JP6666213B2 - (1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoyl ) 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-toluoyl) tartrate, and (1S) -1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran using the tartrate -5-carbonitrile and a method for producing the 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 the structure (6), whose oxalate (7) is a well-known antidepressant.

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

  (1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoyl ) Tartrate (4) is an important intermediate of escitalopram, and racemic 4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl There is known a method for producing a compound by reacting) -benzonitrile (3) with (+)-di- (p-toluoyl) tartaric acid (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 after the production of (p-toluoyl) tartrate (a derivative of (3)), an optical resolution is carried out to give a tartrate (4) having an enantioselectivity of 99%.

Japanese Patent No. 4969633

  In the production method of Patent Document 1, the produced tartrate is isolated from the reaction system by crystallization, and the isolated tartrate is purified by reslurry of 1-propanol. However, the tartrate obtained by this method has a maximum enantioselectivity of 99.6%, and there is no process for improving the optical purity in the process of producing escitalopram and its salts after tartrate. In the process of obtaining tartaric acid, it has been desired to obtain a tartrate salt with higher optical purity.

  Therefore, an object of the present invention is to provide (1S) -4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxy Obtaining methyl) -benzonitrile hemi (+)-di- (p-toluoyl) tartrate provides escitalopram with higher optical purity and a salt thereof.

  The present inventors have intensively studied a method for obtaining a tartrate salt having high optical purity. A method for obtaining a tartrate salt having a high optical purity (4b shown below) by recrystallization after obtaining a tartrate salt (4a shown below) as a crude product was examined. The recrystallization was performed by using a mixed solvent of alcohol and water. And that the optical purity can be improved. Furthermore, as a result of studying the recrystallization conditions of the above tartrate with a mixed solvent system of alcohol and water, the use of a specific amount of water in a mixed solvent of alcohol and water resulted in an extremely high optical purity of 99.9% or more. They have found that a tartrate salt with high optical purity can be obtained, and have completed the present invention.

That is, the present invention is each invention of [1] to [6].
[1]
(1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoyl ) A process for producing tartrate,
1) From racemic 4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile to (1S) -4- [4- Step of obtaining a crude form of (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoyl) tartrate And 2) (1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi obtained by the above step. The crude product of (+)-di- (p-toluoyl) tartrate was converted to a mixed solvent of alcohol and water, and the content of water in the mixed solvent of alcohol and water was 3.0 to 15.0% by mass. A refining step of recrystallizing with a mixed solvent that is:
[2]
The method according to [1], wherein the alcohol has 3 to 4 carbon atoms.
[3]
The method according to [1], wherein the alcohol is at least one selected from the group consisting of 1-propanol, 2-propanol and 1-butanol.
[4]
(1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3-by the production method according to any one of [1] to [3]. After producing a recrystallized form of (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoyl) tartrate, (1S) -1- A method for producing [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile and a salt thereof.
[5]
(1S) -4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi () having an optical purity of 99.90% or more +)-Di- (p-toluoyl) tartrate.

  According to the present invention, (1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- having an extremely high optical purity by a simple operation of recrystallization. It is possible to obtain (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoyl) tartrate. By producing escitalopram and its salt from the tartrate obtained by this production method, escitalopram and its salt with extremely high optical purity can be provided.

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

  In the present invention, the `` crude body '' is an optically active substance obtained by an optical resolution operation from a racemic body, or an optically resolved substance obtained by improving the optical purity by a purification operation, of the present invention described below. A compound whose optical purity can be improved by a method.

  In the present invention, the “crude substance” particularly refers to (1S) -4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxy Methyl) -benzonitrile hemi (+)-di- (p-toluoyl) tartrate crude (refer to 4a below).

  In the present invention, the term “recrystallization” refers to completely dissolving a crude tartrate and then depositing crystals.

  In the present invention, in particular, "recrystallization" is used in order to obtain a further purified tartaric acid recrystallized product (4b) from the crude tartrate (4a).

<Production method of crude body in the present invention>
The crude body (4a) in the present invention can be produced by the following synthesis route.

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

  Incidentally, the racemic 4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile acid salt is, for example, Can be manufactured as follows. That is, a Grignard reaction of the compound (1) with 4-bromofluorobenzene and a Grignard reaction of the obtained compound (2) with 3,3-dimethylaminopropyl chloride can give the acid salt. .

  Various acids can be used as the acid in the acid salt, 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 solvent for the liberation, for example, ethyl acetate, diethyl ether, toluene, chloroform, dichloromethane can be used, and preferably, chloroform can be used. As the solvent amount of the solvent for the liberation, 4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile was 100 parts by mass. On the other hand, 300 to 2,000 parts by mass, preferably 400 to 800 parts by mass of the solvent can be used. The reaction temperature for the liberation can be appropriately determined in the range of 0 to 60 ° C.

  Racemic 4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoyl ) The free form (3b) can be tartarized to obtain the crude product of the 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, a solution in which di- (p-toluoyl) tartaric acid is dissolved is added, and the educt (3a) is tartarized, whereby the tartrate is precipitated. At this time, when (+)-di- (p-toluoyl) tartaric acid is used as di- (p-toluoyl) tartaric acid, (1S) -4- [4- (dimethylamino) -1- (4 '-Fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoyl) tartrate (4a) is selectively precipitated. On the other hand, when (-)-di- (p-toluoyl) tartaric acid is used as di- (p-toluoyl) tartaric acid, (1R) -4- [4- (dimethylamino) -1- (4'- Fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoyl) tartrate is selectively precipitated. Therefore, depending on the di- (p-toluoyl) tartaric acid used, an optically resolved tartrate having an optical purity of about 93% or more can be obtained.

  The crude body (4a) is not particularly limited in optical purity as long as the optical purity is improved in the recrystallization of the present invention, but the viewpoint that the purity can be efficiently improved. Therefore, it is preferable to use the crude body (4a) having an optical purity of preferably from 80.00% to less than 99.90%, particularly preferably from 90.00% to less than 99.90%. Although there is no particular limitation on the chemical purity, it is preferable to use the crude product (4a) having a range of preferably 90.0% or more, particularly preferably 99.0% or more.

  Before subjecting the crude product (4a) obtained by the above method to the following method for producing a recrystallized product, the crude product (4a) is reslurried with 1-propanol, isopropyl alcohol, 2-propanol, 1-butanol or the like. May be improved in chemical purity.

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

  The amount of (+)-di- (p-toluoyl) tartaric acid used for the tartarization is 4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3 It is possible to use 0.25 to 1.0 equivalent of the tartaric acid, preferably 0.3 to 0.5 equivalent of the tartaric acid based on-(hydroxymethyl) -benzonitrile (3a).

<Method for producing recrystallized product according to the present invention>
As a solvent for recrystallization of the crude product (4a), a mixed solvent of alcohol and water, and a mixed solvent in which the content of water in the mixed solvent of alcohol and water is 3.0 to 15.0 mass%. It is necessary to be. Examples of the alcohol include alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, and 1-pentanol. Of these, alcohols preferably have 3 to 4 carbon atoms in view of a large difference in solubility depending on the temperature of the tartrate salt and ease of mixing with water, particularly 1-propanol, 2-propanol and 2-propanol. It is preferably at least one selected from the group consisting of 1-butanol. Alcohol may be used alone or in combination of two or more.

  The amount of water in the mixed solvent is not particularly limited as long as the content of water in the mixed solvent of alcohol and water is within the above range. From the viewpoint of the effect of improving the optical purity and the yield in recrystallization, particularly, 5. It is preferably from 0 to 10.0% by mass. The water content when a plurality of alcohols are used as the alcohol is the ratio of the water content to the total of the plurality of alcohols and water.

  The solvent amount of the mixed solvent of alcohol and water is preferably 100 to 2,000 parts by mass per 100 parts by mass of the crude tartrate. In particular, it is preferably in the range of 200 to 1000 parts by mass, most preferably 300 to 800 parts by mass.

  If the tartrate salt does not dissolve in the mixed solvent, heating may be performed to dissolve the tartrate salt. A preferred range of the heating temperature can be 60 to 80 ° C.

  After dissolving the crude body (4a) in a solvent, cooling is performed to precipitate crystals. A preferred range of the cooling rate is 10 to 50 ° C / hr, preferably 25 to 35 ° C / hr. Preferred ranges of the holding temperature and the holding time are 0 to 30 ° C. and 1 to 24 hours, respectively.

  For the isolation of the recrystallized product (4b) obtained by recrystallization, for example, a known separation method such as pressure filtration, vacuum filtration, and centrifugation can be used.

  For drying the recrystallized product (4b) after the isolation, for example, a method such as drying under reduced pressure can be used. In drying under reduced pressure, a temperature of 20 to 50C can be used, and preferably 30 to 40C.

<Recrystallized product according to the present invention>
The recrystallized product obtained by the production method of the present invention, that is, (1S) -4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl ) -Benzonitrile hemi (+)-di- (p-toluoyl) tartrate (4b) has an optical purity of at least 99.9%, an extremely high optical purity that was not the known tartrate.

<Method for producing escitalopram and its salt>
The recrystallized product (4b) according to the present invention is subjected to a liberation reaction by detartaric acid to give a free product (5), and then a cyclization reaction of the free product gives escitalopram (6). Further, a salt of escitalopram can be obtained by a salification reaction in which acid is added 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 measurement of the optical purity of the crude product and the recrystallized product according to the present invention was performed using HPLC under the following conditions.
Apparatus: 2695 manufactured by Waters
Detector: UV absorption spectrophotometer (2489 manufactured by Waters)
Detection wavelength: 240 nm
Column: CHIRALCEL OD-H (4.6 mm inner diameter, 25 cm long stainless tube filled with silica gel coated with 5 μm cellulose derivative)
Mobile phase: hexane / ethanol / diethylamine = 98/2 / 0.1
Flow rate: 0.7 mL / min
Column temperature: Constant temperature around 30 ° C. Injection volume: 10 μL
Sample concentration: 2.0mg / mL

  The optical purity of the tartrate (4) is a value expressed as a percentage of the peak area value of the tartrate salt (4) in the obtained chromatogram with respect to the sum of the area values of the S-form and the R-form. The retention time of the tartrate (4) in the HPLC analysis under the above conditions is around 34.1 minutes. The retention time of the R-tartrate is around 37.5 minutes.

<Rough body in the present invention>
10 g of racemic 4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile free product (3b) is added to 10 mL of 1-propanol Was added, and 35 mL of a 1-propanol solution in which 4.5 g of (+)-di- (p-toluoyl) tartaric acid was dissolved was added. The free form (3b) was tartarized and precipitated to give an optically active crude product. That is, (1S) -4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p- Toluoyl) tartrate (4a) (4.7 g) was obtained (optical purity: 94.14%, purity: 99.86%).

<Recrystallized product according to the present invention>
The crude body (4a) was crystallized using each solvent and the amount of the solvent in Table 1 (Examples 1 to 6), and cooled to obtain a crystallized body. The operations of Examples 1 to 6 and Comparative Examples 1 to 3 are shown below.

Example 1
In a 100 mL three-necked flask equipped with a stirring blade and a thermometer, 10 g (18.7 mmol, optical purity 94.14%, purity 99.86%) of tartrate (4a) and 70 mL of 2-propanol (tartrate (4a)) were added. ) Per 100 parts by mass) and 3.5 mL of water (35 parts by mass per 100 parts by mass of tartrate (4a), 6% by mass per 100 parts by mass of solvent). The obtained mixture was stirred at 70 ° C. for 10 minutes, and the dissolution of the tartrate salt (4a) was visually confirmed. After confirming dissolution, the mixture was cooled to 5 ° C. at a cooling rate of 30 ° C./hr, and aged at the same temperature for 1 hour to precipitate crystals. After aging, the crystals precipitated by filtration under reduced pressure were separated by filtration, and the crystals separated by filtration were washed twice with 10 mL of a recrystallization solvent. The obtained white crystals were dried under reduced pressure at 40 ° C. for 12 hours to obtain 8.7 g (16.2 mmol) of tartrate (4b) as white crystals (yield: 87%, chemical purity: 99.95%, Optical purity: 99.87%).

Examples 2 to 6
A recrystallized tartrate (4a) was obtained in the same manner as in Example 1 except that the solvent, the amount of the solvent, and the content of water were changed to the conditions shown in Table 1. Table 1 shows the results.

Comparative Examples 1-3
When the mixture was heated and stirred at the temperature shown in Table 1 for 10 minutes under the conditions shown in Table 1 with the solvent, the amount of the solvent, and the content of water, the tartrate salt (4a) was not completely dissolved. Thereafter, the mixture was cooled to 5 ° C. at a cooling rate of 30 ° C./hr, and aged at the same temperature for 1 hour to precipitate crystals. After aging, the crystals precipitated by filtration under reduced pressure were separated by filtration, and the crystals separated by filtration were washed twice with 10 mL of a recrystallization solvent. The obtained white crystals were dried under reduced pressure at 40 ° C. for 12 hours to obtain (tartrate salt (4b) as white crystals. The results are shown in Table 1.

<Optical purity of recrystallized product according to the present invention>
The optical purity of the recrystallized product (4b) according to the present invention obtained from Examples 1 to 6 from the optical purity of the crude product (4a) of 94.14% (see the section <Rough product in the present invention>). Showed an extremely high optical purity of 99.88 to 99.95%. This optical purity far exceeds the optical purity (96.73% or 97.01%) of the recrystallized product (4b) obtained by a conventional method or the like (Comparative Examples 1 and 2). Note that Comparative Example 1 is based on the method of Patent Document 1.

<Recrystallized salt according to the present invention>
The recrystallized product (4b) according to the present invention is subjected to a liberation reaction by detartaric acid to give a free product (5), and then a cyclization reaction of the free product gives escitalopram (6). Further, a salt of escitalopram can be obtained by a salification reaction in which acid is added 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 7
(1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoyl ) Example of preparation of escitalopram oxalate (7) from tartrate (4b) <(1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- Production of (hydroxymethyl) -benzonitrile free form (5)>
In a 100 mL three-necked flask equipped with a stirring blade and a thermometer, 4.3 g (8.0 mmol, purity 99.87%, optical purity 99.95%) of the recrystallized product (4b) obtained in Example 1, 43 mL of diethyl ether, 43 mL of water and 4 mL of a 2M aqueous sodium hydroxide solution were added, and the mixture was stirred at 25 ° C for 30 minutes. After stirring, the organic layer and the aqueous layer were separated, and the organic layer was washed with 4.3 mL of water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give (1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl)- 2.7 g (8.0 mmol, 100% yield) of a free form of benzonitrile was obtained.

<Manufacture of escitalopram (6)>
(1S) -4- [4- (Dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile (2.7 g), toluene (24 mL) and triethylamine (1.8 g) Was added and stirred at 5 ° C. for 30 minutes. A toluene solution of tosyl chloride (1.7 g / 8 mL) was added, and the mixture was stirred at 5 ° C. for 1 hour. Next, 5 mL of water and 1.4 g of 25% ammonia water were added, and the mixture was stirred at 25 ° C for 30 minutes. After stirring, an organic layer and an aqueous layer were separated, and the organic layer was washed with 5 mL of water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give (1S) -1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile 2.3 g (7.2 mmol, 89% yield) of a free form of (escitalopram) was obtained as a yellow oil.

<Production of escitalopram oxalate (7)>
2.3 g (7.2 mmol) of the obtained escitalopram (6) was added to a 100 mL three-necked flask equipped with a stirring blade and a thermometer, and dissolved by adding 18 mL of acetone, followed by stirring at 45 ° C. for 30 minutes. After stirring, 0.7 g (7.9 mmol) of oxalic acid was added, and the mixture was stirred for 30 minutes, and the precipitation of crystals was confirmed. The solution was cooled to 25 ° C. and aged for 1 hour. The white crystals obtained by performing filtration under reduced pressure and washing twice with 2.3 mL of acetone were dried under reduced pressure at 40 ° C. for 15 hours to obtain (1S) -1- [3- (dimethylamino) propyl] -1- ( 2.4 g (5.8 mmol) of white crystals of (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile oxalate (escitalopram oxalate) were obtained (yield 81%, purity 99.99%). 49%, optical purity 99.94%).

Claims (2)

(1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoyl ) A process for producing tartrate,
1) From racemic 4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile to (1S) -4- [4- Step of obtaining a crude form of (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoyl) tartrate And 2) (1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzo obtained by the above step of the salt. Nitoriruhemi (+) - di - a (p- toluoyl) crude product of the tartrate, 2-propanol and mixed solvent of water and the content of water in the mixed solvent of 2-propanol and water 3.0 A purification step of recrystallization with a mixed solvent of １５15.0% by mass,
And a manufacturing method. By the manufacturing method according to claim 1 (1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) - benzonitrile hemi ( After producing a recrystallized form of (+)-di- (p-toluoyl) tartrate, the obtained (1S) -4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1- Hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoyl) tartrate salt was used to give (1S) -1- [3- (dimethylamino) propyl] A method for producing -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile.