JPS6348269B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides for the oxidation and defhenylsulfinylation of α- or β-substituted-γ-phenylthio-γ-butyrolactones, which have not been previously described in the literature, for example, in the pharmaceutical field, agriculture and horticulture field, etc.
α- or β-substituted - △α, β- or - that exhibits physiological activity expected to be useful as a bactericidal or insecticide
This invention relates to a method for producing Δβ,γ-butenolides. More specifically, the present invention is based on the following formula () However, in the formula, R ₁ and R ₂ each represent a group selected from the group consisting of a hydrogen atom, a lower alkyl group, a phenyl group which may have a substituent, and _a benzyl group; One of R ₂ is a hydrogen atom, and the other is a group other than a hydrogen atom. And the double bond shown by ... is α, β or β,
The present invention relates to a method for producing α- or β-substituted -Δα, β- or -Δβ, γ-butenolides, which are between γ and γ-substituted. The present inventors have conducted research on the synthesis of γ-phenylthio-γ-butyrolactone compounds, and this time, we have investigated the synthesis of γ-phenylthio-γ-butyrolactone compounds.
We have discovered that -substituted-△α,β- or -△β,γ-butenolides can be synthesized by easy means. α- or β-substitution represented by the above formula () -△
Several reports have been known regarding the synthesis of α,β- or -Δβ,γ-butenolides. For example, J.Am.Chem.Soc., 95 , 6840
(1973); Bull.Chem.Soc., Japan, 50 , 242
(1977); Chem.Rev., 76 , 625 (1975); Ark.
Kemi., 29 , 229 (1968), etc. These conventional proposals only describe synthesis from α- or β-phenylthio-γ-butyrolactones, and do not disclose anything about synthesis from α- or β-substituted-γ-phenylthio-γ-butyrolactones. do not have. This time, we have been able to synthesize α- or β-substituted-γ-phenylthio-γ-butyrolactones, which are shown by the following formula () and have not been described in the literature, and from this, we can synthesize butenolides shown by the above formula () using a new reaction method. It has been discovered that these can be prepared easily and in good yields. Therefore, an object of the present invention is to provide a method for producing the compound of the above formula (). The above objects and many other objects and advantages of the present invention will become more apparent from the following description. Examples of lower alkyl groups in R ₁ and R ₂ of the compound of formula () are methyl, ethyl, propyl (n-, iso-), butyl (n-, iso-, sec-,
Preferred examples include C ₁ -C ₄ alkyl groups such as tert-). Examples of substituents that the phenyl group may have include halogen and lower alkyl groups as exemplified above. The compound of formula () can be produced, for example, as shown in the following formula. α- or β-substitution represented by the above formula ()
α in diethyl phenylthio-ethylmalonate
- Substituted product is, for example, the following formula, Accordingly, β-bromoethyl phenyl sulfide and diethyl malonate are reacted in a suitable solution, such as an ethanol solution, in the presence of a suitable condensing agent, such as sodium ethoxide, and further reacted with a suitable acid acceptor. For example, by reacting with sodium ethoxide and causing an alkylation reaction with an alkylating agent represented by R ₁ -X (R ₁ has the same meaning as described for formula (), but a group other than a hydrogen atom, and X represents a halogen atom). It can be formed by For example, the reaction between β-bromoethyl phenyl sulfide and diethyl malonate is carried out at a temperature of about 50° to about 80°
It can be carried out at a molar ratio of about 1 to about 2:1 under temperature conditions such as °C. The reaction between the formed diethyl β-phenylthio-ethylmalonate and R ₁ -X is carried out under temperature conditions such as, for example, from about 50 to about 80°C.
The molar ratio can be from about 1 to about 1.5:1. Further, in the α- or β-substituted-γ-phenyl-thio-ethyl diethylmalonate represented by the above formula (), the β-substituted product is, for example, the following formula, Accordingly, phenylthioketones are reacted with sodium borohydride, for example in a methanol solvent, to form β-phenylthio-isopropanols, and then with, for example, phosphorus tribromide in a carbon tetrachloride medium, for example.

[Formula] (β-phenylthioisopropyl bromides) can be formed by reacting with diethyl malonate in the presence of sodium ethoxide in an ethanol solvent, for example, in the same manner as described above. In the above formula, R ₂ has the same meaning as described for formula (), but represents a group other than a hydrogen atom. The above formula

The reaction between [Formula] and NaBH ₄ can be carried out under low temperature conditions, such as from about 0° to about -10° C., in a methanol solvent.
The amount of NaBH ₄ to be used can be selected as appropriate, and may be about 1 to about 1.5 mol per 1 mol of the compound of the above formula. The reaction of the compound formed with phosphorus tribromide is, for example, about 20° to about 60°
It can be carried out at temperatures such as °C. The amount of phosphorus tribromide to be used can be selected as appropriate, and may be, for example, about 1 to about 1.2 mol per 1 mol of the formed compound. obtained in this way

[Formula] is reacted with diethyl malonate under the same temperature conditions and molar ratio as described for the reaction of β-bromoethyl phenyl sulfide and diethyl malonate, and the β-substituted It can form a body. The α- or β-substituted-γ-phenylthiobutyric acid of the formula () used to form the α- or β-substituted-γ-phenylsulfinylbutyric acid of the formula () can be obtained, for example, as described above. Expressions that can be used () However, in the formula, R ₁ and R ₂ have the same meanings as stated in the formula (). can do. The reaction involves alkaline hydrolysis in a suitable aqueous medium, such as water, an aqueous mixture system of water and a water-miscible medium such as alcohols, and further decomposition in a similar aqueous medium. This can be carried out by carrying out a decarboxylation reaction in the presence of a carbonating agent. Examples of the alkali used in the above-mentioned alkaline hydrolysis include alkalis such as sodium hydroxide and potassium hydroxide. Examples of the decarboxylating agent used in the decarboxylation reaction include inorganic or organic acids such as sulfuric acid and sulfonic acids. The concentrations of the alkalis and acids to be used can be changed and selected depending on the type, reaction temperature, etc., but for example, an alkali concentration of about 5 to about 20% and an acid concentration of about 4 to about 6N An example is concentration. The reaction concentration of the above-mentioned alkaline hydrolysis and decarboxylation reaction in the presence of acids can be selected as appropriate, but the hydrolysis temperature is, for example, about 70° to about 90°C;
Decarboxylation temperatures such as 90 to about 110°C can be exemplified. The compound of formula () can be obtained, for example, as described above. However, in the formula, R ₁ and R ₂ have the same meanings as stated in the formula (), and can be formed by oxidizing α- or β-substituted-γ-phenylthiobutyric acid represented by the following with an oxidizing agent. The reaction can be carried out in a suitable aqueous solvent, ie, a water-water miscible solvent system. Examples of such water-miscible solvents include alcohols such as methyl alcohol and ethyl alcohol. Also, examples of oxidizing agents used in the reaction are:
Examples include periodates such as _NaIO4 . The reaction can be carried out at low temperatures, such as from about 0° to about -10°C. According to the method of the invention, for example, the formula (), which can be formed as described above, However, in the formula, R ₁ and R ₂ have the same meanings as stated in the formula (). α- or β-substituted-γ-phenylsulfinylbutyric acid represented by ) By carrying out a rearrangement reaction, the following formula (), which is a raw material for the synthesis of the compound of formula () of the present invention, is obtained. However, in the formula, R ₁ and R ₂ each represent a group selected from the group consisting of a hydrogen atom, a lower alkyl group, a phenyl group which may have a substituent, and _a benzyl group; It is possible to produce α- or β-substituted-γ-butyrolactones represented by the following, in which either one of R ₂ is a hydrogen atom and the other is a group other than a hydrogen atom. The raw material compound of the formula () is also a compound that has not been previously described in any known literature, and the compound of the formula () can be obtained by the method of the present invention.
It can be advantageously used to form a compound which has not been described in any known literature. The conversion of a compound of formula () to a compound of formula () can be carried out in the presence of an acid catalyst such as acetic anhydride and an organic acid catalyst such as para-toluenesulfonic acid, monochloroacetic acid, phosphoric acid. The reaction can be carried out in the presence of a suitable solvent, e.g.
It can be carried out under temperature conditions such as from to about 120°C.
Examples of the solvent used include organic inert solvents such as benzene, toluene, xylene, chloroform, and tetrahydrofuran. The reaction proceeds almost quantitatively, and the compound of formula () can be obtained with high yield and high purity. The amount of acetic anhydride used in the reaction can be selected as appropriate, but for example, approximately 1
Examples of the amount used include from about 6 mol to about 6 mol, more preferably from about 1 to about 3 mol. In addition, the amount of acid catalyst used can be selected appropriately, for example, about 1% based on the compound ().
~ about 10% by weight, more preferably about 2 to about 8% by weight
An example of the usage amount is as follows. Further, the amount of the solvent to be used can be appropriately selected, and for example, the amount to be used can be about 5 to about 40 times the volume of the compound of formula (). According to the present invention, for example, the formula () obtained as described above, However, in the formula, R ₁ and R ₂ each represent a group selected from the group consisting of a hydrogen atom, a lower alkyl group, a phenyl group which may have a substituent, and _a benzyl group; One of R ₂ is a hydrogen atom and the other is a group other than a hydrogen atom, and the α- or β-substituted-γ-phenylthio-γ-butyrolactones represented by the following are oxidized with methachloroperbenzoic acid. By de-phenylsulfinylating with pyridine, a γ-phenylsulfinyl compound of the formula (), However, in the formula, R ₁ and R ₂ have the same meanings as above, and α- or β-substituted -Δα,β- or -Δβ,γ-butenolides represented by these can be obtained. The reaction is preferably carried out in a solvent, and examples thereof include halogenated hydrocarbon solvents such as methylene chloride, chloroform, and the like. The reaction is preferably carried out under low temperature conditions, e.g., about 0 to about -10°C.
Examples of temperature conditions include: The amount of methachloroperbenzoic acid used can be selected as appropriate, but
For example, about 1 to about 1 mole of the compound of formula ()
A usage amount such as 1.2 mol can be exemplified.
The amount of the solvent to be used can be selected as appropriate, and for example, the amount used can be about 5 to about 40 times the volume of the compound of formula (). The reaction proceeds quantitatively and the product is washed with alkaline if desired and
It can be separated and collected by removing the solvent. α- or β-substitution obtained as described above
The compound of the formula () can be formed by defhenylsulfinylation of γ-phenylsulfinyl-γ-butyrolactone using pyridine. The reaction can be easily carried out, for example, by heating in pyridine. The amount of pyridine to be used can be selected as appropriate, and for example, it can be used in an amount of about 5 to about 20 times the weight of the above-mentioned butyrolactone of formula (). The reaction can be carried out under reflux temperature conditions. The reaction time can be selected as appropriate, but
An example of a reaction time is about 30 minutes to about 2 hours.
After the reaction is completed, pyridine can be distilled off and separated and purified, for example, by column chromatography. Hereinafter, several examples of implementing the method of the present invention can be illustrated in more detail by way of examples. Reference Example 1 Synthesis of β-bromoethyl phenyl sulfide: - 4.00 g (0.10 mol) in 100 ml of ethyl alcohol
of sodium hydroxide and thiophenol 1 1.00g
(0.10 mol) is reacted at room temperature with stirring to synthesize sodium thiophenoxide. This solution was added dropwise to an ethanol solution (50 ml) containing an excess amount of 1,2-dibromoethane (56.40 g, 0.30 mol) for reaction. The mixture was stirred at room temperature for 4 hours to react. The white precipitate of sodium bromide produced is filtered off, and the ethanol is concentrated under reduced pressure. Add 10% hydrochloric acid to the residue to neutralize it, and then extract with ether. After drying the ether layer over anhydrous sodium sulfate, the ether is removed and the residue is distilled. 95-100℃/6mmHg, 14.38g (66%). Reference Example 2 Synthesis of diethyl β-(phenylthio)ethylmalonate 4.60 g of sodium metal in 50 ml of absolute ethanol
(0.20 mol) was added to synthesize sodium ethoxide, and diethyl malonate (32.00 g, 0.20 mol) was added to synthesize sodium ethoxide.
mol) and reflux for 15 minutes. After cooling to room temperature, an ethanol solution (10 ml) of β-bromoethyl phenyl sulfide (20.72 g, 0.10 mol) obtained in Reference Example 1 was added dropwise, followed by refluxing for 4 hours. The produced sodium bromide is filtered off, and the ethanol is concentrated under reduced pressure. Add 10% hydrochloric acid to the residue to neutralize it, and then extract with ether. After drying the ether layer over anhydrous sodium sulfate, the ether and excess diethyl malonate are removed by distillation. The residue was separated by column chromatography using silica gel, and β-(phenylthio) was extracted from the benzene distillate.
16.69 g of diethyl ethylmalonate was obtained. 56%.
IR (NaCl): 1730 cm ^-1 (C=O), NMR (CDCl ₃ );
δ=1.23 (6H, t), 2.16 (2H, f), 2.96 (2H,
t), 3.58 (1H, t), 4.15 (4H, q), 7.04-7.42
(5H, m). Reference Example 3 Diethyl benzyl-β(phenylthio)ethylmalonate [Formula (): R ₁ = benzyl]
Synthesis: - Diethyl β(phenylthio)ethylmalonate (0.023 mol) obtained in Reference Example 2 was mixed with an ethanol solution of sodium ethoxide (30 ml of absolute ethanol).
Synthesized from 0.69g, 0.030mol of sodium metal)
and reflux for 15 minutes. After cooling the mixture to room temperature, a solution of 5.13 g (0.030 mol) of benzyl bromide in ethanol (5 ml) was added dropwise, and the mixture was refluxed for 4 hours.
After cooling to room temperature and filtering off a white precipitate (sodium bromide), the mixture is concentrated under reduced pressure. After neutralizing the residue by adding 10% hydrochloric acid, perform ether extraction. After drying the ether layer over anhydrous sodium sulfate, the ether is removed. The residue was separated using silica gel column chromatography, and benzyl β was extracted from the benzene distillate.
Diethyl (phenylthio)ethylmalonate 7.80
g (88%) was obtained. IR (NaCl): 1720cm ^-1 (C=O), NMR
(CDCl ₃ ): δ=1.17 (6H, t), 1.90−2.30 (2H,
m), 2.40-3.06 (2H, m), 3.18 (2H, s), 4.08
(4H, q), 6.74-7.36 (10H, m). Reference Example 4 Synthesis of α-benzyl-γ-phenylthiobutyric acid [formula (): R ₁ = benzyl]: - 3.18 g of diethyl β(phenylthio)ethylmalonate obtained in Reference Example 3 was added to 20 ml of 10% aqueous sodium hydroxide solution. g (0.0082 mol) dissolved in 20 ml of ethanol is added and refluxed for 6 hours. After refluxing, only ethanol is removed, and 10% hydrochloric acid is added to make it acidic, followed by ether extraction. Take out the ether layer, remove the ether, and add 30ml of 6N sulfuric acid to the residue.
and reflux for 12 hours. After refluxing, ether extraction is performed, and the ether layer is dried using anhydrous sodium sulfate. After removing the ether, the residue was separated using silica gel column chromatography, and 1.35 g (57%) of α-benzyl-γ-phenylthiobutyric acid was obtained from the benzene-ether (10:1) distillate. IR (NaCl): 1720cm ^-1 (C=O), NMR
(CDCl ₃ ): δ=1.00-1.36 (2H, m), 2.42-3.36
(4H, m), 3.84-4.30 (1H, m), 7.02-7.30
(10H, m), 10.77 (1H, s). Reference Example 5 Synthesis of α-benzyl-γ-phenylsulfinylbutyric acid [formula (): R ₁ = benzyl]:
- Dissolve 1.10 g of sodium periodate in 25 ml of water and cool it to 0°C, and add 1.25 g of α-benzyl-γ-phenylthiobutyric acid obtained in Reference Example 4.
Add the solution dissolved in 25 ml of ethanol and cool on ice.
Stir for 12 hours. After stirring, the precipitated white precipitate is filtered and only the liquid ethanol is concentrated under reduced pressure. The remaining aqueous layer is extracted with ether, and the ether layer is dried using anhydrous sodium sulfate. By removing the ether, almost pure α-benzyl-γ-phenylsulfinylbutyric acid is obtained. 1.10g. Reference example 6 α-benzyl-γ-phenylthio-γ
-Butyrolactone [formula (): R ₁ = benzyl]
Synthesis: - 0.60 g (0.002 mol) of α-benzyl-γ-phenylsulfinylbutyric acid obtained in Reference Example 5 and 1.00 g (0.01 mol) of acetic anhydride were added to 20 ml of anhydrous toluene, and a catalytic amount of para Add toluenesulfonic acid and react under reflux for 1 hour. From the reaction mixture,
Toluene and excess acetic anhydride are concentrated under reduced pressure. The residue was separated using silica gel column chromatography, and α-benzyl-
0.35 g of γ-phenylthio-γ-butyrolactone was obtained. Yield 63%. IR: 1770cm ^-1 (C=O), NMR
( _CDCl3 ): δ=1.36-3.50 (5H, m), 5.50, 5.80
(1H, m), 7.00-7.58 (10H, m). Example 1 Synthesis of α-benzyl-△α,β-butenolide [formula (): R ₁ = benzyl]: - 1.42 g (0.005 mol) of α-benzyl-γ-phenylthio-γ-butyrolactone obtained in Reference Example 6 and 0.86 g (0.005 mol) of methachloroperbenzoic acid were reacted in methylene chloride (30 ml) at 0° C. for 1 hour with stirring. The reaction mixture was thoroughly shaken with 30 ml of 10% aqueous sodium bicarbonate solution in a separatory funnel to remove methachlorobenzoic acid. The methylene chloride layer is dried using anhydrous sodium sulfate. Removal of methylene chloride yields α-benzyl-γ-phenylsulfinyl-γ-butyrolactone, which is added to 20 ml of pyridine without further purification.
Perform reflux for an hour. Add to 20 ml of pyridine and reflux for 1 hour. Pyridine was concentrated under reduced pressure and the residue was separated using silica gel column chromatography to obtain 0.56 g (64%) of α-benzyl-Δα,β-butenolide from the benzene distillate. The physicochemical data are shown in Table 2 below. Reference Example 7 Synthesis of β-phenylthio-isopropanol: - A solution of 6.64 g (0.04 mol) of phenylthioacetone in anhydrous methanol (40 ml) was cooled to 0°C, and 2 g (0.05 mol) of sodium borohydride was added little by little while stirring. Add. After the addition, the reaction mixture is stirred for an additional 3 hours while cooling to 0°C. After the reaction, 10 ml of acetic acid is added to decompose excess sodium borohydride, and then methanol is removed under reduced pressure. The residue was distilled under reduced pressure to obtain 5.29 g of β-phenylthio-isopropanol as a fraction at 115°C/9 mmHg. Reference Example 8 Synthesis of β-phenylthioisopropylbromide: - 10 g (0.06 mol) of β-phenylthioisopropanol obtained in Reference Example 7 was dissolved in 50 ml of anhydrous carbon tetrachloride, and 16.26 g of phosphorus tribromide was added thereto. (0.06 mol)
Drip little by little. Reflux is performed for 4 hours after the addition.
After refluxing, pour the reaction mixture into 100 ml of water, stir well, and separate the carbon tetrachloride layer. The aqueous layer is further extracted with ether, mixed with the carbon tetrachloride layer, and dried over anhydrous sodium sulfate. After removing the organic solvent, the residue was distilled under reduced pressure and the boiling point was 115-122℃/10
11.00 g of β-phenylthio-isopropyl bromide was obtained as a mmHg fraction (80%). Reference Example 9 Synthesis of β-methyl-phenylsulfinylbutyric acid [formula (): R ₂ = methyl]: - Instead of β-bromoethyl phenyl sulfide in Reference Example 2, the above Reference Example 7 was used. β obtained from
Using phenylthioisopropyl bromide, the same procedure as in Reference Example 2 was carried out, and thereafter, the above-mentioned Reference Examples 3 to 5 were carried out.
β-methyl-γ-phenylsulfinylbutyric acid was obtained in a yield of 30%. Reference example 10 β-methyl-γ-phenylthio-γ-
Synthesis of butyrolactone [formula (): R ₂ = methyl]: - 0.68 g (0.003 mol) of β-methyl-γ-phenylsulfinylbutyric acid obtained in Reference Example 9 and 1.53 g (0.015 mol) of acetic anhydride. Add to 30 ml of anhydrous toluene, add a catalytic amount of p-toluenesulfonic acid, and react under reflux conditions for 1 hour. The reaction product was treated in the same manner as in Reference Example 6 to obtain β-methyl-γ-
Phenylthio-γ-butyrolactone 0.32g (52
%) was obtained. IR: 1740cm ^-1 (C=O), MS (m/
e): 208, NMR (CDCl ₃ ): δ = 1.35-1.47 (3H,
m), 5.18-5.37 (1H, m), 7.10-7.63 (5H, m). Example 2 Synthesis of β-methyl-Δβ,γ-butenolide [formula (): R ₂ = methyl]: - 1.04 g (0.005 mol) of β-methyl-γ-phenylthio-γ-butyrolactone obtained in Reference Example 10 and 0.56 g (0.005 mol) of methachloroperbenzoic acid were reacted in methylene chloride (30 ml) at 0° C. for 1 hour with stirring. The reaction mixture is thoroughly shaken with 30 ml of 10% aqueous sodium bicarbonate solution in a separatory funnel to remove benzoic acid methacrylate. The methylene chloride layer is collected and dried using anhydrous sodium sulfate to remove methylene chloride to obtain β-methyl-γ-phenylsulfinyl-γ-butyrolactone. Without further purification, pyridine 20
ml was added and boiled under reflux for 1 hour, the pyridine was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography using benzene.
Collect the benzene distillate, remove the benzene, and
-Methyl-△β,γ-butenolide 0.36g (73%)
I got it. The physicochemical data are shown in Table 1. Examples 3 to 6 Compounds shown in Tables 1 and 2 below were obtained by following the procedure of Example 1 or 2, except that the compounds of formula () were variously changed. In addition, Table 1 shows
The compound obtained in Example 2 and the compound obtained in Example 1 are also shown in Table 2.

【table】

【table】

[Claims]

1 General formula [In the formula, R ¹ is a lower alkyl group, a naphthyl group,
A mono- or diphenyl lower alkyl group (the phenyl ring may be substituted with a lower alkyl group), a phenyl group (a halogen atom on the ring, a lower alkyl group, a halogen-substituted lower alkyl group, a lower alkoxy group) may have one or two substituents), or the formula

In the group represented by the formula (m=an integer of 1 to 3), R ² represents a hydrogen atom or a lower alkoxycarbonyl group. However, this excludes cases where R ² is a hydrogen atom and R ¹ is a benzyl group.] 2(5H)-furanone derivatives represented by:

Claims (1)

However, in the formula, R ₁ and R ₂ have the same meanings as above, and a method for producing α- or β-substituted -Δα,β- or -Δβ,γ-butenolides represented by: