JP2006008617A - Method for producing 5-phthalancarbonitrile compound, its intermediate and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a safe and easy method for producing a 5-phthalancarbonitrile compound applying little load on the environment and provide an intermediate and its production method. <P>SOLUTION: A 5-phthalancarbonitrile compound useful as an intermediate for citalopram is produced by using a new compound expressed by formula [II] as a key intermediate. In the formula, X<SP>1</SP>and X<SP>2</SP>are each independently chlorine atom, bromine atom or iodine atom. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a method for producing a 5-phthalanecarbonitrile compound that is useful as an intermediate of citalopram, which is an antidepressant, its intermediate, and a method for producing the same. Specifically, the present invention relates to a novel method for producing a 5-phthalanecarbonitrile compound via a compound represented by the formula [I] described later.

  Formula [V]

The 5-phthalancarbonitrile compound represented by formula [VI]

It is a compound useful as a synthetic intermediate of citalopram, which is an antidepressant represented by As a method for producing a 5-phthalanecarbonitrile compound, a method as shown in the following scheme is known (see Patent Document 1).

(In the formula, R represents a cyano group, an alkyloxycarbonyl group having 2 to 6 carbon atoms, or an alkylaminocarbonyl group having 2 to 6 carbon atoms, and Hal represents a halogen atom.)

  In this method, when R is other than a cyano group, it is necessary to perform cyanation after the reduction and ring-closing reaction. For example, when R is an alkyloxycarbonyl group, cyanation is carried out in three steps of hydrolysis, amidation, and reaction with chlorosulfonyl isocyanate, and when R is an alkylaminocarbonyl group, Cyanation is carried out by reaction with thionyl or phosphorus pentachloride. In these methods, environmentally undesirable reagents such as chlorosulfonyl isocyanate, thionyl chloride and phosphorus pentachloride are used, and when R is an alkyloxycarbonyl group, cyanation is performed in 3 steps. It is not a simple method.

  When R is a cyano group, there is a point to be improved in the process for producing 5-cyanophthalide as a starting material. That is, it is known that 5-cyanophthalide is obtained by allowing potassium cyanide to act on a diazonium salt derived from 5-aminophthalide in the presence of copper sulfate (see Non-Patent Document 1). In this reaction, potassium cyanide or copper sulfate is used, which is not a preferable method in terms of using poisonous substances or heavy metal salts. In addition, when synthesizing 5-aminophthalide, it is necessary to perform a dangerous reaction of nitration of phthalimide (see Non-Patent Document 2). Further, reduction to an amino group with tin chloride and half reduction reaction of phthalimide with zinc ( Non-Patent Document 3) is necessary, and it is not industrially preferable from the viewpoint of generating waste heavy metals.

  Further, in Patent Document 2, the formula [B]

(Wherein R ² represents an alkanoyl group having 2 to 5 carbon atoms)
And a compound represented by the formula [II-b]

Wherein R ^1b is an alkyl group having 1 to 5 carbon atoms, a tetrahydropyran-2-yl group, an alkoxymethyl group having 1 to 5 carbon atoms in the alkoxyl group, and an alkoxyl group having 1 to 10 carbon atoms. A 1-alkoxyethyl group or a trialkylsilyl group in which each alkyl group has 1 to 5 carbon atoms, and X represents a chlorine atom, a bromine atom or an iodine atom)

A method for producing 5-phthalanecarbonitrile is disclosed by passing a compound represented by the formula:
WO98 / 19511 pamphlet JP 2001-121161 A Bull. Soc. Sci. Bretagne, 26, 1951, 35 Organinc Synthesis II, 459 J. et al. Chem. Soc. , 1931,867

  The production method of 5-phthalancarbonitrile disclosed in Patent Document 1 and Non-Patent Documents 1 to 3 using 5-cyanophthalide or the like as a starting material is an industrially preferable method by discharging toxic substances and heavy metals. I can't say that.

  In addition, the method for producing 5-phthalanecarbonitrile disclosed in Patent Document 2 is a safer and less environmental burden than the above-described production method using 5-cyanophthalide or the like as a starting material. There are industrially preferred methods.

However, in this method, in order to convert the compound of the formula [B] into the compound of the formula [II-b], it is necessary to substitute R ^1b after deprotecting R ² , so that the number of steps becomes long. For this reason, if this method can be improved and the number of processes can be reduced, it will become an industrially more preferable manufacturing method.

  An object of the present invention is to provide a 5-phthalanecarbonitrile compound production method, an intermediate thereof, and a production method thereof, which have a low environmental burden and are safe and simple.

  As a result of intensive studies on a method that can produce a 5-phthalanecarbonitrile compound that has a low environmental burden and is safe and simple, the present inventors have found that a compound represented by the following formula [A] (hereinafter also referred to as compound [A]). 5-phthalane useful as an intermediate of citalopram by passing through a novel compound represented by the following formula [II] (hereinafter also referred to as compound [II]) as a key intermediate It has been found that a carbonitrile compound (compound represented by the formula [V] described later) can be produced in a safe and low environmental load method without using thionyl chloride and in a short process, and Novel compounds represented by the formulas [I] and [III] that can be used in the method for producing a 5-phthalancarbonitrile compound of the present invention (hereinafter referred to as compound [I], respectively) [III] also referred to) and devised their preparation, and accomplished the present invention.

That is, the present invention is as follows.
(1) Formula [I]

(In formula, X < ¹ > and X < ² > represent a chlorine atom, a bromine atom, or an iodine atom each independently.)
A compound represented by
(2) The compound according to (1), wherein X ¹ is a chlorine atom and X ² is a bromine atom.
(3) Formula [II]

(In the formula, X ² represents a chlorine atom, a bromine atom or an iodine atom.)
A compound represented by
(4) The compound according to (3), wherein X ² is a bromine atom.
(5) Formula [III]

A compound represented by
(6) Formula [A]

(In the formula, X ¹ represents a chlorine atom, a bromine atom or an iodine atom.)
Wherein the compound represented by formula [I] is subjected to either chlorination, bromination or iodination

(In formula, X < ¹ > and X < ² > represent a chlorine atom, a bromine atom, or an iodine atom each independently.)
The manufacturing method of the compound represented by these.
(7) Formula [1]

(Wherein, X ¹ and X ² each independently represent a chlorine atom, a bromine atom or an iodine atom.)
Wherein the compound represented by formula [II] is reacted with t-butoxide

(In the formula, X ² represents a chlorine atom, a bromine atom or an iodine atom.)
The manufacturing method of the compound represented by these.
(8) Formula [II]

(In the formula, X ² represents a chlorine atom, a bromine atom or an iodine atom.)
Wherein the compound represented by formula (III) is converted into a Grignard reagent or a lithium compound, and (ii) is reacted with parafluorobenzaldehyde.

The manufacturing method of the compound represented by these.
(9) The production method according to any one of (6) to (8), wherein X ² is a bromine atom.
(10) Formula [III]

The compound represented by formula [IV] is subjected to a de-t-butylation reaction and a cyclization reaction.

The manufacturing method of the compound represented by these.
(11) The production method according to (10), wherein the de-t-butylation reaction and the cyclization reaction are acid-catalyzed reactions.
(12) Formula [A]

(In the formula, X ¹ represents a chlorine atom, a bromine atom or an iodine atom.)
A compound represented by the formula [I] is subjected to either chlorination, bromination or iodination.

(In formula, X < ¹ > and X < ² > represent a chlorine atom, a bromine atom, or an iodine atom each independently.)
A first step of synthesizing a compound represented by:
The compound represented by the formula [I] obtained in the first step is reacted with t-butoxide to obtain the formula [II].

(In the formula, X ² represents a chlorine atom, a bromine atom or an iodine atom.)
A second step of synthesizing a compound represented by:
The compound represented by the formula [II] obtained in the second step is converted into (i) a Grignard reagent or a lithium compound, and (ii) reacted with parafluorobenzaldehyde to obtain a compound of the formula [III].

A third step of synthesizing a compound represented by:
The compound represented by the formula [III] obtained in the third step is subjected to a de-t-butylation reaction and a cyclization reaction to give a formula [IV]

A fourth step of synthesizing a compound represented by:
The hydroxylmethyl group of the compound represented by the formula [IV] obtained in the fourth step is converted into a cyano group, and the formula [V]

And a fifth step of synthesizing a 5-phthalanecarbonitrile compound represented by formula (V): A method for producing a 5-phthalanecarbonitrile compound represented by the formula [V].
(13) The fifth step includes
An oxidation step of oxidizing the hydroxymethyl group of the compound represented by the formula [IV] into an aldehyde form,
An oximation step of reacting the aldehyde form with hydroxylamine or a mineral salt thereof to form an oxime form,
The oxime obtained in the oximation step as it is or without isolation, and then subjected to a dehydration reaction to form a carbonitrile compound, and the production according to (12) Method.

  According to the present invention, a high-yield, industrially advantageous 5-phthalan carbo which does not use an environment-intensive reagent such as heavy metal, metal cyanide, or thionyl chloride (low environmental load). A method for producing a nitrile compound can be provided. The 5-phthalanecarbonitrile compound thus obtained can provide citalopram useful as an antidepressant.

Hereinafter, the present invention will be described in detail.
Production Method of Compound [I] Novel compound [I] can be obtained by subjecting compound [A] to any one of chlorination, bromination and iodination, and this reaction is preferably carried out in the presence of a base. To do. Here, X ¹ in the compound [A] is any ^one of a chlorine atom, a bromine atom and an iodine atom. X ¹ is substituted with a t-butoxy group in a later step, and therefore may be any of these halogen atoms from the viewpoint of easiness of elimination, but from the viewpoint of using an inexpensive raw material, X ¹ is preferably a chlorine atom or a bromine atom. From the viewpoint of molecular weight, X ¹ is more preferably a chlorine atom.

The conversion from compound [A] to compound [I], chlorination, bromination or iodination, preferably bromination, is obtained by reacting compound [A] with a halogenating agent in a reaction solvent. Can do. Here, X ² is preferably a bromine atom in consideration of a later step (conversion to a lithium compound or a Grignard reagent).

  As reaction solvents used for chlorination, bromination and iodination, glacial acetic acid, aqueous acetic acid (concentration: 40 to 100% by weight, preferably 60 to 100% by weight), water, monochlorobenzene, orthodichlorobenzene, ethyl acetate , Tert-butyl methyl ether; which may contain water, methanol, ethanol, isopropyl alcohol, acetone, acetonitrile and the like are preferable, and glacial acetic acid, aqueous acetic acid solution, methanol, orthodichlorobenzene and ethyl acetate are preferable. The amount of the reaction solvent to be used is generally 1 L-20 L, preferably 3 L-10 L, per 1 kg of compound [A].

  Examples of the base used for chlorination, bromination and iodination include sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, preferably acetic acid. Examples thereof include sodium, potassium acetate, sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate. The amount of the base to be used is generally 0.1 equivalent to 10 equivalents, preferably 0.8 equivalent to 6 equivalents, relative to compound [A].

Examples of halogenating agents used for chlorination, bromination and iodination include bromine, chlorine, iodine, N-bromosuccinimide (N-bromosuccinimide), N-chlorosuccinimide, N-iodosuccinimide, And sulfuryl chloride. As described above, when the X ² from the point a bromine atom, among which bromine, N- although bromosuccinimide is preferred, the use of less expensive reagents, mass production of generation of waste From the viewpoint of applicability to bromine, bromine is more preferable.

  In addition, a catalyst may be added to accelerate the reaction when chlorination, bromination or iodination is performed. Examples of the catalyst include simple metals such as iron, copper, zinc, and aluminum; ferrous chloride, ferric chloride, aluminum chloride, aluminum bromide, cuprous chloride, cupric chloride, magnesium chloride, magnesium bromide , Magnesium iodide, titanium tetrachloride, zinc chloride, zinc bromide and zinc iodide. The amount of the catalyst to be used is generally 0.0001 mol to 0.5 mol, preferably 0.001 mol to 0.2 mol, per 1 mol of compound [A].

  The reaction temperature in chlorination, bromination and iodination is usually −30 ° C. to 80 ° C. However, from the viewpoint of industrial mass synthesis, it is preferably 10 ° C. to 50 ° C. in consideration of the cost required for cooling or heating. The reaction time is usually 30 minutes to 24 hours, preferably 2 hours to 18 hours. However, since it is not preferable in view of efficiency that the reaction takes a long time, it is preferable that the reaction temperature is 20 ° C. to 40 ° C. and the reaction time is 4 to 10 hours.

  It is considered that when compound [A] is subjected to chlorination, bromination or iodination, 2,6-di-substituted product is by-produced in addition to compound [I] which is 2,4-di-substituted product as a halide. In order to remove such by-products, for example, the reaction solution is poured into a reducing aqueous solution (for example, an aqueous sodium sulfite solution or an aqueous sodium thiosulfate solution) under ice-cooling, or the reducing aqueous solution is used as a reaction solution. Injecting, then adding an organic solvent thereto, extraction, and distilling off the solvent can be mentioned. If a by-product remains even after performing this operation, the target product can be isolated from the mixture by silica gel column chromatography, recrystallization or the like. This isolation operation using silica gel column chromatography, recrystallization, etc. may be carried out at this stage, but the reaction is continued as a mixture and the isolation operation is carried out at any stage until the final product is reached. Also good.

Production Method of Compound [II] Compound [II] can be obtained by reacting compound [I] with t-butoxide in t-butanol as a reaction solvent.

The usage-amount of t-butanol which is a reaction solvent is 1L-20L normally with respect to 1 kg of compound [I], Preferably, it is 3L-10L.
As a reagent used for the reaction with t-butoxide, t-butoxy potassium, t-butoxy sodium or the like is used. The amount of the t-butoxylation reagent to be used is generally 0.9 equivalent to 2.5 equivalents, preferably 1 equivalent to 1.6 equivalents, relative to compound [I].

  The reaction temperature in t-butoxylation is usually 40 ° C. to reflux temperature (85 ° C.), preferably 60 ° C. to 85 ° C. Moreover, reaction time is 1 to 24 hours normally, Preferably it is 2 to 10 hours.

  After completion of the reaction, a predetermined amount of water is added, t-butanol is distilled off, an organic solvent is added, an aqueous hydrochloric acid solution is added to neutralize, the organic layer is washed, and then the organic layer is decompressed. If it removes according to conditions, compound [II] will be obtained. The obtained compound [II] can be directly used in the next reaction without performing an isolation operation unless the raw material compound [I] contains the 2,6-di-substituted product that is a by-product of the previous reaction. Can be used. Alternatively, when a mixture of 2,6-di-substituted product that is a by-product of the previous reaction is used as a raw material, there is a by-product derived from the 2,6-di-substituted product. An isolation operation using silica gel column chromatography, recrystallization or the like is performed, or the reaction proceeds to the next reaction while containing a by-product derived from the 2,6-disubstituted product.

Production method of compound [III] Compound [III] is obtained by converting compound [II] obtained in the previous step into (i) a Grignard reagent or a lithium compound,
(Ii) It can be obtained by reacting it with parafluorobenzaldehyde.

The above (i) and (ii) will be described in order below.
Regarding (i), the method of converting the compound [II] into a Grignard reagent or a lithium reagent may be a conventionally known method for obtaining a Grignard reagent or a lithium compound from a halide. For example, a compound [II] is converted to a metal in an organic solvent. Magnesium may be allowed to act, or an organic solvent solution of an organolithium compound may be added dropwise. The metal magnesium or organolithium compound is usually added in an amount necessary to convert the halide into a Grignard reagent or lithium compound. For example, the metal magnesium is usually 0 per 1 mol of the compound [II]. 0.9 mol to 3 mol, preferably 1 mol to 1.5 mol may be added, and the organolithium compound is added in an amount of usually 0.9 mol to 1.5 mol, preferably 1 mol to 1.3 mol. . Examples of the organic lithium compound include n-butyl lithium, phenyl lithium, methyl lithium, sec-butyl lithium, and tert-butyl lithium, and preferably n-butyl lithium and methyl lithium. In addition, when compound [II] is converted to a Grignard reagent, iodine, 2-bromopropane, bromoethane, or the like may be added to activate metallic magnesium.

  Examples of the organic solvent include ether solvents (for example, tetrahydrofuran, tert-butyl methyl ether, dimethoxyethane, dibutyl ether, ethyl ether, etc.), hexane, heptane, toluene, xylene and the like, preferably hexane, tetrahydrofuran, tert -Butyl methyl ether, dimethoxyethane are mentioned. 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].

  The reaction temperature in (i) is usually −78 ° C. to 60 ° C., preferably 20 ° C. to 50 ° C., and the reaction time is usually 10 minutes to 6 hours, preferably 10 minutes to 2 hours. The reaction solution obtained in (i) can be isolated and purified by a conventional method, but may be subjected to the next reaction as it is.

  About (ii): Reaction can be performed by dripping parafluorobenzaldehyde to the reaction liquid of (i). The amount of the parafluorobenzaldehyde to be used is generally 0.8 mol-3 mol, preferably 1 mol-1.5 mol, per 1 mol of compound [II]. Parafluorobenzaldehyde may be added as an organic solvent solution, and the organic solvent at this time is not particularly limited, and examples thereof include tetrahydrofuran, tert-butyl methyl ether, dimethoxyethane, hexane, heptane and the like.

  The reaction temperature in (ii) is usually −78 ° C. to 60 ° C., preferably −10 ° C. to 30 ° C. The reaction time is usually 10 minutes to 6 hours, preferably 10 minutes to 2 hours.

  After completion of the reaction, the reaction product is hydrolyzed by adding a basic aqueous solution (for example, ammonium chloride aqueous solution) or an acidic aqueous solution (for example, acetic acid aqueous solution). The hydrolyzed compound can be isolated, for example, by liquid separation and distilling off the solvent.

Production Method of Compound [IV] Compound [IV] can be obtained by subjecting compound [III] to a de-t-butyl reaction and a cyclization reaction. The de-t-butyl reaction and the cyclization reaction may be sequentially performed in separate steps. For example, the de-t-butyl reaction and the subsequent cyclization reaction are performed almost simultaneously by reacting under acid catalyst conditions. Conveniently, the number of steps can be omitted.

  The addition method of the acid catalyst used for this acid catalyst reaction is not specifically limited, For example, what is necessary is just to add an acid catalyst to the reaction solvent solution of compound [III]. In addition, the reaction is usually performed at a temperature of 50 ° C. to boiling point, preferably 60 to 80 ° C., while removing 2-methylpropene derived from the t-butyl group eliminated by the acid-catalyzed reaction. This is more preferable in terms of suppressing the formation of by-products.

  As the reaction solvent, water alone can proceed sufficiently, and a suitable organic solvent may be added. The organic solvent to be added may be miscible with water or separated from water, and examples thereof include methanol, ethanol, isopropyl alcohol, n-butanol, acetone, tetrahydrofuran, toluene, and xylene. The amount of the reaction solvent to be used is generally 0.5 L to 20 L, preferably 1 L to 10 L, per 1 kg of compound [III].

  Examples of the acid catalyst include general mineral acids, acidic ion exchange resins, and Lewis acids. Preferably, phosphoric acid, sulfuric acid, hydrochloric acid, paratoluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfone. Examples include acids. The acid catalyst is generally 0.1 mmol-30 mol, preferably 0.1 mol-20 mol, per 1 mol of compound [III]. The acid catalyst can also be used in the form of an aqueous solution.

  Isolation of the target compound [IV] can be carried out by a usual method (for example, filtration, recrystallization, etc.).

Production Method of Compound [V] Compound [V] can be obtained by oxidizing compound [IV] to obtain an aldehyde form, and subjecting this aldehyde form to oximation and dehydration reactions. Hereinafter, the production method of compound [V] will be described separately in an oxidation step and an oximation and dehydration step.

In the oxidation step compound [IV], 1-position and 3-position carbons exist as an easily oxidizable site in addition to the hydroxymethyl group at the 5-position of the 1,3-dihydroisobenzofuran ring. For this reason, there is concern that oxidation of the 1st and 3rd carbons may occur as a side reaction due to the oxidation of the compound [IV]. However, for example, by oxidizing compound [IV] with hypochlorite in the presence of an N-oxyl radical catalyst, the hydroxymethyl group is selectively oxidized. Specifically, for example, hypochlorite is added to an organic solvent solution of compound [IV] in the presence of a base, a catalyst, and an N-oxyl radical catalyst, preferably by dropwise addition as an aqueous solution. An aldehyde form can be obtained.

  Examples of the hypochlorite used for the oxidation include sodium hypochlorite, potassium hypochlorite, calcium hypochlorite, and preferably sodium hypochlorite. The amount of the hypochlorite to be used is generally 0.8 mol to 2 mol, preferably 0.85 mol to 1.3 mol, per 1 mol of compound [IV]. Sodium hypochlorite is preferably used in the form of an aqueous solution, and the concentration of the aqueous solution is usually 8% to 15% by weight, preferably 11% to 14% by weight.

  As the N-oxyl radical catalyst used for the oxidation, 4-substituted-2,2,6,6-tetramethyl-1-piperidinyloxy can be exemplified, and the amount of the catalyst used can be determined according to the compound [ IV] It is usually 0.0001 mol to 0.1 mol, preferably 0.0001 mol to 0.01 mol, relative to 1 mol. Examples of the 4-position substituent include a hydrogen atom, a hydroxyl group, an alkoxyl group having 1 to 10 carbon atoms, an acyloxy group having an aliphatic hydrocarbon residue having 1 to 10 carbon atoms, and 1 to 10 carbon atoms. Examples thereof include a carbonylamino group having an aliphatic hydrocarbon residue, and a hydroxyl group is particularly preferred from the viewpoint of yield.

  The “alkoxyl group having 1 to 10 carbon atoms” is preferably a linear or branched alkoxyl group 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.

  The “acyloxy group having an aliphatic hydrocarbon residue having 1 to 10 carbon atoms” is preferably an acyloxy group having a linear or branched aliphatic hydrocarbon residue having 1 to 6 carbon atoms. For example, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy, hexanoyloxy, heptanoyloxy, octanoyloxy, nonanoyloxy, decanoyloxy, undecanoyloxy, acryloyloxy , Methacryloyloxy, preferably acetyloxy and methacryloyloxy.

  The “carbonylamino group having an aliphatic hydrocarbon residue having 1 to 10 carbon atoms” is preferably a carbonyl having a linear or branched aliphatic hydrocarbon residue having 1 to 6 carbon atoms. Amino groups such as acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino, isovalerylamino, pivaloylamino, hexanoylamino, heptanoylamino, octanoylamino, nonanoylamino, decanoylamino, undecanoyl Examples include amino, acryloylamino, and methacryloylamino, and preferably acetylamino.

  The 4-substituted-2,2,6,6-tetramethyl-1-piperidinyloxy is preferably 4-hydroxy-2,2,6,6-tetramethyl-1-piperidinyloxy, 4- Methacryloyloxy-2,2,6,6-tetramethyl-1-piperidinyloxy, 4-acetyloxy-2,2,6,6-tetramethyl-1-piperidinyloxy, 4-acetylamino-2 , 2,6,6-tetramethyl-1-piperidinyloxy, particularly preferably 4-hydroxy-2,2,6,6-tetramethyl-1-piperidinyl from the viewpoint of yield. Oxy is mentioned.

  The base is not particularly limited as long as it does not inhibit the reaction, and examples thereof include sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate, lithium carbonate and the like, preferably sodium hydrogen carbonate and potassium hydrogen carbonate. . The amount of the base to be used is generally 0.01 mol to 2 mol, preferably 0.1 mol to 0.9 mol, per 1 mol of compound [IV].

  Examples of the catalyst include phase transfer catalysts such as tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, tetrabutylammonium sulfate, benzyltriethylammonium chloride, benzyltrimethylammonium chloride, potassium iodide, potassium bromide, iodine Examples thereof include metal halide catalysts such as sodium iodide and sodium bromide, preferably tetrabutylammonium bromide, benzyltriethylammonium chloride, potassium iodide and potassium bromide. The amount of the catalyst to be used is generally 0.0001 mol to 0.3 mol, preferably 0.01 mol to 0.2 mol, per 1 mol of compound [IV].

  The organic solvent is not particularly limited, and examples thereof include ethyl acetate, butyl acetate, acetone, ethyl methyl ketone, isobutyl methyl ketone, toluene, xylene, tert-butyl methyl ether, and preferably ethyl acetate, acetone, ethyl methyl. Examples include ketones, isobutyl methyl ketone, and toluene. The amount of the solvent to be used is 1 L to 20 L, preferably 3 L to 10 L, per 1 kg of compound [IV].

  The reaction temperature is usually −30 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C., and the reaction time is usually 10 minutes to 10 hours, preferably 10 minutes to 2 hours.

  The target product can be isolated by conventional methods such as extraction and crystallization.

Oximation and dehydration step In this step, the aldehyde obtained in the previous step is reacted with hydroxylamine or a mineral salt thereof to oxime, and then subjected to a dehydration reaction to obtain the target compound [V].

  From the viewpoint of simplicity of operation, a) It is preferable to subject the oxime form directly to the dehydration reaction without isolation. For example, after adding the aldehyde form and hydroxylamine or its mineral acid salt in an organic solvent, heat it as it is. Can give compound [V].

  Further, from the viewpoint of improving the purity of the compound [V], it is preferable that the oxime body is isolated and then subjected to a dehydration reaction. The oxime form is obtained by reacting the aldehyde form with hydroxylamine or a mineral acid salt thereof, and the compound [V] can be produced by dehydrating the oxime form. Specifically, in an organic solvent, an aldehyde compound and hydroxylamine or a mineral acid salt thereof are added and then stirred to obtain an oxime compound, and the obtained oxime compound is isolated and heated to obtain a compound [V]. Can be obtained. Isolation of the oxime body can be performed by a conventional method.

  Examples of the hydroxylamine mineral salt include salts of hydroxylamine with hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid and the like, preferably hydroxylamine hydrochloride and hydroxylamine sulfate.

  The amount of hydroxylamine or its mineral acid salt used is usually 0.8 equivalents to 5 equivalents, preferably 0.9 equivalents to 2 equivalents, relative to the aldehyde form. Hydroxylamine or its mineral acid salt is used as it is, preferably as a solution (for example, methanol, ethanol, isopropyl alcohol, water, etc.). Although it depends on the reaction scale, it is particularly preferable to drop a methanol solution of hydroxylamine or its mineral acid salt at 20 to 50 ° C.

  In particular, when hydroxylamine mineral acid salt is used, it is preferable to add 1 to 5 equivalents of an appropriate base with respect to hydroxylamine mineral acid salt. The base is not particularly limited as long as it has little influence on the cyano group. For example, organic bases (for example, triethylamine, tributylamine, dimethylaniline, pyridine, sodium methoxide, sodium ethoxide, potassium t- Butoxide, sodium t-butoxide, etc.) and inorganic bases (for example, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, etc.), preferably triethylamine. It is industrially preferable to add the base before adding the hydroxylamine mineral salt.

  In order to perform the dehydration reaction of the oxime body under mild conditions, a dehydrating agent may be further acted on. As the dehydrating agent, for example, acid anhydrides (for example, acetic anhydride, phthalic anhydride, etc.), methanesulfonyl chloride, paratoluenesulfonyl chloride and the like can be used, and it is preferable to use acetic anhydride from the viewpoint of environment and yield. . In the case of a) above, the amount of the dehydrating agent used is preferably 0.8 to 5 equivalents relative to hydroxylamine or its mineral salt, and in the case of b) above, the amount used is usually 1 Equivalent to 10 equivalents, preferably 1 to 5 equivalents. In the above a), the dehydrating agent may be added at the same time as hydroxylamine or its mineral acid salt, but is preferably added after the addition of hydroxylamine or its mineral acid salt.

  The organic solvent is not particularly limited as long as it does not inhibit the reaction, and is methanol, ethanol, isopropyl alcohol, ethyl acetate, acetonitrile, toluene, xylene, chlorobenzene, 1,2-dichlorobenzene, N-methylpyrrolidone, nitroethane, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, dichloromethane and the like; and mixed solvents thereof, preferably acetonitrile, toluene, xylene, N-methylpyrrolidone, nitroethane, ethyl acetate, 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. In the case of a), the amount of the organic solvent used is usually 0.5 L to 50 L, preferably 1 L to 20 L, based on 1 kg of the aldehyde, and in the case of b), it is usually 0 per 1 kg of the oxime. .5L-50L, preferably 1L-20L.

  The reaction temperature in a) is usually 50 ° C. to 220 ° C., preferably 80 ° C. to 150 ° C., and the reaction time is usually 1 hour to 20 hours, preferably 2 hours to 8 hours.

  In the above b), the oximation is usually carried out at 20 ° C. to 120 ° C., preferably 40 ° C. to 100 ° C., usually 10 minutes to 4 hours, preferably 30 minutes to 2 hours, and the dehydration reaction is usually 60 ° C. to 160 ° C. The reaction is preferably performed at 120 ° C. to 150 ° C., more preferably 125 ° C. to 150 ° C., usually for 30 minutes to 8 hours, preferably 90 minutes to 6 hours.

  The target product can be isolated by, for example, conventional methods such as extraction and crystallization after neutralizing the reaction solution.

  Compound [A] as a starting material can be produced, for example, according to the chlorination of xylene, the method described in JP-B-63-79843, and can also be obtained as a commercial product.

  As described above, in the method of the present invention, a 5-phthalancarbonitrile compound can be produced without using a reagent having a heavy load on the environment such as heavy metals, metal cyanides, and thionyl chloride. Furthermore, the reaction proceeds with good yield in all steps.

  The 5-phthalancarbonitrile compound can be derived into citalopram by the method described in WO98 / 19511. Thereby, citalopram useful as an antidepressant can be produced.

  EXAMPLES Hereinafter, although an Example is shown and this invention is demonstrated more concretely, this invention is not limited to these. Moreover, all the% units with respect to the reagent in an Example mean weight%.

Example 1
Synthesis of 2,4-bis (chloromethyl) bromobenzene
200.0% aqueous sodium hydroxide solution (80.0 g), water (8.8 g), acetic acid (144 mL) and m-xylylene dichloride (70.0 g) were mixed, and bromine (320 g) was added dropwise at 25 to 35 ° C, followed by stirring at 25 to 35 ° C for 8 hours. The reaction solution was added dropwise to 776.8 g of 28% aqueous sodium sulfite solution to stop the reaction. This was extracted three times with 140 mL of ethyl acetate, and the resulting organic layer was washed twice with 490 g of a 14.3% aqueous sodium carbonate solution. The solvent was distilled off from the organic layer under reduced pressure to obtain 100.7 g of 2,4-bis (chloromethyl) bromobenzene (GC area percentage 74.9%) as a pale yellow oil. Apparent yield 99.1%.

¹ H-NMR (CDCl ₃ , 400 MHz) δ = 4.54 (2H, s), 4.69 (2H, s), 7.21 (1H, dd, J = 8 Hz, J = 2 Hz), 7.51 (1H, d, J = 2 Hz ), 7.57 (1H, d, J = 8Hz) ppm

Example 2
Synthesis of 2,4-bis (t-butoxymethyl) bromobenzene
127 mL of t-butyl alcohol and 28.1 g of t-butoxy potassium were mixed, and 25.4 g of 2,4-bis (chloromethyl) bromobenzene was added dropwise at 75 to 83 ° C., followed by stirring at 75 to 83 ° C. for 10 hours. 100 g of water was added to the reaction solution, and most of t-butyl alcohol was distilled off under reduced pressure. 50 mL of toluene and 5.8 g of 35% hydrochloric acid aqueous solution were added thereto, and after neutralization, the organic layer was washed with water. The solvent was distilled off from the organic layer under reduced pressure to obtain 30.9 g of 2,4-bis (t-butoxymethyl) bromobenzene (LC area percentage 71.7%) as a light brown oily substance. Apparent yield 93.9%.

¹ H-NMR (CDCl ₃ , 400 MHz) δ = 1.28 (9H, s), 1.31 (9H, s), 4.41 (2H, s), 4.48 (2H, s), 7.12 (1H, dd, J = 8 Hz, J = 2Hz), 7.45 (1H, d, J = 8Hz), 7.49 (1H, d, J = 2Hz) ppm

Example 3
Synthesis of 2,4-bis (t-butoxymethyl) phenyl- (4′-fluorophenyl) methanol 1.7 g of dispersed magnesium in THF was dispersed in 20 mL of THF, 15 mg of iodine was added, and 0.3 g of 2-bromopropane was introduced. . Then, a THF (40 mL) solution of 20.0 g of 2,4-bis (t-butoxymethyl) bromobenzene was added dropwise at 40 to 50 ° C., followed by stirring at 40 to 50 ° C. for 2 hours. The obtained mixture of Grignard reagents was cooled, and 8.7 g of parafluorobenzaldehyde was added dropwise thereto at 0 to 4 ° C. After the dropwise addition, the reaction solution was stirred at 0 to 4 ° C. for 1 hour, then quenched with 66.5 g of a 9.8% aqueous ammonium chloride solution and then neutralized with 17.1 g of a 27.3% aqueous citric acid solution. After separation, the organic layer was washed with 10% brine. By distilling off the solvent from the organic layer under reduced pressure, 2,4-bis (t-butoxymethyl) phenyl- (4′-fluorophenyl) methanol 22.9 g (LC area percentage 68.7%) was obtained as a light brown oil. . Apparent yield 100.7%.

¹ H-NMR (CDCl ₃ , 400 MHz) δ = 1.29 (9H, s), 1.29 (9H, s), 4.26 (1H, d, J = 8 Hz), 4.42 (2H, s), 4.51 (1H, d, J = 8Hz), 4.60 (1H, d, J = 5Hz), 5.96 (1H, d, J = 5Hz), 6.98-7.06 (3H, m), 7.23 (1H, dd, J = 8Hz, J = 2Hz) , 7.28 (1H, d, J = 2Hz), 7.36 (2H, dd, J = 8Hz, 5Hz) ppm

Example 4
Synthesis of 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-ylmethanol
2,4-bis (t-butoxymethyl) phenyl- (4′-fluorophenyl) methanol 20.0 g, isopropyl alcohol 100 mL and 35% hydrochloric acid aqueous solution 16.7 g were mixed and stirred at 70 ° C. for 12 hours. The reaction solution was poured into 33.7 g of a 20% aqueous sodium hydroxide solution, extracted with 100 mL of ethyl acetate, and the organic layer was washed 3 times with 17% brine. The solvent was distilled off from the organic layer under reduced pressure to obtain crude 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-ylmethanol. By recrystallizing this from an ethyl acetate-heptane (3: 8) mixed solvent, 5.64 g (LC of almost pure 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-ylmethanol 95.1%). Apparent yield 43.3%.

Melting point 101-104 ° C;
IR (KBr) ν = 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 ^-1 ;
¹ H-NMR (CDCl ₃ , 400 MHz) δ = 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 = 8Hz), 7.03 (2H, t, J = 9Hz), 7.24 (1H, d, J = 8Hz), 7.29 (2H, dd, J = 9Hz, J = 6Hz), 7.32 (1H, s) ppm

Example 5
Synthesis of 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran- 5-carbaldehyde 20.6 g of 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-ylmethanol To a solution dissolved in 160 ml of ethyl acetate was added 2.9 g of sodium hydrogen carbonate, 1.6 g of tetrabutylammonium bromide and 0.13 g of 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxide. After cooling to 5 ° C., 52.7 g of a 12.9% aqueous sodium hypochlorite solution was added dropwise at 5-10 ° C. and stirred for 1 hour. 100 ml of water was added to the reaction solution, followed by extraction twice with 100 ml of ethyl acetate. The extract was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, then 3 g of silica gel was added, followed by filtration and evaporation of the solvent. As a result, 17.2 g (84.2%) of 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbaldehyde was obtained.

n _D ²⁴ 1.5823;
IR (neat) ν = 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 ^-1 ;
¹ H-NMR (CDCl ₃ , 400 MHz) δ = 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 = 8Hz), 7.30 (2H, d, J = 9Hz, J = 5Hz), 7.77 (1H, J = 8Hz), 7.83 (1H, s), 10.03 (1H, s) ppm

Example 6
Synthesis of 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran -5-carbaldehyde oxime 1.96 g of 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbaldehyde Was dissolved in 30 ml of toluene, and 2.75 g of triethylamine was allowed to flow in. Then 1.88 g of hydroxylamine hydrochloride was added and reacted at 80 to 90 ° C. for 1 hour. 30 ml of hot water was added to the reaction solution, and the mixture was separated at 90 ° C. with heating. The crystals formed by cooling the organic layer to 0-5 ° C were collected by filtration to give 5.02 g (yield: 79.2%) of the title compound.

Mp 158-159 ° C;
¹ H-NMR (CDCl ₃ , 400 MHz) δ = 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 = 9Hz), 7.29 (2H, dd, J = 9Hz, J = 5Hz), 7.43 (1H, d, J = 8Hz), 7.53 (1H, s), 7.82 (1H, br), 8.16 (1H, s) ppm

Example 7
Synthesis of 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran- 5-carbonitrile 17.00 g of 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbaldehyde Dissolved in 200 ml of toluene, 5.5 g of hydroxylamine hydrochloride and 8.0 g of triethylamine were added thereto, and the mixture was stirred at 80 to 100 ° C. for 2 hours. The resulting triethylamine hydrochloride was filtered, the solvent was distilled off, 36.5 g of acetic anhydride was further added, and the mixture was stirred at 125 to 130 ° C. for 5 hours. The reaction solution was poured into 300 ml of 10% aqueous sodium hydroxide and extracted twice with 200 ml of toluene. The toluene layer was washed with 5% aqueous sodium hydroxide solution, water and saturated brine in this order, dehydrated over magnesium sulfate, added with 5 g of silica gel, stirred well, filtered, and evaporated to remove crude solvent. 14.2 g of 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile was obtained. This was recrystallized from an ethanol / hexane mixed solvent to obtain 9.52 g (59.8%) of 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile.

Melting point 96-98 ° C .;
IR (KBr) ν = 3050 (w), 2867 (m), 2228 (s), 1603 (s), 1510 (s), 1224 (s), 1157 (m), 1048 (s), 1031 (s) , 832 (s) cm ^-1 ;
¹ H-NMR (CDCl ₃ , 400 MHz) δ = 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 = 8Hz), 7.27 (2H, dd, J = 9Hz, J = 5Hz), 7.55 (1H, d, J = 8Hz), 7.60 (1H, s) ppm

  The present invention relates to a method for producing a 5-phthalanecarbonitrile compound useful as an intermediate of citalopram, which is an antidepressant, an intermediate thereof, and a method for producing the same. The manufacturing method of a nitrile compound, its intermediate body, and its manufacturing method can be provided.

Claims (13)

Formula [I]

(In formula, X < ¹ > and X < ² > represent a chlorine atom, a bromine atom, or an iodine atom each independently.)
A compound represented by The compound according to claim 1, wherein X ¹ is a chlorine atom and X ² is a bromine atom. Formula [II]

(In the formula, X ² represents a chlorine atom, a bromine atom or an iodine atom.)
A compound represented by The compound according to claim 3, wherein X ² is a bromine atom. Formula [III]

A compound represented by Formula [A]

(In the formula, X ¹ represents a chlorine atom, a bromine atom or an iodine atom.)
Wherein the compound represented by formula [I] is subjected to either chlorination, bromination or iodination

(In formula, X < ¹ > and X < ² > represent a chlorine atom, a bromine atom, or an iodine atom each independently.)
The manufacturing method of the compound represented by these. Formula [1]

(Wherein, X ¹ and X ² each independently represent a chlorine atom, a bromine atom or an iodine atom.)
Wherein the compound represented by formula [II] is reacted with t-butoxide

(In the formula, X ² represents a chlorine atom, a bromine atom or an iodine atom.)
The manufacturing method of the compound represented by these. Formula [II]

(In the formula, X ² represents a chlorine atom, a bromine atom or an iodine atom.)
Wherein the compound represented by formula (III) is converted into a Grignard reagent or a lithium compound, and (ii) is reacted with parafluorobenzaldehyde.

The manufacturing method of the compound represented by these. X ² is a bromine atom, A process according to any one of claims 6-8. Formula [III]

The compound represented by formula [IV] is subjected to a de-t-butylation reaction and a cyclization reaction.

The manufacturing method of the compound represented by these.   The production method according to claim 10, wherein the de-t-butylation reaction and the cyclization reaction are acid-catalyzed reactions. Formula [A]

(In the formula, X ¹ represents a chlorine atom, a bromine atom or an iodine atom.)
A compound represented by the formula [I] is subjected to either chlorination, bromination or iodination.

(In formula, X < ¹ > and X < ² > represent a chlorine atom, a bromine atom, or an iodine atom each independently.)
A first step of synthesizing a compound represented by:
The compound represented by the formula [I] obtained in the first step is reacted with t-butoxide to obtain the formula [II].

(In the formula, X ² represents a chlorine atom, a bromine atom or an iodine atom.)
A second step of synthesizing a compound represented by:
The compound represented by the formula [II] obtained in the second step is converted into (i) a Grignard reagent or a lithium compound, and (ii) reacted with parafluorobenzaldehyde to obtain a compound of the formula [III].

A third step of synthesizing a compound represented by:
The compound represented by the formula [III] obtained in the third step is subjected to a de-t-butylation reaction and a cyclization reaction to give a formula [IV]

A fourth step of synthesizing a compound represented by:
The hydroxylmethyl group of the compound represented by the formula [IV] obtained in the fourth step is converted into a cyano group, and the formula [V]

And a fifth step of synthesizing a 5-phthalanecarbonitrile compound represented by formula (V): A method for producing a 5-phthalanecarbonitrile compound represented by the formula [V]. The fifth step includes
An oxidation step of oxidizing the hydroxymethyl group of the compound represented by the formula [IV] into an aldehyde form,
An oximation step of reacting the aldehyde form with hydroxylamine or a mineral salt thereof to form an oxime form,
The oxime obtained in the oximation step is directly or without isolation, and then subjected to a dehydration reaction to obtain a carbonitrile compound. Method.