Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-07-21
2002-08-13
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C544S046000
Reexamination Certificate
active
06433168
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to (E)-10-(1-azabicyclo[2.2.2]oct-3-ylidenemethyl)phenothiazine of the formula [A]
which is a synthetic intermediate for pharmaceutically useful mequitazine having antihistaminic action and the like, and which has a purity of not less than 85 mol % (hereinafter to be also referred to as compound [A]) and a production method thereof. In addition, the present invention relates to a production method of a compound of the formula [I]
wherein X is a halogen atom, which is an intermediate for the above-mentioned compound [A], (hereinafter to be also referred to as compound [I]), and to a hydrate and a novel crystal of compound [III], which are used for the production of compound [I].
BACKGROUND OF THE INVENTION
The mequitazine of the following formula
is a pharmaceutically useful substance having various actions such as antihistaminic action, cholinergic action-inhibitory action, antiadrenergic action, neurosedative action, ataractic action, spasmolytic action and the like. Mequitazine can be produced by the following reaction
werein R
1
and R
2
are the same or different and each is hydrogen atom, halogen atom, alkyl, alkoxy or alkylthio, in which 10-(3-chloro-1-azabicyclo[2.2.2]oct-3-ylmethyl)phenothiazine is reduced in the presence of a reducing agent or hydrogenation catalyst to give mequitazine (JP-B-2835413).
According to this method, the reaction proceeds at a high temperature. Up-scaling, therefore, leads to the occurrence of thermal decomposition and elimination of hydrogen halide. This in turn causes degradation of the quality and yield of mequitazine, the need for column purification and hydrogenation, and the like. For use at an industrial level, therefore, an improvement is essential. When a boron compound is used as a reaction reagent, moreover, an adduct of the product and boron is generated, which requires addition of an acid (e.g., acetic acid) and heat treatment of the mixture.
Other production method of mequitazine may be the following series of reactions:
wherein R
1
and R
2
are as defined above (JP-A-5-140157). According to this method, 10-(3-chloro-1-azabicyclo[2.2.2]oct-3-ylmethyl)phenothiazine is subjected to elimination of hydrogen halide in an inert solvent in the presence of a base, such as hydroxide, hydride or alcholate of an alkali metal, to give three kinds of intermediates, which are hydrogenated without separation to produce mequitazine. In this method, hydrogenation is carried out using an expensive hydrogenation catalyst, such as palladium carbon, in the same amount as the intermediate, thereby resulting in higher production costs.
In view of such situation, there has been a demand for a method for industrial production of mequitazine at a high purity, a high yield and at a lower cost.
According to the present invention, it has been found with regard to the above-mentioned three kinds of intermediates (compound [A′], compound [B′], compound [C′]) as disclosed in JP-A-5-140157, that, of the compounds wherein R
1
and R
2
are hydrogen atoms [compound [A], (Z)-10-(1-azabicyclo[2.2.2]oct-3-ylidenemethyl)phenothiazine (hereinafter to be also referred to as compound [B]) and 10-(1-azabicyclo[2.2.2]oct-2-en-3-ylmethyl)phenothiazine (hereinafter to be also referred to as compound [C]), respectively], compound [B] is hardly subject to hydrogenation, and that compound [C], which is most susceptible to hydrogenation among the three kinds of intermediates, suffers from lower purity and lower yield when reacted under the conditions that selectively afford this compound, that is, the reaction of 10-(3-chloro-1-azabicyclo[2.2.2]oct-3-ylmethyl)phenothiazine and alkali metal alcholate in an alcohol solvent, because 10-(3-alkoxy-1-azabicyclo[2.2.2]oct-3-ylmethyl)phenothiazine is by-produced. In addition, it has been found that compound [A] is susceptible to hydrogenation and that this compound is most suitable as a synthetic intermediate for mequitazine. In short, the present inventors have found that production of compound [A] at a high purity is most beneficial for the production of mequitazine.
Compound [I] is useful as a starting material for compound [A]. Compound [I] can be obtained by reacting 3-methylenequinuclidine oxide of the formula [II]
hereinafter to be also referred to as Compound [II], and an alkali metal salt of phenothiazine (JP-B-2835413). 3-Methylene-quinuclidine oxide to be used as a starting material can be produced by a known synthetic method (U.S. Pat. No. 3,725,410, U.S. Pat. No. 3,792,053, JP-A-61-280497, JP-A-2-62883) via dimsyl sodium. However, dimsyl sodium is unstable and dangerous (
Anzen Kogaku
(Safe Engineering) Vol. 23, No. 5, 269-274 (1984)).
In JP-A-61-280497, Example 1. (a)-(ii), teaches how to scale up the production of 3-methylenequinuclidine oxide. In this Example, a dispersion of toluene, 3-quinuclidinone, trimethyloxo-sulfonium iodide and sodium hydride in paraffin is charged and then dimethyl sulfoxide is added dropwise. According to this method, sodium hydride and trimethyloxosulfonium iodide are added in advance and dimethyl sulfoxide is subsequently added. As a result, dimethyl sulfoxide reacts with sodium hydride to form dimsyl sodium, and then dimsyl sodium reacts with trimethyloxosulfonium iodide to form dimethyloxosulfonium methylide as well as dimethyl sulfoxide. In other words, the addition of even a single drop of dimethyl sulfoxide in this method theoretically results in the completion of the reaction, because it generates dimethyl sulfoxide which automatically reacts successively with previously-added sodium hydride.
Anzen Kogaku
, ibid, teaches the instability of this reaction system by stating that a dimsyl sodium solution placed under adiabatic conditions at 55° C. for 5 hr moves on to a runaway reaction. In fact, a reproductive testing of the method of JP-A-61-280497 in a reaction vessel of a 2000 L level ended up in carbonization of the contents due to a runaway reaction occurred therein. To conclude, this method allows reaction of dimsyl sodium immediately after formation thereof, but once dimethyl sulfoxide is added, the above-mentioned series of reactions occur, thereby producing dimethyl sulfoxide, and the newly-generated dimethyl sulfoxide causes another cycle of the above-mentioned reactions. This makes termination of the reaction difficult, and the reaction heat causes run away of the reaction due to the autoexothermicity of dimsyl sodium, to the degree that the reaction may induce an explosion. An enlarged reaction scale increases the risk of explosion.
In Example 1(II) of JP-A-61-280497, 3-quinuclidinone is reacted with dimethyloxosulfonium methylide, and the resulting reaction mixture of 3-methylenequinuclidine oxide is poured into water and subjected to extraction with chloroform for post-treatment. This method includes a loss in the amount of the final product, which loss becomes even greater by the concentration after extraction. 3-Methylenequinuclidine oxide isolated by the method disclosed in this publication and an alkali metal salt of phenothiazine were condensed to give 10-(3-hydroxy-1-azabicyclo[2.2.2]oct-3-ylmethyl)phenothiazine of the formula [III]
(hereinafter to be also referred to as Compound [III]) only at an unstable yield of 0-50%. This is because 3-methylene-quinuclidine oxide cannot be isolated at a constant percentage, the method includes a great loss as mentioned above, and because extraction solvent chloroform remains from isolation and forms carbene with the alkali metal, causing resinification. Consequently, the compound [III] cannot be obtained at a constantly high yield.
In Example 2 of JP-B-2835413, compound [III] was reacted with phospho
Igi Masami
Yamazaki Shigeya
Yumoto Hiroyuki
Habte Kahsay
Leydig , Voit & Mayer, Ltd.
Raymond Richard L.
Sumika Fine Chemicals Co., Ltd.
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