JPS6154031B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula () [In the formula, R ₁ is a carboxyl group, a cyano group, a benzhydryloxycarbonyl group, or a lower alkoxycarbonyl group, and R ₂ is a hydrogen atom, a cyano group, a carboxyl group, a sulfamoyl group, a vinyl group, or an optionally substituted carbamoyl group. group, lower alkyl group, lower alkoxy group, aroyl group, optionally substituted aryl group, optionally substituted monocyclic heterocyclic group, RCO- or R-S(O) _o- (wherein R is (n represents a lower alkoxy group or a lower alkyl group which may have a hydroxyl group or may be interrupted by a hetero atom; n represents 0, 1 or 2)
In the group represented by, R ₃ represents a hydrogen atom or a lower alkyl group. ] The present invention relates to a 1,3-dithiethane compound represented by the following and a method for producing the same. The term "lower alkyl group" herein refers to a linear or branched group having 1 to 6 carbon atoms, such as a methyl group, ethyl group, isopropyl group, butyl group, tert-butyl group, hexyl group, etc. The group means a straight chain or branched group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, an isopropoxy group, a butoxy group, and a tert-butoxy group. Moreover, the monocyclic heterocyclic group means a 5- or 6-membered ring group containing a sulfur atom and/or a nitrogen atom, such as a pyrrolyl group, a pyrrolidinyl group, an imidazolyl group, a thienyl group, a thiadiazolyl group, a pyridyl group, and a piperidino group. Examples of the aroyl group include a benzoyl group, and examples of the aryl group include a phenyl group and a naphthyl group. Examples of the optionally substituted carbamoyl group include a carbamoyl group substituted with a hydroxyl group, a lower alkyl group, a di-lower alkyl group, and an unsubstituted carbamoyl group. Further, the monocyclic heterocyclic group and the aryl group may be substituted with a hydroxyl group, a lower alkoxy group, a lower alkyl group, a lower alkylthio group, or the like. The compound of the present invention () is a novel compound that has not been described in any literature, and has the general formula () (In the formula, R ₁ and R ₂ represent the same meanings as above, R ₄ is a hydrogen atom or a methoxy group, and R ₅ is a lower alkyl group which may have a hydroxyl group or may be interrupted by a hetero atom. It is useful as a raw material for the cephalosporin compound represented by This cephalosporin compound has a unique chemical structure with a substituted dithiethanecarboxylic acid amide residue at the 7-position, and is a novel and useful compound with antibacterial activity.For example, the compound of the present invention () and the general formula () (In the formula, R ₄ and R ₅ have the same meanings as above.) It can be produced by reacting with a 7β-aminocephalosporin compound represented by the following formula. The compound of the present invention () has the general formula () (In the formula, R ₁ and R ₂ have the same meanings as above.) Ethylene dithiol compound represented by the general formula () (In the formula, X represents a halogen atom, and R ₃ represents the same meaning as above.) It can be produced by reacting with a dihalogenoacetic acid compound represented by the following formula. This reaction is preferably carried out using Compound () and an equimolar to excess molar amount of Compound () in an organic solvent that does not participate in the reaction, in the presence of chlorine, and under cooling or heating. Examples of organic solvents that do not participate in the reaction include methanol, ethanol, butanol, tert-butanol, chloroform, methylene chloride, tetrahydrofuran, benzene, toluene, dimethoxyethane, anisole, acetone, dimethoxyethane, dimethyl sulfoxide,
Examples of bases include pyridine, triethylamine, dicyclohexylamine, alkali metals (metallic potassium, etc.), alkali metal hydrides (sodium hydride, potassium hydride, etc.), alkyllithium (methyllithium, etc.), and dimethylformamide, dimethylaniline, etc. tert-butyllithium, etc.), sodium carbonate, potassium carbonate, lithium diisopropylamine, etc. The halogen atom in the compound () used in this reaction is preferably a chlorine atom, a bromine atom, or an iodo atom;
When R ₃ is a hydrogen atom, its alkali salts such as sodium salts and potassium salts can be used. When R ₃ is a lower alkyl group in the compound (), the compound () in which R ₃ is a hydrogen atom can be obtained by hydrolysis in the organic solvent in the presence of an acid such as hydrochloric acid, acetic acid, or trifluoroacetic acid. Obtainable. In addition, when R ₂ is a carbamoyl group in the compound (), an inorganic chloride, such as phosphorus oxychloride, phosphorus pentachloride,
It can be converted to a cyano group by carrying out a dehydration reaction in the presence of thionyl chloride, sulfuryl chloride, or the like. The ethylenediol compound () used as a raw material in the present invention includes not only known compounds but also new ones, and these include, for example, the general formula () R ₁ --CH ₂ --R ₂ () (in the formula, R ₁ and R ₂ has the same meaning as above.) It can be produced by reacting the compound represented by (2) with carbon disulfide in the organic solvent, also in the presence of the base, under cooling or heating. The specific structures of the compounds of the present invention will be explained below using Examples. Example 1 2.1 g of disodium 2,2-bis(methoxycarbonyl)ethylene-1,1-dithiolate is suspended in 10 ml of anhydrous tetrahydrofuran, then 2.2 g of sodium dibromoacetate is added and stirred at room temperature for 2 hours. The solvent of the reaction solution was distilled off under reduced pressure, the residue was dissolved in 5 ml of water, and the pH was adjusted to 3.5 to 4.0 with dilute hydrochloric acid.
Extract with ethyl acetate. After drying the extract over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was filtered with ether to give 4-[bis(methoxycarbonyl)methylene]-1,3-dithiethane-
1.5 g of 2-carboxylic acid is obtained. Nuclear magnetic resonance spectrum (DMSO-d ₆ ) δ (ppm); 3.70 (6H,

【formula】) 5.20 (1H,

[Formula]) Example 2 By treating disodium 2,2-bis(tert-butoxycarbonyl)ethylene-1,1-dithiolate in the same manner as in Example 1, 4-[bis(tert-butoxycarbonyl)methylene]-1,
3-dithiethane-2-carboxylic acid is obtained. Nuclear magnetic resonance spectrum (DMSO-d ₆ ) δ (ppm); 1.46 (18H, 20(CH ₃ ) ₃ COOC-) 5.18 (1H,

[Formula]) Example 3 In 15.6 g of a tert-butanol solution containing 15% potassium tort-butoxy, 4 g of tort-butyl phenyl acetate was added, followed by carbon disulfide, while stirring at room temperature.
Add 1.6g. After stirring for 15 minutes, add 20 ml of anhydrous tetrahydrofuran and 31.2 g of a tert-butanol solution containing 15% tert-butoxypotassium, then drop 2.7 g of dichloroacetic acid at 30-40°C, and stir at the same temperature for 30 minutes to react. end. After adding dichloroacetic acid until the reaction mixture becomes slightly alkaline, the solvent is distilled off under reduced pressure, ice water is added, and the mixture is washed with ether. Next, add 0.5ml of 3N hydrochloric acid, extract with ether, add 0.5ml of 3N hydrochloric acid,
Extract with ether, repeat this operation, track each extracted fraction obtained by silica gel thin layer chromatography, collect fractions containing the target product, and dry over anhydrous magnesium sulfate. Next, when the solvent was distilled off under reduced pressure, 4-(α-tert-butoxycarbonylbenzylidene)-1,3-dithiethane-2
-About 1 g of carboxylic acid is obtained. Nuclear magnetic resonance spectrum (DMSO-d ₆ ) δ (ppm); 1.40 (9H, (CH ₃ ) ₃ COOC-) 5.17 (1H,

【formula】) Approximately 7.30 (5H,

[Formula]) Example 4 By treating tert-butyl 4-tert-butoxyphenylacetate in the same manner as in Example 3, 4-
(4-tert-butoxy-α-tert-butoxycarbonylbenzylidene)-1,3-dithiethane-2-
Obtain carboxylic acid.

【table】

[Table] Example 5 By treating tert-butyl dimethylcarbamoylacetate in the same manner as in Example 3, 4-[(tert
-butoxycarbonyl)(dimethylcarbamoyl)methylene]-1,3-dithiethane-2-carboxylic acid is obtained. Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm); 1.50 (9H, (CH ₃ ) ₃ COOC—) 3.02 (6H,

【formula】) 4.97 (1H,

[Formula]) Example 6 By treating tert-butyl 3-pyridylacetate in the same manner as in Example 3, 4-[(tert-butoxycarbonyl)(3-pyridyl)methylene]-
1,3-dithiethane-2-carboxylic acid is obtained.

[Table] Example 7 By treating tert-butyl 3-butenoate in the same manner as in Example 3, 4-(1-tert-butoxycarbonyl-2-propene-1-ylidene)-
1,3-dithiethane-2-carboxylic acid is obtained. Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm); 1.51 (9H, (CH ₃ ) ₃ COOC—) 4.98 (1H,

[Formula]) 5.00 to 5.40 (2H, CH ₂ = CH -) 6.10 to 6.50 (1H, CH ₂ = CH -) Example 8 4.8g of sodium hydride (50% oily)
Add to 150ml of butanol, then acetoacetic acid tert.
- Add 15.8g of butyl little by little. Add 7.6 g of carbon disulfide to this under ice cooling, and stir at room temperature for 18 hours. Next, add 4.8 g of sodium hydride (50% oily) little by little under ice cooling, stir at room temperature for 2 hours, then add 16.7 g of potassium dichloroacetate and stir for another 2 hours. The resulting reaction solution is concentrated under reduced pressure, 300 ml of ethyl acetate and 200 ml of ice water are added to adjust the pH to 1N hydrochloric acid from 3 to 4, the organic layer is washed with an aqueous sodium chloride solution, and then extracted with a saturated aqueous sodium bicarbonate solution. This sodium bicarbonate extract is washed with 50 ml of ethyl acetate, adjusted to pH 3-4 with 1N hydrochloric acid, and extracted with 200 ml of ethyl acetate. This ethyl acetate extract is washed with an aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. After washing the residue with 50 ml of petroleum ether/ether mixture (volume ratio 10:1), dissolve in 5 ml of ether and add 50 ml of petroleum ether.
When adding ml little by little and removing the crystals that precipitate, 4
-[(acetyl)(tert-butoxycarbonyl)methylene]-1,3-dithiethane-2-carboxylic acid
Get 10g. Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm): 1.53 (9H, (CH ₃ ) ₃ COOC—) 2.49 (3H, CH ₃ OC—) 4.94 (1H,

[Formula]) Example 9 1.58g of metallic potassium in 100ml of tert-butanol
Add 10 g of tert-butyl 5-methylthio-1,3,4-thiadiazole-2-acetate to
Stir for a minute, then drop in 3.25 g of carbon disulfide over 10 minutes. After stirring for 1 hour, add 4.55 g of tert-butoxypotassium little by little, and add 20 g of tert-butoxypotassium little by little.
Stir for a minute, add 6.83 g of potassium dichloroacetate, and stir for 18 hours. The resulting reaction solution was concentrated under reduced pressure, 300 ml of ethyl acetate and 200 ml of ice water were added, the pH was adjusted to 3-4 with 1N hydrochloric acid, and the organic layer was washed with an aqueous sodium chloride solution, followed by a saturated aqueous sodium bicarbonate solution.
Extract with 1000ml. This sodium hydrogen carbonate extract was washed with 100ml of ethyl acetate, and the pH was adjusted with 5N hydrochloric acid.
After adjusting to 3-4, extract with 200 ml of ethyl acetate.
This ethyl acetate extract is washed with an aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated.
The residue was subjected to silica gel column chromatography, using first chloroform and then a chloroform/methanol mixture (volume ratio 50:1) as the eluent.
using 4-[(5-methylthio-1,3,4-
Thiadiazol-2-yl)(tert-butoxycarbonyl)methylene]-1,3-dithiethane-2
- Obtain 1 g of carboxylic acid. Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm); 1.59 (9H, (CH ₃ ) ₃ COOC—) 2.79 (3H, CH ₃ S—) 4.99 (1H,

[Formula]) Example 10 0.24 g of sodium hydride (50% oily), 2.2 g of tert-butyl benzoyl acetate and 20 g of tert-butanol
ml of mixed solution and 0.6 ml of carbon disulfide at 15-20℃.
Add and stir for 40 minutes, then add 0.24 g of sodium hydride (50% oily) and stir for 1 hour. Add sodium dichloroacetate to the resulting reaction solution.
Add 1.52g of the mixture, stir at room temperature for 4 hours, concentrate under reduced pressure, add 30ml of 1N hydrochloric acid to the residue, and add 30ml of benzene.
Extract in ml. The extract was washed with water, dried, and then concentrated under reduced pressure. To the resulting residue, a mixed solution of benzene and n-hexane (volume ratio 3:1) was added to form 4-[(benzoyl)(tert-butoxycarbonyl)methylene]-
0.9 g of yellowish crystals of 1,3-dithiethane-2-carboxylic acid are obtained. Melting point 147-148℃ (decomposed) Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm); 1.23 (9H, (CH ₃ ) ₃ COOC—) 5.02 (1H,

【formula】) 7.3~7.5 (5H,

[Formula]) 8.22 (1H, -COOH) Example 11 Hexane solution containing 15% n-butyllithium 18.2
ml of tert-butyl methoxyacetate and 10 ml of tetrahydrofuran was added to a lithium diisopropylamine solution obtained by adding 4.5 g of tert-butyl methoxyacetate and 10 ml of tetrahydrofuran to a mixture of 3 g of diisopropylamine and 20 ml of tetrahydrofuran at -40 to -70°C, and then carbon disulfide was added to the solution.
Add 0.9ml at -40℃ or below and stir at the same temperature for 20 minutes. After adding 1/2 amount of the above-mentioned lithium diisopropylamine solution and 1/2 amount of carbon disulfide to the resulting reaction solution at -40 to -70°C and reacting, add 1/4 amount of the lithium diisopropylamine solution. Then, 9 g of sodium diiodoacetate was added and the temperature was gradually raised, and the mixture was stirred at 0 to 5° C. for 1 hour and then at room temperature for 1 hour. The resulting reaction solution was concentrated under reduced pressure, 20 ml of 10% hydrochloric acid was added to the residue, and benzene was added.
Extract with 100ml. The extract was washed with water, concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography, using a chloroform/ethanol mixture (volume ratio 10:2-5) as the eluent.
[(tert-butoxycarbonyl)(methoxy)methylene]-1,3-dithiethane-2-carboxylic acid
Obtain 5.6g. Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm): 1.52 (9H, (CH ₃ ) ₃ COOC—) 3.67 (3H, CH ₃ O—) 4.88 (1H,

[Formula]) 8.64 (1H, -COOH) Example 12 Suspend 0.96 g of sodium hydride (50% oil) in 14 ml of anhydrous tetrahydrofuran, then drop a mixture of 20 ml of tert-butanol and 15 ml of anhydrous tetrahydrofuran, and stir at room temperature for 10 minutes. A mixed solution of 1.62 g of tert-butyl methylthioacetate and 5 ml of anhydrous tetrahydrofuran was added to the mixture at 3 to 5° C. After 30 minutes, 0.6 ml of carbon disulfide was added at the same temperature and stirred for 50 minutes. Next, add 3.34 g of sodium diiodoacetate at 7°C.
Add the following and react for 50 minutes under ice cooling. The solvent was distilled off under reduced pressure, and the residue was dissolved in 50 ml of ice water and washed twice with ether. The aqueous layer was adjusted to pH 2 with 10% hydrochloric acid,
Extract twice with ether. The extracts are combined, dried over anhydrous magnesium sulfate, and then the ether is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and an oily 4-[(tert-butoxycarbonyl)(methylthio)methylene]- 1.3 g of 1,3-dithiethane-2-carboxylic acid is obtained. Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm): 1.52 (9H, (CH ₃ ) ₃ COOC—) 2.22 (3H, CH ₃ S—) 4.74 (1H,

[Formula]) 9.12 (1H, -COOH) Example 13 Example 12: 3.4 g of tert-butyl ethylthioacetate
By processing in the same manner as above, oily 4-
[(tert-butoxycarbonyl)(ethylthio)methylene]-1,3-dithiethane-2-carboxylic acid
Obtain 4.05g. Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm): 1.42 (3H, CH ₃ CH ₂ S—) 1.52 (9H, (CH ₃ ) ₃ COOC—) 2.68 (2H, CH ₃ C H ₂ S—) 4.76 (1H,

[Formula]) 9.52 (1H, -COOH) Example 14 1ml of N-isopropylcyclohexylamine and 3.43ml of hexane solution containing 15% n-butyllithium
dimethoxyethane, which has been distilled in advance to remove oxygen.
Add to a mixture of 40 ml and 10 ml of anhydrous tetrahydrofuran at -70°C or below in a nitrogen stream. Add 0.65g of tert-butyl propionate to this, stir at -70℃ or below for 30 minutes, then add 0.332ml of carbon disulfide to -75~
Apply over 30 minutes at -73℃. After reacting at -70°C for 10 minutes, 3.4 ml of a hexane solution containing 15% n-butyllithium was added over 30 minutes at the same temperature.
After further reacting at the same temperature for 15 minutes, add 0.24 g of sodium hydride (50% oil) and diiodoacetic acid in advance.
Add sodium diiodoacetate obtained by reacting 1.56 g of 1.56 g with 1.56 g of dimethoxyethane under ice-cooling in 10 ml of dimethoxyethane, return to room temperature, and stir overnight. The solvent of the resulting reaction solution was distilled off under reduced pressure, and the residue was added with cold ether, acidified with 1N hydrochloric acid, and extracted. The ether extract was washed with cold saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the ether was distilled off to obtain 1.42 g of a brown oil. This was subjected to silica gel column chromatography, and the eluent was a mixture of chloroform, methanol, and formic acid (volume ratio 95:5:2).
to obtain 0.5 g of oily 4-(1-tert-butoxycarbonylethylidene)-1,3-dithiethane-2-carboxylic acid. Nuclear magnetic resonance spectrum (DMSO-d ₆ ) δ (ppm): 1.42 (9H, (CH ₃ ) ₃ COOC-) 1.53 (3H,

【formula】) 5.14 (1H,

[Formula]) Infrared spectrum (cm ^-1 ) 2970 ((CH ₃ ) ₃ C—), 2520 to 2650 (—COOH) 1640 to 1740 ((CH ₃ ) ₃ COOC—, —COOH) 1360, 1250, 840 ((CH ₃ ) ₃ C―) Example 15 2ml of N-isopropylcyclohexylamine and 6.86ml of a hexane solution containing 15% n-butyllithium
Add to a mixture of 80 ml of dimethoxyethane, which has been previously distilled to remove oxygen, and 2 ml of anhydrous tetrahydrofuran at -70°C or below in a nitrogen stream. Add tert acetic acid to this
-Drop 1.16 g of butyl, stir at -70°C or below for 30 minutes, then add 0.664 ml of carbon disulfide at -72°C or below over 30 minutes. After reacting at -70℃ or below for 20 minutes, 6.8ml of a hexane solution containing 15% n-butyllithium was added dropwise at -72℃ or below over 15 minutes.
Incubate for 20 minutes at 70℃ or below. Next, add 0.48 g of sodium hydride (50% oil-based) and 3.12 g of diiodoacetic acid in advance.
Add sodium diiodoacetate obtained by reacting the mixture with g in 15 ml of dimethoxyethane, return to room temperature, and stir overnight. The solvent of the resulting reaction solution was distilled off under reduced pressure, 20 ml of 1N hydrochloric acid was added to the residue, and 50 ml of cold ether was added.
Extract in ml. The aqueous layer was further extracted with 30 ml of cold ether, the ether extracts were combined, washed twice with 30 ml each of saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and the ether was distilled off to form a brown oil.
get g. This was subjected to silica gel column chromatography, and 4-(tert-butoxycarbonylmethylene)-
0.564 g of 1,3-dithiethane-2-carboxylic acid is obtained. Nuclear magnetic resonance spectrum (DMSO-d ₆ ) δ (ppm): 1.45 (9H, (CH ₃ ) ₃ COOC-) 5.03 (1H,

【formula】) 5.69 (1H,

[Formula]) Example 16 2.05g of tert-butyl methylsulfonylacetate
Dissolve in 65 ml of tert-butanol, add 1.32 g of tert-butoxypotassium, and stir for 5 minutes. Add 0.91 g of carbon disulfide and stir for 5 minutes, then add 1.32 g of potassium tert-butoxy and stir for 1 hour. Then 3.8g of diiodoacetic acid and tert.
-Add 1.32g of butoxypotassium and stir overnight. The solvent of the resulting reaction solution was distilled off under reduced pressure, water was added to the residue, the pH was adjusted to 2 with 10% hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract is washed with water and then with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and 4-[(tert-butoxycarbonyl)(methylsulfonyl)methylene]-1,3-dithiethane was extracted using a chloroform/methanol mixture (volume ratio 50:1) as the eluent. Obtain 1.7 g of -2-carboxylic acid. Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm): 1.52 (9H, (CH ₃ ) ₃ COOC—) 3.20 (3H, CH ₃ SO ₂ —) 4.88 (1H,

[Formula]) Example 17 Disodium 2-carbamoyl-2-cyano-
Dissolve 4.8 g of ethylene-1,1-dithiolate in 50 ml of dimethyl sulfoxide and add dibromoacetic acid tert.
-Add 6.28g of butyl and stir at room temperature for 48 hours. The solvent of the resulting reaction solution was distilled off under reduced pressure, and the mixture was extracted with ethyl acetate. The extract is washed with water, then with an aqueous sodium chloride solution, and then with anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography using a mixture of chloroform and ethyl acetate (volume ratio 7:1) as the eluent.
4-[(carbamoyl)(cyano)methylene]-1,3-dithiethane-2-carboxylic acid tert using
- Obtain 0.8 g of butyl. Nuclear magnetic resonance spectrum (DMSO-d ₆ ) δ (ppm): 1.47 (9H, (CH ₃ ) ₃ COOC-) 5.42 (1H,

[Formula]) Example 18 2 ml of anisole and 8 ml of trifluoroacetic acid were added to 0.4 g of tert-butyl 4-[(carbamoyl)(cyano)methylene]-1,3-dithiethane-2-carboxylate obtained in Example 17, and the mixture was heated at room temperature for 1 hour. Stir. The solvent was distilled off under reduced pressure, 10 ml of ether was added to the residue, and the mixture was stirred for 1 hour. The resulting precipitate was collected, washed with ether, and dried under reduced pressure.
[(carbamoyl)(cyano)methylene]-1,3
0.15 g of -dithiethane-2-carboxylic acid is obtained. Example 19 0.28 g of tert-butyl 4-[(carbamoyl)(cyano)methylene]-1,3-dithiethane-2-carboxylate obtained in Example 17 was added to 15 ml of methylene chloride.
in addition to 0.33 g of pyridine and 0.43 g of phosphorus pentachloride.
Add g and stir at room temperature for 30 minutes. Next, 30 ml of chloroform is added, and the mixture is washed successively with 1N sulfuric acid, 5% aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography using chloroform as an eluent to obtain 0.23 g of tert-butyl 4-dicyanomethylene-1,3-dithiethane-2-carboxylate. Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm): 1.54 (9H, -COOC(CH ₃ ) ₃ ) 5.02 (1H,

[Formula]) Example 20 Add 2 ml of anisole and 6 ml of trifluoroacetic acid to 4-dicyanomethylene-1,3- obtained in Example 19.
tert-butyl dithiethane-2-carboxylate 0.23g
and stir at room temperature for 3 hours. The solvent is distilled off under reduced pressure, 10 ml of hexane is added to the residue, and the mixture is stirred for 10 minutes. The same operation was performed twice on the residue obtained by decanting the solvent and drying under reduced pressure to obtain 4-dicyanomethylene-1,3-dithiethane-2-carboxylic acid.
Obtain 0.18g. Example 21 Add 30 ml of anhydrous tetrahydrofuran and 20 ml of tert-butanol to benzhydryl sulfamoyl acetate.
In addition to 1.12 g, cool to -20°C, add 0.177 g of sodium hydride (50% oil-based), and stir for 15 minutes. Add 0.3g of carbon disulfide to this and -10 to -5℃
Stir for 30 minutes, then add sodium hydride (50
% oily) and 1.05 g of diiodoacetic acid, -
Stir at 10-0°C for 20 minutes, then return to room temperature and stir overnight. The solvent of the resulting reaction solution was distilled off under reduced pressure, and ice water and 5% hydrochloric acid were added to the residue to adjust the pH to 2.
Extract with ethyl acetate. The extract is washed twice with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography using a chloroform/methanol mixture (volume ratio 10:
1) using 4-[(benzhydryloxycarbonyl)(sulfamoyl)methylene]-1,3
0.2 g of -dithiethane-2-carboxylic acid is obtained. Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm): 4.66 (1H,

[Formula]) 6.96 (1H, (C ₆ H ₅ ) ₂ CH -) 7.33 (10H, (C ₆ H ₅ ) ₂ CH -) Example 22 15% (W/W) potassium tert-butoxide
N- in 3 ml of tert-butanol solution at room temperature under stirring.
Add 540 mg of tert-butyl methylmalonamate and 12 ml of dry tetrahydrofuran. After stirring for 5 minutes, drop 0.0935 ml of carbon disulfide and stir for 10 minutes. Add 1.5 ml of 15% potassium tert-butoxide in tert-butanol and stir for 10 minutes. Add 0.046 ml of carbon disulfide and stir for 10 minutes, then add 15% potassium tert-butoxide in tert-butanol and stir for 10 minutes.
- Add 0.8 ml of butanol solution and stir for 10 minutes, then add 0.023 ml of carbon disulfide and stir for 10 minutes. Next, a suspension of sodium diiodoacetate in tetrahydrofuran, prepared by previously dissolving 0.98 g of diiodoacetic acid in 7 ml of dry tetrahydrofuran and adding 115 mg of 50% sodium hydride under stirring under ice cooling, was added to the above reaction solution, and the mixture was heated at room temperature. The reaction was completed by stirring for 1 hour. After distilling off the solvent under reduced pressure, ether 150
ml, add 50 ml of 0.2N hydrochloric acid cooled to 0°C, extract with ether, and wash twice with 50 ml of water. Next, the ether layer is back-extracted with 50 ml of 2% sodium bicarbonate water, and the aqueous layer is neutralized to pH approximately 7.5 with 1N hydrochloric acid and extracted with 100 ml of ether. The aqueous layer is also 1N-hydrochloric acid 0.5
ml and extracted with 100 ml of ether.For the aqueous layer, add 0.5 ml of 1N hydrochloric acid and extract with 100 ml of ether. By repeating this operation, each fraction of the ether extraction was subjected to thin-layer silica gel column chromatography and developed with a mixed solvent of acetonitrile: ethyl acetate: water (mixing ratio 3:1:1) to contain the target product. The fractions were collected and the solvent was distilled off under reduced pressure to obtain 600 mg of candy-like 4-[(tert-butoxycarbonyl)(methylcarbamoyl)methylene]-1,3-dithiethane-2-carboxylic acid. Nuclear magnetic resonance spectrum (CDCl ₃ ) δ: 1.52 (9H, -C(CH ₃ ) ₃ ) 2.84 (3H, -NHC H ₃ ) 4.83 (1H,

[Formula]) Example 23 Cool a mixture of 120 ml of dimethoxyethane and 30 ml of tetrahydrofuran to -74°C in a dry ice-acetone bath, and add isopropylcyclohexylamine.
4.0 ml, then n-butyllithium (15% n-
Add 13.72ml (hexane solution). (from −73℃−
The temperature rose to 62℃. ) Add 3.17 g of tert-butyl butyrate and heat for 30 minutes, -74~
After reacting at -75℃, approximately 664μ of carbon disulfide was added to the
It takes 10 minutes to drop and react at that temperature for 20 minutes. Next, after dropping 6.86 ml of n-butyllithium (15% n-hexane solution) at -72℃ or less for about 15 minutes,
The reaction was allowed to proceed for 30 minutes. 332μ of carbon disulfide was added in the same manner over 10 minutes, and after 20 minutes of reaction, 3.43ml of n-butyllithium (15% n-hexane solution) was added for 13 minutes.
After dropping at -72°C or lower for 20 minutes, the reaction was carried out at -74 to -73°C. Also, 166μ of carbon disulfide was heated at -74℃ for 6 minutes.
Added before and after. After about 25 minutes of reaction, diiodoacetic acid sodium salt previously prepared from 0.84 g of 50% sodium hydride and 5.46 g of diiodoacetic acid in 25 ml of dimethoxyethane is added. After the addition, the mixture was reacted for 30 minutes at 0 to +5°C, and then overnight at room temperature. The solvent was distilled off under reduced pressure, and 50 ml of cold ether and 40 ml of cold 1N hydrochloric acid aqueous solution were added to the residue for extraction. The obtained ether layer was extracted twice with 20 ml each of saturated sodium bicarbonate water to obtain an aqueous layer. Further, the aqueous layer was adjusted to pH 1 with 1N hydrochloric acid, extracted twice with 30 ml and 20 ml of ether, washed with water, dried over anhydrous magnesium sulfate, and the ether was distilled off to obtain 1.08 g of an oily product. If this oily substance is subjected to silica gel column chromatography (emitted using a mixed solvent of chloroform:methanol = 10:1) and the fraction containing the target product is collected, a brown oily 4-[(tert-butoxycarbonyl)(ethyl)methylene] is obtained. 630 mg of -1,3-dithiethane-2-carboxylic acid is obtained. Nuclear magnetic resonance spectrum (CDCl ₃ ) δ: 1.24 (3H, t, -C H ₃ ) 1.47 (9H, s, -C (C H ₃ ) ₃ ) 2.01 (2H, q, -C H ₂ - 4.87 (1H ,S,

[Formula]) Example 24 Disodium 2-tert-butoxycarbonyl-
2-cyanoethylene-1,1-dithiolate 3.3
g and 1.0 g of dichloroacetic acid in tetrahydrofuran.
Suspend in 10 ml of sodium hydride under ice cooling.
Add 372 mg. After addition, remove the ice bath and stir at room temperature for 2 hours. After the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in 5 ml of water, and the pH was adjusted with dilute hydrochloric acid.
Extract with ether as 3.5-4. After drying the extract over anhydrous magnesium sulfate and distilling off the solvent,
4-(tert-butoxycarbonylcyanomethylene)-1,3-dithiethane-2-carboxylic acid 0.5
get g. Nuclear magnetic resonance spectrum (DMSO-d ₆ ) δ (ppm): 1.44 (9H, (CH ₃ ) ₃ COOC-) 5.46 (1H,

[Formula]) Example 25 4-(acetyl tert-butoxycarbonylmethylene)-1,3 dithiethane-2-carboxylic acid 3g
was dissolved in 30 ml of methylene chloride, and a solution of 2.42 g of diphenyldiazomethane dissolved in 5 ml of methylene chloride was added dropwise to this solution under ice cooling. After applying, stir at room temperature for 20 minutes. After concentrating the reaction solution, it was subjected to silica gel column chromatography and eluted with a chloroform:n-hexane mixture (volume ratio 4:1) to yield 4-(acetyl tert-butoxycarbonylmethylene)-1,3 dithiethane-2- 3 g of benzhydryl carboxylate are obtained. Then 4-(acetyl tert-butoxycarbonylmethylene)-1,
Add a mixture of 24 ml of trifluoroacetic acid and 6 ml of anisole to 3 g of benzhydryl 3-dithiethane-2-carboxylate under ice cooling. After stirring at room temperature for 1 hour and 30 minutes, the mixture was concentrated, powdered with petroleum ether, and filtered. Dissolve this in 200 ml of ether, add 2 ml of methylene chloride and filter. 4-(acetylcarboxymethylene)-
1.3 g of 1,3-dithiethane-2-carboxylic acid is obtained. Nuclear magnetic resonance spectrum (DMSO-d ₆ ) δ (ppm): 2.39 (3H, H ₃ COC-) 5.22 (1H,

【formula】)

Claims (1)

[Claims] 1. General formula [In the formula, R ₁ is a carboxyl group, a cyano group, a benzhydryloxycarbonyl group, or a lower alkoxycarbonyl group, and R ₂ is a hydrogen atom, a cyano group, a carboxyl group, a sulfamoyl group, a vinyl group, or an optionally substituted carbamoyl group. group, lower alkyl group, lower alkoxy group, aroyl group, optionally substituted aryl group, optionally substituted monocyclic heterocyclic group, RCO- or R-S(O) _o- (wherein R is (n represents a lower alkoxy group or a lower alkyl group which may have a hydroxyl group or may be interrupted by a hetero atom; n represents 0, 1 or 2)
In the group represented by, R ₃ represents a hydrogen atom or a lower alkyl group. ] A 1,3-dithiethane compound represented by: 2 General formula (In the formula, R ₁ and R ₂ have the same meanings as above.) An ethylenedithiol compound represented by the general formula (In the formula, X represents a halogen atom, and R ₃ represents the same meaning as above.) A general formula characterized by reacting with a dihalogenoacetic acid compound represented by A method for producing a 1,3-dithiethane compound represented by the formula (wherein R ₁ , R ₂ and R ₃ have the same meanings as above).