JP2018016569A - Production method of (1s)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile oxalate - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a (1S)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (escitalopram) oxalate having extremely high optical purity and extremely little residual solvent.SOLUTION: The following production method is used: (1S)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile oxalate, by 1 part by mass, is dissolved and heated in an organic solvent containing 8-15 parts by volume of ethanol, then the solution is cooled at a rate of at least 25°C/h or more to crystallize so as to obtain the oxalate as a crystallized product.SELECTED DRAWING: None

Description

  The present invention relates to a process for producing (1S) -1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile succinate.

  (1S) -1- [3- (Dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (hereinafter also referred to as “escitalopram”) oxalate It is a well-known antidepressant having the following structure.

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

  As a method for purifying escitalopram succinate obtained by the above synthesis route, a method by recrystallization is known. For example, it is dissolved in ethanol at an escitalopram: ethanol mass ratio (range of 1: 2.5 to 5, volume ratio of 1: 3.2 to 6.4) at reflux temperature, and cooled to 7 to 15 ° C. (cooling rate: 12-30 / h), and a method for producing crystalline particles of escitalopram succinate having a range of 50 to 200 μm, including a step of isolating the produced crystals from the mother liquor is disclosed (see Patent Document 2 below) .

Japanese Patent No. 3038204 Japanese Patent No. 4971477

  Escitalopram succinate can be obtained with high purity by the method of the patent document. However, as a result of further tests by the present inventors, it has been found that there is a problem that the solvent remains in the obtained crystal and cannot be completely removed by drying treatment. Although the residual solvent depends on the type, it is desirable to reduce the residual amount as much as possible from the viewpoint of toxicity, and there is still room for improvement in this respect.

  Therefore, an object of the present invention is to provide a production method for obtaining escitalopram succinate having a very high purity and a very small amount of residual solvent.

  As a result of intensive studies on crystallization conditions, the present inventors have found that the amount of residual solvent can be reduced by adjusting the amount of solvent used for crystallization and the cooling rate after dissolution, thereby completing the present invention. It came to.

That is, the present invention
[1]
A process for producing (1S) -1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile succinate,
(1S) -1- [3- (Dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile A method characterized in that after heating and dissolving in an organic solvent containing 15 parts by volume of ethanol, the solution is cooled at a rate of at least 25 ° C./h to crystallize to obtain the oxalate as a crystallized body,
It is.

  According to the present invention, it is possible to produce escitalopram succinate having very high optical purity and very little residual solvent.

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

  4- (4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile, (+) or (-) as a raw material (+) (1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) by salt formation with 2-di-p-toluoyl tartaric acid -Selectively obtain benzonitrile. Subsequently, escitalopram succinate can be obtained by performing a ring closure reaction and a oxalate reaction (see Patent Document 1 above).

  That is, escitalopram succinate (7) in the present invention can be produced by the following synthesis route.

<Production of tartrate (4)>
Racemic 4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoyl) A known method can be used for producing the tartrate. For example, a racemic 4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile acid salt is mixed with an organic solvent and water 2 A base is reacted in a layered solvent to obtain a free form (3), and then the free form is reacted with (+)-di- (p-toluoyl) tartaric acid to obtain a tartrate salt.

  By the way, 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, the acid salt can be obtained by carrying out a Grignard reaction between the compound (1) and 4-bromofluorobenzene, and carrying out a Grignard reaction between the obtained compound (2) and 3,3-dimethylaminopropyl chloride. .

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

  As the liberation solvent, for example, ethyl acetate, diethyl ether, toluene, chloroform, or dichloromethane can be used, and preferably, chloroform can be used. The amount of the liberation solvent 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 liberation reaction temperature can be appropriately determined in the range of 0 to 60 ° C.

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

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

  The crude tartrate salt (4) is obtained by 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-toluoyl) tartaric acid or (-)-di- (p-toluoyl) tartaric acid is dissolved is added to tartarate the educt (3). Then, after precipitation, a method obtained by optical resolution can be used.

  The crude tartrate salt (4) can be used as it is as the tartrate salt (4) in the production method according to the present invention, but the crude tartrate salt (4) is purified by a known purification method such as recrystallization. It is preferable to improve chemical purity and optical purity.

<Production of tartrate free form (5)>
A known method can be used for the production of the free tartrate salt (5), and the free salt (5) can be obtained by reacting the tartrate salt (4) with a base. In the production of the free tartrate salt (5), for example, in a solvent containing at least a poorly water-soluble organic solvent selected from aromatic hydrocarbons and / or halogenated hydrocarbons and water, in the presence of a base, From the tartrate salt (4), the free tartrate salt (5) having both extremely high optical purity and chemical purity can be obtained.

<Manufacture of escitalopram (6)>
Escitalopram (6) can be obtained by ring-closing reaction of the educt (5). As the method for producing escitalopram (6), a known method can be used without particular limitation.

  In the ring-closing reaction of the educt (5), for example, 850 parts by mass of toluene and 1.1 equivalents of triethylamine are added to the educt and stirred and dissolved at 5 ° C. After dissolution, 1.1 equivalent of p-toluenesulfonyl chloride is added dropwise. After 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 equivalent of aqueous ammonia are added and stirred for 30 minutes. After stirring, the organic layer and the aqueous layer are separated, and after separation, the organic layer can be concentrated at 60 ° C. to obtain escitalopram (6) free form.

<Manufacture of escitalopram succinate (7)>
A salt of escitalopram can be obtained by a chlorination reaction for acid addition to the escitalopram (6). In particular, escitalopram succinate (7) is preferred for obtaining as an individual. As this production method, a known method can be used without particular limitation.

  In the succination of the 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 equivalent 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 crystal is dried at 40 ° C. for 6 hours or more to obtain a precipitate of escitalopram (6) free form.

<Method for Crystallizing Escitalopram Succinate (7) According to the Present Invention>
In the crystallization method of escitalopram succinate (7) according to the present invention, a solvent containing ethanol is used as a crystallization solvent, and the solvent is in the range of 8 to 15 parts by volume with respect to escitalopram succinate. It is characterized by that.

  Examples of the solvent containing ethanol include ethanol alone or a mixed solvent of ethanol and another organic solvent. Other organic solvents used for the mixed solvent include alcohols containing methanol, 1-propanol and 2-propanol, and esters containing methyl acetate, ethyl acetate and propyl acetate. As a method for preparing the mixed solvent, a method in which all or a part of these solvents are mixed in advance may be used, or they may be sequentially mixed in the solution preparing step. From the viewpoint of efficiently removing the residual solvent, it is preferable to use only ethanol. In addition, it is preferable to set it as 30 volume parts or less as a mixing ratio of the other organic solvent when setting it as a mixed solvent per 100 volume parts of total solvent amount.

  The escitalopram succinate (7) can be dissolved in a solvent containing ethanol at a heating temperature equal to or lower than the reflux temperature. As the said heating temperature, the temperature range of 60 to 80 degreeC is preferable.

  In the crystallization method of escitalopram succinate (7) according to the present invention, a solution prepared by dissolving in the solvent containing ethanol is cooled at a cooling rate of at least 25 ° C./h for crystallization. Cooling. After cooling, a holding time of 1 hour or more is taken.

  The cooling rate is preferably 30 to 60 ° C./h, more preferably 30 to 50 ° C./h, and particularly preferably 30 to 40 ° C./hr.

  In the crystallization, seed crystals may be added, and the temperature to be added depends on the amount of the solvent used, but is preferably added in a supersaturated state. For example, when the amount of solvent used is 10 parts by volume, the addition temperature is preferably 50 ° C. or less, more preferably 45 ° C. or less, and particularly preferably 40 ° C. or less. Moreover, it is preferable that the chemical purity and optical purity of a seed crystal are 99.9% or more, and it is preferable to determine suitably the quantity to add in the range of 0.1-10 wt% of a rough body.

  The crystallized body obtained by the crystallization can be isolated by a method such as pressure filtration, vacuum filtration, and centrifugal separation.

  The isolated crystallized body can be dried, for example, at 60 ° C. for 12 hours.

<Crystalline produced by crystallization method of escitalopram succinate (7) according to the present invention>
The crystallized escitalopram oxalate produced by the crystallization method has very high optical purity and very little residual solvent.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not restrict | limited by these Examples.

<Measurement of optical purity>
The optical purity of escitalopram succinate (7) produced by the method according to the present invention was measured using the HPLC method under the following conditions.

Evaluation of optical purity of escitalopram succinate (7) The optical purity of escitalopram succinate (7) was measured by high performance liquid chromatography (HPLC). The apparatus used for the HPLC measurement and the measurement conditions are as follows. The optical purity of escitalopram succinate (7) is a value expressed as a percentage of the total area value of S and R isomers of the peak area value of escitalopram succinate (7) in the obtained chromatogram. . In addition, the retention time of escitalopram succinate (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.
Apparatus: 2695 manufactured by Waters
Detector: Ultraviolet absorptiometer (Waters 2489)
Detection wavelength: 240 nm
Column: A 4.6 mm inside diameter, 15 cm long stainless steel tube packed with 5 μm ovomucoid covalently aminated silica gel Mobile phase: buffer / acetonitrile = 85/15
Flow rate: 0.6 mL / min
Column temperature: constant temperature around 30 ° C. Injection amount: 15 μL
Sample concentration: 0.125 mg / mL

<Measurement of residual solvent>
The residual solvent of escitalopram succinate (7) was measured by gas chromatography (GC). The apparatus used for GC measurement and the measurement conditions are as follows. The residual solvent amount of escitalopram succinate (7) was calculated by a calibration curve method from the peak area value of the obtained solvent. Here, the amount of residual solvent indicates the ratio of the mass of the solvent to the mass of the sample. Further, the retention time of ethanol in the GC analysis under these conditions is around 2.3 minutes.
Equipment: 6890N manufactured by Agilent Technologies
Detector: Flame ionization detector Column: DB-WAX (30 m, 0.53 mm ID, 1.0 μm) manufactured by Agilent Technologies
Column temperature: After injection, 40 ° C. was raised to 230 ° C. at 10 ° C. for 5 minutes, and then held for 10 minutes.
Inlet temperature: 220 ° C
Detector temperature: 300 ° C
Carrier gas: helium average linear velocity: 33 cm / sec

  The escitalopram succinate (7) used in the following examples and comparative examples of the present invention was produced by the following method.

<Production of tartrate (4)>
Racemic 4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl)-in a 2000 mL 4-neck flask equipped with a thermometer and stirring blades 200 g of benzonitrile (3a) and 800 mL of isopropyl alcohol were added and dissolved by stirring at 35 ° C. Further, 88 g of (+)-di- (p-toluoyl) and 700 mL of isopropyl alcohol were added to a 1000 mL four-necked flask equipped with a thermometer and stirring blades, and dissolved by stirring at 25 ° C. After confirming dissolution, a solution of (+)-di- (p-toluoyl) tartaric acid is added to a 2000 mL four-necked flask, and the free form (3a) is precipitated and precipitated to form an optically active crude substance, that is, (1S) -4- [4- (Dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-toluoyl) tartrate 80 g of a crude product of (4) was obtained (chemical purity: 99.787%, optical purity: 95.94%). The crude product was recrystallized with 5 mL of methanol (0.8 parts by mass with respect to 1 part by mass of the tartrate salt) and 45 mL of acetonitrile (7.1 parts by mass with respect to 1 part by mass of the tartrate salt), and white As crystals (4.2 g (7.8 mmol) of the tartrate salt was obtained (yield: 25.6%, chemical purity: 99.882%, optical purity: 99.91%).

<Manufacture of free body (5)>
In a 100 mL three-necked flask equipped with a stirring blade and a thermometer, 4.3 g (8.0 mmol, chemical purity: 99.925%, impurity 1: undetected, obtained in Example 1) Impurity 2: 0.002%, optical purity: 99.96%), diethyl ether 25 mL (4.2 parts by mass relative to 1 part by mass of tartrate (4b)), purified water 25 mL (tartrate (4b) 1 mass) 5.8 parts by mass) and 2 mL of a 2M aqueous sodium hydroxide solution (16.0 mmol, 2.0 equivalents) were added and stirred, and the resulting mixture was stirred at 25 ° C. for 30 minutes to give the tartrate salt ( After stirring, the organic layer and the aqueous layer were separated by a 200 mL separatory funnel, and 4.3 mL of purified water (1 part by mass of tartrate (4b) was added to the organic layer). 0.0 parts by mass) and washed with water. After washing, the organic layer and the aqueous layer are separated, and the organic layer is concentrated under reduced pressure to give (1S) -4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3. 2.7 g (8 mmol, 100% yield) of-(hydroxymethyl) -benzonitrile free product (5) was obtained.

<Manufacture of escitalopram (6) and its salt>
The obtained (1S) -4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile educt (5) was stirred with a stirring blade. In addition to a 100 mL three-necked flask equipped with a thermometer, toluene 24 mL ((1S) -4- [4- (dimethylamino) -1- (4′-fluorophenyl) -1-hydroxybutyl] -3- (Hydroxymethyl) -benzonitrile free product (5) 8.5 parts by mass) and 1.8 g (8.8 mmol, 1.1 equivalents) of triethylamine were added and stirred at 5 ° C. for 30 minutes. After stirring, 1.7 g (8.8 mmol, 1.1 equivalents) of paratoluenesulfonyl chloride was added and 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 educt (5 ) 2.0 parts by mass with respect to 1 part by mass) and 1.4 g (8.8 mmol, 1.1 equivalents) of 25% aqueous ammonia, and heated to 25 ° C. and stirred for 30 minutes. After stirring, the reaction solution is separated into an organic layer and an aqueous layer with a 100 mL separatory funnel, and the organic layer is purified with 5 mL of purified water ((1S) -4- [4- (dimethylamino) -1- (4′-fluorophenyl). ) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile educt (5) to 2.0 parts by mass). 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).

<Manufacture of escitalopram succinate (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 parts by mass with respect to 1 part by mass of escitalopram (6)) was added. Stir for 30 minutes. After stirring, 0.7 g (7.9 mmol, 1.1 equivalents) 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 precipitated crystals were collected by filtration under reduced pressure, 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 succinate (7) as white crystals (yield: 85%, chemical purity: 99.900%, Optical purity: 99.95%).

<Manufacture of crystallized body of escitalopram succinate (7)>
The following Examples 1-4 and Comparative Examples 5-10 were implemented by changing the ethanol capacity and the cooling temperature, respectively, and the ethanol residual concentration and the optical purity were measured. The results are shown in Table 1 below.

Example 1
In a 100 mL three-necked flask equipped with a stirring blade and a thermometer, 10.0 g (24.1 mmol) of crude escitalopram succinate (7) and 100 mL of ethanol (10 parts by mass for 1 part by mass of escitalopram succinate (7)) Mass part) was added and stirred. The obtained mixed liquid was stirred at 70 ° C. for 15 minutes, and it was visually confirmed that escitalopram succinate (7) was dissolved. After starting cooling at a cooling rate of 30 ° C./h, crystal precipitation was confirmed at 50 ° C. The mixture was cooled to 5 ° C. and aged at the same temperature for 1 hour. After aging, the precipitated crystals were filtered off under reduced pressure, and the filtered crystals were washed twice with 10 mL of ethanol (1 part by mass with respect to 1 part by mass of escitalopram succinate (7)). The obtained white crystals were dried under reduced pressure at 60 ° C. for 12 hours to obtain 9.4 g (22.6 mmol) of escitalopram succinate (7) as white crystals (yield: 93.7%, chemical purity: 99. 86%, optical purity: 99.96%) The residual solvent amount of this crystal was measured, and the result is shown in Table 1.

Examples 2-5, Comparative Examples 1-5
In Example 1, the same operation was performed except that the amount of dissolved solvent and the cooling rate were changed to the values shown in Table 1, and the results of measuring the amount of residual solvent for the obtained crystals of escitalopram succinate (7) are shown in Table 1. It was shown in 1.

As apparent from the examples and comparative examples of Table 1, 1 part by mass of the oxalate (7) is dissolved by heating in 8 to 15 parts by volume of ethanol, and the solution is at least 25 ° C. / It was found that when the crystallization was performed by cooling at a rate of h or higher, the residual solvent of the obtained oxalate crystallized substance was extremely small. Moreover, it turned out that the optical purity of these crystallized bodies is very high.

Claims (1)

A process for producing (1S) -1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile succinate,
(1S) -1- [3- (Dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile A method characterized in that after heating and dissolving in an organic solvent containing 15 parts by volume of ethanol, the solution is cooled and crystallized at a rate of at least 25 ° C./h to obtain the oxalate as a crystallized body.