U.S. patent application number 10/176721 was filed with the patent office on 2002-10-17 for production methods of 5-phthalancarbonitrile compound and an intermediate therefor.
This patent application is currently assigned to Sumika Fine Chemicals Co., Ltd.. Invention is credited to Igi, Masami, Ikemoto, Tetsuya.
Application Number | 20020151728 10/176721 |
Document ID | / |
Family ID | 18020462 |
Filed Date | 2002-10-17 |
United States Patent
Application |
20020151728 |
Kind Code |
A1 |
Ikemoto, Tetsuya ; et
al. |
October 17, 2002 |
Production methods of 5-phthalancarbonitrile compound and an
intermediate therefor
Abstract
The present invention provides a production method of a
5-phthalancarbonitrile compound, which comprises the use of a novel
compound of the formula [I] 1 wherein X is chlorine atom, bromine
atom or iodine atom, as a key intermediate. The method of the
present invention imposes small environmental burden (without use
of a reagent imposing great burden on the environment, such as
heavy metal, metal cyanide, thionyl chloride and the like) and is
safe. The inventive method is based on a completely new strategy
which is different from conventional production methods of
5-phthalancarbonitrile compound.
Inventors: |
Ikemoto, Tetsuya;
(Osaka-shi, JP) ; Igi, Masami; (Osaka-shi,
JP) |
Correspondence
Address: |
LEYDIG VOIT & MAYER, LTD
TWO PRUDENTIAL PLAZA, SUITE 4900
180 NORTH STETSON AVENUE
CHICAGO
IL
60601-6780
US
|
Assignee: |
Sumika Fine Chemicals Co.,
Ltd.
1-21, Utajima 3-chome, Nishiyodogawa-ku
Osaka-shi
JP
555-0021
|
Family ID: |
18020462 |
Appl. No.: |
10/176721 |
Filed: |
June 21, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10176721 |
Jun 21, 2002 |
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09997992 |
Nov 30, 2001 |
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6433195 |
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09997992 |
Nov 30, 2001 |
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09909596 |
Jul 20, 2001 |
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6395910 |
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09909596 |
Jul 20, 2001 |
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09648048 |
Aug 25, 2000 |
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6310222 |
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Current U.S.
Class: |
549/467 ;
549/468; 556/489; 560/254; 568/811 |
Current CPC
Class: |
C07D 307/79 20130101;
C07C 43/313 20130101; C07C 69/63 20130101; C07C 33/46 20130101;
C07C 2601/16 20170501; C07D 307/87 20130101; C07C 29/095 20130101;
C07C 33/46 20130101; C07C 29/095 20130101 |
Class at
Publication: |
549/467 ;
549/468; 556/489; 560/254; 568/811 |
International
Class: |
C07D 307/94; C07C
067/02 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 1, 1999 |
JP |
311703/1999 |
Claims
What is claimed is
1. A compound of the formula [I] 12wherein X is chlorine atom,
bromine atom or iodine atom.
2. A compound of the formula [II] 13wherein R.sup.1 is alkanoyl
having 2 to 5 carbon atoms, alkyl having 1 to 5 carbon atoms,
tetrahydropyran-2-yl, alkoxymethyl wherein an alkoxyl moiety has 1
to 5 carbon atoms, 1-alkoxyethyl wherein an 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.
3. The compound of claim 2 wherein R.sup.1 is acetyl and X is
bromine atom.
4. A compound of the formula [III] 14
5. A compound of the formula [IV] 15
6. An oxime compound of the formula [V] 16
7. A production method of a compound of the formula [I] 17wherein X
is chlorine atom, bromine atom or iodine atom, which comprises
subjecting a compound of the formula [A] 18wherein R.sup.2 is
alkanoyl having 2 to 5 carbon atoms, to chlorination, bromination
or iodination and then to elimination of the alkanoyl group.
8. A production method of a compound of the formula [III] 19which
comprises the steps of (1) converting a compound of the formula
[II-b] 20 wherein R.sup.1b is alkyl having 1 to 5 carbon atoms,
tetrahydropyran-2-yl, alkoxymethyl wherein an alkoxyl moiety has 1
to 5 carbon atoms, 1-alkoxyethyl wherein an alkoxyl moiety has 1 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, to a Grignard reagent or lithium compound, (2) coupling same
with p-fluorobenzaldehyde, and (3) subjecting the obtained coupling
compound to deprotection of R.sup.1b and cyclization.
9. A production method of the formula [IV] 21which comprises
oxidizing a compound of the formula [III] 22
10. A production method of an oxime compound of the formula [V]
23which comprises reacting a compound of the formula [IV] 24with
hydroxylamine or a mineral acid salt thereof.
11. A production method of a 5-phthalancarbonitrile compound of the
formula [VI] 25which comprises dehydrating an oxime compound of the
formula [V] 26
12. A production method of 5-phthalancarbonitrile compound of the
formula [VI] 27which comprises reacting a compound of the formula
[IV] 28with hydroxylamine or a mineral acid salt thereof and
dehydrating the resulting compound.
13. A production method of a compound of the formula [II']
29wherein R.sup.1' is alkanoyl having 2 to 5 carbon atoms, alkyl
having 1 to 5 carbon atoms, tetrahydropyran-2-yl, alkoxymethyl
wherein an alkoxyl moiety has 1 to 5 carbon atoms, 1-alkoxyethyl
wherein an alkoxyl moiety has 1 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, which
comprises (1) converting the hydroxyl group of a compound of the
formula [I] 30wherein X is chlorine atom, bromine atom or iodine
atom, to alkoxy having 1 to 5 carbon atoms,
tetrahydropyran-2-yloxy, alkoxymethoxy wherein an alkoxyl moiety
has 1 to 5 carbon atoms, 1-alkoxyethoxy wherein an alkoxyl moiety
has 1 to 10 carbon atoms, or trialkylsilyloxy wherein each alkyl
moiety has 1 to 5 carbon atoms, or (2) subjecting a compound of the
formula [A] 31wherein R.sup.2 is alkanoyl having 2 to 5 carbon
atoms, to chlorination, bromination or iodination.
Description
TECHNICAL FIELD OF THE INVENTION
[0001] 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
[0002] The 5-phthalancarbonitrile compound of the formula [VI]
2
[0003] (hereinafter to be also referred to as compound [VI]) is a
compound useful as a synthetic intermediate for citalopram of the
3
[0004] which is an antidepressant. The production method of the
5-phthalancarbonitrile compound is known to be as shown in the
following scheme (WO98/19511). 4
[0005] 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.
[0006] According to this method, when R is other than cyano,
cyanation is necessary after reduction and ring closure
reaction.
[0007] 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.
[0008] 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.
[0009] 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
[0010] Such object can be achieved by the present invention
detailed in the following.
[0011] 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] 5
[0012] wherein R.sup.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] 6
[0013] 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: 7
[0014] wherein R.sup.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
[0015] The symbols used in the present specification are defined in
the following.
[0016] 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.
[0017] The alkanoyl having 2 to 5 carbon atoms at R.sup.1, R.sup.2,
R.sup.1' and R.sup.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.
[0018] The alkyl having 1 to 5 carbon atoms at R.sup.1, R.sup.1'
and R.sup.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.
[0019] The alkoxymethyl at R.sup.1, R.sup.1' and R.sup.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.
[0020] The 1-alkoxyethyl at R.sup.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.
[0021] The 1-alkoxyethyl at R.sup.1' and R.sup.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.
[0022] The alkyl of the trialkylsilyl at R.sup.1, R.sup.1' and
R.sup.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,
triisobutylsilyl, tripentylsilyl, triisopentylsilyl,
tert-butyldimethylsilyl and the like, with preference given to
trimethylsilyl, tributylsilyl and tert-butyldimethylsilyl.
[0023] The present invention is explained in detail in the
following.
[0024] Production Method of Compound [I]
[0025] 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, chlorination, bromination or iodination, preferably
bromination, is performed by reacting compound [A] with a
halogenating agent in a reaction solvent to give a compound of the
formula [II-a] 8
[0026] wherein X is chlorine atom, bromine atom or iodine atom and
R.sup.1a is alkanoyl having 2 to 5 carbon atoms (hereinafter to be
also referred to as compound [II-a]). This reaction is preferably
carried out in the presence of a base. As used herein, X is
preferably bromine atom in consideration of conversion of the
compound of the formula [I-b] to a lithium compound or a Grignard
reagent in the later step and R.sup.1a is particularly preferably
acetyl in view of the easiness of synthesis and deprotection. The
alkanoyl group is eliminated by adding the obtained compound [II-a]
or a solution of compound [II-a] in an organic solvent, to an
aqueous solution of an acid or base, preferably an acidic aqueous
solution, to allow hydrolysis.
[0027] The starting compound [A] is preferably m-xylylene glycol
diacetate, m-xylylene glycol dipropionate or m-xylylene glycol
dipivalate.
[0028] The reaction solvent to be used for chlorination,
bromination and iodination is, for example, glacial acetic acid,
aqueous acetic acid solution (concentration:60-100 wt %, preferably
80-100 wt %), water, monochlorobenzene, o-dichlorobenzene, ethyl
acetate, tert-butyl methyl ether, and methanol, ethanol, isopropyl
alcohol, acetone etc., that may contain water, with preference
given to glacial acetic acid, aqueous acetic acid solution,
methanol, o-dichlorobenzene and ethyl acetate. The reaction solvent
is used in an amount of generally 1 L-20 L, preferably 3 L-10 L,
per 1 kg of compound [A].
[0029] The base to be used for chlorination, bromination and
iodination is sodium acetate, potassium acetate, sodium hydroxide,
potassium hydroxide, sodium carbonate, potassium carbonate, sodium
methoxide, sodium ethoxide and the like, preferably sodium acetate,
potassium acetate, sodium hydroxide, potassium hydroxide, sodium
carbonate and potassium carbonate. The base is used in an amount of
generally 0.1 equivalent-10 equivalents, preferably 0.8
equivalent-6 equivalents, per the amount of compound [A].
[0030] The halogenating agent to be used for chlorination,
bromination and iodination is bromine, chlorine,
N-bromosuccinimide, N-chlorosuccinimide, sulfuryl chloride and the
like, preferably bromine and N-bromosuccinimide. The halogenating
agent is used in an amount of generally 0.8 mol-8 mol, preferably 2
mol-6 mol, per 1 mol of compound [A].
[0031] For chlorination and bromination, a catalyst may be added to
accelerate the reaction. The catalyst may be a single metal such as
iron, copper, zinc, aluminum and the like; or a metal halide such
as iron(I) chloride, iron(II) chloride, aluminum chloride, aluminum
bromide, copper(I) chloride, copper(II) chloride, magnesium
chloride, magnesium bromide, magnesium iodide, titanium
tetrachloride, zinc chloride, zinc bromide, zinc iodide and the
like, with preference given to iron, iron(I) chloride, iron(II)
chloride, magnesium chloride, magnesium bromide, zinc chloride,
zinc bromide and zinc iodide. The catalyst is used in an amount of
generally 0.0001 mol-0.5 mol, preferably 0.001 mol-0.2 mol, per 1
mol of compound [A].
[0032] The reaction temperature of chlorination, bromination and
iodination is generally from -30.degree. C. to 80.degree. C.,
preferably from 0.degree. C. to 50.degree. C., and the reaction
time is generally 30 min-24 hr, preferably 2 hr-18 hr.
[0033] When compound [A] is subjected to chlorination, bromination
or iodination, a 2,6-disubstituted compound may be produced as a
halide, besides the compound [II-a] which is a 2,4-disubstituted
compound. Such halide is isolated by, for example, pouring the
reaction mixture to a reducing aqueous solution (e.g., aqueous
sodium sulfite solution and aqueous sodium thiosulfate solution
etc.) under ice-cooling, or pouring a reducing aqueous solution
into the reaction mixture, adding an organic solvent, extraction
and evaporation of the solvent. The compound [II-a] can be isolated
from the mixture of halide by silica gel column chromatography,
recrystallization and the like. The compound [II-a] may or may not
be isolated from the mixture of halide. When the compounds are
subjected to the next step without isolation, the corresponding
2,6-disubstituted compound, such as 2,6-disubstituted compound of
compound [I] and 2,6-disubstituted compound of the compound of the
formula [II-b] to be mentioned later, is obtained in each step
together with the reaction product.
[0034] The amount of water to be used for elimination of the
alkanoyl group is generally 0.5 L-20 L, preferably 3 L-10 L, per 1
kg of halide (mixture when halide is a mixture). A solvent inert to
the reaction may be concurrently used, such as alcohol solvent
(e.g., methanol, ethanol etc.), tetrahydrofuran (THF), dioxane and
the like, which may be used to dissolve halide. When the solvent is
used for dissolution of halide, it is used in an amount of
generally 0.5 L-20 L, preferably 2 L-10 L, per 1 kg of halide
(mixture when halide is a mixture).
[0035] The acid to be used for the elimination of the alkanoyl
group is not particularly limited as long as it is typically used
for this purpose. Examples thereof include inorganic acid such as
hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric
acid, phosphoric acid and the like; organic acid such as formic
acid, acetic acid, propionic acid, trifluoroacetic acid,
methanesulfonic acid, trifluoromethanesulfoni- c acid and the like;
and the like, with preference given to hydrochloric acid,
hydrobromic acid and sulfuric acid. The amount of the acid to be
used is generally 0.001 kg-10 kg, preferably 0.01 kg-0.3 kg, per 1
kg of halide (mixture when halide is a mixture).
[0036] The base to be used for the elimination of the alkanoyl
group is not particularly limited as long as it is typically used
for this purpose. Examples thereof include inorganic base such as
hydroxide, carbonate or hydrogencarbonate of alkali metal (e.g.,
lithium, sodium, potassium etc.) or alkaline earth metal (e.g.,
calcium, magnesium etc.) and alkoxide (e.g., methoxide, ethoxide
etc.) of alkali metal, and organic base such as trialkylamine
(e.g., trimethylamine, triethylamine etc.), with preference given
to sodium hydroxide, potassium hydroxide, potassium carbonate and
sodium methoxide. The amount of the base to be used is generally
0.8 equivalent-10 equivalents, preferably 1 equivalent-5
equivalents, per halide (mixture when halide is a mixture).
[0037] The reaction temperature of the elimination of the alkanoyl
group is generally from -20.degree. C. to 100.degree. C.,
preferably from 10.degree. C. to 80.degree. C., and the reaction
time is generally 10 min-24 hr, preferably 30 min-8 hr.
[0038] The compound [I] is isolated by a conventional method, such
as crystallization after neutralization of the reaction
mixture.
[0039] Production Method of Compound [II']
[0040] A compound of the formula [II'] 9
[0041] wherein R.sup.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 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 referred to as compound [II']), consists of compound [II-a] and
a compound of the formula [II-b] 10
[0042] wherein R.sup.1b is 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
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 referred to as compound [II-b]). A compound
wherein only 1-ethoxyethyl is excluded from the substituents at
R.sup.1' of compound [II'] corresponds to novel compound [II]. The
compound [II'] can be obtained by
[0043] (a) converting the hydroxyl group of compound [I] to alkoxy
having 1 to 5 carbon atoms, tetrahydropyran-2-yloxy, alkoxyethoxy
wherein the alkoxyl moiety has 1 to 5 carbon atoms, 1-alkoxyethoxy
wherein the alkoxyl moiety has 1 to 10 carbon atoms or
trialkylsilyloxy wherein each alkyl moiety has 1 to 5 carbon atoms,
or by
[0044] (b) subjecting compound [A] to chlorination, bromination or
iodination.
[0045] The step (a) is explained in the following. By (a), compound
[II-b] can be obtained. The hydroxyl group can be converted to each
group by any method generally used for converting hydroxyl group to
such group. It is converted to 1-alkoxyethoxy by, for example,
reacting compound [I] with alkyl vinyl ether of the formula:
R.sup.3CH.dbd.CH.sub.2 wherein R.sup.3 is alkoxy having 1 to 10
carbon atoms, in a reaction solvent in the presence of a
catalyst.
[0046] The starting compound [I] is preferably
2,4-bis(hydroxymethyl)bromo- benzene in consideration of conversion
to a lithium compound or a Grignard reagent of the compound [III]
in the later step.
[0047] The alkoxy having 1 to 10 carbon atoms at R.sup.3 of the
above formula corresponds to alkoxy of 1-alkoxyethyl at the
substituent R.sup.1' in compound [II'], wherein the alkoxyl moiety
has 1 to 10 carbon atoms. The alkyl vinyl ether to be used for the
reaction is, for example, methyl vinyl ether, ethyl vinyl ether,
propyl vinyl ether, isopropyl vinyl ether, butyl vinyl ether,
pentyl vinyl ether, cyclohexyl vinyl ether, hexyl vinyl ether,
heptyl vinyl ether, octyl vinyl ether, nonyl vinyl ether, decyl
vinyl ether and the like, preferably ethyl vinyl ether, propyl
vinyl ether, butyl vinyl ether or cyclohexyl vinyl ether. The
amount of the alkyl vinyl ether to be used is generally 2 mol-4
mol, preferably 2 mol-3 mol, per 1 mol of compound [I].
[0048] As the catalyst, for example, p-toluenesulfonic acid,
methanesulfonic acid, sulfuric acid, hydrochloric acid,
trifluoroacetic acid, trifluoromethanesulfonic acid, and an acidic
ion exchange resin such as Amberlyst 15E, Amberlite IR-118 etc. are
used, with preference given to p-toluenesulfonic acid,
methanesulfonic acid, sulfuric acid and hydrochloric acid. These
catalysts can be also used in the form of a hydrate. The amount of
the catalyst to be used is generally 0.0001 mol-0.2 mol, preferably
0.0005 mol-0.01 mol, per 1 mol of compound [I].
[0049] The reaction solvent may be, for example, toluene, xylene,
monochlorobenzene, methylene chloride, acetone, methyl ethyl
ketone, methyl isobutyl ketone, ethyl acetate and the like, with
preference given to toluene, xylene, monochlorobenzene and
methylene chloride. The amount of the reaction solvent to be used
is generally IL-20 L, preferably 2 L-12 L, per 1 kg of compound
[I].
[0050] The reaction temperature is generally from -20.degree. C. to
120.degree. C., preferably from 0.degree. C. to 60.degree. C., and
the reaction time is generally 10 min-10 hr, preferably 30 min-6
hr. The objective compound can be isolated by a conventional method
(e.g., extraction, etc.).
[0051] Conversion to a group other than 1-alkoxyethoxy is performed
according to a conventional method. For the conversion to alkoxy,
for example, a reagent such as R.sup.4OH wherein R.sup.4 is alkyl
having 1 to 5 carbon atoms, R.sup.4Br wherein R.sup.4 is as defined
above, R.sup.4I wherein R.sup.4 is as defined above, and
(R.sup.4).sub.2SO.sub.4 wherein R.sup.4 is as defined above is
used; for the conversion to tetrahydropyran-2-yloxy, for example, a
reagent such as 3,4-dihydro-2[H]-pyran is used; for the conversion
to alkoxymethoxy, for example, a reagent, such as
R.sup.5OCH.sub.2OH wherein R.sup.5 is alkyl having 1 to 5 carbon
atoms, R.sup.5OCH.sub.2OR.sup.5 wherein R.sup.5 is as defined
above, R.sup.5OCH.sub.2Cl wherein R.sup.5 is as defined above and
R.sup.5OCH.sub.2Br wherein R.sup.5 is as defined above is used; and
for the conversion to trialkylsilyloxy, for example, a reagent,
such as (R.sup.6).sub.3SiCl wherein R.sup.6 is alkyl having 1 to 5
carbon atoms, is used. The definition of the above R.sup.4-R.sup.6
is the same as in the corresponding R.sup.1'.
[0052] Then, compound [II-a] can be obtained by (b). The
chlorination, bromination and iodination of compound [A] in (b) are
carried out in the same manner as in those for the production of
compound [I]. Bromination is preferably carried out in
consideration of conversion of the compound [II-b] to a lithium
compound or a Grignard reagent in the later step.
[0053] The compound [II-b] can be also obtained by a method other
than the above-mentioned (a). For example, a compound [II-b]
wherein R.sup.1b is alkyl having 1 to 5 carbon atoms can be
obtained by
[0054] Step 1: m-xylylene dichloride is reacted with an alkali
metal alkoxide of the formula R'OM, wherein R' is alkyl having 1 to
5 carbon atoms and M is alkali metal, in a reaction solvent to give
1,3-bis(alkoxymethyl)benzene, and
[0055] Step 2: the resulting compound is subjected to chlorination,
bromination or iodination.
[0056] Step 1 is explained in detail in the following. In this
step, alkali metal alkoxide is added to m-xylylene dichloride in a
reaction solvent to give 1,3-bis(alkoxymethyl)benzene.
[0057] The reaction solvent in Step 1 is exemplified by alcohol
solvent (e.g., methanol, ethanol, isopropyl alcohol, tert-butyl
alcohol etc.), tetrahydrofuran (THF), tert-butyl methyl ether,
toluene, monochlorobenzene, N,N-dimethylformamide, dimethyl
sulfoxide and the like. The amount of the solvent to be used is
generally 1 L-30 L, preferably 2 L-15 L, per 1 kg of m-xylylene
dichloride.
[0058] The alkyl moiety of the alkali metal alkoxide in Step 1 is
the same as those exemplified for the alkyl at R.sup.1b and
examples of alkali metal include sodium, potassium and the like.
Preferable examples of alkali metal alkoxide include sodium
methoxide and potassium tert-butoxide. The amount of the alkali
metal alkoxide to be used is generally 1.8 mol-4 mol, preferably 2
mol-3.2 mol, per 1 mol of m-xylylene dichloride.
[0059] The reaction temperature in Step 1 is generally from
-30.degree. C. to 100.degree. C., preferably 20.degree.
C.-70.degree. C., and the reaction time is generally 0.5 hr-10 hr,
preferably 1 hr-6 hr.
[0060] The isolation of 1,3-bis(alkoxymethyl)benzene can be carried
out by a conventional method, such as extraction and drying after
evaporation of the solvent.
[0061] Step 2 can be carried out in the same manner as in
chlorination, bromination, iodination in the production method of
compound [I] and under the same reaction conditions. The reaction
solvent, base, halogenating agent and catalyst to be used for the
chlorination, bromination and iodination are the same as those
exemplified for the production method of compound [I], wherein they
are used in the same amounts as in the production method of
compound [I]. The reaction product can be isolated in the same
manner as in the production method of compound [I].
[0062] Production Method of Compound [III]
[0063] A novel compound [III] can be obtained by
[0064] (a) converting compound [II-b] to Grignard reagent or
lithium compound,
[0065] (b) coupling the resulting compound with
p-fluorobenzaldehyde and
[0066] (c) subjecting the obtained coupling compound to
deprotection of R.sup.1b and cyclization.
[0067] The compound [II-b] is compound [I], wherein hydroxyl group
has been protected, which is, after conversion to a lithium
compound or a Grignard reagent, reacted with p-fluorobenzaldehyde.
Therefore, X in the compound [II-b] is free of any particular
limitation as long as compound [II-b] can be converted to a lithium
compound or a Grignard reagent. Preferred is bromine atom in view
of the quick conversion and the stability of the lithium compound
or Grignard reagent after conversion. For easy deprotection,
tetrahydropyran-2-yl, alkoxymethyl, where alkoxy has 1 to 5 carbon
atoms, 1-alkoxyethyl, where alkoxy has 1 to 10 carbon atoms, and
trialkylsilyl, where each alkyl has 1 to 5 carbon atoms, are
preferable as R.sup.1b, with more preference given to
tetrahydropyran-2-yl, methoxymethyl and 1-alkoxyethyl, where alkoxy
has 1 to 10 carbon atoms, particularly preferably 1-ethoxyethyl,
1-propoxyethyl, 1-butoxyethyl and 1-cyclohexyloxyethyl. From the
easiness of synthesis, methyl and tert-butyl are particularly
preferable.
[0068] As compound [II-b], preferred are 2,4-bis(1'-ethoxy
ethoxymethyl)bromobenzene,
2,4-bis(1'-butoxyethoxymethyl)-bromobenzene and
2,4-bis(1'-cyclohexyloxyethoxymethyl)bromobenzene.
[0069] The above-mentioned (a) to (c) are explained in this order
in the following.
[0070] (a): The compound [II-b] can be converted to a Grignard
reagent or a lithium compound by a method conventionally known,
which is used for obtaining a Grignard reagent or a lithium
compound from halide. For example, compound [II-b] is reacted with
metal magnesium in an organic solvent, or a solution of an organic
lithium compound in an organic solvent, and may be added dropwise
to compound [II-b]. The metal magnesium or organic lithium compound
is added in an amount generally necessary for converting a halide
to a Grignard reagent or a lithium compound. For example, metal
magnesium is added in an amount of generally 0.9 mol-3 mol,
preferably 1 mol-1.5 mol, and the organic lithium compound is added
in an amount of generally 0.9 mol-1.5 mol, preferably 1 mol-1.3
mol, both per 1 mol of compound [II-b]. Examples of the organic
lithium compound include n-butyl lithium, phenyl lithium, methyl
lithium, sec-butyl lithium and tert-butyl lithium, preferably
n-butyl lithium and methyl lithium. For the easiness of the
operation and the yield of the reaction, compound [II-b] is
preferably converted to a lithium compound.
[0071] The organic solvent is exemplified by ether solvents (e.g.,
tetrahydrofuran (THF), tert-butyl methyl ether, dimethoxyethane,
dibutyl ether, ethyl ether etc.), hexane, heptane, toluene, xylene
and the like, with preference given to hexane, THF, tert-butyl
methyl ether and dimethoxyethane. The amount of the organic solvent
to be used is generally 1 L-30 L, preferably 5 L-20 L, per 1 kg of
compound [II-b].
[0072] The reaction temperature in (a) is generally from
-78.degree. C. to 30.degree. C., preferably from -50.degree. C. to
-10.degree. C., and the reaction time is generally 10 min-6 hr,
preferably 10 min-2 hr. The reaction mixture obtained in (a) can be
isolated or purified by a conventional method. Alternatively, it
may be subjected to the next reaction as it is obtained.
[0073] (b): p-Fluorobenzaldehyde is added dropwise to the reaction
mixture of (a) for coupling reaction. The amount of
p-fluorobenzaldehyde to be used is generally 0.8 mol-3 mol,
preferably 1 mol-1.5 mol, per 1 mol of compound [II-b].
p-Fluorobenzaldehyde can be added as a solution in an organic
solvent, wherein the organic solvent is free of any particular
limitation and exemplified by tetrahydrofuran, tert-butyl methyl
ether, dimethoxyethane, hexane, heptane and the like.
[0074] The reaction temperature in (b) is generally from
-78.degree. C. to 60.degree. C., preferably from -50.degree. C. to
30.degree. C., and the reaction time is generally 10 min-6 hr,
preferably 10 min-2 hr.
[0075] After the completion of the reaction, a basic aqueous
solution (e.g., aqueous ammonium chloride solution), an acidic
aqueous solution (e.g., aqueous acetic acid solution) and the like
are added to hydrolyze the reaction product. The coupling compound
after hydrolysis can be isolated by, for example, partitioning and
evaporation of the solvent.
[0076] (c): The isolated coupling compound is reacted with an acid
catalyst in a reaction solvent for the deprotection of R.sup.1b and
cyclization. The method of addition is not particularly limited.
For example, an acid catalyst may be added to the reaction mixture
of the coupling compound. The reaction is preferably carried out
under pressure of generally 2 kPa-110 kPa, preferably 5 kPa-80 kPa,
while removing deprotected aldehydes having a low boiling point,
thereby suppressing the occurrence of by-product.
[0077] The reaction solvent may be water alone, because the
reaction proceeds sufficiently. A suitable organic solvent may be
further added. The organic solvent to be added may be miscible with
water or non-miscible with water. Examples thereof include
methanol, ethanol, isopropyl alcohol, acetone, tetrahydrofuran,
toluene and xylene. The amount of the reaction solvent to be used
is generally 0.5 L-20 L, preferably 1 L-10 L, per 1 kg of compound
[II-b].
[0078] The acid catalyst may be a typical mineral acid, acidic ion
exchange resin and Lewis acid, preferably phosphoric acid, sulfuric
acid, hydrochloric acid, p-toluenesulfonic acid, methanesulfonic
acid, trifluoroacetic acid and trifluoromethanesulfonic acid. The
amount of the acid catalyst to be used is generally 0.1 mmol-30
mol, preferably 0.1 mol-20 mol, per 1 mol of compound [II-b]. The
acidic catalyst can be also used in the form of an aqueous
solution.
[0079] The reaction temperature in (c) is generally 30.degree.
C.-150.degree. C., preferably 50.degree. C.-100.degree. C., and the
reaction time is generally 10 min-20 hr, preferably 1 hr-6 hr.
[0080] The objective compound (compound [III]) can be isolated by a
conventional method (e.g., filtration, recrystallization etc.).
[0081] The compound [III] can be obtained via a Grignard reagent or
lithium compound of compound [II-b] and then through a coupling
compound of the formula 11
[0082] wherein R.sup.1 is as defined above.
[0083] Production Method of Compound [IV]
[0084] The novel compound [IV] can be obtained by oxidation of
compound [III]. The compound [III] has, as an easily oxidizable
moiety, the 1-position and 3-position carbons, besides
hydroxymethyl at the 5-position of the 1,3-dihydroisobenzofuran
ring. Therefore, oxidation of compound [III] may accompany
oxidation of the 1-position and 3-position carbons as a side
reaction. However, when compound [III] is oxidized with
hypochlorite in the presence of an N-oxy radical catalyst,
hydroxymethyl is selectively oxidized to give compound [IV] at a
high yield. To be specific, hypochlorite is added, preferably added
dropwise as an aqueous solution, to a solution of compound [III] in
an organic solvent in the presence of a base, a catalyst and an
N-oxy radical catalyst, to give compound [IV].
[0085] The hypochlorite to be used for the oxidation may be, for
example, sodium hypochlorite, potassium hypochlorite, calcium
hypochlorite and the like, preferably sodium hypochlorite. The
amount of the hypochlorite to be used is generally 0.8 mol-2 mol,
preferably 0.85 mol-1.3 mol, per 1 mol of compound [III]. Sodium
hypochlorite is preferably used in the form of an aqueous solution,
where the concentration of the aqueous solution is generally 8 wt
%-15 wt %, preferably 11 wt %-14 wt %.
[0086] The N-oxy radical catalyst to be used for the oxidation may
be, for example, 4-substituted-2,2,6,6-tetramethyl-1-piperidinoxy.
The amount of the catalyst to be used is generally 0.0001 mol-0.1
mol, preferably 0.0001 mol-0.01 mol, per 1 mol of compound [III].
Examples of the 4-position substituent include hydrogen atom,
hydroxyl group, alkoxy having 1 to 10 carbon atoms, acyloxy having
an aliphatic hydrocarbon residue having 1 to 10 carbon atoms,
carbonylamino having an aliphatic hydrocarbon residue having 1 to
10 carbon atoms and the like, particularly preferably hydroxyl
group from the viewpoint of the yield.
[0087] The alkoxy having 1 to 10 carbon atoms is preferably linear
or branched chain alkoxy having 1 to 5 carbon atoms, such as
methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,
sec-butoxy, tert-butoxy, pentoxy, isopentoxy, hexyloxy, heptyloxy,
octyloxy, nonyloxy and decyloxy, preferably methoxy, ethoxy and
isopropoxy.
[0088] The acyloxy having an aliphatic hydrocarbon residue having 1
to 10 carbon atoms is linear or branched chain acyloxy having an
aliphatic hydrocarbon residue preferably having 1 to 6 carbon
atoms, such as acetyloxy, propionyloxy, butyryloxy, isobutyryloxy,
valeryloxy, isovaleryloxy, pivaloyloxy, hexanoyloxy, heptanoyloxy,
octanoyloxy, nonanoyloxy, decanoyloxy, undecanoyloxy, acryloyloxy
and methacryloyloxy, preferably acetyloxy and methacryloyloxy.
[0089] The carbonylamino having an aliphatic hydrocarbon residue
having 1 to 10 carbon atoms is a linear or branched chain
carbonylamino that has aliphatic hydrocarbon residue preferably
having 1 to 6 carbon atoms, such as acetylamino, propionylamino,
butyrylamino, isobutyrylamino, valerylamino, isovalerylamino,
pivaloylamino, hexanoylamino, heptanoylamino, octanoylamino,
nonanoylamino, decanoylamino, undecanoylamino, acryloylamino and
methacryloylamino, preferably acetylamino.
[0090] Examples of 4-substituted-2,2,6,6-tetramethyl-1-piperidinoxy
preferably include 4-hydroxy-2,2,6,6-tetramethyl-1-piperidinoxy,
4-methacryloyloxy-2,2,6,6-tetramethyl-1-piperidinoxy,
4-acetyloxy-2,2,6,6-tetramethyl-1-piperidnoxy and
4-acetylamino-2,2,6,6-t- etramethyl-1-piperidinoxy, particularly
preferably 4-hydroxy-2,2,6,6-tetra- methyl-1-piperidinoxy from the
aspect of yield.
[0091] The base is free of any particular limitation as long as it
does not interfere with the reaction, and is exemplified by sodium
hydrogencarbonate, sodium carbonate, potassium hydrogencarbonate,
potassium carbonate, lithium carbonate and the like, with
preference given to sodium hydrogencarbonate and potassium
hydrogencarbonate. The amount of the base to be used is generally
0.01 mol-2 mol, preferably 0.1 mol-0.9 mol, per 1 mol of compound
[III].
[0092] Examples of the catalyst include phase transfer catalyst
such as tetrabutylammonium bromide, tetrabutylammonium chloride,
tetrabutylammonium iodide, tetrabutylammonium sulfate,
benzyltriethylammonium chloride, benzyltrimethylammonium chloride
and the like, and metal halide catalyst such as potassium iodide,
potassium bromide, sodium iodide, sodium bromide and the like, with
preference given to tetrabutylammonium bromide,
benzyltriethylammonium chloride, potassium iodide and potassium
bromide. The amount of the catalyst to be used is generally 0.0001
mol-0.3 mol, preferably 0.01 mol-0.2 mol, per 1 mol of compound
[III].
[0093] The organic solvent is not particularly limited and may be,
for example, ethyl acetate, butyl acetate, acetone, ethyl methyl
ketone, isobutyl methyl ketone, toluene, xylene, tert-butyl methyl
ether and the like, with preference given to ethyl acetate,
acetone, ethyl methyl ketone, isobutyl methyl ketone and toluene.
The amount of the solvent to be used is generally 1 L-20 L,
preferably 3 L-10 L, per 1 kg of compound [III].
[0094] The reaction temperature is generally from -30.degree. C. to
100.degree. C., preferably 0.degree. C.-50.degree. C., and the
reaction time is generally 10 min-10 hr, preferably 10 min-2
hr.
[0095] The objective compound can be isolated by a conventional
method such as extraction and crystallization.
[0096] Production Method of 5-phthalancarbonitrile Compound
[0097] The compound [VI] (5-phthalancarbonitrile compound) is an
intermediate for the production of citalopram. It can be obtained
by reacting a novel compound [IV] with hydroxylamine or a mineral
acid salt thereof and via a novel compound [V] (compound [V] in the
present invention includes both syn-compound and anti-compound),
namely, through oximation (condensation) and dehydration reaction.
It is preferable to (a) directly subject the compound [V] to
dehydration reaction without isolation to make the manipulation
simpler. For example, compound [IV] and hydroxylamine or a mineral
acid salt thereof are added to an organic solvent and the mixture
is heated as it is to give compound [VI].
[0098] For a higher purity of the compound [VI], (b) compound [V]
is preferably isolated and then subjected to dehydration reaction.
The compound [V] is obtained by reacting compound [IV] with
hydroxylamine or a mineral acid salt thereof. By dehydrating
compound [V], compound [VI] is obtained. To be specific, compound
[IV] and hydroxylamine or a mineral acid salt thereof are added to
an organic solvent, and the mixture is stirred to give compound
[V]. The obtained compound [V] is isolated and heated to give
compound [VI]. The compound [V] is isolated by a conventional
method.
[0099] Examples of mineral acid salt of hydroxylamine include salts
of hydroxylamine with hydrochloric acid, sulfuric acid, phosphoric
acid, nitric acid and the like, with preference given to
hydroxylamine hydrochloride and hydroxylamine sulfate.
[0100] The amount of the hydroxylamine or a mineral acid salt
thereof to be used is generally 0.8 equivalent-5 equivalents,
preferably 0.9 equivalent-2 equivalents, per compound [IV]. The
hydroxylamine and a mineral acid salt thereof are used as they are
or preferably in a solution state (e.g., methanol, ethanol,
isopropyl alcohol, water, etc.). Depending on the scale of the
reaction, it is particularly preferably added dropwise as a
solution of hydroxylamine or a mineral acid salt thereof in
methanol at 20-50.degree. C.
[0101] Particularly when a hydroxylamine mineral acid salt is used,
a suitable base is preferably added in an amount of 1 equivalent to
5 equivalents per hydroxylamine mineral acid salt. The base is free
of any particular limitation as long as it exerts less influence on
cyano, and examples thereof include organic base (e.g.,
triethylamine, tributylamine, dimethylaniline, pyridine, sodium
methoxide, sodium ethoxide, potassium t-butoxide, sodium t-butoxide
etc.), inorganic base (e.g., sodium carbonate, sodium
hydrogencarbonate, sodium hydroxide, potassium carbonate, potassium
hydrogencarbonate, potassium hydroxide etc.), with preference given
to triethylamine. It is industrially preferable to add a base
before the addition of a hydroxylamine mineral acid salt.
[0102] To carry out the dehydration reaction of compound [V] under
mild conditions, a dehydrating agent may be further added. Examples
of the dehydrating agent include acid anhydride (e.g., acetic
anhydride, phthalic anhydride etc.), methanesulfonyl chloride,
p-toluenesulfonyl chloride and the like, with preference given to
the use of acetic anhydride from the aspects of the environment and
yield. The amount of the dehydrating agent to be used is preferably
0.8 equivalent-5 equivalents, per hydroxylamine or a mineral acid
salt thereof in the case of above (a), and 1 equivalent-10
equivalents, preferably 1 equivalent-5 equivalents, per compound
[V] in the case of above (b). In the above (a), the dehydrating
agent may be added simultaneously with hydroxylamine or a mineral
acid salt thereof. However, the addition after the addition of
hydroxylamine or a mineral acid salt thereof is preferable.
[0103] The organic solvent is free of any particular limitation as
long as it does not interfere with the reaction, and examples
thereof include methanol, ethanol, isopropyl alcohol, ethyl
acetate, acetonitrile, toluene, xylene, chlorobenzene,
1,2-dichlorobenzene, N-methylpyrrolidone, nitroethane,
dimethylformamide, dimethylacetamide, dimethyl sulfoxide,
dichloromethane, and mixed solvents of the above, with preference
given to acetonitrile, toluene, xylene, N-methylpyrrolidone,
nitroethane, ethyl acetate, a mixed solvent of ethyl acetate and
methanol, a mixed solvent of ethyl acetate and ethanol, a mixed
solvent of ethyl acetate and isopropyl alcohol, and a mixed solvent
of toluene and methanol. The amount of the organic solvent to be
used is generally 0.5 L-50 L, preferably 1 L-20 L, per 1 kg of
compound [IV] in the case of above (a), and generally 0.5 L-50 L,
preferably 1 L-20 L, per 1 kg of compound [IV] in the case of above
(b).
[0104] The reaction temperature in the above (a) is generally
50.degree. C.-220.degree. C., preferably 80.degree. C.-150.degree.
C., and the reaction time is generally 1 hr-20 hr, preferably 2
hr-8 hr.
[0105] In the above (b), oximation (condensation) is conducted
generally at 20-120.degree. C., preferably 40-100.degree. C.,
generally for 10 min-4 hr, preferably 30 min-2 hr, and dehydration
reaction is carried out generally at 60-160.degree. C., preferably
120-150.degree. C., more preferably 125-150.degree. C., generally
for 30 min-8 hr, preferably 90 min-6 hr.
[0106] The objective compound is isolated by a conventional method
such as extraction and crystallization after neutralization of the
reaction mixture.
[0107] The starting compound [A] can be produced according to the
method described in, for example, J. Phys. Org. Chem., 3(12),
789-98 (1990).
[0108] According to the method of the present invention, a
5-phthalancarbonitrile compound can be produced without using a
reagent that imposes a great burden on the environment, such as
heavy metal, metal cyanide and thionyl chloride. Moreover, the
reaction proceeds efficiently throughout the entire steps.
[0109] The 5-phthalancarbonitrile compound can be converted to
citalopram according to the method described in WO98/19511, thereby
producing citalopram useful as an antidepressant.
[0110] The present invention is explained in detail by referring to
illustrative examples, but the present invention is not limited by
these examples in any way. In the examples, the unit % relative to
the reagent is wt %.
EXAMPLE 1
Synthesis of 2,4-bis(acetoxymethyl)bromobenzene
[0111] To a suspension of m-xylylene glycol diacetate (28.4 g) and
sodium acetate (55.2 g) dispersed in glacial acetic acid (130 ml)
was added dropwise bromine (102.5 g) over 30 min at 15-20.degree.
C., and the mixture was stirred at 20-30.degree. C. for 13 hr. The
reaction mixture was poured into 10% aqueous sodium sulfite
solution (700 ml) in an ice bath. The mixture was stirred and
extracted twice with ethyl acetate (250 ml). The ethyl acetate
layer was washed 3 times with 10% aqueous sodium hydrogencarbonate
solution (300 ml) and the solvent was evaporated to give an about
93:7 mixture (37.6 g, 97.6%) of 2,4-bis(acetoxymethyl)bromo-
benzene and 2,6-bis(acetoxymethyl)bromobenzene as a yellow oil.
2,4-bis(Acetoxymethyl)bromobenzene was isolated by preparative HPLC
and used in the measurement.
[0112] the mixture:
[0113] n.sub.D.sup.24 1.5310; IR(neat).nu.=2957(w), 1743(s),
1476(m), 1378(m), 1226(s), 1028(s), 858(w), 820(w)cm.sup.-1
[0114] 2,4-bis(Acetoxymethyl)bromobenzene:
[0115] .sup.1H-NMR(CDCl.sub.3, 400 MHz).delta.=2.11(3H,s),
2.15(3H,s), 5.07(2H,s), 5.19(2H,s), 7.19(1H,dd,J=8 Hz,J=2 Hz),
7.39(1H,d,J=2 Hz), 7.57(1H,d,J=8 Hz) ppm
EXAMPLE 2
Synthesis of 2,4-bis(hydroxymethyl)bromobenzene
[0116] An about 93:7 mixture (36.7 g) of
2,4-bis(acetoxymethyl)-bromobenze- ne and
2,6-bis(acetoxymethyl)bromobenzene was dissolved in methanol (183
ml) and cooled to 10.degree. C. To this solution was added dropwise
10% aqueous sodium hydroxide solution (133 g). The reaction mixture
was stirred at room temperature for 1 hr, and the solvent (about
200 ml) was evaporated. The residue was neutralized with dilute
hydrochloric acid (about 200 ml). To the neutralized solution was
added toluene (150 ml) and the mixture was stirred at 80-85.degree.
C. for 1 hr and cooled. The resulting crystals were collected by
filtration and dried under reduced pressure to give an about 93:7
mixture (22.2 g, 83.7%) of 2,4-bis(hydroxymethyl)bromobenzene and
2,6-bis(hydroxymethyl)-bromobenzen- e as almost white crystals.
2,4-bis(Hydroxymethyl)-bromobenzene was isolated by preparative
HPLC and used in the measurement.
[0117] mixture:
[0118] melting point 106-108.degree. C.; IR(KBr).nu.=3307(br),
1467(s), 1413(s), 1228(s), 1158(s), 1063(s), 1002(s), 824(s),
741(s), 641(s) cm.sup.-1
[0119] 2,4-bis(Hydroxymethyl)bromobenzene:
[0120] .sup.1H-NMR(DMSO-d.sub.6, 400 MHz).delta.=4.46(2H,d,J=5 Hz),
4.49(2H,d,J=5 Hz), 5.26(1H,t,J=5 Hz), 5.41(1H,t,J=5 Hz),
7.12(1H,dd,J=8 Hz,J=2 Hz), 7.48(1H,d,J=8 Hz), 7.50(1H,d,J=2 Hz)
ppm
EXAMPLE 3
Synthesis of 2,4-bis(1'-ethoxyethoxymethyl)bromobenzene
[0121] To a suspension obtained by dispersing an about 93:7 mixture
(22.1 g) of 2,4-bis(hydroxymethyl)bromobenzene and
2,6-bis(hydroxymethyl)bromob- enzene, and p-toluenesulfonic acid
monohydrate (0.1 g) in toluene (220 ml) was added dropwise ethyl
vinyl ether (18.4 g) at 24-32.degree. C., and the mixture was
stirred at room temperature for 2 hr. The reaction mixture was
poured into 5% aqueous sodium carbonate solution (100 ml), and the
organic layer was washed with 5% aqueous sodium carbonate solution
(100 ml), and dried over potassium carbonate. The solvent was
evaporated to give an about 93:7 mixture (35.7 g, 97.1%) of
2,4-bis(1'-ethoxyethoxymethyl)bromobenzene and
2,6-bis(1-ethoxyethoxymeth- yl)bromobenzene as a yellow oil.
2,4-bis(1-Ethoxyethoxymethyl)bromobenzene was isolated by
preparative HPLC and used in the measurement.
[0122] 2,4-bis(1'-Ethoxyethoxymethyl)bromobenzene:
[0123] .sup.1H-NMR(CDCl.sub.3, 400 MHz).delta.=1.22(3H,t,J=7 Hz),
1.23(3H,t,J=7 Hz), 1.36(3H,d,J=5 Hz), 1.41(3H,d,J=5 Hz),
3.48-3.59(2H,m), 3.63-3.75(2H,m), 4.49(1H,d,J=12 Hz),
4.58(1H,d,J=13 Hz), 4.61(1H,d,J=12 Hz), 4.69(1H,d,J=13 Hz),
4.81(1H,q,J=5 Hz), 4.88(1H,q,J=5 Hz), 7.14(1H,dd,J=8 Hz,J=2 Hz),
7.47(1H,d,J=2 Hz), 7.50(1H,d,J=8 Hz) ppm
EXAMPLE 4
Synthesis of 2,4-bis(methoxymethyl)bromobenzene
[0124] To a solution of m-xylylene dichloride (25.0 g) in methanol
(125 ml) was added a 28% methanol solution (82.6 g) containing
sodium methoxide at room temperature, and the mixture was stirred
with heating at 60.degree. C. for 3 hr. The solvent was evaporated
and water (150 ml) was added to the residue. The mixture was
extracted twice with heptane (80 ml) and heptane was evaporated
under reduced pressure to give m-xylylene glycol dimethyl ether
(25.3 g). m-Xylylene glycol dimethyl ether (25.3 g) was dissolved
in acetic acid (125 ml) and sodium acetate (68 g) was added, which
was followed by dropwise addition of bromine (68 g) at room
temperature. The mixture was stirred at room temperature for 3 hr
and poured into 10% aqueous sodium sulfite solution (750 ml), which
mixture was extracted twice with heptane (350 ml). The heptane
layer was extracted twice with 10% aqueous sodium hydroxide
solution (150 ml) and once with water (150 ml). The solvent was
evaporated and the residue was purified by silica gel column
chromatography using heptane-ethyl acetate (15:1) as an eluent to
give the title compound (10.4 g, yield:29.7%) as a colorless
transparent oil.
[0125] 2,4-bis(Methoxymethyl)bromobenzene:
[0126] .sup.1H-NMR(CDCl.sub.3, 400 MHz).delta.=3.38(3H,s),
3.53(3H,s), 4.42(2H,s), 4.52(2H,s), 7.13(1H,dd,J=8 Hz,J=2 Hz),
7.43(1H,d,J=2 Hz), 7.51(1H,d,J=8 Hz) ppm
EXAMPLE 5
Synthesis of
1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-ylmethanol
[0127] An about 93:7 mixture (34.7 g) of
2,4-bis(1'-ethoxyethoxymethyl)bro- mobenzene and
2,6-bis(1'-ethoxyethoxymethyl)bromobenzene was dissolved in
dehydrated tetrahydrofuran (250 ml) under a nitrogen atmosphere and
cooled to -40.degree. C. Thereto was added dropwise a hexane
solution (1.57 mol/L, 64.3 ml) of n-butyllithium at a temperature
of from -40.degree. C. to -30.degree. C. The mixture was heated to
-20.degree. C. and thereto was added dropwise p-fluorobenzaldehyde
(12.5 g). The mixture was allowed to warm to 15.degree. C. over 1
hr. The reaction mixture was poured into 20% aqueous ammonium
chloride solution (200 ml) and the organic layer was separated. The
aqueous layer was extracted with toluene (200 ml). The combined
organic layer was washed twice with 20% brine (250 ml) and the
solvent was evaporated. To the residue (38.5 g) was added 60%
phosphoric acid (300 g) and the resulting solution was stirred at
80-85.degree. C., 9.31-13.3 kPa (70-100 Torr) for 2 hr with heating
and cooled to 10.degree. C. The resulting crystals were collected
by filtration, washed thoroughly with ethanol and dried to give
1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-ylmethanol (20.8 g,
88.7%) as fine yellow crystals.
[0128] melting point 101-104.degree. C.; IR(KBr).nu.=3214(br),
2848(w), 1606(s), 1511(s), 1225(s), 1157(m), 1135(m), 1046(s),
1015(s), 824(s), 810(s), 783(m) cm.sup.-1; .sup.1H-NMR(CDC13, 400
MHz).delta.=4.72(2H,s), 5.19(1H,d,J=12 Hz), 5.31(1H,d,J=12 Hz),
6.14(1H,s), 6.98(1H,d,J=8 Hz), 7.03(2H,t,J=9 Hz), 7.24(1H,d,J=8
Hz), 7.29(2H,dd,J=9 Hz,J=6 Hz), 7.32(1H,s) ppm
EXAMPLE 6
Synthesis of
1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbaldehyde
[0129] 1-(4'-Fluorophenyl)-1,3-dihydroisobenzofuran-5-ylmethanol
(20.6 g) was dissolved in ethyl acetate (160 ml) and to the
obtained solution were added sodium hydrogencarbonate (2.9 g),
tetrabutylammonium bromide (1.6 g) and
4-hydroxy-2,2,6,6-tetramethyl-1-piperidinoxy (0.13 g). The mixture
was cooled to 5.degree. C. Thereto was added dropwise 12.9% aqueous
sodium hypochlorite solution (52.7 g) at 5-10.degree. C. and the
mixture was stirred for 1 hr. Water (100 ml) was added to the
reaction mixture and the mixture was extracted twice with ethyl
acetate (100 ml). The extract was washed with 5% aqueous sodium
hydrogencarbonate solution and saturated brine, and silica gel (3
g) was added. The mixture was filtered and the solvent was
evaporated to give 1-(4'-fluorophenyl)-1,3-dihydroiso-
benzofuran-5-carbaldehyde (17.2 g, 84.2%).
[0130] n.sub.D.sup.24 1.5823; IR(neat).nu.=3071(w), 2857(m),
2743(w), 1697(s), 1605(s), 1509(s), 1225(s), 1157(m), 1144(m),
1045(s), 832(s), 816(s), 786(m) cm.sup.-1; .sup.1H-NMR(CDCl.sub.3,
400 MHz).delta.=5.25(1H,d,J=13 Hz), 5.38(1H,d,J=13 Hz), 6.18(1H,s),
7.06(2H,t,J=9 Hz), 7.16(1H,d,J=8 Hz), 7.30(2H,d,J=9 Hz,J=5 Hz),
7.77(1H,d,J=8 Hz), 7.83(1H,s), 10.03(1H,s) ppm
EXAMPLE 7
Synthesis of
1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbaldehyde
oxime
[0131] 1-(4'-Fluorophenyl)-1,3-dihydroisobenzofuran-5-carbaldehyde
(5.96 g) was dissolved in toluene (30 ml) and triethylamine (2.75
g) was flown in. Thereto was added hydroxylamine hydrochloride
(1.88 g) and the mixture was reacted at 80-90.degree. C. for 1 hr.
Hot water (30 ml) was added to the reaction mixture and the mixture
was partitioned while hot at 90.degree. C. The organic layer was
cooled to 0-5.degree. C. and the resulting crystals were collected
by filtration to give the title compound (5.02 g, yield:79.2%).
[0132] melting point 158-159.degree. C.; .sup.1H-NMR(CDCl.sub.3,
400 MHz).delta.=5.19(1H,d,J=13 Hz), 5.32(1H,d,J=13 Hz), 6.14(1H,s),
7.01(1H,d,J=8 Hz), 7.04(2H,t,J=9 Hz), 7.29(2H,dd,J=9 Hz,J=5 Hz),
7.43(1H,d,J=8 Hz), 7.53(1H,s), 7.82(1H,br), 8.16(1H,s) ppm
EXAMPLE 8
Synthesis of
1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile
[0133] 1-(4'-Fluorophenyl)-1,3-dihydroisobenzofuran-5-carbaldehyde
(17.00 g) was dissolved in toluene (200 ml) and hydroxylamine
hydrochloride (5.5 g) and triethylamine (8.0 g) were added. The
mixture was stirred at 80-100.degree. C. for 2 hr. The obtained
triethylamine hydrochloride was filtered and the solvent was
evaporated. Thereto was added acetic anhydride (36.5 g) and the
mixture was stirred at 125-130.degree. C. for 5 hr. The reaction
mixture was poured into 10% aqueous sodium hydroxide solution (300
ml) and extracted twice with toluene (200 ml). The toluene layer
was washed successively with 5% aqueous sodium hydroxide solution,
water and saturated brine and dried over magnesium sulfate. Silica
gel (5 g) was added and the mixture was thoroughly stirred and
filtered. The solvent was evaporated to give crude
1-(4'-fluorophenyl)-1,3-dihydroisobe- nzofuran-5-carbonitrile (14.2
g). This was recrystallized from a mixed solvent of ethanol/hexane
to give 1-(4,-fluorophenyl)-1,3-dihydroisobenzo-
furan-5-carbonitrile (9.52 g, 59.8%).
[0134] melting point 96-98.degree. C.; IR(KBr).nu.=3050(w),
2867(m), 2228(s), 1603(s), 1510(s), 1224(s), 1157(m), 1048(s),
1031(s), 832(s) cm.sup.-1; .sup.1H-NMR(CDC13, 400
MHz).delta.=5.21(1H,d,J=13 Hz), 5.34(1H,d,J=13 Hz), 6.16(1H,s),
7.06(2H,t,J=9 Hz), 7.10(1H,d,J=8 Hz), 7.27(2H,dd,J=9 Hz,J=5 Hz),
7.55(1H,d,J=8 Hz), 7.60(1H,s) ppm
REFERENCE EXAMPLE 1
Synthesis of m-xylylene Glycol Diacetate
[0135] m-Xylylene dichloride (25.0 g, 143 mmol) and potassium
acetate (34.0 g, 171 mmol) were suspended in acetone (125 ml). To
the suspension was added benzyltriethylammonium chloride (4.8 g)
and the mixture was refluxed for 2.5 hr. The reaction mixture was
cooled and filtered. The solvent was evaporated and toluene (50 ml)
was added. The toluene layer was washed with water (50 ml) and
saturated brine (50 ml) and the solvent was evaporated to give
m-xylylene glycol diacetate (31.3 g, 98.7%) as an oil.
REFERENCE EXAMPLE 2
Synthesis of
1-(3'-dimethylaminopropyl)-1-(4'-fluorophenyl)-1,3-dihydroiso-
benzofuran-5-carbonitrile (citalopram)
[0136] 60% Sodium hydride (0.92 g) was dispersed in THF (30 ml). To
the obtained suspension was added dropwise a solution of
1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (4.80
g) in THF (10 ml) at 40-50.degree. C. The mixture was stirred at
the same temperature for 30 min, and a solution of
3-dimethylaminopropyl chloride (3.2 g) in toluene (20 ml) was added
dropwise, which was followed by stirring for 10 min. Then, dimethyl
sulfoxide (30 ml) was further added dropwise and the mixture was
stirred at 65-70.degree. C. for 3 hr. The reaction mixture was
poured into ice water (200 ml) and extracted 3 times with toluene
(60 ml). The organic layer was extracted twice with 20% aqueous
acetic acid (60 ml). The aqueous layer was neutralized, extracted
twice with toluene (60 ml) and washed with water. Anhydrous
potassium carbonate (2 g) and silica gel (2 g) were added and the
mixture was stirred and filtered. The solvent was evaporated to
give
1-(3'-dimethylaminopropyl)-1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-
-carbonitrile (citalopram base) as a viscous oil (3.37 g,
51.6%).
[0137] This oil was converted to hydrobromide by a conventional
method. The melting point of the obtained crystals was
184-186.degree. C.
[0138] .sup.1H-NMR(CDCl.sub.3, 400 MHz).delta.=1.26-1.52(2H,m),
2.11-2.26(4H,m), 2.13(6H,s), 5.15(1H,d,J=13 Hz), 5.19(1H,d,J=13
Hz), 7.00(2H,t,J=9 Hz), 7.41(1H,d,J=8 Hz), 7.43(2H,dd,J=9 Hz,J=5
Hz), 7.50(1H,s), 7.59(1H,d,J=8 Hz) ppm
[0139] According to the present invention, an industrially
advantageous production method capable of producing a
5-phthalancarbonitrile compound at a high yield can be provided
without using a reagent that imposes a great burden on the
environment (with small environmental burden), such as heavy metal,
metal cyanide and thionyl chloride. From the obtained
5-phthalancarbonitrile compound, citalopram useful as an
antidepressant can be provided.
[0140] This application is based on a patent application No.
311703/1999 filed in Japan, the contents of which are hereby
incorporated by reference.
* * * * *