GLOBODERA PALLIDA CONTROL AGENT

Abstract

An object of the present invention is to provide an industrially easily available hatching factor on Globodera pallida larvae, a control agent and a control method using the same. The Globodera pallida control agent of the present invention contains, as an active ingredient, at least one selected from a compound of formula (I) below, a stereoisomer thereof, and a salt thereof [wherein Ar represents a substituted or unsubstituted phenyl group or the like; R.sup.1 each independently represents a group such as a substituted or unsubstituted C1 to 6 alkyl group and a substituted or unsubstituted C2 to 6 alkenyl group; R.sup.2 represents a hydrogen atom or a substituted or unsubstituted C1 to 6 alkyl group; the partial structure YX represents a group represented by *N(Rb)C(?X.sup.1)**; X.sup.1 each independently represents an oxygen atom or a sulfur atom; Rb represents hydrogen atom or the like; where * indicates a binding position to the carbon atom having two R1, and ** indicates a binding position to Z; and Z represents a substituted or unsubstituted methylene group, or a substituted or unsubstituted dimethylene group.]

##STR00001##

Claims

1. A Globodera pallida control agent comprising, as an active ingredient, at least one selected from a compound of formula (I) below, a stereoisomer thereof, and a salt thereof: ##STR00121## wherein Ar represents a substituted or unsubstituted phenyl group, or a substituted or unsubstituted naphthyl group; R.sup.1 each independently represents a substituted or unsubstituted C1 to 6 alkyl group, a substituted or unsubstituted C2 to 6 alkenyl group, a substituted or unsubstituted C2 to 6 alkynyl group, a substituted or unsubstituted C3 to 6 cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted naphthyl group; R.sup.2 represents a hydrogen atom, or a substituted or unsubstituted C1 to 6 alkyl group; a partial structure YX represents a group represented by *CH.sub.2C(?X.sup.1)**, a group represented by *OC(?X.sup.1)**, a group represented by *SC(?X.sup.1)**, a group represented by *N(R.sup.b)C(?X.sup.1)**, or a group represented by *NHSO.sub.2**; where * indicates a binding position to the carbon atom having two R.sup.1, and ** indicates a binding position to Z; X.sup.1 each independently represents an oxygen atom, or a sulfur atom; R.sup.b represents a hydrogen atom, a hydroxyl group, a group represented by R.sup.b1C(?O), a group represented by R.sup.b1OC(?O), a group represented by R.sup.b1NHC(?O), or a group represented by R.sup.b1.sub.2NC(?O); R.sup.b1 each independently represents a substituted or unsubstituted C1 to 6 alkyl group, a substituted or unsubstituted C2 to 6 alkenyl group, a substituted or unsubstituted C2 to 6 alkynyl group, a substituted or unsubstituted C3 to 6 cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted naphthyl group; Z represents a substituted or unsubstituted methylene group, or a substituted or unsubstituted dimethylene group; and in the case of Z being a substituted methylene group, R.sup.2 together with the substituent on the methylene group optionally form a single bond or a methylene group.

2. The Globodera pallida control agent according to claim 1, wherein Z in formula (I) is a substituted or unsubstituted methylene group.

3. The Globodera pallida control agent according to claim 1, wherein Z in formula (I) is a substituted or unsubstituted dimethylene group.

4. The Globodera pallida control agent according to claim 1, wherein the partial structure YX in formula (I) is a group represented by *OC(?X.sup.1)**, a group represented by *SC(?X.sup.1)**, or a group represented by *N(R)C(?X.sup.1)**.

5. The Globodera pallida control agent according to claim 1, wherein the partial structure YX in formula (I) is a group represented by *CH.sub.2C(?X.sup.1)**.

6. The Globodera pallida control agent according to claim 1, wherein the partial structure YX in formula (I) is a group represented by *NHSO.sub.2**.

7. The Globodera pallida control agent according to claim 2, wherein the partial structure YX in formula (I) is a group represented by *OC(?O)**, a group represented by *OC(?S)**, a group represented by *SC(?O)**, a group represented by *NHC(?O)**, a group represented by *N(OH)C(?O)**, or a group represented by *NHC(?S)**.

8. The Globodera pallida control agent according to claim 2, wherein the partial structure YX in formula (I) is a group represented by *OC(?O)**, a group represented by *SC(?O)**, or a group represented by *NHC(?O)**.

9. (canceled)

10. A method for controlling Globodera pallida, comprising a step of applying the control agent according to claim 1 to a field soil inhabited by Globodera pallida.

11. A compound selected from the group consisting of: (a) a compound of formula (I-a) below, a stereoisomer thereof, or a salt thereof: ##STR00122## wherein Ar represents a substituted or unsubstituted phenyl group, or a substituted or unsubstituted naphthyl group; R.sup.1 each independently represents a substituted or unsubstituted C1 to 6 alkyl group, a substituted or unsubstituted C2 to 6 alkenyl group, a substituted or unsubstituted C2 to 6 alkynyl group, a substituted or unsubstituted C3 to 6 cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted naphthyl group; R.sup.2 represents a hydrogen atom, or a substituted or unsubstituted C1 to 6 alkyl group; a partial structure Y.sup.aX.sup.a represents a group represented by *OC(?X.sup.1a)**, a group represented by *SC(?X.sup.1a)**, or a group represented by *NHC(?X.sup.1a)**; where * indicates a binding position to the carbon atom having two R.sup.1, and ** indicates a binding position to Z.sup.a; X.sup.1a each independently represents an oxygen atom or a sulfur atom; and Z.sup.a represents a substituted or unsubstituted dimethylene group; (b) a compound of formula (I-b) below, a stereoisomer thereof, or a salt thereof: ##STR00123## wherein Ar represents a substituted or unsubstituted phenyl group, or a substituted or unsubstituted naphthyl group; R.sup.1 each independently represents a substituted or unsubstituted C1 to 6 alkyl group, a substituted or unsubstituted C2 to 6 alkenyl group, a substituted or unsubstituted C2 to 6 alkynyl group, a substituted or unsubstituted C3 to 6 cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted naphthyl group; R.sup.2 represents a hydrogen atom or a substituted or unsubstituted C1 to 6 alkyl group; a partial structure Y.sup.bX.sup.b represents a group represented by *OC(?S)**, a group represented by *SC(?O)**, or a group represented by *NHSO.sub.2**; where * indicates a binding position to the carbon atom having two R.sup.1, and ** indicates a binding position to Z.sup.b; and Z.sup.b represents a substituted or unsubstituted methylene group; and (c) a compound of formula (I-c) below, a stereoisomer thereof, or a salt thereof: ##STR00124## wherein Ar represents a substituted or unsubstituted phenyl group, or a substituted or unsubstituted naphthyl group; R.sup.1 each independently represents a substituted or unsubstituted C1 to 6 alkyl group, a substituted or unsubstituted C2 to 6 alkenyl group, a substituted or unsubstituted C2 to 6 alkynyl group, a substituted or unsubstituted C3 to 6 cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted naphthyl group; and X.sup.1 represents an oxygen atom or a sulfur atom.

12.-13. (canceled)

14. A hatching factor for Globodera pallida, comprising, as an active ingredient, any one or more of 5,5-dimethyl-4-phenyl-2-pyrrolidinone having a specific rotation of (?), 5,5-dimethyl-4-(4-methylphenyl)-2-pyrrolidinone having a specific rotation of (?), 5,5-dimethyl-4-(4-chlorophenyl)-2-pyrrolidinone having a specific rotation of (?), or 4-(4-chlorophenyl)-3,3-dimethylisothiazolidine-1,1-dioxide having a specific rotation of (?).

15. The Globodera pallida control agent according to claim 1, wherein the Globodera pallida control agent promotes hatching of Globodera pallida larvae.

Description

EXAMPLES

Production Example of Compound (I)

Production Example 1

Synthesis of 6,6-dimethyl-5-(p-tolyl)piperidin-2-one (Compound A-3)

[Step 1]

[0216] ##STR00052##

[0217] A mixture of 4-methylcinnamaldehyde (98.89 g), dichloromethane (2.5 L), 2-nitropropane (122.32 g), and diethylamine (100.27 g) was stirred overnight at room temperature.

[0218] 1N Hydrochloric acid was added to the resulting mixture, and the mixture was extracted with dichloromethane. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. 150.54 g of intermediate 1 represented by the aforementioned formula was obtained with a yield of 95.9%.

[0219] .sup.1H-NMR data of intermediate 1 obtained are shown below. .sup.1H-NMR (CDCl.sub.3, 399.78 MHz): ?=952 (s, 1H, CHO), 7.26-7.05 (m, 4H, ArH), 3.97-3.94 (m, 1H, C(Ar)H), 3.07-2.65 (m, 2H, CH2-), 2.32 (s, 3H, ArCH3), 1.57 (s, 3H, CH3), 1.47 s (s, 3H, CH3).

[Step 2]

[0220] ##STR00053##

[0221] Potassium tert-butoxide (3.14 g) was added to a mixture of (methoxymethyl)triphenylphosphonium chloride (10.28 g) and THF (100 ml) under cooling with ice, followed by stirring for 30 minutes. Intermediate 1 (4.71 g) was added thereto, followed by further stirring for 30 minutes.

[0222] The temperature was raised to room temperature, followed by stirring for 4.5 hours. Water was added to the resulting mixture, and the mixture was extracted with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was subjected to silica gel chromatography (hexane:ethyl acetate=9:1) to obtain 4.26 g of intermediate 2 represented by the aforementioned formula with a yield of 80.9%.

[Step 3]

[0223] ##STR00054##

[0224] 4N Hydrochloric acid was added to a mixture of intermediate 2 (4.26 g) and THF (30 ml) under cooling with ice. The temperature was raised to room temperature, followed by stirring for 1.5 hours.

[0225] Water was added to the resulting mixture, and the mixture was extracted with dichloromethane. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Sodium chlorite (5.86 g), sodium hydrogen phosphate (5.05 g), amylene (11.36 g), tert-butyl alcohol (50 ml), and water (16 ml) were added to the concentrated residue obtained, followed by stirring overnight at room temperature.

[0226] Water was added to the resulting mixture, and the mixture was extracted with dichloromethane. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Methanol (80 ml) was added to the concentrated residue, and a 10% hexane solution of trimethylsilyldiazomethane (55.5 g) was added dropwise thereto at room temperature.

[0227] The resulting mixture was stirred at room temperature for 1.5 hours and concentrated under reduced pressure. The residue obtained was subjected to silica gel chromatography (hexane:ethyl acetate=9:1) to obtain 2.58 g of intermediate 3 represented by the aforementioned formula with a yield of 57.0%.

[0228] .sup.1H-NMR data of the resulting intermediate 3 are shown below. .sup.1H-NMR (CDCl.sub.3, 399.78 MHz): ?=7.20 (d, 2H, J=8.4 Hz, ArH), 7.06 (d, 2H, J=8.4 Hz, ArH), 3.60 (s, 3H, COOCH3), 3.33-3.29 (m, 1H, C(Ar)H), 2.33 (s, 3H, ArCH3), 2.14-1.84 (m, 4H, CH2CH2-), 1.60 (s, 3H, CH3), 1.43 s (s, 3H, CH3).

[Step 4]

[0229] ##STR00055##

[0230] A mixture of intermediate 3 (2.58 g), acetic acid (50 ml), and zinc (12.02 g) was stirred overnight at 60? C.

[0231] The resulting mixture was allowed to cool to room temperature and filtered through celite. Water was added to the resulting filtrate, and the mixture was extracted with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was subjected to silica gel chromatography (ethyl acetate:methanol=9:1) to obtain 0.81 g of compound A-3 with a yield of 40.5%.

Production Example 2

Synthesis of 5-(4-chlorophenyl)-6,6-dimethyl tetrahydro-2H-thiopyran-2-one (Compound A-6)

[Step 1]

[0232] ##STR00056##

[0233] A 1.03 M hexane solution of DIBAL-H (4.7 ml) was added to a mixture of ethyl (E)-3-(4-chlorophenyl)-2-methylacrylate (4.63 mg) and THF (9.7 ml) at ?78? C. The temperature was raised to 0? C., followed by stirring for 1 hour.

[0234] A saturated sodium potassium tartrate aqueous solution was added to the resulting mixture, and the mixture was stirred at room temperature for 1 hour and then extracted with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.

[0235] Toluene (9.7 ml), triethyl orthoacetate (3.5 ml), and propionic acid (14.5 ?l) were added to the concentrated residue, followed by stirring overnight under reflux. After cooling to room temperature, water was added, and the mixture was extracted with diethyl ether. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was subjected to silica gel chromatography (hexane:ethyl acetate=98:2) to obtain 400.2 mg of intermediate 4 represented by the aforementioned formula with a yield of 82.0%.

[0236] .sup.1H-NMR data of the resulting intermediate 4 are shown below.

.sup.1H-NMR (CDCl.sub.3, 500.16 MHz): ?=7.26 (d, 2H, J=6.3 Hz, ArH), 7.16 (d, 2H, J=8.1 Hz, ArH), 4.89 (s, 2H, ?CH2), 4.09-4.02 (m, 2H, COOCH2-), 3.76 (t, 1H, J=8.0 Hz, (Ar)CH), 2.84 (dd, 1H, J=7.5 Hz, 15.5 Hz, CH2COO), 2.69 (dd, 1H, J=8.1 Hz, 14.9 Hz, CH2COO), 1.60 (s, 3H, CH3), 1.17 (t, 3H, J=7.4 Hz, COOCH2CH3).

[Step 2]

[0237] ##STR00057##

[0238] A 1.03 M hexane solution of DIBAL-H (1.91 ml) was added to a mixture of intermediate 4 (199.3 mg) and dichloromethane (3.9 ml) at ?78? C. The temperature was raised to 0? C., followed by stirring for 30 minutes.

[0239] A saturated sodium potassium tartrate aqueous solution was added to the resulting mixture, and the mixture was stirred at room temperature for 1 hour and then extracted with dichloromethane. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was subjected to silica gel chromatography (hexane:ethyl acetate=8:2) to quantitatively obtain 165.8 mg of intermediate 5 represented by the aforementioned formula.

[0240] .sup.1H-NMR data of the resulting intermediate 5 are shown below.

.sup.1H-NMR (CDCl.sub.3, 500.16 MHz): ?=7.27 (d, 2H, J=8.6 Hz, ArH), 7.16 (d, 2H, J=8.6 Hz, ArH), 4.94 (s, 1H, ?CH2), 4.87 (s, 1H, ?CH2), 3.63 (td, 1H, J=6.3 Hz, 10.4 Hz, CH2-), 3.56 (t, 1H, J=6.3 Hz, 10.4 Hz, CH2-), 3.41 (t, 1H, J=8.0 Hz, CH2O), 2.13 (qd, 1H, J=6.9 Hz, 13.8 Hz, (Ar)CH), 1.96-1.88 (m, 1H, CH2-), 1.57 (s, 3H, CH3).

[Step 3]

[0241] ##STR00058##

[0242] A mixture of intermediate 5 (165.8 mg), dichloromethane (3.9 ml), triethylamine (285 ?l), tosyl chloride (195.5 mg), and 4-dimethylaminopyridine (4.8 mg) was stirred overnight at room temperature.

[0243] Saturated sodium bicarbonate water was added to the resulting mixture, and the mixture was extracted with dichloroethane. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was subjected to silica gel chromatography (hexane:ethyl acetate=95:5) to obtain 269.1 mg of intermediate 6 represented by the aforementioned formula with a yield of 93.0%.

[0244] .sup.1H-NMR data of the resulting intermediate 6 are shown below.

.sup.1H-NMR (CDCl.sub.3, 500.16 MHz): ?=7.74 (d, 2H, J=8.1 Hz, SO2ArH), 7.33 (d, 2H, J=8.0 Hz, ArH), 7.19 (d, 2H, J=8.1 Hz, ArH), 7.01 (d, 2H, J=8.6 Hz, SO2ArH), 4.84 (s, 1H?CH2), 4.81 (s, 1H, ?CH2), 4.01 (td, 1H, J=5.7 Hz, 9.8 Hz, CH2-), 3.86-3.82 (m, 1H, CH2-), 3.29 (t, 1H, J=8.1 Hz, (Ar)CH), 2.46 (s, 3H, ArCH3), 2.23 (qd, 1H, J=6.9 Hz, 14.3 Hz, CH2-), 1.99-1.92 (m, 1H, CH2-), 1.50 (s, 3H, CH3).

[Step 4]

[0245] ##STR00059##

[0246] A mixture of intermediate 6 (168.2 mg), dimethylsulfoxide (0.92 ml), and sodium cyanide (113 mg) was stirred at 75? C. for 1 hour.

[0247] The resulting mixture was allowed to cool to room temperature, saturated sodium bicarbonate water was added thereto, and the mixture was extracted with diethyl ether. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was subjected to silica gel chromatography (hexane:ethyl acetate=95:5) to quantitatively obtain 105.3 mg of intermediate 7 represented by the aforementioned formula.

[0248] .sup.1H-NMR data of the resulting intermediate 7 are shown below.

.sup.1H-NMR (CDCl.sub.3, 500.16 MHz): ?=7.30 (d, 2H, J=8.6 Hz, ArH), 7.15 (d, 2H, J=8.0 Hz, ArH), 4.94 (s, 2H, ?CH2), 3.32 (t, 1H, J=8.0 Hz, (Ar)CH), 2.33-2.27 (m, 1H, CH2-), 2.24-2.16 (m, 2H, CH2-), 2.04-1.97 (m, 1H, CH2-), 1.57 (s, 3H, CH3).

[Step 5]

[0249] ##STR00060##

[0250] A 1.03 M hexane solution of DIBAL-H (895 ?l) was added to a mixture of intermediate 7 (105.3 mg) and dichloromethane (2.3 ml) at ?78? C. The temperature was raised to 0? C., followed by stirring for 30 minutes.

[0251] A 10% tartaric acid aqueous solution was added to the resulting mixture, and the mixture was stirred at room temperature for 1 hour and then extracted with dichloromethane. The resulting organic layer was washed with saturated sodium bicarbonate water, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure.

[0252] Sodium chlorite (208.5 mg), sodium hydrogen phosphate (179.8 mg), amylene (497 ?l), tert-butyl alcohol (1.73 ml), and water (576 ?l) was added to the residue obtained, followed by stirring at room temperature for 30 minutes.

[0253] Water was added to the resulting mixture, and the mixture was extracted with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.

[0254] Methanol (2.3 ml) was added to the concentrated residue, and a 10% hexane solution of trimethylsilyldiazomethane (1.15 ml) was added dropwise at room temperature.

[0255] The resulting mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure. The residue obtained was subjected to silica gel chromatography (hexane:ethyl acetate=98:2) to obtain 106.1 mg of intermediate 8 represented by the aforementioned formula with a yield of 91%.

[0256] .sup.1H-NMR data of the resulting intermediate 8 are shown below. .sup.1H-NMR (CDCl.sub.3, 500.16 MHz): ?=7.27 (d, 2H, J=8.6 Hz, ArH), 7.14 (d, 2H, J=8.6 Hz, ArH), 4.92 (s, 1H, ?CH2), 4.88 (s, 1H, ?CH2), 3.65 (s, 3HCOOCH3), 3.18 (t, 1H, J=7.5 Hz, (Ar)CH), 2.30-2.21 (m, 2H, CH2-), 2.18-2.11 (m, 1H, CH2-), 2.05-1.97 (m, 1H, CH2-), 1.55 (s, 3H, CH3).

[Step 6]

[0257] ##STR00061##

[0258] Potassium thiocyanate (197.3 mg), ethanol (8.1 ml), intermediate 8 (51.3 mg), and sodium borohydride (49.1 mg) were added to a mixture of iron(III) oxalate hexahydrate (491.1 mg) and water (8.5 ml) under cooling with ice, followed by stirring for 1.5 hours under an argon atmosphere.

[0259] Ammonia water was added to the resulting mixture, and the mixture was extracted with dichloromethane. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was subjected to silica gel chromatography (hexane:ethyl acetate=8:2) to obtain 40.0 mg of intermediate 9 represented by the aforementioned formula with a yield of 64.0%.

[0260] .sup.1H-NMR data of the resulting intermediate 9 are shown below.

.sup.1H-NMR (CDCl.sub.3, 500.16 MHz): ?=7.33 (d, 2H, J=8.0 Hz, ArH), 7.16 (d, 2H, J=8.6 Hz, ArH), 3.63 (s, 3H, COOCH3), 2.91-2.88 (m, 1H, (Ar)CH), 2.40-2.33 (m, 1H, CH2-), 2.13-2.03 (m, 3H, CH2CH2-), 1.51 (s, 3H, CH3), 1.48 (s, 3H, CH3).

[Step 7]

[0261] ##STR00062##

[0262] A mixture of intermediate 9 (7.6 mg), benzene (240 ?l), trimethylaluminum 2M toluene solution (24.4 ?l), and bis(tri-tert-butylphosphine)palladium (0) (2.5 mg) was stirred at room temperature for 30 minutes under an argon atmosphere.

[0263] Saturated sodium bicarbonate water was added to the resulting mixture, and the mixture was extracted with diethyl ether. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was subjected to silica gel chromatography (hexane:ethyl acetate=9:10) to obtain 3.3 mg of compound A-6 with a yield of 53.0%.

Production Example 3

Synthesis of 5,5-dimethyl-4-(p-tolyl)dihydrofuran-2 (3H)-thione (Compound B-2)

[0264] ##STR00063##

[0265] A mixture of compound 18 (0.23 g), toluene (10 ml), and a Lawesson's reagent (0.89 g) was stirred overnight under reflux.

[0266] The resulting mixture was allowed to cool to room temperature, concentrated under reduced pressure. The residue obtained was subjected to silica gel chromatography (hexane:ethyl acetate=9:1) to obtain 0.19 g of compound B-2 with a yield of 81.9%.

Production Example 4

Synthesis of 5,5-dimethyl-4-(p-tolyl)dihydrothiophene-2 (3H)-one (Compound B-6)

[0267] ##STR00064##

[0268] A mixture of compound B-2 (0.19 g), 1,2-dichloroethane (9 mL), and a 1M ethyl aluminum dichloride hexane solution (1.4 mL) was stirred overnight at 70? C.

[0269] The resulting mixture was allowed to cool to room temperature, and the mixture was extracted with dichloromethane. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was subjected to silica gel chromatography (hexane:ethyl acetate=95:5) to obtain 0.10 g of compound B-6 with a yield of 50.5%.

Production Example 5

Synthesis of 4-(4-chlorophenyl)-3,3-dimethylisothiazolidine-1,1-dioxide (Compound B-12)

[Step 1]

[0270] ##STR00065##

[0271] Sulfuryl chloride (13.4 ml) was added to DMF (12.8 ml) under cooling with ice. After stirring at room temperature for 30 minutes, 4-chloro-styrene (11.50 g) was added thereto. The resulting mixture was stirred at 90? C. for 3 hours.

[0272] The resulting mixture was allowed to cool to room temperature, water was added thereto, and the mixture was extracted with dichloromethane. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.

[0273] Dichloromethane (300 ml) and triethylamine (12.6 g) were added to the concentrated residue obtained, and phenol (8.21 g) was added thereto under cooling with ice. The resulting mixture was stirred overnight at room temperature.

[0274] Saturated saline was added thereto, and the mixture was extracted with dichloromethane. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was subjected to silica gel chromatography (hexane:ethyl acetate=9:1) to obtain 10.94 g of intermediate 10 represented by the aforementioned formula with a yield of 44.7%.

[0275] .sup.1H-NMR data of the resulting intermediate 10 are shown below.

.sup.1H-NMR (CDCl.sub.3, 399.78 MHz): ?=7.50-7.24 (m, 10H, ArH, CH?CH), 6.84 (d, 2H, J=15.6 Hz, CH?CH).

[Step 2]

[0276] ##STR00066##

[0277] A mixture of intermediate 10 (10.94 g), acetonitrile (100 ml), 2-nitropropane (4.96 g), and DBU (8.48 g) was stirred overnight at room temperature.

[0278] 1N hydrochloric acid was added thereto, and the mixture was extracted with diethyl ether. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was subjected to silica gel chromatography (hexane:ethyl acetate=9:1) to obtain 9.43 g of intermediate 11 represented by the aforementioned formula with a yield of 66.2%.

[0279] .sup.1H-NMR data of the resulting intermediate 11 are shown below.

.sup.1H-NMR (CDCl.sub.3, 399.78 MHz): ?=7.36-7.26 (m, 5H, ArH), 7.18-7.15 (m, 2H, ArH), 6.99-6.97 (m, 2H, ArH), 3.96-3.74 (m, 3H, C(Ar)HCH2-), 1.58 (s, 6H, CH3).

[Step 3]

[0280] ##STR00067##

[0281] A mixture of intermediate 11 (1.15 g), acetic acid (15 ml), and zinc (3.92 g) was stirred overnight at 50? C. The resulting mixture was allowed to cool to room temperature and filtered through celite. Water was added to the resulting filtrate, and the mixture was extracted with ethyl acetate.

[0282] The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was subjected to silica gel chromatography (ethyl acetate:methanol=8:2) to obtain 0.42 g of intermediate 12 represented by the aforementioned formula with a yield of 39.5%. .sup.1H-NMR data of the resulting intermediate 12 are shown below.

.sup.1H-NMR (CDCl.sub.3, 399.78 MHz): ?=7.33-7.22 (m, 7H, ArH), 7.00-6.97 (m, 2H, ArH), 4.12-4.08 (m, 1H, CH2-), 3.77-3.75 (m, 1H, CH2-), 3.24-3.20 (m, 1H, C(Ar)H), 1.15 (s, 3H, CH3), 1.03 (s, 3H, CH3).

[Step 3] Intermediate

[0283] ##STR00068##

[0284] A mixture of intermediate 12 (0.42 g) and toluene (6.0 ml) was stirred overnight under reflux.

[0285] The resulting mixture was allowed to cool to room temperature, concentrated under reduced pressure. The residue obtained was subjected to silica gel chromatography (hexane:ethyl acetate=5:5) to obtain 0.21 g of compound B-12 with a yield of 79.4%.

Production Example 6

Synthesis of 4,4-dimethyl-5-phenyl-3-azabicyclo[3.1.0]hexan-2-one (Compound C-1)

[Step 1]

[0286] ##STR00069##

[0287] THF (10 ml) was added to a 1.9 M NaHMDS/THF solution (39.5 ml) and cooled to ?10? C. A mixed solution of benzyl cyanide (3.51 g) and THF (45 ml) was added dropwise to this solution, followed by stirring at ?10? C. for 10 minutes. Epichlorohydrin (2.54 ml) was added to the resulting mixture, followed by stirring overnight at room temperature.

[0288] 4 M dioxane hydrochloric acid (30 ml) was added to the resulting mixture, and the mixture was stirred at room temperature for 1.5 hours and then extracted with diethyl ether. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

[0289] THF (50 ml) and a 3 M MeMgCl/THF solution (32 ml) were sequentially added to the concentrated residue obtained, and the mixture was stirred for 30 minutes under heating reflux. The resulting mixture was allowed to cool to room temperature, and then titanium tetraisopropoxide (8.18 ml) was added dropwise thereto, followed by stirring at room temperature for 3 days.

[0290] A saturated ammonium chloride aqueous solution and 2N hydrochloric acid were added to the resulting mixture under cooling with ice, and the mixture was filtered through celite. After the filtrate was washed with ethyl acetate, saturated sodium bicarbonate water was added to the resulting aqueous layer to make it basic. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

[0291] Dichloromethane (25 ml) and di-tert-butyl dicarbonate (2.60 g) were added to the concentrated residue obtained, followed by stirring overnight at room temperature.

[0292] The resulting mixture was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (hexane:ethyl acetate=2:1) to obtain 1.13 g of intermediate 13 represented by the aforementioned formula with a yield of 12.3%.

[0293] .sup.1H-NMR data of the resulting intermediate 13 are shown below.

.sup.1H-NMR (CDCl.sub.3, 399.78 MHz): ?=7.35-7.19 (m, 5H, ArH), 5.41-5.35 (m, 1H, NH), 4.31 (s, 1H, OH), 4.11-3.77 (m, 2H, CH2-), 1.48 (s, 3H, CH3), 1.46 (s, 9H, (CH3)3), 1.29 (s, 3H, CH3), 1.28-1.24 (m, 1H, CH2-), 1.15-1.11 (m, 1H, CH2-), 0.77-0.65 (m, 1H, C(C)H).

[Step 2]

[0294] ##STR00070##

[0295] A mixture of intermediate 13 (1.13 g), DMF (30 ml), molecular sieves 4A (4 g), and pyridinium dichromate (4.18 g) was stirred overnight at room temperature.

[0296] The resulting mixture was cooled with ice and filtered through celite. Water and 2N hydrochloric acid were added to the resulting filtrate, and the mixture was extracted with diethyl ether. The resulting organic layer was washed with saturated saline, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was subjected to silica gel chromatography (hexane:ethyl acetate=4:1) to obtain 0.91 g of intermediate 14 represented by the aforementioned formula with a yield of 81.6%.

[0297] .sup.1H-NMR data of the resulting intermediate 14 are shown below.

.sup.1H-NMR (CDCl.sub.3, 399.78 MHz): ?=7.35-7.31 (m, 5H, ArH), 2.25 (dd, 1H, COC(C)H), 1.60 (s, 3H, CH3), 1.53 (s, 9H, (CH3)3), 1.36-1.30 (m, 2H, CH2-), 1.25 (s, 3H, CH3).

[Step 3]

[0298] ##STR00071##

[0299] A mixture of intermediate 14 (0.50 g), dichloromethane (7 ml), and 4 M dioxane hydrochloric acid (3.32 ml) was stirred at room temperature for 3 hours.

[0300] Saturated sodium bicarbonate water was added to the resulting mixture under cooling with ice, and the mixture was extracted with dichloromethane. The resulting organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (hexane:ethyl acetate=1:1) to obtain 0.32 g of compound C-1 with a yield of 95.2%.

[0301] Tables 2 to 5 show examples of compound (I) produced by the same method as in compounds of Production Examples above. The melting point is also shown as a physical property value.

TABLE-US-00002 TABLE 2 Compound No. Structural formula Properties etc. A-1 [00072] * A-2 [00073] m.p. 182-185? C. A-3 [00074] * A-4 [00075] * A-5 [00076] * A-6 [00077] * A-7 [00078] *

TABLE-US-00003 TABLE 3 Compound No. Structural formula Properties etc. B-1 [00079] * B-2 [00080] * B-3 [00081] * B-4 [00082] * B-5 [00083] * B-6 [00084] m.p. 61-62? C. B-7 [00085] m.p. 87-89? C. B-8 [00086] m.p. 121-122? C. B-9 [00087] * B-10 [00088] * B-11 [00089] m.p. 128-130? C. B-12 [00090] *

TABLE-US-00004 TABLE 4 Compound No. Structural formula Properties etc. C-1 [00091] *

TABLE-US-00005 TABLE 5 Compound No. Structural formula Properties etc. D-1 [00092] m.p. 91-92? C. D-2 [00093] * D-3 [00094] m.p. 75-77? C. D-4 [00095] * D-5 [00096] * D-6 [00097] m.p. 114-115? C. D-7 [00098] m.p. 174-176? C. D-8 [00099] m.p. 141-142? C. D-9 [00100] m.p. 154-156? C. D-10 [00101] m.p. 128-130? C. D-11 [00102] m.p. 148-150? C. D-12 [00103] m.p. 165-170? C. D-13 [00104] m.p. 100-102? C. D-14 [00105] m.p. 78-80? C. D-15 [00106] m.p. 81-83? C. D-16 [00107] m.p. 56-58? C. D-17 [00108] m.p. 51-53? C. D-18 [00109] m.p. 163-165? C. D-19 [00110] *

[0302] Among the compounds described in Tables 2 to 5, the compounds marked with * in the column of melting point were amorphous or had properties of viscous oil. .sup.1H-NMR data thereof are shown below.

compound No. A-1: 1H-NMR (CDCl.sub.3, 500.16 MHz): ?=7.32-7.21 (m, 5H, ArH), 5.64 (brs, 1H, NH), 2.87-2.84 (m, 1H, C(Ar)H), 2.60-1.91 (m, 4H, CH2CH2-), 1.20 (s, 3H, CH3), 1.08 (s, 3H, CH3).
compound No. A-3: 1H-NMR (CDCl.sub.3, 399.78 MHz): ?=7.26-7.08 (m, 4H, ArH), 5.61 (brs, 1H, NH), 2.84-2.80 (m, 1H, C(Ar)H), 2.60-1.87 (m, 4H, CH2CH2-), 2.31 (s, 3H, ArCH3), 1.19 (s, 3H, CH3), 1.07 (s, 3H, CH3).
compound No. A-4: 1H-NMR (CDCl.sub.3, 500.16 MHz): ?=7.99 (d, 2H, J=8.1 Hz, ArH), 7.30 (d, 2H, J=8.1 Hz, ArH), 5.79 (brs, 1H, NH), 3.92 (s, 3H, COOCH3), 2.94-2.91 (m, 1H, C(Ar) H), 2.61-1.92 (m, 4H, CH2CH2-), 1.21 (s, 3H, CH3), 1.08 (s, 3H, CH3).
compound No. A-5: .sup.1H-NMR (CDCl.sub.3, 500.16 MHz): ?=7.33-7.28 (m, 3H, ArH), 7.22-7.20 (m, 2H, ArH), 3.15-3.13 (m, 1H, C(Ar)H), 2.85-2.10 (m, 4H, CH2CH2-), 1.39 (s, 3H, CH3), 1.32 (s, 3H, CH3).
compound No. A-6: 1H-NMR (CDCl.sub.3, 500.16 MHz): ?=7.32-7.31 (d, 2H, J=8.6 Hz, ArH), 7.16-7.14 (d, 2H, J=8.0 Hz, ArH), 3.14 (dd, 1H, J=1.7 Hz, 12.0 Hz, C(Ar)H), 2.86-2.81 (m, 1H, CH2CH2-), 2.74 (ddd, 1H, J=5.8 Hz, 12.1 Hz, 17.8 Hz, CH2CH2-), 2.58-2.49 (m, 1H, CH2CH2-), 2.10-2.05 (m, 1H, CH2CH2-), 2.85-2.06 (m, 4H, CH2CH2-), 1.36 (s, 3H, CH3), 1.30 (s, 3H, CH3).
compound No. A-7: 1H-NMR (CDCl.sub.3, 500.16 MHz): ?=7.13 (d, 2H, J=8.1 Hz, ArH), 7.09 (d, 2H, J=8.0 Hz, ArH), 3.11-3.09 (m, 1H, C(Ar)H), 2.85-2.06 (m, 4H, CH2CH2-), 2.34 (s, 3H, ArCH3), 1.37 (s, 3H, CH3), 1.30 (s, 3H, CH3). compound No. B-1: 1H-NMR (CDCl.sub.3, 500.16 MHz): ?=7.37-7.18 (m, 5H, ArH), 3.55-3.49 (m, 3H, C(Ar)HCH2-), 1.64 (s, 3H, CH3), 1.12 (s, 3H, CH3). compound No. B-2: 1H-NMR (CDCl.sub.3, 500.16 MHz): ?=7.17-7.07 (m, 4H, ArH), 3.50-3.48 (m, 3H, C(Ar)HCH2-), 2.35 (s, 3H, ArCH3), 1.62 (s, 3H, CH3), 1.12 (s, 3H, CH3). compound No. B-3: 1H-NMR (CDCl.sub.3, 500.16 MHz): ?=7.26-6.94 (m, 3H, ArH), 3.79-3.39 (m, 3H, C(Ar)HCH2-), 2.30 (s, 3H, ArCH3), 2.28 (s, 3H, ArCH3), 1.64 (s, 3H, CH3), 1.16 (s, 3H, CH3). compound No. B-4: 1H-NMR (CDCl.sub.3, 500.16 MHz): ?=7.36-7.22 (m, 5H, ArH), 3.63-2.87 (m, 3H, C(Ar)HCH2-), 1.57 (s, 3H, CH3), 1.31 (s, 3H, CH3).
compound No. B-5: 1H-NMR (CDCl.sub.3, 500.16 MHz): ?=7.49 (d, 2H, J=8.6 Hz, ArH), 7.13 (d, 2H, J=8.6 Hz, ArH), 3.58-2.87 (m, 3H, C(Ar)HCH2-), 1.55 (s, 3H, CH3), 1.29 (s, 3H, CH3).
compound No. B-9: .sup.1H-NMR (CDCl.sub.3, 500.16 MHz): ?=7.39-7.24 (m, 5H, ArH), 4.26 (brs, 1H, NH), 3.79-3.53 (m, 3H, C(Ar)HCH2-), 1.40 (s, 3H, CH3), 1.11 (s, 3H, CH3).
compound No. B-10: 1H-NMR (CDCl.sub.3, 500.16 MHz): ?=7.52-7.12 (m, 4H, ArH), 4.20 (brs, 1H, NH), 3.75-3.54 (m, 3H, C(Ar)HCH2-), 1.40 (s, 3H, CH3), 1.11 (s, 3H, CH3).
compound No. B-12: 1H-NMR (CDCl.sub.3, 500.16 MHz): ?=7.37-7.18 (m, 4H, ArH), 4.27 (brs, 1H, NH), 3.74-3.55 (m, 3H, C(Ar)HCH2-), 1.40 (s, 3H, CH3), 1.10 (s, 3H, CH3).
compound No. C-1: 1H-NMR (CDCl.sub.3, 399.78 MHz): ?=7.35-7.28 (m, 5H, ArH), 5.06 (s, 1H, NH), 2.20-2.16 (m, 1H, COCH), 1.38 (s, 3H, CH3), 1.35-1.33 (dd, 1H, CH2-), 1.28-1.25 (dd, 1H, CH2-), 1.08 (s, 3H, CH3).
compound No. D-2: 1H-NMR (CDCl.sub.3, 399.78 MHz): ?=7.06-7.01 (m, 3H, ArH), 3.77-3.73 (m, 1H, C(Ar)H), 3.04-2.81 (m, 2H, CH2-), 2.32 (s, 3H, ArCH3), 2.30 (s, 3H, ArCH3), 1.54 (s, 3H, CH3), 1.09 (s, 3H, CH3).
compound No. D-4: 1H-NMR (CDCl.sub.3, 399.78 MHz): ?=6.94 (s, 1H, ArH), 6.81 (s, 1H, ArH), 3.45-3.41 (m, 1H, C(Ar)H), 3.02-2.82 (m, 2H, CH2-), 2.32 (s, 6H, ArCH3), 1.54 (s, 3H, CH3), 1.06 (s, 3H, CH3).
compound No. D-5: 1H-NMR (CDCl.sub.3, 399.78 MHz): ?=7.20-7.12 (m, 4H, ArH), 3.51-3.47 (m, 1H, C(Ar)H), 3.03-2.83 (m, 2H, CH2-), 2.65 (q, 2H, J=7.6 Hz, 15.6 Hz, ArCH2-), 1.54 (s, 3H, CH3), 1.23 (t, 3H, J=7.2 Hz, CH2CH3), 1.05 (s, 3H, CH3).
compound No. D-19: 1H-NMR (CDCl.sub.3, 399.78 MHz): ?=7.09 (s, 1H, ArH), 7.05-7.00 (m, 2H, ArH), 6.41 (brs, 1H, NH), 5.86 (d, 1H, J=2 Hz, ?CH), 2.50 (s, 3H, ArCH3), 2.24 (s, 3H, ArCH3), 1.41 (s, 6H, CH3).

[Method for Producing Optically Active Compound]

[0303] Optically active compound No. 2 (referred to also as compound No. 2 (?)) shown below was produced. The symbol * in the formula indicates an enantiomeric excess compound.

##STR00111##

[0304] The specific rotation of Compound 2 (?) was (?) Specifically, it was specific rotation [?] (365 nm, 25? C.)=?98.8 (c1.057, dichloromethane). The melting point was 154? C. to 155? C. The enantiomer excess was 99.8% ee.

[0305] The production method thereof is shown below.

Production Example 7

Synthesis of (?)-5,5-dimethyl-4-(4-methylphenyl)-2-pyrrolidinone (Compound 2 (?))

[Step 1]

[0306] ##STR00112##

[0307] A mixture of ethyl (E)-3-(p-tolyl)acrylate (118.59 g), acetonitrile (300 ml), 2-nitropropane (140.24 mL), and DBU (232.60 mL) was stirred overnight at room temperature.

[0308] 1N hydrochloric acid was added thereto, and the mixture was extracted with diethyl ether. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was subjected to silica gel chromatography (hexane:ethyl acetate=95:5) to obtain 150.35 g of intermediate 15 represented by the aforementioned formula with a yield of 86.3%.

[0309] .sup.1H-NMR data of the resulting intermediate 15 are shown below.

.sup.1H-NMR (CDCl.sub.3, 399.78 MHz): ?=7.12-7.07 (m, 4H, ArH), 4.02-3.90 (m, 2H, COOCH2-), 3.88-3.84 (m, 1H, C(Ar)H), 2.89-2.60 (m, 2H, CH2COO), 2.31 (s, 3H, ArCH3), 1.57 (s, 3H, CH3), 1.48 (s, 3H, CH3), 1.05 (t, 3H, J=6.8 Hz, CH2CH3).

[Step 2]

[0310] ##STR00113##

[0311] A mixture of intermediate 15 (5.58 g), methanol (20 ml), and potassium hydroxide (1.68 g) was stirred overnight at room temperature.

[0312] Water was added to the resulting mixture, and the mixture was extracted with diethyl ether. Concentrated hydrochloric acid was added to the resulting aqueous layer, and the mixture was extracted with dichloroethane. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, to obtain 3.75 g of intermediate 16 represented by the aforementioned formula with a yield of 74.6%.

[0313] .sup.1H-NMR data of the resulting intermediate 16 are shown below.

.sup.1H-NMR (CDCl.sub.3, 399.78 MHz): ?=7.12-7.05 (m, 4H, ArH), 3.83-3.79 (m, 1H, C(Ar)H), 2.91-2.61 (m, 2H, CH2COO), 2.31 (s, 3H, ArCH3), 1.54 (s, 3H, CH3), 1.45 (s, 3H, CH3).

[Step 3]

[0314] ##STR00114##

[0315] A mixture of intermediate 16 (2.51 g), dichloromethane (200 ml), (S)-1-(naphthalen-2-yl)ethan-1-amine (2.10 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.83 g), and 4-dimethylaminopyridine (0.37 g) was stirred overnight at room temperature.

[0316] Water was added to the resulting mixture, and the mixture was extracted with dichloroethane. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was subjected to silica gel chromatography (hexane:ethyl acetate=1:1) to obtain 1.91 g of intermediate 17-1 represented by the aforementioned formula with a yield of 94.6% and 1.84 g of intermediate 17-2 represented by the aforementioned formula with a yield of 91.1%.

[0317] .sup.1H-NMR data of intermediate 17-1 obtained are shown below.

.sup.1H-NMR (CDCl.sub.3, 399.78 MHz): ?=7.80-7.73 (m, 3H, ArH), 7.53 (s, 1H, ArH), 7.49-7.43 (m, 2H, ArH), 7.19-7.17 (m, 1H, ArH), 7.13-7.06 (m, 4H, ArH), 5.48 (brd, 1H, J=7.6 Hz, NH), 5.09-5.02 (m, 1H, C*(Me)H), 3.78-3.74 (m, 1H, C(Ar)H), 2.71-2.62 (m, 2H, CH2CO), 2.32 (s, 3H, ArCH3), 1.55 (s, 3H, CH3), 1.52 (s, 3H, CH3), 1.28-1.23 (m, 3H, C*CH3).

[0318] .sup.1H-NMR data of intermediate 17-2 obtained are shown below.

.sup.1H-NMR (CDCl.sub.3, 399.78 MHz): ?=7.78-7.75 (m, 1H, ArH), 7.69-7.66 (m, 1H, ArH), 7.61 (d, 1H, J=8 Hz, ArH), 7.47-7.41 (m, 2H, ArH), 7.38 (s, 1H, ArH), 7.05-7.01 (m, 4H, ArH), 6.89-6.86 (m, 1H, ArH), 5.48 (brd, 1H, J=8.4 Hz, NH), 5.13-5.05 (m, 1H, C*(Me)H), 3.79-3.75 (m, 1H, C(Ar)H), 2.72-2.61 (m, 2H, CH2CO), 2.27 (s, 3H, ArCH3), 1.55 (s, 3H, CH3), 1.54 (s, 3H, CH3), 1.44-1.42 (m, 3H, C*CH3).

[Step 4]

[0319] ##STR00115##

[0320] A mixture of intermediate 17-1 (1.90 g), acetic acid (15 ml), acetic anhydride (30 ml), and sodium nitrite (3.24 g) was stirred overnight at room temperature.

[0321] Sodium bicarbonate water was added to the resulting mixture, and the mixture was extracted with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. THF (30 mL), water (15 mL), and lithium hydroxide (0.22 g) were added to the residue obtained, followed by stirring overnight at room temperature.

[0322] Water was added to the resulting mixture, and the mixture was extracted with diethyl ether. Concentrated hydrochloric acid was added to the resulting aqueous layer, and the mixture was extracted with dichloroethane. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, to obtain 0.75 g of intermediate 16-1 represented by the aforementioned formula with a yield of 63.6%.

[Step 5]

[0323] ##STR00116##

[0324] A 10% hexane solution of trimethylsilyldiazomethane (3.0 ml) was added to a mixture of intermediate 16-1 (0.75 g), diethyl ether (12 ml), and methanol (3 ml) under cooling with ice. The temperature was raised to room temperature, followed by stirring for 1 hour.

[0325] Acetic acid was added to the resulting mixture, and the mixture was concentrated under reduced pressure. The residue obtained was subjected to silica gel chromatography (hexane:ethyl acetate=9:1) to obtain 0.70 g of intermediate 18-1 represented by the aforementioned formula with a yield of 88.4%.

[0326] .sup.1H-NMR data of the resulting intermediate 18-1 are shown below.

.sup.1H-NMR (CDCl.sub.3, 399.78 MHz): ?=7.12-7.07 (m, 4H, ArH), 3.88-3.85 (m, 1H, C(Ar) H), 3.51 (s, 3H, COOCH3), 2.91-2.61 (m, 2H, CH2COO), 2.31 (s, 3H, ArCH3), 1.56 (s, 3H, CH3), 1.47 (s, 3H, CH3).

[Step 6]

[0327] ##STR00117##

[0328] A mixture of intermediate 18-1 (0.70 g), ethanol (12 mL), a saturated ammonium chloride aqueous solution (3 ml), and zinc (1.46 g) was stirred overnight under reflux.

[0329] The resulting mixture was allowed to cool to room temperature and filtered through celite. Water was added to the resulting filtrate, and the mixture was extracted with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was subjected to silica gel chromatography (ethyl acetate:methanol=9:1) to obtain 0.43 g of compound 2 (?) (99.8% ee) with a yield of 76.7%.

[0330] Likewise, optically active compound No. 1 shown below (referred to as compound No. 1 (?)) was also produced. The symbol * in the formula indicates an enantiomeric excess compound.

##STR00118##

[0331] The specific rotation of compound 1 (?) was (?). Specifically, it was specific rotation [?] (365 nm, 25? C.)=?110.4 (c1. 087, dichloromethane). The melting point was 119-121? C. The enantiomer excess was 99.7% ee.

[0332] Likewise, optically active compound No. 3 (referred to as compound No. 3 (?)) shown below was also produced. The symbol * in the formula indicates an enantiomeric excess compound.

##STR00119##

[0333] The specific rotation of compound 3 (?) was (?) Specifically, it was specific rotation [?] (365 nm, 25? C.)=?86.3 (c1. 629, dichloromethane). The melting point was 174-175? C. The enantiomer excess was 99.2% ee.

[0334] Optically active compound No. B-12 (referred to as compound No. B-12 (?)) shown below was also produced. The symbol * in the formula indicates an enantiomeric excess compound.

##STR00120##

[0335] This compound was prepared by preparative purification using a chiral separation column.

[0336] The specific rotation of compound B-12 (?) was (?) Specifically, it was specific rotation [?] (365 nm, 25? C.)=?53.88 (c1.629, dichloromethane). The enantiomer excess was 99.9% ee.

[0337] The conditions for fractionation are shown below. A preparative sample was prepared by adding 2-propanol to compound B-12 to prepare a solution with a concentration of 20 mg/mL, and further adding n-heptane to make a solution with a concentration of 10 mg/mL.

(Preparative Conditions)

[0338] Column: CHIRALART Cellulose-C (5 ?m) 250?30 mm I.D. [0339] Eluent: n-Heptane/2-propanol (50/50) [0340] Flow rate: 21.3 mL/min [0341] Temperature: Ambient [0342] Detection: UV at 230 nm [0343] Load: 330 mg (10 mg/mL) [0344] System: LC-Forte/R (YMC)

[0345] A compound having a specific rotation of (+) was also produced with reference to the aforementioned production method. The respective physical property data are shown below.

Compound No. 1 (+): (+)-5,5-dimethyl-4-phenyl-2-pyrrolidinone Specific rotation [?] (365 nm, 25? C.)=+110.2 (c1.375, dichloromethane). The melting point was 120-121? C. The enantiomer excess was 99.7% ee.
Compound No. 2 (+): (+)-5,5-dimethyl-4-(4-methylphenyl)-2-pyrrolidinone Specific rotation [?] (365 nm, 25? C.)=+94.2 (c1.143, dichloromethane). The melting point was 154? C.-155? C. The enantiomer excess was 98.8% ee.
Compound No. 3 (+): (+)-5,5-dimethyl-4-(4-chlorophenyl)-2-pyrrolidinone Specific rotation [?] (365 nm, 25? C.)=+86.3 (c0.792, dichloromethane). The melting point was 174-175? C. The enantiomer excess was 99.6% ee.
Compound No. B-12 (+): (+)-4-(4-chlorophenyl)-3,3-dimethylisothiazolidine-1,1-dioxide Specific rotation [?](365 nm, 25? C.)=+56.09 (c0.792, dichloromethane). The melting point was 179-180? C. The enantiomer excess was 99.9% ee.

[Formulation Examples]

[0346] A few formulation examples of the control agent of the present invention are shown. Compound (I) (active ingredient), additives, and added ratios are not limited to such examples and can be changed in a wide range. Parts in the formulation examples indicates parts by weight.

(Formulation Example 1) Wettable Powder

[0347] Compound (I): 20 parts [0348] White carbon: 20 parts [0349] Diatomaceous earth: 52 parts [0350] Sodium alkyl sulfate: 8 parts

[0351] The aforementioned materials were uniformly mixed and finely pulverized to obtain a wettable powder containing 20% of the active ingredient.

(Formulation Example 2) Emulsifiable Concentrate

[0352] Compound (I): 20 parts [0353] Xylene: 55 parts [0354] Dimethylformamide: 15 parts [0355] Polyoxyethylene phenyl ether: 10 parts

[0356] The aforementioned materials were mixed and dissolved to obtain an emulsifiable concentrate containing 20% of the active ingredient.

(Formulation Example 3) Granule

[0357] Compound (I): 5 parts [0358] Talc: 40 parts [0359] Clay: 38 parts [0360] Bentonite: 10 parts [0361] Sodium alkyl sulfate: 7 parts

[0362] The aforementioned materials were uniformly mixed and finely pulverized, and the mixture was granulated into granules having a diameter of 0.5 to 1.0 mm to obtain a granule containing 5% of the active ingredient.

(Formulation Example 4) Liquid Formulation

[0363] Compound (I): 10 parts [0364] Dimethylsulfoxide: 75 parts [0365] Polyoxyethylene alkyl ether: 5 parts [0366] Polyoxyethylene higher fatty acid ether: 10 parts

[0367] The aforementioned materials were mixed and dissolved to obtain a solution containing 10% of the active ingredient.

Biological Experimental Examples

[0368] (Experimental Examples 1) Hatching Accelerating Effect Evaluation Test for Globodera pallida (Liquid Immersion Test)

(1) Preparation of Test Reagent Solution

[0369] A predetermined amount of compound (I) was dissolved in an aqueous solution containing 0.05% (v/v) of polyoxyethylene sorbitan monolaurate (Tween20) to prepare a 100 ppm solution of compound (I).

[0370] The 100 ppm solution of compound (I) was further diluted with a 0.05% (v/v) Tween20 aqueous solution to prepare a test reagent solution with a concentration of compound (I) of 2 ppm.

(2) Test Method

[0371] The cysts of Globodera pallida increased in a greenhouse before the previous year were isolated from the soil, immersed in distilled water and kept at 16? C. for about 2 weeks were crushed with a scalpel and the eggs were taken out to obtain an egg suspension. After preparing a density of approximately 600 eggs per mL, Tween 20 was added to a concentration of 0.05% (v/v). 1 mL of this egg suspension was put into a 13.5 mL screw cap glass vial (inner diameter: 2.1 cm, height: 4.8 cm), and 1 mL each of a test reagent solution with a concentration of compound (I) of 2 ppm was added. It was covered and kept at 16? C.

[0372] About 2 weeks later, 1 mL was taken out, and the number of hatching larvae and the number of eggs were counted under a stereomicroscope. Two replicates were installed for each compound, and the average hatching rate was calculated.

(3) Test Results

[0373] Table 6 shows the test results.

TABLE-US-00006 TABLE 6 Compound Average hatching No. rate (%) 1 83.0 2 94.3 3 95.2 4 97.9 5 95.6 6 38.0 7 86.6 8 94.1 9 72.3 10 69.2 11 72.9 12 65.4 13 62.6 14 37.6 15 77.3 16 69.2 17 58.6 18 97.1 19 84.6 20 63.1 21 76.6 A-1 77.4 A-2 97.4 A-3 97.2 A-4 68.8 A-5 92.6 A-6 93.6 A-7 93.9 B-1 70.4 B-2 86.6 B-3 21.2 B-4 96.3 B-5 96.9 B-6 97.1 B-7 96.6 B-8 51.2 B-9 69.5 B-10 82.7 B-11 80.2 B-12 93.0 C-1 94.0 D-1 65.6 D-2 94.7 D-3 58.8 D-4 40.1 D-5 56.6 D-6 67.5 D-7 95.2 D-8 91.8 D-9 50.1 D-10 36.4 D-11 59.0 D-12 52.0 D-13 60.1 D-14 63.7 D-15 94.9 D-16 66.5 D-17 55.4 D-18 58.8 D-19 95.7

(4) Test Results for Optically Active Compounds

[0374] Table 7 shows the test results for optically active compounds among compound (I). Some compounds were also tested at even lower concentrations.

TABLE-US-00007 TABLE 7 Average Average Average hatching hatching hatching rate at rate at rate at Compound No. 1 ppm (%) 100 ppb (%) 10 ppb (%) 1 (?) 87.7 47.2 1 (+) 37.8 12.8 2 (?) 91.8 93.1 79.9 2 (+) 63.6 31.6 7.7 3 (?) 92.0 95.1 93.2 3 (+) 93.2 63.3 5.9 B-12(?) 94.6 95.4 93.5 B-12(+) 95.2 80.9 14.5

(Experimental Examples 2) Reduction Test of Globodera Pallida Egg Density (Pot Test)

(1) Preparation of Test Reagent Solution

[0375] After 20 mg of compound (I) was dissolved in 1 mL of dimethylsulfoxide, 199 mL of a 0.1% polyoxyethylene sorbitan monolaurate aqueous solution was added thereto, to obtain a test reagent solution with a concentration of compound (I) of 100 ppm. Further, this was diluted 10-fold with distilled water, to prepare a 10 ppm test reagent solution.

(2) Test Method

[0376] Soil was collected from a field infected with Globodera pallida, and the egg density was investigated, as follows. The cysts were separated from 100 g of the dried soil by dry flotation-sieving method and crushed to release nematode eggs, and the number of eggs was counted under a stereomicroscope. This was taken as the initial density.

[0377] 32 mL of the test reagent solution adjusted to 100 ppm or 10 ppm was added to 800 mL of the collected field soil, followed by stirring well. It was packed in a plastic pot (upper diameter: 10.5 cm, height: 22.5 cm), and placed in a greenhouse without any planting for 30 days. Each pot was watered with 26 mL of distilled water every 6 to 7 days.

[0378] After 30 days, the soil was spread on an aluminum bat and air-dried, and the cysts were separated from 100 g of the dry soil in the same manner as above, to count the number of remaining eggs (density after treatment). Three pots were installed per concentration for each compound, and the average density reduction rate was calculated from the initial density and the density after treatment.

(3) Test Results

[0379] This test was performed for Compound Nos. 2, 3, 4, 5, 12, 18, A-3, and D-15. A pot that was no treated with any compound was taken as a control.

[0380] Table 8 shows the test results.

TABLE-US-00008 TABLE 8 Average density Average density reduction reduction rate at rate at Compound No. 100 ppm (%) 10 ppm (%) 2 98.0 95.4 3 98.5 97.4 4 98.9 98.8 5 98.2 94.1 12 98.8 97.7 18 96.2 81.7 A-3 97.2 94.9 D-15 98.2 85.8 control 6.9 12.7

(Experimental Examples 3) Reduction Test of Globodera Pallida Egg Density (Field Plot Test)

(1) Preparation of Test Reagent Solution

[0381] With reference to Formulation Example 4, a 10% solution of compound No. 2 was prepared. This 10% solution was diluted with distilled water, to prepare test reagent solutions with concentrations of 300 ppm, 30 ppm, and 3 ppm.

(2) Test Method

[0382] Round plots (diameter: 30 cm) were installed in a field infected with Globodera pallida, and the reducing effect of reagent solution treatment on the nematode egg density in soil was investigated. Each plot was prepared by burying a cylinder (30 cm in diameter and 25 cm in height) made of polyethylene sheet to a depth of 20 cm. Test plots were installed in the field and soil samples in each plot were collected for the initial density survey. Then, the test reagent solution of each concentration was sprayed at a ratio of 5 or 1 L per square meter and the soil in the plot was mixed with a shovel to a depth of 15 cm. As a result, treatments with four different doses of compound (1500, 300, 30 and 3 g per 10 a) were prepared.

[0383] About 80 days later, the soil in each plots was collected, and the nematode egg density in the soil was investigated, as follows. The cysts were separated from 100 g of dried soil by a sieving cyst flow method, crushed with a scalpel to extract eggs, suspended in distilled water to extract a certain amount, and the number of eggs was counted under a stereomicroscope.

[0384] Four plots were installed for each concentration, and the average density reduction rate was calculated from the initial density and final density.

(3) Test Results

[0385] The treatment with the compound (compound No. 2) greatly reduced the Gp density in the soil. The Gp density reduction rate for each dose of the compound was as follows. Treatment of compound at a dose of 30 g or more per 10a could reduce by 80% or more of Gp density in the soil. It is demonstrating the compound has remarkable reducing effect on Gp density. [0386] Dose: 1500 g/10 a: 98.4% [0387] 300 g/10 a: 94.4% [0388] g/10 a: 88.8% [0389] 3 g/10 a: 65.6% [0390] 0 g/10 a (control): 9.0%

(All are Averages of the Four Plots)

[0391] Since compounds randomly selected from compound (I) showed remarkable reducing effect to Gp density, it can be assumed that compounds belong to compound (I) including compounds that could not be mentioned have high Gp control effect widely.