Optically active pyrrolidine derivatives or acidic salts thereof, optically active α-carboline derivatives, and methods for producing the same

Abstract

To provide a chiral pyrrolidine catalyst that can produce an optically active α-carboline derivative, one of heterocyclic compounds.SOLUTION: The present invention provides an optically active pyrrolidine derivative, represented by general formula (1), or an acidic salt thereof (where R1 is an optionally substituted, C1-10 aliphatic hydrocarbon group or C6-20 aryl group, R2 is an optionally substituted C7-21 arylmethyl group, but substituents optionally included in an aryl group and the like independently represent an alkyl group optionally substituted with a halogen atom or a fluorine atom, and the like).SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to an optically active pyrrolidine derivative or an acidic salt thereof, an optically active α-carboline derivative, and a method for producing the same.

Background Art

[0002] A carboline structure having a piperidine structure condensed with indole is present as a part of the structure of various natural products. Depending on the position of the nitrogen atom of piperidine, an α-carboline structure, a β-carboline structure, and a γ-carboline structure exist.

[0003] Since many optically active α-carboline derivatives have physiological activities such as oxaline, comunesine F, and perophoramide, stereoselective synthesis thereof is required. As a similar compound of an optically active α-carboline derivative, for example, a method for stereoselective synthesis of α-carbolinone using a heterocyclic carbene catalyst has been proposed (see Non-Patent Document 1). In addition, as a method for synthesizing an α-carboline derivative, a diastereoselective synthesis method of an α-carboline derivative using a pyrrolidine compound has been disclosed (see Non-Patent Document 2). The method of Non-Patent Document 2 is a method for synthesizing a racemate.

Prior Art Documents

Non-Patent Documents

[0004]

Non-Patent Document 1

Non-Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0005] The stereoselective reaction of heterocyclic compounds is one of the challenging issues in this field, and chiral pyrrolidine catalysts such as prolinol derivatives have been used in various enantioselective molecular transformation reactions as organic enamine catalysts. However, chiral pyrrolidine catalysts are generally catalysts with limited applicable reactions.

[0006] If there is a chiral pyrrolidine catalyst applicable to the reaction of an α,β-unsaturated imide indole derivative and an aldehyde compound, it is expected to synthesize an optically active α-carboline derivative. Since many optically active α-carboline derivatives have physiological activities as described above, they can be expected to be used in fields such as drug discovery.

[0007] One of the problems of the present invention is to provide a chiral pyrrolidine catalyst capable of producing an optically active α-carboline derivative, which is one of heterocyclic compounds, and a method for producing the same. Another problem of the present invention is to provide an optically active α-carboline derivative that can be expected to be used in fields such as drug discovery and a method for producing the same.

Means for Solving the Problems

[0008] As a result of intensive studies, the present inventors have found that a chiral pyrrolidine catalyst in which a sulfonyl group and an arylmethyl group are introduced into the amino group of (S)-(2-aminomethyl)pyrrolidine can be used as an asymmetric catalyst for the [4+2] cycloaddition reaction of an α,β-unsaturated imide indole derivative and an aldehyde compound, and have completed the present invention. That is, the gist of the present invention is as follows.

[0009] [1] An optically active pyrrolidine derivative represented by the following general formula (1) or an acidic salt thereof.

Chemical formula

Chemical formula

[0010] The chiral pyrrolidine catalyst of the present invention can produce an optically active α-carboline derivative, which is one of heterocyclic compounds. Further, the method for producing the chiral pyrrolidine catalyst of the present invention can produce a chiral pyrrolidine catalyst capable of synthesizing an optically active α-carboline derivative, which is one of heterocyclic compounds.

[0011] The optically active α-carboline derivative of the present invention can be expected to be used in fields such as drug discovery. In particular, when R 7 in the above formula (2) is a hydrogen atom, a compound in which R 5 and R 6 are trans becomes the main product and is useful as a raw material for new compounds in fields such as drug discovery. In addition, the method for producing the optically active α-carboline derivative of the present invention can produce an optically active α-carboline derivative that can be expected to be used in fields such as drug discovery. In particular, when R in the above formula (4) 7 is a hydrogen atom, an optically active α-carboline derivative can be stereoselectively synthesized.

Mode for Carrying Out the Invention

[0012] Hereinafter, an example of a preferred embodiment for carrying out the present invention will be described. However, the following embodiments are examples for explaining the present invention, and the present invention is not limited to the following embodiments at all.

[0013] [Optically Active Pyrrolidine Derivative or Its Acid Salt] The optically active pyrrolidine derivative or its acid salt of the present invention is represented by the following general formula (1).

Chemical Formula

[0014] In the above general formula (1), R 1 represents an aliphatic hydrocarbon group having 1 to 10 carbon atoms or an aryl group having 6 to 20 carbon atoms, which may have a substituent. Also, R 2 represents an arylmethyl group having 7 to 21 carbon atoms, which may have a substituent.

[0015] The aliphatic hydrocarbon group is a linear, branched, or cyclic saturated or unsaturated hydrocarbon group. For example, a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkenyl group having 2 to 8 carbon atoms, a linear or branched alkynyl group having 2 to 8 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, a cycloalkenyl group having 3 to 10 carbon atoms, a cycloalkynyl group having 3 to 10 carbon atoms, etc. can be mentioned.

[0016] An aryl group is a group formed by the removal of one hydrogen atom bonded to the ring of an aromatic hydrocarbon. Examples of aryl groups having 6 to 20 carbon atoms include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, a 3-phenanthryl group, and a 2-anthryl group, etc.

[0017] The substituents that an aliphatic hydrocarbon group, an aryl group, or an arylmethyl group may have are each independently at least one group selected from the group consisting of a halogen atom, an alkyl group optionally substituted with a fluorine atom, a cycloalkyl group optionally substituted with a fluorine atom, an alkoxyl group, a cycloalkoxyl group, an alkylthio group, a cycloalkylthio group, an aryl group, an aryloxy group, an arylthio group, an arylalkyl group, an arylcycloalkyl group, an arylalkenyl group, an arylalkynyl group, an acyl group, an acid imide group, an alkoxycarbonyl group, a cycloalkoxycarbonyl group, an aryloxycarbonyl group, a carboxyl group, a nitrile group, and a nitro group. Note that the number of substituents can be changed according to the type of substituent. The carbon number of the substituents shall not be included in the carbon number of the aliphatic hydrocarbon group, aryl group, or arylmethyl group.

[0018] The halogen atom refers to any one of a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. As the halogen atom, a fluorine atom is preferred. When an aryl group having 6 to 20 carbon atoms has an iodine atom or a chlorine atom as a substituent, the iodine atom or the chlorine atom does not substitute only at the 4-position of the aryl group. Note that when substituting with a halogen atom, the number of substituents is preferably 2 or more, and more preferably 5.

[0019] The alkyl group which may be substituted with a fluorine atom may be linear or branched. The number of carbon atoms of the alkyl group is usually 1 to 6. Examples of the alkyl group having 1 to 6 carbon atoms which may be substituted with a fluorine atom include a methyl group, a difluoromethyl group, a trifluoromethyl group, an ethyl group, a perfluoroethyl group, an n-propyl group, an isopropyl group, a perfluoropropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, a 2,2-dimethylpropyl group, an n-hexyl group, and a 2-methylpentyl group. As the alkyl group which may be substituted with a fluorine atom, a methyl group and a trifluoromethyl group are preferable. When substituting with an alkyl group which may be substituted with a fluorine atom, the number of substituents is preferably 1 to 3, and more preferably 1 to 2.

[0020] The number of carbon atoms of the cycloalkyl group which may be substituted with a fluorine atom is usually 3 to 10. Examples of the cycloalkyl group having 3 to 10 carbon atoms which may be substituted with a fluorine atom include a cyclopropyl group, a perfluorocyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.

[0021] The alkoxyl group may be linear or branched. The number of carbon atoms of the alkoxyl group is usually 1 to 20. Examples of the alkoxyl group having 1 to 20 carbon atoms include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, a sec-butoxy group, a tert-butoxy group, an n-pentyloxy group, a 2,2-dimethylpropoxy group, an n-hexyloxy group, an n-heptyloxy group, an n-octyloxy group, an n-nonyloxy group, an n-decyloxy group, an n-undecyloxy group, an n-dodecyloxy group, an n-tridecyloxy group, an n-tetradecyloxy group, an n-pentadecyloxy group, an n-hexadecyloxy group, an n-heptadecyloxy group, an n-octadecyloxy group, an n-nonadecyloxy group, and an n-icosyloxy group. As the alkoxyl group, a methoxy group is preferable. When substituting with an alkoxyl group, the number of substituents is preferably 1 to 3, more preferably 1.

[0022] The number of carbon atoms in the cycloalkoxyl group is usually 3 to 20. Examples of the cycloalkoxyl group having 3 to 20 carbon atoms include a cyclopropyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, a cycloheptyloxy group, and a cyclooctyloxy group.

[0023] The number of carbon atoms in the alkylthio group is usually 1 to 20. Examples of the alkylthio group having 1 to 20 carbon atoms include a methylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, an n-butylthio group, an isobutylthio group, a sec-butylthio group, a tert-butylthio group, an n-pentylthio group, an n-hexylthio group, an n-heptylthio group, an n-octylthio group, a 2-ethylhexylthio group, an n-nonylthio group, an n-decylthio group, a 3,7-dimethyloctylthio group, and an n-dodecylthio group.

[0024] The number of carbon atoms in the cycloalkylthio group is usually 3 to 20. Examples of the cycloalkylthio group having 3 to 20 carbon atoms include a cyclopropylthio group, a cyclopentylthio group, a cyclohexylthio group, a cycloheptylthio group, and a cyclooctylthio group.

[0025] The aryl group has the same meaning as described above.

[0026] The number of carbon atoms in the aryl group of the aryloxy group is usually 6 to 20. Examples of the aryloxy group include a phenoxy group, a naphthyloxy group, a phenanthryloxy group, and an anthryloxy group. The aryloxy group is a group in which an aryl group is bonded to an oxy group.

[0027] The number of carbon atoms in the aryl group of the arylthio group is usually 6 to 20. Examples of the arylthio group include a phenylthio group and a naphthylthio group.

[0028] In the arylalkyl group, the number of carbon atoms of the aryl group is usually 6 to 20, and the number of carbon atoms of the alkyl group is usually 1 to 20. Note that the arylalkyl group is an alkyl group having an aryl group as a substituent.

[0029] In the arylcycloalkyl group, the number of carbon atoms of the aryl group is usually 6 to 20, and the number of carbon atoms of the cycloalkyl group is usually 3 to 20. Note that the arylcycloalkyl group is a cycloalkyl group having an aryl group as a substituent.

[0030] In the arylalkenyl group, the number of carbon atoms of the aryl group is usually 6 to 20, and the number of carbon atoms of the alkenyl group is usually 2 to 8. Examples of the alkenyl group having 2 to 8 carbon atoms include a vinyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-methyl-2-butenyl group, 1-pentenyl group, 2-pentenyl group, 1-hexenyl group, 2-hexenyl group, and 1-octenyl group. Examples of the arylalkenyl group include a phenylalkenyl group and a naphthylalkenyl group. Note that the arylalkenyl group is an alkenyl group having an aryl group as a substituent.

[0031] In the arylalkynyl group, the number of carbon atoms of the aryl group is usually 6 to 20, and the number of carbon atoms of the alkynyl group is usually 2 to 8. Examples of the alkynyl group having 2 to 8 carbon atoms include an ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 1-pentynyl group, 2-pentynyl group, 1-hexynyl group, 2-hexynyl group, and 1-octynyl group. Examples of the arylalkynyl group include a phenylalkynyl group and a naphthylalkynyl group. Note that the arylalkynyl group is an alkynyl group having an aryl group as a substituent.

[0032] The acyl group is a group represented by R’CO-, where R’ represents a hydrocarbon group having 1 to 10 carbon atoms. Examples of the acyl group include aliphatic acyl groups such as acetyl group, propionyl group, butyryl group, and isobutyryl group; and aromatic acyl groups such as benzoyl group and naphthoyl group.

[0033] The acid imide group is a group represented by (R’CO)2N-, where R’ has the same meaning as described above, and the two R’s may be the same or different. The two R’s may be bonded to each other to form a ring together with the carbon atom to which they are bonded and the nitrogen atom bonded to the carbon atom. The number of carbon atoms in the acid imide group is preferably 4 to 20, more preferably 4 to 18, and even more preferably 4 to 16.

[0034] Examples of the acid imide group include the groups shown below.

Chemical formula

[0035] The alkoxycarbonyl group is a group in which an alkoxyl group is bonded to a carbonyl group. The alkoxyl group has the same meaning as described above. Examples of the alkoxycarbonyl group include methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, n-pentyloxycarbonyl group, n-hexyloxycarbonyl group, n-heptyloxycarbonyl group, n-octyloxycarbonyl group, 2-ethylhexyloxycarbonyl group, n-nonyloxycarbonyl group, n-decyloxycarbonyl group, 3,7-dimethyloctyloxycarbonyl group, n-dodecyloxycarbonyl group, trifluoromethoxycarbonyl group, pentafluoroethoxycarbonyl group, perfluorobutoxycarbonyl group, perfluorohexyloxycarbonyl group, and perfluorooctyloxycarbonyl group.

[0036] A cycloalkoxycarbonyl group is a group in which a cycloalkoxyl group is bonded to a carbonyl group. The cycloalkoxyl group has the same meaning as described above. Examples of the cycloalkoxycarbonyl group include a cyclohexyloxycarbonyl group.

[0037] An aryloxycarbonyl group is a group in which an aryloxy group is bonded to a carbonyl group. The aryloxy group has the same meaning as described above. Examples of the aryloxycarbonyl group include a phenoxycarbonyl group and a naphthoxycarbonyl group.

[0038] When substituting with a nitro group, the number of substituents is preferably 2 or more, more preferably 2.

[0039] In the above general formula (1), the group represented by R 1 is preferably an aryl group optionally substituted with at least one group selected from the group consisting of an alkyl group having 1 to 6 carbon atoms optionally substituted with a fluorine atom, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, and a nitro group, more preferably a methyl group, a methoxy group, a trifluoromethyl group, or a phenyl group substituted with a fluorine atom, and even more preferably a group represented by any one of the following formulas (R 1 -1) to (R 1 -4).

Chemical formula

[0040] In the above general formula (2), the group represented by R 2 is preferably an arylmethyl group optionally substituted with at least one group selected from the group consisting of an alkyl group having 1 to 6 carbon atoms optionally substituted with a fluorine atom, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, and a nitro group, more preferably a methyl group or a phenylmethyl group optionally substituted with a nitro group, and even more preferably a group represented by any one of the following formulas (R 2 -1) to (R 2 -3). [Chemical formula] (In the formula, the wavy line indicates a bond with a nitrogen atom.)

[0041] Examples of the acid salt include hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfonate, naphthalenesulfonate, acetate, trifluoroacetate, malate, tartrate, citrate, lactate, oxalate, succinate, fumarate, maleate, benzoate, salicylate, phenylacetate, and mandelate. As the acid salt, trifluoroacetate is preferred.

[0042] As the optically active pyrrolidine derivative represented by the above general formula (1) or its acid salt, compounds represented by the following formulas (1-1) to (1-7) are preferred, and the compound represented by the following formula (1-7) is more preferred. [Chemical formula] (In the formula, TFA represents a trifluoroacetate anion.)

[0043] [Method for producing an optically active pyrrolidine derivative or its acid salt] The method for producing the optically active pyrrolidine derivative or its acid salt of the present invention includes a step of obtaining a precursor compound by subjecting the amino group of (S)-1-tert-butoxycarbonyl-2-(aminomethyl)pyrrolidine to a sulfonylation reaction and a reaction with an arylmethyl halide which may have a substituent (hereinafter also referred to as "step (1)"), and a step of deprotecting the tert-butoxycarbonyl group of the precursor compound with an acid to obtain an optically active pyrrolidine derivative represented by the general formula (1) or its acid salt (hereinafter also referred to as "step (2)").

[0044] (Step (1)) Step (1) is a step of obtaining a precursor compound by subjecting the amino group of (S)-1-tert-butoxycarbonyl-2-(aminomethyl)pyrrolidine to a sulfonylation reaction and a reaction with an arylmethyl halide which may have a substituent. The following describes an example in which, after the sulfonylation reaction, a reaction with an arylmethyl halide which may have a substituent is carried out. However, the method for producing the optically active pyrrolidine derivative or its acidic salt of the present invention is not limited to this order, and the sulfonylation reaction may be carried out after the reaction with an arylmethyl halide which may have a substituent.

[0045] (S)-1-tert-Butoxycarbonyl-2-(aminomethyl)pyrrolidine may be purchased as a commercial product and used, or may be synthesized and used. As a commercial product, it is available for purchase from Sigma-Aldrich. When synthesizing, for example, starting from L-proline, it can be synthesized by the following method.

[0046] First, after obtaining (2-hydroxymethyl)pyrrolidine by a reduction treatment using a reducing agent such as lithium aluminum hydride from L-proline, it is reacted with di-tert-butyl dicarbonate. The said synthesis process is shown in following formula (5). [Chemical formula]

[0047] The reduction treatment can be carried out, for example, by stirring L-proline with a reducing agent such as lithium aluminum hydride, sodium borohydride, diisobutylaluminum hydride, etc. in a solvent such as methanol, ethanol, tetrahydrofuran, diethyl ether, etc. under a nitrogen atmosphere. The amount of the solvent is an amount such that the concentration of L-proline is usually 0.6 to 0.7 mol / L, and the amount of the reducing agent used is an amount that becomes 0.045 (0.040 to 0.050) mol with respect to 0.030 mol of L-proline. The reaction temperature and reaction time are usually 85 to 95 °C and 2 to 3 hours.

[0048] The reaction with di-tert-butyl dicarbonate can be carried out, for example, by stirring (2-hydroxymethyl)pyrrolidine in a solvent such as dimethylformamide or dichloromethane under basic conditions such as triethylamine or sodium hydrogen carbonate in a nitrogen atmosphere. The amount of the solvent is such that the concentration of (2-hydroxymethyl)pyrrolidine is usually 0.3 - 0.8 mol / L, and the amount of di-tert-butyl dicarbonate used is an amount that becomes 0.036 (0.036 - 0.040) mol with respect to 0.03 mol of (2-hydroxymethyl)pyrrolidine. The reaction temperature and reaction time are usually 20 - 30 °C and 18 - 24 hours.

[0049] Next, the hydroxyl group is substituted with an amino group to obtain (S)-1-tert-butoxycarbonyl-2-(aminomethyl)pyrrolidine. Examples of the method for substituting the hydroxyl group with an amino group include conventionally known methods. For example, (S)-1-tert-butoxycarbonyl-2-(hydroxymethyl)pyrrolidine and p-toluenesulfonyl chloride are reacted under basic conditions to obtain a reaction intermediate, and the obtained intermediate is reacted with sodium azide. Then, by performing reduction treatment with hydrogen, the target (S)-1-tert-butoxycarbonyl-2-(aminomethyl)pyrrolidine can be obtained. The said synthesis step is shown in the following formula (6).

Chemical formula

[0050] The reaction with p-toluenesulfonyl chloride can be carried out, for example, by stirring (S)-1-tert-butoxycarbonyl-2-(hydroxymethyl)pyrrolidine and p-toluenesulfonyl chloride in a solvent such as tetrahydrofuran or pyridine under basic conditions such as pyridine or potassium hydroxide in a nitrogen atmosphere. The amount of the solvent is such that the concentration of (S)-1-tert-butoxycarbonyl-2-(hydroxymethyl)pyrrolidine is usually 0.3 to 0.8 mol / L, and the amount of paratoluenesulfonyl chloride used is such that it is 0.018 to 0.023 mol with respect to 0.015 mol of (S)-1-tert-butoxycarbonyl-2-(hydroxymethyl)pyrrolidine. The reaction temperature and reaction time are usually 20 to 30 °C (room temperature) and 18 to 24 hours.

[0051] The reaction with sodium azide can be carried out, for example, by stirring the reaction intermediate with sodium azide in a solvent such as dimethylformamide under a nitrogen atmosphere. The amount of the solvent is such that the concentration of the reaction intermediate is usually 0.1 to 0.3 mol / L, and the amount of sodium azide used is such that it is 0.036 mol with respect to 0.012 mol of the reaction intermediate. The reaction temperature and reaction time are usually 80 °C and 15 to 18 hours.

[0052] The reduction reaction can be carried out, for example, by stirring the reaction product with sodium azide in a solvent such as methanol under a hydrogen atmosphere in the presence of palladium / carbon. The amount of the solvent is such that the concentration of the reaction product is 1.0 mol / L. The reaction temperature and reaction time are usually 20 to 30 °C and 18 to 24 hours.

[0053] (Sulfonylation reaction) The sulfonylation reaction is a reaction for sulfonylating an amino group. Examples of methods for sulfonylating an amino group include conventionally known methods. For example, it can be carried out by reacting (S)-1-tert-butoxycarbonyl-2-(aminomethyl)pyrrolidine with a sulfonyl halide under basic conditions such as pyridine. The said synthesis step is shown in the following formula (7). [Chemical formula] (In the formula, R 1is the same definition as above, and X represents a halogen atom.)

[0054] The halogen atom in the formula is the same as the aforementioned definition. The sulfonylation of the amino group can be carried out, for example, by stirring (S)-1-tert-butoxycarbonyl-2-(aminomethyl)pyrrolidine and a sulfonyl halide such as sulfonyl chloride in a solvent such as dichloromethane under basic conditions such as pyridine or triethylamine in a nitrogen atmosphere. The amount of the solvent is such that the concentration of (S)-1-tert-butoxycarbonyl-2-(aminomethyl)pyrrolidine is usually 0.2 - 0.3 mol / L, and the amount of the sulfonyl halide used is such that it is 1.2 (1.2 - 1.3) mmol with respect to 1.0 mmol of (S)-1-tert-butoxycarbonyl-2-(aminomethyl)pyrrolidine. The reaction temperature and reaction time are usually 20 - 30 °C and 18 - 24 hours, respectively.

[0055] (Reaction with arylmethyl halide) The reaction with arylmethyl halide is a reaction between an amino group and an arylmethyl halide which may have a substituent. Examples of the method for reacting an amino group with an arylmethyl halide which may have a substituent include conventionally known methods. For example, in the presence of a basic reagent such as potassium carbonate, a (S)-N-sulfonylpyrrolidine derivative is reacted with an arylmethyl halide which may have a substituent to obtain the target precursor compound. The said synthesis step is shown in the following formula (8).

Chemical formula

[0056] The halogen atom in the formula is the same as the aforementioned definition. (S)-N-Sulfonylpyrrolidine derivatives can react with arylmethyl halides which may have substituents on the amino group. For example, under a nitrogen atmosphere, in a solvent such as dimethylformamide, in the presence of a basic reagent such as potassium carbonate, the reaction can be carried out by stirring the (S)-N-sulfonylpyrrolidine derivative and an arylmethyl halide such as arylmethyl bromide. The amount of the solvent is such that the concentration of the (S)-N-sulfonylpyrrolidine derivative is usually 0.2 - 0.3 mol / L. The amount of the arylmethyl halide used is such that it is 1.2 (1.1 - 1.3) mmol with respect to 1.0 mmol of the (S)-N-sulfonylpyrrolidine derivative. The amount of the basic reagent used is such that it is 1.5 (1.4 - 1.6) mmol with respect to 1.0 mmol of the (S)-N-sulfonylpyrrolidine derivative. The reaction temperature and reaction time are usually 20 - 80 °C and 18 - 24 hours, respectively.

[0057] (Step (2)) Step (2) is a step of deprotecting the tert-butoxycarbonyl group of the precursor compound with an acid to obtain an optically active pyrrolidine derivative represented by the general formula (1) or its acidic salt. As a method for deprotecting the tert-butoxycarbonyl group of the precursor compound with an acid, conventionally known methods can be mentioned. For example, in the presence of an acidic reagent such as trifluoroacetic acid, by stirring the precursor compound in a dichloromethane solvent, the acidic salt of the target optically active pyrrolidine derivative can be obtained. The optically active pyrrolidine derivative can be synthesized by stirring the acidic salt of the optically active pyrrolidine derivative and an anion exchange resin. The synthesis process is shown in the following formula (9).

Chemical formula

[0058] The deprotection reaction of the precursor compound can be carried out, for example, by stirring in a dichloromethane solvent in the presence of an acidic reagent such as hydrochloric acid, acetic acid, trifluoroacetic acid, etc. The amount of the acidic reagent is such that the concentration of the precursor compound is usually 0.3 - 0.4 mol / L, and the amount of the solvent is such that the concentration of the precursor compound is 0.1 mol / L. The reaction temperature and reaction time are usually 20 - 30 °C and 18 - 24 hours.

[0059] [Optically active α-carboline derivative] The optically active α-carboline derivative of the present invention is represented by the following general formula (2). [Chemical formula] (In the formula, R 3 ~R 7 and n have the same definitions as above)

[0060] In general formula (2), R 3 each independently represents a halogen atom, an alkyl group having 1 - 6 carbon atoms, an alkenyl group having 2 - 8 carbon atoms, an alkynyl group having 2 - 8 carbon atoms, a cycloalkyl group having 3 - 10 carbon atoms, a cycloalkenyl group having 6 - 10 carbon atoms, a cycloalkynyl group having 6 - 10 carbon atoms, an alkoxyl group having 1 - 20 carbon atoms, a cycloalkoxyl group having 3 - 20 carbon atoms, an alkylthio group having 1 - 20 carbon atoms, a cycloalkylthio group having 3 - 20 carbon atoms, an aryl group having 6 - 20 carbon atoms which may have a substituent, an aryloxy group having 6 - 20 carbon atoms, an arylthio group having 6 - 20 carbon atoms, an arylalkyl group having 7 - 21 carbon atoms, an arylalkenyl group having 8 - 20 carbon atoms, an arylalkynyl group having 8 - 20 carbon atoms, an alkoxycarbonyl group having 1 - 20 carbon atoms, a nitro group, a nitrile group, or an acid imide group, and n represents an integer of 0 - 4.

[0061] A halogen atom, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, an alkoxyl group having 1 to 20 carbon atoms, a cycloalkoxyl group having 3 to 20 carbon atoms, an alkylthio group having 1 to 20 carbon atoms, a cycloalkylthio group having 3 to 20 carbon atoms, an aryl group having 6 to 20 carbon atoms which may have a substituent, an aryloxy group having 6 to 20 carbon atoms, an arylthio group having 6 to 20 carbon atoms, an arylalkyl group having 7 to 21 carbon atoms, an arylalkenyl group having 8 to 20 carbon atoms, an arylalkynyl group having 8 to 20 carbon atoms, an alkoxycarbonyl group having 1 to 20 carbon atoms, and an acid imide group are the same as those defined above.

[0062] The alkyl group may be linear or branched. Examples of the alkyl group having 1 to 6 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, a 2,2-dimethylpropyl group, an n-hexyl group, and a 2-methylpentyl group.

[0063] Examples of the cycloalkyl group having 3 to 10 carbon atoms include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.

[0064] Examples of the cycloalkenyl group having 6 to 10 carbon atoms include a cyclohexenyl group, a cycloheptenyl group, and a cyclooctenyl group. Examples of the cycloalkynyl group having 6 to 10 carbon atoms include a cyclohexynyl group, a cycloheptynyl group, and a cyclooctynyl group.

[0065] R 3 The group represented by is preferably a halogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkoxyl group having 1 to 20 carbon atoms, more preferably a bromine atom, a methyl group, or a methoxy group. n represents an integer of 0 to 4, and 0 or 1 is preferred.

[0066] In the general formula (2), R 4represents a sulfonyl protecting group. Examples of the sulfonyl protecting group include a metal sulfonyl group, a p-toluenesulfonyl group, an o-nitrobenzenesulfonyl group, and a trifluoromethanesulfonyl group. R 4 The group represented as is preferably a p-toluenesulfonyl group.

[0067] In General Formula (2), R 5 represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, a cycloalkenyl group having 6 to 10 carbon atoms, a cycloalkynyl group having 6 to 10 carbon atoms, an aryl group having 6 to 20 carbon atoms which may have a substituent, an arylalkyl group having 7 to 21 carbon atoms, an arylalkenyl group having 8 to 20 carbon atoms, an arylalkynyl group having 8 to 20 carbon atoms, an alkoxycarbonyl group having 1 to 20 carbon atoms, or a heteroaryl group.

[0068] The alkyl group having 1 to 6 carbon atoms, the alkenyl group having 2 to 8 carbon atoms, the alkynyl group having 2 to 8 carbon atoms, the cycloalkyl group having 3 to 10 carbon atoms, the cycloalkenyl group having 6 to 10 carbon atoms, the cycloalkynyl group having 6 to 10 carbon atoms, the aryl group having 6 to 20 carbon atoms which may have a substituent, the arylalkyl group having 7 to 21 carbon atoms, the arylalkenyl group having 8 to 20 carbon atoms, the arylalkynyl group having 8 to 20 carbon atoms, and the alkoxycarbonyl group having 1 to 20 carbon atoms are the same as the above-mentioned definitions.

[0069] The heteroaryl group is a group in which a carbon atom constituting the ring of the aryl group is substituted with a hetero atom or a carbonyl group. Examples of the heteroaryl group include groups represented by General Formulas (ha1) to (ha5).

[0070] [Chemical formula] (In the formula, R represents a fluorine atom, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkylthio group, a cycloalkylthio group, an aryl group, an aryloxy group, an arylthio group, an arylalkyl group, an arylcycloalkyl group, an arylalkenyl group, an arylalkynyl group, an acyl group, an acid imide group, an alkoxycarbonyl group, a cycloalkoxycarbonyl group, an aryloxycarbonyl group, a carboxy group, a nitrile group, or a nitro group. p represents an integer from 0 to 4. Y represents a sulfur atom, an oxygen atom, or a group represented by -NR Y -. R Y represents a hydrogen atom, an alkyl group which may have a substituent, or an aryl group which may have a substituent. Also, ring A represents a heterocyclic ring or an aromatic ring.

[0071] Examples of the groups represented by the general formulas (ha1) to (ha4) include groups represented by the following general formulas (ha1-1) to (ha4-9).

Chemical formula

[0072]

Chemical formula

[0073] R 5The group represented as [group] is preferably an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, an aryl group having 6 to 20 carbon atoms which may have a substituent, a heteroaryl group, an arylalkenyl group having 8 to 20 carbon atoms, an arylalkynyl group having 8 to 20 carbon atoms, or an alkoxycarbonyl group having 1 to 20 carbon atoms, more preferably an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 20 carbon atoms which may have a substituent, or a heteroaryl group, and even more preferably an ethyl group, a phenyl group, a p-methylphenyl group, a p-fluorophenyl group, a p-chlorophenyl group, a p-bromophenyl group, a p-methoxyphenyl group, a p-trifluoromethylphenyl group, a p-nitrophenyl group, an m-methylphenyl group, an o-methylphenyl group, a p,m-dichlorophenyl group, an m,m-difluorophenyl group, a 2-naphthyl group, or a 3-thienyl group.

[0074] In general formula (2), R 6 represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, an alkoxyalkyl group having 2 to 20 carbon atoms, an alkoxyarylalkyl group having 8 to 20 carbon atoms, an arylalkyl group having 7 to 21 carbon atoms, a benzyloxyalkyl group, or an aryl group having 6 to 20 carbon atoms which may have a substituent.

[0075] The alkyl group having 1 to 6 carbon atoms, the alkenyl group having 2 to 8 carbon atoms, the alkynyl group having 2 to 8 carbon atoms, the alkoxyalkyl group having 2 to 20 carbon atoms, the arylalkyl group having 7 to 21 carbon atoms, the benzyloxyalkyl group, or the aryl group having 6 to 20 carbon atoms which may have a substituent is the same as the aforementioned definition.

[0076] Examples of the alkoxyarylalkyl group having 8 to 20 carbon atoms include a methoxyphenylmethyl group.

[0077] R 6The group represented as [group] is preferably an alkyl group having 1 to 6 carbon atoms, an arylalkyl group having 7 to 21 carbon atoms, an alkoxyarylalkyl group having 8 to 20 carbon atoms, or a benzyloxyalkyl group, more preferably an alkyl group having 1 to 3 carbon atoms, and even more preferably a methyl group or an ethyl group.

[0078] In the general formula (2), R 7 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, an alkoxyalkyl group having 2 to 20 carbon atoms, an alkoxyarylalkyl group having 8 to 20 carbon atoms, an arylalkyl group having 7 to 21 carbon atoms, a benzyloxyalkyl group, or an aryl group having 6 to 20 carbon atoms which may have a substituent.

[0079] The alkyl group having 1 to 6 carbon atoms, the alkenyl group having 2 to 8 carbon atoms, the alkynyl group having 2 to 8 carbon atoms, the alkoxyalkyl group having 2 to 20 carbon atoms, the alkoxyarylalkyl group having 8 to 20 carbon atoms, the arylalkyl group having 7 to 21 carbon atoms, the benzyloxyalkyl group, or the aryl group having 6 to 20 carbon atoms which may have a substituent is the same as the above definition.

[0080] R 7 The group represented as [group] is preferably a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and more preferably a hydrogen atom.

[0081] As the optically active α-carboline derivative represented by the above general formula (2), those represented by the following general formula (2-1) are preferred, and those represented by the following general formulas (2-1-1) to (2-1-20) are more preferred.

Chemical formula

[0082]

Chemical formula

[0083] [Chemical formula]

[0084] [Method for producing optically active α-carboline derivative] The method for producing an optically active α-carboline derivative of the present invention includes a step of reacting an indole derivative represented by the following general formula (3) with an aldehyde compound or acetaldehyde represented by the following general formula (4) in the presence of the above-mentioned optically active pyrrolidine derivative or its acidic salt. [Chemical formula] (In the formula, R 3 ~R 5 and n have the same definitions as above) [Chemical formula] (In the formula, R 6 and R 7 have the same definitions as above)

[0085] The indole derivative represented by the general formula (3) can be synthesized by the method described in Katsuhiko Moriyama et al., Chem. Commun. 2015, 51, pp.2273-2276. Examples of the indole derivative represented by the general formula (3) include compounds represented by the following formulas (3-1) to (3-27). [Chemical formula]

[0086] [Chemical formula]

[0087] Examples of the indole derivative represented by the general formula (3) include compounds represented by the above formulas (3-1) to (3-19) are preferred.

[0088] As the aldehyde compound or acetaldehyde represented by the general formula (4), commercially available products can be used. Examples of the aldehyde compound represented by the general formula (4) include compounds represented by the following formulas (4-1) to (4-9).

Chemical formula

[0089] As the aldehyde compound represented by the general formula (4), compounds represented by the above formulas (4-1) to (4-2) are preferred.

[0090] As the optically active pyrrolidine derivative or its acidic salt, compounds represented by the above formulas (1-1) to (1-7) are preferred, and the compound represented by the formula (1-7) is more preferred.

[0091] As the reaction solvent, tetrahydrofuran, methylene chloride, chloroform, toluene, tert-butyl methyl ether, diethyl ether, etc. can be used. As the solvent, tert-butyl methyl ether is preferred. The amount of the solvent is such that the concentration of the indole derivative is usually 0.05 to 0.5 mol / L, preferably 0.1 to 0.3 mol / L, and more preferably 0.2 to 0.25 mol / L.

[0092] The amount of the aldehyde compound or acetaldehyde used is usually 1 to 20 mol, preferably 3 to 15 mol, and more preferably 5 to 10 mol, per 1 mol of the indole derivative. The amount of the optically active pyrrolidine derivative or its acidic salt used is usually 1 to 20 mol%, preferably 3 to 15 mol%, and more preferably 5 to 10 mol%, per 1 mol of the indole derivative.

[0093] The reaction temperature is usually 10 to 60 °C, preferably 15 to 40 °C, and more preferably 20 to 30 °C. The reaction time is usually 12 to 336 hours, preferably 24 to 266 hours, and more preferably 48 to 196 hours.

[0094] As long as the progress of the reaction is not inhibited, an additive may be added to the reaction system. Examples of the additive include N,N-dimethylaniline. The reaction is usually carried out under an inert atmosphere such as argon.

Examples

[0095] Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

[0096] 1 1H NMR and 13 13C NMR] were measured using JNM-ECS (400 MHz) manufactured by JEOL Ltd. Unless otherwise specified, CDCl3 was used as the deuterated solvent and tetramethylsilane was used as the internal standard substance.

[0097] [Diastereoselectivity]: 1 The diastereoselectivity was calculated by 1H NMR. The diastereoselectivity (dr) means (trans / cis).

[0098] [Enantiomeric excess (%ee)]: Analysis was performed under the following conditions using high performance liquid chromatography. Column: AS-H, AD-H (4.6 mm × 250 mm, particle size 5 μm) Column temperature: 25 °C Mobile phase: hexane:isopropanol = 90:10, 75:25, hexane:ethanol = 90:10 Flow rate: 0.6 to 1.0 mL / min

[0099] [Mass spectrometry] was measured using a bench top LC-mass spectrometer manufactured by Thermo Fisher Scientific.

[0100] (Example 1-1) ​To a 200 mL eggplant flask were added lithium aluminum hydride (2.85 g, 75 mmol) and tetrahydrofuran (75 mL), and the mixture was cooled to 0 °C. To this was slowly added L-proline (5.76 g, 50 mmol). After stirring at 0 °C for 5 minutes, the mixture was stirred under heating reflux conditions. After 2 hours, it was cooled to room temperature, 20% potassium hydroxide (7 mL) was added, and the residue was filtered. The filtrate was stirred under heating reflux conditions for 45 minutes and then dried over sodium sulfate to obtain L-prolinol (4.95 g, 98%).

[0101] To a 100 mL eggplant flask were added L-prolinol (4.95 g, 49 mmol) and dichloromethane (61 mL), and the mixture was cooled to 0 °C. To this was slowly added di-tert-butyl dicarbonate (12.8 g, 59 mmol) dissolved in dichloromethane (24 mL), and after adding triethylamine (6.1 mL), the temperature was raised to room temperature and the mixture was stirred. After 16 hours, 1 N hydrochloric acid was added, and the organic phase was washed with saturated aqueous sodium chloride solution and 1 N aqueous sodium hydroxide solution, and then liquid-liquid extraction was performed using chloroform (15 mL × 3). The residue was purified by column chromatography (hexane:ethyl acetate = 2:1) to obtain (S)-1-tert-butoxycarbonyl-2-(hydroxymethyl)pyrrolidine (9.80 g, >99%).

[0102] (S)-1-tert-Butoxycarbonyl-2-(hydroxymethyl)pyrrolidine (3.02 g, 15 mmol) and pyridine (9.4 mL) were added to a 100 mL eggplant flask, cooled to 0 °C, and p-toluenesulfonyl chloride (3.23 g, 17 mmol) dissolved in pyridine (9.4 mL) was slowly added dropwise thereto. After stirring at 0 °C for 2 hours, the temperature was raised to room temperature. After 22 hours, the solvent was removed, and liquid separation extraction was performed using ethyl acetate (15 mL × 3). The organic phase was washed with hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and water, and dried over sodium sulfate. The residue was purified by column chromatography (hexane:ethyl acetate = 3:1) to obtain (S)-1-tert-butoxycarbonyl-2-(hydroxymethyl)pyrrolidine (4.33 g, 81%). (S)-1-tert-Butoxycarbonyl-2-(hydroxymethyl)pyrrolidine (2.92 g, 8.2 mmol) and dimethylformamide (59 mL) were added to a 200 mL eggplant flask, sodium azide (1.60 g, 24.7 mmol) was added thereto, and the mixture was stirred at 80 °C. After 16 hours, water (15 mL) was added, and liquid separation extraction was performed with ethyl acetate (15 mL × 3) and dried over sodium sulfate. The residue was purified by column chromatography (hexane:ethyl acetate = 20:1) to obtain the reaction intermediate (1.45 g, 78%). This reaction intermediate (1.45 g, 6.4 mmol) and methanol (6.4 mL) were added to a 30 mL eggplant flask, palladium-carbon (145.2 mg, 10 mol% w / w) was added thereto, and the mixture was stirred at room temperature under a hydrogen atmosphere. After 15 hours, the residue was filtered to obtain (S)-1-tert-butoxycarbonyl-2-(aminomethyl)pyrrolidine (1.26 g, 98%).

[0103] To a 100 mL eggplant flask were added (S)-1-tert-butoxycarbonyl-2-(aminomethyl)pyrrolidine (432.5 mg, 2.2 mmol), triethylamine (452.6 μL, 3.2 mmol) and dichloromethane (25 mL). The mixture was stirred at 0 °C, and p-toluenesulfonyl chloride (493.9 mg, 2.6 mmol) was added thereto. After that, the temperature was raised to room temperature and the mixture was stirred. After 20 hours, saturated aqueous ammonium chloride solution (5 mL) was added, and liquid separation extraction was carried out with chloroform (15 mL × 3). The organic phase was washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. The residue was purified by column chromatography (hexane:ethyl acetate = 5:1) to obtain a sulfonyl derivative (683.6 mg, 89%).

[0104] To a 30 mL eggplant flask containing potassium carbonate (165.9 mg, 1.2 mmol), the sulfonyl derivative (283.6 mg, 0.80 mmol) was dissolved in dimethylformamide (4.0 mL) dropwise, and benzyl bromide (114.2 μL, 0.96 mmol) was added dropwise. After that, the mixture was stirred at 80 °C. After 15 hours, water (5 mL) was added, and liquid separation extraction was carried out with ethyl acetate (15 mL × 3). The organic phase was washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. The residue was purified by column chromatography (hexane:ethyl acetate = 5:1) to obtain a final product precursor. (353.9 mg, >99%).

[0105] To a 30 mL eggplant flask containing the final product precursor (353.9 mg, 0.80 mmol) and dichloromethane (8.0 mL), trifluoroacetic acid (2.3 mL) was added and the mixture was stirred at room temperature. After 12 hours, dichloromethane was removed, and diethyl ether was added to the obtained residue to precipitate a solid, thereby obtaining a compound represented by the following formula (1-1) (yield 363.1 mg, yield 88% (3 steps)).

[0106]

Chemical formula

[0107] (Example 1-2) Except that the amount of substance of (S)-1-tert-butoxycarbonyl-2-(aminomethyl)pyrrolidine in (Example 1-1) was changed to 1.0 mmol and paratoluenesulfonyl chloride was changed to 4-(methoxy)benzenesulfonyl chloride, a compound represented by the following formula (1-2) was obtained in the same manner as in (Example 1-1) (yield 433.3 mg, yield 91% (3 steps)).

[0108]

Chemical formula

[0109] (Example 1-3) Except that the amount of substance of (S)-1-tert-butoxycarbonyl-2-(aminomethyl)pyrrolidine in (Example 1-1) was changed to 1.0 mmol and paratoluenesulfonyl chloride was changed to 4-(trifluoromethyl)benzenesulfonyl chloride, a compound represented by the following formula (1-3) was obtained in the same manner as in (Example 1-1) (yield 341.4 mg, yield 67% (3 steps)).

[0110]

Chemical formula

[0111] (Example 1-4) Except that the amount of substance of (S)-1-tert-butoxycarbonyl-2-(aminomethyl)pyrrolidine in (Example 1-1) was changed to 5.0 mmol, the amount of substance of the sulfonyl derivative was changed to 1.0 mmol, and the reaction temperature was changed to room temperature, and paratoluenesulfonyl chloride was changed to pentafluorobenzenesulfonyl chloride, a compound represented by the following formula (1-4) was obtained in the same manner as in (Example 1-1) (yield 273.3 mg, yield 59% (3 steps)).

[0112]

Chemical formula

[0113] (Example 1-5) Benzyl bromide was changed to 2,6-dimethylbenzyl bromide, the amount of substance of (S)-1-tert-butoxycarbonyl-2-(aminomethyl)pyrrolidine in (Example 1-1) was changed to 2.2 mmol, and the amount of substance of the sulfonyl derivative was changed to 0.80 mmol. Otherwise, the same procedure as in (Example 1-1) was followed to obtain the compound represented by the following formula (1-5) (yield 328.2 mg, yield 75% (3 steps)).

[0114] [Chemical formula]

[0115] (Example 1-6) p-Toluenesulfonyl chloride was changed to pentafluorobenzenesulfonyl chloride, benzyl bromide was changed to 2,6-dimethylbenzyl bromide, the amount of substance of (S)-1-tert-butoxycarbonyl-2-(aminomethyl)pyrrolidine in (Example 1-1) was changed to 3.4 mmol, and the amount of substance of the sulfonyl derivative was changed to 0.92 mmol. Otherwise, the same procedure as in (Example 1-1) was followed to obtain the compound represented by the following formula (1-6) (yield 148.8 mg, yield 15% (3 steps)).

[0116] [Chemical formula]

[0117] (Example 1-7) p-Toluenesulfonyl chloride was changed to pentafluorobenzenesulfonyl chloride, benzyl bromide was changed to 3,5-dinitrobenzyl bromide, the amount of substance of (S)-1-tert-butoxycarbonyl-2-(aminomethyl)pyrrolidine in (Example 1-1) was changed to 5.0 mmol, and the amount of substance of the sulfonyl derivative was changed to 0.98 mmol. The reaction temperature was changed to room temperature. Otherwise, the same procedure as in (Example 1-1) was followed to obtain the compound represented by the following formula (1-7) (yield 419.9 mg, yield 55% (3 steps)).

[0118] [Chemical formula]

[0119] The various physical property values of the compound represented by the formula (1-7) are shown below. 1 H NMR (DMSO-d6): δ: 9.29 - 9.12 (brs, 1H), 8.80 (t, J = 2.0Hz, 1H), 8.65 - 8.49 (brds, 1H), 8.58 (d, J = 2.0Hz, 2H), 4.83 (s, 2H), 3.70 (d, J = 7.2Hz, 2H), 3.53 - 3.35 (m, 1H), 3.26 - 3.14 (m, 1H), 3.14 - 2.97 (m, 1H), 1.96 - 1.68 (m, 3H), 1.64 - 1.47 (m, 1H). 13 C NMR (DMSO-d6): δ: 158.7, 148.3 (2C), 144.4 (2C), 143.9, 140.4, 137.9 (2C), 128.7 (2C), 128.5, 118.3, 114.2, 57.4, 51.3, 50.0, 45.1, 27.8, 22.5. MS (ESI) m / z: calcd for C18H16F5N4O6S [M + H - TFA]+ 511.0705, found 511.0699.

[0120] (Example 2-1) Under an Ar atmosphere, 1.0 ml of tert-butyldimethyl ether was added to 11.5 mg (0.025 mmol) of the compound represented by the above formula (1-1). To this, 93.615 mg (0.25 mmol) of the compound represented by the following formula (3-1) and 179.3 μL (2.5 mmol) of propionaldehyde were added. This was stirred at room temperature for 48 hours, saturated aqueous sodium hydrogen carbonate solution (5 mL) was added, and liquid separation extraction was carried out with ethyl acetate (15 mL × 3), washed with saturated aqueous sodium chloride solution, and dried over sodium sulfate. The residue was purified by column chromatography (hexane:diethyl ether = 3:1) to obtain the compound represented by the following formula (2-1-1) (yield 86.5 mg, yield 80%).

[0121] [Chemical formula]

[0122] The various physical property values of the compound represented by formula (2-1-1) are shown below. Major diastereomer 1 H NMR (CDCl3): δ : 8.98 (s, 1H), 7.64 - 7.56 (m, 2H), 7.32 (d, J = 8.4Hz, 1H), 7.28 (d, J = 8.4Hz, 2H), 7.22 - 7.12 (m, 3H), 7.10 - 7.04 (m, 1H), 6.92 - 6.71 (m, 3H), 6.48 (d, 7.6Hz, 1H), 5.57 (t, J = 3.0Hz, 1H), 3.71 (d, J = 11.2Hz, 1H), 2.81 - 2.70 (m, 1H), 2.41 (s, 3H), 1.24 - 1.13(m, 1H), 0.89 (d, J = 7.8Hz, 3H). 13 C NMR (CDCl3): δ : 144.8, 142.5, 134.4, 133.7, 130.1 (2C), 128.6 (3C), 128.2 (2C), 126.8 (2C), 126.6, 125.6, 121.4, 119.6, 119.1, 110.7, 102.9, 83.9, 41.2, 40.2, 21.6, 14.8. MS (ESI) m / z: calcd for C25H25N2O3S [M+H] + 433.1580, found 433.1577. dr = 94:6, 63% ee.

[0123] (Examples 2-2 to 2-7) A compound represented by formula (2-1-1) was obtained in the same manner as in Example 2-1 except that the conditions shown in Table 1 were changed. The yield, diastereoselectivity, and enantioselectivity of the compound represented by formula (2-1-1) are shown in Table 1.

[0124]

Table 1

[0125] (Comparative Example) Instead of the compound represented by the above formula (1-1), the compound represented by the following formula (1’) was used, but the reaction did not proceed.

[0126]

Chemical Formula

[0127] (Example 3-1) Under an Ar atmosphere, 1.0 mL of tert-butyldimethyl ether was added to 15.6 mg (0.025 mmol) of the compound represented by the above formula (1-7). To this, 97.1 mg (0.25 mmol) of the compound represented by the following formula (3-2) and 179.3 μL (2.5 mmol) of propionaldehyde were added. This was stirred at room temperature for 48 hours, saturated aqueous sodium hydrogen carbonate solution (5 mL) was added, and liquid separation extraction was performed with ethyl acetate (15 mL × 3), washed with saturated aqueous sodium chloride solution, and dried over sodium sulfate. The residue was purified by column chromatography (hexane:diethyl ether = 3:1) to obtain the compound represented by the following formula (2-1-2) (yield 101.8 mg, yield 91%).

[0128]

Chemical Formula

[0129] The various physical property values of the compound represented by formula (2-1-2) are shown below. Major diastereomer 11H NMR (CDCl3): δ : 8.97 (s, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.4 Hz, 2H), 7.11 - 7.01 (m, 1H), 6.97 (d, J = 8.0 Hz, 2H), 6.84 - 6.75 (m, 1H), 6.74 - 6.63 (m, 2H), 6.52 (d, J = 8.0 Hz, 1H), 5.56 (m, 1H), 3.67 (d, J = 10.8 Hz, 1H), 2.91 - 2.75 (m, 1H), 2.41 (s, 3H), 2.30 (s, 3H), 1.24 - 1.09 (m, 1H), 0.88 (d, J = 7.2 Hz, 3H). 13 13C NMR (CDCl3): δ : 144.8, 139.3, 136.0, 134.4, 133.8, 130.1 (2C), 128.9 (2C), 128.6, 128.4 (2C), 126.8 (2C), 125.7, 121.3, 119.5, 119.2, 110.6, 103.1, 84.0, 40.8, 40.2, 21.6, 21.1, 14.8. MS (ESI) m / z: calcd for C26H27N2O3S [M + H]+ 447.1737, found 447.1737. dr = 92:8, 94% ee.

[0130] (Example 3 - 2) A compound represented by the following formula (2 - 1 - 3) was obtained (yield 111.4 mg, yield 99%) in the same manner as in Example (3 - 1), except that 97.1 mg (0.25 mmol) of the compound represented by the following formula (3 - 3) was used instead of the compound represented by formula (3 - 2).

[0131] [Chemical formula]

[0132] The various physical property values of the compound represented by formula (2-1-3) are shown below. Major diastereomer 1 H NMR (CDCl3): δ : 9.00 (s, 1H), 7.59 (d, J = 8.2Hz, 2H), 7.33 (d, J = 8.4Hz, 1H), 7.28(d, J = 8.2Hz, 2H), 7.12-7.04 (m, 1H), 6.92-6.70 (m, 5H), 6.48 (d, J = 8.0Hz, 1H), 5.64-5.52 (m, 1H), 3.71 (d, J = 11.2Hz, 1H), 3.04-2.84 (m, 1H), 2.41 (s, 3H), 1.18-1.06 (m, 1H), 0.88 (d, J = 6.8Hz, 3H). 13 C NMR (CDCl3): δ : 161.6 (d, JC-F = 245.3Hz), 144.8, 138.2 (d, JC-F = 3.0Hz, 2C), 134.4, 133.8, 130.0 (2C), 129.9 (d, JC-F = 10.0Hz, 2C), 128.7, 126.8 (2C), 125.5, 121.4, 119.6, 119.0,115.0 (d, JC-F = 20.0Hz), 110.8, 102.7, 83.9, 40.5, 40.3, 21.6, 14.7. MS (ESI) m / z: calcd for C25H24FN2O3S [M+H] + 451.1486, found 451.1485. dr=90:10, 92%ee.

[0133] (Example 3-3) A compound represented by the following formula (2-1-4) was obtained (yield 109.5 mg, yield 94%) in the same manner as in Example (3-1), except that 102.2 mg (0.25 mmol) of a compound represented by the following formula (3-4) was used instead of the compound represented by formula (3-2).

[0134]

Chemical formula

[0135] The various physical property values of the compound represented by the formula (2-1-4) are shown below. Major diastereomer 1 H NMR (CDCl3): δ : 9.00 (s, 1H), 7.59 (d, J = 8.4Hz, 2H), 7.33 (d, J = 8.0Hz, 1H), 7.28 (d, J = 8.4Hz, 2H), 7.13 (d, J = 8.8Hz, 2H), 7.12 - 7.05 (m, 1H), 6.83 (t, J = 8.0Hz, 1H), 6.79 - 6.71 (m, 2H), 6.49 (d, J = 8.0Hz, 1H), 5.62 - 5.52 (m, 1H), 3.70 (d, J = 10.4Hz, 1H), 2.91 (brs, 1H), 2.41 (s, 3H), 1.17 - 1.05 (m, 1H), 0.88 (d, J = 6.8Hz, 3H). 13 C NMR (CDCl3): δ : 144.9, 141.1, 134.4, 133.7, 132.2, 130.1 (2C), 129.8 (2C), 128.8, 128.4 (2C), 126.8 (2C), 125.4, 121.5, 119.7, 119.0, 110.8, 102.3, 83.8, 40.7, 40.2, 21.6, 14.7. MS (ESI) m / z: calcd for C25H24ClN2O3S [M+H] + 467.1191, found 467.1188. dr = 94:6, 95% ee.

[0136] (Example 3-4) A compound represented by the following formula (2-1-5) was obtained (yield 117.6 mg, yield 92%) in the same manner as in Example (3-1), except that 113.3 mg (0.25 mmol) of the compound represented by the following formula (3-5) was used instead of the compound represented by the formula (3-2).

[0137]

Chem.

[0138] The various physical property values of the compound represented by formula (2-1-5) are shown below. Major diastereomer 1 H NMR (CDCl3): δ : 9.05 (s, 1H), 7.56 (d, J = 8.4Hz, 2H), 7.31 (d, J = 8.8Hz, 1H), 7.28 - 7.20 (m, 4H), 7.12 - 7.02 (m, 1H), 6.82 (t, J = 7.6Hz, 1H), 6.74 - 6.58 (m, 2H), 6.49 (d, J = 7.6Hz, 1H), 5.55 (d, J = 1.2Hz, 1H), 3.66 (d, J = 10.8Hz, 1H), 3.62 - 3.32 (brs, 1H), 2.38 (s, 3H), 1.11 - 0.98 (m, 1H), 0.85 (d, J = 3.6Hz, 3H). 13 C NMR (CDCl3): δ : 144.8, 141.7, 134.3, 133.8, 131.3 (2C), 130.2 (2C), 130.0 (2C), 128.8, 126.8 (2C), 125.4, 121.4, 120.2, 119.7, 118.9, 110.8, 102.3, 83.8, 40.8, 40.1, 21.6, 14.7. MS (ESI) m / z: calcd for C25H24BrN2O3S [M+H] + 511.0686, found 511.0682. dr = 94:6, 95% ee.

[0139] (Example 3 - 5) A compound represented by the following formula (2-1-6) was obtained (yield 104.0 mg, yield 90%) in the same manner as in Example (3-1), except that 101.1 mg (0.25 mmol) of the compound represented by the following formula (3-6) was used instead of the compound represented by formula (3-2).

[0140]

Chemical formula

[0141] The various physical property values of the compound represented by formula (2-1-6) are shown below. Major diastereomer 1 H NMR (CDCl3): δ :8.99 (s, 1H), 7.61-7.55 (m, 2H), 7.31 (d, J = 8.0Hz, 1H), 7.26 (d, J = 8.4Hz, 2H), 7.11-7.01 (m, 1H), 6.84-6.77 (m, 1H), 6.76-6.65 (m, 4H), 6.53 (d, J = 8.0Hz, 1H), 5.56 (d, J = 2.4Hz, 1H), 3.77 (s, 3H), 3.65 (d, J = 11.2Hz, 1H), 3.18-2.98 (brs, 1H), 2.39 (s, 3H), 1.18-1.06 (m, 1H), 0.87 (d, J = 6.8Hz, 3H). 13 C NMR (CDCl3): δ :158.2, 144.7, 134.5, 134.4, 133.8, 130.0 (2C), 129.4 (2C) 128.6, 126.8 (2C), 125.7, 121.3, 119.6, 119.2, 113.5 (2C), 110.7, 103.1, 84.0, 55.1, 40.4, 40.3, 21.6, 14.8. MS (ESI) m / z: calcd for C26H27N2O4S [M+H] + 463.1686, found 463.1680. dr=93:7, 92%ee.

[0142] (Example 3-6) A compound represented by the following formula (2-1-7) was obtained (yield 109.1 mg, yield 87%) in the same manner as in Example (3-1), except that 110.6 mg (0.25 mmol) of the compound represented by the following formula (3-7) was used instead of the compound represented by formula (3-2).

[0143] [Chemical formula]

[0144] The various physical property values of the compound represented by formula (2-1-7) are shown below. Major diastereomer 1 H NMR (CDCl3): δ : 9.07 (s, 1H), 7.59 (d, J = 8.4Hz, 2H), 7.41 (d, J = 8.4Hz, 2H), 7.33 (d, J = 8.4Hz, 1H), 7.27 (d, J = 8.4Hz, 2H), 7.15-7.02 (m, 1H), 6.97-6.86 (m, 2H), 6.86-6.77 (m, 1H), 6.44 (d, J = 8.0Hz, 1H), 5.59 (d, J = 1.6Hz, 1H), 3.79 (d, J = 11.2Hz, 1H), 3.43-3.28 (brs, 1H), 2.41 (s, 3H), 1.19-1.06 (m, 1H), 0.88 (d, J = 6.8Hz, 3H). 13 C NMR (CDCl3): δ :147.0, 145.0, 134.4, 133.8, 130.1 (2C), 128.90 (q, JC-F = 32.4Hz), 128.88, 128.86 (2C), 126.8 (2C), 125.3, 125.2 (q, JC-F = 3.8Hz, 2C), 124.1 (q, JC-F = 276.3Hz), 121.5, 119.8, 118.8, 110.9, 102.0, 83.7, 41.2, 40.2, 21.6, 14.7. MS (ESI) m / z: calculated for C26H24F3N2O3S [M+H] + 501.1454, found 501.1450。 dr = 90:10, 96% ee。

[0145] (Example 3-7) A compound represented by the following formula (2-1-8) was obtained (yield 81.2 mg, yield 68%) in the same manner as in Example (3-1), except that 104.9 mg (0.25 mmol) of a compound represented by the following formula (3-8) was used instead of the compound represented by formula (3-2).

[0146]

Chemical formula

[0147] The various physical property values of the compound represented by formula (2-1-8) are shown below. Major diastereomer 1 H NMR (CDCl3): δ : 9.16 - 9.05 (m, 1H), 8.01 (d, J = 8.8Hz, 2H), 7.59 (d, J = 8.8Hz, 2H), 7.34 (d, J = 8.0Hz, 1H), 7.28 (d, J = 8.0Hz, 2H), 7.13 - 7.04 (m, 1H), 7.03 - 6.87 (m, 2H), 6.86 - 6.77 (m, 1H), 6.40 (d, J = 8.0Hz, 1H), 5.59 (d, J = 2.0Hz, 1H), 3.84 (d, J = 10.8Hz, 1H), 3.66 - 3.25 (m, 1H), 2.41 (s, 3H), 1.17 - 1.04 (m, 1H), 0.88 (d, J = 6.8Hz, 3H). 1313C NMR (CDCl3): δ : 150.9, 146.8, 145.1, 134.3, 133.8, 130.1 (2C), 129.3 (2C), 129.0, 126.8 (2C), 125.1, 125.3 (2C), 121.7, 119.9, 118.5, 110.0, 101.3, 83.6, 41.4, 40.2, 21.6, 14.7。 MS (ESI) m / z: calcd for C25H24N3O5S [M+H] + 478.1431, found 478.1425。 dr = 89:11, 95% ee。

[0148] (Example 3-8) A compound represented by the following formula (2-1-9) was obtained (yield 104.3 mg, yield 93%) in the same manner as in Example (3-1), except that the reaction time was 72 hours and 97.1 mg (0.25 mmol) of a compound represented by the following formula (3-9) was used instead of the compound represented by formula (3-2).

[0149]

Chemical formula

[0150] The various physical property values of the compound represented by formula (2-1-9) are shown below. Major diastereomer 11H NMR (CDCl3): δ: 8.99 (s, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 8.4 Hz, 2H), 7.10 - 7.01 (m, 2H), 6.98 (d, J = 8.0 Hz, 1H), 6.80 (t, J = 7.6 Hz, 1H), 6.72 - 6.59 (m, 1H), 6.54 (d, J = 8.0 Hz, 2H), 5.56 (m, 1H), 3.65 (d, J = 10.8 Hz, 1H), 3.33 - 2.99 (brs, 1H), 2.39 (s, 3H), 2.19 (s, 3H), 1.21 - 1.06 (m, 1H), 0.86 (d, J = 6.8 Hz, 3H). 13 13C NMR (CDCl3): δ: 144.7, 142.4, 137.6, 134.4, 133.8, 130.1 (2C), 129.0, 128.5, 127.9, 127.3, 126.8 (2C), 125.9, 125.7, 121.3, 119.5, 119.2, 110.6, 103.3, 84.0, 41.2, 40.1, 21.6, 21.4, 14.9. MS (ESI) m / z: calcd for C26H27N2O3S [M + H]+ 447.1737, found 447.1739. dr = 94:6, 93% ee.

[0151] (Example 3 - 9) A compound represented by the following formula (2 - 1 - 10) was obtained (yield 92.6 mg, yield rate 83%) in the same manner as in Example (3 - 1), except that the reaction time was 120 hours and 97.1 mg (0.25 mmol) of a compound represented by the following formula (3 - 10) was used instead of the compound represented by formula (3 - 2).

[0152] [Chemical formula]

[0153] The various physical property values of the compound represented by the formula (2-1-10) are shown below. Major diastereomer 1 H NMR (CDCl3): δ : 9.00 (s, 1H), 7.60 (d, J = 8.2Hz, 2H), 7.30 (d, J = 8.0Hz, 1H), 7.26 (d, J = 8.0Hz, 2H), 7.19-7.09 (m, 1H), 7.09-6.97 (m, 2H), 6.92-6.65 (m, 2H), 6.40 (d, J = 8.0Hz, 1H), 6.30-5.90 (m, 1H), 5.60 (m, 1H), 4.10 (d, J = 10.4Hz, 1H), 3.38-3.14 (brs, 1H), 2.62-2.30 (m, 3H), 2.39 (s, 3H), 1.37-1.14 (m, 1H), 0.88 (d, J = 6.6Hz, 3H). 13 C NMR (CDCl3): δ : 144.8, 141.0, 136.6, 134.5, 133.7, 130.1 (2C), 129.9, 128.4, 127.1, 126.8 (2C), 126.1 (2C), 125.6, 121.3, 119.7, 118.7, 110.7, 103.8, 84.0, 41.4, 35.2, 21.6, 20.3, 14.5. MS (ESI) m / z: calcd for C26H27N2O3S [M+H] + 447.1737, found 447.1735. dr = 93:7, 94% ee.

[0154] (Example 3-10) A compound represented by the following formula (2-1-11) was obtained (yield 119.7 mg, yield 96%) in the same manner as in Example (3-1), except that the reaction time was 54 hours and 110.8 mg (0.25 mmol) of the compound represented by the following formula (3-11) was used instead of the compound represented by the formula (3-2).

[0155] [Chemical]

[0156] The various physical property values of the compound represented by formula (2-1-11) are shown below. Major diastereomer 1 H NMR (CDCl3): δ : 8.99 (s, 1H), 7.56 (d, J = 8.0Hz, 2H), 7.39 - 7.22 (m, 4H), 7.16 - 7.08 (m, 1H), 6.94 - 6.59 (m, 3H), 6.55 (d, J = 8.0Hz, 1H), 5.56 (d, J = 2.4Hz, 1H), 3.67 (d, J = 10.8Hz, 1H), 3.12 - 2.90 (brs, 1H), 2.42 (s, 3H), 1.07 - 0.92 (m, 1H), 1.73 (d, J = 6.8Hz, 3H). 13 C NMR (CDCl3): δ : 145.2, 143.3, 134.0, 133.9, 132.4, 130.5, 130.2 (2C), 130.0, 129.7, 128.7, 128.4, 126.7 (2C), 125.2, 121.6, 119.8, 118.8, 110.9, 102.2, 83.8, 40.8, 40.1, 21.7, 14.7. MS (ESI) m / z: calcd for C25H23Cl2N2O3S [M+H] + 501.0801, found 501.0795. dr = 92:8, 95% ee.

[0157] (Example 3-11) A compound represented by the following formula (2-1-12) was obtained (yield 111.6 mg, yield 95%) in the same manner as in Example (3-1), except that 102.6 mg (0.25 mmol) of the compound represented by the following formula (3-12) was used instead of the compound represented by formula (3-2).

[0158] [Chemistry]

[0159] The various physical property values of the compound represented by formula (2-1-12) are shown below. Major diastereomer 1 H NMR (CDCl3): δ : 8.99 (s, 1H), 7.55 (d, J = 8.4Hz, 2H), 7.34 (d, J = 8.4Hz, 1H), 7.29 (d, J = 8.4Hz, 2H), 7.17 - 7.05 (m, 1H), 6.93 - 6.80 (m, 1H), 6.69 - 6.54 (m, 2H), 6.17 - 6.37 (m, 2H), 5.57 (d, J = 1.6Hz, 1H), 3.68 (d, J = 10.8Hz, 1H), 3.32 - 2.86 (m, 1H), 2.40 (s, 3H), 1.12 - 0.98 (m, 1H), 0.89 (d, J = 6.8Hz, 3H). 13 C NMR (CDCl3): δ :162.8 (dd, JC-F = 249.1, 12.5Hz, 2C), 147.2 (t, JC-F = 8.7Hz), 145.4, 134.0, 133.8, 130.2 (2C), 128.7, 126.7 (2C), 125.3, 121.7, 119.9, 118.7, 111.2 (d, JC-F = 24.0Hz, 2C), 110.9, 102.2 (t, JC-F = 25.9Hz), 102.2, 83.9, 41.4, 40.0, 21.5, 14.7. MS (ESI) m / z: calcd for C25H23F2N2O3S [M+H] + 469.1392, found 469.1389. dr = 90:10, 95%ee.

[0160] (Example 3-12) A compound represented by the following formula (2-1-13) was obtained (yield 107.9 mg, yield 89%) in the same manner as in Example (3-1), except that 106.1 mg (0.25 mmol) of the compound represented by the following formula (3-13) was used instead of the compound represented by formula (3-2).

[0161]

Chemical formula

[0162] The various physical property values of the compound represented by formula (2-1-13) are shown below. Major diastereomer 1 H NMR (CDCl3): δ : 9.06 (s, 1H), 7.79 - 7.73 (m, 1H), 7.69 (d, J = 7.2Hz, 1H), 7.62 (d, J = 8.4Hz, 2H), 7.56 (d, J = 8.8Hz, 1H), 7.52 - 7.37 (m, 3H), 7.35 - 7.25 (m, 3H), 7.08 - 6.97 (m, 1H), 6.78 - 6.59 (m, 2H), 6.48 (d, J = 8.0Hz, 1H), 5.67 - 5.55 (m, 1H), 3.89 (d, J = 10.8Hz, 1H), 3.48 - 3.18 (m, 1H), 2.41 (s, 3H), 1.32 - 1.16 (m, 1H), 0.89 (d, J = 6.8Hz, 3H). 13 C NMR (CDCl3): δ : 144.8, 140.0, 134.4, 133.8, 133.2, 132.5, 130.1 (2C), 128.7, 127.9, 127.6 (2C), 127.5, 126.9 (2C), 126.3, 125.9, 125.7, 125.4, 121.4, 119.6, 119.1, 110.7, 102.9, 84.0, 41.4, 40.0, 21.6, 14.8. MS (ESI) m / z: calcd for C29H27N2O3S [M+H] + 483.1737, found 483.1735。 dr = 87:13, 93% ee。

[0163] (Example 3-13) A compound represented by the following formula (2-1-14) was obtained (yield 101.1 mg, yield 92%) in the same manner as in Example (3-1), except that 95.1 mg (0.25 mmol) of a compound represented by the following formula (3-14) was used instead of the compound represented by formula (3-2).

[0164]

Chemical formula

[0165] The various physical property values of the compound represented by formula (2-1-14) are shown below. Major diastereomer 1 H NMR (CDCl3): δ : 9.00 (s, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.0 Hz, 1H), 7.28 - 7.22 (m, 2H), 7.15 - 7.04 (m, 2H), 6.96 - 6.90 (m, 1H), 6.90 - 6.81 (m, 1H), 6.62 (d, J = 7.6 Hz, 1H), 6.30 (dd, J = 5.0, 1.0 Hz, 1H), 5.55 (d, J = 2.0 Hz, 1H), 3.88 (d, J = 10.8 Hz, 1H), 3.15 - 2.90 (m, 1H), 2.39 (s, 3H), 1.24 - 1.12 (m, 1H), 0.91 (d, J = 6.8 Hz, 3H). 1313C NMR (CDCl3): δ : 144.8, 143.1, 134.5, 133.6, 130.1 (2C), 128.1, 127.0, 126.7 (2C), 125.7, 125.5, 122.0, 121.4, 119.7, 118.8, 110.7, 102.3, 83.7, 39.3, 36.3, 21.6, 15.0。 MS (ESI) m / z: calcd for C23H23N2O3S2 [M+H] + 439.1145, found 439.1139。 dr = 85:15, 89% ee。

[0166] (Example 3-14) A compound represented by the following formula (2-1-15) was obtained (yield 62.1 mg, yield 65%) in the same manner as in Example (3-1), except that 81.6 mg (0.25 mmol) of a compound represented by the following formula (3-15) was used instead of the compound represented by formula (3-2).

[0167] [Chemical formula]

[0168] The various physical property values of the compound represented by the formula (2-1-15) are shown below. Major diastereomer 1 1H NMR (CDCl3): δ : 8.95 (s, 1H), 7.54 - 7.46 (m, 3H), 7.37 - 7.31 (m, 1H), 7.23 - 7.03 (m, 4H), 5.46 (d, J = 2.8 Hz, 1H), 3.14 - 2.88 (brs, 1H), 2.79 (dt, J = 10.4, 4.0 Hz, 1H), 2.34 (s, 3H), 2.21 - 2.05 (m, 1H), 1.62 - 1.48 (m, 1H), 1.21 - 1.08 (m, 1H), 1.00 (d, J = 7.2 Hz, 3H), 0.13 (t, J = 7.6 Hz, 3H)。 1313C NMR (CDCl3): δ : 144.5, 134.3, 133.9, 129.9 (2C), 128.9, 126.8 (2C), 125.9, 121.2, 119.6, 119.0, 110.9, 102.3, 83.8, 34.0, 33.9, 21.5, 21.1, 14.9, 7.3。 Minor diastereomer 1 1H NMR (CDCl3): δ : 9.29 (s, 1H), 7.76 - 7.68 (m, 2H), 7.44 - 7.39 (m, 1H), 7.37 - 7.31 (m, 1H), 7.23 - 7.03 (m, 4H), 5.38 (d, J = 2.4Hz, 1H), 3.32 - 3.14 (brs, 1H), 2.41 - 2.49 (m, 1H), 2.36 (s, 3H), 1.99 - 1.87 (m, 1H), 1.87 - 1.71 (m, 2H), 1.03 (t, J = 7.6Hz, 3H), 0.31 (d, J = 7.2Hz, 3H)。 13 13C NMR (CDCl3): δ : 144.7, 136.1, 133.0, 129.9 (2C), 127.2, 127.1, 126.7 (2C), 120.6, 119.7, 117.8, 110.8, 98.9, 85.1, 38.5, 33.7, 27.5, 21.6, 17.8, 12.6。 MS (ESI) m / z: calcd for C21H25N2O3S [M+H] + 385.1580, found 385.1581。 dr = 82:18, 82% ee。

[0169] (Example 3 - 15) A compound represented by the following formula (2 - 1 - 16) was obtained (yield 101.5 mg, yield 91%) in the same manner as in Example (3 - 1), except that 97.1 mg (0.25 mmol) of the compound represented by the following formula (3 - 16) was used instead of the compound represented by formula (3 - 2).

[0170] [Chemical formula]

[0171] The various physical property values of the compound represented by formula (2-1-16) are shown below. Major diastereomer 1 H NMR (CDCl3): δ : 8.90 (s, 1H), 7.57 (d, J = 8.4Hz, 2H), 7.25 (d, J = 8.4Hz, 2H), 7.21 - 7.10 (m,4H), 6.88 (dd, J = 8.4, 1.6Hz, 1H), 6.84 - 6.73 (m, 2H), 6.26 (s, 1H), 5.56 (d, J = 2.4Hz, 1H), 3.66 (d, J = 11.2Hz, 1H), 3.29 - 2.93 (brs, 1H), 2.39 (s, 3H), 2.15 (s, 3H), 1.20 - 1.08 (m, 1H), 0.87 (d, J = 7.2Hz, 3H). 13 C NMR (CDCl3): δ : 144.7, 142.5, 134.4, 132.1, 130.0 (2C), 128.7, 128.64, 128.55 (2C), 128.1 (2C), 126.8 (2C), 126.5, 125.8, 122.8, 118.9, 110.4, 102.6, 83.9, 41.3, 40.2, 21.6, 21.4, 14.8. MS (ESI) m / z: calcd for C26H27N2O3S [M+H] + 447.1737, found 447.1735. dr = 95:5, 95% ee.

[0172] (Example 3-16) A compound represented by the following formula (2-1-17) was obtained (yield 103.6 mg, yield 90%) in the same manner as in Example (3-1), except that 101.1 mg (0.25 mmol) of the compound represented by the following formula (3-17) was used instead of the compound represented by formula (3-2).

[0173]

Chem.

[0174] The various physical property values of the compound represented by the formula (2-1-17) are shown below. Major diastereomer 1 H NMR (CDCl3): δ : 8.88 (s, 1H), 7.59 (d, J = 8.4Hz, 2H), 7.27 (d, J = 8.4Hz, 2H), 7.22 - 7.11 (m, 4H), 6.90 - 6.74 (m, 2H), 6.69 (dd, J = 8.8, 2.4Hz, 1H), 5.91 (d, J = 2.4Hz, 1H), 5.57 (d, J = 2.4Hz, 1H), 3.68 (d, J = 10.8Hz, 1H), 3.46 (s, 3H), 3.33 - 3.11 (brs, 1H), 2.40 (s, 3H), 1.24 - 1.12 (m, 1H), 0.88 (d, J = 6.8Hz, 3H). 13 C NMR (CDCl3): δ : 153.7, 144.7, 142.3, 134.5, 130.1 (2C), 129.2, 128.7, 128.6 (2C), 128.2 (2C), 126.8 (2C), 126.6, 126.2, 111.3, 110.6, 102.7, 101.6, 83.9, 55.4, 41.3, 40.0, 21.6, 14.8. MS (ESI) m / z: calcd for C26H27N2O4S [M+H] + 463.1686, found 463.1682. dr = 91:9, 94% ee.

[0175] (Example 3-17) A compound represented by the following formula (2-1-18) was obtained (yield 118.4 mg, yield 93%) in the same manner as in Example (3-1), except that 113.3 mg (0.25 mmol) of the compound represented by the following formula (3-18) was used instead of the compound represented by formula (3-2).

[0176] [Chemical formula]

[0177] The various physical property values of the compound represented by formula (2-1-18) are shown below. Major diastereomer 1 H NMR (CDCl3): δ : 9.09 (s, 1H), 7.60 - 7.52 (m, 2H), 7.26 (d, J = 8.0Hz, 2H), 7.22 - 7.07 (m, 5H), 6.84 - 6.67 (m, 2H), 6.58 - 6.52 (m, 1H), 5.58 (d, J = 2.4Hz, 1H), 3.74 - 3.41 (m, 1H), 3.65 (d, J = 10.8Hz, 1H), 2.39 (s, 3H), 1.19 - 1.07 (m, 1H), 0.87 (d, J = 6.8Hz, 3H). 13 C NMR (CDCl3): δ : 145.0, 141.9, 134.2, 132.4, 130.1 (2C), 129.6, 128.4 (2C), 128.3 (2C), 127.3, 126.8, 126.7 (2C), 124.1, 121.4, 112.8, 112.2, 102.7, 83.9, 41.1, 40.1, 21.6, 14.7. MS (ESI) m / z: calcd for C25H24BrN2O3S [M+H] + 511.0686, found 511.0681. dr = 85:15, 96%ee.

[0178] (Example 3-18) A compound represented by the following formula (2-1-19) was obtained (yield 114.7 mg, yield 90%) in the same manner as in Example (3-1), except that 113.3 mg (0.25 mmol) of a compound represented by the following formula (3-19) was used instead of the compound represented by formula (3-2).

[0179]

Chemical formula

[0180] Various physical property values of the compound represented by formula (2-1-19) are shown below. Major diastereomer 1 H NMR (CDCl3): δ : 9.05 (s, 1H), 7.55 (d, J = 8.6Hz, 2H), 7.41 (d, J = 2.0Hz, 1H), 7.26 (d, J = 8.6Hz, 2H), 7.21 - 7.09 (m, 3H), 6.85 (dd, J = 8.8, 2.0Hz, 1H), 6.81 - 6.65 (m, 2H), 6.28 (d, J = 8.8Hz, 1H), 5.58 (d, J = 2.4Hz, 1H), 3.96 - 3.38 (m, 1H), 3.67 (d, J = 11.2Hz, 1H), 2.39 (s, 3H), 1.18 - 1.05 (m, 1H), 0.87 (d, J = 6.8Hz, 3H). 13 C NMR (CDCl3): δ : 145.0, 142.2, 134.5, 134.2, 130.1 (2C), 129.1, 128.5 (2C), 128.2 (2C), 126.8 (2C), 126.7, 124.5, 122.8, 120.2, 114.7, 113.6, 103.1, 84.0, 41.1, 40.0, 21.6, 14.8. MS (ESI) m / z: calcd for C25H24BrN2O3S [M+H] + 511.0686, found 511.0686. dr = 88:12, 97%ee.

[0181] (Example 3-19) A compound represented by the following formula (2-1-20) was obtained (yield 62.5 mg, yield 56%) in the same manner as in Example (2-1), except that the reaction time was 168 hours and 225.1 μL (2.5 mmol) of 1-butanol was used instead of propionaldehyde.

[0182] [Chemical formula]

[0183] Various physical property values of the compound represented by formula (2-1-20) are shown below. Major diastereomer 1 H NMR (CDCl3): δ : 8.96 (s, 1H), 7.59 (d, J = 8.4Hz, 2H), 7.34 - 7.23 (m, 3H), 7.20 - 7.11 (m, 3H), 7.10 - 7.02 (m, 1H), 6.86 - 6.69 (m, 3H), 6.47 (d, J = 8.4Hz, 1H), 5.76 (d, J = 2.8Hz, 1H), 3.72 (d, J = 11.2Hz, 1H), 3.28 - 2.60 (brs, 1H), 2.40 (s, 3H), 1.46 - 1.33 (m, 1H), 1.30 - 1.18 (m, 1H), 0.96 - 0.82 (m, 1H), 0.75 (t, J = 7.4Hz, 3H). 13 C NMR (CDCl3): δ : 144.9, 142.7, 134.3, 133.8, 130.0 (2C), 128.8 (2C), 128.4, 128.2 (2C), 127.0 (2C), 126.6, 125.7, 121.4, 119.6, 119.1, 110.7, 103.4, 80.8, 46.4, 40.5, 21.6, 21.0, 11.7. MS (ESI) m / z: calcd for C26H27N2O3S [M+H] + 447.1737, found 447.1734。 dr = 94:6, 94% ee。

Claims

1. An optically active pyrrolidine derivative represented by the following general formula (1) or an acidic salt thereof. 【Chemical 1】 (In the formula, R １ represents a linear or branched alkyl group or phenyl group having 1 to 6 carbon atoms which may have a substituent, R ２ represents a phenylmethyl group which may have a substituent on the phenyl moiety, Each of the substituents is independently at least one group selected from the group consisting of a halogen atom, an alkyl group having 1 to 6 carbon atoms which may be substituted with a fluorine atom, an alkoxyl group having 1 to 6 carbon atoms, and a nitro group. R １ When R is a phenyl group, １ R ２ at least one of them has a substituent, and an iodine atom or a chlorine atom does not substitute only at the 4-position of the phenyl group.)

2. The optically active pyrrolidine derivative or an acidic salt thereof according to claim 1, wherein each of the substituents is independently at least one group selected from the group consisting of a methyl group, a trifluoromethyl group, a methoxy group, a fluorine atom, and a nitro group.

3. R of the general formula (1) １ is any one of the following formulas (R １ -1) to (R １ -4), the optically active pyrrolidine derivative or its acid salt according to claim 1 or 2. [Chemical 2] (In the formula, the wavy line indicates a bond with a sulfur atom)

4. R in the general formula (1) ２ is any one of the following formulas (R ２ -1) to (R ２ -3), the optically active pyrrolidine derivative or its acidic salt according to any one of claims 1 to 3. 【Chemical Formula 3】 (In the formula, the wavy line indicates a bond with a nitrogen atom)

5. A method for producing an optically active pyrrolidine derivative represented by any one of claims 1 to 4 or an acidic salt thereof, comprising: A step of obtaining a precursor compound by subjecting the amino group of (S)-1-tert-butoxycarbonyl-2-(aminomethyl)pyrrolidine to a sulfonylation reaction and a reaction with an arylmethyl halide represented by the general formula X-R2 which may have a substituent on the aryl moiety (wherein R2 and the substituent have the same definitions as in claim 1, and X represents a halogen atom), and A step of deprotecting the tert-butoxycarbonyl group of the precursor compound with an acid to obtain an optically active pyrrolidine derivative represented by the general formula (1) or an acidic salt thereof.

6. An optically active α-carboline derivative represented by the following general formula (2). 【Chemical Formula 4】 (In the formula, R ３ each independently represents a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, a cycloalkenyl group having 6 to 10 carbon atoms, a cycloalkynyl group having 6 to 10 carbon atoms, an alkoxyl group having 1 to 20 carbon atoms, a cycloalkoxyl group having 3 to 20 carbon atoms, an alkylthio group having 1 to 20 carbon atoms, a cycloalkylthio group having 3 to 20 carbon atoms, an aryloxy group having 6 to 20 carbon atoms, an arylthio group having 6 to 20 carbon atoms, an arylalkyl group having 7 to 21 carbon atoms, an arylalkenyl group having 8 to 20 carbon atoms, an arylalkynyl group having 8 to 20 carbon atoms, an alkoxycarbonyl group having 1 to 20 carbon atoms, a nitro group, a nitrile group, or an aryl group having 6 to 20 carbon atoms which may have a substituent, R ４ represents a methanesulfonyl group, a p-toluenesulfonyl group, an o-nitrobenzenesulfonyl group, or a trifluoromethanesulfonyl group, and R ５ represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, a cycloalkenyl group having 6 to 10 carbon atoms, a cycloalkynyl group having 6 to 10 carbon atoms, an arylalkyl group having 7 to 21 carbon atoms, an arylalkenyl group having 8 to 20 carbon atoms, an arylalkynyl group having 8 to 20 carbon atoms, an alkoxycarbonyl group having 1 to 20 carbon atoms, a heteroaryl group, or an aryl group having 6 to 20 carbon atoms which may have a substituent, R ６ represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, an alkoxyalkyl group having 2 to 20 carbon atoms, an alkoxyarylalkyl group having 8 to 20 carbon atoms, an arylalkyl group having 7 to 21 carbon atoms, a benzyloxyalkyl group, or an aryl group having 6 to 20 carbon atoms which may have a substituent, R ７ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, an alkoxyalkyl group having 2 to 20 carbon atoms, an alkoxyarylalkyl group having 8 to 20 carbon atoms, an arylalkyl group having 7 to 21 carbon atoms, a benzyloxyalkyl group, or an aryl group having 6 to 20 carbon atoms which may have a substituent, n represents an integer of 0 to 4, The substituent that the aryl group may have is independently at least one group selected from the group consisting of a halogen atom, an alkyl group which may be substituted with a fluorine atom, a cycloalkyl group which may be substituted with a fluorine atom, an alkoxyl group, a cycloalkoxyl group, an alkylthio group, a cycloalkylthio group, an aryl group, an aryloxy group, an arylthio group, an arylalkyl group, an arylcycloalkyl group, an arylalkenyl group, an arylalkynyl group, an alkoxycarbonyl group, a cycloalkoxycarbonyl group, an aryloxycarbonyl group, a carboxyl group, a nitrile group, and a nitro group.)

7. The optically active α-carboline derivative according to claim 6, represented by the following general formula (2-1). 【Chemical Formula 5】 (wherein, R ３ ~R ６ and n have the same definitions as described above)

8. A process for producing an optically active α-carboline derivative, which comprises reacting an indole derivative represented by the following general formula (3) with an aldehyde compound represented by the following general formula (4) or acetaldehyde in the presence of an optically active pyrrolidine derivative or an acidic salt thereof according to any one of claims 1 to 4. 【Chemical Formula 6】 (In the formula, R 3 each independently represents a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, a cycloalkenyl group having 6 to 10 carbon atoms, a cycloalkynyl group having 6 to 10 carbon atoms, an alkoxyl group having 1 to 20 carbon atoms, a cycloalkoxyl group having 3 to 20 carbon atoms, an alkylthio group having 1 to 20 carbon atoms, a cycloalkylthio group having 3 to 20 carbon atoms, an aryloxy group having 6 to 20 carbon atoms, an arylthio group having 6 to 20 carbon atoms, an arylalkyl group having 7 to 21 carbon atoms, an arylalkenyl group having 8 to 20 carbon atoms, an arylalkynyl group having 8 to 20 carbon atoms, an alkoxycarbonyl group having 1 to 20 carbon atoms, a nitro group, a nitrile group, or an aryl group having 6 to 20 carbon atoms which may have a substituent, R 4 represents a methanesulfonyl group, a p-toluenesulfonyl group, an o-nitrobenzenesulfonyl group, or a trifluoromethanesulfonyl group, R 5 represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, a cycloalkenyl group having 6 to 10 carbon atoms, a cycloalkynyl group having 6 to 10 carbon atoms, an arylalkyl group having 7 to 21 carbon atoms, an arylalkenyl group having 8 to 20 carbon atoms, an arylalkynyl group having 8 to 20 carbon atoms, an alkoxycarbonyl group having 1 to 20 carbon atoms, a heteroaryl group, or an aryl group having 6 to 20 carbon atoms which may have a substituent, n represents an integer of 0 to 4, provided that The substituent that the aryl group may have is each independently at least one group selected from the group consisting of a halogen atom, an alkyl group optionally substituted with a fluorine atom, a cycloalkyl group optionally substituted with a fluorine atom, an alkoxyl group, a cycloalkoxyl group, an alkylthio group, a cycloalkylthio group, an aryl group, an aryloxy group, an arylthio group, an arylalkyl group, an arylcycloalkyl group, an arylalkenyl group, an arylalkynyl group, an alkoxycarbonyl group, a cycloalkoxycarbonyl group, an aryloxycarbonyl group, a carboxyl group, a nitrile group, and a nitro group.) 【Chemical Formula 7】 (In the formula, R6 represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, an alkoxyalkyl group having 2 to 20 carbon atoms, an alkoxyarylalkyl group having 8 to 20 carbon atoms, an arylalkyl group having 7 to 21 carbon atoms, a benzyloxyalkyl group, or an aryl group having 6 to 20 carbon atoms which may have a substituent, R7 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, an alkoxyalkyl group having 2 to 20 carbon atoms, an alkoxyarylalkyl group having 8 to 20 carbon atoms, an arylalkyl group having 7 to 21 carbon atoms, a benzyloxyalkyl group, or an aryl group having 6 to 20 carbon atoms which may have a substituent, provided that the substituent that the aryl group may have is each independently at least one group selected from the group consisting of a halogen atom, an alkyl group optionally substituted with a fluorine atom, a cycloalkyl group optionally substituted with a fluorine atom, an alkoxyl group, a cycloalkoxyl group, an alkylthio group, a cycloalkylthio group, an aryl group, an aryloxy group, an arylthio group, an arylalkyl group, an arylcycloalkyl group, an arylalkenyl group, an arylalkynyl group, an alkoxycarbonyl group, a cycloalkoxycarbonyl group, an aryloxycarbonyl group, a carboxyl group, a nitrile group, and a nitro group.) **Claim 9**: A catalyst for producing an optically active α-carboline derivative represented by the following general formula (2), comprising an optically active pyrrolidine derivative represented by the following general formula (1) or an acidic salt thereof. (In the formula, [Chemical 8] R1 represents a linear or branched alkyl group having 1 to 6 carbon atoms or a phenyl group which may have a substituent, ​ R2 represents a phenylmethyl group which may have a substituent on the phenyl moiety, provided that each of the substituents is independently at least one group selected from the group consisting of a halogen atom, an alkyl group having 1 to 6 carbon atoms which may be substituted with a fluorine atom, an alkoxyl group having 1 to 6 carbon atoms, and a nitro group; when R1 is a phenyl group, at least one of R1 and R2 has a substituent, and an iodine atom or a chlorine atom does not substitute only at the 4-position of the phenyl group. 【Chemical Formula 9】 (In the formula, R3 each independently represents a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, a cycloalkenyl group having 6 to 10 carbon atoms, a cycloalkynyl group having 6 to 10 carbon atoms, an alkoxyl group having 1 to 20 carbon atoms, a cycloalkoxyl group having 3 to 20 carbon atoms, an alkylthio group having 1 to 20 carbon atoms, a cycloalkylthio group having 3 to 20 carbon atoms, an aryloxy group having 6 to 20 carbon atoms, an arylthio group having 6 to 20 carbon atoms, an arylalkyl group having 7 to 21 carbon atoms, an arylalkenyl group having 8 to 20 carbon atoms, an arylalkynyl group having 8 to 20 carbon atoms, an alkoxycarbonyl group having 1 to 20 carbon atoms, a nitro group, a nitrile group, or an aryl group having 6 to 20 carbon atoms which may have a substituent; R4 represents a methanesulfonyl group, a p-toluenesulfonyl group, an o-nitrobenzenesulfonyl group, or a trifluoromethanesulfonyl group; R5 represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, a cycloalkenyl group having 6 to 10 carbon atoms, a cycloalkynyl group having 6 to 10 carbon atoms, an arylalkyl group having 7 to 21 carbon atoms, an arylalkenyl group having 8 to 20 carbon atoms, an arylalkynyl group having 8 to 20 carbon atoms, an alkoxycarbonyl group having 1 to 20 carbon atoms, a heteroaryl group, or an aryl group having 6 to 20 carbon atoms which may have a substituent; R6 represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, an alkoxyalkyl group having 2 to 20 carbon atoms, an alkoxyarylalkyl group having 8 to 20 carbon atoms, an arylalkyl group having 7 to 21 carbon atoms, a benzyloxyalkyl group, or an aryl group having 6 to 20 carbon atoms which may have a substituent. R7 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, an alkoxyalkyl group having 2 to 20 carbon atoms, an alkoxyarylalkyl group having 8 to 20 carbon atoms, an arylalkyl group having 7 to 21 carbon atoms, a benzyloxyalkyl group, or an aryl group having 6 to 20 carbon atoms which may have a substituent, n represents an integer of 0 to 4, the substituent which the aryl group may have is at least one group independently selected from the group consisting of a halogen atom, an alkyl group which may be substituted with a fluorine atom, a cycloalkyl group which may be substituted with a fluorine atom, an alkoxyl group, a cycloalkoxyl group, an alkylthio group, a cycloalkylthio group, an aryl group, an aryloxy group, an arylthio group, an arylalkyl group, an arylcycloalkyl group, an arylalkenyl group, an arylalkynyl group, an alkoxycarbonyl group, a cycloalkoxycarbonyl group, an aryloxycarbonyl group, a carboxyl group, a nitrile group, and a nitro group.

10. The catalyst according to claim 9, wherein the substituents in R1 and R2 in the general formula (1) are each independently at least one group selected from the group consisting of a methyl group, a trifluoromethyl group, a methoxy group, a fluorine atom, and a nitro group.

11. The catalyst according to claim 9 or 10, wherein R1 in the general formula (1) is any one of the following formulas (R1-1) to (R1-4). 【Chemical 10】 (In the formula, the wavy line indicates a bond with a sulfur atom)

12. The catalyst according to any one of claims 9 to 11, wherein R2 in the general formula (1) is any one of the following formulas (R2-1) to (R2-3). 【Chemical 11】 (In the formula, the wavy line indicates a bond with a nitrogen atom)

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