JP6856985B2 - A method for producing S-4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile, and the compound used (1S). Method for producing -1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile and its salt - Google Patents

Description

The present invention uses a method for producing S-4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile, and the compound thereof. It relates to a method for producing (1S) -1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile and a salt thereof.

(1S) -1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (hereinafter, also referred to as "escitalopram") is as follows. It has structure (5) and its oxalate is a well-known antidepressant.

The method for producing escitalopram (6) by the following synthetic route is known, and it has been isolated as escitalopram oxalate (7).

(1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toroil) ) Tartrate (4) is an important intermediate of escitaloplum and is a racemic 4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl). )-A method for producing by reacting benzonitrile (3) with di- (p-tortaric acid) tartaric acid is known (see Patent Document 2 below).

In the above method, the racemic 4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di-( It is known that optical resolution is performed after the production of p-toluoil) tartrate (a derivative of (3)) to obtain tartrate (4) having an enantioselectivity of 99%. The tartrate (4) is desalted to form a free form (5), and escitalopram and a salt thereof are produced by a ring closure reaction.

Japanese Patent No. 3038204 Japanese Patent No. 4966933

In the production method of the above patent document, the reaction is carried out at 40 to 50 ° C. when producing tartrate. In addition, the isolated tartrate is purified by reslurry at 50 ° C. using 1-propanol. However, when the present inventors conducted a follow-up test, it was confirmed that tartrate salt having a relatively high optical purity was obtained, but it was found that impurities may be produced as a by-product and the chemical purity may be low. Furthermore, it was also found that when escitalopram and its salt were produced using the above tartrate, the chemical purity was not improved and impurities could not be completely removed by recrystallization or the like.

Therefore, an object of the present invention is to provide a production method for improving the chemical purity, which is a problem in the production method of the patent document, and obtaining the free substance (5) having extremely high optical purity and chemical purity.

The present inventors have diligently studied the above-mentioned problems. First, as a result of analyzing the structure of impurities contained in tartaric acid salt (4), these impurities are the following impurities (i) and (ii), and tartaric acid (8) and (1S) -4- [4- ( It was found to be a mixture of esters (9-12) of dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile (5).

Therefore, as a result of further studies on the method for removing the impurities, the present inventors have performed desalting treatment in the presence of a specific solvent when desalting the tartrate (4) with a base. We have found that the content of the impurities can be reduced, and have completed the present invention.

That is, the present invention is each of the inventions [1] to [5].
[1]
From (1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile tartrate, the tartrate in the presence of a base. A method for producing (1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile, which is a free form of a salt. There,
A method characterized by reacting in a solvent containing water with at least one poorly water-soluble organic solvent selected from the group consisting of aromatic hydrocarbons and halogenated hydrocarbons.
[2]
The method according to [1], wherein the base is an inorganic base.
[3]
The method according to [1] or [2], wherein the aromatic hydrocarbon is toluene.
[4]
The method according to [1] or [2], wherein the halogenated hydrocarbon is chloroform.
[5]
S-4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) by the method according to any one of [1] to [4]. )-After producing benzonitrile, using the obtained compound, (1S) -1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran- A method for producing 5-carbonitrile and a salt thereof.

According to the present invention, S-4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl), which is a free form of tartrate (4). -Benzonitrile (5) can be obtained with extremely high optical and chemical purity. By producing escitalopram and its salt from the free product (5) obtained by this production method, escitalopram and its salt having extremely high optical purity and chemical purity can be produced.

Hereinafter, embodiments of the present invention will be described in detail.

<Method for producing tartrate (4) in the present invention>
The tartrate salt (4) in the present invention can be produced by the following synthetic route.

Racemic 4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoil) (3) A known method can be used for the production of the free form. For example, the acid salt of 4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile (3) in the racemic form is used as an organic solvent. A free substance (3) can be obtained by reacting a base with a two-layer solvent of water and water.

By the way, the acid salt of 4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile of the racemic mixture is, for example, as follows. Can be manufactured as That is, the acid salt can be obtained by performing a Grignard reaction between compound (1) and 4-bromofluorobenzene and performing a Grignard reaction between the obtained compound (2) and 3,3-dimethylaminopropyl chloride. ..

As the acid in the acid salt, various acids can be used, and examples thereof include hydrobromic acid and acetic acid. As the base to be reacted with the acid salt, various bases can be used, and examples thereof include sodium hydroxide and potassium carbonate.

As the liberation solvent, for example, ethyl acetate, diethyl ether, toluene, chloroform, dichloromethane can be used, and chloroform can be preferably used. The amount of the solvent for the liberation is 100 parts by mass of 4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile. On the other hand, a solvent of 300 to 2000 parts by mass, preferably 400 to 800 parts by mass can be used. The reaction temperature for the liberation can be appropriately determined in the range of 0 to 60 ° C.

The racemic 4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toroil) ) The free form of (3) can be tartrate-ized to obtain the tartrate (4). As a method for obtaining the tartrate (4), 4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile (3) Is dissolved in an organic solvent, and a solution in which (+)-di- (p-toluoil) tartaric acid or (-)-di- (p-toluoil) tartaric acid is dissolved is added to tartrate the free form (3) and precipitate. By letting it, tartrate is precipitated. At this time, when (+)-di- (p-tolu oil) tartaric acid was used as the di- (p-tolu oil) tartaric acid, (1S) -4- [4- (dimethylamino) -1- (4) '-Fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoil) tartrate (4a) is selectively precipitated. On the other hand, when (-)-di- (p-toluoil) tartaric acid is used as the di- (p-toluoil) tartaric acid, (1R) -4- [4- (dimethylamino) -1- (4'-) Fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoil) tartrate is selectively precipitated. Therefore, depending on the di- (p-tor oil) tartaric acid used, it is possible to obtain an optically resolution tartrate having an optical purity of about 93% or more.

As the solvent for tartrate formation, for example, IPA, 1-butanol and the like can be used, and IPA can be preferably used. The amount of solvent for tartrate formation is 4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile (3) 100 parts by mass. A solvent of 300 to 2000 parts by mass, preferably a solvent of 500 to 1000 parts by mass can be used.

The amount of (+)-di- (p-toluoil) tartaric acid used for tartrate formation is 4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3. 0.25 to 1.0 equivalents of the tartaric acid can be used with respect to-(hydroxymethyl) -benzonitrile (3), preferably 0.3 to 0.5 equivalents of the tartaric acid.

The purity of the tartrate (4) used in the method for producing the free substance (5) below is not particularly limited, and the tartrate (4) obtained in the above production method may be used as it is. From the viewpoint of obtaining a high-purity free substance (5), it is preferable to use tartrate (4) having a purity of 98% or more and a total content of impurities (i) and impurities (ii) of 1% or less. In particular, it is preferable to use tartrate (4) having a purity of 99% or more and a total content of impurities (i) and impurities (ii) of 0.5% or less. The purity of tartrate (4) and the content of impurities outside the above range should be improved by a known method such as reslurry or crystallization (including recrystallization). Can be done. Examples of the solvent used for reslurry and crystallization (including recrystallization) include 1-propanol, isopropyl alcohol, 2-propanol, 1-butanol and the like.

<Method for producing free form of tartrate (4) according to the present invention>
The free form (5) can be obtained by reacting tartrate (4) with a base. The method for producing a free form (5) of tartrate (4) according to the present invention comprises at least one poorly water-soluble organic solvent selected from the group consisting of aromatic hydrocarbons and / or halogenated hydrocarbons and water. In the solvent containing, in the presence of a base, (1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile tartaric acid From the salt (4), the free form of the tartrate (1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -It is characterized by obtaining benzonitrile (5).

The reason why the free substance (5) having extremely high optical purity and chemical purity can be obtained by the production method according to the present invention is unclear in detail, but the present inventors speculate as follows. That is, as described above, the impurities produced as by-products during the production of tartrate (4) are tartaric acid (8) and 4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl]-. It is an ester (9-12) with 3- (hydroxymethyl) -benzonitrile (5). Therefore, when desalting with a base, it is presumed that the hydrolysis reaction of the above ester is proceeding along with the desalting of tartaric acid. In the present invention, it is presumed that the use of a specific solvent promotes this hydrolysis reaction, and as a result, the chemical purity of the free substance (5) is improved.

In the method for producing a free form (5) of tartrate (4) according to the present invention, "water-resistant water-resistant" in at least one poorly water-soluble organic solvent selected from the group consisting of the aromatic hydrocarbons and / or halogenated hydrocarbons. The "sexual organic solvent" refers to an organic solvent having a solubility of water at 25 ° C. of 60 g / L or less.

In Patent Document 1, the tartrate (4) is liberated with diethyl ether (solubility in water: 69 g / L). In the method for producing a free tartrate salt (5) according to the present invention, the solubility of water at 25 ° C. is 60 g / L, which is lower than that of ethyl acetate (solubility in water: 83 g / L) and diethyl ether. By using the following organic solvent, a free substance (5) having extremely high optical purity and chemical purity can be obtained. Table 1 below shows the solubility of some solvents in water.

The poorly water-soluble organic solvent is at least one selected from the group consisting of aromatic hydrocarbons and halogenated hydrocarbons. These solvents may be used alone or in combination of two or more.

Examples of the aromatic hydrocarbon include toluene, benzene, xylene and the like. Examples of the halogenated hydrocarbon include dichloromethane, chloroform and the like.

Among the above-mentioned solvents, toluene is preferable as the aromatic hydrocarbon and chloroform is preferable as the halogenated hydrocarbon from the viewpoint of being available to the industrial body and being toxic.

As the amount of the poorly soluble organic solvent used, it is preferable to use an amount in which the obtained free substance (5) is sufficiently dissolved, and specifically, 2 to 10 parts by mass with respect to 1 part by mass of the tartrate salt salt. Preferably, 4 to 6 parts by volume is particularly preferable.

The method for producing a free form (5) of tartrate (4) according to the present invention is characterized by reacting in a solvent containing water in addition to a poorly water-soluble organic solvent. It is presumed that this is because the presence of water in the solvent is indispensable in order to achieve the effect of the present invention that the impurities (esters) are hydrolyzed in the liberation and the impurities are reduced. Further, in the method for producing the free substance (5) of the present invention, the obtained free substance (5) is dissolved in the above-mentioned poorly water-soluble organic solvent, and other by-products (for example, salts of tartaric acid and base) are dissolved. Dissolves in water. Therefore, it is presumed that a high-purity free substance (5) can be obtained by carrying out the reaction in the above solvent system.

If the amount of water used is too small, the tartrate (4) will not be dissolved, and if it is too large, the base concentration will be low, and it will take time to dissolve the tartrate (4). Specifically, 2 to 8 parts by mass is preferable, and 4 to 6 parts by mass is particularly preferable with respect to 1 part by mass of the tartrate salt (4).

In the method for producing a free form (5) of tartrate (4) according to the present invention, either an organic base or an inorganic base can be used as the base.

Examples of the organic base include triethylamine, diethylamine, DIPEA, DBU and the like.

Examples of the inorganic base include sodium hydroxide, potassium hydroxide, potassium carbonate and the like.

Among these bases, it is preferable to use an inorganic base because the obtained free substance (5) can be easily separated from the base, and the effect of improving the chemical purity of the free substance (5) is particularly high. Sodium hydroxide is preferred.

The amount of the base used is preferably 1 to 10 equivalents, more preferably 1 to 5 equivalents, and particularly preferably 1.5 to 2.5 equivalents, relative to the tartrate salt (4).

The reaction temperature during production of the free form (5) of tartrate (4) according to the present invention is preferably 5 to 50 ° C, more preferably 10 to 40 ° C, and particularly preferably 20 to 30 ° C. The reaction time is preferably 0.1 to 10 hours, preferably 0.5 to 3 hours, and particularly preferably 0.5 to 1 hour.

After the reaction for producing the free form (5) of tartrate (4) according to the present invention, the desired free form (5) can be obtained by performing each operation of liquid separation, washing, and solvent distillation.

<Method for producing escitalopram and its salt using the free form of the present invention>
By producing escitalopram and a salt thereof from the free product (5) obtained by the method for producing the free product (5) of tartrate (4) according to the present invention, escitalopram having extremely high optical purity and chemical purity and its salt are produced. Salt can be produced.

Escitalopram (6) can be obtained by the ring closure reaction of the free form (5) obtained by the liberation reaction according to the present invention. Further, a salt of escitalopram can be obtained by a chloride reaction of adding an acid to escitalopram (6). In particular, it is preferable to use escitalopram oxalate (7) in order to obtain it as a solid. As these production methods, known methods can be used without particular limitation.

In the ring closure reaction of the free product (5), for example, 850 parts by mass of toluene and 1.1 equivalents of triethylamine are added to the free product (5), and the mixture is stirred and dissolved at 5 ° C. After dissolution, 1.1 equivalent of paratoluenesulfonyl chloride is added dropwise. After the dropping, the mixture is stirred at 5 ° C. for 1 hour. After stirring for 1 hour, 200 parts by mass of water and 1.1 equivalents of aqueous ammonia are added, and the mixture is stirred for 30 minutes. After stirring, the organic layer and the aqueous layer are separated, and after the separation, the organic layer is concentrated at 60 ° C. to obtain an escitalopram (6) free form.

In the oxalate formation of escitalopram, for example, 800 parts by mass of acetone is added to the escitalopram (6) free form and dissolved by heating at 50 ° C. After heating and dissolving, 1.1 equivalents of oxalic acid is added to precipitate crystals. After confirmation of crystallization, the mixture is cooled to 25 ° C. at a rate of 20 to 30 ° C./hr and aged at 25 ° C. for 1 hour. After aging, solid-liquid separation is performed by filtration, and the obtained crystals are dried at 40 ° C. for 6 hours or more to obtain recrystallized escitalopram oxalate (7).

Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.

<Measurement of chemical purity and optical purity>
The chemical purity and optical purity of the tartrate (4), the free form (5), and the escitalopram oxalate (7) according to the present invention were measured by the following conditions using the HPLC method.

(1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-tolu oil) ) Evaluation of chemical purity of tartrate (4), free form (5) of tartrate (4), and escitaloplum oxalate (7) Purity and specific impurities of tartrate (4) and free form (5) , And escitaloplum oxalate (7) were measured by high performance liquid chromatography (HPLC). The equipment used for the HPLC measurement and the measurement conditions are as follows. The purity is a value indicated by a percentage of the peak area value of the target substance in the obtained chromatogram to the total of the area values of all the peaks. The retention time of the tartrate (4) and the free form (5) in the HPLC analysis under the conditions is around 22.2 minutes. The retention time of the specific impurity (i) is around 40.1 minutes, the retention time of the specific impurity (ii) is around 41.7 minutes, and the retention time of escitalopram oxalate (7) is around 35.1 minutes. is there.
Equipment: Waters 2695
Detector: Ultraviolet absorptiometer (2489 manufactured by Waters)
Detection wavelength: 237 nm
Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 25 cm filled with 5 μm of octadecylsilylated silica gel for liquid chromatography Mobile phase A: Acetonitrile / buffer solution = 10/90
Mobile phase B: acetonitrile / buffer = 65/35
Buffer solution: Dissolve 3.4 g of potassium dihydrogen phosphate in 1000 mL of water and add phosphoric acid to adjust the pH to 3.0.
Liquid transfer of mobile phase: The concentration gradient is controlled by changing the mixing ratio of mobile phase A and mobile phase B as follows.

Column temperature: Constant temperature around 45 ° C Injection amount: 20 μL
Sample concentration: 0.5 mg / mL

(1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toroil) ) Evaluation of the optical purity of tartrate (4) and the free form (5) of the tartrate (4) The measurement of the optical purity of tartrate (4) and the free form (5) is performed by high performance liquid chromatography (HPLC). ). The equipment used for the HPLC measurement and the measurement conditions are as follows. The optical purity of the tartrate (4) and the free form (5) is the peak area value of the tartrate (4) and the free form (5) in the obtained chromatogram of the S-form and the R-form. It is a value shown as a percentage of the total area value. The retention time of the tartrate (4) and the free form (5) in the HPLC analysis under the conditions is around 34.1 minutes. The retention time of R-form tartrate is around 37.5 minutes.
Equipment: Waters 2695
Detector: Ultraviolet absorptiometer (2489 manufactured by Waters)
Detection wavelength: 240 nm
Column: CHIRALCEL OD-H (Stainless steel tube with an inner diameter of 4.6 mm and a length of 25 cm filled with silica gel coated with a 5 μm cellulose derivative)
Mobile phase: Hexane / Ethanol / Diethylamine = 98/2 / 0.1
Flow velocity: 0.7 mL / min
Column temperature: Constant temperature around 30 ° C Injection amount: 10 μL
Sample concentration: 2.0 mg / mL

Evaluation of Optical Purity of Escitalopram Oxate (7) The optical purity of escitalopram oxalate (7) was measured by high performance liquid chromatography (HPLC). The equipment used for the HPLC measurement and the measurement conditions are as follows. The optical purity of escitalopram oxalate (7) is a value shown as a percentage of the total area value of S-form and R-form of the peak area value of escitalopram oxalate (7) in the obtained chromatogram. .. The retention time of escitalopram oxalate (7) in the HPLC analysis under these conditions is around 19.3 minutes. The retention time of R-form citalopram is around 25.3 minutes.
Equipment: Waters 2695
Detector: Ultraviolet absorptiometer (2489 manufactured by Waters)
Detection wavelength: 240 nm
Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm filled with 5 μm ovomucoid covalently bonded aminated silica gel Mobile phase: Buffer solution / acetonitrile = 85/15
Flow velocity: 0.6 mL / min
Column temperature: Constant temperature around 30 ° C Injection amount: 15 μL
Sample concentration: 0.125 mg / mL

<Tartrate (4) in the present invention>
Lasemi-form 4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl)-in a 2000 mL four-necked flask equipped with a thermometer and stirring blade. 200 g of benzonitrile (3a) and 800 mL of isoppil alcohol were added, and the mixture was stirred and dissolved at 35 ° C. Further, 88 g of (+)-di- (p-toll oil) and 700 mL of isoppil alcohol were added to a 1000 mL 4-neck flask equipped with a thermometer and a stirring blade, and the mixture was stirred and dissolved at 25 ° C. After confirmation of dissolution, a solution of (+)-di- (p-tartaric acid) tartaric acid was added to a 2000 mL 4-port flask to tartrate the free form (3a) and precipitate it, and (1S) -4- [4-( Dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoil) tartrate (4) 80 g was obtained. (Yield 25.6%, chemical purity: 99.787%, impurity 1: 0.030%, impurity 2: 0.034%, optical purity: 95.94%).

<Crystalline of tartrate (4) in the present invention>
The tartrate (4) was crystallized using a solvent and the amount of the solvent, and cooled to obtain a crystallized product.

In a 1000 mL three-necked flask equipped with a stirring blade and a thermometer, 50.0 g (93.0 mmol, chemical purity: 99.787%, impurities 1: 0.030%, impurities 2: 0) of the tartrate salt of (4). .034%, optical purity: 95.94%), 350 mL of 2-propanol (5.6 parts by mass with respect to 1 part by mass of the tartrate), 1.5 mL of purified water (0. 0 with respect to 1 part by mass of tartrate). 3 parts by mass) was added and stirred. The obtained mixed solution was stirred at 70 ° C. for 5 hours, and it was visually confirmed that the tartrate salt was dissolved. After confirming the dissolution, the mixture was cooled to 5 ° C. at a rate of 20 ° C./h and aged at the same temperature for 1 hour. After aging, the crystals precipitated by vacuum filtration were filtered off, and the filtered crystals were washed twice with 50 mL of 2-propanol (0.8 parts by mass with respect to 1 part by mass of the tartrate salt). The obtained white crystals were dried under reduced pressure at 40 ° C. for 12 hours to obtain 43.0 g (7.9 mmol) of the tartrate salt as white crystals (yield: 85%, chemical purity: 99.196%, impurities 1). : 0.388, Impurity 2: 0.137%, Optical Purity: 99.96%).

<Production of free form (5) of tartrate (4) according to the present invention>
The free form (5) of tartrate (4) according to the present invention can be obtained by carrying out a liberation reaction in which the crystallized product of tartrate (4) in the present invention is detartaric acid to obtain a free form (5). .. Examples 1 to 6 and Comparative Examples 1 to 3 are shown below for the liberation reaction.

Example 1
<Production of (1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile free form (5)>
5.0 g (9.3 mmol) of (tartrate (4b)) obtained in Example 1 in a 100 mL three-necked flask equipped with a stirring blade and a thermometer, chemical purity: 99.196%, impurities 1: 0.388. %, Impurities 2: 0.137%, Optical purity: 99.96%), 25 mL of toluene (5.0 parts by mass with respect to 1 part by mass of tartrate (4b)), 25 mL of purified water (tartrate (4b) 1) 3.2 g (18.7 mmol, 2.0 equivalents) of a 23% aqueous sodium hydroxide solution was added (5.0 parts by mass) and stirred. The obtained mixed solution was stirred at 25 ° C. for 30 minutes. , Tartrate (4b) was visually confirmed to be dissolved. After stirring, the organic layer and the aqueous layer were separated by a 200 mL liquid separation funnel, and 5.0 mL of purified water (1 part by mass of tartrate (4b)) was added to the organic layer. After washing with water, the organic layer and the aqueous layer were separated, and the organic layer was concentrated under reduced pressure to (1S) -4- [4- (dimethylamino) -1-). 3.2 g (9.3 mmol, 100% yield) of (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile free product (5) was obtained.

Examples 2-6, Comparative Examples 1-3
(1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl)) in the same manner as in Example 1 except that the solvent, the amount of the solvent, and the content of water were set to the conditions shown in Table 1. -1-Hydroxybutyl] -3- (hydroxymethyl) -benzonitrile free form (5) was obtained. The results are shown in Table 1.

The results of Examples 1 to 6 and Comparative Examples 1 to 3 are shown in Table 3 below. The free product obtained by using the method for producing the free product according to the present invention has a content of the impurities (i) and (ii) as compared with Comparative Examples 1 to 6 as in Examples 1 to 6. It can be seen that it is suppressed to a low level and a very high chemical purity of about 99.9% is obtained.

<Production of escitalopram (6) and its salt according to the invention>
Escitalopram (6) can be obtained by the ring closure reaction of the free substance (5), and further, a salt of escitalopram can be obtained by the chloride reaction of acid addition to the escitalopram. In particular, it is preferable to use escitalopram oxalate (7) in order to obtain it as an individual. As these production methods, known methods can be used without particular limitation.

Example 7
(1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoil) ) Production example from (5) to escitalopram oxalate (7)

Production of Escitaloplum (6) Obtained (1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile free form Add (5) to a 100 mL three-necked flask equipped with a stirring blade and a thermometer, and add 24 mL of toluene ((1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-). Hydroxybutyl] -3- (hydroxymethyl) -benzonitrile free form (5) 8.5 parts by mass with respect to 1 part by mass), 1.8 g of triethylamine (8.8 mmol, 1.1 equivalent) was added, and 5 ° C. Was stirred for 30 minutes. After stirring, 1.7 g (8.8 mmol, 1.1 eq) of paratoluenesulfonyl chloride was added, and the mixture was stirred at 5 ° C. for 1 hour. After stirring, 5 mL of purified water ((1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile free form (5) ) 2.0 parts by mass with respect to 1 part by mass), 1.4 g (8.8 mmol, 1.1 equivalents) of 25% aqueous ammonia was added, and the mixture was heated to 25 ° C. and stirred for 30 minutes. After stirring, the reaction solution was separated into an organic layer and an aqueous layer with a 100 mL separation funnel, and the organic layer was separated into 5 mL of purified water ((1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl). )-1-Hydroxybutyl] -3- (Hydroxymethyl) -benzonitrile free substance (5) 2.0 parts by mass with respect to 1 part by mass) was washed with water. After washing with water, the organic layer and the aqueous layer were separated, and the organic layer was concentrated under reduced pressure to obtain 2.3 g (7.2 mmol, yield 89%) of escitalopram (6).

Production of escitalopram oxalate (7) The obtained escitalopram (6) was added to a 100 mL three-necked flask equipped with a stirring blade and a thermometer, and 18 mL of acetone (7.9 mass with respect to 1 part by mass of escitalopram (6)). Part) was added, and the mixture was stirred at 45 ° C. for 30 minutes. After stirring, 0.7 g (7.9 mmol, 1.1 eq) of oxalic acid was added, and precipitation of crystals was confirmed. After confirming the precipitation of crystals, the mixture was cooled to 25 ° C. and aged at the same temperature for 1 hour. After aging, the crystals precipitated by vacuum filtration were filtered off, and the filtered crystals were washed twice with 2.3 mL of acetone (0.8 parts by mass with respect to 1 part by mass of escitalopram (6)). The obtained white crystals were dried under reduced pressure at 40 ° C. for 12 hours to obtain 2.5 g (6.1 mmol) of escitalopram (6) oxalate (7) as white crystals (yield: 85%, chemical purity: 99. 900%, optical purity: 99.95%).

Claims (3)

From (1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile tartrate, the tartrate in the presence of a base. A method for producing (1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile, which is a free salt. A method characterized by reacting in a solvent containing chloroform and water. The method according to claim 1, wherein the base is an inorganic base. S-4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile was produced by the method according to claim 1 or 2. Then, using the obtained compound, (1S) -1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile and a salt thereof. How to manufacture.