkyloxycarbonyl, axyloxycarbonyl and arylalkoxycarbonyl;
R
2
is selected from the group consisting of aryl and heteroaryl, wherein any one or more of said aryl and heteroaryl are optionally substituted by the group consisting of alkyl, halogen, alkoxy, nitro, acylamino, methylenedioxy, alkyl sulfonyl, aryl sulfonyl, alkaryl sulfonyl and aralkyl sulfonyl, and
R
3
is selected from the group consisting of alkyl, aryl, aralkyl and alkaryl.
In another aspect, the present invention provides a process for preparing N-methylparoxetine comprising reacting CIPMA with sesamol-tetrabutylammonium salt in an organic solvent.
In another aspect, the present invention provides for sesamol-tetrabutylammonium salt.
DETAILED DESCRIPTION OF THE INVENTION
The term “yield” as used herein refers to the moles of the intermediate obtained (VII) (preferably N-methylparoxetine) compared to the moles of compound (V) (preferably CIPMA) used.
The term “NBu
4
” as used herein refers to tetrabutylammonium ion.
Attempts by the Applicant to produce a reaction with a high yield, other than the present invention, have failed. CIPMA and sesamol were reacted in the presence of polar solvents such as dimethylformamide, acetone or methylethylketone and strong bases such as sodium hydroxide, sodium methoxide and potassium tert-butoxide, and non-polar solvents such as toluene, dichloromethane or methyl-iso-butyl ketone in liquid—liquid PTC (phase transfer catalysis) reactions.
CIPMA was also reacted by the Applicant with sesamol in liquid-solid PTC reactions in the presence of solvents such as toluene or acetonirile. The PTC reactions were performed in the presence of bases such as sodium hydroxide, potassium hydroxide, potassium carbonate or barium hydroxide. Tetrabutylammonium bromide and tricaprylmethylammonium chloride, tributylbenzylammonium bromide, PEG 400 were used as PTC catalysts. However all of above described experiments, carried out by the Applicant, gave low yields of N-methylparoxetine and complex mixture of products including mostly CIPMA.
The present invention provides a process for producing N-methylparoxetine and similar intermediates with reactions that result in a higher yield than that obtained in the prior art. Specifically, the process of the present invention obtains a yield of about 86%, which is much higher than the 25% yield of the prior art.
The present invention is directed to the use of sesamol-tetrabutylammonium salt to increase the yield of N-methylparoxetine obtained. The salt may be prepared by dissolving sesamol and tetrabutylammonium hydroxide in an alcohol or a mixture of alcohols. Preferably the alcohol used is a mixture of isopropanol and methanol. The solvents are then evaporated, preferably under reduced pressure to obtain a residue, the salt. One skilled in the art may appreciate that instead of adding tetrabutylamonium hydroxide, a salt of tetrabutylammonium, such as the bromide salt, may be added in conjunction with a base, such as sodium hydroxide.
The salt is added to a mixture of CIPMA and a solvent such as acetonitrile, toluene or isopropanol. The reaction mixture comprising CIPMA, sesamol-tetrabutylammonium salt and a solvent is preferably heated for a few hours, most preferably for about 4 hours at reflux. The reaction mixture is then cooled and the solvent is removed to obtain a residue. Preferably the solvent is removed by evaporation under reduced pressure.
The residue is then dissolved in an organic solvent, such as toluene and is washed with a polar solvent such as water and a base such as sodium hydroxide. The reaction mixture is then dried by using a drying agent such as sodium sulfate and the solvent is evaporated to obtain N-methylparoxetine. The present invention obtains a yield of about 86%, more than 3 times that of the prior art.
The present invention provides a process for preparing compound
Chang Celia
Kenyon & Kenyon
Teva Pharmaceutical Industries Ltd.
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