JPH08333367A - Oxathiolane derivative - Google Patents

Abstract

PURPOSE: To obtain a new oxathiolane derivative having excellent antifungal action and effective against fungal diseases of man and animal. CONSTITUTION: This oxathiolane derivative is a compound expressed by formula I (Ar<1> is phenyl substituted with 1-3 substituents selected from phenyl, halogen and trifluoromethyl; Ar<2> is phenyl, pyridyl, furyl, a lower alkyl, a halogen, nitro, etc.; R<1> is a lower alkyl; R<2> is H or a lower alkyl; R<3> to R<6> are each H, a lower alkyl, etc.; (p) is 0 or 1) or its acid addition salt, e.g. (2S,4R,5R)-5-(2,4- difluorophenyl)-4-methyl-2-[(E)-2-[4-(methylsulfonyl)phenyl]vinyl-5-[( 1H-1,2,4- trmazol-1-yl)methyl]oxothiolane. The compound of formula I can be produced by reacting a triazolylmercaptoalcohol derivative of formula II with a carbonyl compound of formula III, etc., under acidic condition.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an oxathiolane compound represented by the formula (1), which is particularly effective against human and animal fungal diseases.

[0002]

In JP-A-3-223266, the 2-position substituent of the oxathiolane ring in formula (1) is an alkyl group, an unsubstituted or substituted aryl group, an aralkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, It has been described that compounds related to the compound of the present invention, such as a halogeno lower alkyl group, have antifungal activity.

[0003]

However, there is no disclosure of the compound of the present invention. The inventors have found that the compounds of the present invention have excellent antifungal activity and completed the present invention.

[0004]

The present invention is a compound having the formula (1) or an acid addition salt thereof.

[0005]

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In the formula, Ar ¹ is a phenyl group or a substituent 1 to 3 selected from a halogen atom and trifluoromethyl.
Phenyl been Ar ² represents a phenyl group substituted by number, pyridyl, furyl or thienyl, or a lower alkyl, lower alkoxy, halogen atom, substituted lower alkyl with a halogen atom, lower alkoxy substituted by halogen atom, nitro, Cyano, S (O) _m R ⁷ (R ⁷ represents a lower alkyl group optionally substituted by a halogen atom, m represents 0, 1 or 2) and NHCOR
⁸ (R ⁸ represents a lower alkyl group) represents a phenyl group, a pyridyl group, a furyl group or a thienyl group substituted with 1 to 3 substituents, R ¹ represents a lower alkyl group and R ² Represents a hydrogen atom or a lower alkyl group, R
³ , R ⁴ , R ⁵ and R ⁶ are the same or different and are a hydrogen atom: a lower alkyl group: or a substituted lower alkyl group (wherein the substituent is a halogen atom, a hydroxyl group, a lower alkoxy, a lower atom substituted with a halogen atom). Alkoxy, lower alkanoyloxy, —S (O) _m R ⁷ (R ⁷ and m are as defined above) and NHCOR ⁸ (R ⁸
Represents the same meaning as described above)), p
Represents 0 or 1.

Examples of the above halogen atom include fluorine, chlorine and bromine atoms. Lower alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl. Lower alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy or tert-butoxy. Lower alkanoyloxy groups include, for example, formyloxy, acetoxy, propionyloxy, butyryloxy or pivaloyloxy.

Preferred compounds of formula (1) are 2,4-dichlorophenyl, 2,4-difluorophenyl, 4-chlorophenyl or 4- (trifluoromethyl) phenyl for Ar ¹ , particularly preferably 2 , 4-dichlorophenyl, 2,4-difluorophenyl or 4
A compound that is-(trifluoromethyl) phenyl.

Compounds in which R ¹ is methyl, ethyl, propyl, especially methyl.

Compounds in which R ² is a hydrogen atom, methyl, ethyl, propyl, particularly preferably a hydrogen atom or methyl.

Ar ² is 4-fluorophenyl, 4-chlorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 4- (trifluoromethyl) phenyl, 4- (trichloromethyl) phenyl, 2-fluoro-4. -(Trifluoromethyl) phenyl, 4- (difluoromethoxy) phenyl, 3- (trifluoromethoxy) phenyl, 4- (trifluoromethoxy) phenyl, 4- (2,2,2-trifluoroethoxy) phenyl, 4 -(1,1,2,2-tetrafluoroethoxy)
Phenyl, 4- (2,2,3,3-tetrapropoxy)
Phenyl, 2-fluoro-4- (2,2,3,3-tetrapropoxy) phenyl, 4-nitrophenyl, 2-fluoro-4-nitrophenyl, 4-cyanophenyl, 2
-Chloro-4-cyanophenyl, 4- (methylthio) phenyl, 4- (methylsulfinyl) phenyl, 4-
(Methylsulfonyl) phenyl, 4- (trifluoromethylthio) phenyl, 4- (trifluoromethylsulfonyl) phenyl, 6-chloro-3-pyridyl, 6- (trifluoromethyl) -3-pyridyl, 5-chloro-2 −
Pyridyl, 5- (trifluoromethyl) -2-furyl,
5-chloro-2-thienyl or 5- (trifluoromethyl) -2-thienyl, especially 4-chlorophenyl,
2,4-difluorophenyl, 4- (trifluoromethyl) phenyl, 4- (trifluoromethoxy) phenyl, 4- (2,2,3,3-tetrapropoxy) phenyl, particularly preferred Ar ² is 4-chlorophenyl, 4- (trifluoromethyl) phenyl, 4-
A compound which is (2,2,3,3-tetrafluoropropoxy) phenyl or 4- (trifluoromethoxy) phenyl.

R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and are a hydrogen atom, methyl, trifluoromethyl,
Hydroxymethyl, methoxymethyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, methylthiomethyl, trifluoromethylthiomethyl, or acetamidomethyl, preferably a hydrogen atom, methyl, trifluoromethyl or acetoxymethyl , Particularly preferred compounds wherein R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen or methyl.

A compound in which p is 0 or 1, particularly preferably a compound in which p is 1.

Specific examples of the preferred compound (1) include:
Ar ¹ is 2,4-difluorophenyl or 4-a (trifluoromethyl) phenyl, R ¹ is methyl, R ² and ^{-CR 3 = CR 4 - (CR} 5 = CR 6)
Compounds in which _p Ar ₂ is a group as shown in Table 1 can be mentioned.

[0015]

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[0016]

[Chemical 4]

[0017]

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[0018]

[Chemical 6]

[0019]

[Chemical 7]

[0020]

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[0021]

[Chemical 9]

[0022]

[Chemical 10]

[0023]

[Chemical 11]

[0024]

[Chemical 12]

[0025]

[Chemical 13]

The oxathiolane derivative (1) of the present invention is 2
It has asymmetric carbon atoms and exists in optical isomers and diastereomers. Optical enantiomers can be obtained as both antipodes by a general optical resolution method or an asymmetric synthesis method. The diastereomers can be separated by using a usual separation method such as fractional recrystallization or chromatography. Formula (1) includes one or a mixture of these isomers.

The oxathiolane derivative (1) of the present invention is
It can be used as it is or in the form of an acid addition salt as an antifungal agent. The acid addition salt of compound (1) is, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitrate, oxalic acid or methanesulfonate.

The compound having the formula (1) of the present invention can be produced by the following method.

[0029]

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(In the above formula, Ar ¹ , Ar ² , R ¹ ,
R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and p have the same meanings as described above, and R ⁹ represents a lower alkyl group such as methylethylpropyl. ) That is, JP-A-3-24
The carbonyl compound (3) or its acetal derivative (4) with respect to the triazolyl mercaptoalcohol derivative (2) described in 0778 (flat 3.10.28).
Is a reaction method under acidic conditions to produce the target compound (1). Examples of the solvent used in the reaction include diethyl ether, tetrahydrofuran, dioxane, benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, benzene, toluene and the like. The acid used is, for example, hydrogen chloride, sulfuric acid, nitric acid, boron trifluoride, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoromethanesulfonic acid trimethylsilyl ester, etc., and is used. The amount of acid is 1 to 2 equivalents relative to (2). (3) or (4)
Is used in 1 to 3 equivalents. The reaction is carried out in the range of -20 ° C to the boiling point of the solvent, and the reaction time is 10 minutes to 5 hours. Water or alcohol R ⁹ OH produced in the reaction can be removed by azeotropic distillation, but molecular sieves may be used as a dehydrating agent. After completion of the reaction, the compound (1) can be obtained by neutralizing the reaction solution with aqueous sodium hydrogen carbonate and the like and then separating and purifying according to a conventional method.

The carbonyl compound (3) or its acetal derivative (4) used in the above reaction can be obtained according to the following reaction route. Specifically, compounds (3) and (4) are obtained according to Reference Examples 1 to 6.

[0032]

[Chemical 15]

(In the above formula, Ar ² , R ² , R ³ , R ⁴ ,
R ⁵ , R ⁶ , R ⁹ and p are as defined above, and R ² ′ is a lower alkyl group. DIBAL-
H represents diisobutylaluminum hydride. ) Regarding the compound (1) of the present invention, Candida albicans 4-9 × 10 ⁶
Mice inoculated with 10 mice (-group, 10 mice) were orally administered with 20 mg / kg for 1,4 and 24 hours, and the survival rate up to 21 days after infection was examined. (1) showed excellent activity as compared with known ketoconazole.

The compound (1) of the present invention is formulated alone or in combination with other excipients, diluents, dispersants, and other additives as a dosage form for oral or parenteral administration. used.

The dose and the number of doses vary depending on the symptoms, age, body weight, dosage form and the like, but in the case of oral administration, it is usually 50 to 1000 mg, preferably 100 to 100, per adult per day.
500 mg can be administered once or in several divided doses.

A more detailed description will be given below with reference to examples.

[0037]

【Example】

Example 1 (2S, 4R, 5R) -5- (2,4-difluorophenyl) -4-methyl-2-[(E) -2- [4- (methylsulfonyl) phenyl] vinyl-5-[( 1H-1,
2,4-triazol-1-yl) methyl] oxothiolane

[0038]

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(2R, 3R) -2- (2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,
4-triazol-1-yl) -2-butanol 104
mg (0.36 mmol) and trans-4- (methylsulfonyl) cinnamaldehyde 227 mg (1.08 m
mol) in dichloromethane (20 ml) and p-toluenesulfonic acid monohydrate 70 mg (0.37 mmol)
And Molecular Sieves 4A (0.8g) at room temperature for 30
Stir for minutes. Then, the mixture was cooled to 0 ° C. and stirred, and trifluoromethanesulfonic acid trimethylsilyl ester 25 mg
(0.11 mmol) was added. After 10 minutes, aqueous sodium hydrogen carbonate was added and the mixture was extracted with ethyl acetate. 2 ml of ethyl acetate was added to the residue obtained by distilling the solvent off, and 155 mg of the insoluble material (starting aldehyde) was filtered off. The residual oil obtained by concentrating the filtrate was subjected to column chromatography using 5 g of silica gel and ethyl acetate-hexane (2: 1).
72 mg (41% yield) of the title compound eluted with a mixed solvent
Was obtained as an oil.

NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.13
(3H, d, J = 6.6Hz), 3.06 (3H, s), 4.00 (1H, qd, J = 6.6,4.0Hz),
4.68 (1H, d, J = 14.5Hz), 5.13 (1H, d, J = 14.5Hz), 6.17 (1H, d,
J = 7.3Hz), 6.44 (1H, dd, J = 15.8,7.3Hz), 6.79 (1H, d, J = 15.8
Hz), 6.75-7.0 (2H, m), 7.30 (1H, m), 7.47 (1H, s), 7.62 (2H,
d, J = 8.6Hz), 7.78 (1H, s), 7.92 (2H, d, J = 8.6Hz) Example 2 (2S, 4R, 5R) -5- (2,4-difluorophenyl) -4- Methyl-2-[(E) -2- [4- (trifluoromethyl) phenyl] vinyl] -5-[(1H-
1,2,4-triazol-1-yl) methyl] oxothiolane

[0041]

[Chemical 17]

(2R, 3R)-(2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,4-
50 mg of triazol-1-yl) -2-butanol
(0.175 mmol) and trans-4- (trifluoromethyl) cinnamaldehyde 71 mg (0.36 mm
ol) was dissolved in 10 ml of dichloromethane, 38 mg (0.20 mmol) of p-toluenesulfonic acid monohydrate and 0.4 g of Molecular Sieves 4A were added, and the mixture was stirred at room temperature for 30 minutes. Then, the mixture was cooled to 0 ° C. and stirred with trifluoromethanesulfonic acid trimethylsilyl ester 18 mg
(0.08 mmol) was added. After 10 minutes, aqueous sodium hydrogen carbonate was added and the mixture was extracted with ethyl acetate. The residue obtained by distilling off the solvent was purified by column chromatography using 3 g of silica gel. Elution with a 20% ethyl acetate-hexane mixed solvent is a stereoisomer of the title compound (2R, 4R, 5).
2.9 mg (yield 3.5%) of R) -isomer (2A) was obtained as an oil. Further eluted with a 30-50% ethyl acetate-hexane mixed solvent to give 42.4 m of the title compound (2B).
g (52% yield) was obtained as an oil.

Specific rotation: (2B), [α] ²⁵ _D + 51 ° (C =
0.85, CHCl ₃ ) NMR spectrum (270 MHz, CDCl ₃ ) δppm: (2A), 1.21 (3H, d, J
= 7.1Hz), 4.06 (1H, qd, J = 7.1,3.0Hz), 4.79 (1H, d, J = 14.4H
z), 4.98 (1H, d, J = 14.4Hz), 6.07 (1H, d, J = 7.5Hz), 6.54 (1H,
dd, J = 15.8,7.5Hz), 6.81 (1H, d, J = 15.8Hz), 6.75-6.95 (2H,
m), 7.35 (1H, td, J = 8.9,6.5Hz), 7.55 (2H, d, J = 8.4Hz), 7.63
(2H, d, J = 8.4Hz), 7.75 (1H, s), 7.85 (1H, s); (2B), 1.13 (3H,
d, J = 6.8Hz), 3.99 (1H, qd, J = 6.8,3.9Hz), 4.69 (1H, d, J = 14.
9Hz), 5.13 (1H, d, J = 14.9Hz), 6.15 (1H, d, J = 7.6Hz), 6.38 (1
H, dd, J = 15.8,7.6Hz), 6.77 (1H, d, J = 15.8Hz), 6.75-6.95 (2
H, m), 7.32 (1H, td, J = 8.9,6.5Hz), 7.49 (1H, s), 7.53 (2H, d,
J = 8.5Hz), 7.60 (2H, d, J = 8.5Hz), 7.78 (1H, s). Example 3 (2S, 4R, 5R) -5- (2,4-difluorophenyl) -4-methyl -2-[(1E, 3E) -4- [4
-(Trifluoromethoxy) phenyl] -1,3-butadiene-1-yl] -5-[(1H-1,2,4-triazol-1-yl) methyl] oxothiolane

[0044]

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(2R, 3R)-(2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,4-
250 mg of triazol-1-yl) -2-butanol
(0.88 mmol) and (2E, 3E) -5- [4-
(Trifluoromethoxy) phenyl] -2,4-pentadienyl (425 mg, 1.75 mmol) was dissolved in dichloromethane (50 ml), p-toluenesulfonic acid monohydrate (183 mg, 0.96 mmol) and molecular sieves 4A (2 g) were added, and the mixture was stirred at room temperature for 30 minutes. Stir for minutes. Then 0
The mixture was cooled to ° C and 86 mg (0.39 mmol) of trifluoromethanesulfonic acid trimethylsilyl ester was added with stirring. After 10 minutes, aqueous sodium hydrogen carbonate was added and the mixture was extracted with ethyl acetate.
The residue obtained by distilling off the solvent was purified by column chromatography using 10 g of silica gel. 25
(2R, 4R, 5R) -isomer (3) which is a stereoisomer of the title compound by eluting with a mixed solvent of ethyl acetate-hexane (3%).
A) 27 mg (yield 6%) was obtained as an oil.

Further elution with a 30-50% ethyl acetate-hexane mixed solvent gave 220 mg (yield 49%) of the title compound (3B) as an oil.

Specific rotation: (3A), [α] ²⁵ _D + 184 ° (C
= 0.51, CHCl ₃ ) ;: (3B), [α] ²⁵ _D + 46 ° (C = 0.48, CHCl ₃ ) NMR spectrum (270MHz, CDCl ₃ ) δppm: (3A), 1.19 (3H, d, J
= 7.0Hz), 4.03 (1H, qd, J = 7.0,3.2Hz), 4.78 (1H, d, J = 14.3H
z), 4.93 (1H, d, J = 14.3Hz), 5.99 (1H, d, J = 8.0Hz), 6.06 (1H,
dd, J = 14.2,8.0Hz), 6.57 (1H, dd, J = 14.2,10.4Hz), 6.63 (1
H, d, J = 15.4Hz), 6.81 (1H, dd, J = 15.4,10.4Hz), 6.75-6.9 (2
H, m), 7.19 (2H, d, J = 8.7Hz), 7.32 (1H, td, J = 8.8,6.6Hz), 7.
45 (1H, d, J = 8.7Hz), 7.72 (1H, s), 7.97 (1H, s); (3B), 1.10 (3
H, d, J = 6.6Hz), 3.95 (1H, qd, J = 6.6,2.8Hz), 4.67 (1H, d, J = 1
4.9Hz), 5.10 (1H, d, J = 14.9Hz), 5.95 (1H, dd, J = 14.7,8.0H
z), 6.05 (1H, d, J = 8.0Hz), 6.52 (1H, dd, J = 14.7,10.2Hz), 6.
62 (1H, d, J = 15.8Hz), 6.77 (1H, dd, J = 15.8,10.2Hz), 6.7-6.
95 (2H, m), 7.18 (2H, d, J = 8.7Hz), 7.30 (1H, td, J = 8.8,6.5H
z), 7.42 (2H, d, J = 8.7Hz), 7.51 (1H, s), 7.77 (1H, s). Reference Example 1 Ethyl (2E, 4E) -5- [4- (trifluoromethoxy) phenyl ] -2,4-Pentadienoate

[0048]

[Chemical 19]

55% sodium hydride 610 mg (1
(4.0 mmol) was washed with hexane and then suspended in 25 ml of 1,2-dimethoxyethane, and 3.50 g (13.9 mmol) of triethyl-4-phosphonocrotonate was slowly added while stirring at 0 ° C. under a nitrogen atmosphere. Dropped.
After the dropwise addition, the mixture was stirred at the same temperature for 30 minutes, and then 4- (trifluoromethoxy) benzaldehyde (2.00 mg, 10.
(5 mmol) in 5 ml of 1,2-dimethoxyethane was added dropwise over 5 minutes. After dropping, the mixture was stirred at the same temperature for 15 minutes. After adding water to the reaction solution, it was extracted with benzene. The oily substance obtained by distilling off the solvent is 40 g of silica gel.
Column chromatography using, and eluting with a 3-4% ethyl acetate-hexane mixed solvent to give the title compound 2.
Obtained as a solid with 16 g (72% yield), melting point 30-32 ° C.

Infrared absorption spectrum ν _max (CHCl ₃ ) cm ⁻¹ : 170
5,1629 NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.32 (3H, t, J = 7.2H
z), 4.24 (2H, q, J = 7.2Hz), 6.02 (1H, d, J = 15.2Hz), 6.75-6.9
5 (2H, m), 7.20 (2H, d, J = 8.2Hz), 7.35-7.5 (1H, m), 7.49 (2H,
d, J = 8.2 Hz). Reference Example 2 (2E, 4E) -5- [4- (trifluoromethoxy)
Phenyl] -2,4-pentadiene-1-ol

[0051]

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2.14 g (7.50 mmol) of ethyl (2E, 4E) -5- [4- (trifluoromethoxy) phenyl] -2,4-pentadienoate was added to 30 parts of toluene.
Dissolve in 1.5 ml, 12.5 ml of 1.5M diisobutylaluminum hydride-toluene solution with stirring at 0 ° C.
(18.7 mmol) was added dropwise over 5 minutes. After 15 minutes, 5.5 ml of a saturated ammonium chloride solution was slowly added, then 17 g of anhydrous magnesium sulfate was added, and the mixture was stirred for 30 minutes. The insoluble matter was filtered off using Celite. The crystalline residue obtained by concentrating the filtrate was recrystallized from a mixed solvent of benzene and hexane to give 1.19 g of the title compound (yield: 65).
%), Mp 90-91 ° C.

Infrared absorption spectrum ν _max (CHCl ₃ ) cm ⁻¹ : 331
0 NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.40 (3H, t, J = 5.9H
z), 4.27 (2H, t, J = 5.9Hz), 5.99 (1H, dt, J = 15.2,5.9Hz), 6.4
3 (1H, dd, J = 15.2,10.3Hz), 6.53 (1H, d, 15.6Hz), 6.76 (1H, d
d, J = 15.6,10.3Hz), 7.16 (2H, d, J = 8.4Hz), 7.41 (2H, d, J = 8.
4 Hz). Reference Example 3 (2E, 4E) -5- [4- (trifluoromethoxy)
Phenyl] -2,4-pentadienal

[0054]

[Chemical 21]

(2E, 4E) -5- [4- (trifluoromethoxy) phenyl] -2,4-pentadiene-1-
All 657 mg (2.70 mmol) was dissolved in 32 ml of methylene chloride, 3.04 g of active manganese dioxide was added, and the mixture was stirred at room temperature for 1.5 hours. The solid was filtered off and the solvent was evaporated to give 650 mg of the title compound as an oil.

Infrared absorption spectrum ν _max (CHCl ₃ ) cm ⁻¹ : 168
1,1624 NMR spectrum (270 MHz, CHCl ₃ ) δppm: 6.30 (1H, dd, J = 15.
2,7.9Hz), 6.9-7.05 (2H, m), 7.2-7.35 (3H, m), 7.53 (2H, d, J
= 8.6Hz), 9.64 (1H, d, J = 7.9Hz) Reference Example 4 (2E, 4E) -5- (4-chlorophenyl) -2,4
-Pentadienal

[0057]

[Chemical formula 22]

According to Reference Example 1-3, the title compound was prism-crystallized from 4-chlorobenzaldehyde through 3 steps.
Obtained as a melting point of 69-71 ° C.

NMR spectrum (270 MHz, CDCl ₃ ) δppm: 6.28
(1H, dd, J = 15.2,7.9Hz), 6.9-7.05 (2H, m), 7.2-7.3 (1H, m),
7.36 (2H, d, J = 8.5Hz), 7.44 (2H, d, J = 8.5Hz), 9.63 (1H, d, J =
7.9 Hz) Reference Example 5 (3E, 5E) -6- (4-chlorophenyl) -3,5
-Hexadiene-2-ol

[0060]

[Chemical formula 23]

1.25 g (6.59) of (2E, 4E) -5- (4-chlorophenyl) -2,4-pentadienal
(mmol) was dissolved in 40 ml of ether, and 3.63 ml (7.26 mmol) of 2.0 M methylmagnesium iodide ether solution was added dropwise with stirring at 0 ° C under a nitrogen atmosphere. After the dropping was completed, the reaction solution was stirred at room temperature for 30 minutes. Then, a saturated ammonium chloride solution was added at 0 ° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was distilled off. The residue was subjected to column chromatography using 80 g of silica gel and ethyl acetate-hexane (3:
2) Elution with a mixed solvent gave 1.08 g of the title compound (yield 7
9%) as a solid.

NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.33
(3H, d, J = 6.6Hz), 1.49 (1H, d, J = 4.0Hz), 4.43 (1H, m), 5.89
(1H, dd, J = 15.2,5.9Hz), 6.37 (1H, dd, J = 15.2,10.6Hz), 6.4
9 (1H, d, J = 15.8Hz), 6.73 (1H, dd, J = 15.8,10.6Hz), 7.25-7.
35 (4H, m). Reference Example 6 (3E, 5E) -6- (4-chlorophenyl) -3,5
-Hexadien-2-one

[0063]

[Chemical formula 24]

1.03 g of (3E, 5E) -6- (4-chlorophenyl) -3,5-hexadiene-2-ol
(5.17 mmol) was dissolved in 20 ml of methylene chloride, 10 g of active manganese dioxide was added, and the mixture was stirred at room temperature for 1.5 hours. The solid was filtered off and the solvent was distilled off to obtain 1.00 g (yield 93%) of the title compound as a solid.

NMR spectrum (270 MHz, CDCl ₃ ) δppm:
2.32 (3H, s), 6.27 (1H, d, J = 1
5.8 Hz), 6.8-6.95 (2H, m), 7.2
-7.35 (1H, m), 7.33 (2H, d, J =
8.6 Hz), 7.41 (2H, d, J = 8.6H
z).

Claims (1)

[Claims] (1) Formula (1) Or a acid addition salt thereof. In the formula, Ar ¹ represents a phenyl group or a phenyl group substituted with 1 to 3 substituents selected from a halogen atom and trifluoromethyl, and Ar ² represents phenyl, pyridyl, furyl or thienyl, or lower alkyl, lower alkoxy. A halogen atom, a lower alkyl substituted with a halogen atom, a lower alkoxy substituted with a halogen atom, nitro, cyano,
S (O) _m R ⁷ (R ⁷ represents a lower alkyl group optionally substituted with a halogen atom, and m represents 0, 1 or 2)
And NHCOR ⁸ (R ⁸ represents a lower alkyl group) represents a phenyl group substituted by 1 to 3 substituents, pyridyl group, furyl group or thienyl group, R ¹ represents a lower alkyl group, R ² represents a hydrogen atom or a lower alkyl group, and R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and are a hydrogen atom: a lower alkyl group: or a substituted lower alkyl group (wherein the substituent is a halogen atom). , Hydroxyl group,
Lower alkoxy, lower alkoxy substituted with a halogen atom, lower alkanoyloxy, -S (O) _m R ⁷ (R
⁷ and m are as defined above and NHC
OR ⁸ (wherein R ⁸ has the same meaning as defined above), and p represents 0 or 1.