Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-05
2002-08-13
Shippen, Michael L. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C562S409000, C562S460000, C568S807000
Reexamination Certificate
active
06433196
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a production method of citalopram useful as an antidepressant, a synthetic intermediate therefor and a production method of the intermediate.
BACKGROUND OF THE INVENTION
Citalopram having the formula [A]
is useful as an antidepressant. As a production method of citalopram, there is known a method comprising the use of a 5-phthalancarbonitrile compound of the formula [VI]
hereinafter to be also referred to as compound [VI]. For example, compound [VI] is reacted with 3-(dimethylamino)propyl halide in the presence of a condensing agent (JP-B-61-35986). In this publication, sodium hydride is used as a condensing agent. According to this method, citalopram is obtained at a low yield, and therefore, this method is not necessarily a preferable one. Moreover, this publication does not teach how to increase the yield, not to mention the use of a different additive besides the condensing agent to improve the yield.
As a different production method of citalopram, there is reported reaction of compound [VI] with 3-(dimethylamino)propyl halide under basic conditions (W098/19511). In this publication, lithium diisopropylamide obtained from n-butyllithium and diisopropylamine is used as a base. While the yield is improved, expensive n-butyllithium is necessary and a reaction at a very low temperature (Example, from −50° C. to −40° C.) is required, which makes the method industrially unpreferable. This publication does not teach an economical base that permits reaction in a typical temperature range, or industrial and economical production of citalopram at a high yield under basic conditions wherein specific bases are combined.
It is therefore an object of the present invention to provide an economical and industrially advantageous production method of citalopram, which affords production of citalopram at high yields.
Another object of the present invention is to provide a novel production method of a compound represented by the formula [III] to be mentioned later.
SUMMARY OF THE INVENTION
For this purpose, the method described in JP-B-61-35986 utilizing a condensing agent has been improved. According to the present invention, a method comprising adding, besides a condensing agent, at least one of N,N,N′,N′-tetramethylethylenediamine and 1,3-dimethyl-2-imidazolidinone is suggested.
The present inventors have already reported (JP application No. 11-311703) a method based on a completely new strategy for the safe production of a 5-phthalancarbonitrile compound, which method imposes a small environmental burden and utilizes a compound of the formula [III]
also referred to as compound [III]. They have now found that the compound [III], a key compound in this production method, can be produced easily from a compound of the formula [II]
also referred to as compound [II], as a starting material. They have also found that compound [II] can be produced safely and with less burden on the environment by the independent use of 1,3-dimethyl-4-(4′-fluorobenzoyl)benzene (hereinafter to be also referred to as compound [I′]), trimellitic anhydride or a novel compound of the formula [I]
hereinafter to be referred to as compound [I], as the starting material. In addition, the present invention provides novel production methods of these starting materials.
Accordingly, the present invention relates to the following reactions.
Conversion of 4-bromofluorobenzene to 4-fluorophenylmagnesium bromide, and reaction thereof with 2,4-dimethylbenzaldehyde to give compound [I].
Friedel-Crafts reaction of 4-fluorobenzoyl halide using m-xylene as a starting material and solvent to give compound [I′].
The following respective reactions (1) to (4) to give compound [II].
(1) Oxidation of compound [I].
(2) Friedel-Crafts reaction of 4-fluorobenzoyl halide using m-xylene as a starting material and solvent to give compound [I′], which is then subjected to oxidation.
(3) Friedel-Crafts reaction of 2,4-dimethylbenzoyl halide with fluorobenzene to give compound [I′], which is then subjected to oxidation.
(4) Friedel-Crafts reaction of trimellitic anhydride with fluorobenzene in a dichloro-substituted or trichloro-substituted benzene solvent.
The following respective reactions (1) and (2) to give compound [III].
(1) Reduction and cyclization of compound [II].
(2) Friedel-Crafts reaction of trimellitic anhydride with fluorobenzene to give a mixture of compound [II], an isomer thereof, and a compound of the formula [IV]
hereinafter to be also referred to as compound [IV], which mixture is then subjected to reduction and cyclization, and then isolation.
Oxidation of compound [III] using manganese dioxide to give a compound of the formula [V]
hereinafter to be also referred to as compound [V].
A reaction of compound [VI] with 3-(dimethylamino)propyl chloride in the presence of at least one of N,N,N′,N′-tetramethylethylenediamine and 1,3-dimethyl-2-imidazolidinone and a condensing agent to give citalopram.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is explained in detail in the following. In the present invention, by the reaction time is meant the period of time from the addition of all the reagents necessary for the reaction to the completion of the reaction.
Production Method of Compound [I]
The compound [I] is novel and can be produced by, for example, a Grignard reaction of 2,4-dimethylbenzaldehyde with a Grignard reagent of 4-bromofluorobenzene. To be specific, a Grignard reagent of 4-bromofluorobenzene is prepared in a reaction solvent, to which is added, preferably by dropwise addition, 2,4-dimethylbenzaldehyde to give compound [I]. The order of addition of the reaction reagents is subject to no particular limitation.
Production of the Grignard reagent of 4-bromofluorobenzene follows a conventional method, which includes, for example, dispersing metal magnesium in an organic solvent and dropwise addition of 4-bromofluorobenzene thereto generally at a temperature of from −30° C. to 100° C., preferably 15° C.-70° C. The amount of the metal magnesium to be used is that necessary for conversion of 4-bromofluorobenzene to a Grignard reagent, which is, for example, generally 0.9 mol-2 mol, preferably 0.95 mol-1.3 mol, per 1 mol of 4-bromofluorobenzene.
2,4-Dimethylbenzaldehyde is used in an amount of generally 0.5 mol-2 mol, preferably 0.8 mol-1.2 mol, per 1 mol of 4-bromofluorobenzene.
The reaction solvent in this reaction is subject to no particular limitation as long as it does not interfere with the Grignard reaction. A solvent which can be used for the preparation of a Grignard reagent can be applied to the Grignard reaction without isolation after preparation of the Grignard reagent, thereby preferably making the reaction step simple. Preferable solvent may be, for example, ether solvent (e.g., diethyl ether, diisopropyl ether, dibutyl ether, dipentyl ether, dihexyl ether, t-butyl methyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,3-dioxolan etc.) and the like, with more preference given to THF, diethyl ether, ethylene glycol dimethyl ether and diethylene glycol dimethyl ether. The amount of the reaction solvent to be used in this reaction is generally 1 L-30 L, preferably 2 L-20 L, per 1 kg of 4-bromofluorobenzene.
The temperature of this reaction is generally from −30° C. to 100° C., preferably from −10° C. to 50° C., and the reaction time is generally 5 min-6 hr, preferably 10min-3 hr.
After inactivation of the Grignard reagent by the addition of water etc. to the reaction mixture, compound [I&
Arai Nobuhiro
Gao Wei-Guo
Igi Masami
Ikemoto Tetsuya
Leydig , Voit & Mayer, Ltd.
Shippen Michael L.
Sumika Fine Chemicals Co., Ltd.
LandOfFree
Production method of citalopram, intermediate therefor and... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Production method of citalopram, intermediate therefor and..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Production method of citalopram, intermediate therefor and... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2893575