Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-12-13
2003-04-01
Chang, Ceila (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C514S321000
Reexamination Certificate
active
06541637
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for drying paroxetine hydrochloride anhydrate. More specifically, the present invention relates to a process for drying paroxetine hydrochloride anhydrate to reduce the amount of remaining isopropyl alcohol.
BACKGROUND ART
Paroxetine hydrochlorides such as paroxetine hydrochloride anhydrate are useful compounds as antidepressants.
Conventionally, paroxetine hydrochloride anhydrate obtained by reacting paroxetine with hydrogen chloride in the presence of isopropyl alcohol contains isopropyl alcohol. Therefore, in order not to deform its crystal form, the paroxetine hydrochloride anhydrate is dried by a vacuum drying process employing a vacuum oven which is temperature-adjusted to a temperature lower than 80° C. However, it has been difficult to sufficiently remove isopropyl alcohol contained in the paroxetine hydrochloride anhydrate by the vacuum drying process. Therefore, there is a defect in the process such that a long period of time of not less than about 100 hours is required to dry until the content of isopropyl alcohol attains to not more than 5% by weight.
Therefore, as a process capable of eliminating the above defect, there has been proposed a process comprising isolating the paroxetine hydrochloride anhydrate containing isopropyl alcohol, drying under vacuum, removing isopropyl alcohol liberated from or not bonded to the paroxetine hydrochloride anhydrate, and thereafter replacing isopropyl alcohol bonded to the paroxetine hydrochloride anhydrate with a substituting agent such as water or supercritical carbon dioxide [Japanese Patent Laid-Open No. Hei 8-245620, column 9, lines 1 to 9].
However, in this process, when water (steam) is used as a substituting agent, there is a possibility of causing crystal conversion to paroxetine hydrochloride hemihydrate, and there is a defect that complicated procedures such that the replaced moisture should be removed by vacuum drying are necessitated. In addition, when the supercritical carbon dioxide is used, since carbon dioxide must be pressurized to a high pressure of 2500 psi (170 atm.) or so during the course of preparing the supercritical carbon dioxide [Ibid, column 20, lines 19 to 38], there arises a defect that a large-scaled apparatus for preparing supercritical carbon dioxide is required.
Accordingly, since complicated procedures and large-scaled apparatus are necessary for the conventional processes for drying paroxetine hydrochloride anhydrate, there is a defect such that the processes are poor in production efficiency.
An object of the present invention is to provide a process for drying paroxetine hydrochloride anhydrate capable of efficiently reducing the amount of remaining isopropyl alcohol in the paroxetine hydrochloride anhydrate, which is obtained by crystallizing in the presence of isopropyl alcohol, without the necessity of a large-scaled apparatus.
DISCLOSURE OF INVENTION
According to the present invention, there can be provided a process for drying paroxetine hydrochloride anhydrate comprising:
(A) reacting a paroxetine compound with hydrogen chloride in the presence of isopropyl alcohol and crystallizing the resulting product, to obtain paroxetine hydrochloride anhydrate, and drying the resulting paroxetine hydrochloride anhydrate at a temperature of not more than 60° C. and under normal pressure or lower in an atmosphere which does not substantially contain moisture until the content of isopropyl alcohol attains to not more than 15% by weight; and
(B) further drying the paroxetine hydrochloride anhydrate at a temperature of 80° to 110° C. in an atmosphere reduced to not more than 20 mm Hg until the content of isopropyl alcohol attains to not more than 5% by weight.
BEST MODE FOR CARRYING OUT THE INVENTION
As described above, the drying process of the present invention employs a two-step drying process comprising:
(A) reacting a paroxetine compound with hydrogen chloride in the presence of isopropyl alcohol and crystallizing the resulting product, to obtain paroxetine hydrochloride anhydrate, and drying the resulting paroxetine hydrochloride anhydrate at a temperature of not more than 60° C. and under normal pressure or lower in an atmosphere which does not substantially contain moisture until the content of isopropyl alcohol attains to not more than 15% by weight; and
(B) further drying the paroxetine hydrochloride anhydrate at a temperature of 80° to 110° C. in an atmosphere reduced to not more than 20 mm Hg until the content of isopropyl alcohol attains to not more than 5% by weight.
The paroxetine hydrochloride anhydrate can be obtained by, for instance, a process comprising dissolving a paroxetine compound in isopropyl alcohol, and thereafter reacting the paroxetine compound with hydrogen chloride, whereby reacting the paroxetine compound with hydrogen chloride in the presence of isopropyl alcohol; and crystallizing the resulting product. This paroxetine hydrochloride anhydrate usually contains 30 to 70% by weight or so of isopropyl alcohol.
The paroxetine compound includes, for instance, paroxetine, N-tert-butoxycarbonylparoxetine, and the like. The N-tert-butoxycarbonylparoxetine is (3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[3,4-methylenedioxyphenyl)oxymethyl]piperidine.
It is preferable that the amount of hydrogen chloride used in the reaction with the paroxetine compound is usually 1 to 5 mol or so per 1 mol of the paroxetine compound.
The amount of the paroxetine compound is not limited to specified ones. It is preferable that the amount of the paroxetine hydrochloride anhydrate is 5 to 60 parts by weight, based on 100 parts by weight of isopropyl alcohol.
The reaction temperature of the paroxetine compound with hydrogen chloride may be usually within the range of ambient temperature to the boiling point of isopropyl alcohol.
In addition, isopropyl alcohol may be used alone, or used in combination with, for instance, other organic solvents, organic acids, and the like in an amount which would not hinder the object of the present invention. In addition, it is preferable that water is not contained in isopropyl alcohol from the viewpoint of shortening the drying time. Therefore, it is preferable that isopropyl alcohol is substantially non-water-containing isopropyl alcohol, i.e. one having a water content of not more than 0.1%.
The reaction time is not limited to specified ones. The reaction time can be usually up to the termination of the reaction.
In the reaction solution of the formed paroxetine hydrochloride anhydrate, impurities are contained in some cases. In this case, in order to remove the impurities, the reaction solution can be treated with activated charcoal.
By gradually cooling the reaction solution, a relatively large paroxetine hydrochloride anhydrate having good filterability can be obtained as crystals.
In the crystals of the resulting paroxetine hydrochloride anhydrate, isopropyl alcohol is contained. The crystals of paroxetine hydrochloride anhydrate containing isopropyl alcohol are extremely thermally unstable. For instance, when the crystals of paroxetine hydrochloride anhydrate containing isopropyl alcohol are dried at a temperature of not less than 80° C., a portion of the crystals of paroxetine hydrochloride anhydrate is dissolved in the isopropyl alcohol contained, and thereby its crystal form is deformed, so that a desired crystal form cannot be obtained [see Comparative Example 2 described below].
In the present invention, first, this paroxetine hydrochloride anhydrate containing isopropyl alcohol is dried at a temperature of not more than 60° C. and under normal pressure or lower in an atmosphere which does not substantially contain moisture until the content of isopropyl alcohol attains to not more than 15% by weight.
One of great features of the present invention resides in that the above procedure is employed. When drying the paroxetine hydrochloride anhydrate, the paroxetine hydrochloride anhydrate would not be converted to paroxetine hydrochloride hem
Ishibashi Taro
Kawata Yoshihiro
Okatake Mitsuru
Chang Ceila
Sumika Fine Chemicals Co., Ltd.
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