JP2012041277A - Improved method for producing 1, 3-disubstituted pyrrolidine compound or salt thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an industrially practicable method for efficiently producing a predetermined 1, 3-disubstituted pyrrolidine compound and a salt thereof with high purity.SOLUTION: The production method comprises making water to coexist in an organic solvent solution containing a free base of a 1, 3-disubstituted pyrrolidine compound and subsequently adding a hydrohalic acid to cause crystallization. Thereby, the high-purity 1, 3-disubstituted pyrrolidine compound and a salt thereof having been satisfactorily deprived of hardly removable impurities composed of specific analogues and coloring components without purification by column chromatography are obtained.

Description

  The present invention relates to a method for producing a highly pure 1,3-position-2-substituted pyrrolidine compound or a salt thereof.

  The 1,3-position-2-substituted pyrrolidine compound is useful as a compound having an antagonistic action on a muscarinic receptor, and darifenacin is marketed as a therapeutic drug for urinary incontinence.

  Darifenacin is usually produced as a hydrobromide salt. For example, 3- (S)-(1-carbamoyl-1,1-diphenylmethyl) pyrrolidine is added to potassium carbonate and acetonitrile in an acetonitrile solvent. After synthesizing darifenacin by a coupling reaction such as by a method in which 5- (2-bromoethyl) -2,3-dihydrobenzofuran is allowed to act, foamy darifenacin is obtained by column chromatography purification, and this is obtained in an acetone solvent. There is a method of obtaining darifenacin as a hydrobromide salt by dissolving it in a solution and adding hydrobromic acid for crystallization (Patent Document 1).

JP-A-2-282360

  However, in the above production method, purification by column chromatography is carried out in order to purify the target product. Therefore, it was not a preferable method in terms of practicality in industrial production.

  In addition, when the present inventors carried out the method described in Patent Document 1 without purification by column chromatography, the specific analog impurities by-produced in the coupling reaction could not be sufficiently removed. Moreover, the subject that the obtained hydrobromic salt of darifenacin was colored light red was observed.

  In view of the above problems, an object of the present invention is to provide a method for producing darifenacin or a salt thereof that is industrially feasible and efficiently purified.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that high-purity darifenacin in which impurities and coloring components that are difficult to remove without sufficiently purifying by column chromatography are sufficiently removed. We have found a method by which hydrohalates can be obtained.

  That is, the present invention has the following formula (1) in which water coexists.

(In the formula, * 1 represents an asymmetric carbon.) Crystallization is performed by adding hydrohalic acid to an organic solvent solution of the 1,3-position-2-substituted pyrrolidine compound free base represented. Following formula (2):

(Wherein HX represents hydrohalic acid and * 1 represents an asymmetric carbon).

  According to the method of the present invention, high-purity darifenacin hydrohalic acid from which impurities and coloring components that are difficult to remove without sufficiently purifying by a complicated method such as column chromatography are sufficiently removed. It is possible to obtain salt.

  Hereinafter, the present invention will be described in detail.

  First, the following formula (1):

The following formula (3), which is one of the methods for producing the free base of the 1,3-position-2-substituted pyrrolidine compound represented by the following (hereinafter referred to as free base (1)):

And a pyrrolidine derivative represented by the following formula (4):

A method for producing a free base (1) of a 1,3-position-2-substituted pyrrolidine compound using a dihydrobenzofuran body represented by the following (hereinafter referred to as dihydrobenzofuran body (4)) will be described.

  In the above formulas (1) and (3), the asymmetric carbon represented by * 1 may have an absolute configuration of R isomer or may have an absolute configuration of S isomer. When these compounds are used as the absolute configuration of the compounds represented by the formulas (1) and (3), the S form is preferable.

  The compound represented by the formula (3) can be produced by the method described in JP-A-2-282360. The compound represented by the formula (3) may be used after being purified by column chromatography or crystallization, for example.

  In the above formula (4), Y is a leaving group, specifically, fluorine atom, chlorine atom, bromine atom, iodine atom, methanesulfonyloxy group, benzenesulfonyloxy group, toluenesulfonyloxy group or trifluoromethanesulfonyl. An oxy group is mentioned, Preferably it is a bromine atom.

  The coupling reaction of the pyrrolidine derivative (3) and the dihydrobenzofuran (4) is performed in an organic solvent in the presence of a base.

  The organic solvent used in this reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene, chlorobenzene and xylene, n-hexane, cyclohexane, methylcyclohexane and the like. Aliphatic hydrocarbons, ethers such as diethyl ether, diisopropyl ether and tetrahydrofuran (THF), halogenated carbons such as methylene chloride, chloroform and 1,1,1-trichloroethane, and aliphatic esters such as ethyl acetate, propyl acetate and butyl acetate , Ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, methanol, ethanol, n-propanol, n-butanol, sec-butanol, isobutanol, tert-butanol, pentanol, hexanol, octanol, etc. Lumpur, may be mentioned acetonitrile, nitriles butyronitrile, N, N- dimethylformamide, N, etc. amides such as N- dimethylacetamide. Of these, acetonitrile is particularly preferred. These solvents may be used alone or in combination of two or more, and the mixing ratio is not particularly limited.

  It does not restrict | limit especially as a base to be used, An inorganic base or an organic base can be used.

  Examples of the inorganic base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, and alkali metal hydrogen carbonates such as sodium hydrogen carbonate. be able to.

  Examples of the organic base include primary amines such as methylamine, ethylamine and butylamine, secondary amines such as dimethylamine, diethylamine, dipropylamine, diisopropylamine and dibutylamine, trimethylamine, triethylamine and tripropylamine. There may be mentioned tertiary amines. Among these, an inorganic base is preferable, and potassium carbonate is particularly preferable.

  The amount of the solvent used is not particularly limited, but the lower limit is 0.1 parts by weight, preferably 1 part by weight, and the upper limit is 50 parts by weight, preferably 10 parts by weight with respect to 1 part by weight of the pyrrolidine derivative (3). Part.

  The reaction temperature is not particularly limited, but the lower limit is 30 ° C, preferably 50 ° C or higher, and the upper limit is 120 ° C or lower, preferably 100 ° C or lower.

  Although the usage-amount of a base should just be about stoichiometric or more with respect to 1 mol of pyrrolidine derivatives (3) normally, it is 0.8-10 mol normally, Preferably it is 1.0-5.0 mol. .

  The amount of dihydrobenzofuran (4) used may be about stoichiometric or more, but usually 0.8 to 5.0 mol, preferably 0.9 to 2 with respect to 1 mol of pyrrolidine derivative (3). 0.0 mol, more preferably 1.0 to 1.5 mol.

  Regarding the rate of addition of the dihydrobenzofuran (4), it is preferable to add it slowly in order to suppress the by-product of the darifenacin analog (RRT1.32 impurity) described later. Specifically, it is preferable to add the total amount of dihydrobenzofuran (4) used over 1 hour. More preferably, it is 3 hours or more, Especially preferably, it is 7 hours or more. The dihydrobenzofuran (4) may be added in the form of a powder, or may be added after being dissolved in an appropriate organic solvent.

In addition, RRT is a relative retention time in HPLC analysis, and is a value calculated by the following calculation formula. The above RRT1.32 impurity is the retention time in the HPLC analysis of darifenacin free base (1). When it is 1 minute, it is an impurity detected at 1.32 minutes.
RRT (relative retention time) = impurity peak detection time (minutes) / darifenacin peak detection time (minutes)

  The post-reaction after addition of the dihydrobenzofuran (4) is preferably performed for a long time in order to decompose the RRT1.32 impurity. Preferably it is 10 hours or more, More preferably, it is 15 hours or more, Most preferably, it is 20 hours or more.

The above reaction operation is generally carried out with stirring. The stirring intensity, the stirring power required per unit volume, preferably at 0.01 kW / m ³ or more, more preferably 0.05 kW / m ³ or more, still more preferably at 0.1 kW / m ³ or more .

  Next, the free base (1) is subjected to a crystallization step, and the following formula (2):

A method for obtaining a darifenacin hydrohalide salt represented by the following formula (hereinafter referred to as a hydrohalide salt (2)) as a crystal will be described.

  In the formula (2), HX represents hydrohalic acid. Examples of the hydrohalic acid include hydrofluoric acid, hydrochloric acid, hydrobromic acid, and hydroiodic acid, and hydrobromic acid is preferable.

  In the formula (2), * 1 represents an asymmetric carbon. The asymmetric carbon represented by * 1 may have the absolute configuration of the R isomer or the absolute configuration of the S isomer, but when these compounds are used for pharmaceutical purposes, the general formula As the absolute configuration of the compound represented by (2), S-form is preferable.

  Next, the reaction will be described.

  The free base (1) may be obtained by the above method or may be obtained by another method. When the free base (1) is obtained from the reaction solution of the coupling reaction performed by the above method, a general post-treatment may be performed. For example, an organic layer containing the free base (1) may be obtained by adding an aqueous solution containing water or an inorganic base and an organic solvent to the reaction solution, followed by liquid separation. The obtained organic layer is washed with water as necessary, and the solvent is distilled off by concentration under reduced pressure. Moreover, it is also possible to perform solvent substitution as needed.

  The inorganic salt used in the post-treatment is not particularly limited, and examples thereof include alkali metal carbonates such as sodium carbonate and potassium carbonate, and alkali metal hydrogen carbonates such as sodium hydrogen carbonate. Among these, an alkali metal carbonate is preferable, and potassium carbonate is particularly preferable.

  The organic solvent used in the post-treatment is not particularly limited, for example, aromatic hydrocarbons such as benzene, toluene, chlorobenzene and xylene, halogenated carbons such as methylene chloride and chloroform, ethyl acetate, propyl acetate, butyl acetate and the like. Aliphatic esters, ketones such as methyl ethyl ketone and methyl isobutyl ketone, and alcohols such as n-butanol and sec-butanol. Of these, ethyl acetate is particularly preferred.

  Water was allowed to coexist in the organic solvent solution of the free base (1) obtained in this way, and then hydrohalic acid (2) was obtained as crystals by adding hydrohalic acid and performing crystallization. can do.

  In the organic solvent solution of the free base (1), as the organic solvent, the solvent used in the post-treatment may be used as it is, or a different organic solvent may be added after the solvent is distilled off. From the viewpoint of removing impurities, it is preferable to use ketone or alcohol.

  It does not restrict | limit especially as a ketone, For example, acetone, methyl ethyl ketone, methyl isobutyl ketone etc. are mentioned, Preferably it is acetone.

  It does not restrict | limit especially as alcohol, For example, methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, sec-butanol, isobutanol etc. are mentioned, Preferably it is ethanol.

  The amount of the solvent used is not particularly limited, but the lower limit is usually 0.1 parts by weight, preferably 0.5 parts by weight, more preferably 1 part by weight with respect to 1 part by weight of the free base (1). Yes, the upper limit is 50 parts by weight, preferably 20 parts by weight, more preferably 10 parts by weight.

  The amount of water to be coexisted in the organic solvent solution of the free base (1) before crystallization is comprehensively considered by the contents of impurities to be removed, the degree of coloring, the yield, etc. Usually, the lower limit is 1 mol or more, preferably 3 mol or more, more preferably 5 mol or more, and the upper limit is 50 mol or less, preferably 1 mol per 1 mol of the free base (1). 20 mol or less, more preferably 10 mol or less. In order to obtain a high-quality hydrohalide (2), the amount of water contained in the organic solvent solution of the free base (1) is 7 per mol of the free base (1) at the time of crystallization. It is preferable that it is more than mol.

  The hydrohalic acid used is as described above.

  The usage-amount of hydrohalic acid is 0.7-5.0 mol normally with respect to 1 mol of free bases (1), Preferably it is 0.9-2.0 mol, More preferably, it is 1.0- 1.5 moles.

  Regarding the addition speed of hydrohalic acid, it is preferable to add it slowly in order to avoid deterioration of the fluidity of the slurry and deterioration of crystal quality due to rapid crystal precipitation. Specifically, it is preferable to add the entire amount of hydrohalic acid used over 1/2 hour. More preferably, it is 1 hour or more, More preferably, it is 2 hours or more, Most preferably, it is 3 hours or more.

  Regarding the addition temperature of hydrohalic acid, when added at a low temperature, the filterability at the time of crystal separation is poor, and the crystal is strongly colored. Specifically, it is 30 ° C. or higher, more preferably 50 ° C. or higher.

The above operation is usually carried out with stirring. The stirring intensity, as preferably agitation power per unit volume is at 0.01 kW / m ³ or more, more preferably 0.05 kW / m ³ or more, still more preferably 0.1 kW / m ³ or more.

  The hydrohalic acid to be added may be dissolved in water or a suitable organic solvent and then added to the organic solvent solution of the free base (1), or may be blown as a gas.

  The crystallization method carried out in this step is not particularly limited. For example, a cooling crystallization method, a concentrated crystallization method, a crystallization method using solvent substitution, a crystallization method by mixing a poor solvent, and / or Commonly used crystallization methods such as a salting out method can be carried out alone or in appropriate combination. In this crystallization, seed crystals may be added as necessary.

  As described above, by making water coexist in advance before adding hydrohalic acid, a more excellent impurity removal effect can be expected. When the amount of water in the organic solvent solution of the free base (1) is large, the crystallization yield is reduced, but the above-mentioned darifenacin analog can be efficiently and sufficiently controlled by appropriately controlling the amount of water added in advance. While removing, the coloration of the crystals can be reduced, and a highly pure darifenacin hydrohalide (2) can be obtained.

  Darifenacin hydrohalide (2) thus obtained can be collected as crystals using a general solid-liquid separation method such as centrifugal separation, pressure separation, or vacuum filtration. The obtained crystal can be further obtained as a dry crystal by, for example, drying under reduced pressure (vacuum drying) as necessary.

  Needless to say, the crystals of darifenacin hydrohalide (2) obtained according to the present invention are high-purity crystals. That is, the chemical purity is 96% or higher, preferably 98% or higher, more preferably 99% or higher, especially 99.5% or higher. Further, examples of the impurities contained in the hydrohalide (2) include the above-mentioned analogs. The amount of impurities in the hydrohalide (2) obtained by the method of the present invention is usually 0. .2% or less, preferably 0.1% or less, more preferably 0.05% or less, and particularly preferably no detection. The acquired crystal is not colored and is a white crystal.

  Hereinafter, the present invention will be described in detail with reference to examples. Of course, these examples do not limit the present invention in any way.

  The chemical purity and the amount of related impurities of the free base (1) and the hydrohalide (2) of darifenacin described in the examples were analyzed by the following HPLC method.

[Analytical method of chemical purity and related impurities]
Column Phenomenex {Luna 5μ C18 (2) 250 × 4.6 mm}, mobile phase A: phosphate buffer aqueous solution (pH = 7.0), mobile phase B: acetonitrile, flow rate: 1.0 ml / min, detection: UV 215 nm, column temperature : 40 ℃
Gradient condition time (min) A liquid (%) B liquid (%)
0 50 50
20 30 70
35 30 70
35.1 50 50

Retention time: 3- (S)-(1-carbamoyl-1,1-diphenylmethyl) -1- [2- (2,3-dihydrobenzofuran-5-yl) ethyl] pyrrolidine, Darifenacin free base (1) 9.1 minutes, RRT 1.32 impurity; 12.0 minutes

(Calculation formula of impurity amount)
Impurity amount (area%) = area value of impurity peak / area value of darifenacin peak

Example 1 3- (S)-(1-carbamoyl-1,1-diphenylmethyl) -1- [2- (2,3-dihydrobenzofuran-5-yl) ethyl] pyrrolidine (in formula (1) Represented compounds)
455 g of acetonitrile was added to 65.5 g (0.2318 mol, purity: 99.3 wt%) of 3- (S)-(1-carbamoyl-1,1-diphenylmethyl) pyrrolidine and 60.9 g (0.4406 mol) of potassium carbonate. A slurry solution was obtained. The slurry solution was heated to 80 ° C., and 258.2 g of an acetonitrile solution containing 63.2 g (0.2783 mol) of 5- (2-bromoethyl) -2,3-dihydrobenzofuran was added over 7 hours. After adding 5- (2-bromoethyl) -2,3-dihydrobenzofuran, the mixture was stirred for 20 hours and cooled to near room temperature. Next, 520 g of ethyl acetate and 325 g of 10% potassium carbonate aqueous solution were added to the reaction solution, and the mixture was separated to discard the aqueous layer to obtain an organic layer. The organic layer was further washed with 130 g of water. Subsequently, the solution was concentrated under reduced pressure to about 190 g, further added with 2208 g of acetone and concentrated under reduced pressure to give 3- (S)-(1-carbamoyl-1,1-diphenylmethyl) -1- [2- ( 950 g of an acetone solution containing 94.9 g (0.2225 mol) of 2,3-dihydrobenzofuran-5-yl) ethyl] pyrrolidine was obtained (yield 96%). As a result of HPLC analysis, it was RRT1.32 impurity: 1.4area%.

Example 2 3- (S)-(1-carbamoyl-1,1-diphenylmethyl) -1- [2- (2,3-dihydrobenzofuran-5-yl) ethyl] pyrrolidine hydrobromide (Compound represented by the general formula (2))
3- (S)-(1-carbamoyl-1,1-diphenylmethyl) -1- [2- (2,3-dihydrobenzofuran-5-yl) ethyl] pyrrolidine (free base of darifenacin) 94.6 g (0 .2218 mol) was adjusted so that the water content in 950 g of the acetone solution contained was 4.7 mol per mol of the free base of darifenacin, and the solution was heated to 50 ° C. Next, 42.0 g (0.2440 mol) of 47% HBr water was added over 2 hours. Crystals precipitated during the 47% HBr water addition. The obtained slurry was stirred for 1 hour, then gradually cooled to 0 ° C. and stirred overnight at the same temperature, and then the precipitated crystals were filtered under reduced pressure, and the obtained crystals were washed with 450 mL of cold acetone. . The obtained wet crystals were dried under reduced pressure to give 3- (S)-(1-carbamoyl-1,1-diphenylmethyl) -1- [2- (2,3-dihydrobenzofuran-5-yl) ethyl] pyrrolidine. 94.7 g (0.1866 mol) of hydrobromide was obtained as white crystals (crystallization yield 84%). As a result of HPLC analysis, the chemical purity was 99.9 area%, and the RRT 1.32 impurity was 0.04 area%. In addition, the filterability at the time of crystal separation was very good.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 11.41 (1H, bs); 7.15-7.40 (10H, m); 7.02 (1H, s); 6.8 7 (1H, d); 6.65 (1H, d) ; 5.78 (1H, s); 5.59 (1H, s); 4.53 (2H, t); 3.80-3.98 (1H, m); 3.70 (1H, s); 3.49 (1H, t); 3.18-3.29 (1H, m); 3.14 (2H, t); 3.00-3.15 (4H, m); 2.81-2.99 (2H, m); 2.10-2.25 (1H, m).

¹³ C NMR (400 MHz, CDCl ₃ ): δ = 175.1; 159.0; 142.3; 141.9; 129.0; 128.8; 128.7; 128.5; 127.9; 127.7; 127.6; 127.5; 125.2; 109.3; 71.2; 62.7; 57.0; 56.3; 53.9 ; 43.6; 31.2; 29.6; 28.1.

IR (KBr): 3468, 3259, 3209, 3096, 2959, 2854, 2696, 2361, 2343, 1668, 1576, 1493, 1443, 1364, 1350, 1248, 983, 704 cm ^-1

Main diffraction angles (2θ ± 0.1) in powder X-ray (Cu-Kα): 8.1 °, 11.4 °, 17.0 °, 18.2 °, 18.7 °, 19.0 °, 19.5 °, 20.0 °, 20.2 °, 20.7 °, 21.9 ° , 22.0 °, 24.5 °, 24.6 °, 25.1 °, 25.8 °, 26.7 °, 27.2 °, 27.5 °, 28.6 °, 28.7 °

Melting point: 231-232 ° C
Optical rotation: [α] _D ²⁵ = + 45.8 (c 1.0, EtOH)

(Examples 3 and 4) 3- (S)-(1-carbamoyl-1,1-diphenylmethyl) -1- [2- (2,3-dihydrobenzofuran-5-yl) ethyl] pyrrolidine / hydrogen bromide Acid salt (compound represented by formula (2))
Crystallization was carried out according to the method of Example 2 so that the amount of water present before crystallization was 1.2 mol or 3.5 mol with respect to 1 mol of darifenacin free base.

  The results of crystallization by changing the amount of coexisting water before crystallization are shown in the following table.

Comparative Example 1 3- (S)-(1-carbamoyl-1,1-diphenylmethyl) -1- [2- (2,3-dihydrobenzofuran-5-yl) ethyl] pyrrolidine hydrobromide (Compound represented by the general formula (2))
2- (S)-(1-carbamoyl-1,1-diphenylmethyl) pyrrolidine 20.0 g (71.3 mmol) and 5- (2-bromoethyl) -2,3-dihydrobenzofuran 19.4 g (85.4 mmol) Then, 200 g of acetonitrile was added to 18.5 g (133.9 mmol) of potassium carbonate, and the temperature was raised to 80 ° C. After heating, the mixture was stirred for 2 hours and cooled to near room temperature. Next, 200 g of methylene chloride and 200 g of a 10% potassium carbonate aqueous solution were added to the reaction solution, and the mixture was separated. The organic layer was concentrated to dryness and crude 3- (S)-(1-carbamoyl-1,1-diphenylmethyl) -1- [2- (2,3-dihydrobenzofuran-5-yl) ethyl] pyrrolidine ( 34.2 g of darifenacin free base) was obtained as a foam.

  Next, 10 g of an acetone solution containing 1 g (2.3 mmol) of the free base of darifenacin was adjusted to 25 ° C., and then 443.1 mg (2.5 mmol) of 47% HBr water was added in about 5 minutes. Crystals precipitated during the 47% HBr water addition. The obtained slurry was stirred for 1 hour and then gradually cooled to 0 ° C. and stirred overnight at the same temperature. The precipitated crystals were filtered under reduced pressure, and the obtained crystals were washed with 5 mL of cold acetone. The obtained wet crystals were dried under reduced pressure to give 3- (S)-(1-carbamoyl-1,1-diphenylmethyl) -1- [2- (2,3-dihydrobenzofuran-5-yl) ethyl] pyrrolidine. 0.95 g (1.9 mmol, crystallization yield 80%) of hydrobromide was obtained as pale red crystals. As a result of HPLC analysis, the chemical purity was 98.9 area%, and the RRT 1.32 impurity was 0.7 area%. The filterability at the time of crystal separation was good.

Comparative Example 2 3- (S)-(1-carbamoyl-1,1-diphenylmethyl) -1- [2- (2,3-dihydrobenzofuran-5-yl) ethyl] pyrrolidine hydrobromide (Compound represented by the general formula (2))
3- (S)-(1-carbamoyl-1,1-diphenylmethyl) -1- [2- (2,3-dihydrobenzofuran-5-yl) ethyl] pyrrolidine (darifenacin) obtained by the production method of Example 1 The amount of water in 10 g of an acetone solution containing 1 g (2.3 mmol) of the free base was adjusted to 0.5 mol with respect to 1 mol of darifenacin free base, and the solution was adjusted to 5 ° C. Next, 443.1 mg (2.5 mmol) of 47% HBr water was added in about 5 minutes. Crystals precipitated during the 47% HBr water addition. The obtained slurry was stirred for 1 hour and then gradually cooled to 0 ° C. and stirred overnight at the same temperature. The precipitated crystals were filtered under reduced pressure, and the obtained crystals were washed with 5 mL of cold acetone. The obtained wet crystals were dried under reduced pressure to give 3- (S)-(1-carbamoyl-1,1-diphenylmethyl) -1- [2- (2,3-dihydrobenzofuran-5-yl) ethyl] pyrrolidine. 1.02 g (2.0 mmol, crystallization yield 86%) of hydrobromide was obtained as dark red crystals. As a result of HPLC analysis, the chemical purity was 99.3 area%, and the RRT 1.32 impurity was 0.26 area%. The filterability during crystal separation was poor.

Claims (11)

In the presence of water, the following formula (1):

(In the formula, * 1 represents an asymmetric carbon.) Crystallization is performed by adding hydrohalic acid to an organic solvent solution of the free base of the 1,3-position-2-substituted pyrrolidine compound represented. The following formula (2):

(In the formula, HX is hydrohalic acid and * 1 represents an asymmetric carbon.) A process for producing a hydrohalic acid salt of a 1,3-position-2-substituted pyrrolidine compound.   The method according to claim 1, wherein the amount of water to be coexisted is 1 mol or more per 1 mol of the free base (1) of the 1,3-position-2-substituted pyrrolidine compound.   The production method according to claim 1 or 2, wherein the organic solvent is a ketone or an alcohol.   The production method according to claim 3, wherein the ketone is acetone.   The production method according to claim 3, wherein the alcohol is ethanol.   The production method according to claim 1, wherein the addition temperature of hydrohalic acid is 30 ° C. or higher. The free base (1) of the 1,3-position-2-substituted pyrrolidine compound is represented by the following formula (3) in a base and an organic solvent:

(Wherein * 1 represents an asymmetric carbon) and the pyrrolidine derivative represented by the following formula (4):

The production method according to any one of claims 1 to 6, which is obtained by allowing a dihydrobenzofuran body represented by the formula (wherein Y represents a leaving group) to act. 8. The production method according to claim 7, wherein the following i) to iii) are sequentially performed.
i) A free pyrrolidine derivative (3), a base and an organic solvent are mixed.
ii) Warm the mixture obtained in i).
ii) Dihydrobenzofuran (4) is added sequentially.   The method according to claim 8, wherein the addition time of the dihydrobenzofuran (4) is 1 hour or more.   The production method according to claim 8 or 9, wherein the addition temperature of the dihydrobenzofuran (4) is 30 ° C or higher.   The process according to any one of claims 7 to 10, wherein the reaction is carried out for 10 hours or longer after the dihydrobenzofuran (4) is added.