JP2010095453A - Method for producing optically active 1-aryl-3-pyrrolidinol - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for readily producing an optically active 1-aryl-3-pyrrolidinol or a salt thereof, useful as an intermediate of a medicine without carrying out complicated operation from an inexpensive general-purpose starting raw material. <P>SOLUTION: The method for producing the optically active 1-aryl-3-pyrrolidinol or the salt thereof includes reacting an aniline compound and hydrogen with an easily available optically active 4-substituted-3-hydroxybutyronitrile in the presence of a metal catalyst. The optically active 1-aryl-3-substituted pyrrolidine and the optically active 3-substituted pyrrolidine can readily and efficiently be obtained from the optically active 1-aryl-3-pyrrolidinol. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a method for producing optically active 1-aryl-3-pyrrolidinol or a salt thereof which is important as a raw material for pharmaceuticals and agricultural chemicals, and further optically active 1-aryl-3-substituted pyrrolidine or a salt thereof.

  The following methods have been reported as production methods of optically active 1-aryl-3-pyrrolidinol and optically active 1-aryl-3-substituted pyrrolidine.

(1) Synthesis of (R) -1- (3-fluorophenyl) -pyrrolidinol by N-arylation by reaction of the amino group of (R) -3-pyrrolidinol with 1-bromo-3-fluorobenzene Manufacturing method to do. (Patent Document 1).
(2) (R) -1- (3-ethoxycarbonylphenyl) -3-pyrrolidinol is obtained by N-arylation by reaction of the amino group of (R) -3-pyrrolidinol with ethyl 3-bromobenzoate. Manufacturing method to synthesize. (Patent Document 2).
(3) Protecting the amino group at position 1 of (S) -aminopyrrolidine with tert-butoxycarbonyl (Boc), then acetyl-protecting the amino group at position 3 and deprotecting the 1-position in sequence (S) -3-Acetylaminopyrrolidine is obtained. Subsequently, N-arylation is performed with 2-chloro-5-trifluoromethylpyridine, and finally the amino group at the 3-position is deprotected to give 2-[(3S) -3-aminopyrrolidin-1-yl]- A production method for synthesizing 5-trifluoromethylpyridine. (Patent Document 3)
WO2005 / 037803 WO2007 / 149031 WO1998 / 01426

  However, both prior arts (1) and (2) require the use of expensive and special palladium catalysts for N-arylation. Moreover, since silica gel column chromatography is used for purification, there are problems in industrial implementation (Patent Documents 1 and 2).

  The prior art (3) needs to carry out many protection and deprotection operations and cannot be said to be suitable for industrial implementation. In addition, although N-arylation does not use an expensive and special palladium catalyst, it is limited to reactions with a very limited number of heteroaryl compounds and lacks versatility as a method for producing 1-aryl-3-substituted pyrrolidine compounds. (Patent Document 3).

  In view of the above, as a result of intensive studies by the present inventors, an optically active 4-substituted-3-hydroxy that is readily available in the presence of an inexpensive and highly versatile metal catalyst without performing expensive catalysts and complicated operations. It has been found that optically active 1-aryl-3-pyrrolidinol can be produced simply by reacting butyronitrile with an aniline derivative and hydrogen. Furthermore, a method capable of easily and efficiently deriving from optically active 1-aryl-3-pyrrolidinol to optically active 1-aryl-3-substituted pyrrolidine and optically active 3-substituted pyrrolidine has been found to complete the present invention. It came.

  That is, the present invention provides the following formula (1);

（式中、Ｌ^１は脱離基を表す。＊は不斉炭素原子を表す。）で表される光学活性４−置換−３−ヒドロキシブチロニトリルに、金属触媒存在下、下記式（２）；

(Wherein, L ¹ represents a leaving group. * Represents. An asymmetric carbon atom) to the optically active 4-substituted-3-hydroxybutyronitrile represented by the presence of a metal catalyst, the following formula (2 );

（式中、Ａｒは置換基を有していてもよい炭素数６〜２０のアリール基、又は置換基を有していてもよい炭素数３〜２０のヘテロアリール基を表す。）で表されるアニリン化合物と水素を作用させることを特徴とする、下記式（３）；

(In the formula, Ar represents an aryl group having 6 to 20 carbon atoms which may have a substituent, or a heteroaryl group having 3 to 20 carbon atoms which may have a substituent). The following formula (3), characterized by reacting an aniline compound with hydrogen:

（式中、Ａｒ、＊は前記に同じ。）で表される光学活性１−アリール−３−ピロリジノール、又はその塩の製造法に関する。

(Wherein Ar and * are the same as above), and a method for producing an optically active 1-aryl-3-pyrrolidinol or a salt thereof.

  Further, the present invention provides the following formula (8):

（式中、＊は不斉炭素原子を表す。）において、Ｒ^２が１−シアノ−１，１−ジフェニルメチル基、ベンジルオキシ基、ベンゾイルオキシ基、又はアミノ基である、光学活性１−（４−メチルオキシフェニル）−３−置換ピロリジン又はその塩に関する。

(Wherein * represents an asymmetric carbon atom), R ² is a 1-cyano-1,1-diphenylmethyl group, a benzyloxy group, a benzoyloxy group, or an amino group. 4-methyloxyphenyl) -3-substituted pyrrolidine or a salt thereof.

  Furthermore, the present invention provides the following formula (10):

（式中、Ｒ^１は置換基を有していてもよい炭素数１〜２０のアルキル基、又は置換基を有していてもよい炭素数６〜２０のアリール基を表す。＊は不斉炭素原子を表す。）で表される光学活性１−（４−メチルオキシフェニル）−３−（スルホニルオキシ）−ピロリジンにも関する。

(In the formula, R ¹ represents an optionally substituted alkyl group having 1 to 20 carbon atoms or an optionally substituted aryl group having 6 to 20 carbon atoms. * Represents an asymmetric group. It also relates to an optically active 1- (4-methyloxyphenyl) -3- (sulfonyloxy) -pyrrolidine represented by:

  According to the method of the present invention, the optical activity can be easily carried out by a method that can be industrially carried out from inexpensive and easily available raw materials without using expensive and special catalysts as in the past and complicated operations. 1-aryl-3-pyrrolidinol and optically active 1-aryl-3-substituted pyrrolidines can be prepared.

  Next, the present invention will be specifically described. The production methods of optically active 1-aryl-3-pyrrolidinol and optically active 1-aryl-3-substituted pyrrolidine in the present invention are shown as follows. Each process is demonstrated in order.

Process 1
In this step, the optically active 4-substituted-3-hydroxybutyronitrile represented by the formula (1) is represented by the formula (3) by allowing an aniline compound and hydrogen to act in the presence of a metal catalyst. Optically active 1-aryl-3-pyrrolidinol or a salt thereof is produced.

  Here, * represents an asymmetric carbon atom. Of the enantiomers, a slight excess of one enantiomer is included in the present invention.

L ¹ represents a leaving group, specifically, for example, an alkylsulfonyloxy group having 1 to 20 carbon atoms which may have a substituent, or 6 to 6 carbon atoms which may have a substituent. Examples include 20 arylsulfonyloxy groups, an aralkylsulfonyloxy group having 7 to 20 carbon atoms which may have a substituent, and a halogen atom. Examples of the substituent include halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom, nitro group, nitroso group, cyano group, amino group, hydroxyamino group, alkylamino group having 1 to 12 carbon atoms, carbon number 1-12 dialkylamino groups, C7-12 aralkylamino groups, C7-12 diaralkylamino groups, C1-12 alkylsulfonylamino groups, sulfonic acid groups, sulfonamido groups, azide groups , A trifluoromethyl group, a carboxyl group, an acyl group having 1 to 12 carbon atoms, an aroyl group having 7 to 12 carbon atoms, a hydroxyl group, an alkyloxy group having 1 to 12 carbon atoms, an aralkyloxy group having 7 to 12 carbon atoms, C6-C12 aryloxy group, C1-C12 acyloxy group, C7-C12 aroyloxy group, C3-C12 Silyloxy group, an alkylsulfonyloxy group having 1 to 12 carbon atoms, or the like alkylthio group having 1 to 12 carbon atoms and the like, the number of the substituent include the 0-5.

L ¹ is preferably an alkylsulfonyloxy group having 1 to 20 carbon atoms which may have a substituent, an arylsulfonyloxy group having 6 to 20 carbon atoms which may have a substituent, or a chlorine atom. More preferably, a methanesulfonyloxy group, an ethanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a benzenesulfonyloxy group, a 4-methylbenzenesulfonyloxy group, a 4-chlorobenzenesulfonyloxy group, a 2-nitrobenzenesulfonyloxy group, 3 -A nitrobenzenesulfonyloxy group, a 4-nitrobenzenesulfonyloxy group, or a chlorine atom, and particularly preferably a chlorine atom.

A process for producing optically active 4-chloro-3-hydroxybutyronitrile in which L ¹ is a chlorine atom is described, for example, in JP-A-2-85249 and JP-B-5-69818. It can be easily produced by a method in which an alkali metal cyanide is allowed to act on chlorohydrin.

An optically active 4-sulfonyloxy-3-hydroxybutyronitrile derivative in which L ¹ is a sulfonyloxy group is described in JP-A-3-176463 and is optically active 4-chloro-3-hydroxy under basic conditions. It can be easily produced by a production method in which a sulfonylating agent is allowed to act on butyronitrile.

  The aniline compound used in this step is represented by the formula (2).

  Here, Ar represents a C6-C20 aryl group which may have a substituent, or a C3-C20 heteroaryl group which may have a substituent.

  Examples of the aryl group include a phenyl group, a naphthyl group, and a biphenyl group. Examples of the heteroaryl group include pyridyl group, furanyl group, thienyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, pyrazolyl group, benzofuranyl group, benzothiazolyl group, indolyl group and the like. Examples of the substituent include halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom, nitro group, nitroso group, cyano group, amino group, hydroxyamino group, alkylamino group having 1 to 12 carbon atoms, carbon number 1-12 dialkylamino groups, C7-12 aralkylamino groups, C7-12 diaralkylamino groups, C1-12 alkylsulfonylamino groups, sulfonic acid groups, sulfonamido groups, azide groups , A trifluoromethyl group, a carboxyl group, an acyl group having 1 to 12 carbon atoms, an aroyl group having 7 to 12 carbon atoms, a hydroxyl group, an alkyloxy group having 1 to 12 carbon atoms, an aralkyloxy group having 7 to 12 carbon atoms, C6-C12 aryloxy group, C1-C12 acyloxy group, C7-C12 aroyloxy group, C3-C12 Silyloxy group, an alkylsulfonyloxy group having 1 to 12 carbon atoms, or the like alkylthio group having 1 to 12 carbon atoms and the like, the number of the substituent include the 0-5.

  Ar is particularly preferably a phenyl group, a 4-methyloxyphenyl group, a 3-fluorophenyl group, or a 3-ethyloxycarbonylphenyl group.

  When the amount of the compound (2) used is too large, it is not preferable in terms of cost and post-treatment, and therefore it is preferably 5 times or less by weight with respect to the compound (1), more preferably 0.1-3. The weight is 0.0 times the weight, and particularly preferably 0.5 to 2 times the weight.

  Examples of the metal catalyst include metals such as platinum, rhodium, palladium, nickel, cobalt, ruthenium, iridium, and rhenium, alloys, and chlorides thereof. These catalysts are preferably used in the form of a catalyst dispersed in a powder carrier from the viewpoints of catalyst activity, reproducibility, storage stability, operability, and recycling.

  Examples of the powder carrier include carbon, alumina, silica-alumina, silica, barium carbonate, barium sulfate, calcium carbonate, titanium oxide, zirconium oxide, and zeolite, and preferably platinum supported on these powder carriers. , Rhodium, or palladium metal, sulfide thereof, or hydroxide. Specifically, for example, platinum-carbon, platinum (II) sulfide-carbon, platinum-alumina, platinum-silica-alumina, platinum-silica, platinum-barium carbonate, platinum-barium sulfate, platinum-calcium carbonate, platinum-oxidation Titanium, platinum-zirconium oxide, platinum-zeolite, platinum-asbestos, platinum rhodium alloy-carbon, platinum palladium alloy-carbon, rhodium-carbon, rhodium-alumina, rhodium-silica, rhodium-calcium carbonate, palladium-carbon, hydroxylation Palladium (II) -carbon, palladium (II) sulfide-carbon, palladium-alumina, palladium-silica-alumina, palladium-silica, palladium-barium carbonate, palladium-barium sulfate, palladium-calcium carbonate, palladium-titanium oxide, palladium -Zirconium oxide Chloride, palladium - zeolite, palladium - asbestos, ruthenium - carbon, ruthenium - alumina, ruthenium - silica, ruthenium - calcium carbonate, iridium - carbon, iridium - alumina, iridium - silica, iridium - calcium carbonate.

  These metal catalysts may be used alone or in combination of two or more. Preferred is palladium-carbon, rhodium-carbon, platinum-carbon, or palladium (II) hydroxide-carbon, more preferably rhodium-carbon, palladium-carbon, or palladium (II) hydroxide-carbon, Particularly preferred is palladium-carbon.

  If the amount of the metal catalyst used is too large, it is not preferable in terms of cost and post-treatment, and therefore it is preferably 5 times or less, more preferably 0.01 to 1. weight with respect to the compound (1). The weight is 0 times, particularly preferably 0.05 to 0.5 times the weight.

  The solvent for this reaction is not particularly limited as long as it does not affect the reaction. For example, water; alcohol solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, and ethylene glycol Ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tert-butyl ether and ethylene glycol dimethyl ether; ester solvents such as ethyl acetate, n-propyl acetate and isopropyl acetate; aromatic carbonization such as benzene and toluene Examples include hydrogen solvents; ketone solvents such as acetone and methyl ethyl ketone; and aliphatic hydrocarbon solvents such as pentane, hexane, heptane, and methylcyclohexane. Preferably, water; alcohol solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, ethylene glycol; ester solvents such as ethyl acetate, n-propyl acetate, isopropyl acetate; benzene, toluene An aromatic hydrocarbon solvent such as water, methanol, ethanol, isopropanol, ethyl acetate, or toluene is more preferable. Particularly preferred is methanol.

  These may be used alone or in combination of two or more. When using 2 or more types together, the mixing ratio is not particularly limited.

  If the amount of the solvent used is too large, it is not preferable in terms of cost and post-treatment, and therefore it is preferably 50 times or less by weight, more preferably 20 times or less by weight with respect to the compound (1).

  The reaction temperature is not particularly limited and may be set as appropriate. However, in order to reduce the formation of by-products, it is preferably -20 to 100 ° C, more preferably 0 to 50 ° C, and particularly preferably 5 It is 30 degreeC.

  Moreover, the hydrogen pressure in this reaction is preferably 5.0 MPa or less, more preferably 0.1 to 1.0 MPa.

  There is no restriction | limiting in particular about reaction time, Preferably it is 0.1 to 48 hours, More preferably, it is 0.5 to 24 hours.

  Although there is no restriction | limiting in particular about the mixing order of the said compound (1), the said compound (2), a solvent, a metal catalyst, and hydrogen, From a viewpoint of safety, Preferably the said compound (1), the said compound (2), and a metal catalyst Hydrogen may be added to the solvent mixture.

  As post-treatment after the reaction, a general treatment for obtaining a product from the reaction solution may be performed. For example, when the metal catalyst is filtered off from the reaction solution after completion of the reaction, and the reaction solvent is distilled off from the filtrate by heating under reduced pressure, the desired product is obtained.

  The target product thus obtained has sufficient purity that can be used in the subsequent steps, but for the purpose of further increasing the purity, crystallization, fractional distillation, solution washing, the compound (3) and an acid are used. The purity may be further increased by a general purification method such as a method of forming a salt from crystallization from a solvent and column chromatography.

The following method is preferably used as the purification method.
Purification method 1 : A method in which the compound (3) is dissolved in an organic solvent and washed with an aqueous solution containing an acid to remove contaminating impurities.
Purification method 2 : A method of separating the compound (3) as a crystal by crystallizing it from a solvent and removing the mixed impurities.
Purification method 3 : A method in which a salt is formed from the compound (3) and an acid, dissolved in water, washed with an organic solvent, and the contaminated impurities are removed in the organic solvent.

First, the purification method 1 will be described.

  The organic solvent is not particularly limited as long as it is not compatible with water. For example, ether solvents such as diethyl ether and ethylene glycol dimethyl ether; aromatic hydrocarbon solvents such as benzene and toluene; carbon tetrachloride, chloroform Halogen solvents such as methylene chloride, 1,2-dichloroethane and chlorobenzene; ester solvents such as ethyl acetate, isopropyl acetate and tert-butyl acetate. Preferably, aromatic hydrocarbon solvents such as benzene and toluene; halogen solvents such as carbon tetrachloride, chloroform, methylene chloride, 1,2-dichloroethane and chlorobenzene; esters such as ethyl acetate, isopropyl acetate and tert-butyl acetate It is a system solvent, More preferably, it is ethyl acetate, toluene, or chlorobenzene, Most preferably, it is toluene or chlorobenzene.

  These may be used alone or in combination of two or more. When using 2 or more types together, the mixing ratio is not particularly limited.

  If the amount of the solvent used is too large, it is not preferable in terms of cost and post-treatment, and therefore it is preferably 50 times weight or less, more preferably 20 times weight or less with respect to the compound (3).

  Examples of the acid include hydrogen fluoride, hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, nitric acid, phosphoric acid, boric acid and other inorganic acids; formic acid, acetic acid, propionic acid, butyric acid, pivalic acid, chloro Carboxylic acids such as acetic acid, trichloroacetic acid, trifluoroacetic acid, oxalic acid, L-tartaric acid, D-tartaric acid, mandelic acid; methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, camphorsulfonic acid And sulfonic acids such as Preferably, it is hydrogen chloride, hydrogen bromide, sulfuric acid, acetic acid, phosphoric acid, methanesulfonic acid, or 4-methylbenzenesulfonic acid, more preferably hydrogen chloride, sulfuric acid, acetic acid, phosphoric acid, or methanesulfonic acid, especially Preferred is hydrogen chloride, acetic acid, or phosphoric acid.

  The amount of acid used is preferably 0.5 to 20 times the molar amount, and more preferably 0.5 to 10 times the molar amount.

  As the amount of water used in the aqueous solution containing an acid, too much is not preferable in terms of cost and post-treatment, and therefore it is preferably 50 times weight or less, more preferably 20 times weight or less with respect to the compound (3). It is.

Next, the purification method 2 will be described.

  There is no restriction | limiting in particular as a solvent, For example, water; Alcohol solvents, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, ethylene glycol; Tetrahydrofuran, diethyl ether, 1, 4- dioxane, ethylene Ether solvents such as glycol dimethyl ether; aromatic hydrocarbon solvents such as benzene and toluene; aliphatic hydrocarbon solvents such as pentane, hexane, heptane and methylcyclohexane; carbon tetrachloride, chloroform, methylene chloride, 1,2- Halogen solvents such as dichloroethane and chlorobenzene; ester solvents such as ethyl acetate, isopropyl acetate and tert-butyl acetate; sulfoxide solvents such as dimethyl sulfoxide; N, N-dimethylformamide, N, N-dimethyl Amide solvents such as acetamide; urea solvents such as dimethylpropylene urea; phosphonic acid triamide solvents such as hexamethylphosphonic acid triamide; ketone solvents such as acetone and methyl ethyl ketone; nitrile solvents such as acetonitrile and propionitrile It is done.

  Preferably, water; alcohol solvent such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, ethylene glycol; aromatic hydrocarbon solvent such as benzene, toluene; carbon tetrachloride, chloroform, chloride Halogen solvents such as methylene, 1,2-dichloroethane and chlorobenzene; ester solvents such as ethyl acetate, isopropyl acetate and tert-butyl acetate; ketone solvents such as acetone and methyl ethyl ketone; nitrile solvents such as acetonitrile and propionitrile More preferred is isopropanol, acetone, ethyl acetate, toluene, hexane, or chlorobenzene, and particularly preferred is toluene, ethyl acetate, or chlorobenzene.

  These may be used alone or in combination of two or more. When using 2 or more types together, the mixing ratio is not particularly limited. If the amount of the solvent used is too large, it is not preferable in terms of cost and post-treatment, and therefore it is preferably 50 times weight or less, more preferably 20 times weight or less with respect to the compound (3).

Moreover, the crystallization method for isolating the compound (3) is not particularly limited, and examples thereof include the following methods.
(A) A method of crystallizing the compound (3) by dissolving the compound (3) in a solvent and then concentrating and distilling off the solvent.
(B) A method in which the compound (3) is dissolved in a solvent and then cooled and crystallized.
(C) A method in which the compound (3) is dissolved in a solvent and then crystallized by adding a poor solvent or concentrating and replacing the poor solvent.

Moreover, it can also crystallize combining the method of (a), (b), (c) suitably.
Examples of the poor solvent used in the method (c) include hexane. In addition, seed crystals may be added during crystallization.

  Although the implementation temperature in the crystallization method of (a)-(c) is not specifically limited, What is necessary is just to select suitably by the kind of solvent to be used, Preferably the said compound (3) is used for the solvent seed | species or mixed solvent kind to be used. It may be set in accordance with the target precipitation amount and crystal quality at a temperature lower than the temperature at which the solution dissolves.

  The compound (3) precipitated by the crystallization methods (a) to (c) can be separated and obtained by a method such as vacuum filtration, pressure filtration, or centrifugal separation. Further, when the mother liquor remains in the acquired crystal and the purity of the crystal is lowered, the quality can be improved by further washing with an organic solvent as necessary.

  As a method for drying the crystals, it is desirable to dry under reduced pressure (vacuum drying) at about 60 ° C. or less, avoiding thermal decomposition and melting.

Next, the purification method 3 will be described.

  Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid; and organic acids such as formic acid, acetic acid, oxalic acid, and citric acid. Preferred is hydrogen chloride or sulfuric acid, and more preferred is hydrogen chloride. In particular, hydrochloric acid in which hydrogen chloride is dissolved in water is preferable.

  The amount of acid used is determined according to the pH of the aqueous solution. That is, an acid is added so that the aqueous solution has a predetermined pH. Preferably pH is 7 or less, More preferably, it is 1-5.

  The organic solvent used for washing is not particularly limited as long as it is not compatible with water, preferably toluene, chlorobenzene, ethyl acetate, or methyl tert-butyl ether, more preferably toluene, chlorobenzene, or ethyl acetate. And particularly preferably toluene or chlorobenzene.

  If the amount of the organic solvent used is too large, it is not preferable in terms of cost and post-treatment, and therefore it is preferably 50 times or less, more preferably 20 times or less, with respect to the compound (3).

  The aqueous solution containing the compound (3) thus obtained is further subjected to operations such as extraction, concentration and the like by liberating the compound (3) by adjusting the pH by further adding a base. The compound (3) having improved purity can also be isolated.

  Further, the methods of purification method 1, purification method 2 and purification method 3 may be appropriately combined, and may be appropriately combined with the general purification method described above.

Process 2
In this step, the compound (3) produced in Step 1 is treated with a base and a sulfonylating agent to obtain the following formula (4);

で表される光学活性1−アリール−３−（スルホニルオキシ）−ピロリジンを製造する。

An optically active 1-aryl-3- (sulfonyloxy) -pyrrolidine represented by the formula:

  Here, Ar and * are the same as described above.

R ¹ represents an alkyl group having 1 to 20 carbon atoms which may have a substituent, or an aryl group having 6 to 20 carbon atoms which may have a substituent. Examples of the substituent include halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom, nitro group, nitroso group, cyano group, amino group, hydroxyamino group, alkylamino group having 1 to 12 carbon atoms, carbon number 1-12 dialkylamino groups, C7-12 aralkylamino groups, C7-12 diaralkylamino groups, C1-12 alkylsulfonylamino groups, sulfonic acid groups, sulfonamido groups, azide groups , A trifluoromethyl group, a carboxyl group, an acyl group having 1 to 12 carbon atoms, an aroyl group having 7 to 12 carbon atoms, a hydroxyl group, an alkyloxy group having 1 to 12 carbon atoms, an aralkyloxy group having 7 to 12 carbon atoms, C6-C12 aryloxy group, C1-C12 acyloxy group, C7-C12 aroyloxy group, C3-C12 Silyloxy group, an alkylsulfonyloxy group having 1 to 12 carbon atoms, or the like alkylthio group having 1 to 12 carbon atoms and the like, the number of the substituent include the 0-5. Examples of the alkyl group include a methyl group, an ethyl group, and a tert-butyl group. Examples of the aryl group include a phenyl group, a naphthyl group, and a biphenyl group.

R ¹ is preferably a methyl group, a trifluoromethyl group, a phenyl group, a 4-methylphenyl group, a 4-chlorophenyl group, a 2-nitrophenyl group, a 3-nitrophenyl group, or a 4-nitrophenyl group, and A methyl group or a 4-methylphenyl group is preferable, and a methyl group is particularly preferable.

  The sulfonylating agent is preferably methanesulfonyl chloride, anhydrous methanesulfonyl, anhydrous trifluoromethanesulfonyl, benzenesulfonyl chloride, 4-methylbenzenesulfonyl chloride, 4-chlorobenzensulfonyl chloride, 2-nitrobenzenesulfonyl chloride, 3-nitrobenzenesulfonyl chloride, Or 4-nitrobenzenesulfonyl chloride etc. are mentioned, More preferably, they are methanesulfonyl chloride or 4-methylbenzenesulfonyl chloride, Most preferably, it is methanesulfonyl chloride.

  The amount of the sulfonylating agent to be used is preferably 2 to 10-fold mol amount, more preferably 2 to 5-fold mol amount based on the compound (3).

  Examples of the base include triethylamine, tri-n-butylamine, N-methylmorpholine, N-methylpiperidine, diisopropylethylamine, pyridine, N, N-dimethylaminopyridine, 1,4-diazabicyclo [2,2,2] octane, etc. Tertiary hydroxides; metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, magnesium hydroxide; metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate; lithium hydrogen carbonate And metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate. Preferred is triethylamine, pyridine, sodium hydroxide, potassium carbonate, or sodium hydrogen carbonate, more preferred is triethylamine, pyridine, sodium hydroxide, or potassium carbonate, and particularly preferred is triethylamine.

  The amount of the base used is preferably 2 to 20 times the molar amount, more preferably 2 to 10 times the molar amount relative to the compound (3).

  Moreover, in this process, you may add a solvent as needed.

  The solvent is not particularly limited as long as it does not affect the reaction. For example, ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene and toluene Solvent: Aliphatic hydrocarbon solvent such as pentane, hexane, heptane, methylcyclohexane; Halogen solvent such as carbon tetrachloride, chloroform, methylene chloride, 1,2-dichloroethane, chlorobenzene; Ethyl acetate, isopropyl acetate, tert-acetate Ester solvents such as butyl; sulfoxide solvents such as dimethyl sulfoxide; amide solvents such as N, N-dimethylformamide and N, N-dimethylacetamide; urea solvents such as dimethylpropylene urea; hexamethylphosphonic acid triamide Phosphonic acid triamide solvents; acetone, ketone solvents such as methyl ethyl ketone; acetonitrile, and a nitrile solvent such as propionitrile. Preferably, ester solvents such as ethyl acetate, n-propyl acetate and isopropyl acetate; aromatic hydrocarbon solvents such as benzene and toluene; halogens such as carbon tetrachloride, chloroform, methylene chloride, 1,2-dichloroethane and chlorobenzene It is a system solvent, More preferably, it is ethyl acetate, toluene, or chlorobenzene, Most preferably, it is ethyl acetate. These may be used alone or in combination of two or more. When using 2 or more types together, the mixing ratio is not particularly limited.

  If the amount of the solvent used is too large, it is not preferable in terms of cost and post-treatment, and therefore it is preferably 50 times weight or less, more preferably 20 times weight or less with respect to the compound (3).

There is no restriction | limiting in particular in reaction temperature, What is necessary is just to set suitably, In order to reduce the production | generation of a by-product, Preferably it is -40-80 degreeC, More preferably, it is -20-50 degreeC, Most preferably -5 ° C to 30 ° C.
There is no restriction | limiting in particular about reaction time, Preferably it is 0.1 to 24 hours, More preferably, it is 0.5 to 12 hours.

  There is no restriction | limiting in particular about the mixing order of the said compound (3), a sulfonylating agent, a base, and a solvent.

  After completion of the reaction, the resulting reaction solution may be used as it is in the next step, but a general post-treatment may be performed to isolate the compound (4) from the reaction solution. For example, the reaction solution after completion of the reaction is neutralized by adding water or an aqueous acid solution such as an aqueous hydrochloric acid solution or an aqueous sulfuric acid solution as necessary, and a common extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, Extraction is performed using hexane or the like. When the reaction solvent and the extraction solvent are distilled off from the resulting extract by an operation such as heating under reduced pressure, the desired product is obtained.

  The target product thus obtained has a sufficient purity that can be used in the subsequent steps. However, in order to further increase the purity, crystallization, fractional distillation, solution washing, column chromatography, and the like are generally used. The purity may be further increased by a simple purification method. Preferably, the purification method includes a method of separating the compound (4) as a crystal by crystallization from a solvent and removing impurities.

  The solvent used for crystallization, the crystallization method, and the like are the same as those described in the purification method 2 in step 1.

  Moreover, in the said compound (4) obtained at this process, Ar is 4-methyloxyphenyl following formula (10);

で表される光学活性１−（４−メチルオキシフェニル）−３−（スルホニルオキシ）−ピロリジンは文献未知の新規化合物である。

The optically active 1- (4-methyloxyphenyl) -3- (sulfonyloxy) -pyrrolidine represented by the formula is a novel compound unknown in the literature.

Process 3
In this step, nucleophilic substitution reaction is performed on the 3-position of the compound (4) produced in Step 2 to obtain the following formula (5);

で表される光学活性１−アリール−３−置換ピロリジン、又はその塩を製造する。

The optically active 1-aryl-3-substituted pyrrolidine represented by these, or its salt is manufactured.

  Here, Ar and * are the same as described above.

R ² is an optionally substituted alkyl group having 1 to 20 carbon atoms, an optionally substituted cycloalkyl group having 3 to 20 carbon atoms, and an optionally substituted carbon. It has an alkenyl group having 2 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms which may have a substituent, an aryl group having 6 to 20 carbon atoms which may have a substituent, and a substituent. An optionally substituted heteroaryl group having 3 to 20 carbon atoms, a cyano group, a hydroxyl group, an optionally substituted alkyloxy group having 1 to 20 carbon atoms, and an optionally substituted carbon atom having 7 to 7 carbon atoms. It has 20 aralkyloxy groups, an aryloxy group having 6 to 20 carbon atoms which may have a substituent, an acyloxy group having 2 to 20 carbon atoms which may have a substituent, and a substituent. It has a C7-20 aroyloxy group, thiol group, and substituent An optionally substituted alkylthio group having 1 to 20 carbon atoms, an optionally substituted arylthio group having 6 to 20 carbon atoms, an acylthio group having 2 to 20 carbon atoms, an amino group, a hydroxyamino group, and a methoxyamino group , An azide group, a phthalimide group, a nitro group, an alkylamino group having 1 to 20 carbon atoms which may have a substituent, an aralkylamino group having 7 to 20 carbon atoms which may have a substituent, and a substituent An arylamino group having 6 to 20 carbon atoms which may have a dialkylamino group having 1 to 20 carbon atoms which may have a substituent, or 7 to 7 carbon atoms which may have a substituent. Twenty diaralkylamino groups are represented.

  Examples of the substituent include halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom, nitro group, nitroso group, cyano group, amino group, hydroxyamino group, alkylamino group having 1 to 12 carbon atoms, carbon number 1-12 dialkylamino groups, C7-12 aralkylamino groups, C7-12 diaralkylamino groups, C1-12 alkylsulfonylamino groups, sulfonic acid groups, sulfonamido groups, azide groups , A trifluoromethyl group, a carboxyl group, an acyl group having 1 to 12 carbon atoms, an aroyl group having 7 to 12 carbon atoms, a hydroxyl group, an alkyloxy group having 1 to 12 carbon atoms, an aralkyloxy group having 7 to 12 carbon atoms, C6-C12 aryloxy group, C1-C12 acyloxy group, C7-C12 aroyloxy group, C3-C12 Silyloxy group, an alkylsulfonyloxy group having 1 to 12 carbon atoms, or the like alkylthio group having 1 to 12 carbon atoms and the like, the number of the substituent include the 0-5.

  Examples of the alkyl group include a methyl group, an ethyl group, an isopropyl group, and a tert-butyl group.

  Examples of the cycloalkyl group include a cyclopropyl group, a cyclopentyl group, and a cyclohexyl group.

  Examples of the alkenyl group include a vinyl group, an allyl group, and a methallyl group.

  Examples of the aralkyl group include a benzyl group and a phenethyl group.

  Examples of the aryl group include a phenyl group, a naphthyl group, and a biphenyl group.

  Examples of the heteroaryl group include pyridyl group, furanyl group, thienyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, pyrazolyl group, benzofuranyl group, benzothiazolyl group, indolyl group and the like.

R ² is preferably a methyl group, 1-cyano-1,1-diphenylmethyl group, phenyl group, cyano group, hydroxyl group, methyloxy group, benzyloxy group, acetyloxy group, benzoyloxy group, thiol group, methylthio group , Phenylthio group, acetylthio group, amino group, azide group, phthalimide group, methylamino group, ethylamino group, tritylamino group, benzylamino group, 1-phenethylamino group, phenylamino group, dimethylamino group, pyrrolidinyl group, piperidinyl Group, morpholinyl group or dibenzylamino group, more preferably 1-cyano-1,1-diphenylmethyl group, benzyloxy group, benzoyloxy group or amino group.

In this step, since the introduction method varies depending on the type of R ² of the compound (5), an optimal introduction method may be appropriately selected.

  In general, in the case of a nucleophilic substitution reaction with a carbon atom, when a nucleophilic reagent such as a carbanion or a cyanide ion is allowed to act on the compound (4), the compound (4) can be removed from the opposite side of the leaving group. The nucleophilic reagent approaches to form a bond with carbon, and at the same time, the leaving group is released, and the compound (5) into which a new substituent is introduced is generated.

  Examples of carbanions include lithium reagents such as methyl lithium, n-butyl lithium, and phenyl lithium; Grignard reagents such as n-butyl magnesium chloride and phenyl magnesium bromide; diethyl zinc, phenyl copper, tetraphenyl lead, and tetraphenyl titanium. And transition metal reagents such as tetraphenylzirconium, dicyclopentadiethyliron, and phenylpalladium bromide. Or a base is allowed to act on a hydrocarbon compound having active hydrogen such as aldehyde, ketone, ester, nitrile, sulfoxide, sulfone, sulfoxonium compound, imine compound, nitro compound, phosphonium compound, phosphine oxide, phosphonic acid ester, and so on. Anions may be generated.

Specifically, for example, in the case of R ² is 1-cyano-1,1-diphenylmethyl group, carbanion with the compound prepared from diphenyl acetonitrile and a base (4) may be reacted.

  The amount of diphenylacetonitrile used is preferably 1 to 10 times the molar amount, more preferably 1 to 5 times the molar amount relative to the compound (4).

  Preferred bases are metal hydrides such as sodium hydride and potassium hydride; metal alkoxides such as sodium tert-butoxide and potassium tert-butoxide, more preferably metal alkoxides such as sodium tert-butoxide and potassium tert-butoxide. And particularly preferably potassium tert-butoxide.

  The amount of the base used is preferably 1 to 20 times the molar amount, more preferably 1 to 10 times the molar amount relative to the compound (4).

  The solvent in this step is not particularly limited as long as it does not affect the reaction, but is preferably an ether solvent such as tetrahydrofuran, diethyl ether, 1,4-dioxane, ethylene glycol dimethyl ether, more preferably tetrahydrofuran. Or 1,4-dioxane, particularly preferably tetrahydrofuran. These may be used alone or in combination of two or more. When using 2 or more types together, the mixing ratio is not particularly limited.

  If the amount of the solvent used is too large, it is not preferable in terms of cost and post-treatment, and therefore it is preferably 50 times weight or less, more preferably 20 times weight or less, relative to the compound (4).

  The reaction temperature is not particularly limited and may be set as appropriate, but is preferably 20 to 120 ° C, more preferably 40 to 100 ° C, and particularly preferably 50 ° C in order to reduce the formation of by-products. ~ 80 ° C.

  There is no restriction | limiting in particular about reaction time, Preferably it is 0.1 to 24 hours, More preferably, it is 0.5 to 12 hours.

  There is no restriction | limiting in particular about the mixing order of the said compound (4), diphenylacetonitrile, a base, and a solvent.

  After completion of the reaction, the obtained reaction solution may be used for the next step as it is, but a general post-treatment may be performed to isolate the target product from the reaction solution. For example, the reaction solution after completion of the reaction is neutralized by adding water or an aqueous acid solution such as an aqueous hydrochloric acid solution or an aqueous sulfuric acid solution as necessary, and a common extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, Extraction is performed using hexane or the like. When the reaction solvent and the extraction solvent are distilled off from the resulting extract by an operation such as heating under reduced pressure, the desired product is obtained.

  The target product thus obtained has a sufficient purity that can be used in the subsequent steps. However, in order to further increase the purity, crystallization, fractional distillation, solution washing, column chromatography, and the like are generally used. The purity may be further increased by a simple purification method.

  Subsequently, the case of a nucleophilic substitution reaction with heteroatoms such as oxygen, sulfur, nitrogen, and phosphorus will be described. In this case, a nucleophilic agent such as hydroxide ion, alkoxide ion, carboxylide ion, mercaptide ion, azide ion, phthalimide ion, nitrite ion, amide ion, phosphide ion, etc. with respect to the compound (4). , The nucleophilic reagent approaches from the opposite side of the leaving group of the compound (4) to form a bond with carbon, and at the same time, the leaving group is separated, and the compound (5) in which a new substituent is introduced. ) Is generated. The ions may be prepared by allowing a base to act on alcohol, carboxylic acid, thiol, phthalimide, amine, phosphine, or the like.

Specifically, for example, when R ² is an amino group, the compound (4) may be reacted with ammonia. Further, in this step, a base may be further added for the purpose of accelerating the reaction, and ammonia may be used in excess and a part thereof may be used as the base. The base is preferably ammonia or triethylamine, and more preferably ammonia. In particular, ammonia is preferably ammonia water dissolved in water.

  The amount of ammonia used is preferably 2 to 100 times the molar amount, more preferably 2 to 50 times the molar amount relative to the compound (4).

  Although a solvent is not required for this step, a solvent may be added for the purpose of increasing the solubility of raw materials and products.

  The solvent is not particularly limited as long as it does not affect the reaction, preferably water; alcohol solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, ethylene glycol, More preferred is water or methanol, and particularly preferred is water.

  The reaction temperature is not particularly limited and may be set as appropriate, but is preferably 20 to 150 ° C, more preferably 40 to 120 ° C, and particularly preferably 50 ° C in order to reduce the formation of by-products. ~ 80 ° C.

  There is no restriction | limiting in particular about reaction time, Preferably it is 0.1 to 24 hours, More preferably, it is 0.5 to 12 hours.

  There is no restriction | limiting in particular about the mixing order of the said compound (4), ammonia, a base, and a solvent.

  After completion of the reaction, the obtained reaction solution may be used for the next step as it is, but a general post-treatment may be performed to isolate the target product from the reaction solution. For example, the reaction solution after completion of the reaction is neutralized by adding water or an aqueous acid solution such as an aqueous hydrochloric acid solution or an aqueous sulfuric acid solution as necessary, and a common extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, Extraction is performed using hexane or the like. When the reaction solvent and the extraction solvent are distilled off from the resulting extract by an operation such as heating under reduced pressure, the desired product is obtained.

  The target product thus obtained has a sufficient purity that can be used in the subsequent steps. However, in order to further increase the purity, crystallization, fractional distillation, solution washing, column chromatography, and the like are generally used. The purity may be further increased by a simple purification method.

Next, the stereochemistry of this step will be described. Since the nucleophilic substitution reaction of step is type ₂ S _N, 3-position stereochemistry will proceed with inversion. That is, when the absolute configuration of the compound (4) is S, the absolute configuration of the product (5) is R, and when the absolute configuration of the compound (4) is R, the product The absolute configuration of the compound (5) is S.

Process 4
In this step, the compound (3) produced in Step 1 is mixed with a base and the following formula (6);

で表される化合物を作用させることにより、下記式（７）；

By the action of a compound represented by the following formula (7):

で表される光学活性１−アリール−３−ピロリジノール誘導体又はその塩を製造する。

An optically active 1-aryl-3-pyrrolidinol derivative represented by the formula:

Wherein, R ³ is have an alkyl group having 1 to 20 carbon atoms that may have a substituent, a cycloalkyl group having 3 to 20 carbon atoms which may have a substituent, a substituent May be an alkenyl group having 2 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms which may have a substituent, an acyl group having 1 to 20 carbon atoms which may have a substituent, or a substituent. Represents an aroyl group having 7 to 20 carbon atoms which may have Examples of the substituent include halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom, nitro group, nitroso group, cyano group, amino group, hydroxyamino group, alkylamino group having 1 to 12 carbon atoms, carbon number 1-12 dialkylamino groups, C7-12 aralkylamino groups, C7-12 diaralkylamino groups, C1-12 alkylsulfonylamino groups, sulfonic acid groups, sulfonamido groups, azide groups , A trifluoromethyl group, a carboxyl group, an acyl group having 1 to 12 carbon atoms, an aroyl group having 7 to 12 carbon atoms, a hydroxyl group, an alkyloxy group having 1 to 12 carbon atoms, an aralkyloxy group having 7 to 12 carbon atoms, C6-C12 aryloxy group, C1-C12 acyloxy group, C7-C12 aroyloxy group, C3-C12 Silyloxy group, an alkylsulfonyloxy group having 1 to 12 carbon atoms, or the like alkylthio group having 1 to 12 carbon atoms and the like, the number of the substituent include the 0-5. Examples of the alkyl group include a methyl group, an ethyl group, an isopropyl group, and a tert-butyl group. Examples of the cycloalkyl group include a cyclopropyl group, a cyclopentyl group, and a cyclohexyl group. Examples of the alkenyl group include a vinyl group, an allyl group, and a methallyl group. Examples of the aralkyl group include a benzyl group and a phenethyl group. Examples of the acyl group include an acetyl group, a propionyl group, an n-butyryl group, an isobutyryl group, and a pivaloyl group. Examples of aroyl groups include benzoyl groups and naphthoyl groups.

R ³ is preferably a methyl group, an allyl group, a benzyl group, an acetyl group, a pivaloyl group, or a benzoyl group, and more preferably a benzyl group or a benzoyl group. L ² represents a leaving group, and examples thereof include a sulfonyloxy group, a sulfonic acid group, a phosphate ester group, a halogen atom, an acyloxy group, and an aroyloxy group. The compound (6) is preferably methyl bromide, methyl iodide, methyl methanesulfonate, dimethyl sulfate, trimethyl phosphate, allyl chloride, allyl bromide, benzyl chloride, benzyl bromide, acetyl chloride, acetyl bromide, Acetic anhydride, pivaloyl chloride, benzoyl chloride, and benzoic anhydride are preferable, and benzyl chloride or benzoyl chloride is more preferable.

  In this step, since the introduction method varies depending on the type of the compound (6), an optimal introduction method may be appropriately selected.

Specifically, for example, when R ³ is a benzyl group, the compound (3) is reacted with a benzyl halide such as benzyl chloride, benzyl bromide, or benzyl iodide in the presence of a base. Well, 12-crown-4, 15-crown-5, 18-crown-6, 24-crown-8, dibenzo-18-crown-6, dibenzo-24-crown-8, dicyclohexyl-18- Crown ethers such as crown-6 and dicyclohexyl-24-crown-8; Cryptands such as cryptand [2,2], cryptand [2,2,1], cryptand [2,2,2]; trioctylmethyl chloride Ammonium [trade name: ALIQUAT 336], trioctylmethylammonium bromide, methyltrialkyl chloride (carbon number 8 to 10) A phase transfer catalyst such as quaternary ammonium salts such as ammonium [trade name: Adogen 464], tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, etc. may be added.

When R ³ is a benzoyl group, the compound (3) may be reacted with benzoyl chloride, benzoyl bromide, benzoic anhydride, or the like in the presence of a base.

Further, as the base, an optimal base may be appropriately selected according to the method for introducing R ^3. For example, triethylamine, tri-n-butylamine, N-methylmorpholine, N-methylpiperidine, diisopropylethylamine, pyridine, N , N-dimethylaminopyridine, tertiary amines such as 1,4-diazabicyclo [2,2,2] octane; metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, magnesium hydroxide Metal hydroxides such as lithium carbonate, sodium carbonate and potassium carbonate; Metal hydrogen carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; Organic lithium reagents such as n-butyl lithium and phenyl lithium; Grini such as n-butylmagnesium and tert-butylmagnesium chloride An alkali metal amide such as sodium amide, potassium amide, sodium hexamethyldisilazide, potassium hexamethyldisilazide; alkali metal hydride such as lithium hydride, sodium hydride, potassium hydride; sodium methoxide, Examples thereof include alkyl metal alkoxides such as sodium ethoxide, sodium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide and the like. Preferably, a third compound such as triethylamine, tri-n-butylamine, N-methylmorpholine, N-methylpiperidine, diisopropylethylamine, pyridine, N, N-dimethylaminopyridine, 1,4-diazabicyclo [2,2,2] octane, etc. Secondary amines; metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, magnesium hydroxide; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; sodium methoxy Alkyl alkoxides such as sodium ethoxide, sodium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, and more preferably triethylamine, sodium hydroxide, potassium hydroxide. Beam, sodium hydride, potassium hydride, or potassium tert- butoxide, particularly preferably triethylamine, sodium hydroxide, sodium hydride, or potassium tert- butoxide.

  The amount of the base used is preferably 2 to 20 times the molar amount, more preferably 2 to 10 times the molar amount relative to the compound (3).

  Moreover, in this process, you may add a solvent as needed.

  The solvent is not particularly limited as long as it does not affect the reaction. For example, water; ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether; ethyl acetate, Ester solvents such as n-propyl acetate and isopropyl acetate; aromatic hydrocarbon solvents such as benzene and toluene; aliphatic hydrocarbon solvents such as pentane, hexane, heptane and methylcyclohexane; carbon tetrachloride, chloroform and methylene chloride Halogen solvents such as 1,2-dichloroethane and chlorobenzene; ketone solvents such as acetone and methyl ethyl ketone; nitrile solvents such as acetonitrile and propionitrile; sulfoxide solvents such as dimethyl sulfoxide; N, N-dimethylform Amide solvents such as amide, N, N-dimethylacetamide, N, N-diethylacetamide, N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, N-methyl-ε-caprolactam, hexamethylphosphoramide A urea solvent such as dimethylpropylene urea; a phosphonic acid triamide solvent such as hexamethylphosphonic acid triamide;

  Preferably, water; ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, ethylene glycol dimethyl ether; aromatic hydrocarbon solvents such as benzene and toluene; carbon tetrachloride, chloroform, methylene chloride, 1,2-dichloroethane , Halogen solvents such as chlorobenzene; sulfoxide solvents such as dimethyl sulfoxide; N, N-dimethylformamide, N, N-dimethylacetamide, N, N-diethylacetamide, N-methyl-2-pyrrolidone, N-ethyl-2 Amide solvents such as pyrrolidone, N-methyl-ε-caprolactam, hexamethylphosphoramide, more preferably water, tetrahydrofuran, toluene, chlorobenzene, dimethyl sulfoxide, N, N-dimethylformamide, or N, N A dimethylacetamide, particularly preferably water, tetrahydrofuran, toluene, or N, N- dimethylacetamide.

  These may be used alone or in combination of two or more. When using 2 or more types together, the mixing ratio is not particularly limited.

  If the amount of the solvent used is too large, it is not preferable in terms of cost and post-treatment, and therefore it is preferably 50 times weight or less, more preferably 20 times weight or less with respect to the compound (3).

  There is no restriction | limiting in particular in reaction temperature, What is necessary is just to set suitably, In order to reduce the production | generation of a by-product, Preferably it is -40-150 degreeC, More preferably, it is -20-120 degreeC, Most preferably -5 ° C to 100 ° C.

  There is no restriction | limiting in particular about reaction time, Preferably it is 0.1 to 48 hours, More preferably, it is 0.5 to 24 hours.

  There is no restriction | limiting in particular about the mixing order of the said compound (3), the said compound (6), a base, a solvent, and the phase transfer catalyst added as needed.

  After completion of the reaction, the obtained reaction solution may be directly used in the next step, but the compound (7) may be isolated from the reaction solution by performing general post-treatment. For example, the reaction solution after completion of the reaction is neutralized by adding water or an aqueous acid solution such as an aqueous hydrochloric acid solution or an aqueous sulfuric acid solution as necessary, and a common extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, Extraction is performed using hexane or the like. When the reaction solvent and the extraction solvent are distilled off from the resulting extract by an operation such as heating under reduced pressure, the desired product is obtained.

  The target compound thus obtained has a sufficient purity that can be used in subsequent steps, but for the purpose of further increasing the purity, crystallization, fractional distillation, solution washing, the compound (7) and an acid are used. The purity may be further increased by a general purification method such as a method of forming a salt from crystallization from a solvent and column chromatography.

  This completes the description of the method for producing the optically active 1-aryl-3-substituted pyrrolidine or the salt thereof in the present invention.

  Next, in the formula (3), (5), or (9) produced in the step 1, 3, or 4, the following formula (8) in which Ar is a 4-methyloxyphenyl group;

で表される光学活性１−（４−メチルオキシフェニル）−３−置換ピロリジン、又はその塩の、１位の４−メチルオキシフェニル基を脱離することにより、下記式（９）；

By eliminating the 4-methyloxyphenyl group at the 1-position of the optically active 1- (4-methyloxyphenyl) -3-substituted pyrrolidine represented by the formula:

で表される光学活性３−置換ピロリジン又はその塩を製造する方法について説明する。

A method for producing an optically active 3-substituted pyrrolidine represented by the formula or a salt thereof will be described.

Here, R ² and * are the same as described above. The optically active form of 1- (4-methyloxyphenyl) -3-substituted pyrrolidine is unknown in the literature, and the present invention is the first production example. In particular, the compound (8) in which R ² is a 1-cyano-1,1-diphenylmethyl group, a benzyloxy group, a benzoyloxy group, or an amino group is a useful novel compound.

  As a method for eliminating a 4-methyloxyphenyl group on a nitrogen atom in this step, a method of acting an oxidizing agent in the presence of an acid aqueous solution is known. For example, Tetrahedron Letters, 47, (2006), p. 8109-8113.

  Preferred oxidizing agents are ceric ammonium nitrate, iodosobenzene acetate, Dess-Martin reagent, hydrogen peroxide, potassium permanganate, peracetic acid, periodic acid, sodium periodate, potassium periodate, hypochlorous acid Sodium hypochlorite, potassium hypochlorite, trichloroisocyanuric acid, N-chlorosuccinimide, N-brominated succinimide, N-iodinated succinimide, chlorine, iodine, or bromine, and Trichloroisocyanuric acid, N-brominated succinimide, or bromine is preferable, and N-brominated succinimide is particularly preferable.

  The amount of the oxidizing agent used is preferably 0.5 to 5 times the molar amount, more preferably 0.5 to 3 times the molar amount relative to the compound (8).

  Examples of acids include inorganic acids such as hydrogen fluoride, hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, nitric acid, phosphoric acid and boric acid; formic acid, acetic acid, propionic acid, butyric acid, pivalic acid, chloroacetic acid , Carboxylic acids such as trichloroacetic acid, trifluoroacetic acid, oxalic acid, L-tartaric acid, D-tartaric acid, mandelic acid; methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, camphorsulfonic acid, etc. Of the sulfonic acid. Preferred is hydrogen chloride, hydrogen bromide, sulfuric acid, methanesulfonic acid, or 4-methylbenzenesulfonic acid, more preferred is hydrogen chloride, hydrogen bromide, sulfuric acid, or 4-methylbenzenesulfonic acid, and particularly preferred is chloride. Hydrogen, sulfuric acid, or 4-methylbenzenesulfonic acid. These may be used alone or in combination of two or more. When using 2 or more types together, the mixing ratio is not particularly limited.

  The amount of the acid used is preferably 0.5 to 10 times the molar amount, more preferably 0.5 to 5 times the molar amount relative to the compound (8).

  Moreover, in this process, you may add a solvent as needed.

  The solvent is not particularly limited as long as it does not affect the reaction. For example, water; ester solvents such as ethyl acetate, n-propyl acetate, isopropyl acetate; tetrahydrofuran, diethyl ether, 1,4-dioxane, methyl Ether solvents such as tert-butyl ether and ethylene glycol dimethyl ether; ketone solvents such as acetone and methyl ethyl ketone; nitrile solvents such as acetonitrile and propionitrile; aromatic hydrocarbon solvents such as benzene and toluene; sulfoxide such as dimethyl sulfoxide Amide solvents such as N, N-dimethylformamide and N, N-dimethylacetamide; urea solvents such as dimethylpropylene urea; and phosphonic acid triamide solvents such as hexamethylphosphonic acid triamide. Kill.

  Preferably, water; ester solvents such as ethyl acetate, n-propyl acetate, isopropyl acetate; ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether; acetonitrile, propionitrile Nitrile solvents such as benzene, toluene and other aromatic hydrocarbon solvents; pentane, hexane, heptane, methylcyclohexane and other aliphatic hydrocarbon solvents; methylene chloride, 1,2-dichloroethane, chlorobenzene and other halogen solvents More preferred are water, ethyl acetate, acetonitrile, toluene, or chlorobenzene, and particularly preferred is water or acetonitrile.

  These may be used alone or in combination of two or more. When using 2 or more types together, the mixing ratio is not particularly limited.

  If the amount of the solvent used is too large, it is not preferable in terms of cost and post-treatment, and therefore it is preferably 50 times the weight or less, more preferably 20 times the weight or less relative to the compound (8).

  There is no restriction | limiting in particular in reaction temperature, What is necessary is just to set suitably, In order to reduce the production | generation of a by-product, Preferably it is -40-80 degreeC, More preferably, it is -20-50 degreeC, Most preferably -5 ° C to 30 ° C.

  There is no restriction | limiting in particular about reaction time, Preferably it is 0.1 to 24 hours, More preferably, it is 0.5 to 12 hours.

  There is no restriction | limiting in particular about the mixing order of the said compound (8), an oxidizing agent, an acid, and a solvent.

  After completion of the reaction, the obtained reaction solution may be directly used in the next step, but the compound (9) may be isolated from the reaction solution by performing a general post-treatment. For example, after concentrating the reaction solution after completion of the reaction, it is neutralized by adding water or an aqueous base solution such as an aqueous sodium hydroxide solution or an aqueous potassium carbonate solution if necessary, and a common extraction solvent such as ethyl acetate or diethyl acetate. Extraction is performed using ether, methylene chloride, toluene, hexane or the like. When the reaction solvent and the extraction solvent are distilled off from the resulting extract by an operation such as heating under reduced pressure, the desired product is obtained.

  The target product thus obtained has sufficient purity that can be used in the subsequent steps, but for the purpose of further increasing the purity, crystallization, fractional distillation, solution washing, the compound (9) and an acid are used. The purity may be further increased by a general purification method such as a method of forming a salt from crystallization from a solvent and column chromatography.

  EXAMPLES Hereinafter, although an Example is shown and this invention is demonstrated further in detail, these Examples do not limit this invention at all.

  The purity and optical purity of optically active 1-aryl-3-pyrrolidinol, optically active 1-aryl-3-substituted pyrrolidine, or optically active 3-substituted pyrrolidine described in Examples were analyzed by the following HPLC method. . In addition, “wt%” which is a title of purity means weight%, and “area%” means area percentage.

[ Chemical purity analysis and content analysis (gradient method) ]
Column manufactured by Nakarai {Cosmosil 5C18 ARII 250 × 4.6 mm}, mobile phase A: 0.1% phosphoric acid aqueous solution, mobile phase B: acetonitrile (mobile phase A% / mobile phase B% = 90/10 to 40/60), Flow rate: 1.0 ml / min, detection: UV 210 nm, column temperature: 40 ° C.
* However, for Example 22, content analysis was performed by ¹ H-NMR (internal standard method: using methyl benzoate as a standard product).

[ Optical purity analysis method (Isocratech method) ]
It is described in each example.

Example 1 Production of (S) -1- (4-methyloxyphenyl) -3-pyrrolidinol (S) -4-chloro-3-hydroxybutyronitrile 2.44 g (20 mmol), methanol 21.65 g, A solution consisting of 4.93 g (2.0 equivalents) of 4-methyloxyaniline and 963 mg of 10 wt% palladium-carbon was stirred at 25 ° C. for 40 hours under a normal pressure hydrogen atmosphere. The palladium was filtered off under reduced pressure, and the filtrate was concentrated under reduced pressure (yield 73%).

To this concentrate, 21.65 g of toluene, 21.65 g of distilled water and 4.17 g (2.0 equivalents) of concentrated hydrochloric acid were added to extract the target product into the aqueous layer, and the organic layer was discarded. When 27.86 g of chlorobenzene and 8.01 g (3.0 equivalents) of a 30 wt% aqueous sodium hydroxide solution were added to the obtained aqueous layer, crystals were precipitated. Since it melt | dissolved when it heated to 47 degreeC, the water layer was discarded and the crystal | crystallization precipitated when it cooled to 25 degreeC. After stirring at 25 ° C. for 30 minutes, the mixture was further stirred at 5 ° C. for 30 minutes, and the crystals were filtered off under reduced pressure, washed with 5 ml of toluene and dried in vacuo to give the title compound as white crystals (2.16 g) (chemical purity). 99.3 area%, optical purity 99.9% ee, yield 55%).
Title compound:
Chemical purity analysis method and content analysis method (gradient method) Retention time: 6.2 minutes

Optical purity analysis method (Isocratech method)
Column: manufactured by Daicel Chemical Industries, Ltd. {CHIRALCEL OD-H 250 × 4.6 mm}, mobile phase: hexane / isopropanol = 90/10 (volume ratio), flow rate: 1.0 ml / min, detector: UV 210 nm, column temperature: 30 ° C.
Retention time: (S) -1- (4-methyloxyphenyl) -3-pyrrolidinol: 14.0 minutes, (R) -1- (4-methyloxyphenyl) -3-pyrrolidinol: 16.6 minutes

_{^{1 H-NMR (CDCl 3)}} : δ (ppm) 1.75 (br, 1H), 2.07 (m, 1H), 2.20 (m, 1H), 3.25 (m, 2H), 3 .46 (m, 2H), 3.77 (s, 3H), 4.57 (m, 1H), 6.54 (d, 2H), 6.85 (d, 2H)

(Example 2) Production of (S) -1- (4-methyloxyphenyl) -3-pyrrolidinol (S) -4-chloro-3-hydroxybutyronitrile 1.22 g (10 mmol), methanol 5.41 g, A solution composed of 616 mg (5.0 mmol) of 4-methyloxyaniline and 244 mg of 10 wt% palladium-carbon was stirred at 25 ° C. for 16 hours under a normal pressure hydrogen atmosphere. After filtering off palladium under reduced pressure, the title compound in the filtrate was quantified (yield 89% based on 4-methyloxyaniline).
Title compound:
Chemical purity analysis method and content analysis method (gradient method) Retention time: 6.2 minutes

Example 3 Production of (S) -1- (3-fluorophenyl) -3-pyrrolidinol (S) -4-Chloro-3-hydroxybutyronitrile 1.22 g (10 mmol), methanol 10.74 g, 3 A solution consisting of 2.22 g of fluoroaniline (2.0 equivalents) and 488 mg of 10 wt% palladium-carbon was stirred at 25 ° C. for 20 hours under a normal pressure hydrogen atmosphere. After the palladium was filtered off under reduced pressure, the filtrate was concentrated under reduced pressure, and 10.74 g of toluene, 10.74 g of distilled water and 1.47 g (1.1 equivalents) of a 30 wt% aqueous sodium hydroxide solution were added and stirred, and the aqueous layer was discarded. The organic layer was washed twice with 10.74 g of distilled water and then concentrated under reduced pressure. Distilled water (10.74 g), toluene (10.74 g) and acetic acid (1.32 g (2.2 equivalents)) were added to the concentrate and stirred, and the aqueous layer was discarded. The organic layer was washed with 5.37 g of a saturated aqueous sodium hydrogen carbonate solution and further washed twice with 5.37 g of distilled water. The obtained organic layer was concentrated under reduced pressure and dried under vacuum to obtain 1.80 g of the title compound as a pale brown oily substance (chemical purity 71.6 area%, content 55.4 wt%, yield 55%).

When 1.80 g of isopropanol, 2.47 g (2.0 equivalents) of 30 wt% isopropanolic hydrogen chloride, and 9.00 g of ethyl acetate were added to this oily substance, crystals of 3-fluoroaniline hydrochloride were precipitated. . The obtained filtrate was concentrated under reduced pressure, and 9.00 g of ethyl acetate was added, and further crystals of 3-fluoroaniline hydrochloride were precipitated. The obtained filtrate was concentrated under reduced pressure, 10.74 g of toluene and 10.74 g of distilled water were added, and a 30 wt% aqueous sodium hydroxide solution was added until the pH reached 14. After discarding the aqueous layer, 10.74 g of distilled water and 210 mg (0.2 equivalent) of concentrated hydrochloric acid were added to the organic layer and stirred, and the aqueous layer was discarded. The obtained organic layer was washed with 10.74 g of distilled water, concentrated under reduced pressure, and vacuum dried to obtain 768 mg of a pale brown oily substance (chemical purity 94.1 area%, content 97.6 wt%, yield). Rate 41%).
Title compound:
Chemical purity analysis method and content analysis method (gradient method) Retention time: 14.6 minutes
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.69 (br, 1H), 2.07 (m, 1H), 2.17 (m, 1H), 3.25 (dd, 1H), 3 .34 (m, 1H), 3.49 (m, 2H), 4.61 (m, 1H), 6.24 (dt, 1H), 6.31 (dd, 1H), 6.37 (m, 1H), 7.14 (m, 1H)

Example 4 Production of (S) -1- (3-fluorophenyl) -3-pyrrolidinol (S) -4-chloro-3-hydroxybutyronitrile 305 mg (2.5 mmol), toluene 2.69 g, 3 -A solution consisting of 557 mg (2.0 equivalents) of fluoroaniline and 124 mg of 10 wt% palladium-carbon was stirred at 25 ° C for 20 hours under an atmospheric pressure of hydrogen. After the palladium was filtered off under reduced pressure, the title compound in the filtrate was quantified (yield 37%).
Title compound:
Chemical purity analysis method and content analysis method (gradient method) Retention time: 14.6 minutes

Example 5 Production of (S) -1- (3-fluorophenyl) -3-pyrrolidinol (S) -4-Chloro-3-hydroxybutyronitrile 305 mg (2.5 mmol), ethyl acetate 2.69 g, A solution composed of 557 mg (2.0 equivalents) of 3-fluoroaniline and 122 mg of 10 wt% palladium-carbon was stirred at 25 ° C. for 20 hours under a normal pressure hydrogen atmosphere. After the palladium was filtered off under reduced pressure, the title compound in the filtrate was quantified (yield 12%).
Title compound:
Chemical purity analysis method and content analysis method (gradient method) Retention time: 14.6 minutes

Example 6 Production of (S) -1- [3- ( ethyloxycarbonyl ) phenyl] -3-pyrrolidinol (S) -4-Chloro-3-hydroxybutyronitrile 1.22 g (10 mmol), methanol 10 A solution consisting of .74 g, 3.30 g (2.0 equivalents) of 3- (ethyloxycarbonyl) aniline, and 488 mg of 10 wt% palladium-carbon was stirred at 25 ° C. for 21 hours under a normal pressure hydrogen atmosphere. After the palladium was filtered off under reduced pressure, the filtrate was concentrated under reduced pressure, and 10.74 g of toluene, 10.74 g of distilled water and 1.47 g (1.1 equivalents) of a 30 wt% aqueous sodium hydroxide solution were added and stirred, and the aqueous layer was discarded. The organic layer was washed twice with 10.74 g of distilled water and then concentrated under reduced pressure. Distilled water (10.74 g), toluene (10.74 g) and acetic acid (1.32 g (2.2 equivalents)) were added to the concentrate and stirred, and the aqueous layer was discarded. The organic layer was washed with 5.37 g of a saturated aqueous sodium hydrogen carbonate solution and further washed twice with 5.37 g of distilled water. The obtained organic layer was concentrated under reduced pressure and vacuum dried to obtain 3.44 g of the title compound as a pale red oily substance (chemical purity 39.1 area%, content 40.2 wt%, yield 59%).

To this oily substance, 10.74 g of toluene, 10.74 g of distilled water and 209 mg (1.2 equivalents) of concentrated hydrochloric acid were added and stirred, and the aqueous layer was discarded. Furthermore, this organic layer was washed with an aqueous solution consisting of 10.74 g of distilled water and 834 mg (0.8 equivalents) of concentrated hydrochloric acid. Distilled water (10.74 g) and concentrated hydrochloric acid (3.12 g, 3.0 equivalents) were added to the obtained organic layer, the target product was extracted into the aqueous layer, and the organic layer was discarded. To the aqueous layer was added 10.74 g of toluene and 4.41 g (3.3 equivalents) of a 30 wt% aqueous sodium hydroxide solution to extract the target product into the organic layer, and the resulting organic layer was washed twice with 10.74 g of distilled water. After concentration under reduced pressure, vacuum drying gave the title compound as a pale brown oily substance 815 mg (content 94.0 wt%, yield 33%).
Title compound:
Chemical purity analysis method and content analysis method (gradient method) Retention time: 15.1 minutes
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.38 (t, 3H), 1.72 (br, 1H), 2.10 (m, 1H), 2.19 (m, 1H), 3 .33 (d, 1H), 3.41 (m, 1H), 3.56 (m, 2H), 4.36 (m, 2H), 4.63 (m, 1H), 6.74 (dd, 1H), 7.23-7.29 (m, 2H), 7.36 (d, 1H)

Example 7 Production of (S) -1-phenyl-3-pyrrolidinol (S) -4-Chloro-3-hydroxybutyronitrile 1.22 g (10 mmol), methanol 10.74 g, aniline 1.87 g (2 0.0 equivalent) and a solution consisting of 488 mg of 10 wt% palladium-carbon was stirred at 25 ° C. for 18 hours under a normal pressure hydrogen atmosphere. The palladium was filtered off under reduced pressure, and the filtrate was concentrated under reduced pressure (yield 39%).

To this concentrate was added 10.74 g of toluene, and the toluene layer was washed three times with an aqueous solution consisting of 1.02 g (2.0 equivalents) of acetic acid and 10.74 g of distilled water. Distilled water (10.74 g) was added to the obtained organic layer, and after adjusting to pH 2 with phosphoric acid, the aqueous layer was discarded. The organic layer was washed twice with 10.74 g of distilled water, concentrated under reduced pressure, and dried under vacuum to give 333 mg of the title compound (chemical purity 98.5 area%, content 99.6 wt%, yield 20). %).
Title compound:
Chemical purity analysis method and content analysis method (gradient method) Retention time: 11.3 minutes
_{^{1 H-NMR (CDCl 3)}} : δ (ppm) 1.68 (br, 1H), 2.07 (m, 1H), 2.17 (m, 1H), 3.27 (d, 1H), 3 .35 (m, 1H), 3.51 (m, 2H), 4.59 (m, 1H), 6.57 (d, 2H), 6.70 (t, 1H), 7.24 (t, 2H)

(Example 8) Production of (S) -1- (4-methyloxyphenyl) -3-sulfonyloxy-pyrrolidine (S) -1- (4-methyloxyphenyl) -3-pyrrolidinol produced in Example 1 To 1.45 g (7.5 mmol), 13.05 g of ethyl acetate and 1.14 g (1.5 equivalents) of triethylamine were added, and 1.20 g (1.4 equivalents) of methanesulfonyl chloride was added dropwise at 5 ° C. After stirring at 5 ° C. for 3 hours, 1.56 g of potassium carbonate and 13.05 g of distilled water were added to precipitate crystals. 52.20 g of ethyl acetate was added and heated to 47 ° C. to dissolve the crystals. After discarding the aqueous layer, the organic layer was washed twice with 13.05 g of distilled water. Crystals precipitated when the organic layer was cooled to 25 ° C., and thus concentrated under reduced pressure to 8.00 g and heated to 47 ° C. again. The mixture was stirred at 47 ° C. for 10 minutes, cooled to 25 ° C., stirred for 30 minutes, and further stirred at 5 ° C. for 30 minutes. The crystals were filtered off under reduced pressure, washed with 1 ml of ethyl acetate and dried in vacuo to give the title compound as 1.46 g of white crystals (chemical purity 99.1 area%, yield 71%).
Title compound:
Chemical purity analysis method and content analysis method (gradient method) Retention time: 15.0 minutes
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.36 (m, 2H), 3.03 (s, 3H), 3.35 (m, 1H), 3.43 to 3.54 (m, 2H), 3.63 (m, 1H), 3.76 (s, 3H), 5.41 (m, 1H), 6.53 (d, 2H), 6.85 (d, 2H)

Example 9 Production of (S) -1- (4-methyloxyphenyl) -3- (1-cyano-1,1-diphenylmethyl) -pyrrolidine hydrochloride (S) -1 produced in Example 9 To 550 mg (2.0 mmol) of-(4-methyloxyphenyl) -3-sulfonyloxy-pyrrolidine, 5 ml of tetrahydrofuran and 471 mg (2.1 equivalents) of potassium tert-butoxide were added, and 470 mg (1.2 equivalents) of diphenylacetonitrile under reflux. ) And 3 ml of tetrahydrofuran were added dropwise. After stirring for 17 hours under reflux, the mixture was cooled to 20 ° C., 2 ml of distilled water was added, and the target product was extracted into the organic layer. The organic layer was concentrated under reduced pressure to obtain a concentrate (yield 82%).

The obtained concentrate was dissolved in 5 ml of ethyl acetate, 372 mg (1.5 equivalents) of 30 wt% isopropanolic hydrogen chloride was added, and the mixture was concentrated under reduced pressure. When 2.5 ml of ethyl acetate was added to the concentrate, crystals were precipitated. The mixture was stirred at 20 ° C. for 10 minutes, and further 2.5 ml of ethyl acetate was added and stirred at 20 ° C. for 2 hours. The crystals were filtered off under reduced pressure, washed with 2 ml of ethyl acetate and dried in vacuo to give the title compound as white crystals (537 mg) (chemical purity 99.8 area%, yield 66%).
Title compound:
Chemical purity analysis method and content analysis method (gradient method) Retention time: 35.7 minutes
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.26 (m, 1H), 2.70 (m, 1H), 3.32 (m, 1H), 3.63 (m, 1H), 3 .80 (s, 3H), 3.90 (m, 1H), 4.00 (m, 1H), 4.27 (m, 1H), 6.94 (d, 2H), 7.30-7. 40 (m, 6H), 7.51 (d, 4H), 7.69 (d, 2H)

(Example 10) Production of (S) -1- (4-methyloxyphenyl) -3- (1-cyano-1,1-diphenylmethyl) -pyrrolidine (S) -1- ( 4-methyloxyphenyl) -3- (1-cyano-1,1-diphenylmethyl) -pyrrolidine hydrochloride 101 mg (0.25 mmol) in toluene 5 ml, distilled water 0.5 ml, 30 wt% sodium hydroxide 38 mg (1. 1 equivalent) was added and stirred. The aqueous layer was discarded and the title compound in the organic layer was quantified (95% yield).
Title compound:
Chemical purity analysis method and content analysis method (gradient method) Retention time: 35.7 minutes

(Example 11) Production of (R) -1- (4-methyloxyphenyl) -3-aminopyrrolidine (S) -1- (4-methyloxyphenyl) -3- (produced in Example 9 in an autoclave. 1.30 g (4.8 mmol) of sulfonyloxy) -pyrrolidine was added, and 0.56 g of toluene and 10.09 g (50 equivalents) of 40 wt% aqueous ammonia solution were added at 5 ° C. After stirring at 80 ° C. for 15 hours, the mixture was cooled to 5 ° C., and the reaction solution was concentrated under reduced pressure to 8.97 g (yield 64%). To the concentrate, 9.02 g of toluene and 700 mg (1.1 equivalents) of a 30 wt% aqueous sodium hydroxide solution were added and stirred, and the target product was extracted into the organic layer. The organic layer was washed twice with 9.02 g of distilled water, 9.02 g of distilled water and 315 mg (1.1 equivalents) of acetic acid were added, and the target product was extracted into the aqueous layer. To the aqueous layer, 9.02 g of toluene and 760 mg (1.2 equivalents) of a 30 wt% aqueous sodium hydroxide solution were added to extract the target product into the organic layer, followed by washing twice with 9.02 g of distilled water. The obtained organic layer was concentrated under reduced pressure and dried under vacuum to obtain the title compound as a brown oily substance 482 mg (chemical purity 94.5 area%, yield 47%).
Title compound:
Chemical purity analysis method and content analysis method (gradient method) Retention time: 7.4 minutes
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.56 (br, 2H), 1.78 (m, 1H), 2.22 (m, 1H), 2.98 (dd, 1H), 3 .26 (m, 1H), 3.41 (m, 1H), 3.46 (m, 1H), 3.69 (m, 1H), 3.75 (s, 3H), 6.51 (d, 2H), 6.84 (d, 2H)

(Example 12) Production of (R) -1- (4-methyloxyphenyl) -3-aminopyrrolidine dihydrochloride (R) -1- (4-methyloxyphenyl) -3- produced in Example 12 To 467 mg (2.2 mmol) of aminopyrrolidine, 4.20 g of ethyl acetate was added and dissolved. When 659 mg (2.5 equivalents) of 30 wt% isopropanolic hydrogen chloride was added dropwise, crystals were precipitated, and the mixture was stirred at 25 ° C. for 30 minutes. The crystals were filtered off under reduced pressure, washed with 1 ml of isopropanol, and dried under vacuum to give the title compound as 601 mg of pale yellow crystals (chemical purity 96.0 area%, yield 100%).
Title compound:
Chemical purity analysis method and content analysis method (gradient method) Retention time: 7.4 minutes
¹ H-NMR (D ₂ O): δ (ppm) 2.33 (m, 1H), 2.70 (m, 1H), 3.73 (m, 2H), 3.84 (s, 3H), 3.85 (m, 1H), 4.03 (m, 1H), 4.29 (m, 1H), 7.09 (d, 2H), 7.28 (d, 2H)

(Example 13) Production of (R) -1- (4-methyloxyphenyl) -3-aminopyrrolidine di (4-methylbenzenesulfonic acid) salt (R) -1- (4- Methyloxyphenyl) -3-aminopyrrolidine hydrochloride 111 mg (0.4 mmol), toluene 5 ml, distilled water 0.5 ml, 30 wt% sodium hydroxide 134 mg (2.5 equivalents) were added and stirred, organic layer and aqueous layer Was separated. To the aqueous layer, 5 ml of toluene was added for further extraction, and combined with the previous organic layer. To the organic layer, 1.5 ml of distilled water and 252 mg (3.3 equivalents) of 4-methylbenzenesulfonic acid monohydrate were added and stirred, and the organic layer was discarded. The title compound in the obtained aqueous layer was quantified (yield 87%).
Title compound:
Chemical purity analysis method and content analysis method (gradient method) Retention time: 7.4 minutes

Example 14 Production of (S) -1- (4-methyloxyphenyl) -3-benzyloxy-pyrrolidine (S) -1- (4-methyloxyphenyl) -3-pyrrolidinol produced in Example 1 484 mg (2.5 mmol) was dissolved in 5 ml of toluene, 5.00 g (5.0 equivalents) of a 10 wt% aqueous sodium hydroxide solution, 81 mg (0.1 equivalent) of tetrabutylammonium bromide, 43 mg (0.1 equivalent) of potassium iodide. Equivalent) and 411 mg (1.3 equivalents) of benzyl chloride were added and stirred at 50 ° C. for 22 hours. After discarding the aqueous layer, the organic layer was washed twice with 5 ml of distilled water. An organic layer consisting of 5 ml of distilled water and 320 mg (1.2 equivalents) of concentrated hydrochloric acid was added to the organic layer and stirred. The organic layer obtained by removing the aqueous layer was concentrated under reduced pressure and then vacuum dried to obtain the title compound. Obtained as 716 mg of a black-brown oily substance (content 87.5 wt%, yield 88%).
Title compound:
Chemical purity analysis method and content analysis method (gradient method) Retention time: 18.7 minutes
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.17 (m, 2H), 3.25-3.55 (m, 4H), 3.76 (s, 3H), 4.29 (m, 1H), 4.56 (s, 2H), 6.54 (br, 2H), 6.84 (d, 2H), 7.25-7.37 (m, 5H)

(Example 15) Production of 1- (4-methyloxyphenyl) -3-benzoyloxy -pyrrolidine 194 mg of (S) -1- (4-methyloxyphenyl) -3-pyrrolidinol produced in Example 1 (1. 0 mmol) was dissolved in 5 ml of acetonitrile, and 180 mg (1.3 equivalents) of potassium carbonate was added. To this solution, 169 mg (1.2 equivalent) of benzoyl chloride and 13 mg (0.1 equivalent) of dimethylaminopyridine were added at 5 ° C., and the mixture was heated to 25 ° C. and stirred for 19 hours. The reaction mixture was cooled to 5 ° C., 132 mg (1.3 equivalents) of triethylamine and 169 mg (1.2 equivalents) of benzoyl chloride were added, and the mixture was further stirred at 25 ° C. for 5 hours. The reaction solution was concentrated under reduced pressure, 4 ml of toluene, 4 ml of distilled water and 231 mg (2.2 equivalents) of concentrated hydrochloric acid were added and stirred, and the aqueous layer was discarded. The organic layer was washed with 2 ml of saturated aqueous sodium hydrogen carbonate solution and further washed twice with 0.5 ml of distilled water. The obtained organic layer was concentrated under reduced pressure and vacuum-dried to obtain 272 mg of a black brown oily substance.

  This oily substance was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/9 (volume ratio)), and the fraction containing the desired product was concentrated under reduced pressure.

When 1.2 ml of a solution composed of ethyl acetate / hexane = 1/5 (volume ratio) was added to the obtained concentrate, crystals were precipitated, and the mixture was stirred at 25 ° C. for 30 minutes. The crystals were filtered off under reduced pressure, washed with 1 ml of hexane, and dried in vacuo to give 78 mg of the title compound as white crystals (chemical purity 99.4 area%, yield 26%).
Title compound:
Chemical purity analysis method and content analysis method (gradient method) Retention time: 24.3 minutes
¹ H-NMR (CDCl ₃ ): δ (ppm) 2.32 (m, 1H), 2.38 (m, 1H), 3.44 (m, 3H), 3.73 (m, 1H), 3 .76 (s, 3H), 5.66 (m, 1H), 6.57 (d, 2H), 6.86 (d, 2H), 7.42 (t, 2H), 7.55 (t, 1H), 8.01 (d, 2H)

Example 16 Production of (S) -3- (1-cyano-1,1-diphenylmethyl) -pyrrolidine (S) -1- (4-methyloxyphenyl) -3- (produced in Example 10 203 mg (0.5 mmol) of 1-cyano-1,1-diphenylmethyl) -pyrrolidine hydrochloride was dissolved in 2 ml of a solution consisting of distilled water / acetonitrile = 1/1 (volume ratio), and 62 mg (1.3 equivalents) of sulfuric acid. ) And 63 mg (0.6 equivalents) of trichloroisocyanuric acid were added and stirred at 20 ° C. for 1 hour (yield 59%).

The reaction solution was concentrated under reduced pressure, 5 ml of distilled water and 6 ml of chlorobenzene were added to the concentrate, and the target product was extracted into an aqueous layer. To the aqueous layer, 6 ml of toluene and 269 mg (2.0 equivalents) of a 30 wt% aqueous sodium hydroxide solution were added to extract the target product into the organic layer, which was washed twice with 3 ml of distilled water. The obtained organic layer was concentrated under reduced pressure and dried under vacuum to obtain the title compound as a brown oily substance 57 mg (chemical purity 78.3 area%, yield 33%).
Title compound:
Chemical purity analysis method and content analysis method (gradient method) Retention time: 10.4 minutes
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.74 (m, 1H), 1.92 (m, 1H), 2.04 (br, 1H), 2.88-2.95 (m, 2H), 3.00 (dd, 1H), 3.13 (m, 1H), 3.30 (m, 1H), 7.27 (m, 2H), 7.33 (m, 4H), 7. 45 (m, 4H)

Example 17 Production of (S) -3- (1-cyano-1,1-diphenylmethyl) -pyrrolidine (S) -1- (4-methyloxyphenyl) -3- (produced in Example 10 101 mg (0.2 mmol) of 1-cyano-1,1-diphenylmethyl) -pyrrolidine hydrochloride was dissolved in 1 ml of a solution consisting of distilled water / acetonitrile = 1/1 (volume ratio). At 5 ° C., 20 mg (1.0 equivalent) of sulfuric acid and 36 mg (1.0 equivalent) of N-brominated succinimide were added and stirred at 5 ° C. for 1 hour to quantify the title compound in the reaction solution (yield 63 %).
Title compound:
Chemical purity analysis method and content analysis method (gradient method) Retention time: 10.4 minutes

Example 18 Production of (S) -3- (1-cyano-1,1-diphenylmethyl) -pyrrolidine (S) -1- (4-methyloxyphenyl) -3- (produced in Example 10 102 mg (0.2 mmol) of 1-cyano-1,1-diphenylmethyl) -pyrrolidine hydrochloride was dissolved in 1 ml of a solution composed of distilled water / acetonitrile = 1/1 (volume ratio). Sulfuric acid 20 mg (1.0 equivalent) and bromine 16 mg (1.0 equivalent) were added at 5 ° C., and the mixture was stirred at 5 ° C. for 1 hour. Further, 24 mg (1.5 equivalents) of bromine was added and stirred at 5 ° C. for 1 hour to quantify the title compound in the reaction solution (yield 49%).
Title compound:
Chemical purity analysis method and content analysis method (gradient method) Retention time: 10.4 minutes

(Example 19) (S)-3-(1-cyano-1,1-diphenylmethyl) - pyrrolidine was prepared in Example 17 of hydrobromide (S)-3-(1-cyano -1 , 1-Diphenylmethyl) -pyrrolidine 57 mg (0.17 mmol) was dissolved in 2 ml of isopropanol, and 105 mg (3.6 equivalents) of 47 wt% hydrobromic acid was added. The solution was concentrated under reduced pressure, 2 ml of isopropanol and seed crystals were added, and 0.5 ml of ethyl acetate was added dropwise to precipitate crystals, which were stirred at 20 ° C. for 30 minutes. The crystals were separated by filtration under reduced pressure, washed with 1 ml of ethyl acetate, and dried under vacuum to obtain the title compound as 29 mg of pale pink crystals (chemical purity 97.8 area%, optical purity 100% ee, yield 50%).
Title compound:
Chemical purity analysis method and content analysis method (gradient method) Retention time: 10.4 minutes

Optical purity analysis method (Isocratech method)
Measurement was performed after protecting the amino group of 3- (1-cyano-1,1-diphenylmethyl) -pyrrolidine with tert-butoxycarbonyl (hereinafter referred to as Boc).
Column: manufactured by Daicel Chemical Industries, Ltd. {CHIRALCEL OD-H 250 × 4.6 mm}, mobile phase: hexane / isopropanol = 99/1 (volume ratio), flow rate: 1.0 ml / min, detector: UV 210 nm, column temperature: 30 ° C.
Retention time: Boc protector of (R) -3- (1-cyano-1,1-diphenylmethyl) -pyrrolidine: 28.7 minutes, (S) -3- (1-cyano-1,1-diphenylmethyl) ) -Pyrrolidine Boc protector: 31.1 min

¹ H-NMR (D ₂ O): δ (ppm) 2.03 (m, 1H), 2.23 (m, 1H), 3.22 (dd, 1H), 3.40 (m, 1H), 3.53-3.59 (m, 2H), 3.95 (m, 1H), 7.43 (t, 2H), 7.47 (t, 4H), 7.59 (d, 4H)

(Example 20) (S)-3-(1-cyano-1,1-diphenylmethyl) - were prepared in Example 11 of pyrrolidine hydrobromide (S)-1-(4-methyloxyphenyl ) -3- (1-Cyano-1,1-diphenylmethyl) -pyrrolidine in toluene (87 mg, 0.24 mmol) was concentrated under reduced pressure, and 1.5 ml of distilled water, 1.5 ml of acetonitrile, 4-methyl were added to the concentrate. 105 mg (2.2 equivalents) of benzenesulfonic acid monohydrate was added. The solution was cooled to 5 ° C., 50 mg (1.2 equivalents) of N-brominated succinimide was added, and the mixture was stirred at 5 ° C. for 1 hour (yield 75%, optical purity 99.9% ee).

  After concentration of the reaction solution under reduced pressure, 0.5 ml of distilled water and 5 ml of toluene were added to the concentrate, the aqueous layer was adjusted to pH 14 with a 30 wt% aqueous sodium hydroxide solution, and the target product was extracted into the organic layer. The aqueous layer was further extracted with 5 ml of toluene, and combined with the previous organic layer. The obtained organic layer was concentrated under reduced pressure, 3 ml of toluene, 3 ml of distilled water and 99 mg (2.2 equivalents) of 47 wt% hydrobromic acid were added to the concentrate, and the target product was extracted into the aqueous layer. The separated organic layer was further extracted with 3 ml of distilled water and combined with the previous aqueous layer. 6 ml of isopropanol was added to the obtained aqueous layer and concentrated under reduced pressure, 6 ml of isopropanol was added to the concentrate, and the mixture was again concentrated under reduced pressure.

When 1 ml of ethyl acetate was added to the obtained concentrate, crystals were precipitated, and the mixture was stirred at 25 ° C. for 30 minutes. The crystals were filtered off under reduced pressure, washed with 1 ml of ethyl acetate, and dried in vacuo to give the title compound as white crystals (66 mg) (chemical purity 99.5 area%, optical purity 100% ee, yield 65%).
Title compound:
Chemical purity analysis method and content analysis method (gradient method) Retention time: 10.4 minutes

Optical purity analysis method (Isocratech method)
Measurement was performed after protecting the amino group of 3- (1-cyano-1,1-diphenylmethyl) -pyrrolidine with tert-butoxycarbonyl (hereinafter referred to as Boc).
Column: manufactured by Daicel Chemical Industries, Ltd. {CHIRALCEL OD-H 250 × 4.6 mm}, mobile phase: hexane / isopropanol = 99/1 (volume ratio), flow rate: 1.0 ml / min, detector: UV 210 nm, column temperature: 30 ° C.
Retention time: Boc protector of (R) -3- (1-cyano-1,1-diphenylmethyl) -pyrrolidine: 28.7 minutes, (S) -3- (1-cyano-1,1-diphenylmethyl) ) -Pyrrolidine Boc protector: 31.1 min

(Example 21) Production of (R) -3-aminopyrrolidine di (4-methylbenzenesulfonic acid) salt (R) -1- (4-methyloxyphenyl) -3-aminopyrrolidine di-acid produced in Example 14 To an aqueous solution containing 188 mg (0.35 mmol) of (4-methylbenzenesulfonic acid) salt, 1.5 ml of acetonitrile was added. After cooling to 5 ° C., 79 mg (1.3 equivalents) of N-brominated succinimide was added and stirred at 5 ° C. for 1 hour (yield 98%).
The reaction solution was concentrated under reduced pressure, 5 ml of isopropanol was added to the concentrate, and the mixture was concentrated under reduced pressure. 5 ml of isopropanol was added, and the mixture was concentrated again under reduced pressure.

When 1 ml of isopropanol was added to the concentrate, crystals were precipitated, and the mixture was stirred at 25 ° C. for 1 hour. The crystals were filtered off under reduced pressure, washed with 1.5 ml of isopropanol and dried in vacuo to give 107 mg of the title compound as pale purple crystals (content 99.5 wt%, optical purity 96.2% ee, yield 71%). .
Title compound:

Optical purity analysis method (Isocratech method)
The measurement was performed after protecting the 1-position and 3-position amino groups of (R) -3-aminopyrrolidine with benzyloxycarbonyl (hereinafter, Cbz).
Column manufactured by Daicel Chemical Industries, Ltd. {CHIRALCEL OD-H 250 × 4.6 mm}, mobile phase: hexane / isopropanol / triethylamine = 85/15 / 0.1 (volume ratio), flow rate: 1.0 ml / min, detector: UV254 nm Column temperature: 40 ° C
Retention time: (R) -3-aminopyrrolidine protected Cbz: 13.7 minutes, (S) -3-aminopyrrolidine protected Cbz: 18.8 minutes

¹ H-NMR (CD ₃ OD): δ (ppm) 2.14 (m, 1H), 2.37 (s, 6H), 2.49 (m, 1H), 3.35-3.46 (m , 2H), 3.55 (m, 1H), 3.75 (dd, 1H), 4.08 (m, 1H), 7.24 (d, 4H), 7.69 (d, 4H)

(Example 22) Production of (S) -3- (benzyloxy) -pyrrolidine 649 mg of (S) -1- (4-methyloxyphenyl) -3- (benzyloxy) -pyrrolidine produced in Example 15 (2 0.0 mmol)) is dissolved in 4 ml of a solution of distilled water / acetonitrile = 1/1 (volume ratio), and 256 mg (0.6 equivalents) of trichloroisocyanuric acid and 458 mg (2.2 equivalents) of concentrated hydrochloric acid are added. Stir at 1.5 ° C. for 1.5 hours. 150 mg (0.3 equivalent) of trichloroisocyanuric acid was added, and the mixture was further stirred at 5 ° C. for 1 hour (yield 36%).

The reaction mixture was concentrated under reduced pressure, and 4 ml of ethyl acetate, 5 ml of toluene and 5 ml of saturated brine were added to the resulting concentrate to extract the target product into an aqueous layer. Since an insoluble material was precipitated, it was filtered off, and then the organic layer was discarded. To the obtained aqueous layer, 8 ml of ethyl acetate and 975 mg (3.7 equivalents) of a 30 wt% aqueous sodium hydroxide solution were added to extract the target product into the organic layer, which was washed 3 times with 2 ml of distilled water. 20 ml of ethyl acetate was added to the washing water for further extraction, and combined with the previous organic layer and concentrated under reduced pressure. Ethanol (4 ml) was added to the concentrate, and the mixture was concentrated under reduced pressure and dried in vacuo to give the title compound as a black brown oily substance (139 mg) (chemical purity 90.7 area%, yield 33%).
Title compound:
Chemical purity analysis method and content analysis method (gradient method) Retention time: 7.7 minutes
¹ H-NMR (CDCl ₃ ): δ (ppm) 1.85-1.92 (m, 3H), 2.80-2.85 (m, 2H), 3.06-3.13 (m, 2H) ), 4.10 (m, 1H), 4.48 (s, 2H), 7.24-7.34 (m, 5H)

(Example 23) Production of (S) -3- (benzoyloxy) -pyrrolidine hydrochloride (S) -1- (4-methyloxyphenyl) -3- (benzoyloxy) -pyrrolidine 20 mg produced in Example 16 (0.07 mmol) was dissolved in 1 ml of a solution consisting of distilled water / acetonitrile = 1/1 (volume ratio), and concentrated hydrochloric acid 14 mg (2.0 equivalents) and N-brominated succinimide 14 mg (1 .2 equivalents) was added. After stirring at 5 ° C. for 1 hour, the title compound in the reaction solution was quantified (yield 96%).
Title compound:
Chemical purity analysis method and content analysis method (gradient method) Retention time: 7.7 minutes
¹ H-NMR (D ₂ O): δ (ppm) 2.44 (m, 2H), 3.58 (m, 2H), 3.68 (m, 2H), 5.71 (m, 1H), 7.56 (t, 2H), 7.71 (t, 1H), 8.02 (d, 2H)

Claims (14)

Following formula (1);

(In the formula, L ¹ represents a leaving group. * Represents an asymmetric carbon atom.) In the presence of a metal catalyst, an optically active 4-substituted-3-hydroxybutyronitrile represented by the following formula (2) );

(In the formula, Ar represents an aryl group having 6 to 20 carbon atoms which may have a substituent, or a heteroaryl group having 3 to 20 carbon atoms which may have a substituent). The following formula (3), characterized by reacting an aniline compound with hydrogen:

(Wherein Ar and * are the same as defined above). A method for producing optically active 1-aryl-3-pyrrolidinol or a salt thereof represented by:   Furthermore, the process of melt | dissolving the optically active 1-aryl-3-pyrrolidinol represented by said Formula (3) in the organic solvent, and wash | cleaning with the aqueous solution containing an acid, The manufacturing of Claim 1 characterized by the above-mentioned. Law.   Furthermore, the manufacturing method of Claim 1 including the process of crystallizing the optically active 1-aryl-3-pyrrolidinol represented by said Formula (3) from a solvent.   The method further comprises a step of forming a salt from the optically active 1-aryl-3-pyrrolidinol represented by the formula (3) and an acid, dissolving the salt in water, and washing with an organic solvent. The production method described in 1. By treating the optically active 1-aryl-3-pyrrolidinol represented by the formula (3) produced by the method according to any one of claims 1 to 4 or a salt thereof with a base and a sulfonylating agent, Formula (4);

(In the formula, R ¹ represents an alkyl group having 1 to 20 carbon atoms which may have a substituent, or an aryl group having 6 to 20 carbon atoms which may have a substituent. Ar and * The same as the above), and an optically active 1-aryl-3- (sulfonyloxy) -pyrrolidine represented by the following formula (5):

(In the formula, R ² has an optionally substituted alkyl group having 1 to 20 carbon atoms, an optionally substituted cycloalkyl group having 3 to 20 carbon atoms, and a substituent. An optionally substituted alkenyl group having 2 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms which may have a substituent, an aryl group having 6 to 20 carbon atoms which may have a substituent, and a substituent. May have a C3-C20 heteroaryl group, a cyano group, a hydroxyl group, a C1-C20 alkyloxy group that may have a substituent, or a substituent. An aralkyloxy group having 7 to 20 carbon atoms, an aryloxy group having 6 to 20 carbon atoms which may have a substituent, an acyloxy group having 2 to 20 carbon atoms which may have a substituent, and a substituent; Aroyloxy group having 7 to 20 carbon atoms, thiol group, substituted An alkylthio group having 1 to 20 carbon atoms which may have a group, an arylthio group having 6 to 20 carbon atoms which may have a substituent, an acylthio group having 2 to 20 carbon atoms, an amino group, and a hydroxyamino group , A methoxyamino group, an azido group, a phthalimide group, a nitro group, an optionally substituted alkylamino group having 1 to 20 carbon atoms, and an optionally substituted aralkylamino group having 7 to 20 carbon atoms Group, an arylamino group having 6 to 20 carbon atoms which may have a substituent, a dialkylamino group having 1 to 20 carbon atoms which may have a substituent, or a substituent. Represents a diaralkylamino group having 7 to 20 carbon atoms, Ar and * are the same as defined above), and a method for producing an optically active 1-aryl-3-substituted pyrrolidine or a salt thereof. The production method according to claim 5, wherein R ¹ is a methyl group, and R ² is a 1-cyano-1,1-diphenylmethyl group, a benzyloxy group, a benzoyloxy group, or an amino group. An optically active 1-aryl-3-pyrrolidinol represented by the formula (3) produced by the method according to claim 1 or a salt thereof, a base and the following formula (6);

(In the formula, R ³ has an optionally substituted alkyl group having 1 to 20 carbon atoms, an optionally substituted cycloalkyl group having 3 to 20 carbon atoms, and a substituent. An optionally substituted alkenyl group having 2 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms which may have a substituent, an acyl group having 1 to 20 carbon atoms which may have a substituent, or a substituent An aroyl group having 7 to 20 carbon atoms which may have a group, L ² represents a leaving group, and a compound represented by the following formula (7):

(Wherein Ar, R ³ and * are the same as defined above). A method for producing an optically active 1-aryl-3-pyrrolidinol derivative represented by the formula: The manufacturing method of Claim 7 whose R < ³ > is a benzyl group or a benzoyl group.   The production method according to any one of claims 1 to 8, wherein Ar is a phenyl group, a 4-methyloxyphenyl group, a 3-fluorophenyl group, or a 3-ethyloxycarbonylphenyl group.   The process according to claim 9, wherein Ar is a 4-methyloxyphenyl group. The following formula (8) produced by the method according to claim 10;

(In the formula, R ² has an optionally substituted alkyl group having 1 to 20 carbon atoms, an optionally substituted cycloalkyl group having 3 to 20 carbon atoms, and a substituent. An optionally substituted alkenyl group having 2 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms which may have a substituent, an aryl group having 6 to 20 carbon atoms which may have a substituent, and a substituent. May have a C3-C20 heteroaryl group, a cyano group, a hydroxyl group, a C1-C20 alkyloxy group that may have a substituent, or a substituent. An aralkyloxy group having 7 to 20 carbon atoms, an aryloxy group having 7 to 20 carbon atoms which may have a substituent, an acyloxy group having 2 to 20 carbon atoms which may have a substituent, and a substituent; Aroyloxy group having 7 to 20 carbon atoms, thiol group, substituted An optionally substituted acylthio group having 1 to 20 carbon atoms, an optionally substituted arylthio group having 6 to 20 carbon atoms, an acetylthio group having 2 to 20 carbon atoms, an amino group, and a hydroxyamino group , A methoxyamino group, an azido group, a phthalimide group, a nitro group, an optionally substituted alkylamino group having 1 to 20 carbon atoms, and an optionally substituted aralkylamino group having 7 to 20 carbon atoms A group, an arylamino group having 7 to 20 carbon atoms which may have a substituent, a dialkylamino group having 1 to 20 carbon atoms which may have a substituent, or a substituent. 4 represents a diaralkylamino group having 7 to 20 carbon atoms. * Represents the same as above. 4 of 1-position of optically active 1- (4-methyloxyphenyl) -3-substituted pyrrolidine represented by -Methyloxyphenyl group Wherein the desorption, the following equation (9);

(Wherein R ² and * are the same as above), a method for producing an optically active 3-substituted pyrrolidine or a salt thereof. The production method according to claim 11, wherein R ² is a 1-cyano-1,1-diphenylmethyl group, a benzyloxy group, a benzoyloxy group, or an amino group. Following formula (8);

(Wherein * represents an asymmetric carbon atom), R ² is a 1-cyano-1,1-diphenylmethyl group, a benzyloxy group, a benzoyloxy group, or an amino group. 4-methyloxyphenyl) -3-substituted pyrrolidine or a salt thereof. Following formula (10);

(In the formula, R ¹ represents an optionally substituted alkyl group having 1 to 20 carbon atoms or an optionally substituted aryl group having 6 to 20 carbon atoms. * Represents an asymmetric group. An optically active 1- (4-methyloxyphenyl) -3- (sulfonyloxy) -pyrrolidine represented by: