Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-20
2002-05-28
Solola, T. A. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C560S130000, C568S662000, C568S729000
Reexamination Certificate
active
06395910
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a production method of a 5-phthalancarbonitrile compound useful as an intermediate for citalopram, which is an antidepressant, an intermediate for the 5-phthalancarbonitrile compound and a production method of the intermediate for the 5-phthalancarbonitrile compound. More particularly, the present invention relates to a production method of a 5-phthalancarbonitrile compound via a novel compound of the formula [I] to be mentioned later, based on a completely new viewpoint.
BACKGROUND OF THE INVENTION
The 5-phthalancarbonitrile compound of the formula [VI]
(hereinafter to be also referred to as compound [VI]) is a compound useful as a synthetic intermediate for citalopram of the formula [VII]
which is an antidepressant. The production method of the 5-phthalancarbonitrile compound is known to be as shown in the following scheme (WO98/19511).
wherein R is cyano, alkyloxycarbonyl having 2 to 6 carbon atoms or alkylaminocarbonyl having 2 to 6 carbon atoms, and Hal is a halogen atom.
According to this method, when R is other than cyano, cyanation is necessary after reduction and ring closure reaction. For example, when R is alkyloxycarbonyl, cyanation is carried out by the three steps of hydrolysis, amidation and reaction with chlorosulfonyl isocyanate, and when R is alkylaminocarbonyl, cyanation is carried out by a reaction with thionyl chloride or phosphorus pentachloride. In these methods, reagents undesirable to the environment, such as chlorosulfonyl isocyanate, thionyl chloride and phosphorus pentachloride, are used, and when R is alkyloxycarbonyl, cyanation is carried out by 3 steps, which is not necessarily simple or easy.
When R is cyano, the production method of the starting material, 5-cyanophthalide, needs to be improved. To be specific, 5-cyanophthalide is known to be obtained by the reaction of a diazonium salt derived from 5-aminophthalide with potassium cyanide in the presence of copper sulfide (Bull. Soc. Sci. Bretagne, 26, 1951, 35). This method is not desirable in that a toxin and a heavy metal salt are involved, such as potassium cyanide and copper sulfide. In addition, synthesis of 5-aminophthalide requires a dangerous reaction of nitration of phthalimide (Organic Synthesis II, 459), and further, reduction to amino by tin chloride and semi-reduction of phthalimide by zinc (J. Chem. Soc., 1931, 867), generating a waste heavy metal that is industrially undesirable.
It is therefore an object of the present invention to provide a production method of a 5-phthalancarbonitrile compound, which places only a small burden on the environmental and which is safe.
SUMMARY OF THE INVENTION
Such object can be achieved by the present invention detailed in the following.
In accordance with the present invention, there are provided a method of producing a 5-phthalancarbonitrile compound (compound of the aforementioned formula [VI]) useful as an intermediate for citalopram, which is safe and imposes less environmental burden, the method comprising using a compound of the formula [A]
wherein R
2
is alkanoyl having 2 to 5 carbon atoms (hereinafter to be also referred to as compound [A]) as a starting material, and a novel compound of the formula [I]
wherein X is chlorine atom, bromine atom or iodine atom (hereinafter to be also referred to as compound [I]) as a key intermediate, without using thionyl chloride and the like; novel compounds of the following formulas [II], [III], [IV] and [V], that can be used for the production method of the 5-phthalancarbonitrile compound of the present invention:
wherein R
1
is alkanoyl having 2 to 5 carbon atoms, alkyl having 1 to 5 carbon atoms, tetrahydropyran-2-yl, alkoxymethyl wherein the alkoxyl moiety has 1 to 5 carbon atoms, 1-alkoxyethyl wherein the alkoxyl moiety has 1 or 3 to 10 carbon atoms, or trialkylsilyl wherein each alkyl moiety has 1 to 5 carbon atoms, and X is chlorine atom, bromine atom or iodine atom (hereinafter to be also referred to as compound [II], compound [III], compound [IV] and compound [V], respectively); and the production methods thereof. Every conventional production method of citalopram goes through a 5-substituted phthalide compound (e.g., 5-formylphthalide), but the method of the present invention goes through the compound [I], employing a completely new synthetic strategy.
DETAILED DESCRIPTION OF THE INVENTION
The symbols used in the present specification are defined in the following.
With regard to alkyl, alkoxy and the like used in the present invention, they are linear unless a prefix (e.g., iso, neo etc.) or a symbol (e.g., sec-, tert- etc.) is attached. For example, a simple “propyl” means linear propyl.
The alkanoyl having 2 to 5 carbon atoms at R
1
, R
2
, R
1′
and R
1a
is linear or branched chain alkanoyl preferably having 2 to 5 carbon atoms, such as acetyl, butanoyl, propanoyl, isopropanoyl, pentanoyl, pivaloyl and the like, with preference given to acetyl, propanoyl and pivaloyl.
The alkyl having 1 to 5 carbon atoms at R
1
, R
1′
and R
1b
is linear or branched chain alkyl preferably having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl and the like, with preference given to methyl and tert-butyl.
The alkoxymethyl at R
1
, R
1′
and R
1b
, wherein the alkoxyl moiety has 1 to 5 carbon atoms, is alkoxymethyl having linear or branched chain alkoxy preferably having 1 or 2 carbon atoms, such as methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, isobutoxymethyl, sec-butoxymethyl, tert-butoxymethyl, pentoxymethyl, isopentoxymethyl and the like, with preference given to methoxymethyl and ethoxymethyl.
The 1-alkoxyethyl at R
1
, wherein the alkoxyl moiety has 1 or 3 to 10 carbon atoms, is linear, branched chain or cyclic 1-alkoxyethyl wherein the alkoxyl moiety preferably has 1 or 3 to 6 carbon atoms, such as 1-methoxyethyl, 1-propoxyethyl, 1-isopropoxyethyl, 1-butoxyethyl, 1-isobutoxyethyl, 1-sec-butoxyethyl, 1-tert-butoxyethyl, 1-pentoxyethyl, 1-isopentoxyethyl, 1-hexyloxyethyl, 1-cyclohexyloxyethyl, 1-heptyloxyethyl, 1-octyloxyethyl, 1-nonyloxyethyl, 1-decyloxyethyl and the like, with preference given to 1-propoxyethyl, 1-butoxyethyl and 1-cyclohexyloxyethyl.
The 1-alkoxyethyl at R
1′
and R
1b
, wherein the alkoxyl moiety has 1 to 10 carbon atoms, is linear, branched chain or cyclic 1-alkoxyethyl wherein the alkoxyl moiety preferably has 1 to 6 carbon atoms, such as 1-methoxyethyl, 1-ethoxyethyl, 1-propoxyethyl, 1-isopropoxyethyl, 1-butoxyethyl, 1-isobutoxyethyl, 1-sec-butoxyethyl, 1-tert-butoxyethyl, 1-pentoxyethyl, 1-isopentoxyethyl, 1-hexyloxyethyl, 1-cyclohexyloxyethyl, 1-heptyloxyethyl, 1-octyloxyethyl, 1-nonyloxyethyl, 1-decyloxyethyl and the like, with preference given to 1-ethoxyethyl, 1-propoxyethyl, 1-butoxyethyl and 1-cyclohexyloxyethyl.
The alkyl of the trialkylsilyl at R
1
, R
1′
and R
1b
, wherein each alkyl moiety has 1 to 5 carbon atoms, is independently linear or branched chain alkyl preferably having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl and the like, with preference given to methyl and tert-butyl. The trialkylsilyl may be, for example, trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, tributylsilyl, triisobutylsilyl, trisec-butylsilyl, tripentylsilyl, triisopentylsilyl, tert-butyldimethylsilyl and the like, with preference given to trimethylsilyl, tributylsilyl and tert-butyldimethylsilyl.
The present invention is explained in detail in the following.
Production Method of Compound [I]
The novel compound [I] can be efficiently obtained by subjecting compound [A] to one of chlorination, bromination and iodination, and then to the elimination of the alkanoyl group. For example, chlorina
Igi Masami
Ikemoto Tetsuya
Leydig , Voit & Mayer, Ltd.
Solola T. A.
Sumika Fine Chemicals Co., Ltd.
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