Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-02-15
2004-02-03
Chang, Ceila (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S198000, C546S205000, C546S236000, C514S317000, C514S319000, C514S320000
Reexamination Certificate
active
06686473
ABSTRACT:
This application claims the benefit of priority under 35 U.S.C. §119 from The Netherlands patent application serial number 1017421, filed Feb. 21, 2001, the entire contents of which are incorporated herein by reference.
BACKGROUND OF THE INVENTION
The present invention relates to a process for preparing the pharmaceutically active compound paroxetine.
Pharmaceutical products with antidepressant and anti-Parkinson properties are described in U.S. Pat. No. 4,007,196. An especially important compound is paroxetine, the (−) trans isomer of 4-(p-fluorophenyl)-3-(3,4-methylenedioxy-phenoxymethyl)-piperidine of the formula (1).
The compound has been used in therapy as the hydrochloride hemihydrate salt to treat e.g. depression, obsessive compulsive disorder and panic.
U.S. Pat. No. 4,007,196 discloses the formation of paroxetine by the demethylation of N-methylparoxetine of the formula (2):
via a paroxetine phenylcarbamate intermediate of the formula (3).
The paroxetine phenylcarbamate is subsequently hydrolyzed to paroxetine in an appropriate solvent. Specifically, the formation of the paroxetine phenylcarbamate (3) is formed by a reaction of N-methylparoxetine with phenyl chloroformate in dichloromethane at 0° C.-5° C. The solution after reaction was washed with aqueous NaOH and HCl and evaporated. A solid mixture was obtained which was suspended in benzene, filtered and evaporated again. The evaporation residue (i.e. the crude phenylcarbamate (3)) was refluxed with solid KOH in methylcellosolve (2-methoxyethanol) for 4 hours. The obtained solution of paroxetine was evaporated, whereby the residue after evaporation was subjected to water/benzene extraction and paroxetine was isolated from the benzene layer as the maleate salt.
EP152273 discloses a similar process wherein phenylcarbamate of a paroxetine analogue was prepared from the N-methylated precursor in toluene, isolated and purified by recrystallization from ethanol, and the solid phenylcarbamate product hydrolyzed to the desired paroxetine analogue by solid KOH under 2-4 hours reflux in 2-methoxyethanol. The remainder of KOH and water soluble by-products were removed from the reaction mixture by adding a mixture of water and toluene to the reaction mixture and removal of the aqueous layer. The toluene layer contained the desired product.
In EP 190496, a solid-state phenylcarbamate (3) was hydrolysed by KOH in 2-methoxyethanol. The KOH was added at 60° C. for a period of one hour whereafter the mixture was heated to reflux for 2.5 hours. The crude mixture was treated with water and the product was extracted into toluene.
A common procedure is disclosed in EP223403, and corresponding U.S. Pat. No. 4,721,723, wherein a solid-state paroxetine phenylcarbamate (3) was dissolved in toluene and KOH was added. The mixture was refluxed for 2 hours with good agitation. The slurry was then cooled to 20° C. and the toluene washed with water. The obtained solution of paroxetine free base in toluene was further treated with HCI to isolate paroxetine in a form of its hydrochloride salt. Similar procedures for the synthesis of paroxetine and various salts of paroxetine have been disclosed in WO 99-32484, GB 2336364, WO 99-52901, WO 00-39090 and WO 00-32594.
However, WO 00-78753 reports that the above described processes suffer from several disadvantages. Specifically, the use of 2-methoxyethanol produces an undesired transesterified intermediate that is slow to hydrolyze and that leaves a residue that is difficult to remove from the hydrolyzed product. Alternatively, the method disclosed in EP 223403, in which no 2-methoxyethanol was used, could not be easily scaled up; long and/or incomplete reactions were encountered. Apparently, the KOH melts at the toluene reflux temperature and can react with carbamate derivatives to form an insoluble complex mass. If this mass forms, complete reaction is not possible and reactor clean up is difficult.
To overcome these disadvantages, WO 00-78753 discloses an improved method of hydrolysis of the solid-state paroxetine phenylcarbamate that comprises forming a complex of KOH and carbamate derivative in toluene, but below the reflux temperature. The complex is sand-like and is easily stirrable. The well-stirred mixture or suspension is then further heated to complete the hydrolytic reaction.
But this method suffers from the need to carefully control the reaction conditions to obtain the desired finely divided suspension instead of the insoluble complex mass. The suspension is only temporarily formed at a certain temperature which should be maintained for a certain time to complete the formation. Further, the process requires slow and step-wise heating and vigorous stirring. If these conditions are not met, e.g. if the reaction mixture is overheated, the same problems as reported for the other toluene based hydrolysis techniques are likely to occur.
EP 810 225 discloses the preparation of paroxetine by a similar demethylation and hydrolysis procedure but using carbamate derivatives other than phenylcarbamate. Example 1 shows the hydrolysis of an ethoxycarbamate derivative using KOH in a mixture of toluene and ethanol at reflux, while example 3 uses ethanol as the only solvent. However, these reactions took two days and three days, respectively. Thus, scale up of the teachings in EP 810 225 seems difficult and/or not commercially justifiable.
It would be desirable to have a more convenient process for making paroxetine. It would further be desirable to provide a process that eliminated or reduced the need to use liquid-solid suspension reaction systems.
SUMMARY OF THE INVENTION
The present invention relates to a process for making paroxetine wherein the solvent system provides for improved operating ease. Accordingly, a first aspect the present invention provides a process for the production of paroxetine, which comprises hydrolyzing a paroxetine phenylcarbamate of formula (3)
with a hydrolyzing agent in a solvent system comprising an aliphatic alcohol and a hydrocarbon co-solvent, to form a paroxetine compound of formula (1).
The aliphatic alcohol preferably has a boiling point in the range of about 70° C. to about 150° C., such as ethanol, propanol, isopropanol, 1-butanol, 2-butanol, or tertiary butanol; most preferably 1-butanol. The hydrocarbon solvent is typically benzene, toluene, xylene or cyclohexane, and preferably is toluene.
The hydrolysis of paroxetine phenylcarbamate to paroxetine according to the present invention enables the reaction to be carried out in an easily controllable, robust and reproducible manner in industrial scale.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to the discovery that a solvent system comprised of a non-hydrocarbon solvent and a hydrocarbon co-solvent, preferably wherein the solvent and the co-solvent are at least partly miscible, can be formed that will more easily handle the hydrolysis of paroxetine phenylcarbamate. It has now been discovered that alkanols derived from alkane hydrocarbons do not exhibit the above reported disadvantages associated with structurally related methyl cellosolve. For clarity, the aliphatic alcohols used in the present invention do not include other alcohols such as ether alcohols and specifically does not include methylcellosolve. The aliphatic alcohol includes one or more of ethanol, propanol, isopropanol, 1-butanol, 2-butanol, or tertiary butanol, and most preferably is 1-butanol.
The presence of the non-hydrocarbon solvent in the hydrolytic process of the invention minimizes technical difficulties associated with previous process arrangements employing a hydrocarbon such as toluene as a solvent. The so improved process does not exhibit the difficulties associated with stirring or melting of solid potassium hydroxide, allows the hydrolytic reaction to proceed in a more controllable way and does not require careful control of the course of the reaction, namely of the heating regimen.
The co-solvent is a hydrocarbon of a boiling point from 50° C. to 150° C., such as one or more of benzene, toluene, xyle
Lemmens Jacobus M.
Peters Theodorus H. A.
Picha Frantisek
Buscher Mark R.
Chang Ceila
Synthon BCT Technologies, LLC
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