JPH11246522A - Agent for optical resolution and production of optically active 1-benzyl-3-pyrrolidinol by using the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an agent for optical resolution comprising a new tetrahydroisoquinoline carboxylic acid derivative and useful for producing an optically active l-benzyl-3-pyrrolidinol useful as a synthetic intermediate for drugs. SOLUTION: This agent comprises an optically active 1,2,3,4- tetrahydro-3-isoquinoline carboxylic acid derivative of formula I (R is H, a halogen, an 1-4C alkyl, 1-4C alkoxyl, nitro; (n) is 1 to 3; and (*) is an asymmetric carbon atom). A compound of formula I is exemplified by (S)- or (R)-2-(phenylsulfonyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-3-isoquinoline carboxyhc acid. A compound of formula is obtained by reacting a highly purified optically active 6,7-dimethoxy-1,2,3,4-tetrahydro-3-isoquinoline carboxylic acid of formula II with a benzenesulfonyl chloride of formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to optically active 1,2,2
The present invention relates to a novel optical resolving agent comprising a 3,4-tetrahydro-3-isoquinolinecarboxylic acid derivative. Further, the present invention provides an optically active 1-benzyl-3 using a novel optical resolving agent.
It relates to a process for producing pyrrolidinol. Optically active 1-benzyl-3-pyrrolidinol is useful as a pharmaceutical intermediate.

[0002]

2. Description of the Related Art Conventionally, racemic amines to be optically resolved using an optical resolving agent have been led to diastereomeric salts,
In the diastereomer method for obtaining the desired optically active amines using a crystallization technique, (+)-tartaric acid, (−)-dibenzoyltartaric acid,
Synthesis of natural products such as (+)-10-camphorsulfonic acid, (+)-aspartic acid, optically active α-phenylethanesulfonic acid, mandelic acid, α-phenylglycine, α-methylbenzyl isocyanate, etc. Products are known (Paul P. Newman, "Optical Resolution P
rocedures for Chemical Compounds, Vol. 1: Amines an
d Related Compounds ", 1978 (Optical Resolution I
nformation Center, New York); edited by The Chemical Society of Japan, “Quarterly Chemistry Review No. 6,“ Separation of Optical Isomers ”, 1989 (Society Press Center).

An optically resolving agent used for the production of optically active 1-benzyl-3-pyrrolidinol, one of optically active amines, is an optically active mandelic acid (Japanese Patent Application Laid-Open No.
1-267577), an optically active phenylglycine derivative or a phenylalanine derivative (Japanese Patent Laid-Open No. 4-1).
No. 3659).

[0004]

The present inventors have searched for a new optical resolving agent which can be used for the industrial production of optically active 1-benzyl-3-pyrrolidinol by the diastereomer method. The optically active 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid derivative represented by the general formula (I) has been found to be useful as an optical resolving agent, and the optically active 1,2,3,4 When (RS) -1-benzyl-3-pyrrolidinol is optically resolved using a tetrahydro-3-isoquinolinecarboxylic acid derivative as an optical resolving agent, highly pure optically active 1-benzyl-3-pyrrolidinol can be produced in good yield. Was found.

[0005]

That is, the present invention provides a compound of the general formula (I)

[0006]

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Wherein R represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxyl group having 1 to 4 carbon atoms, or a nitro group; n represents 1, 2 or 3; Represents an asymmetric carbon atom.) An optically resolving agent comprising an optically active 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid derivative represented by the following general formula (I): Optical activity 1,2,3
Using a 4-tetrahydro-3-isoquinolinecarboxylic acid derivative as an optical resolving agent, (RS) -1-benzyl-3
-A method for producing optically active 1-benzyl-3-pyrrolidinol, which comprises optically resolving pyrrolidinol.

[0008]

DETAILED DESCRIPTION OF THE INVENTION The optical resolving agent of the present invention is a novel optical resolving agent comprising an optically active 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid derivative represented by the above general formula (I). And both the (R) -form and the (S) -form can be used as an optical resolving agent.

Representative compounds include (S)-or (R) -2- (phenylsulfonyl) -6,7-dimethoxy-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid, S)-or (R) -2- (4-
(Chlorophenylsulfonyl) -6,7-dimethoxy-
1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid, (S)-or (R) -2- (2,5-dichlorophenylsulfonyl) -6.7-dimethoxy-1,
2,3,4-tetrahydro-3-isoquinolinecarboxylic acid, (S)-or (R) -2- (2- or 4-bromophenylsulfonyl) -6,7-dimethoxy-1,2,2
3,4-tetrahydro-3-isoquinolinecarboxylic acid,
(S)-or (R) -2- (4-methylphenylsulfonyl) -6,7-dimethoxy-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid, (S)-or (R)- 2- (4-ethylphenylsulfonyl)-
6,7-dimethoxy-1,2,3,4-tetrahydro-
3-isoquinolinecarboxylic acid, (S)-or (R)-
2- (2,4,6-trimethylphenylsulfonyl)-
6,7-dimethoxy-1,2,3,4-tetrahydro-
3-isoquinolinecarboxylic acid, (S)-or (R)-
2- (4-t-butylphenylsulfonyl) -6,7-
Dimethoxy-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid, (S)-or (R) -2- (4
-Methoxyphenylsulfonyl) -6,7-dimethoxy-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid, (S)-or (R) -2- (2-, 3-,
Or 4-nitrophenylsulfonyl) -6,7-dimethoxy-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid, (S)-or (R) -2- (2,4
-Dinitrophenylsulfonyl) -6,7-dimethoxy-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid.

[0010] The optically active 1,2,3,4-tetrahydro-3- represented by the general formula (I) which is the optical resolving agent of the present invention.
Isoquinoline carboxylic acid derivatives are, for example,

[0011]

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[0012] As shown in the above, the precursor, high-purity optically active 6,7-dimethoxy-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid (II) or an acid salt thereof is represented by the general formula (I). III) (wherein R and n have the same meanings as described above), and can be industrially produced by a usual method of reacting with a benzenesulfonyl chloride represented by the formula:

The precursor (II) or an acid salt thereof is, for example,

[0014]

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As shown in the above, an azlactone compound (V) synthesized from 3,4-dimethoxybenzaldehyde (IV) by Erlenmeyer azlactone synthesis is hydrolyzed to give an N-benzoylcinnamic acid derivative ( VI) and (R)-or (S) -PROPHOS for ligand (L *)
Asymmetric catalytic reduction of compound VI in the presence of a rhodium complex asymmetric reduction catalyst prepared using a chiral diphosphine such as (1,2-bis (diphenylphosphino) propane) to produce optically active N-benzoyl-3,4 A method of producing dimethoxyphenylalanine (VII) and further hydrolyzing compound VII to cause an optically active 3,4-dimethoxyphenylalanine or its hydrochloride (VIII) to undergo a Pictet-Spengler reaction with formaldehyde. (JP-A-2-180870; NJ O'Reilly, et al.)
al., Synthesis, 1990 (7), 550-556; MD Fryzuk, et.
al., J. Am. Chem. Soc., 99 (19), 6262-6267 (1977);
MD Fryzuk, et al., J. Am. Chem. Soc., 100 (17), 5
491-5494 (1978)).

The optical resolving agent of the present invention is not substantially racemized in the operation used in a usual diastereomer method and retains optical activity, so that it can be reused.

When the optical resolving agent of the present invention is used, (RS)
-1-Benzyl-3-pyrrolidinol can be optically resolved, and high-purity optically active 1-benzyl-3-pyrrolidinol can be produced in high yield. Here, (RS) -1-benzyl-3-pyrrolidinol used as a raw material is a racemic mixture containing equal amounts of (R) -1-benzyl-3-pyrrolidinol and (S) -1-benzyl-3-pyrrolidinol. But also a mixture containing at least one of the optical isomers in an equal amount or more.

(RS) -1 using the optical resolving agent of the present invention
Optical resolution of -benzyl-3-pyrrolidinol can be performed by a usual method.

That is, the optically active 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid derivative, which is the optical resolving agent of the present invention, is added to one equivalent of (RS) -1-benzyl-3-pyrrolidinol in a solvent. On the other hand, 0.1 to 2.
Contact with one equivalent, preferably 0.3 to 1.1 equivalents, to form the diastereomeric salt. At this time, a mineral acid such as hydrochloric acid, sulfuric acid and phosphoric acid or an organic acid such as acetic acid is added to 0.1%.
1 to 1.0 equivalent, preferably 0.3 to 0.7 equivalent may coexist.

The solvent used at this time dissolves the optically active 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid derivative and (RS) -1-benzyl-3-pyrrolidinol, and dissolves these in the solvent. Any solvent can be used as long as it does not chemically denature the compound of Formula (I) and precipitates diastereomeric salts, for example, alcohols such as methanol, ethanol, propanol, isopropanol, and butanol; , Diethyl ether, diisopropyl ether, tetrahydrofuran, ethers such as ethylene glycol dimethyl ether,
Esters such as methyl acetate and ethyl acetate; and organic solvents such as acetonitrile, dichloromethane, chloroform, 1,4-dioxane, toluene, xylene and chlorobenzene. These solvents may be used alone or as a mixed solvent.

The method of contacting the optical resolving agent of the present invention with (RS) -1-benzyl-3-pyrrolidinol to form a diastereomer salt includes the optical resolving agent of the present invention and (RS) -1-benzyl -3-pyrrolidinol may be added to the solvent at once, or they may be added sequentially, or the optical resolving agent of the present invention and (RS)
The diastereomer salt prepared from -1-benzyl-3-pyrrolidinol may be dissolved in the solvent, or they may be added sequentially. The order in which they are added is not particularly limited. When the solution containing the formed diastereomer salt is cooled and / or concentrated, crystals of the sparingly soluble diastereomer salt precipitate from the solution.
The temperature at which the sparingly soluble diastereomer salt is precipitated from the solution may be appropriately selected depending on the purpose, and is usually in the range of O ° C to 100 ° C.

Crystallized crystals of the hardly soluble diastereomer salt can be easily separated by ordinary solid-liquid separation methods such as filtration and centrifugation. The separated hardly soluble diastereomer salt can be subjected to a recrystallization operation to obtain a desired high-purity diastereomer salt.

When the mother liquor from which the hardly soluble diastereomer salt has been separated is cooled and / or concentrated, a readily soluble diastereomer salt is crystallized, which can be separated into a solid and a liquid. By performing a recrystallization operation on the separated easily soluble diastereomer salt, a highly pure easily soluble diastereomer salt can be obtained.

When a mineral acid or an organic acid is allowed to coexist, the mother liquor is precipitated as a mineral acid salt or an organic acid salt when cooled and / or concentrated, and can be separated.

By subjecting the diastereomer salt thus obtained to salting by an appropriate method, the desired optically active 1-benzyl-3-pyrrolidinol and the optical resolving agent can be separated and collected.

As a method for desolving the diastereomer salt, a usual method, that is, a method of treating with an acid or an alkali in an aqueous solvent, a method of using an ion exchange resin, and the like can be used. For example, a diastereomer salt is dissolved or dispersed in water, an aqueous solution of an alkali such as sodium hydroxide is added to demineralize the salt, and then extracted with an organic solvent such as dichloromethane or toluene.
-Benzyl-3-pyrrolidinol is extracted, and the desired optically active 1-benzyl-3-pyrrolidinol is obtained by concentrating and distilling the extracted solution, while an aqueous layer in which the sodium salt of the optical resolving agent is dissolved When a mineral acid such as hydrochloric acid or sulfuric acid is added to the mixture, the optical resolving agent is precipitated. Alternatively, the diastereomeric salt is dissolved or dispersed in water, hydrochloric acid,
When a mineral acid such as sulfuric acid is added to demineralize, an optically resolving agent hardly soluble in water is precipitated, and the desired optically active 1-benzyl-3-
The mineral acid salt of pyrrolidinol dissolves in the water. After recovering the precipitated optical resolving agent by solid-liquid separation by ordinary means,
The desired optically active 1-benzyl-3-pyrrolidinol can be obtained by adding an aqueous alkali solution such as sodium hydroxide to the mother liquor, extracting the solution with an organic solvent such as dichloromethane or toluene, and concentrating and distilling the extracted solution. .

The optical resolving agent of the present invention can be recovered in a high yield by any ordinary method, and retains optical activity without being substantially racemized in the recovery process. it can.

[0028]

EXAMPLES The present invention will be specifically described below with reference to examples of the present invention, but the present invention is not limited to these examples.

The optically active 1-benzyl-
The optical purity (% ee) of 3-pyrrolidinol was measured by high performance liquid chromatography (HPLC) under the following conditions. Column: CHIRALCEL OJ (Daicel Corporation) Column temperature: 25 ° C Moving layer: n-hexane / isopropyl alcohol /
Diethylamine mixture (100: 2: 0.1) Flow rate: 0.8 ml / min Detector wavelength: UV 263 nm

Example 1 (a) (S) -2- (4-methylphenylsulfonyl)
Synthesis of -6,7-dimethoxy-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid (S) -6,7 synthesized by the Pictet-Spengler reaction of L-3,4-dimethoxyphenylalanine with formaldehyde. -Dimethoxy-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid hydrochloride (specific rotation [α] ²⁵ _D = -98.4 ° (c = 1.0.1N-HC)
l)) A 48% aqueous sodium hydroxide solution is added dropwise to a mixture of 100 g, water and toluene at 15 ° C or lower while stirring. Then, while maintaining the reaction temperature at room temperature, a toluene solution containing 65.4 g of p-toluenesulfonyl chloride is added dropwise over 2 hours, and stirring is continued for another 3 hours. After completion of the reaction, concentrated hydrochloric acid was added to the separated aqueous layer, and the precipitated crystals were washed with water, dried, and recrystallized with methanol to obtain the desired product 12
4.7 g are obtained.

Melting point: 193.5-194.5 ° C. Specific rotation [α] ²⁵ _D = + 7.5 ° (c = 2.0, MeO
H) Infrared absorption spectrum, ν _max cm ^-1 (KBr): 1742,
1520, 1455, 1340, 1255, 1157, 1230, 1179, 1158, 11
23 ¹ H-nuclear magnetic resonance spectrum, δ ppm (CD ₃ O
D, TMS internal standard): 7.67 (2H, d, J = 8.
0 Hz), 7.22 (2H, d, J = 8.0 Hz),
6.57 (2H, s), 4.64-5.03 (2H,
m), 3.68 (6H, s), 2.86-3.16 (2
H, m), 2.33 (3H, s) (b) Optical resolution of (RS) -1-benzyl-3-pyrrolidinol (RS) -1-benzyl-3-pyrrolidinol 8.87
g, (S) -2- (4-methylphenylsulfonyl) -6,7-dimethoxy-1,2,3,4 prepared in (a)
-Tetrahydro-3-isoquinolinecarboxylic acid 19.5
A mixture of 7 g and methyl ethyl ketone was heated to 70 ° C. to dissolve, then cooled to 10 ° C. or lower and allowed to stand.
The precipitated crystals were separated by filtration, dried, and recrystallized from methyl ethyl ketone to give (S) -1-benzyl-3-pyrrolidinol and (S) -2- (4-methylphenylsulfonyl).
9.21 g of white crystals of a diastereomer salt with -6,7-dimethoxy-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid were obtained.

The crystals were dissolved in a 2N aqueous sodium hydroxide solution with stirring, and extracted with dichloromethane. The extracted solution was washed with water, dried and concentrated under reduced pressure to obtain 2.38 g of (S) -1-benzyl-3-pyrrolidinol as a pale yellow oil. Its optical purity measured by HPLC was 99.8% ee.

On the other hand, the aqueous layer was acidified by adding concentrated hydrochloric acid with stirring, and the precipitated crystals were filtered, washed with water and dried to give (S) -2- (4-methylphenylsulfonyl) -6,6.
7-dimethoxy-1,2,3,4-tetrahydro-3-
6.13 g of isoquinoline carboxylic acid was recovered (recovery rate 88.5%). The recovered (S) -2- (4-methylphenylsulfonyl) -6,7-dimethoxy-1,2,3,
The specific rotation measured by recrystallizing 4-tetrahydro-3-isoquinolinecarboxylic acid with methanol was the same as the value described in (a).

Example 2 (a) (R) -2- (4-methylphenylsulfonyl)
Synthesis of -6,7-dimethoxy-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid (R) -6,7 synthesized by the Pictet-Spengler reaction of D-3,4-dimethoxyphenylalanine with formaldehyde. -Dimethoxy-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid (specific rotation [α]
_{^{25 D = + 98.2 ° (c}} = 1.0,1N-HCl)) 1
00g was reacted with 65.4 g of p-toluenesulfonyl chloride in the same manner as described in Example 1 (a), and the obtained product was recrystallized from methanol to obtain 123.4 g of the desired product.
I got

Melting point 192.9 to 193.9 ° C. Specific rotation [α] ²⁵ _D = −7.6 ° (c = 2.0, MeO
H) The measured infrared absorption spectrum and ¹ H-nuclear magnetic resonance spectrum were both synthesized in Example 1 (a) (S).
The spectrum was the same as that of -2- (4-methylphenylsulfonyl) -6,7-dimethoxy-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid.

(B) Optical resolution of (RS) -1-benzyl-3-pyrrolidinol (RS) -1-benzyl-3-pyrrolidinol 8.87
g, (R) -2- (4-methylphenylsulfonyl) -6,7-dimethoxy-1,2,3,4 prepared in (a)
-Tetrahydro-3-isoquinolinecarboxylic acid 19.5
A mixture of 7 g and methyl ethyl ketone was heated to 70 ° C. to dissolve, then cooled to 10 ° C. or lower and allowed to stand.
The precipitated crystals were separated by filtration, dried, and recrystallized from methyl ethyl ketone to give (R) -1-benzyl-3-pyrrolidinol and (R) -2- (4-methylphenylsulfonyl).
9.14 g of a white crystal of a diastereomer salt with -6,7-dimethoxy-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid was obtained.

The crystals were dissolved in a 2N aqueous sodium hydroxide solution with stirring, and extracted with dichloromethane. The extracted solution was washed with water, dried and concentrated under reduced pressure to obtain 2.23 g of (R) -1-benzyl-3-pyrrolidinol as a pale yellow oil. Its optical purity measured by HPLC was 99.6% ee.

On the other hand, the aqueous layer was acidified by adding concentrated hydrochloric acid with stirring, and the precipitated crystals were filtered, washed with water and dried to give (R) -2- (4-methylphenylsulfonyl) -6,6.
7-dimethoxy-1,2,3,4-tetrahydro-3-
5.59 g of isoquinolinecarboxylic acid was recovered (recovery rate 88.9%). The recovered (R) -2- (4-methylphenylsulfonyl) -6,7-dimethoxy-1,2,3,
The specific rotation measured by recrystallizing 4-tetrahydro-3-isoquinolinecarboxylic acid with methanol was the same as the value described in (a).

Example 3 (RS) -1-benzyl-3
17.73 g of pyrrolidinol, (S) -2- (4-methylphenylsulfonyl) -prepared in Example 1 (a)
6,7-dimethoxy-1,2,3,4-tetrahydro-
A mixture consisting of 39.14 g of 3-isoquinolinecarboxylic acid and methyl ethyl ketone was dissolved by heating to 70 ° C., and then cooled to 10 ° C. or lower and allowed to stand. The precipitated crystals were separated by filtration, dried, and recrystallized from methyl ethyl ketone to give (S) -1-benzyl-3-pyrrolidinol and (S) -2- (4-methylphenylsulfonyl) -6,
7-dimethoxy-1,2,3,4-tetrahydro-3-
20.61 g of a white crystal of a diastereomer salt with isoquinolinecarboxylic acid was obtained.

The crystals were dissolved in water and acidified by adding concentrated hydrochloric acid with stirring to precipitate (S) -2- (4-methylphenylsulfonyl) -6,7-dimethoxy-1,
The crystals of 2,3,4-tetrahydro-3-isoquinolinecarboxylic acid were filtered, washed with water and dried to recover 12.80 g of the crystals (recovery rate 90.8%). The filtrate was alkalified with an aqueous sodium hydroxide solution, and extracted with dichloromethane. The extracted solution was washed with water, dried and concentrated under reduced pressure to obtain 5.85 g of (S) -1-benzyl-3-pyrrolidinol as a pale yellow oil. Its optical purity measured by HPLC was 99.6% ee.

The recovered (S) -2- (4-methylphenylsulfonyl) -6,7-cymethoxy-1,2,3,4
-Tetrahydro-3-isoquinolinecarboxylic acid 12.8
To 0 g, 5.80 g of (RS) -1-benzyl-3-pyrrolidinol and methyl ethyl ketone were added, and 70 ° C.
To dissolve, cooled to 10 ° C. or lower, and allowed to stand.
The precipitated crystals were separated by filtration, dried, and recrystallized from methyl ethyl ketone to give (S) -1-benzyl-3-pyrrolidinol and (S) -2- (4-methylphenylsulfonyl).
6.21 g of a white crystal of a diastereomer salt with -6,7-dimethoxy-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid was obtained.

The crystals were dissolved in a 2N aqueous sodium hydroxide solution with stirring, and extracted with dichloromethane. The extracted solution was washed with water, dried and concentrated under reduced pressure to obtain 1.61 g of (S) -1-benzyl-3-pyrrolidinol as a pale yellow oil. Its optical purity measured by HPLC was 99.3% ee.

On the other hand, the aqueous layer was acidified by adding concentrated hydrochloric acid while stirring, and the precipitated crystals were filtered, washed with water and dried to give (S) -2- (4-methylphenylsulfonyl) -6,6.
7-dimethoxy-1,2,3,4-tetrahydro-3-
3.60 g of isoquinolinecarboxylic acid was recovered (recovery rate: 85.3%). The recovered (S) -2- (4-methylphenylsulfonyl) -6,7-dimethoxy-1,2,3,
The specific rotation measured by recrystallizing 4-tetrahydro-3-isoquinolinecarboxylic acid with methanol is shown in Example 1 (a).
Was the same as the value described in.

[0044]

The optical resolving agent of the present invention can be synthesized from a raw material having high optical purity in a high yield, and can be produced industrially efficiently. The optical resolving agent of the present invention can be recovered from a diastereomer salt solution in high yield and high purity, and since it is not substantially racemized, it can be reused. Therefore, by using the optical resolving agent of the present invention, high-purity optically active 1-benzyl-3-pyrrolidinol can be industrially produced.

Claims (2)

[Claims] 1. A compound of the general formula (I) (Wherein, R is a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxyl group having 1 to 4 carbon atoms,
Or a nitro group; n represents 1, 2 or 3; *
Represents an asymmetric carbon atom. ) Represented by optical activity 1, 2,
An optical resolving agent comprising a 3,4-tetrahydro-3-isoquinolinecarboxylic acid derivative. 2. A compound of the general formula (I) (Wherein, R is a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxyl group having 1 to 4 carbon atoms,
Or a nitro group, n represents 1, 2 or 3, *
Represents an asymmetric carbon atom. ) Represented by optical activity 1, 2,
Production of optically active 1-benzyl-3-pyrrolidinol, wherein (RS) -1-benzyl-3-pyrrolidinol is optically resolved by using a 3,4-tetrahydro-3-isoquinolinecarboxylic acid derivative as an optical resolution agent. Law.