JP2005008642A - Method for manufacturing citalopram, intermediate thereof and method for manufacturing the intermediate - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an industrially advantageous method for manufacturing citalopram at a low cost and in high yield, and to provide a new method for manufacturing a compound (compound [III]) represented by formula [III], which compound is a key compound in manufacturing citalopram. <P>SOLUTION: Citalopram can be manufactured by reacting a compound represented by formula [IV] with 3-(dimethylamino)propyl chloride in the presence of at least one condensing agent selected from N,N,N',N'-tetramethylethylenediamine and 1,3-dimethyl-2-imidazolidinone. Further, a compound [III] can be easily manufactured through reduction and cyclization of a compound of formula [II]. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a method for producing citalopram useful as an antidepressant, a synthetic intermediate thereof, and a method for producing the same.

  Formula [A]

Is a compound useful as an antidepressant. As a method for producing citalopram, the formula [VI]

A production method using a 5-phthalancarbonitrile compound represented by the following (hereinafter also referred to as compound [VI]) is known. For example, there is a method of reacting compound [VI] with 3- (dimethylamino) propyl halide in the presence of a condensing agent (Patent Document 1). In this document, although an example using sodium hydride as a condensing agent is mentioned, the yield is low and it cannot be said to be a preferable method. Furthermore, this document does not describe any method for improving the yield, and it does not even suggest that the yield is improved by using an additive in addition to the condensing agent.

Another method for producing citalopram includes a method of reacting compound [VI] with 3- (dimethylamino) propyl halide under basic conditions (Patent Document 2). In this document, an example using lithium diisopropylamide obtained from n-butyllithium and diisopropylamine as a base is described and the yield is improved, but on the other hand, expensive n-butyllithium is used. In addition, since it requires a step of reacting at a very low temperature (-50 to -40 ° C in the examples), it is not an industrially preferable method. Further, in this document, there is no description of an inexpensive base that can be reacted in a normal temperature range, and it is industrially inexpensive and good in yield under basic conditions in which a specific base is combined. There is no description about the ability to produce citalopram.
Japanese Examined Patent Publication No. 61-35986 WO 98/19511

Accordingly, an object of the present invention is to provide an industrially useful method for producing citalopram which is inexpensive and has a good yield.
Another object of the present invention is to provide a novel method for producing a compound represented by the following formula [III].

In order to provide an industrially useful method for producing citalopram that is inexpensive, good in yield, the inventors of the present invention are more keen on the method described in JP-B 61-35986 (method using a condensing agent). As a result of investigation, by adding at least one selected from N, N, N ′, N′-tetramethylethylenediamine and 1,3-dimethyl-2-imidazolidinone in addition to the condensing agent, citalopram The inventors have found that the yield is improved and have completed the present invention.
In addition, the present inventors have already made a completely new method for producing a 5-phthalanecarbonitrile compound with a low environmental burden via a compound represented by the following formula [III] (also referred to as compound [III]). A strategy method (Japanese Patent Application No. 11-3171703) has been reported, and this time, compound [III], which is a key compound in the production method, is represented by the following formula [II] (also referred to as compound [II]) And 1,3-dimethyl-4- (4′-fluorobenzoyl) benzene, trimellitic anhydride and a novel compound represented by the following formula [I] (hereinafter referred to as compound [I]) The compound [II] can be produced safely by using each as a raw material, and the present invention has been completed.

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

Compound [I] represented by
(2) A process for producing compound [I], wherein 4-bromofluorobenzene is converted to 4-fluorophenylmagnesium bromide, and then the 4-fluorophenylmagnesium bromide is reacted with 2,4-dimethylbenzaldehyde;
(3) Formula [II], characterized by oxidizing compound [I]

A process for producing the compound [II] represented by:
(4) 1,3-dimethyl-4- (4′-fluorobenzoyl) benzene (hereinafter referred to as “compound”), characterized by reacting 4-fluorobenzoyl halide with Friedel-Crafts reaction using m-xylene as a raw material and solvent [I '])
(5) Compound [I ′] obtained by reacting 4-fluorobenzoyl halide with Friedel-Crafts using m-xylene as a raw material and solvent, and then oxidizing the compound [I ′] II] manufacturing method,
(6) A process for producing Compound [II], comprising subjecting 2,4-dimethylbenzoyl halide to Friedel-Crafts reaction with fluorobenzene to obtain Compound [I ′], and then oxidizing Compound [I ′] ,
(7) A process for producing compound [II], characterized by reacting trimellitic anhydride with fluorobenzene in a 2-chlorine-substituted or 3-chlorine-substituted benzene solvent and Friedel-Crafts reaction,
(8) The compound [II], wherein the compound [II] is reduced and cyclized

A process for producing the compound [III] represented by
(9) Trimellitic anhydride is reacted with fluorobenzene by Friedel-Crafts to give compound [II] and its isomer, formula [IV]

A compound (III) (hereinafter also referred to as compound [IV]), and then reducing and cyclizing the mixture to isolate the compound [III],
(10) The process according to (9) above, wherein the reaction is carried out in a dichlorinated or trichlorinated benzene solvent,
(11) The method according to (9) or (10), wherein the reduction is performed using sodium borohydride,
(12) The method according to (9) or (10), wherein the reduction is further performed using a Lewis acid or dialkyl sulfate as a catalyst.
(13) The process according to (12) above, wherein the catalyst is sulfuric acid, dimethyl sulfate, diethyl sulfate or boron trifluoride,
(14) The method according to (9) or (10) above, wherein the cyclization is performed using an acid catalyst,
(15) The production method of the above (14), wherein the acid catalyst is an inorganic acid,
(16) The production method of the above (15), wherein the inorganic acid is hydrochloric acid, sulfuric acid or phosphoric acid,
(17) A compound [III] characterized by oxidizing compound [III] with manganese dioxide.

A method for producing a compound represented by formula (hereinafter also referred to as compound [V]),
(18) Compound [VI] is converted to 3- (dimethylamino) in the presence of at least one selected from N, N, N ′, N′-tetramethylethylenediamine and 1,3-dimethyl-2-imidazolidinone and a condensing agent. ) A method for producing citalopram, characterized by reacting with propyl chloride,
(19) The production method of the above (18), wherein the compound [VI] is obtained by sequentially performing an oximation reaction and a dehydration reaction of the compound [V], and (20) a condensing agent It is related with the manufacturing method of said (18) or (19) characterized by being sodium hydride.

  From the above, the production method of the present invention can produce citalopram useful as an antidepressant at low cost, in good yield, and industrially. Further, by providing a novel method for producing compound [III], which is a key compound in the synthesis of citalopram, the options for the synthesis of compound [III] can be expanded.

Hereinafter, the details of the present invention will be described. The reaction time in the present invention refers to the time from when all the reagents necessary for the reaction are added until the reaction is completed.
Production Method of Compound [I] Compound [I] is a novel compound and can be obtained, for example, by Grignard reaction of 4-bromofluorobenzene with a Grignard reagent and 2,4-dimethylbenzaldehyde. Specifically, for example, after preparing a Grignard reagent of 4-bromofluorobenzene in a reaction solvent, compound [I] can be obtained by adding 2,4-dimethylbenzaldehyde, preferably dropwise thereto. In addition, the addition order of the reaction reagent is not particularly limited.

  The preparation of the 4-Bromofluorobenzene Grignard reagent may be performed in the same manner as the preparation of a conventionally known Grignard reagent. For example, 4-bromofluorobenzene is usually added to a dispersion obtained by dispersing metallic magnesium in an organic solvent. It can carry out easily by dripping at -30 degreeC-100 degreeC, Preferably it is 15 degreeC-70 degreeC. The amount of metal magnesium used may be an amount necessary for converting 4-bromofluorobenzene into a Grignard reagent, for example, usually 0.9 to 2 mol, preferably 1 mol to 1 mol of 4-bromofluorobenzene. Is 0.95 to 1.3 mol.

  2,4-dimethylbenzaldehyde is usually 0.5 mol to 2 mol, preferably 0.8 mol to 1.2 mol, relative to 1 mol of 4-bromofluorobenzene.

  The reaction solvent in this reaction is not particularly limited as long as it does not inhibit the Grignard reaction. Any solvent that can be used for the preparation of the Grignard reagent can be used for the Grignard reaction without isolation after the Grignard reagent is prepared. This is preferable without complicating the reaction process. Preferred examples of the solvent include ether solvents (for example, diethyl ether, diisopropyl ether, dibutyl ether, dipentyl ether, dihexyl ether, t-butyl methyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, Tetrahydrofuran (THF), 1,4-dioxane, 1,3-dioxolane, and the like. Preferred are THF, diethyl ether, ethylene glycol dimethyl ether, and diethylene glycol dimethyl ether. The amount of the reaction solvent used in this reaction is usually 1 L to 30 L, preferably 2 L to 20 L, per 1 kg of 4-bromofluorobenzene.

  The reaction temperature in this reaction is usually −30 ° C. to 100 ° C., preferably −10 ° C. to 50 ° C., and the reaction time is usually 5 minutes to 6 hours, preferably 10 minutes to 3 hours.

  Compound [I] can be isolated by a conventional method (for example, extraction) after adding water or the like to the reaction solution to deactivate the Grignard reagent. After isolation, it can be further purified by a conventional method, but may be subjected to the next reaction without purification.

  The compound [I] of the present invention can exist as an optically active substance and a racemate by an asymmetric carbon to which a hydroxyl group is bonded, and the racemate is separated into each optically active substance by a known method. be able to.

Process for producing compound [I '] starting from m-xylene
Method 1 (method using m-xylene as a raw material and solvent)
It is already known from US Pat. No. 3,835,167 that compound [I ′] can be obtained by reacting m-xylene with 4-fluorobenzoyl chloride and Friedel-Crafts. In this document, dichloromethane is used as a solvent, which is environmentally undesirable. For this reason, as a result of intensive studies on a solvent that can be used in the method of the above literature and environmentally preferable, the present inventors have obtained compound [I ′] with high yield by using m-xylene as a raw material and solvent. Found that can be obtained. That is, compound [I ′] can be obtained in high yield by using 4-fluorobenzoyl halide and Friedel-Crafts reaction using m-xylene as a raw material and solvent.

  Specifically, 4-fluorobenzoyl halide is added to a dispersion in which Lewis acid or Bronsted acid is dispersed in m-xylene, preferably by dropping, or into a m-xylene solution of 4-fluorobenzoyl halide. Compound [I ′] can be obtained in good yield by adding, preferably dropping, a Lewis acid or Bronsted acid.

  The halide moiety in 4-fluorobenzoyl halide in Method 1 is not particularly limited, and examples thereof include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and preferably a chlorine atom.

  In Method 1, the amount of m-xylene used as a raw material and solvent is usually 3 L to 30 L, preferably 5 L to 15 L, per 1 kg of 4-fluorobenzoyl halide.

  The Lewis acid in Method 1 is not particularly limited as long as it is usually used for Friedel-Crafts reaction. For example, aluminum chloride, aluminum bromide, zinc fluoride, zinc chloride, zinc bromide, zinc iodide, trifluoride Examples thereof include boron, boron trichloride, silicon tetrachloride, titanium tetrachloride, and aluminum chloride is particularly preferable because of its high reaction rate. The amount of the Lewis acid to be used is generally 2 mol to 6 mol, preferably 3 mol to 4 mol, per 1 mol of 4-fluorobenzoyl halide.

  The Bronsted acid in Method 1 is not particularly limited as long as it is usually used for Friedel-Crafts reaction, and examples thereof include hydrogen fluoride, sulfuric acid, polyphosphoric acid, trifluoromethanesulfonic acid and the like. Preferably, trifluoromethanesulfonic acid is used. Can be mentioned. The amount of the Bronsted acid used is usually 0.0001 mol to 1 mol, preferably 0.01 mol to 0.2 mol, per 1 mol of 4-fluorobenzoyl halide.

  The reaction temperature in Method 1 is usually −20 ° C. to 120 ° C., preferably 10 ° C. to 50 ° C., and the reaction time is usually 0.5 hours to 15 hours, preferably 2 hours to 8 hours.

  Compound [I ′] can be isolated and purified by a conventional method. For example, the compound [I ′] can be isolated by pouring the reaction solution into hydrochloric acid and separating the resulting organic layer by washing with water or an aqueous alkaline solution and then distilling off the solvent. . The isolate can be further purified by a conventional method, but may be directly subjected to the next reaction without purification. In addition, 1,3-dimethyl-2- (4′-fluorobenzoyl) benzene, which is an isomer of compound [I ′], can be obtained simultaneously by this method, but can be easily separated by a conventional method such as recrystallization. Can do. Compound [I ′] may be subjected to the next reaction without separation from the isomer.

Method 2 (Friedel-Crafts reaction between 2,4-dimethylbenzoyl halide and fluorobenzene)
Compound [I ′] can also be obtained by reacting 2,4-dimethylbenzoyl halide with Friedel-Crafts in a reaction solvent. As the reaction solvent, fluorobenzene can be used (Method 2-1), or a solvent usually used in Friedel-Crafts reaction (Method 2-2) can be used. Specifically, Method 2-1: Lewis acid or Bronsted acid is dispersed in fluorobenzene, and 2,4-dimethylbenzoyl halide is added to this dispersion, preferably dropwise, or fluorobenzene and 2, By adding a Lewis acid or Bronsted acid to a mixture with 4-dimethylbenzoyl halide, Method 2-2: a solution obtained by diluting fluorobenzene in a solvent usually used in Friedel-Crafts reaction, Lewis acid or Bren Disperse the Steed acid and add 2,4-dimethylbenzoyl halide to this dispersion, preferably dropwise, or add fluorobenzene and 2,4-dimethylbenzoyl halide to the solvent normally used in Friedel-Crafts reaction And then add Lewis acid or Bronsted acid And, the compound [I '] can be obtained in good yield.

  The amount of fluorobenzene used in Method 2-1 is usually 2 L to 20 L, preferably 4 L to 10 L, per 1 kg of 2,4-dimethylbenzoyl halide.

  The amount of fluorobenzene used in Method 2-2 is usually 1 mol to 5 mol, preferably 1 mol to 3 mol, per 1 mol of 2,4-dimethylbenzoyl halide.

  Examples of the solvent usually used in the Friedel-Crafts reaction in Method 2-2 include methylene chloride, 1,2-dichloroethane, nitrobenzene, carbon disulfide, and the like. 1,2-dichlorobenzene is particularly preferable. The amount of the reaction solvent to be used is generally 1 L to 20 L, preferably 5 L to 15 L, per 1 kg of 2,4-dimethylbenzoyl halide.

  The Lewis acid in Method 2-1 and Method 2-2 is not particularly limited as long as it is usually used in the Friedel-Crafts reaction. For example, aluminum chloride, aluminum bromide, zinc fluoride, zinc chloride, bromide Zinc, zinc iodide, boron trifluoride, boron trichloride, silicon tetrachloride, titanium tetrachloride and the like can be mentioned, and aluminum chloride is particularly preferable because of its high reaction rate. The amount of the Lewis acid used is usually 0.8 mol to 3 mol, preferably 1 mol to 1.5 mol, per 1 mol of 2,4-dimethylbenzoyl halide.

  The Bronsted acid in the methods 2-1 and 2-2 is not particularly limited as long as it is usually used in the Friedel-Crafts reaction, and examples thereof include hydrogen fluoride, sulfuric acid, polyphosphoric acid, trifluoromethanesulfonic acid and the like. Preferably, trifluoromethanesulfonic acid is used. The amount of the Bronsted acid used is usually 0.0001 mol to 1 mol, preferably 0.01 mol to 0.5 mol, per 1 mol of 2,4-dimethylbenzoyl halide.

  The reaction temperature in Method 2-1 and Method 2-2 is usually −20 ° C. to 100 ° C., preferably 0 ° C. to 90 ° C., and the reaction time is usually 0.5 hours to 10 hours, preferably 1 hour to 4 hours.

  Compound [I ′] can be isolated and purified by a conventional method. For example, the compound [I ′] can be isolated by pouring the reaction solution into hydrochloric acid and separating the resulting organic layer by washing with water or an aqueous alkaline solution and then distilling off the solvent.

Process for producing compound [II]
Method a (Production Method of Compound [II] Using Compound [I] as a Raw Material)
Compound [II] can be obtained by oxidizing novel compound [I]. The oxidation of compound [I] can be performed by using, for example, an oxidizing agent. Specifically, compound [II] can be obtained by mixing and stirring a solution of compound [I] and an oxidant solution or dispersion. As solvents for these solutions and dispersions, the following reaction solvents are preferably used.

  The oxidizing agent in method a can be used without particular limitation as long as it can oxidize a methyl group and a hydroxyl group to a carboxyl group and a carbonyl group, respectively. Examples of the oxidizing agent include permanganate and dichromate, and permanganate (for example, potassium permanganate) is preferable from the viewpoint of environmental influence and toxicity. Furthermore, permanganate, when used in oxidation reactions, produces manganese dioxide as a by-product, but manganese dioxide can be reused as an oxidizing agent when synthesizing compound [V] from compound [III] described later, and discarded. This is preferable because it leads to cost reduction. The amount of the oxidizing agent used in Method a is usually 3 mol to 15 mol, preferably 4.6 mol to 10 mol, more preferably 6 mol to 7.5 mol, per 1 mol of compound [I].

  The reaction solvent in method a is not particularly limited as long as it is not easily oxidized by the oxidizing agent used in the oxidation reaction. For example, water, t-butyl alcohol, t-amyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, chloride Examples include methylene, chloroform, 1,2-dichloroethane, benzene, monochlorobenzene, 1,2-dichlorobenzene, acetic acid, propionic acid, butyric acid, and a mixed solvent thereof, preferably water, t-butyl. Examples include alcohol, a mixed solvent of water and t-butyl alcohol, t-amyl alcohol, a mixed solvent of water and t-amyl alcohol, acetone, and a mixed solvent of acetone and water. The amount of the solvent to be used is generally 5 L-50 L, preferably 8 L-24 L, per 1 kg of compound [I].

  The reaction temperature in method a is usually 0 ° C. to 120 ° C., preferably 50 ° C. to 100 ° C., and the reaction time is usually 0.5 hours to 12 hours, preferably 2 hours to 8 hours.

  Isolation of compound [II] may be carried out by a conventional method. For example, the reaction solution is subjected to filtration or the like to remove insoluble matters (including manganese dioxide), and then the filtrate is subjected to, for example, a commonly used inorganic acid (for example, hydrochloric acid or Sulfuric acid or the like) and the like, and the precipitated compound [II] can be filtered off. After isolation, it can be further purified by a conventional method, but may be subjected to the next reaction without purification.

Method b (Production Method of Compound [II] Using Compound [I ′] as a Raw Material)
Compound [II] can also be obtained by oxidizing compound [I ′]. The oxidation at this time can be performed using an oxidizing agent. In Method b, the amount of the oxidizing agent used is generally 2.5 mol to 14 mol, preferably 4 mol to 9 mol, more preferably 5.5 mol to 7 mol, relative to 1 mol of compound [I ′]. Except that the amount of the solvent used is usually 5 L to 50 L, preferably 8 L to 24 L (for example, reaction conditions, isolation conditions, etc.) with respect to 1 kg of compound [I ′]. Can be done in exactly the same way. The isolate can be purified by a conventional method, but may be subjected to the next reaction without purification.

Method c (Method for producing compound [II] using trimellitic anhydride as a raw material)
The Friedel-Crafts reaction between trimellitic anhydride and benzene is already known from US Pat. No. 3,835,167. In the method of this document, nitrobenzene is used as a solvent, which is not environmentally preferable. In addition, the present inventors have found that the Friedel-Crafts reaction hardly proceeds as a result of performing the reaction described in this document under the same conditions or under the reaction conditions at higher temperatures using fluorobenzene instead of benzene. (See Comparative Example 1). For this reason, as a result of intensive studies on a solvent that allows the Friedel-Crafts reaction between trimellitic anhydride and fluorobenzene to proceed smoothly and is environmentally favorable, 2-chlorine-substituted or 3-chlorine-substituted benzene is most suitable. I found out. That is, by performing a Friedel-Crafts reaction between trimellitic anhydride and fluorobenzene in a dichlorinated or trichlorinated benzene solvent, compound [II] is environmentally favorable and can be obtained smoothly.

  Specifically, for example, compound [II] can be obtained by dispersing trimellitic anhydride and fluorobenzene in a reaction solvent, adding Lewis acid or Bronsted acid to this dispersion, and stirring. .

  The amount of fluorobenzene used in method c is usually 1 mol to 10 mol, preferably 1.2 mol to 3 mol, per 1 mol of trimellitic anhydride.

  Examples of the dichlorinated or trichlorinated benzene that is a reaction solvent in the method c include, for example, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,2,4-trichlorobenzene, 1,2,3-trimethyl. Examples thereof include chlorobenzene, and 1,2-dichlorobenzene is particularly preferable in that compound [II] can be obtained with relatively high selectivity. These solvents may be used alone or in combination. The usage-amount of the said reaction solvent is 5L-40L normally with respect to 1 kg of trimellitic anhydride, Preferably it is 10L-25L. In addition to the above-mentioned solvents, there are solvents that can proceed the reaction of method c, such as methylene chloride, 1,2-dichloroethane, nitrobenzene, carbon disulfide, etc., preferably methylene chloride, 1,2-dichloroethane. It is. The usage-amount of the said solvent is 4L-40L with respect to 1 kg of trimellitic anhydride, Preferably it is 8L-25L.

  The Lewis acid in method c is not particularly limited as long as it is usually used in the Friedel-Crafts reaction. For example, aluminum chloride, aluminum bromide, zinc fluoride, zinc chloride, zinc bromide, zinc iodide, three Examples thereof include boron fluoride, boron trichloride, silicon tetrachloride, titanium tetrachloride, and aluminum chloride is particularly preferable because of its high reaction rate. The amount of the Lewis acid used is usually 2.5 mol to 5 mol, preferably 3 mol to 3.5 mol, per 1 mol of trimellitic anhydride.

  The Bronsted acid in the method c is not particularly limited as long as it is usually used in the Friedel-Crafts reaction, and examples thereof include hydrogen fluoride, sulfuric acid, polyphosphoric acid, trifluoromethanesulfonic acid and the like, preferably trifluoromethanesulfone. Examples include acids. The amount of the Bronsted acid used is 0.0001 mol to 1 mol, preferably 0.01 mol to 0.2 mol, relative to 1 mol of trimellitic anhydride.

  The reaction temperature in method c is usually 40 ° C. to 150 ° C., preferably 70 ° C. to 120 ° C., and the reaction time is usually 0.5 hours to 16 hours, preferably 2 hours to 9 hours.

  In method c, compound [II] is obtained as a mixture with its isomer, compound [IV]. This mixture can be easily removed from the reaction solution by a conventional method. For example, the reaction solution is poured into an acidic aqueous solution such as an aqueous hydrochloric acid solution or an aqueous sulfuric acid solution, and the mixture is separated and the organic layer is taken out. . Compound [II] and Compound [IV] can be separated by recrystallization or the like. The mixture may be subjected to the next reaction without separating compound [II] and compound [IV], and the mixture and compound [II] may be subjected to the next reaction without purification.

Novel Process for Producing Compound [III] Compound [III] has already been proposed by the present inventors, Ikemoto and Iki, as an important intermediate for efficiently synthesizing compound [VI] which is a citalopram precursor. No. 311703. As a result of further intensive studies on a method for producing compound [III] by a new route, the present inventors have found that compound [II] is a precursor of compound [III], and further, compound [II] is converted to compound [III]. It has come to find a simple manufacturing method. That is, compound [III] can be easily obtained by reducing and cyclizing compound [II]. The order of reduction and cyclization is not particularly limited, and compound [II] may be cyclized after reduction, or compound [II] may be cyclized after partial reduction (reduction of ketone) and further reduced. Since the process is short, cyclization after reduction is preferred. Compound [II] as a raw material may be used in the production of compound [III] as a mixture with compound [IV] as an isomer. When the mixture of compound [II] and compound [IV] is reduced and cyclized, compound [III] is obtained together with the isomer of compound [III]. However, compound [II] is isolated and reduced and cyclized. Compared with the case of cyclization, the yield of the finally obtained compound [III] is increased. For this reason, it is efficient and preferable to isolate the compound [III] after it is not isolated at the time of the compound [II].

  The compound produced by the reduction reaction of compound [II] is represented by the formula [VII]

In the case where the compound [II] is cyclized after the partial reduction and further reduced, various intermediates exist, for example,

And the like. The production of compound [III] from compound [II] in the present invention consists of two steps: (1) a reduction step and (2) a cyclization step.
In the case of cyclization after reduction, depending on the reaction conditions of (1), not only compound [VII] but also compound [III] may be produced at the same time. Depending on the production ratio of compound [III], (2) In some cases, it can be omitted.

Hereinafter, a method for producing compound [III] by reducing compound [II] and then cyclizing will be described.
First, the condition (1) will be described.
The reduction of the compound [II] can be carried out in the same manner as the conventionally known reduction from a carboxylic acid to an alcohol, and can be carried out by using a reducing agent. Specifically, compound [VII] can be obtained by dispersing a reducing agent in a reaction solvent and adding, preferably dropwise, compound [II] to the dispersion. In this reduction, it is preferable to add an appropriate catalyst in addition to the reducing agent. The catalyst is preferably added after adding the reducing agent and the compound [II].

  The reducing agent in (1) is not particularly limited as long as it is usually used for converting a carboxylic acid into an alcohol. For example, sodium borohydride, lithium aluminum hydride, sodium bis (2- Methoxyethoxy) aluminum, borane THF complex, borane dimethyl sulfide complex, etc., among which sodium borohydride is particularly preferred. The amount of the reducing agent to be used is generally 1.25 to 7.5 mol, preferably 2.5 to 5 mol, per 1 mol of compound [II].

  Examples of the catalyst in (1) include inorganic acids (for example, hydrochloric acid, sulfuric acid, phosphoric acid, boric acid, nitric acid, etc.), organic acids (for example, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfone). Acid), Lewis acid (for example, boron trifluoride, boron trichloride, boron tribromide, zinc fluoride, zinc chloride, zinc bromide, zinc iodide, aluminum fluoride, aluminum chloride, aluminum bromide, fluorine Magnesium chloride, magnesium chloride, magnesium bromide, magnesium iodide, silicon tetrachloride, titanium tetrachloride, etc.), dialkyl sulfates (eg, dimethyl sulfate, diethyl sulfate, etc.), etc., and improved yield and selectivity In view of the above, Lewis acids and dialkyl sulfates are more preferable. Chill is particularly preferred. The amount of the catalyst to be used is generally 1.25 mol to 7 mol, preferably 2 mol to 6 mol, per 1 mol of compound [II].

  The reaction solvent in (1) is not particularly limited as long as it is a solvent that does not easily react under reducing reaction conditions, and ether solvents are preferable. Examples of the ether solvents include diethyl ether, diisopropyl ether, dibutyl ether, and dipentyl. Ether, dihexyl ether, t-butyl methyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,3-dioxolane, and the like. Preferably, THF, diethyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, t-butyl methyl ether, dibutyl ether Ether and the like, particularly preferably THF, t-butyl methyl ether, dibutyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether. The amount of the reaction solvent to be used is generally 1 L to 40 L, preferably 5 L to 20 L, per 1 kg of compound [II].

  In (1), it is preferable to use trialkyl borate (for example, trimethyl borate, triethyl borate, tripropyl borate, tributyl borate, etc.) in terms of preventing the reaction solution from gelling. The amount of trialkyl borate to be used is preferably 0.1 mol to 3 mol, more preferably 0.1 mol to 0.5 mol, per 1 mol of compound [II].

  The reaction temperature in (1) is usually −20 ° C. to 120 ° C., preferably 25 ° C. to 75 ° C., and the reaction time is usually 0.5 hours to 10 hours, preferably 2 hours to 7 hours.

  Compound [VII] can be isolated and purified by a conventional method, for example, by adding water to the obtained reaction solution, cooling and precipitating as crystals. Without isolating compound [VII], the reaction solution containing compound [VII] may be subjected to the next reaction as it is, or the reaction solution in which the reducing agent is deactivated with water is used for the next reaction. It can also be attached.

Next, (2) will be described.
Cyclization of compound [VII] can be performed via dehydration reaction by applying heat. In this case, it is preferable to further add an acid catalyst in order to accelerate the dehydration reaction. Specifically, for example, compound [III] can be obtained by adding an acid catalyst to the reaction solution obtained in (1) or a mixed solution obtained by adding compound [VII] to the reaction solvent.

  Examples of the acid catalyst in (2) include inorganic acids (for example, hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, boric acid, nitric acid, etc.), organic acids (for example, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethane). Romethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, benzoic acid, etc.), Lewis acid (for example, boron trifluoride, boron trichloride, boron tribromide, zinc fluoride, zinc chloride, zinc bromide, iodine) Zinc fluoride, aluminum fluoride, aluminum chloride, aluminum bromide, magnesium fluoride, magnesium chloride, magnesium bromide, magnesium iodide, silicon tetrachloride, titanium tetrachloride, etc.), more preferably inorganic acids. Particularly preferred are hydrochloric acid, sulfuric acid and phosphoric acid. The amount of the acid catalyst is usually 0.01 kg to 50 kg, preferably 0.1 kg to 5 kg with respect to 1 kg of the compound [II] which is the raw material of (1).

  The cyclization reaction easily proceeds with the acid catalyst as described above. For this reason, when the above acid catalyst is used as the catalyst in (1), the rate of progressing not only to the reduction reaction but also to the cyclization reaction is large. Therefore, compound [III] can also be synthesized in one pot by using an excess of the above-mentioned acid catalyst as the catalyst in (1). In this case, the amount of the catalyst used in (1) is usually 2 to 30 mol, preferably 3 to 15 mol, relative to 1 mol of compound [II] which is the raw material of (1).

  The solvent in (2) is not particularly limited as long as it does not inhibit the reaction, and preferably includes the solvent used in (1) and the mixed solvent of water used in (1) and water. By using these solvents, the reaction solution obtained without isolating compound [VII] from the reaction solution after completion of the reaction of (1) can be directly subjected to the step (2). After completion of the reaction in (1), the reaction solution to which water has been added in order to deactivate the reducing agent can be directly applied to the step (2), that is, the isolation / purification operation of compound [VII] can be omitted. It can be said that it is preferable. In addition, when water is added to deactivate the reducing agent, only the solvent used in the reaction solution of (1) is distilled off to make only water, which can be subjected to a cyclization reaction. A suitable solvent other than the solvent used in (1) can be newly added to the water only. The “suitable solvent other than the solvent used in (1)” is not particularly limited, and examples thereof include hydrocarbon solvents such as toluene, xylene, mesitylene, hexane, heptane, and octane. (1) Usually, 0.5 L to 20 L, preferably 3 L to 10 L can be used per 1 kg of the compound [II] which is a raw material.

  The reaction time in (2) is usually 0.5 hours to 15 hours, preferably 1 hour to 7 hours, and the reaction temperature is usually 10 ° C to 100 ° C, preferably 20 ° C to 70 ° C.

  Compound [III] can be isolated by a conventional method, for example, by filtering crystals produced by cooling after adding water to the reaction solution. Moreover, although it can also refine | purify by a conventional method after isolation, you may attach | subject to the next reaction, without refine | purifying.

  In the method in which compound [II] is cyclized after partial reduction and further reduced, a reaction reagent (for example, a reducing agent) that is usually used is selected in order to perform desired partial reduction or cyclization. You can do this.

Method for Producing Compound [V] Compound [V] is useful as an intermediate for efficiently synthesizing compound [VI] which is a citalopram precursor, and the method for efficiently synthesizing compound [V] results in citalopram. This is important because it contributes greatly to the efficient synthesis of. It is already known that compound [V] can be obtained by oxidation using compound [III] as an oxidizing agent (Japanese Patent Application No. 11-311703). In addition to the hydroxymethyl group present at the 5-position of the 1,3-dihydroisobenzofuran ring, the oxidizable sites of compound [III] are the 1- and 3-position carbons. For this reason, there is a concern that oxidation of compound [III] also causes oxidation of the 1st and 3rd carbons in addition to the 5th hydroxymethyl group. For this reason, as a result of intensive studies to eliminate the above-mentioned concerns, the present inventors have hardly caused a side reaction (oxidation reaction of 1st and 3rd carbons) by using manganese dioxide as an oxidizing agent, It has been found that compound [V] can be obtained with good yield. That is, compound [V] can be obtained in good yield by oxidizing compound [III] using manganese dioxide as the oxidizing agent. Specifically, compound [V] can be obtained by dissolving or dispersing compound [III] in a suitable solvent and adding manganese dioxide thereto. However, the order of addition is not particularly limited.

  The amount of manganese dioxide used in this reaction is usually 1 kg to 20 kg, preferably 3 kg to 10 kg, relative to 1 kg of compound [III].

  The solvent used in this reaction is not particularly limited as long as it is difficult to undergo an oxidation reaction. For example, ethers (for example, diethyl ether, diisopropyl ether, dibutyl ether, dipentyl ether, dihexyl ether, t-butyl methyl ether). , Ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,3-dioxolane, etc.), ketones (for example, acetone, methyl ethyl ketone, methyl isobutyl ketone, 2-pentanone, 3-pentanone, cyclopentanone, cyclohexanone, etc.), esters (eg, ethyl acetate, propyl acetate, isopropyl acetate) Butyl acetate, isobutyl acetate, amyl acetate, isoamyl acetate, benzyl acetate, phenyl acetate, methyl propionate, ethyl propionate, propyl propionate, isopropyl propionate, butyl propionate, isobutyl propionate, amyl propionate, propionic acid Isoamyl, benzyl propionate, phenyl propionate, methyl butyrate, ethyl butyrate, propyl butyrate, isopropyl butyrate, butyl butyrate, isobutyl butyrate, amyl butyrate, isoamyl butyrate, benzyl butyrate, phenyl butyrate, etc.), lactones (eg, γ-butyrolactone) Etc.), carbonates (eg dimethyl carbonate, diethyl carbonate, ethylene carbonate, etc.), aromatic hydrocarbons (eg benzene, toluene, xylene, mesitylene, ethylbenzene, t-butyl) Benzene), aliphatic hydrocarbons (eg, pentane, hexane, isohexane, heptane, isoheptane, octane, isooctane, nonane, decane, undecane, dodecane, petroleum ether, etc.), halogen-substituted aromatic hydrocarbons (eg, mono Chlorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,2,4-trichlorobenzene, 1,2,3-trichlorobenzene, etc.), halogen-substituted aliphatic hydrocarbons (for example, dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2-trichloroethane, 1,1,1-trichloroethane, 1-chloropropane, 2-chloropropane, etc.), amide solvents (for example, N, N-dimethylformamide, N, N-dimethyl) Acetamide, N-methylpyrrolidone, etc.), sulfur-containing Solvents (e.g., dimethyl sulfoxide, sulfolane) and the like. Among them, particularly preferred solvents include t-butyl methyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, toluene, xylene, mesitylene, dichloromethane, and monochlorobenzene. The amount of the solvent to be used is generally 3 L-50 L, preferably 5 L-20 L, per 1 kg of compound [III].

  The reaction temperature in this reaction is usually −10 ° C. to 100 ° C., preferably 10 ° C. to 60 ° C., and the reaction time is usually 0.1 hour to 24 hours, preferably 0.5 hour to 5 hours.

  Compound [V] can be isolated by a conventional method, for example, by filtering the reaction solution and distilling off the solvent from the obtained filtrate. Moreover, after filtering a reaction liquid, it can also use for next reaction as it is, without distilling a solvent off from the obtained filtrate. The waste manganese compound separated by filtration can be regenerated into a permanganate or manganese dioxide by a conventional method and can be reused.

Production Method of Compound [VI] Compound [VI] is an intermediate useful as a citalopram precursor. Compound [VI] can be obtained by sequentially performing oxidation, oximation and dehydration reaction using Compound [III] as a starting material. If the following solvents are used, a series of reactions (oxidation, oximation and dehydration reactions) can be performed with a single solvent, so the step of distilling off the solvent can be omitted, and the compound [VI] can be conveniently and efficiently produced. Can be manufactured. Specifically, in the following solvent, compound [III] and an oxidizing agent are added to carry out an oxidation reaction. After the oxidation reaction is completed, the oxidizing agent is removed by filtration, and hydroxylamine or a mineral salt thereof is added to the obtained filtrate. Is added to carry out an oximation reaction, and finally, a dehydrating agent is added to the resulting reaction solution to carry out a dehydration reaction, whereby compound [VI] can be obtained.

  Solvents that can be used for the oxidation, oximation and dehydration reactions are not particularly limited as long as they do not inhibit each reaction. For example, ethers (for example, dibutyl ether, dipentyl ether, dihexyl ether, diethylene glycol dimethyl ether, triethylene). Glycol dimethyl ether, tetraethylene glycol dimethyl ether, etc.), ketones (eg, cyclopentanone, cyclohexanone, etc.), esters (eg, amyl acetate, isoamyl acetate, benzyl acetate, phenyl acetate, butyl propionate, isobutyl propionate, propionic acid) Amyl, isoamyl propionate, benzyl propionate, phenyl propionate, butyl butyrate, isobutyl butyrate, amyl butyrate, isoamyl butyrate, benzyl butyrate, phenyl butyrate, etc.), Kutons (eg, γ-butyrolactone, etc.), carbonates (eg, diethyl carbonate, ethylene carbonate, etc.), aromatic hydrocarbons (eg, xylene, mesitylene, ethylbenzene, t-butylbenzene, toluene, etc.), halogen substitution Aromatic hydrocarbons (for example, monochlorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,2,4-trichlorobenzene, 1,2,3-trichlorobenzene, etc.), amide solvents (for example, , N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, etc.), sulfur-containing solvents (for example, dimethylsulfoxide, sulfolane, etc.) and the like. Among them, particularly preferable solvents include diethylene glycol dimethyl ether, xylene, mesitylene, toluene, t-butylbenzene, and monochlorobenzene. The amount of the solvent used in the oxidation, oximation and dehydration steps is usually 3 L to 50 L, preferably 5 L to 20 L, per 1 kg of compound [III] as the starting material.

The oxidation reaction of compound [III] will be described.
The oxidation of compound [III] can be carried out in the same manner as in the above-mentioned “Production method of compound [V]” except that the solvent is changed to the above. Compound [V] obtained by oxidizing compound [III] can be subjected to the next oximation reaction without isolation from the reaction solution. However, the oxidizing agent is taken out from the reaction solution by a conventional method.

Next, the oximation reaction will be described.
Compound [V] can obtain an oxime by, for example, an oximation reaction with hydroxylamine or a mineral acid salt thereof. Specifically, for example, an oxime can be obtained by adding hydroxylamine or a mineral salt thereof to a solution obtained by removing the oxidizing agent from the reaction solution after the oxidation reaction.

  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 mineral acid salt used in the oximation step is usually 1 mol to 5 mol, preferably 1 mol to 2 mol, relative to 1 mol of compound [III] used in the oxidation step.

  When a hydroxylamine mineral acid salt is used, it is preferable to add 1 mol to 5 mol of an appropriate base with respect to 1 mol of hydroxylamine mineral acid salt. The base may be added, preferably dropwise, simultaneously with or after the 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, sodium t- Butoxide, potassium t-butoxide, etc.), inorganic bases (for example, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, etc.) and the like, preferably triethylamine.

  The reaction temperature in the oximation reaction is usually 20 ° C. to 120 ° C., preferably 40 ° C. to 100 ° C., and the reaction time is usually 10 minutes to 4 hours, preferably 30 minutes to 2 hours.

  The oxime obtained from compound [III] can be subjected to a dehydration reaction without being isolated from the reaction solution.

Finally, the dehydration reaction will be described.
The oxime obtained by the oximation reaction can be dehydrated by using, for example, a dehydrating agent. Specifically, for example, compound [VI] can be obtained by adding a dehydrating agent to the reaction solution after the oximation reaction.

  Examples of the dehydrating agent used in the dehydration step include acid anhydrides (for example, acetic anhydride, phthalic anhydride, etc.), phosphorus oxychloride, methanesulfonyl chloride, paratoluenesulfonyl chloride, etc. To acetic anhydride is particularly preferred. The usage-amount of the said dehydrating agent is 1 mol-10 mol normally with respect to 1 mol of oximes, Preferably it is 2 mol-5 mol.

  The reaction temperature in the dehydration reaction is usually 60 ° C. to 160 ° C., preferably 120 ° C. to 150 ° C., more preferably 125 ° C. to 150 ° C., and the reaction time is usually 0.5 hours to 8 hours, preferably 1. 5 to 6 hours.

  Isolation of compound [VI] can be performed by subjecting the reaction solution to a conventional method (for example, neutralization, extraction, crystallization, etc.).

A method for producing citalopram Citalopram, in the presence of at least one selected from N, N, N ′, N′-tetramethylethylenediamine and 1,3-dimethyl-2-imidazolidinone, together with a condensing agent, The compound [VI] can be obtained with good yield by reacting with 3- (dimethylamino) propyl chloride. Specifically, selected from compound [VI], 3- (dimethylamino) propyl chloride, a condensing agent, and N, N, N ′, N′-tetramethylethylenediamine and 1,3-dimethyl-2-imidazolidinone. Citalopram can be obtained by mixing at least one of the above in an appropriate solvent and heating if necessary to proceed the reaction. The order of addition is not particularly limited. For example, after adding compound [VI] to the reaction solvent, a condensing agent and 3- (dimethylamino) propyl chloride are sequentially added, and compounds [VI] and 3- (dimethyl) are added to the reaction solvent. A method of adding a condensing agent after adding amino) propyl chloride, a method of adding a condensing agent to a reaction solvent and then adding compound [VI] and 3- (dimethylamino) propyl chloride sequentially or as a mixed solution, to the reaction solvent Examples include a method of adding compound [VI] and a condensing agent simultaneously after adding 3- (dimethylamino) propyl chloride. At this time, N, N, N ′, N′-tetramethylethylenediamine and 1,3-dimethyl-2-imidazolidinone may be added at any stage, and added separately before and after the addition of the condensing agent. Is preferable because the reaction easily proceeds. Specifically, after adding compound [VI] to the reaction solvent, 3- (dimethylamino) propyl chloride, N, N, N ′, N′-tetramethylethylenediamine (or 1,3-dimethyl-2-imidazo Lysinone), a condensing agent, and N, N, N ′, N′-tetramethylethylenediamine (or 1,3-dimethyl-2-imidazolidinone) may be added sequentially. The reagent used in the present invention may be added as it is, or diluted with a reaction solvent or another solvent that does not inhibit the reaction (for example, triethylamine, pyridine, N, N-dimethylaniline, etc.).

  In the present invention, by adding a quaternary ammonium salt (for example, tetra n-butylammonium halide, benzyltrialkylammonium halide, etc.) to the reaction system, the reaction can be allowed to proceed without raising the reaction temperature. it can. The amount of the quaternary ammonium salt added is preferably 0.001 mol to 0.1 mol, more preferably 0.01 mol to 0.05 mol, relative to 1 mol of the compound [VI].

  The amount of 3- (dimethylamino) propyl chloride added is preferably 1 mol to 3 mol, more preferably 1 mol to 1.5 mol, per 1 mol of compound [VI]. When 3- (dimethylamino) propyl chloride is in the form of hydrochloride, it is desirable to prepare it in a free form by neutralization before use in the reaction of the present invention.

  The amount of N, N, N ′, N′-tetramethylethylenediamine added is preferably 0.1 mol to 10 mol, more preferably 0.2 mol to 4 mol, per 1 mol of compound [VI]. .

  The amount of 1,3-dimethyl-2-imidazolidinone added is preferably 1 mol to 50 mol, more preferably 3 mol to 30 mol, per 1 mol of compound [VI].

  The condensing agent used in the production of citalopram is not particularly limited as long as it is usually used as a condensing agent. For example, sodium hydride, potassium hydride, calcium hydride, potassium hydroxide, sodium hydroxide, potassium carbonate, Examples include sodium carbonate, tert-butoxypotassium, tert-butoxysodium, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium diisopropylamide, lithium hexamethyldisilazide, and preferably sodium hydride, Tert-butoxy potassium, more preferably sodium hydride. The amount of the condensing agent to be used is generally 0.9 mol to 3 mol, preferably 1 mol to 1.5 mol, per 1 mol of compound [VI].

  Examples of the reaction solvent used in the production of citalopram include dimethyl sulfoxide, sulfolane, N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran (THF), 1,4-dioxane, 1,3-dioxolane, dimethoxy. Ethane, diethylene glycol dimethyl ether, tert-butyl methyl ether, diethyl ether, diisopropyl ether, dibutyl ether, anisole, benzene, toluene, xylene, mesitylene, cyclohexane, heptane, hexane, liquid paraffin and the like, preferably dimethyl sulfoxide, sulfolane, N, N-dimethylformamide, N, N-dimethylacetamide, THF, 1,3-dioxolane, dimethoxyethane, diethylene glycol Methyl ether, toluene, xylene, tert- butyl methyl ether, liquid paraffin and the like, they may be used in combination with one or more. N, N, N ′, N′-tetramethylethylenediamine and 1,3-dimethyl-2-imidazolidinone may also be used as the reaction solvent. The reaction solvent in the present invention is particularly preferably a mixed solvent of toluene and N, N, N ′, N′-tetramethylethylenediamine or 1,3-dimethyl-2-imidazolidinone from the viewpoint of yield.

  The amount of reaction solvent used in the production of citalopram depends on the type of reaction solvent and reaction conditions, but is usually preferably 1 L to 100 L, more preferably 3 L to 30 L, per 1 kg of compound [VI].

  As reaction temperature in manufacture of citalopram, it is -70 degreeC-150 degreeC normally, Preferably it is 20 degreeC-90 degreeC, More preferably, it is 40 degreeC-70 degreeC. The reaction time is not particularly limited, and is usually 30 minutes to 15 hours, preferably 2 hours to 8 hours.

  Citalopram can be isolated and purified by ordinary post-treatment and separation operations. For example, the reaction solution is poured into ice water, and this is extracted with an organic solvent. The resulting organic layer is extracted with an acidic aqueous solution, neutralized, extracted again with an organic solvent, and the solvent is distilled off to remove citalopram. Can be separated. Moreover, it can also refine | purify by a conventional method as needed.

  EXAMPLES Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto.

Example 1
Synthesis of (2,4-dimethylphenyl)-(4′-fluorophenyl) methanol (Compound [I]) In a nitrogen stream, 16.8 g of ground magnesium was dispersed in 116 ml of THF, and 0.1 g of iodine was added. A solution of 116 g of 4-bromofluorobenzene in THF (201 ml) was added dropwise at 15-40 ° C., and the mixture was stirred at 20-40 ° C. for 2 hours. The obtained mixture of Grignard reagents was cooled, and a solution of 81 g of 2,4-dimethylbenzaldehyde in THF (81 ml) was added dropwise thereto at 0-20 ° C. After the dropwise addition, the reaction solution was stirred at 0-20 ° C. for 2 hours, and then the reaction was stopped with a saturated aqueous ammonium chloride solution. The organic layer obtained by separating the reaction solution was retained, the aqueous layer was further extracted with toluene, combined with the previous organic layer, and then washed with saturated brine. The solvent was distilled off from the organic layer under reduced pressure to obtain 139.2 g (100%) of (2,4-dimethylphenyl)-(4′-fluorophenyl) methanol as a colorless oil.

¹ H-NMR (CDCl ₃ , 400 MHz) δ = 2.05 (1H, d, J = 4 Hz), 2.21 (3H, s), 2.31 (3H, s), 5.96 (1H, d , J = 4 Hz), 6.98 (1H, s), 7.00 (2H, t, J = 9 Hz), 7.05 (1H, d, J = 8 Hz), 7.29 (2H, dd, J = 9 Hz, J = 5 Hz), 7.33 (1H, d, J = 8 Hz) ppm

Example 2
Synthesis of (2,4-dimethylphenyl)-(4′-fluorophenyl) methanol (Compound [I]) In a nitrogen stream, 16.8 g of ground magnesium was dispersed in 54 ml of THF, and 0.1 g of iodine was added. A solution of 116 g of 4-bromofluorobenzene in THF (201 ml) was added dropwise at 15-40 ° C., and the mixture was stirred at 20-40 ° C. for 2 hours. The obtained mixture of Grignard reagents was cooled, and a solution of 81 g of 2,4-dimethylbenzaldehyde in THF (81 ml) was added dropwise thereto at 0-20 ° C. After the dropwise addition, the reaction solution was stirred at 0-20 ° C. for 2 hours, and then the reaction was stopped with a saturated aqueous ammonium chloride solution. The organic layer obtained by separating the reaction solution was retained, and then washed with saturated brine. The solvent was distilled off from the organic layer under reduced pressure to obtain 139.2 g (100%) of (2,4-dimethylphenyl)-(4′-fluorophenyl) methanol as a colorless oil. As a result of measuring ¹ H-NMR of the obtained colorless oil, it was the same as that of Example 1.

Example 3
Synthesis of (2,4-dimethylphenyl)-(4′-fluorophenyl) methanol (Compound [I]) In a nitrogen stream, 16.8 g of ground magnesium was dispersed in 46 ml of THF, and 0.1 g of iodine was added. 2.1 g of 4-bromofluorobenzene was added dropwise. After confirming the start of the reaction, 242 ml of THF was introduced. Further, 113.9 g of 4-bromofluorobenzene was added dropwise at 31.8-48.9 ° C., followed by stirring at 38-40 ° C. for 2 hours. The obtained mixture of Grignard reagents was cooled, and 81 g of 2,4-dimethylbenzaldehyde was added dropwise thereto at 5-29.9 ° C. After the dropwise addition, the reaction solution was stirred at 21.3-38.3 ° C. for 1.5 hours, the reaction was stopped with a saturated aqueous solution of ammonium chloride, and the organic layer obtained by separating the reaction solution was washed with saturated brine. did. The solvent was distilled off from the organic layer under reduced pressure to obtain 139.2 g (100%) of (2,4-dimethylphenyl)-(4′-fluorophenyl) methanol as a colorless oil. As a result of measuring ¹ H-NMR of the obtained colorless oil, it was the same as that of Example 1.

Example 4
Synthesis of 4- (4′-fluorobenzoyl) isophthalic acid (compound [II]) To 121 g of (2,4-dimethylphenyl)-(4′-fluorophenyl) methanol, 723 ml of t-butyl alcohol and 1090 ml of water were added. After heating to ° C., 582 g of potassium permanganate was added at 50-75 ° C. over 6 hours. After stirring the reaction solution at 70-85 ° C. for 3 hours, most of the t-butyl alcohol was distilled off under reduced pressure. By-product manganese dioxide was removed by filtration, and the obtained filtrate was neutralized with 6N hydrochloric acid. The produced crystals were filtered and dried to obtain 114.2 g (75%) of substantially pure 4- (4′-fluorobenzoyl) isophthalic acid as white crystals.

¹ H-NMR (DMSO-d ₆ , 400 MHz) δ = 7.31 (2H, t, J = 9 Hz), 7.55 (1H, d, J = 8 Hz), 7.70 (2H, dd, J = 9 Hz, J = 5 Hz), 8.23 (1H, dd, J = 8 Hz, J = 2 Hz), 8.51 (1H, d, J = 2 Hz), 13.52 (2H, br) ppm

Example 5
Synthesis of 4- (4′-fluorobenzoyl) isophthalic acid (compound [II]) To 121 g of (2,4-dimethylphenyl)-(4′-fluorophenyl) methanol, 703 ml of t-butyl alcohol and 578 ml of water were added. After heating to ° C., 548 g of potassium permanganate was added at 70-80 ° C. over 32 hours. After stirring the reaction solution at 70-85 ° C. for 3 hours, most of the t-butyl alcohol was distilled off under reduced pressure. By-product manganese dioxide was removed by filtration, and the obtained filtrate was neutralized with 6N hydrochloric acid. The produced crystals were filtered and dried to obtain 108.1 g (71.4%) of substantially pure 4- (4′-fluorobenzoyl) isophthalic acid as white crystals. As a result of measuring ¹ H-NMR of the obtained white crystals, it was the same as Example 4.

Example 6
Synthesis of 4- (4′-fluorobenzoyl) isophthalic acid (compound [II]) 121 g of (2,4-dimethylphenyl)-(4′-fluorophenyl) methanol, 847 ml of 87% t-butyl alcohol aqueous solution and water 580. After 8 ml was added and heated to 69.9 ° C., 582 g of potassium permanganate was added at 70.0-80.2 ° C. over 31 hours and 20 minutes. After stirring the reaction solution at 70-85 ° C. for 3 hours, most of the t-butyl alcohol was distilled off under reduced pressure. By-product manganese dioxide was removed by filtration, and the obtained filtrate was neutralized with 6N hydrochloric acid. The produced crystals were filtered and dried to obtain 108.4 g (71.5%) of almost pure 4- (4′-fluorobenzoyl) isophthalic acid as white crystals. As a result of measuring ¹ H-NMR of the obtained white crystals, it was the same as Example 4.

Example 7
Synthesis of 1,3-dimethyl-4- (4′-fluorobenzoyl) benzene (compound [I ′]) A suspension in which 19.5 g of anhydrous aluminum chloride was dispersed in 150 ml of m-xylene was cooled under ice cooling. -21.1 g of fluorobenzoyl chloride was added dropwise. After stirring at 0-10 ° C for 3 hours, the reaction solution was separated by pouring into 6N hydrochloric acid. The obtained organic layer was washed successively with water, a 10% aqueous sodium hydroxide solution and water, and the solvent was distilled off to obtain 1,3-dimethyl-4- (4′-fluorobenzoyl) benzene and 1,3- 30.2 g (99%) of a 96: 4 mixture of dimethyl-2- (4′-fluorobenzoyl) benzene was obtained as a slightly yellow oily liquid.

1,3-dimethyl-4- (4′-fluorobenzoyl) benzene
¹ H-NMR (CDCl ₃ , 400 MHz) δ = 2.32 (3H, s), 2.38 (3H, s), 7.05 (1H, d, J = 8 Hz), 7.11 (2H, dd , J = 9 Hz, J = 7 Hz), 7.11 (1H, s), 7.21 (1H, d, J = 8 Hz), 7.82 (2H, dd, J = 9 Hz, J = 5 Hz) ppm

Example 8
Synthesis of 1,3-dimethyl-4- (4′-fluorobenzoyl) benzene (compound [I ′]) To a suspension of 16.2 g of anhydrous aluminum chloride in 150 ml of 1,2-dichlorobenzene, 13 g was added, and 17.0 g of 2,4-dimethylbenzoyl chloride was added dropwise at 0-20 ° C. This was stirred at 10-30 ° C. for 1 hour, heated to 80 ° C., stirred for 1 hour, cooled again and poured into 6N hydrochloric acid, and the reaction solution was diluted with a large excess of toluene and separated. The obtained organic layer was washed successively with 5% aqueous sodium hydroxide and water, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using cyclohexane-ethyl acetate as an eluent to obtain almost pure. 19.4 g (85%) of 1,3-dimethyl-4- (4′-fluorobenzoyl) benzene was obtained as a slightly yellow oily liquid. The spectral data of this product was in agreement with the spectral data confirmed in Example 7.

Example 9
Synthesis of 4- (4′-fluorobenzoyl) isophthalic acid (compound [II]) 45 g of potassium permanganate was dispersed in 110 g of a 25 w% t-butyl alcohol aqueous solution and heated to 65 ° C. To this, 10 g of a 96: 4 mixture of 1,3-dimethyl-4- (4′-fluorobenzoyl) benzene and 1,3-dimethyl-2- (4′-fluorobenzoyl) benzene synthesized in Example 7 was added. A t-butyl alcohol (28 ml) solution was added dropwise. After the dropwise addition, this was reacted at 80-85 ° C. for 3 hours, most of the t-butyl alcohol was distilled off under reduced pressure, and by-produced manganese dioxide was removed by filtration. The obtained filtrate was neutralized with 6N hydrochloric acid, and the resulting crystals were filtered and dried to obtain 9.9 g (78%) of substantially pure 4- (4′-fluorobenzoyl) isophthalic acid as white crystals. It was. The spectral data of this product was consistent with that of Example 4.

Example 10
Synthesis of 4- (4′-fluorobenzoyl) isophthalic acid (compound [II]) After dispersing 20 g of trimellitic anhydride and 18.5 g of fluorobenzene in 200 ml of 1,2-dichlorobenzene, 42 g of anhydrous aluminum chloride was added. And stirred at 70-90 ° C. for 4 hours. The reaction solution was poured into 400 ml of 4N hydrochloric acid and extracted with 400 ml of methyl isobutyl ketone. The organic layer was extracted with 240 g of 5% aqueous sodium hydroxide, and the aqueous layer was neutralized with 64 g of 6N hydrochloric acid. The resulting crystals were filtered, washed with water, and dried to give 22.4 g (75%) of a 7: 3 mixture of 4- (4′-fluorobenzoyl) isophthalic acid and 2- (4′-fluorobenzoyl) terephthalic acid. Was obtained as white crystals.
The resulting mixture was recrystallized from methanol-water (8: 5) to obtain 6.8 g of almost pure 4- (4′-fluorobenzoyl) isophthalic acid. The spectral data of this product was consistent with that of Example 4.

Example 11
Synthesis of 4- (4′-fluorobenzoyl) isophthalic acid (compound [II]) After dispersing 20 g of trimellitic anhydride and 20 g of fluorobenzene in 150 ml of 1,2,4-trichlorobenzene, 42 g of anhydrous aluminum chloride was added. And stirred at 70-90 ° C. for 8 hours. The reaction mixture was poured into 300 ml of 4N hydrochloric acid in an ice bath, stirred at 50 ° C. for 3 hours, and then cooled. The resulting crystals were washed thoroughly with water, filtered and dried to give 19.1 g (64% of a 65:35 mixture of 4- (4′-fluorobenzoyl) isophthalic acid and 2- (4′-fluorobenzoyl) terephthalic acid. ) Was obtained as white crystals.

4- (4'-Fluorobenzoyl) isophthalic acid
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ = 7.31 (2H, t, J = 9 Hz), 7.55 (1H, d, J = 8 Hz), 7.70 (2H, dd, J = 9 Hz, J = 5 Hz), 8.23 (1H, dd, J = 8 Hz, J = 2 Hz), 8.51 (1H, d, J = 2 Hz), 13.52 (2H, br) ppm

2- (4′-Fluorobenzoyl) terephthalic acid
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ = 7.32 (2H, t, J = 9 Hz), 7.71 (2H, dd, J = 9 Hz, J = 5 Hz), 7.87 (1H, d, J = 2 Hz), 8.09 (1H, d, J = 8 Hz), 8.17 (1H, dd, J = 8 Hz, J = 2 Hz), 13.52 (2H, br) ppm

Comparative Example 1
Synthesis of 4- (4′-fluorobenzoyl) isophthalic acid (compound [II]) After dispersing 20 g of trimellitic anhydride and 20 g of fluorobenzene in 200 ml of nitrobenzene, 45 g of anhydrous aluminum chloride was added, and the temperature was 70 to 90 ° C. Stir for 6 hours. As a result of HPLC analysis of the reaction solution, the production rate of 4- (4′-fluorobenzoyl) isophthalic acid was 4%. Thereafter, the mixture was further stirred at 110 to 120 ° C. for 6 hours, but only the by-products (other than isomers) increased, and the production rate of 4- (4′-fluorobenzoyl) isophthalic acid tended to decrease.

Example 12
Synthesis of 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-ylmethanol (Compound [III]) To a suspension of 2.5 g of sodium borohydride dispersed in 40 ml of diethylene glycol dimethyl ether A solution of 5.8 g of diethylene glycol dimethyl ether (29 ml) in a 7: 3 mixture of 4- (4′-fluorobenzoyl) isophthalic acid and 2- (4′-fluorobenzoyl) terephthalic acid obtained in Example 10 The solution was added dropwise at 25 ° C. and stirred for 10 minutes. To this, 10.9 g of boron trifluoride THF complex was added dropwise at 20-45 ° C., and further heated at 40-50 ° C. for 2 hours. The mixture was hydrolyzed with 50 ml of water in an ice bath, 50 ml of 85% phosphoric acid was added, and the mixture was stirred at 60 ° C. for 5 hours. Crystals produced by adding 200 ml of water and cooling are filtered, washed with water, and dried to give 3.23 g of crude 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-ylmethanol. Obtained. This was recrystallized twice from toluene to obtain 2.10 g (43%) of substantially pure 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-ylmethanol.

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 = 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 13
Synthesis of 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-ylmethanol (compound [III]) A suspension of 14.6 g of sodium borohydride dispersed in 120 ml of THF was carried out. A solution of 24.0 g of THF (240 ml) in a 7: 3 mixture of 4- (4′-fluorobenzoyl) isophthalic acid and 2- (4′-fluorobenzoyl) terephthalic acid obtained in the same manner as in Example 10 It was dripped at 30 ° C. The mixture was heated to 55 ° C, and 47.0 g of dimethyl sulfate was added dropwise at 55-65 ° C. After the dropwise addition, this was refluxed for 5 hours, then hydrolyzed with 72 ml of water in an ice bath, and THF was distilled off under reduced pressure. To the residue was added 48 g of 85% phosphoric acid, and the mixture was stirred at 60 ° C. for 5 hours. Crystals produced by adding 72 ml of water and cooling were filtered, washed with water, and dried to give 15.1 g of crude 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-ylmethanol. Obtained. This was recrystallized twice from toluene to obtain 8.2 g (40%) of substantially pure 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-ylmethanol. The various spectral data of this were in agreement with those obtained by Example 12.

Example 14
Synthesis of 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-ylmethanol (compound [III]) A suspension of 15.0 g of sodium borohydride dispersed in 130 ml of THF was carried out. A solution of 26.0 g of 4- (4′-fluorobenzoyl) isophthalic acid synthesized in Example 4 in THF (260 ml) was added dropwise at 20-30 ° C., then heated to 55 ° C., and dimethyl sulfate 51-55 at 55-65 ° C. 0.0 g was added dropwise. After the dropwise addition, this was refluxed for 5 hours, then hydrolyzed with 130 ml of water in an ice bath, and THF was distilled off under reduced pressure. To the residue, 52 g of 85% phosphoric acid was added and stirred at 60 ° C. for 5 hours. Crystals generated by adding 390 ml of water and cooling were filtered, washed with water, and dried to obtain 20.4 g of crude 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-ylmethanol. Obtained. By recrystallizing this from an ethyl acetate-heptane (2: 3) mixed solvent, 18.9 g of substantially pure 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-ylmethanol (86%) was obtained. The various spectral data of this were in agreement with those obtained by Example 12.

Example 15
Synthesis of 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-ylmethanol (Compound [III]) 43.5 g of sodium borohydride was dispersed in 327 ml of THF. 9.1 g of trimethyl acid was added, and a solution of 100.5 g of 4- (4′-fluorobenzoyl) isophthalic acid synthesized in Example 4 in THF (313 ml) was added dropwise at 20-30 ° C., followed by heating to 35 ° C. 181.7 g (boron trifluoride: 45% by weight) of boron trifluoride-THF complex was added dropwise at 35-42 ° C. After dripping, this was heated at 40-50 ° C. for 7 hours, hydrolyzed with 101 ml of water in an ice bath, and THF was distilled off under reduced pressure. To the residue was added 110 g of 30% sulfuric acid, and the mixture was stirred at 60 ° C. for 5 hours. After adding 200 g of 25% aqueous sodium hydroxide and extracting with 450 ml (70 ° C.) of hot toluene, the hot toluene layer was washed with 60 ml of warm water (70 ° C.), and then the crystals formed by adding 450 ml of heptane and cooling were filtered. By drying, 69.0 g (81%) of 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-ylmethanol was obtained. The various spectral data of this were in agreement with those obtained by Example 12.

Example 16
Synthesis of 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-ylmethanol (Compound [III]) To a dispersion obtained by dispersing 1.0 g of lithium aluminum hydride in 10 ml of THF, 4- (4 A solution of 3.0 g of '-fluorobenzoyl) isophthalic acid in THF (30 ml) was added dropwise at room temperature, and the mixture was further stirred for 10 hours. After adding 10 ml of 10% hydrochloric acid to the reduction reaction solution and filtering through Celite, THF was distilled off under reduced pressure, 10 g of 85% phosphoric acid was added, and the mixture was stirred at 60 ° C. for 5 hours. 50 ml of water was added to the reaction solution, the resulting crystals were filtered and dried, and the target product was separated by silica gel column chromatography to give 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5 0.21 g (8%) of ilmethanol was obtained. The various spectral data of this were in agreement with those obtained by Example 12.

Example 17
Synthesis of 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-ylmethanol (Compound [III]) In a nitrogen atmosphere, 40.3 kg of sodium borohydride was added to 280.3 kg of THF. 8.4 kg of trimethyl borate was added dropwise at 20 to 30 ° C., and then a solution of 93.1 kg of 4- (4′-fluorobenzoyl) isophthalic acid prepared in the same manner as in Example 4 in 280.3 kg of THF was added. Added dropwise at ~ 30 ° C. Boron trifluoride-THF complex 173.3 kg (boron trifluoride: 45 wt%) was added dropwise at 35 to 42 ° C., and reacted at 38 to 42 ° C. for 3 hours and then at 48 to 50 ° C. for 4 hours. The reaction solution was cooled to 0 to 5 ° C., and 93.6 kg of water was added dropwise at 0 to 25 ° C. The mixture was heated to 50 to 55 ° C., 372 kg of hot water of 40 to 50 ° C. was introduced, and heated to 50 to 85 ° C. under normal pressure to distill away the solvent (637 kg). The reaction solution was cooled to about 57 ° C., 102 kg of 30% sulfuric acid was introduced at 55-60 ° C., and the mixture was stirred at 60-65 ° C. for 3:50. When confirmed by HPLC, the triol form (compound [VII]) was 0.1%. 186.6 kg of 25% aqueous sodium hydroxide solution was added dropwise at 20 to 40 ° C., 363 kg of toluene was added, and the mixture was heated and extracted at 75 to 80 ° C., followed by liquid separation. The organic layer was washed with 280 kg of hot water at 70 to 80 ° C., and the liquid was left to stand. To the organic layer, 55.6 kg of warm water at 70 to 80 ° C. was added and cooled to 25 to 30 ° C. After 284 kg of heptane was introduced at 25-30 ° C., the mixture was aged for 1 hour, once heated to 40-42 ° C., then cooled to 0-5 ° C. over 5 hours and aged for 1 hour. The crystals were filtered, and the crystals were washed with a solution prepared by mixing 40.7 kg of toluene and 31.5 kg of heptane and cooling to 0 to 5 ° C. Under reduced pressure, drying was carried out at about 45 ° C. for 15 hours and at 60 to 70 ° C. for 12 hours to obtain 64.5 kg of 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-ylmethanol. The yield was 81.8%. The various spectral data of this were in agreement with those obtained by Example 12.

Example 18
Synthesis of 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran -5-carbaldehyde (compound [V]) 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5 299.3 g of ylmethanol and 2.25 kg of manganese dioxide (Tosoh HMH type) were dispersed in t-butyl methyl ether (3.4 L) and stirred at 10-30 ° C. for 6 hours. The reaction solution was filtered and washed with 0.9 L of t-butyl methyl ether, and the solvent was distilled off under reduced pressure to obtain almost pure 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-carba 258.2 g (87%) of aldehyde was obtained as pale yellowish white crystals.

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 = 8 Hz), 7.30 (2H, dd, J = 9 Hz, J = 5 Hz), 7.77 (1H, d, J = 8Hz), 7.83 (1H, s), 10.03 (1H, s) ppm

Example 19
Synthesis of 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran -5-carbaldehyde (compound [V]) 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5 66.0 g of ilmethanol was dispersed in toluene (660 ml), and 594 g of manganese dioxide (HMH type manufactured by Tosoh Corporation) was added at 15-30 ° C. over 1 hour, followed by stirring at 20-30 ° C. for 1 hour. The reaction solution was filtered and washed with 330 ml of toluene, and then the solvent was distilled off under reduced pressure to obtain 57.6 g (88 of almost pure 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbaldehyde). %) As pale yellowish white crystals. Various spectral data of this product were consistent with those obtained by Example 18.

Example 20
Synthesis of 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbaldehyde (compound [V]) 1- (4′-fluorophenyl) prepared in Example 17 in 520.9 kg of toluene 60.5 kg of -1,3-dihydroisobenzofuran-5-ylmethanol was added, and 544.8 kg of manganese dioxide (Tosoh HMH type) was divided into 3 portions at 10 to 30 ° C. and added over 3 hours. It stirred at 23-27 degreeC for 1 hour, and it confirmed that the raw material became 0.03% by HPLC, and added 18.2 kg of high flow supercells (made by Celite) and 30.2 kg of anhydrous magnesium sulfate. It cooled over 2 hours to about 10 degreeC, and stirred for 40 minutes at 2-10 degreeC. The mixture was filtered, and the filtration residue (waste manganese) was washed with 284 kg of toluene. As a result of analysis, 60 kg (yield: about 100%) of 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbaldehyde was contained in 917 kg of the solution. Crystals obtained by concentrating a part of the solution showed the same physical properties as in Example 18.

Example 21
Synthesis of 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran -5-carbonitrile (compound [VI]) 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5 50.0 g of ilmethanol and 200 g of manganese dioxide (HMH type manufactured by Tosoh Corporation) were dispersed in xylene (400 ml) and stirred at 25 to 45 ° C. for 6 hours. After filtering the reaction solution, 14.1 g of hydroxylamine hydrochloride and 20.5 g of triethylamine were added, and the mixture was stirred at 70 to 75 ° C for 1 hour, further added with 75.3 g of acetic anhydride, and stirred at 130 to 140 ° C for 6 hours. . After adding 180 ml of water to the reaction solution, 100 g of a 10% aqueous sodium hydroxide solution was further added for liquid separation. After distilling off the solvent under reduced pressure, 44 ml of xylene and 71 ml of heptane were added at 60 ° C., and the crystals formed by cooling to room temperature were filtered and dried to give 1- (4′-fluorophenyl) -1,3-dihydro 35.8 g (73%) of isobenzofuran-5-carbonitrile was obtained as slightly yellow crystals.

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 = 8 Hz), 7.27 (2H, dd, J = 9 Hz, J = 5 Hz), 7.55 (1H, d, J = 8Hz), 7.60 (1H, s) ppm

Example 22
Synthesis of citalopram In a nitrogen stream, 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile was added to a suspension of 0.96 g of 60% sodium hydride dispersed in 20 ml of THF. 0 g THF (10 ml) solution was added dropwise at 40-50 ° C. To this was added 0.2 g of tetra n-butylammonium bromide, and then a solution of 3.4 g of 3- (dimethylamino) propyl chloride in t-butyl methyl ether (18 ml) was added dropwise and stirred for 10 minutes. Further, 26.1 g (25 ml) of 1,3-dimethyl-2-imidazolidinone was added, and the mixture was stirred at 61 to 64 ° C. for 6 hours. The reaction solution was poured into 83 ml of ice water and extracted three times with 33 ml of toluene. The organic layer was extracted 3 times with 41 ml of 20% aqueous acetic acid, and the resulting aqueous layer was neutralized with 120 g of 25% aqueous sodium hydroxide solution and then extracted 3 times with 40 ml of toluene. The obtained organic layer was washed with water, and the solvent was distilled off to give viscous oily 1- (3- (dimethylamino) propyl) -1- (4′-fluorophenyl) -1,3-dihydroiso 5.36 g (yield 79.1%) of benzofuran-5-carbonitrile (citalopram base) was obtained.

¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.26 to 1.52 (2H, m), 2.11 to 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), 7.39 (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

This was converted to a hydrobromide by a conventional method. The melting point of hydrobromide (crystal) was 184-186 ° C.
HPLC retention time and measurement conditions Retention time; 10.5 minutes Column; Inertsil (registered trademark) manufactured by GL Sciences
ODS-2 4.6mm x 150mm
Buffer solution; 0.01% aqueous trifluoroacetic acid mobile phase; acetonitrile: buffer solution = 2: 8 to 7: 3 (applying a linear gradient over 40 minutes)
Flow rate: 1 ml / min

Example 23
Synthesis of citalopram Instead of 26.1 g (25 ml) of 1,3-dimethyl-2-imidazolidinone, 4.86 g of N, N, N ′, N′-tetramethylethylenediamine and 25 ml of N, N-dimethylformamide were sequentially added. A viscous oily 1- (3- (dimethylamino) propyl) -1- (4′-fluorophenyl) -1,3 was obtained by carrying out the reaction and post-treatment in the same manner as in Example 22 except for adding. -5.13 g (yield 75.7%) of dihydroisobenzofuran-5-carbonitrile (citalopram base) was obtained. The HPLC retention time and melting point of the hydrobromide of this product coincided with those obtained in Example 22.

Example 24
Synthesis of citalopram In a nitrogen stream, 60% sodium hydride 0.58 g was dispersed in 12 ml of THF, and 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile 3. 0 g of THF (6 ml) solution was added dropwise at 40-50 ° C. To this was added 0.12 g of tetra-n-butylammonium bromide, and then a solution of 2.0 g of 3- (dimethylamino) propyl chloride in t-butyl methyl ether (12 ml) was added dropwise and stirred for 10 minutes. Further, 0.73 g of N, N, N ′, N′-tetramethylethylenediamine and 14.2 g (15 ml) of N, N-dimethylformamide were added, and the mixture was stirred at 61 to 64 ° C. for 7 hours. The reaction solution was treated in the same manner as in Example 22 to give a viscous oily 1- (3- (dimethylamino) propyl) -1- (4′-fluorophenyl) -1,3-dihydroiso 3.14 g (yield 77.2%) of benzofuran-5-carbonitrile (citalopram base) was obtained. The HPLC retention time and melting point of the hydrobromide of this product coincided with those obtained in Example 22.

Example 25
Synthesis of citalopram Instead of 0.73 g N, N, N ′, N′-tetramethylethylenediamine and N, N-dimethylformamide (15 ml), 6.3 g (6 ml) 1,3-dimethyl-2-imidazolidinone And N, N-dimethylformamide was added in the same manner as in Example 24 except that 8.5 g (9 ml) was added to give viscous oily 1- (3- (dimethylamino) propyl). There were obtained 2.88 g (yield 70.7%) of -1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (citalopram base). The HPLC retention time and melting point of the hydrobromide of this product coincided with those obtained in Example 22.

Comparative Example 2
Synthesis of citalopram Reaction was carried out in the same manner as in Example 22 except that 16.1 g (25 ml) of 1,3-dimethyl-2-imidazolidinone was not added and the mixture was stirred at 61 to 64 ° C. for 6 hours. The reaction hardly progressed.

Comparative Example 3
Synthesis of citalopram Instead of 26.1 g (25 ml) of 1,3-dimethyl-2-imidazolidinone, 23.6 g (25 ml) of N, N-dimethylformamide was added, and the mixture was stirred at 61-64 ° C. for 7 hours. Was reacted and worked up in the same manner as in Example 22 to give a viscous oily 1- (3- (dimethylamino) propyl) -1- (4′-fluorophenyl) -1,3-dihydroiso 4.12 g (yield 60.8%) of benzofuran-5-carbonitrile (citalopram base) was obtained.

Example 26
Synthesis of Citalopram In a nitrogen stream, 60% sodium hydride 0.58 g was dispersed in 12 ml of toluene, and 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile ( 3.0 g) in THF (6 ml) was added dropwise at 40-50 ° C. To this was added 0.12 g of tetra n-butylammonium bromide, and then a toluene (12 ml) solution of 3- (dimethylamino) propyl chloride (2.0 g) was added dropwise and stirred for 10 minutes. Further, 2.92 g of N, N, N ′, N′-tetramethylethylenediamine and 15 ml of dimethyl sulfoxide were added, and the mixture was stirred at 61 to 64 ° C. for 7 hours. The reaction solution was treated in the same manner as in Example 22 to give a viscous oily 1- (3- (dimethylamino) propyl) -1- (4′-fluorophenyl) -1,3-dihydroiso 2.79 g (yield 68.6%) of benzofuran-5-carbonitrile (citalopram base) was obtained. The HPLC retention time and melting point of the hydrobromide of this product coincided with those obtained in Example 22.

Example 27
Synthesis of Citalopram Under a nitrogen stream, 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (3.0 g) in a solution of N, N-dimethylformamide (15 ml) was added to tetra-n- 0.12 g of butylammonium bromide and 2.92 g of N, N, N ′, N′-tetramethylethylenediamine were added. To this was added dropwise a solution of 3- (dimethylamino) propyl chloride (2.0 g) in toluene (12 ml), and then a suspension of 0.58 g of 60% sodium hydride and 1.5 ml of liquid paraffin was added for 1.5 hours. The mixture was added dropwise and stirred at 61 to 64 ° C. for 7 hours. The reaction solution was treated in the same manner as in Example 22 to give a viscous oily 1- (3- (dimethylamino) propyl) -1- (4′-fluorophenyl) -1,3-dihydroiso 2.69 g (yield 66.1%) of benzofuran-5-carbonitrile (citalopram base) was obtained. The HPLC retention time and melting point of the hydrobromide of this product coincided with those obtained in Example 22.

Example 28
Synthesis of Citalopram By performing the reaction and post-treatment in the same manner as in Example 27 except that dimethyl sulfoxide (15 ml) was used instead of N, N-dimethylformamide (15 ml), a viscous oily 1- ( There was obtained 2.68 g (yield 65.9%) of 3- (dimethylamino) propyl) -1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (citalopram base). The HPLC retention time and melting point of the hydrobromide of this product coincided with those obtained in Example 22.

Example 29
Synthesis of Citalopram Under a nitrogen stream, 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile 9.00 g in a 1,3-dimethyl-2-imidazolidinone (54 ml) solution 1.73 g of 60% sodium hydride was added at room temperature. After neutralizing 8.02 g of 3- (dimethylamino) propyl chloride hydrochloride with 39 g of a 10% aqueous sodium hydroxide solution, the mixture is extracted twice with 13.5 ml of toluene, and the extract is dehydrated with potassium carbonate and molecular sieves 3A. The toluene solution of 3- (dimethylamino) propyl chloride (about 6.1 g) prepared in step 1 was added dropwise to the previous 1,3-dimethyl-2-imidazolidinone solution, which had a reddish brown color, at room temperature under a nitrogen stream. . Further, 0.36 g of tetra n-butylammonium bromide and 4.37 g of N, N, N ′, N′-tetramethylethylenediamine were added and stirred at 60 to 62 ° C. for 5 hours. The reaction solution was poured into 149 ml of ice water and extracted three times with 54 ml of toluene. The organic layer was extracted 3 times with 71 ml of 20% aqueous acetic acid. The obtained aqueous layer was neutralized with 210 g of 25% aqueous sodium hydroxide solution and extracted three times with 54 ml of toluene. After washing the obtained organic layer with water, 3.6 g of potassium carbonate and 1.8 g of silica gel were added and stirred well, followed by filtration and evaporation of the solvent under reduced pressure to give a viscous oily 1- (3- (dimethyl). Amino) propyl) -1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (citalopram base) 10.50 g (yield 86.0%) was obtained. The HPLC retention time and melting point of the hydrobromide of this product coincided with those obtained in Example 22.

Example 30
Synthesis of citalopram (1- (3- (dimethylamino) propyl) -1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile) 19.6 kg of sodium hydroxide was added to 134 kg of water. 60.7 kg of 65.6% aqueous 3- (dimethylamino) propyl chloride hydrochloride was added dropwise at 20 to 25 ° C. Toluene (58.2 kg) was added and stirred, and the mixture was allowed to stand for liquid separation. To the aqueous layer was added 58.2 kg of toluene, and the mixture was stirred and allowed to stand for liquid separation. The organic layers were combined, and 9 kg of powdered anhydrous potassium carbonate and 1.7 kg of molecular sieves 4A were added and stirred for 1 hour. Filtration was performed, and the filtration residue was washed with 27 kg of toluene to obtain a toluene solution of 3- (dimethylamino) propyl chloride.

  639.9 kg (1- (4′-fluorophenyl) -1 of a toluene solution of 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile obtained in the same manner as in Example 21. , 3-dihydroisobenzofuran-5-carbonitrile (corresponding to 44.8 kg) was concentrated under reduced pressure at 30 to 50 ° C., and 539 kg of toluene was distilled off. To this concentrated solution, 27 kg of toluene was added, the previously prepared toluene solution of 3- (dimethylamino) propyl chloride was flowed in, and 10 kg of 1,3-dimethyl-2-imidazolidinone was added. After adding 9.1 kg of 64.8% sodium hydride at 25-30 ° C., 183 kg of 1,3-dimethyl-2-imidazolidinone was immediately added dropwise. The dropping temperature was 25 to 60 ° C. and took 4 hours and 20 minutes. The mixture was reacted at 60 to 63 ° C. for 6 hours and cooled to about 10 ° C. When the reaction solution was analyzed by HPLC, the residual ratio of 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile was 0.1%.

  The reaction solution was added dropwise to 806 kg of water at about 5 ° C., 233.5 kg of toluene was added, and the mixture was stirred and extracted, followed by standing separation. To the aqueous layer was added 233.5 kg of toluene, and the mixture was extracted by stirring and liquid separation. The extracted organic layers were combined, extracted by stirring with 179 kg of 5% hydrochloric acid, and separated. The organic layer was extracted again with 179 kg of 5% hydrochloric acid and separated, and the aqueous layers extracted with hydrochloric acid were combined. 234 kg of toluene was added to the combined aqueous layer, and 89.6 kg of 25% sodium hydroxide was added dropwise at 25 to 35 ° C. to make it alkaline. The mixture was extracted with stirring and liquid separation was allowed to stand. The aqueous layer was extracted again with 156.3 kg of toluene, and the organic layers were combined. The organic layer was washed 3 times with 268.7 kg of water. The organic layer was dehydrated with 17.9 kg of powdered anhydrous potassium carbonate, 6.7 kg of silica gel (Merck 9385) was added, and the mixture was stirred for 1 hour. Filtered and the filter residue was washed with 39.1 kg of toluene. Toluene was distilled off at 40 to 65 ° C. under reduced pressure. The amount of toluene distilled off was 425 kg. The concentrated residue was dissolved by adding 35.5 kg of acetone to obtain an acetone solution of citalopram. In 96.1 kg of the liquid volume, 52.96 kg (yield: 87.2%) of citalopram base was contained. The HPLC retention time of the crystalline hydrobromide obtained by partially distilling off acetone was the same as that obtained in Example 22.

Reference example 1
Preparation of 1- (3- (dimethylamino) propyl) -1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile hydrobromide Example 16 to 163.4 kg of acetone 94.1 kg (including 51.8 kg of citalopram) of citalopram produced in the above was added, and 13.2 kg of hydrogen bromide was blown in at a temperature of 25 to 35 ° C. over 3 hours. After aging for 3 hours, it was cooled to about 5 ° C., and further aged for 3 hours at 0-5 ° C. The filtered crystals were washed with 40.9 kg of acetone cooled to 0-5 ° C. By drying at 30 to 50 ° C. under reduced pressure, 54.9 kg (yield 84.8%) of citalopram hydrobromide was obtained. Melting point: 180-183 ° C.
Bulk density: 0.29 kg / L for static and 0.32 kg / L for dynamic.

Reference example 2
Synthesis of 1- (3- (dimethylamino) propyl) -1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (citalopram base) 4.2 g of 60% sodium hydride in 135 ml of THF A solution of 21.6 g of 1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile in THF (40 ml) was added dropwise at 40-50 ° C. After stirring for 30 minutes at the same temperature, a solution of 14.4 g of 3- (dimethylamino) propyl chloride in t-butyl methyl ether (60 ml) was added dropwise, and after stirring for 10 minutes, 135 ml of dimethyl sulfoxide was further added dropwise. Stir at 70 ° C. for 5 hours. The reaction solution was poured into 800 ml of ice water and extracted three times with 250 ml of toluene. The organic layer was extracted twice with 250 ml of 20% aqueous acetic acid. The aqueous layer was neutralized, extracted twice with 250 ml of toluene, washed with water, and the solvent was distilled off to give 1- (3- 17.9 g (61.1%) of (dimethylamino) propyl) -1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (citalopram base) was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz) δ = 1.26 to 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), 7.39 (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
The melting point of the crystal obtained by converting this into a hydrobromide by a conventional method was 184-186 ° C.

Claims (10)

Formula [I]

A compound represented by Formula [I], characterized in that 4-bromofluorobenzene is converted to 4-fluorophenylmagnesium bromide, and then the 4-fluorophenylmagnesium bromide is reacted with 2,4-dimethylbenzaldehyde.

The manufacturing method of the compound shown by these. Formula [I]

Wherein the compound represented by formula [II] is oxidized

The manufacturing method of the compound shown by these.   A process for producing 1,3-dimethyl-4- (4'-fluorobenzoyl) benzene, characterized by using 4-fluorobenzoyl halide and Friedel-Crafts reaction using m-xylene as a raw material and solvent. Using m-xylene as a raw material and solvent, 4-fluorobenzoyl halide was reacted with Friedel-Crafts to obtain 1,3-dimethyl-4- (4′-fluorobenzoyl) benzene, and then the 1,3-dimethyl- 4- [4′-fluorobenzoyl) benzene is oxidized, the formula [II]

The manufacturing method of the compound shown by these. 2,4-Dimethylbenzoyl halide is subjected to Friedel-Crafts reaction with fluorobenzene to give 1,3-dimethyl-4- (4′-fluorobenzoyl) benzene, and then the 1,3-dimethyl-4- (4 ′ -Fluorobenzoyl) benzene, which is characterized by the oxidation [II]

The manufacturing method of the compound shown by these. Formula [II], characterized in that trimellitic anhydride is reacted with fluorobenzene in Friedel-Crafts reaction in a dichlorinated or trichlorinated benzene solvent

The manufacturing method of the compound shown by these. In the presence of at least one selected from N, N, N ′, N′-tetramethylethylenediamine and 1,3-dimethyl-2-imidazolidinone and a condensing agent, the compound of the formula [VI]

Wherein the compound of formula [A] is reacted with 3- (dimethylamino) propyl chloride

The manufacturing method of citalopram shown by this. The compound represented by the formula [VI] is represented by the formula [V]

The production method according to claim 8, wherein the compound represented by the formula is obtained by sequentially performing an oximation reaction and a dehydration reaction.   The production method according to claim 8 or 9, wherein the condensing agent is sodium hydride.