KR20010094519A - Synthetic Method of 2,2,4,5-tetrasubstituted 3(2H)-furanone derivatives - Google Patents

Abstract

PURPOSE: A process for producing 2,2,4,5-tetrasubstituted 3(2H)-furanone derivatives is provided, thereby the compounds, especially 4,5-diaryl-3(2H)-furanone derivatives can be produced in high yield. CONSTITUTION: The process for producing 2,2,4,5-tetrasubstituted 3(2H)-furanone derivatives of the formula(I) comprises of reacting the compound of formula(II) with 2-haloisobutyryl cyanide or 2-haloisobutyryl halide, if necessary, in the presence of an oxidizing agent, in which X is substituted or unsubstituted aryl or heteroaryl; Y is alkyl, cycloalkyl, substituted or unsubstituted aryl or heteroaryl; and the reaction is carried out in organic solvent in the presence of base, wherein base is sodium hydride, butyllithium, lithium t-butoxide, potassium t-butoxide, sodium t-butoxide, lithium diisopropyl amide, sodium bis(trimethylsillyl) amide, potassium bis(trimethylsillyl) amide, lithium bis(trimethylsillyl) amide or bromomagnesium diisopropyl amide.

Description

Synthetic Method of 2,2,4,5-tetrasubstituted 3 (2H) -furanone derivatives}

The invention 2,2,4,5- fourfold substituted 3 (2H) - it relates to a novel method for fabricating the fuser ranon [2,2,4,5-tetrasubstituted 3 (2H) -furanone] derivative.

3 ( 2H ) -furanone is a substance with flavor, cytotoxic, and anti-tumor activity ( Bioorg. Chem. 1977 , 6 , 287; Tetrahedron 1983 , 39 , 2241; J. Am. Chem. ..... Soc 1976, 98, 2295; Bull Chem Soc Jpn 1983, 56, 3088), recently, 3 (2H) - 2,2,4,5- Pew fourfold substituted 3 (2H) of the ranon-Pugh The inventors have found that lanones, particularly 4,5-diaryl 3 ( 2H ) -furanone derivatives, have an effect of selectively inhibiting cyclooxygenase-2, one of prostaglandin's biosynthetic enzymes. (Korean Patent Application No. 99-13170 (14 April 1999)).

Therefore, interest in 3 ( 2H ) -furanone having such physiological activity has been increased, and a lot of studies on the preparation method have been made.

Conventionally, for the preparation of 2,2,4,5-quad substituted 3 ( 2H ) -furanone derivatives, for example, 4-hydroxy-2-alkain-1-one (4-hydroxy-2-alkyn Tandem CO ₂ addition-elimination method of -1-one) ( Tetrahedron Lett . 1988 , 29 , 5941), oxidative allele ketone using Hg (OAc) ₂ ( Tetrahedron Lett. 1985 , 26 , 703), a method of reducing isoxazoline, followed by cyclization under an acid catalyst ( Tetrahedron Lett . 1983 , 24 , 2079) and γ, γ-double substituted β React with bromo-α, β-butenolide (γ, γ-disubstituted β-bromo-α, β-butenolides), followed by acid treatment ( Tetrahedron Lett . 1980 , 21 , 4057). , 5-Trisubstituted 3 ( 2H ) -furanone derivatives must first be prepared and subjected to, for example, a Suzuki carbon-carbon bonding process using Palladium metal (Korean Patent Application No. 99-13170). Should be. However, this method has a disadvantage in that a large number of by-products are produced, which requires a separate separation and purification process.

On the other hand, without the 2,2,5-trisubstituted 3 ( 2H ) -furanone derivative, a method for directly preparing 2,2,4,5-quad substituted 3 ( 2H ) -furanone derivatives , γ-hydroxy-β-dicarbonyl compound ( J. Am. Chem. Soc. 1981 , 103 , 1501) and 4-hydroxy-2-alkae in a carbon dioxide atmosphere under a calcium carbonate catalyst Methods of reacting phosphine-1-one (4-hydroxy-2-alkyn-1-one) with alkyl halides ( Synthesis 1996 , 1431) are known. However, the former method is obtained through the aldol condensation reaction of 3-methyl-3- (trimethylsiloxy) -2-butanone and aldehyde. It is possible to obtain 3 ( 2H ) -furanone derivatives substituted with 2,2,4,5-quadrate by oxidation / ring reaction of β-hydroxyketone, but it is not easy to obtain a compound represented by the following Chemical Formula 2 various 4,5-diaryl -3 (2H) - Pew ranon producing the derivative, and it is difficult, the latter method due to the use of alkyl halides 3 is 4-and 5-positions is substituted with an aryl group (2H) - There is a problem that can not prepare a furanone derivative.

Where

Y is phenyl, substituted phenyl group and the like.

Accordingly, the present inventors have conducted a study on a method for preparing a new 2,2,4,5-quad substituted 3 ( 2H ) -furanone derivative that can solve the above problems, and as a result, ethanone derivatives and 2,2,4,5-quadrate substitution in very high yields by condensation and cyclization with 2-haloisobutyryl cyanide or 2-haloisobutyryl halide It has been found that the prepared 3 ( 2H ) -furanone derivative can be prepared, thereby completing the present invention.

Accordingly, it is an object of the present invention to provide a novel process for obtaining 2,2,4,5-quaternary substituted 3 ( 2H ) -furanone derivatives in high yield.

In order to achieve the above object, a method for preparing a 2,2,4,5-quarried substituted 3 ( 2H ) -furanone derivative according to the present invention,

The following general formula (II) compound is reacted with 2-haloisobutyryl cyanide or 2-haloisobutyryl halide to give 2,2,4,5-quadically substituted 3 ( 2H )-of general formula (I) Furanone [2,2,4,5-tetrasubstituted 3 ( 2H ) -furanone] derivative is obtained,

If necessary, the oxidation reaction is carried out in the presence of an oxidizing agent.

[Formula 1]

Where

X is a substituted or unsubstituted aryl or hetero aryl group,

Y is an alkyl, cycloalkyl, substituted or unsubstituted aryl or hetero aryl group.

The 2,2,4,5-quaternary substituted 3 ( 2H ) -furanone derivative (I) may be prepared by the method shown in Schemes 1 to 3 below. Therefore, the manufacturing method according to the present invention will be described in detail with reference to the reaction scheme.

The ethanone derivative compound (II), which is used as a starting material in the preparation method of the 2,2,4,5-quarried substituted 3 ( 2H ) -furanone derivative (I) of the present invention, is as in Scheme 1 below. Compounds X (III) and acetyl chloride derivatives (IV) were subjected to methylene chloride under an aluminum chloride (AlCl ₃ ) catalyst according to methods known in the literature ( Kor. J. Med. Chem. 1997 , 7 , 34). Or by reacting in a chloroform solvent in a yield of about 50 to 90%.

Wherein X is a compound having a substituted or unsubstituted aryl or heteroaryl group, and Y is an alkyl, cycloalkyl, substituted or unsubstituted aryl or heteroaryl group.)

Next, as shown in Scheme 2, the ethanone derivative compound (II) is reacted with 2-haloisobutyryl cyanide or 2-haloisobutyryl halide to obtain a C-acylated intermediate compound ( VI) is produced, which is continuously stirred at room temperature without separation and purification to yield 2,2,4,5-quarried 3 ( 2H ) -furanone compound (Ia). This reaction can be carried out in the presence of an unreactive solvent and a base, which is completed in 1 to 7 hours.

(Wherein B is a halogen atom)

In general, the reaction between enolate and acyl halide varies depending on the reaction conditions of C-acylation and O-acylation. In the case of the enolate of compound (II) in Scheme 2, Reaction with 2-haloisobutyryl halide produces mainly O-acylated compounds (Comparative Example 1). Therefore, in a preferred embodiment of the present invention, the C-acylation reaction is carried out by reacting 2-haloisobutyryl cyanide, which has increased softness than the carbonyl group of 2-haloisobutyryl halide, with the enolate of compound (II). This happens selectively.

On the other hand, when using a base having a magnesium ion strongly bound to oxygen, such as bromo magnesium diisopropylamide in the reaction, 2-haloisobutyryl halide instead of 2-haloisobutyryl cyanide Use also yields C-acylated compounds (VI).

Although the kind is not specifically limited in the ethanone derivative compound (II) used by this invention, In general formula (II),

X is phenyl, thienyl, naphthyl, pyridyl, N-methylpyrazolyl, N-methylimidazolyl, pyrazinyl, N-methylpyrroylyl, N-methylindolyl, benzofuranyl, benzothienyl (benzthienyl ), Quinolyl, thiazolyl, oxazolyl, or

An aryl group substituted with alkyl, haloalkyl, alkoxy, alkoxyalkyl, alkylthio, alkylsulfonyl, alkylsulfinyl, dialkylamino, nitrile, nitro, alkylenedioxy, phenyl or morpholino group,

Y is alkyl, cycloalkyl, phenyl, thienyl, naphthyl, pyridyl, N-methylpyrazolyl, N-methylimidazolyl, pyrazinyl, N-methylpyrroyl, N-methylindolyl, benzofuranyl, Benzothienyl, quinolyl, thiazolyl, oxazolyl groups, or

And aryl groups substituted with alkyl, haloalkyl, alkoxy, alkoxyalkyl, alkylthio, alkylsulfonyl, alkylsulfinyl, dialkylamino, nitrile, nitro, alkylenedioxy, phenyl or morpholino group and the like.

Preferably,

X is a phenyl group, or

Halogen, alkyl of 1 to 5 carbon atoms, haloalkyl of 1 to 5 carbon atoms, alkoxy of 1 to 5 carbon atoms, nitro, alkylthio of 1 to 3 carbon atoms, alkylsulfonyl of 1 to 3 carbon atoms, or alkyl of 1 to 3 carbon atoms Finyl is a substituted phenyl group,

Y is alkyl having 1 to 6 carbon atoms, phenyl, thienyl, or

Halogen, alkyl of 1 to 5 carbon atoms, haloalkyl of 1 to 5 carbon atoms, alkoxy of 1 to 5 carbon atoms, nitro, alkylthio of 1 to 3 carbon atoms, alkylsulfonyl of 1 to 3 carbon atoms or alkylsulfonate of 1 to 5 carbon atoms Finyl is a substituted phenyl group.

The 2-haloisobutyryl cyanide and 2-haloisobutyryl halide (V) used in the method of the present invention are not particularly limited in kind, but 2-bromoisobutyryl cyanide, 2-chloroiso Preference is given to butyryl cyanide, 2-bromoisobutyryl bromide, 2-chloroisobutyryl bromide, 2-chloroisobutyryl bromide or 2-chloroisobutyryl chloride.

Although the kind used in the said reaction is not specifically limited, For example, sodium hydride, lithium t -butoxide, a potassium t -butoxide, sodium t -butoxide, lithium diisopropylamide, sodium Bis (trimethylsilyl) amide, Potassium bis (trimethylsilyl) amide, Lithium bis (trimethylsilyl) amide, Bromomagnesium diisopropylamide, and the like are preferable, and sodium hydride, potassium t -butoxide, sodium bis (trimethylsilyl ), Bromo magnesium diisopropylamide, and the like are more preferable.

These can be used in 1 equivalent or more with respect to the ethanone derivative compound (II), Preferably it can be used in 2-3 equivalents. If the base is used in less than about 2 equivalents, the compound (VI) is more produced than the compound (Ia), and there is a problem in that a cyclization reaction is added again. When the compound is used in about 3 equivalents, most of the compound (Ia) is obtained. Therefore, the use of more than 3 equivalents is not a big advantage, it is preferable to use in 2 to 3 equivalents.

As the organic solvent used in the method of the present invention, it is preferable to use a solvent which is not reactive with the above-described base. For example, an ether compound, an aromatic compound, dimethylformamide, dimethyl sulfoxide and the like can be used. Examples of the ether compound include dimethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and the like, and aromatic compounds include benzene, toluene, xylene and the like. Preferred are tetrahydrofuran, dioxane, toluene and dimethylformamide.

In the process of the present invention, the reaction of the ethanone derivative compound (II) with 2-haloisobutyryl cyanide (V) is carried out at a temperature of -70 to 25 ° C, preferably at a temperature of -20 to 5 ° C. desirable.

In the method of the present invention, when the compound prepared by the above Scheme 2 is a compound in which X is an alkylthiophenyl group, the compound (Ib) is oxidized with an oxidizing agent so that X is an alkylsulfonylphenyl group or an alkylsulfinylphenyl group ( Ic) can be prepared (Scheme 3). As the oxidizing agent, m-chloroperoxybenzoic acid (m-chloroperoxybenzoic acid), oxone (potassium peroxymonosulfate (OXONE)), peroxybenzoic acid, sodium percarbonate (Na ₂ CO ₃ -1.5H ₂ O ₂ ), and hydrogen peroxide can be used.

Wherein R is an alkyl group and n is 1 or 2.

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited only to these examples. On the other hand, in Preparation Example 1-16 below is a method for producing the ethanone derivative compound (II) used in the Examples.

Preparatory Example 1. 2- (3-Fluorophenyl) -1- (4-methylthiophenyl) ethanone

77.3 g of aluminum chloride was suspended in 600 ml of methylene chloride. 100 g of 3-fluorophenylacetylchloride was added dropwise in an ice water bath, and after 10 minutes, 68 ml of thioanisole was added dropwise for 10 minutes. After stirring for 1 hour in an ice water bath and 1 hour at room temperature, the reaction solution was poured into 1 L of 8% hydrochloric acid and stirred for 1 hour. The organic layer was separated, washed with brine, and dried over anhydrous magnesium sulfate. The insolubles were filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was crystallized in methylene chloride-hexane to give 142.9 g (94.8%) of the title compound.

m.p .: 94.5 ~ 95.5 ℃

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 2.52 (s, 3H), 4.23 (s, 2H), 6.95-7.05 (m, 3H), 7.25-7.30 (m, 3H), 7.91 (d, J = 8.4 Hz, 2H)

Preparatory Example 2. 1- (4-Methylthiophenyl) -2-phenylethanone

Except for using 18 g of phenylacetyl chloride instead of 100 g of 3-fluorophenylacetyl chloride, the same procedure as in Preparation Example 1 was carried out to obtain 25.8 g (89.9%) of the title compound.

m.p .: 99 ~ 100 ℃

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 2.51 (s, 3H), 4.24 (s, 2H), 7.21-7.39 (m, 7H), 7.92 (d, J = 8.7Hz, 2H)

Preparatory Example 3. 2- (3-Chlorophenyl) -1- (4-methylthiophenyl) ethanone

11.7 g (79.4%) of the title compound was obtained in the same manner as the Preparative Example 1, except that 10.55 g of 3-chlorophenylacetyl chloride was used instead of 100 g of 3-fluorophenylacetylchloride.

m.p .: 81 ~ 82 ℃

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 2.52 (s, 3H), 4.21 (s, 2H), 7.12-7.15 (m, 1H), 7.23-7.28 (m, 5H), 7.90 (d, J = 8.4 Hz, 2H)

Preparatory Example 4. 1- (4-Methylthiophenyl) -2- (3-trifluoromethylphenyl) ethanone

2.61 g (74.9%) of the title compound were obtained in the same manner as the pre-preparation example 1 except that 2.5 g of 3-trifluorophenylacetyl chloride was used instead of 100 g of 3-fluorophenylacetyl chloride.

m.p .: 63 ~ 64 ℃

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 2.53 (s, 3H), 4.31 (s, 2H), 7.28 (d, J = 8.4 Hz, 2H), 7.44-7.46 (m, 2H), 7.52 (br) , 2H), 7.92 (d, J = 8.4 Hz, 2H)

Preparatory Example 5. 2- (4-Nitrophenyl) -1- (4-methylthiophenyl) ethanone

Except for using 3.2 g of 4-nitrophenylacetyl chloride instead of 100 g of 3-fluorophenylacetyl chloride, the same procedure as in Preparation Example 1 was carried out to obtain 2.73 g (59.3%) of the title compound.

m.p .: 186 ~ 187 ℃

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 2.53 (s, 3H), 4.37 (s, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.43 (d, J = 9.0 Hz, 2H), 7.91 (d, J = 8.4 Hz, 2H), 8.20 (d, J = 8.7 Hz, 2H)

Preparatory Example 6. 2- (4-methoxyphenyl) -1- (4-methylthiophenyl) ethanone

4.5 g (56.7%) of the title compound was obtained in the same manner as in Preparative Example 1, except that 5.38 g of 4-methoxyphenylacetyl chloride was used instead of 100 g of 3-fluorophenylacetylchloride.

m.p .: 123 ~ 124 ℃

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 2.50 (s, 3H), 3.77 (s, 3H), 4.17 (s, 2H), 6.85 (d, J = 8.7 Hz, 2H), 7.17 (d, J = 8.7 Hz, 2H), 7.24 (d, J = 8.7 Hz, 2H), 7.90 (d, J = 8.7 Hz, 2H)

Preparatory Example 7. 2- (2,5-Difluorophenyl) -1- (4-methylthiophenyl) ethanone

5.71 g (50.4%) of the title compound was obtained by the same method as the preparative example 1, except that 7.75 g of 2,5-difluorophenylacetyl chloride was used instead of 100 g of 3-fluorophenylacetylchloride.

m.p .: 103 ~ 104 ℃

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 2.53 (s, 3H), 4.25 (s, 2H), 6.94-7.07 (m, 3H), 7.29 (d, J = 8.7 Hz, 2H), 7.93 (d , J = 8.7 Hz, 2H)

Preparatory Example 8. 2- (3,5-Difluorophenyl) -1- (4-methylthiophenyl) ethanone

32.42 g (73.9%) of the title compound was obtained in the same manner as the preparative example 1 except that 30 g of 3,5-difluorophenylacetyl chloride was used instead of 100 g of 3-fluorophenylacetylchloride.

m.p .: 113 ~ 114 ℃

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 2.53 (s, 3H), 4.22 (s, 2H), 6.71-6.81 (m, 3H), 7.27 (d, J = 8.7 Hz, 2H), 7.90 (d , J = 8.7 Hz, 2H)

Preparatory Example 9. 1- (4-Methylthiophenyl) -2- (2-thienyl) ethanone

145 mg (3.6%) of the title compound were obtained in the same manner as in Preparative Example 1, except that 2 ml of 2-thiophene acetyl chloride was used instead of 100 g of 3-fluorophenylacetylchloride.

m.p .: 72 ~ 73 ℃

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 2.52 (s, 3H), 4.44 (s, 2H), 6.93-6.98 (m, 2H), 7.22 (dd, J = 5.7, 1.5 Hz, 1H) , 7.25 (d, J = 7.8Hz, 2H), 7.93 (d, J = 8.4Hz, 2H)

Preparatory Example 10. 1- (4-Methylthiophenyl) propanone

3.7 g (71.3%) of the title compound was obtained in the same manner as the preparative example 1, except that 2.5 ml of propionyl chloride was used instead of 100 g of 3-fluorophenylacetylchloride.

m.p: 63 ~ 64 ℃

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 1.22 (t, J = 6.9 Hz, 3H), 2.52 (s, 3H), 2.96 (q, J = 6.9 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 8.7 Hz, 2H)

Preparatory Example 11 4-Methyl-1- (4-methylthiophenyl) pentanone

4.33 g (83.6%) of the title compound was obtained by the same method as the preparative example 1, except that 3 g of isovaleryl chloride was used instead of 100 g of 3-fluorophenylacetylchloride.

m.p .: 51 ~ 52 ℃

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 0.99 (d, J = 6.6 Hz, 6H), 2.80 (sept, J = 6.6 Hz, 1H), 2.52 (s, 3H), 2.79 (d, J = 7.2 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 7.87 (d, J = 8.7 Hz, 2H)

Preparatory Example 12. 2- (2-Chlorophenyl) -1- (3-fluoro-4-methylthiophenyl) ethanone

3 g of 2-fluorothioanisole was dissolved in 30 ml of methylene chloride, and then 2.81 g of aluminum chloride was added dropwise in an ice water bath. After 10 minutes, 4.39 g of 2-chlorophenylacetylchloride dissolved in 20 ml of methylene chloride was added dropwise for 10 minutes. After stirring for 1 hour in an ice-water bath at room temperature overnight, the reaction solution was poured into 50 ml of 8% hydrochloric acid and stirred for 1 hour. The organic layer was separated and washed with brine. Anhydrous magnesium sulfate was added and dried. The insolubles were filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was crystallized in ethyl acetate-hexane to give 1.55 g (27.8%) of the title compound.

m.p .: 72 ~ 73 ℃

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 2.53 (s, 3H), 4.37 (s, 2H), 7.26 (m, 4H), 7.41 (m, 1H), 7.67 (m, 1H), 7.81 (m , 1H)

Preparatory Example 13. 1- (2-Fluoro-4-methylthiophenyl) -2- (3-fluorophenyl) ethanone

The procedure was carried out in the same manner as in Preparation Example 12, except that 4.12 g of 3-fluorothioanisole and 5 g of 3-fluorophenylacetylchloride were used instead of 3 g of 2-fluorothioanisole and 4.39 g of 2-chlorophenylacetylchloride. This gave 5.4 g (67%) of the title compound.

m.p .: 67 ~ 68 ℃

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 2.51 (s, 3H), 4.24 (s, 2H), 6.91-7.56 (m, 5H), 7.26 (m, 1H), 7.81 (m, 1H)

Preparatory Example 14. 1- (3-Bromo-4-methylthiophenyl) -2- (2,5-difluorophenyl) ethanone

Preparative Example 12 except that 1.7 g of 2-bromothioanisole and 1.79 g of 2,5-difluorophenylacetylchloride were used instead of 3 g of 2-fluorothioanisole and 4.39 g of 2-chlorophenylacetylchloride. 2.32 g (77.6%) of the title compound were prepared in the same manner as the method.

m.p .: 143 ~ 144 ℃

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 2.53 (s, 3H), 4.24 (s, 2H), 6.95 (m, 2H), 7.05 (m, 1H), 7.18 (d, J = 8.1Hz, 1H ), 7.94 (dd, J = 8.1, 1.8 Hz, 1H), 8.16 (d, J = 2.1 Hz, 1H)

Preparatory Example 15. 1- (3-Chloro-4-methylthiophenyl) -2- (3-fluorophenyl) ethanone

In the same manner as in Preparation Example 12, except that 4 g of 2-chlorothioanisole and 5 g of 3-fluorophenylacetyl chloride were used instead of 3 g of 2-fluorothioanisole and 4.39 g of 2-chlorophenylacetyl chloride. 3.3 g (44.4%) of the title compound were obtained.

m.p .: 95 ~ 96 ℃

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 2.52 (s, 3H), 4.23 (s, 2H), 6.99 (m, 3H), 7.19 (d, J = 8.1 Hz, 1H), 7.34 (m, 1H ), 7.86 (dd, J = 8.4, 1.8 Hz, 1H), 7.96 (d, J = 1.8 Hz, 1H)

Preparatory Example 16. 2- (3,5-Difluorophenyl) -1- (3-methyl-4-methylthiophenyl) ethanone

Pre-Production Example 12 except that 1.21 g of 2-methylthioanisole and 1.4 ml of 3,5-difluorophenylacetyl chloride were used instead of 3 g of 2-fluorothioanisole and 4.39 g of 2-chlorophenylacetylchloride. In the same manner, 0.87 g (34%) of the title compound were obtained.

m.p .: 73 ~ 74 ℃

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 2.35 (s, 3H), 2.52 (s, 3H), 4.22 (s, 2H), 6.70 (m, 1H), 6.80 (m, 2H), 7.17 (d , J = 8.1 Hz, 1H), 7.74 (s, 1H), 7.80 (dd, J = 8.3, 2.1 Hz, 1H)

Example 1. 2,2-dimethyl-4- (3-fluorophenyl) -5- (4-methylthiophenyl) -3 ( 2H ) -Furanone

[Method A]

100 g of 2- (3-fluorophenyl) -1- (4-methylthiophenyl) ethanone of Preparative Preparation Example 1 was dissolved in 1 L of tetrahydrofuran, followed by dropwise addition of 26 g of sodium hydride (95%) in an ice water bath. It was stirred at room temperature for 1 hour, cooled again in an ice-water bath, and 69 g of 2-bromoisobutyryl cyanide was added dropwise. After stirring for 5 hours at room temperature, a small amount of purified water was added to the reaction solution and concentrated under reduced pressure. The obtained residue was dissolved in 1 L of ethyl acetate, washed with purified water and brine, and dried over anhydrous magnesium sulfate. Insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was crystallized in methanol to give 102 g (81%) of the title compound.

m.p: 106 ° C

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 1.55 (s, 6H), 2.50 (s, 3H), 6.97-7.11 (m, 3H), 7.18 (d, J = 9.0 Hz, 2H), 7.26-7.36 (m, 1H), 7.55 (d, J = 9.0 Hz, 2H)

[Method B]

1 g of 2- (3-fluorophenyl) -1- (4-methylthiophenyl) ethanone was dissolved in 10 ml of tetrahydrofuran, and then 3.9 ml (1 M / THF) of sodium bis (trimethylsilyl) amide was added dropwise. It was stirred at room temperature for 1 hour, cooled again in an ice water bath, and then 0.69 g of 2-bromoisobutyryl cyanide was added dropwise. After stirring for 7 hours at room temperature, a small amount of purified water was added to the reaction solution and concentrated under reduced pressure. The obtained residue was dissolved in 100 ml of ethyl acetate, washed with purified water and brine, and dried over anhydrous magnesium sulfate. Insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was crystallized in methanol to give 0.78 g (61.8%) of the title compound.

[Method C]

5.76 mL (1 M / Et ₂ O) of ethylmagnesium bromide was added dropwise at 0.92 mL of diisopropylamine dissolved in 50 mL of diethyl ether at room temperature, and stirred for 1 hour. After cooling to −70 ° C., 1 g of 2- (3-fluorophenyl) -1- (4-methylthiophenyl) ethanone dissolved in 10 ml of tetrahydrofuran was added dropwise, and the reaction temperature was gradually raised to room temperature for 1 hour. Stir for a while. 1.06 g of 2-bromoisobutyryl bromide was added dropwise in an ice water bath, stirred at room temperature for 2 hours, and then the reaction solution was washed with purified water, and dried over anhydrous magnesium sulfate. Insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in 50 ml of tetrahydrofuran again, and 0.18 g of sodium hydride (95%) was added dropwise. After stirring for 2 hours at room temperature, a small amount of purified water was added to the reaction solution, and concentrated under reduced pressure. The obtained residue was dissolved in 100 ml of ethyl acetate, washed with purified water and brine, and dried over anhydrous magnesium sulfate. Insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was crystallized in methanol to give 0.88 g (70%) of the title compound.

[Method D]

1 g of 2- (3-fluorophenyl) -1- (4-methylthiophenyl) ethanone was dissolved in 10 ml of dimethylformamide, and then 0.26 g of sodium hydride (95%) was added dropwise in an ice water bath. It was stirred at room temperature for 1 hour and then cooled again in an ice-water bath. 0.69 g of 2-bromoisobutyryl cyanide was added dropwise thereto, stirred at room temperature for 5 hours, and a small amount of purified water was added to the reaction solution, followed by concentration under reduced pressure. The obtained residue was dissolved in 100 ml of ethyl acetate, washed with purified water and brine, and dried over anhydrous magnesium sulfate. The insolubles were filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was crystallized in methanol to obtain 0.45 g (35.7%) of the title compound.

[Method E]

1 g of 2- (3-fluorophenyl) -1- (4-methylthiophenyl) ethanone was dissolved in 15 ml of toluene, and then 1.12 g of potassium fortium t -butoxide was added dropwise in an ice water bath. It was stirred at room temperature for 1 hour, cooled again in an ice water bath, and then 0.69 g of 2-bromoisobutyryl cyanide was added dropwise. Then, the mixture was stirred at room temperature for 5 hours, washed with purified water and brine, and dried over anhydrous magnesium sulfate. Insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was crystallized in methanol to give 0.26 g (20.6%) of the title compound.

Example 2. 2,2-dimethyl-5- (4-methylthiophenyl) -4-phenyl-3 ( 2H ) -Furanone

Except for using 2 g of 1- (4-methylthiophenyl) -2-phenylethanone of Preparative Example 2 instead of 100 g of 2- (3-fluorophenyl) -1- (4-methylthiophenyl) ethanone. Was carried out in the same manner as in Method A of Example 1 to obtain 2.51 g (80.0%) of the title compound.

m.p .: 109 ~ 110 ℃

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 1.55 (s, 6H), 2.49 (s, 3H), 7.16 (d, J = 8.7 Hz, 2H), 7.27-7.55 (m, 5H), 7.56 (d , J = 8.7 Hz, 2H)

Example 3. 4- (3-chlorophenyl) -2,2-dimethyl-5- (4-methylthiophenyl) -3 ( 2H ) -Furanone

11.4 g of 2- (3-chlorophenyl) -1- (4-methylthiophenyl) ethanone of Preparative Example 3 instead of 100 g of 2- (3-fluorophenyl) -1- (4-methylthiophenyl) ethanone Reaction was carried out in the same manner as in Method A of Example 1, except that the pure portion was separated by column chromatography (ethyl acetate: hexane = 1: 6) to obtain 10.98 g (77.3%) of the title compound. .

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 1.55 (s, 6H), 2.49 (s, 3H), 7.15-7.22 (m, 3H), 7.27-7.31 (m, 2H), 7.33-7.36 (m, 1H), 7.54 (d, J = 8.7Hz, 2H)

Example 4. 2,2-dimethyl-5- (4-methylthiophenyl) -4- (3-trifluoromethylphenyl) -3 ( 2H ) -Furanone

2- (3-methylthiophenyl) -2- (3-trifluoromethylphenyl) ethanone of Preparative Example 4 instead of 100 g of 2- (3-fluorophenyl) -1- (4-methylthiophenyl) ethanone 2.25 The reaction was carried out in the same manner as in Method A of Example 1, except that g was used, and then 1.2 g (43.7%) of the titled compound was separated by column chromatography (ethyl acetate: hexane = 1: 6). Got it.

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 1.56 (s, 6H), 2.49 (s, 3H), 7.18 (d, J = 9.0 Hz, 2H), 7.51-7.62 (m, 6H).

Example 5. 2,2-dimethyl-5- (4-methylthiophenyl) -4- (4-nitrophenyl) -3 ( 2H ) -Furanone

Instead of 100 g of 2- (3-fluorophenyl) -1- (4-methylthiophenyl) ethanone, 1 g of 2- (4-nitrophenyl) -1- (4-methylthiophenyl) ethanone of Preparation Example 5 was added. The reaction mixture was carried out in the same manner as in Method A of Example 1, except that the residue was purified by column chromatography (ethyl acetate: hexane = 1: 6) to obtain 0.70 g (56.6%) of the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 1.57 (s, 6H), 2.51 (s, 3H), 7.21 (d, J = 8.7 Hz, 2H), 7.53 (d, J = 8.7 Hz, 2H), 7.54 (d, J = 9.0 Hz, 2H), 8.21 (d, J = 8.7 Hz, 2H)

Example 6. 2,2-dimethyl-4- (4-methoxyphenyl) -5- (4-methylthiophenyl) -3 ( 2H ) -Furanone

2- (4-methoxyphenyl) -1- (4-methylthiophenyl) ethanone 3.01 of Preparative Example 6 instead of 100 g of 2- (3-fluorophenyl) -1- (4-methylthiophenyl) ethanone 1.51 g (40.1%) of the title compound was obtained by the same method as the method A of Example 1, except that g was used.

m.p .: 116 ~ 117 ℃

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 1.54 (s, 6H), 2.49 (s, 3H), 3.83 (s, 3H), 6.91 (d, J = 9.0 Hz, 2H), 7.16 (d, J = 8.7 Hz, 2H), 7.23 (d, J = 9.0 Hz, 2H), 7.53 (d, J = 8.7 Hz, 2H).

Example 7. 4- (2,5-difluorophenyl) -2,2-dimethyl-5- (4-methylthiophenyl) -3 ( 2H ) -Furanone

2- (2,5-difluorophenyl) -1- (4-methylthiophenyl) ethane of Preparative Example 7 instead of 100 g of 2- (3-fluorophenyl) -1- (4-methylthiophenyl) ethanone 2.48 g (33.2%) of the title compound were obtained by the same method as the method A of Example 1, except that 6 g of ON was used.

m.p .: 90.5 ~ 91 ℃

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 1.56 (s, 6H), 2.49 (s, 3H), 7.01-7.06 (m, 3H), 7.17 (d, J = 8.7 Hz, 2H), 7.53 (d , J = 8.4 Hz, 2H)

Example 8. 4- (3,5-difluorophenyl) -2,2-dimethyl-5- (4-methylthiophenyl) -3 ( 2H ) -Furanone

2- (3,5-difluorophenyl) -1- (4-methylthiophenyl) ethane of Preparative Example 8 instead of 100 g of 2- (3-fluorophenyl) -1- (4-methylthiophenyl) ethanone 3.21 g (48.5%) of the title compound were obtained by the same method as the method A of Example 1, except that 5.32 g of ON was used.

m.p .: 122 ~ 123 ℃

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 1.55 (s, 6H), 2.51 (s, 3H), 6.71-6.78 (m, 1H), 6.84-6.92 (m, 2H), 7.21 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 9.0 Hz, 2H)

Example 9. 2,2-dimethyl-5- (4-methylthiophenyl) -4- (2-thienyl) -3 ( 2H ) -Furanone

140 mg of 1- (4-methylthiophenyl) -2- (2-thienyl) ethanone of Preparative Example 9 instead of 100 g of 2- (3-fluorophenyl) -1- (4-methylthiophenyl) ethanone 27.1 mg (15.2%) of the title compound were obtained by the same method as the method A of Example 1 except for using.

m.p .: 113 ~ 114 ℃

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 1.55 (s, 6H), 2.51 (s, 3H), 7.05 (dd, J = 5.1, 3.9 Hz, 2H), 7.11 (dd, J = 3.6, 1.2 Hz , 1H), 7.22 (d, J = 8.4 Hz, 2H), 7.33 (dd, J = 5.1 Hz, 1H), 7.68 (d, J = 9.0 Hz, 2H)

Example 10. 2,2-dimethyl-4-methyl-5- (4-methylthiophenyl) -3 ( 2H ) -Furanone

Example 1, except that 1 g of 1- (4-methylthiophenyl) propanone of Preparative Example 10 is used instead of 1 g of 2- (3-fluorophenyl) -1- (4-methylthiophenyl) ethanone. 0.91 g (66.1%) of the title compound were obtained by the same method as the method B.

m.p .: 140 ~ 141 ℃

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 1.45 (s, 6H), 1.99 (s, 3H), 2.54 (s, 3H), 7.34 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H)

Example 11. 2,2-dimethyl-4-isopropyl-5- (4-methylthiophenyl) -3 ( 2H ) -Furanone

Except for using 1 g of 4-methyl-1- (4-methylthiophenyl) pentanone of Preparative Example 11 instead of 1 g of 2- (3-fluorophenyl) -1- (4-methylthiophenyl) ethanone. After reacting in the same manner as in Method B of Example 1, the pure portion was separated by column chromatography (ethyl acetate: hexane = 1: 6) to obtain 102 mg (7.7%) of the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 1.29 (d, J = 6.9 Hz, 6H), 1.41 (s, 6H), 2.91 (sept, J = 6.9 Hz, 1H), 7.32 (d, J = 8.7 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H)

Example 12. 2,2-dimethyl-4,5-diphenyl-3 ( 2H ) -Furanone

The reaction was carried out in the same manner as in Method A of Example 1, except that 200 mg of deoxybenzoin was used instead of 100 g of 2- (3-fluorophenyl) -1- (4-methylthiophenyl) ethanone, followed by a column Chromatography (ethyl acetate: hexane = 1: 6) separated the pure portion to prepare 176 mg (65.0%) of the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 1.54 (s, 6H), 7.13 (d, J = 8.4 Hz, 2H), 7.24-7.37 (m, 6H), 7.58 (d, J = 8.7 Hz, 2H ).

Example 13. 4- (2-chlorophenyl) -5- (3-fluoro-4-methylthiophenyl) -2,2-dimethyl-3 ( 2H ) -Furanone

2- (2-chlorophenyl) -1- (3-fluoro-4-methylthiophenyl) of Preparative Example 12 instead of 100 g of 2- (3-fluorophenyl) -1- (4-methylthiophenyl) ethanone The reaction was carried out in the same manner as in Method A of Example 1, except that 1.0 g of ethanone was used, and then the pure portion was separated by column chromatography (ethyl acetate: hexane = 1: 6) to give 726 mg (59.0%) of the title compound. )

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 1.58 (s, 6H), 2.46 (s, 3H), 7.10 (m, 1H), 7.26 (m, 3H), 7.34 (m, 2H), 7.49 (m , 1H)

Example 14. 2,2-Dimethyl-5- (2-fluoro-4-methylthiophenyl) -4- (3-fluorophenyl) -3 ( 2H ) -Furanone

1- (2-fluoro-4-methylthiophenyl) -2- (3-fluorophenyl) of Preparative Example 13 instead of 100 g of 2- (3-fluorophenyl) -1- (4-methylthiophenyl) ethanone The reaction was carried out in the same manner as in Method A of Example 1, except that 615 mg of ethanone was used, and then the pure portion was separated by column chromatography (ethyl acetate: hexane = 1: 6) to give 487 mg (63.6%) of the title compound. Got.

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 1.55 (s, 6H), 2.51 (s, 3H), 6.94 (m, 4H), 7.06 (m, 1H), 7.26 (m, 1H), 7.43 (m , 1H)

Example 15. 5- (3-Bromo-4-methylthiophenyl) -4- (2,5-difluorophenyl) -2,2-dimethyl-3 ( 2H ) -Furanone

1- (3-bromo-4-methylthiophenyl) -2- (2,5- of Preparative Example 14 instead of 100 g of 2- (3-fluorophenyl) -1- (4-methylthiophenyl) ethanone The reaction was carried out in the same manner as in Method A of Example 1, except that 2.31 g of difluorophenyl) ethanone was used, and then the pure portion was separated by column chromatography (ethyl acetate: hexane = 1: 6) to obtain the title compound. 1.22 g (44.4%) were obtained.

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 1.57 (s, 6H), 2.47 (s, 3H), 7.04 (m, 4H), 7.44 (dd, J = 8.7, 1.8 Hz 2H), 7.86 (d, J = 1.5 Hz, 1H), 8.09 (m, 1H)

Example 16. 5- (3-Chloro-4-methylthiophenyl) -2,2-dimethyl-4- (3-fluorophenyl) -3 ( 2H ) -Furanone

1- (3-chloro-4-methylthiophenyl) -2- (3-fluorophenyl) of Preparative Example 15 instead of 100 g of 2- (3-fluorophenyl) -1- (4-methylthiophenyl) ethanone The reaction was carried out in the same manner as in Method A of Example 1, except that 2.80 g of ethanone was used, and then 2.98 g (86.5) of the title compound was separated by column chromatography (ethyl acetate: hexane = 1: 6). %) Was obtained.

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 1.55 (s, 6H), 2.49 (s, 3H), 7.05 (m, 3H), 7.06 (d, J = 8.1 Hz, 1H), 7.34 (m, 1H ), 7.44 (dd, J = 8.4, 1.8 Hz, 1H), 7.69 (d, J = 1.8 Hz, 1H)

Example 17. 2,2-dimethyl-4- (3,5-difluorophenyl) -5- (3-methyl-4-methylthiophenyl) -3 ( 2H ) -Furanone

2- (3,5-difluorophenyl) -1- (3-methyl-4-methyl of Preparative Example 16 instead of 100 g of 2- (3-fluorophenyl) -1- (4-methylthiophenyl) ethanone The reaction was carried out in the same manner as in Method A of Example 1, except that 530 mg of thiophenyl) ethanone was used, and then the pure portion was separated by column chromatography (ethyl acetate: hexane = 1: 6) to give 427 mg of the title compound. 65.3%).

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 1.55 (s, 6H), 2.29 (s, 3H), 2.50 (s, 3H), 6.74 (m, 1H), 6.89 (m, 2H), 7.08 (d , J = 8.1 Hz, 1H), 7.41 (dd, J = 8.4, 2.1 Hz, 1H), 7.45 (d, J = 1.5 Hz, 1H)

Example 18. 2,2-dimethyl-4- (3-fluorophenyl) -5- (4-methylsulfonylphenyl) -3 ( 2H ) -Furanone

[Method A]

1 g of 2- (3-fluorophenyl) -1- (4-methylsulfonylphenyl) ethanone was dissolved in 10 ml of tetrahydrofuran, and then 0.23 g of sodium hydride (95%) was added dropwise in an ice water bath. It was stirred at room temperature for 1 hour and then cooled again in an ice-water bath. 0.64 g of 2-bromoisobutyryl cyanide was added dropwise thereto, stirred at room temperature for 7 hours, and a small amount of purified water was added thereto, followed by concentration under reduced pressure. The obtained residue was dissolved in 100 ml of ethyl acetate and washed with purified water and brine. Anhydrous magnesium sulfate was added and dried. Insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was crystallized in ethyl acetate-hexane to give 0.75 g (60.8%) of the title compound.

m.p .: 178 ~ 179 ℃

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 1.58 (s, 6H), 3.08 (s, 3H), 7.05 (m, 3H), 7.33 (m, 1H), 7.83 (d, J = 8.7 Hz, 2H ), 7.95 (d, J = 8.7 Hz, 2H)

[Method B]

5.76 mL (1 M / Et ₂ O) of ethylmagnesium bromide was added dropwise at −70 ° C. to 0.92 mL of diisopropylamine dissolved in 50 mL of diethyl ether, followed by stirring at room temperature for 1 hour. After cooling to -70 ° C, 1 g of 2- (3-fluorophenyl) -1- (4-methylsulfonylphenyl) ethanone dissolved in 20 ml of tetrahydrofuran was added dropwise, and the reaction temperature was gradually raised to room temperature for 1 hour. Stirred. 1.06 g of 2-bromoisobutyryl bromide was added dropwise in an ice water bath, and stirred at room temperature for 2 hours. The reaction solution was washed with purified water and dried over anhydrous magnesium sulfate. Insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in 50 ml of tetrahydrofuran, and 0.18 g of sodium hydride (95%) was added dropwise. After stirring for 2 hours at room temperature, a small amount of purified water was added to the reaction solution, and concentrated under reduced pressure. The obtained residue was dissolved in 100 ml of ethyl acetate, washed with purified water and brine, and dried over anhydrous magnesium sulfate. Insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was crystallized in ethyl acetate-hexane to give 0.57 g (46.2%) of the title compound.

[Method C]

3.03 g of 4- (3-fluorophenyl) -2,2-dimethyl-5- (methylthiophenyl) -3 ( 2H ) -furanone was dissolved in 50 mL / 50 mL / 50 mL of tetrahydrofuran / methanol / purified water. . 10 g of OXONE was added at room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, extracted with 150 ml of methylene chloride, the organic layer was washed with brine, and dried over anhydrous magnesium sulfate. Insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was crystallized in methylene chloride-hexane to give 3.3 g (99.2%) of the title compound.

Example 19. 2,2-dimethyl-4- (3-chlorophenyl) -5- (4-methylsulfinylphenyl) -3 ( 2H ) -Furanone

[Method A]

1.14 g of 2- (3-chlorophenyl) -1- (4-methylsulfinylphenyl) ethanone was dissolved in 20 ml of tetrahydrofuran, and 0.32 g of sodium hydride (95%) was added dropwise at -20 ° C, After stirring for 1 hour at room temperature, the mixture was cooled again in an ice-water bath. 0.87 g of 2-bromoisobutyryl cyanide was added dropwise thereto, stirred at room temperature for 5 hours, and then a small amount of purified water was added to the reaction solution, followed by concentration under reduced pressure. The obtained residue was dissolved in 100 ml of ethyl acetate, washed with purified water and brine, and dried over anhydrous magnesium sulfate. Insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was crystallized in ethyl acetate-hexane to give 0.76 g (56.6%) of the title compound.

m.p .: 109 ~ 111 ℃

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 1.57 (s, 6H), 2.75 (s, 3H), 7.17 (m, 1H), 7.31 (m, 2H), 7.65 (d, J = 8.4 Hz, 2H ), 7.80 (d, J = 8.7 Hz, 2H)

[Method B]

10.98 g of 4- (3-chlorophenyl) -2,2-dimethyl-5- (methylthiophenyl) -3 ( 2H ) -furanone was dissolved in 250 ml of methylene chloride. 6.59 g of m-chloroperoxybenzoic acid dissolved in 150 ml of methylene chloride in an ice water bath was added dropwise. The reaction solution was washed with saturated aqueous NaHCO ₃ solution and brine, dried over anhydrous magnesium sulfate, and then the insolubles were filtered and the filtrate was concentrated under reduced pressure. The residue thus obtained was purified by column chromatography (ethyl acetate: hexane = 2: 1) to obtain a pure part, which was then crystallized in ethyl acetate-hexane to give 6.33 g (55.1%) of the title compound.

Comparative Example 1. 1,2-diphenylvinyl 2-bromo-2-methylpropionate

500 mg of deoxybenzoin was dissolved in 10 ml of tetrahydrofuran, and then 193 mg of sodium hydride (95%) was added dropwise in an ice water bath. After stirring for 1 hour at room temperature, cooled again in an ice-water bath, 700 mg of 2-bromoisobutyryl bromide was added dropwise thereto. Then, the mixture was stirred at room temperature for 5 hours, and a small amount of purified water was added to the reaction solution, followed by concentration under reduced pressure. The obtained residue was dissolved in 30 ml of ethyl acetate, washed with purified water and brine, and dried over anhydrous magnesium sulfate. Insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was crystallized in ethyl acetate-hexane to give 659 mg (74.9%) of the title compound.

m.p .: 42 ~ 44 ℃

¹ H-NMR (CDCl ₃ , 300 MHz, δ) 2.01 (s, 6H), 6.73 (s, 1H), 7.27-7.62 (m, 10H)

As described above, the preparation method of the present invention induces a selective C-acylation reaction and simultaneously proceeds the condensation and cyclization reactions to a 2,2,4,5-quarried substituted 3 ( 2H ) -furanone derivative. In particular, 4,5-diaryl-3 ( 2H ) -furanone derivatives are very effective in producing high yields.

Claims (8)

The compound of the following general formula (II) is reacted with 2-haloisobutyryl cyanide or 2-haloisobutyryl halide to make 2,2,4,5-quadruple 3 ( 2H ) of the general formula (I) -Furanone [2,2,4,5-tetrasubstituted 3 ( 2H ) -furanone] derivative is obtained, A process for the preparation of 2,2,4,5-quadically substituted 3 ( 2H ) -furanone derivatives of the general formula (I), which is carried out in the presence of an oxidizing agent if necessary. [Formula 1] [Formula 3] Where X is a substituted or unsubstituted aryl or hetero aryl group, Y is an alkyl, cycloalkyl, substituted or unsubstituted aryl or hetero aryl group. The process according to claim 1, wherein the reaction of the compound of formula (II) with 2-haloisobutyryl cyanide or 2-haloisobutyryl halide is carried out in the presence of a base in an organic solvent. The method according to claim 1 or 2, X is a phenyl group, or Halogen, alkyl of 1 to 5 carbon atoms, haloalkyl of 1 to 5 carbon atoms, alkoxy of 1 to 5 carbon atoms, nitro, alkylthio of 1 to 3 carbon atoms, alkylsulfonyl of 1 to 3 carbon atoms, or alkyl of 1 to 3 carbon atoms The pinyl group is a substituted phenyl group, Y is alkyl having 1 to 6 carbon atoms, thienyl, phenyl group, or Halogen, alkyl of 1 to 5 carbon atoms, haloalkyl of 1 to 5 carbon atoms, alkoxy of 1 to 5 carbon atoms, nitro, alkylthio of 1 to 3 carbon atoms, alkylsulfonyl of 1 to 3 carbon atoms, or alkyl of 1 to 3 carbon atoms A manufacturing method characterized in that the pinyl group is a substituted phenyl group. The 2-haloisobutyryl cyanide of any one of claims 1 to 3 is 2-bromoisobutyryl cyanide or 2-chloroisobutyryl cyanide, and 2-haloisobutyryl halide. Is 2-bromoisobutyryl bromide, 2-bromoisobutyryl chloride, 2-chloroisobutyryl bromide or 2-chloroisobutyryl chloride. The method of claim 2, wherein the base is sodium hydride, butyllithium, lithium t -butoxide, potassium t -butoxide, sodium t -butoxide, lithium diisopropylamide, sodium bis (trimethylsilyl) amide, potassium bis ( Trimethylsilyl) amide, lithium bis (trimethylsilyl) amide or bromo magnesium diisopropylamide. The organic solvent according to claim 2, wherein the organic solvent is dimethylformamide, dimethyl sulfoxide, dimethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, benzene, toluene or xylene Manufacturing method characterized by The oxidizing agent according to any one of claims 1 to 3, wherein the oxidizing agent is m -chloroperoxybenzoic acid, peroxybenzoic acid, oxone, sodium percarbonate (Na ₂ CO ₃ -1.5H ₂ O ₂ ), or hydrogen peroxide. Manufacturing method. The compound according to any one of claims 1 to 3, wherein, by the oxidation reaction, a compound in which the aryl substituent of X or Y in the general formula (I) is an alkylthio group is converted into a compound having an alkylsulfinyl or alkylsulfonyl group. A manufacturing method characterized by the above-mentioned.