JP6877100B2 - (1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-tolu oil) ) Method for producing tartrate, and (1S) -1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbo using the tartrate. Method for producing nitrile and its salt - Google Patents

Description

The present invention relates to (1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di-. Method for producing (p-toluoil) tartrate, and (1S) -1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran using the tartrate. -5-About the method for producing carbonitrile and its salt.

(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 (6) 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 (6) and is a racemic 4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3-. A method for producing by reacting (hydroxymethyl) -benzonitrile (3) with (+)-di- (p-tortaric acid) tartaric acid is known (see Patent Document 1 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%.

Japanese Patent No. 4966933

In the production method of Patent Document 1, 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 tartaric acid 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 was 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 Patent Document 1, and obtaining tartaric acid having extremely high optical purity and chemical purity.

The present inventors have diligently studied a method for obtaining tartaric acid having extremely high optical purity and chemical purity. As a result of analyzing the structure of the by-produced impurities, these impurities are the following impurities (i) and (ii), which are tartaric acid (8) and (1S) -4- [4- (dimethylamino) -1- (4). It was found to be a mixture of esters (9-12) of'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile (5). Furthermore, when the factors by which these impurities were produced were investigated, there was a correlation with the thermal history of tartrate in the presence of the slurry or solution, and in particular, the time required to hold the slurry or solution at a temperature exceeding 50 ° C. It was found that the longer it is, the more impurities are produced as a by-product.

Therefore, as a result of further studies on a method for purifying tartaric acid, the present inventors have dissolved tartaric acid in a range of 40 ° C. or lower and then crystallized it to obtain tartaric acid having extremely high optical purity and chemical purity. We have found that we can obtain the above, and have completed the present invention.

That is, the present invention is each of the inventions [1] to [7].
[1]
(1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toroil) ) A method for producing tartrate,
(1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toroil) ) A production method characterized in that a crude tartrate salt is dissolved in a range of 40 ° C. or lower and then crystallized to obtain the tartrate salt as a crystallized product.
[2]
The above (1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-) Toluoil) The method according to [1], wherein the crude tartrate is dissolved in a solvent containing at least methanol, and then a poor solvent having a solubility of the tartrate of 50 mg / ml or less is added.
[3]
The method according to [2], wherein the poor solvent is at least one in the group consisting of acetonitrile, acetone and ethyl acetate.
[4]
The amount of methanol in the solvent containing at least methanol is (1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl)-. In any one of [2] to [3], which is 50 parts by mass to 1000 parts by mass with respect to 100 parts by mass of benzonitrile methanol (+)-di- (p-toluoil) tartrate. The method described.
[5]
The method according to any one of [2] to [4], wherein the poor solvent is added in at least two portions.
[6]
According to the production method according to any one of [1] to [5], (1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- After producing a crystallized product of (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoil) tartrate, the obtained crystallized product of tartrate was used to (1S) -1-. [3- (Dimethylamino) Propyl] -1- (4-Fluorophenyl) -1,3-Dihydroisobenzofuran-5-Carbonitrile and a method for producing a salt thereof.
[7]
The optical purity is 99.9% or more, and the chemical purity is 99.9% or more (1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxy. Butyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoil) tartrate.

According to the present invention, it is possible to obtain tartrate salt having extremely high optical purity and chemical purity by a simple operation of crystallization. By producing escitalopram and its salt from tartrate 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.

In the present invention, the "coarse substance" is an optically active substance obtained from a racemic body by an optical resolution operation, or an optically purified body obtained by a purification operation to improve the optical purity and / or the chemical purity. The following compounds that can improve the optical purity and / or the chemical purity by the method of the present invention.

In the present invention, the "crude material" is particularly referred to as (1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxy) after optical resolution. Methyl) -benzonitrile Hemi (+)-di- (p-toluoil) Tartrate crude (4a below).

In the present invention, "crystallization" means that the crude tartrate salt is completely dissolved and then crystals are precipitated.

In the present invention, in particular, "crystallization" is used to obtain a crystallized body (4b) of tartaric acid further purified from the crude tartaric acid salt (4a).

<Method for producing crude material in the present invention>
The crude product (4a) 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) A known method can be used for the production of the free substance (3b). For example, a racemic 4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile acid salt (3a) is used as an organic solvent. A free substance (3b) 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 (3b) can be tartrate-oxidized to obtain the crude tartrate (4a). As a method for obtaining the crude product (4a), 4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile (3a) Is dissolved in an organic solvent, and a solution in which di- (p-tortaric acid) tartaric acid is dissolved is added to tartrate the free form (3a), whereby 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.

The purity of the crude body (4a) to be used in the following method for producing a crystallized product is not particularly limited as long as the optical purity and / or the chemical purity is improved by the method of the present invention. However, from the viewpoint that the purity can be efficiently improved, the optical purity is preferably 80.0% or more and less than 99.90%, particularly preferably 90.0% or more and less than 99.90%, chemical. It is preferable to use a crude product (4a) having a purity of preferably 95.0% or more and less than 99.90%, and particularly preferably 97.0% or more and less than 99.90%.

As the purity of the crude body (4a) used in the following method for producing a crystallized product, the crude body (4a) having either an optical purity or a chemical purity of 99.90% or more, for example, an optical purity of 99.90. Of course, it is also possible to use a crude product (4a) or the like having a chemical purity of% or more and a chemical purity in the above range. However, it is preferable to use the crude product (4a) having both the optical purity and the chemical purity in the above range from the viewpoint that the effect of improving the optical purity and / or the chemical purity is sufficiently exhibited by the method of the present invention.

Further, before the crude product (4a) obtained by the above method is subjected to the following method for producing a crystallized product, the crude product (4a) is subjected to resurrection with 1-propanol, isopropyl alcohol, 2-propanol, 1-butanol or the like. You may improve the purity of.

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 100 parts by mass of 4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile (3a). A solvent of 300 to 2000 parts by mass, preferably a solvent of 500 to 1000 parts by mass can be used.

<Method for producing a crystallized product according to the present invention>
The method for producing tartrate according to the present invention is (1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile. A crude body of (+)-di- (p-toluoil) tartrate is dissolved in a range of 40 ° C. or lower and then crystallized to obtain the tartrate as a crystallizer. By handling at 40 ° C. or lower through dissolution and crystallization of the crude product (4a), the tartrate salt having a high chemical purity and a high optical purity with few impurities can be obtained. Therefore, it is important that the temperature is 40 ° C. or lower through the dissolution and crystallization of the crude body (4a).

The by-products of the impurities (i) and (ii) have a correlation with the thermal history of the tartrate salt in the presence of the slurry or solution, and in particular, the time for holding the slurry or solution at a temperature exceeding 50 ° C. It is considered that the longer the length, the greater the amount of impurities by-produced. This was found by examining the thermal stability of tartrate (4a) (Table 1 below). As shown in Table 1 below, impurities increase significantly over time when the temperature exceeds 50 ° C., so that handling at a temperature of 40 ° C. or lower is required.

Further, the method for producing tartaric acid according to the present invention is handled at 40 ° C. or lower as described above, and the crude tartarate (4a) is further dissolved in a solvent containing at least methanol, and then the solubility of the tartarate is 50 mg. It is characterized by adding a poor solvent of / ml or less. Thereby, the tartrate salt having high chemical purity and high optical purity with few impurities can be obtained.

Regarding the solvent amount of the solvent containing at least methanol, 50 to 1000 parts by mass can be used with respect to 100 parts by mass of the tartrate (4a), and 100 to 200 parts by mass can be preferably used.

The poor solvent requires that the solubility of the tartrate (4a) is 50 mg / ml or less in order to obtain the tartrate having high chemical purity and high optical purity. As the poor solvent, for example, ethanol, IPA, 1-butanol, ethyl acetate, acetone, acetonitrile, toluene, heptane, dichloromethane, and chloroform can be used, preferably ethyl acetate, acetone, acetonitrile, and more preferably acetonitrile. Can be used (see Table 1).

As the solvent amount of the poor solvent, 100 to 2000 parts by mass can be used with respect to 100 parts by mass of the tartrate (4a), and 800 to 1300 parts by mass can be preferably used.

The poor solvent is preferably added in at least two divided doses. When the solvent is added in two portions, 100 to 500 parts by mass can be used with respect to 100 parts by mass of the tartrate (4a), preferably 200 to 400 parts by mass. Can be used. The amount of the poor solvent added from the second time onward can be used without particular limitation as long as the total amount of the poor solvent to be added is within the range of 100 to 2000 parts by mass with respect to 100 parts by mass of the tartrate (4a). ..

In order to obtain the crystallized product according to the present invention, the cooling rate in cooling the solvent can be 10 to 50 ° C./hr, preferably 20 to 30 ° C./hr.

In order to obtain the crystallized product according to the present invention, the temperature and time for holding the solvent are preferably 0 to 30 ° C. and 1 to 24 hours.

For the isolation of the pre-crystallized product (4b) obtained by the crystallization, a known separation method such as pressure filtration, vacuum filtration, or centrifugation can be used.

For drying the crystallized product (4b) after isolation, for example, a method such as vacuum drying can be used. In the vacuum drying, a temperature of 20 to 50 ° C. can be used, preferably 30 to 40 ° C. can be used.

<Crystalline according to the present invention>
The crystallized product obtained by the above-mentioned production method of the present invention, that is, (1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl). )-Benzonitrile hemi (+)-di- (p-toluoil) tartrate (4b) has an extremely high purity of 99.9% or more and a chemical purity of 99.9% or more. Have.

<Manufacturing method of escitalopram and its salt>
An escitalopram (6) can be obtained by carrying out a liberation reaction in which the crystallized product (4b) according to the present invention is detartaric acid to obtain a free product (5), and then a ring closure reaction of the free product. 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 an individual. As these production methods, known methods can be used without particular limitation.

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 optical purity>
The chemical purity and optical purity of the crude body (4a) and the crystallized body (4b) 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) and escitaloplum oxalate (7) Purity of tartrate (4), specific impurities 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 tartrate (4) in the HPLC analysis under these 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-tor oil) ) Evaluation of Optical Purity of Tartrate (4) The optical purity of tartrate (4) 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 tartrate (4) is a value shown as a percentage of the total area value of S-form and R-form of the peak area value of tartrate (4) in the obtained chromatogram. The retention time of tartrate (4) in the HPLC analysis under these 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 amination 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

<Rough material 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) tartaric acid and 700 mL of isoppil alcohol were added to a 1000 mL four-necked 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-tortaric acid) tartaric acid was added to a 2000 mL 4-port flask to tartrate and precipitate the free form (3a), which was an optically active crude substance, that is, (1S). -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoil) tartrate (Yield 25.6%, chemical purity: 99.787%, impurity (i): 0.030%, impurity (ii): 0.034%, optical purity: 95 .94%).

<Thermal stability of tartrate>
The tartrate (4a) was dissolved in double volume acetonitrile / methanol (1: 1) and at 30 ° C., 40 ° C., and 50 ° C., the tartrate salt after 0, 1, 3, and 5 hours, respectively. The concentration ratios of the impurity (i) and the impurity (ii) were measured by the HPLC method and are shown in Table 3.

As is clear from Table 3, it was found that the tartrate (4a) had few by-products of impurities at 30 ° C. and 40 ° C., but increased with time at 50 ° C. From this, it was considered that the handling temperature of the tartrate (4a) should be 40 ° C. or lower.

<Crystallite according to the present invention: Examples 1 to 8>
The crude body (4a) was crystallized using the respective solvents and solvent amounts in Table 4 (Examples 1 to 8), and cooled to obtain a crystallized body. The operations of Examples 1 to 8 and Comparative Example 1 are shown below.

Example 1
5.0 g (9.3 mmol) of tartrate (4a), chemical purity: 99.787%, impurities (i): 0.030%, impurities (ii) in a 100 mL three-necked flask equipped with a stirring blade and a thermometer. ): 0.034%, optical purity: 95.94%), 5 mL of methanol (0.8 parts by mass with respect to 1 part by mass of tartrate (4a)), 5 mL of acetonitrile (with respect to 1 part by mass of tartrate (4a)) 0.8 parts by mass) was added and stirred. The obtained mixed solution was stirred at 30 ° C. for 30 minutes, and it was visually confirmed that tartrate (4a) was dissolved. After confirming the dissolution, 40 mL of acetonitrile (6.3 parts by mass with respect to 1 part by mass of tartrate (4a)) was added, the mixture was cooled to 5 ° 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 5 mL of acetonitrile (0.8 parts by mass with respect to 1 part by mass of tartrate (4a)). The obtained white crystals were dried under reduced pressure at 40 ° C. for 12 hours to obtain 4.2 g (7.8 mmol) of tartrate (4b) as white crystals (yield: 84%, chemical purity: 99.882%, Impurity (i): 0.005, Impurity (ii): 0.009%, Optical purity: 99.91%).

Example 2
5.0 g (9.3 mmol) of tartrate (4a), chemical purity: 99.787%, impurities (i): 0.030%, impurities (ii) in a 100 mL three-necked flask equipped with a stirring blade and a thermometer. ): 0.034%, optical purity: 95.94%), 5 mL of methanol (0.8 parts by mass with respect to 1 part by mass of tartrate (4a)), 5 mL of acetonitrile (with respect to 1 part by mass of tartrate (4a)) 0.8 parts by mass) was added and stirred. The obtained mixed solution was stirred at 30 ° C. for 30 minutes, and it was visually confirmed that tartrate (4a) was dissolved. After confirming the dissolution, 15 mL of acetonitrile (2.3 parts by mass with respect to 1 part by mass of tartrate (4a)) was added, and the mixture was stirred at 30 ° C. for 30 minutes to confirm the precipitation of crystals. After stirring, 25 mL of acetonitrile (3.9 parts by mass with respect to 1 part by mass of tartrate (4a)) was further added, cooled to 5 ° 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 5 mL of acetonitrile (0.8 parts by mass with respect to 1 part by mass of tartrate (4a)). The obtained white crystals were dried under reduced pressure at 40 ° C. for 12 hours to obtain 4.1 g (7.7 mmol) of tartrate (4b) as white crystals (yield: 82%, chemical purity: 99.919%, Impurity (i): undetected, impurity (ii): 0.003%, optical purity: 99.96%).

Example 3
5.0 g (9.3 mmol) of tartrate (4a), chemical purity: 99.787%, impurities (i): 0.030%, impurities (ii) in a 100 mL three-necked flask equipped with a stirring blade and a thermometer. ): 0.034%, optical purity: 95.94%), 5 mL of methanol (0.8 parts by mass with respect to 1 part by mass of tartrate (4a)), 5 mL of acetonitrile (with respect to 1 part by mass of tartrate (4a)) 0.8 parts by mass) was added and stirred. The obtained mixed solution was stirred at 30 ° C. for 30 minutes, and it was visually confirmed that tartrate (4a) was dissolved. After confirming the dissolution, 25 mL of acetonitrile (3.9 parts by mass with respect to 1 part by mass of tartrate (4a)) was added, and the mixture was stirred at 30 ° C. for 30 minutes to confirm the precipitation of crystals. After stirring, 40 mL of acetonitrile (6.3 parts by mass with respect to 1 part by mass of tartrate (4a)) was further added, cooled to 5 ° 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 5 mL of acetonitrile (0.8 parts by mass with respect to 1 part by mass of tartrate (4a)). The obtained white crystals were dried under reduced pressure at 40 ° C. for 12 hours to obtain 4.3 g (8.0 mmol) of tartrate (4b) as white crystals (yield: 86%, chemical purity: 99.919%, Impurity (i): undetected, impurity (ii): 0.002%, optical purity: 99.96%).

Example 4
5.0 g (9.3 mmol) of tartrate (4a), chemical purity: 99.787%, impurities (i): 0.030%, impurities (ii) in a 100 mL three-necked flask equipped with a stirring blade and a thermometer. ): 0.034%, optical purity: 95.94%), 5 mL of methanol (0.8 parts by mass with respect to 1 part by mass of tartrate (4a)), 5 mL of acetonitrile (with respect to 1 part by mass of tartrate (4a)) 0.8 parts by mass) was added and stirred. The obtained mixed solution was stirred at 30 ° C. for 30 minutes, and it was visually confirmed that tartrate (4a) was dissolved. After confirming the dissolution, 15 mL of acetonitrile (2.3 parts by mass with respect to 1 part by mass of tartrate (4a)) was added, and the mixture was stirred at 30 ° C. for 30 minutes to confirm the precipitation of crystals. After stirring, 50 mL of acetonitrile (7.8 parts by mass with respect to 1 part by mass of tartrate (4a)) was further added, cooled to 5 ° 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 5 mL of acetonitrile (0.8 parts by mass with respect to 1 part by mass of tartrate (4a)). The obtained white crystals were dried under reduced pressure at 40 ° C. for 12 hours to obtain 4.3 g (8.0 mmol) of tartrate (4b) as white crystals (yield: 86%, chemical purity: 99.925%, Impurity (i): undetected, impurity (ii): 0.002%, optical purity: 99.96%).

Example 5
5.0 g (9.3 mmol) of tartrate (4a), chemical purity: 99.787%, impurities (i): 0.030%, impurities (ii) in a 100 mL three-necked flask equipped with a stirring blade and a thermometer. ): 0.034%, optical purity: 95.94%), 10 mL of methanol (1.6 parts by mass with respect to 1 part by mass of tartrate (4a)) was added and stirred. The obtained mixed solution was stirred at 25 ° C. for 30 minutes, and it was visually confirmed that tartrate (4a) was dissolved. After confirming the dissolution, 20 mL of acetone (3.2 parts by mass with respect to 1 part by mass of tartrate (4a)) was added, and the mixture was stirred at 25 ° C. for 1 hour to confirm the precipitation of crystals. After stirring, 25 mL of acetone (3.9 parts by mass with respect to 1 part by mass of tartrate (4a)) was further added, cooled to 5 ° C., and aged at the same temperature for 12 hours. After aging, the crystals precipitated by vacuum filtration were filtered off, and the filtered crystals were washed twice with 5 mL of acetone (0.8 parts by mass with respect to 1 part by mass of tartrate (4a)). The obtained white crystals were dried under reduced pressure at 40 ° C. for 12 hours to obtain 3.3 g (6.2 mmol) of tartrate (4b) as white crystals (yield: 66%, chemical purity: 99.910%, Impurity (i): 0.001, Impurity (ii): 0.003%, Optical purity: 99.96%).

Example 6
5.0 g (9.3 mmol) of tartrate (4a), chemical purity: 99.787%, impurities (i): 0.030%, impurities (ii) in a 100 mL three-necked flask equipped with a stirring blade and a thermometer. ): 0.034%, optical purity: 95.94%), 10 mL of methanol (1.6 parts by mass with respect to 1 part by mass of tartrate (4a)) was added and stirred. The obtained mixed solution was stirred at 25 ° C. for 30 minutes, and it was visually confirmed that tartrate (4a) was dissolved. After confirming the dissolution, 90 mL of acetone (14.0 parts by mass with respect to 1 part by mass of tartrate (4a)) was added, and the mixture was stirred at 25 ° C. for 1 hour to confirm the precipitation of crystals. After stirring for 1 hour, the mixture was cooled to 5 ° C. and aged at the same temperature for 12 hours. After aging, the crystals precipitated by vacuum filtration were filtered off, and the filtered crystals were washed twice with 5 mL of acetone (0.8 parts by mass with respect to 1 part by mass of tartrate (4a)). The obtained white crystals were dried under reduced pressure at 40 ° C. for 12 hours to obtain 2.8 g (5.2 mmol) of tartrate (4b) as white crystals (yield: 56%, chemical purity: 99.895%, Impurity (i): 0.003, Impurity (ii): 0.008%, Optical purity: 99.85%).

Example 7
5.0 g (9.3 mmol) of tartrate (4a), chemical purity: 99.787%, impurities (i): 0.030%, impurities (ii) in a 100 mL three-necked flask equipped with a stirring blade and a thermometer. ): 0.034%, optical purity: 95.94%), 10 mL of methanol (1.6 parts by mass with respect to 1 part by mass of tartrate (4a)) was added and stirred. The obtained mixed solution was stirred at 25 ° C. for 30 minutes, and it was visually confirmed that tartrate (4a) was dissolved. After confirming the dissolution, 20 mL of ethyl acetate (3.6 parts by mass with respect to 1 part by mass of tartrate (4a)) was added, and the mixture was stirred at 25 ° C. for 1 hour to confirm the precipitation of crystals. After stirring, 25 mL of ethyl acetate (4.5 parts by mass with respect to 1 part by mass of tartrate (4a)) was further added, cooled to 5 ° C., and aged at the same temperature for 12 hours. After aging, the crystals precipitated by vacuum filtration were filtered off, and the filtered crystals were washed twice with 5 mL of ethyl acetate (0.9 parts by mass with respect to 1 part by mass of tartrate (4a)). The obtained white crystals were dried under reduced pressure at 40 ° C. for 12 hours to obtain 3.9 g (7.3 mmol) of tartrate (4b) as white crystals (yield: 78%, chemical purity: 99.900%, Impurity (i): 0.001, Impurity (ii): 0.003%, Optical purity: 99.85%).

Example 8
5.0 g (9.3 mmol) of tartrate (4a), chemical purity: 99.787%, impurities (i): 0.030%, impurities (ii) in a 100 mL three-necked flask equipped with a stirring blade and a thermometer. ): 0.034%, optical purity: 95.94%), 10 mL of methanol (1.6 parts by mass with respect to 1 part by mass of tartrate (4a)) was added and stirred. The obtained mixed solution was stirred at 25 ° C. for 30 minutes, and it was visually confirmed that tartrate (4a) was dissolved. After confirming the dissolution, 90 mL of ethyl acetate (16.2 parts by mass with respect to 1 part by mass of tartrate (4a)) was added, and the mixture was stirred at 25 ° C. for 1 hour to confirm the precipitation of crystals. After stirring for 1 hour, the mixture was cooled to 5 ° C. and aged at the same temperature for 12 hours. After aging, the crystals precipitated by vacuum filtration were filtered off, and the filtered crystals were washed twice with 5 mL of ethyl acetate (0.9 parts by mass with respect to 1 part by mass of tartrate (4a)). The obtained white crystals were dried under reduced pressure at 40 ° C. for 12 hours to obtain 3.8 g (7.1 mmol) of tartrate (4b) as white crystals (yield: 76%, chemical purity: 99.877%, Impurity (i): 0.001, Impurity (ii): 0.012%, Optical purity: 99.85%).

Comparative Example 1
5.0 g (9.3 mmol) of tartrate (4a), chemical purity: 99.859%, impurities (i): 0.002%, impurities (ii) in a 100 mL three-necked flask equipped with a stirring blade and a thermometer. ): 0.037%, optical purity: 94.14%), 1-propanol 12.5 mL (0.8 parts by mass with respect to 1 part by mass of tartrate (4a)), 5 mL of acetonitrile (tartrate (4a) 1) 2.0 parts by mass with respect to parts by mass) was added and stirred. The obtained mixture was stirred at 50 ° C. for 2 hours, stirred, 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 5 mL of 1-propanol (0.8 parts by mass with respect to 1 part by mass of tartrate (4a)). The obtained white crystals were dried under reduced pressure at 40 ° C. for 12 hours to obtain 4.5 g (8.4 mmol) of tartrate (4b) as white crystals (yield: 90%, chemical purity: 99.815%, Impurity (i): 0.019%, Impurity (ii): 0.046%, Optical purity: 96.73%).

<Optical purity of crystallized product according to the present invention>
Table 4 shows the chemical purity and optical purity of the crystallized product (4b) obtained in Examples 1 to 8 and Comparative Example 1. The chemical purity and optical purity of the crystallized product (4b) according to the present invention obtained in Examples 1 to 8 are 99.88 to 99.92% and 99.81 to 99.96%, respectively, which are extremely high chemical purity. And the optical purity were shown.

<Salt of crystallized product according to the present invention>
An escitalopram (6) can be obtained by carrying out a liberation reaction in which the crystallized product (4b) according to the present invention is detartaric acid to obtain a free product (5), and then a ring closure reaction of the free product. 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 an individual. As these production methods, known methods can be used without particular limitation. Examples of the production of escitalopram (6) and escitalopram oxalate (7) are shown below.

Example 9
(1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toroil) ) Example of production from tartrate (4b) to escitaloplum oxalate (7) <(1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- Production of (Hydroxymethyl) -Benzonitrile Free Form (5)>
4.3 g (8.0 mmol, chemical purity: 99.925%, impurities (i): not yet) obtained in Example 1 in a 100 mL three-necked flask equipped with a stirring blade and a thermometer. Detection, impurities (ii): 0.002%, optical purity: 99.96%), 25 mL of diethyl ether (4.2 parts by mass with respect to 1 part by mass of tartrate (4b)), 25 mL of purified water (tartrate (tartrate (4b)) 4b) 5.8 parts by mass with respect to 1 part by mass), 4 mL (16.0 mmol, 2.0 equivalents) of a 2M aqueous sodium hydroxide solution was added 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 4.3 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-). 2.7 g (8 mmol, 100% yield) of (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile free product (5) was obtained.

<Manufacturing of escitalopram (6)>
The obtained (1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile free form (5) was stirred. , In addition to a 100 mL three-necked flask equipped with a thermometer, 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) and 1.8 g (8.8 mmol, 1.1 equivalents) of triethylamine were added, and the mixture was stirred at 5 ° C. 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 separatory 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).

<Manufacturing of escitalopram oxalate (7)>
The obtained escitalopram (6) is added to a 100 mL three-necked flask equipped with a stirring blade and a thermometer, 18 mL of acetone (7.9 parts by mass with respect to 1 part by mass of escitalopram (6)) is added, and the temperature is 45 ° C. The mixture was stirred 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 (4)

(1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toroil) ) A method for producing tartrate,
(1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toroil) ) The crude tartrate is dissolved in a solvent containing at least methanol at a temperature of 40 ° C. or lower, and then at least one poor solvent in the group consisting of acetonitrile, acetone and ethyl acetate is added to crystallize the crystallized product. A production method characterized by obtaining the tartrate salt as a whole. The amount of methanol in the solvent containing at least methanol is (1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl)-. The method according to claim 1, wherein the amount is 50 parts by mass to 1000 parts by mass with respect to 100 parts by mass of benzonitrile hemi (+)-di- (p-toluoil) tartrate. The method according to claim 1 or 2, wherein the poor solvent is added in at least two portions. According to the production method according to any one of claims 1 to 3, (1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxy) After producing a crystallized product of methyl) -benzonitrile hemi (+)-di- (p-toluoil) tartrate, the obtained crystallized product of tartrate was used to (1S) -1- [3. -(Dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-Carbonitrile and a method for producing a salt thereof.