JPH0460991B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula [] [In the formula, X ¹ represents a halogen atom, and R ¹ represents an optionally protected amino group. ] A compound represented by the formula or a salt thereof is reacted with a dialkyl sulfoxide or a dialkyl sulfoxide to form a compound represented by the general formula [] [In the formula, R ¹ has the same meaning as described above, and R ² represents an alkyl group or an aralkyl group. ] A general formula consisting of obtaining a compound or a salt thereof, protecting the amino group if desired, and then hydrolyzing it [] [In the formula, R ¹ has the same meaning as described above. ] 2-(2-aminothiazole-4-
The present invention relates to a method for producing glyoxylic acid derivatives or salts thereof. Therefore, the object of the present invention is to obtain 2-(2
An object of the present invention is to provide a new method for producing glyoxylic acid derivatives (aminothiazol-4-yl) or salts thereof. In order to achieve the above object, the present inventors conducted extensive research and as a result discovered a new method for producing a compound represented by the general formula [] or a salt thereof, and completed the present invention. The present invention will be explained in detail below. In the present application, the optionally protected amino protecting group in R ¹ includes all groups that can normally be used as amino protecting groups, such as trichloroethoxycarbonyl, tripromoethoxycarbonyl, benzyloxycarbonyl, p -toluenesulfonyl, p-nitrobenzyloxycarbonyl, o-bromobenzyloxycarbonyl, o-nitrophenylsulfinyl,
(mono, di, tri)chloroacetyl, trifluoroacetyl, formyl, tert.-amyloxycarbonyl, tert.-butoxycarbonyl, p-
Methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 4-(4-
Methoxyphenylazo)benzyloxycarbonyl, pyridin-1-oxide-2-yl-methoxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 1-cyclopropyl Examples include acyl groups that are easily eliminated such as ethoxycarbonyl, phthaloyl, succinyl, 1-adamantyloxycarbonyl, and 8-quinolyloxycarbonyl, and furthermore, trityl, 2-nitrophenylthio, 2,4
-dinitrophenylthio, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylmethylene, 3
-Hydroxy-4-pyridylmethylene, 1-methoxycarbonyl-2-propylidene, 1-ethoxycarbonyl-2-propylidene, 3-ethoxycarbonyl-2-butylidene, 1-acetyl-2
-Propylidene, 1-benzoyl-2-propylidene, 1-[N-(2-methoxyphenyl)carbamoyl]-2-propylidene, 1-[N-(4-methoxyphenyl)carbamoyl]-2-propylidene, 2 -Ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3,3-
Examples include easily leaving groups such as dimethyl-5-oxocyclohexylidene or amino protecting groups such as di- or tri-alkylsilyl. Examples of the alkyl group in R ² include:
Examples of lower alkyl groups such as methyl, ethyl, and n-propyl, and aralkyl groups include groups such as benzyl. Examples of the halogen atom in X ¹ include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. In these R ¹ , R ² and X ¹ , R ¹ is an amino group or formylamino group, R ² is a methyl group,
Particularly preferred is the case where X ¹ is a chlorine atom. Salts of the compound represented by the general formula [] include salts with amino groups or salts with carboxyl groups; examples of salts with amino groups include hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, etc. Salts with mineral acids such as oxalic acid, formic acid,
Examples include salts with organic carboxylic acids such as trichloroacetic acid and trifluoroacetic acid, and salts with sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid, and 1- or 2-naphthalenesulfonic acid. Examples include salts with alkali metal atoms such as sodium and potassium, and alkaline earth metal atoms such as calcium and magnesium. Further, the salts of the compounds represented by the general formulas [] and [] refer to salts at the amino group, and specifically include the same salts as mentioned for the compounds represented by the general formulas []. Further, the compounds represented by the general formulas [], [] and [] and their salts form adducts with various solvents, and all of these are included in the present invention. The reaction to obtain the compound of general formula [] or its salt from the compound of general formula [] or its salt can be carried out using a solvent inert to the reaction, such as alcohols such as methanol, ethanol, and isopropyl alcohol, and ethers such as tetrahydrofuran and dioxane. type, N,N-dimethylformamide, N,N
- A compound of the general formula [ ] or a salt thereof, and a dialkyl sulfoxide such as dimethyl sulfoxide or diethyl sulfoxide or a dialkyl sulfoxide such as dibenzyl sulfoxide in an amide such as dimethylacetamide or hexamethylphosphorylamide or a mixed solvent thereof. This is carried out by reacting. It is preferable to use the dialkyl sulfoxide or dialkyl sulfoxide in an amount of 2.0 times or more, particularly 3.0 to 4.0 times the mole of the compound of general formula [] or its salt, and if desired, it may be used as a solvent. When X ¹ is chlorine in the general formula [], it is preferable to carry out the reaction in the presence of a bromide such as hydrogen bromide or potassium bromide, and the amount used is determined according to the compound of the general formula [] or its salt. It is preferably 0.5 times mole or more, particularly 0.5 to 1.0 times mole. This reaction is usually completed in 5 minutes to 20 hours at a reaction temperature of 10 to 80°C. Also, dialkyl sulfides such as dimethyl sulfide and diethyl sulfide, dialkyl disulfides such as dimethyl disulfide and diethyl disulfide, dialkyl sulfides such as dibenzyl sulfide, and dibenzyl disulfide. The reaction is accelerated when dialalkyl disulfide such as hydride, alkyl mercaptan such as methyl mercaptan, ethyl mercaptan, or aralkyl mercaptan such as benzyl mercaptan is added at least 1.0 times the mole of the compound of general formula [] or its salt. . Next, the obtained compound of general formula [] or a salt thereof is subjected to conventional hydrolysis to convert it into a compound of general formula [] or a salt thereof, which is a useful raw material for producing cephalosporin compounds. The hydrolysis here is preferably carried out in the presence of a base, and is carried out in water or an alcohol such as methanol or ethanol. Examples of bases that can be used include sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide,
Examples include inorganic bases such as sodium carbonate and potassium carbonate, and organic bases such as triethylamine and pyridine.The amount used is preferably at least 2.0 times the mole of the compound of general formula [] or its salt. Also, the general formula [] which is the starting material for the method of the present invention
The compound or its salt can be produced as follows. [] or a salt thereof [wherein X ¹ and X ² represent the same or different halogen atoms, and R ¹ has the same meaning as described above. ] In order to dihalogenate butane-2,3-dione of formula [] to obtain 1,4-dirogenobutane-2,3-dione of general formula [], a normal halogenation reaction may be carried out, for example, 1 -Promo-4-
To produce chlorobutane-2,3-dione,
It is preferable to do the following: First, butane-2,3-dione of the formula [] is chlorinated and converted into 1-chlorobutane-2,3-dione. This reaction is carried out without a solvent or with an inert solvent, such as aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dioxane, methylene chloride, chloroform, and tetrachloride. It is carried out in the presence of carbon, halogenated hydrocarbons such as dichloroethane, carboxylic acids such as acetic acid, or a mixed solvent thereof.
Further, examples of the chlorinating agent include chlorine, sulfuryl chloride, N-chlorosuccinimide, N-chlorophthalimide, etc., and an equimolar amount thereof to the butane-2,3-dione of formula [] is sufficient. Further, reaction conditions vary depending on the type of chlorinating agent used, but usually a reaction time of 30 minutes to 10 hours at room temperature to solvent reflux temperature is sufficient. 1-chlorobutane- thus obtained
2,3-dione is brominated to give 1-bromo-4-
Convert to chlorobutane-2,3-dione. This reaction is carried out without a solvent or with an inert solvent, such as aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dioxane, methylene chloride, chloroform, and tetrachloride. It is carried out in the presence of carbon, halogenated hydrocarbons such as dichloroethane, carboxylic acids such as acetic acid, or a mixed solvent thereof. Further, examples of the brominating agent include bromine, sulfuryl bromide, N-bromosuccinimide, N-bromophtylimide, etc., and an equimolar amount is sufficient for 1-chlorobutane-2,3-dione. . In addition, reaction conditions vary depending on the type of brominating agent used, but are usually room temperature to solvent reflux temperature.
30 minutes to 10 hours is sufficient. Then, a 1,4-dihalogenobutane-2,3-dione of the general formula [ ], for example, 1-bromo-
To obtain a compound of general formula [] or a salt thereof by reacting 4-chlorobutane-2,3-dione with a thiourea of general formula [], a solvent inert to the reaction, such as methanol, ethanol, isopropyl Alcohols such as alcohol, ethers such as tetrahydrofuran and dioxane,
The reaction is carried out in the presence of amides such as N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosrylamide, a mixed solvent thereof, or a mixed solvent of these and water. The amount of thioureas to be used is preferably 0.90 times or more, particularly 0.95 to 1.00 times, by mole relative to the compound of general formula []. This ring-closing reaction is usually completed at a reaction temperature of -50 to 10°C in 5 minutes to 20 hours. Next, the present invention will be explained with reference to Examples and Reference Examples, but the present invention is not limited thereto. Reference example (1) In a mixed solution of 172 g of butane-2,3-dione and 172 ml of benzene, 163 ml of sulfuryl chloride was added.
The mixture was added dropwise and stirred at 60°C for 3 hours. After the dropwise addition, the mixture is stirred at the same temperature for 1 hour, then under reflux for 1 hour, and then rectified under reduced pressure to obtain a boiling point of 53.5-55.0.
1-chlorobutane-2,3 showing °C/14mmHg
-124 g of dione (yield 51.5%) are obtained. IR (neat) cm ^-1 :〓C=O1720 NMR (CDCl ₂ ) δ value: 2.45 (3H, s,

【formula】), 4.71 (2H, s,

[Formula]) (2) 1-chlorobutane-2,3-dione 120.5g
160 g of bromine was added dropwise to a mixed solution of 120 ml of dichloroethane and 120 ml of dichloroethane under reflux and stirred over a period of 2 hours. After the dropwise addition was completed, the reaction solution was refluxed for an additional 30 minutes, and then cooled to 20°C. The precipitated crystals are collected by filtration, washed with dichloroethane, and dried to reduce the melting point.
109 g (yield 54.6%) of 1-bromo-4-chlorobutane-2,3-dione having a temperature of 120-121.5°C is obtained. IR (KBr) cm ^-1 :〓C=O1760, 1735 NMR (CD ₂ OD) δ value: 3.70 (1H, s), 3.83 (1H, s), 4.63 (1H, s), 4.81 (1H, s) (3) A suspension of 20.0 g of 1-bromo-4-chlorobutane-2,3-dione and 140 ml of ethanol is cooled to -35°C, and 7.3 g of thiourea is added with stirring. After stirring the reaction solution at -35°C for 4 hours,
It took 30 minutes to raise the temperature to -20℃, and then at the same temperature for two more
Stir for an hour. After that, it took 1 hour and 30 minutes to complete 10
If the temperature is raised to ℃, white crystals will precipitate. The crystals are collected by filtration, washed with ethanol, and then dried to yield 24.9 g of 2-amino-4-chloroacetylthiazole hydrobromide/1-ethanol adduct (yield: 85.4) with a melting point of 191°C (decomposition). %)
get. IR (KBr) cm ^-1 :〓C=O1695 NMR (d ₆ -DMSO) δ value: 1.09 (3H, t, J = 7.5Hz, CH 3 CH ₂ OH), 3.54 (2H _, q, J = 7.5 Hz, CH ₈ C H ₂ CH), 5.17 (2H, s,

【formula】), 8.40 (4H, bs,

[Formula]) Example 1 (1) 2-amino-4-chloroacetylthiazole. Hydrobromide/1-ethanol adduct 30.4
A mixed solution of 91 ml of dimethyl sulfoxide and 11.9 g of potassium bromide is heated to 30°C, and 8.9 ml of dimethyl disulfide is added. After stirring this reaction solution at 30-35°C for 2 hours, it was poured into 300 ml of ice water. Then adjust the pH to 5.5 with sodium hydrogen carbonate. Filter the precipitated solid matter, and
Dissolve in 80 ml of 1N hydrochloric acid, remove a small amount of insoluble matter by filtration, and adjust the pH to 5.5 with sodium hydrogen carbonate. If the precipitated crystals are collected by filtration, washed with water, and then dried, 11.7 g of 2-(2-aminothiazol-4-yl)thioglyoxylic acid-s-methyl ester having a melting point of 130°C (decomposed) (yield 61.4%) is obtained. )
get. IR (KBr) cm ^-1 :〓C=O1675, 1650 NMR ( _d6 -DMSO) δ value: 2.45 (3H, s,

[Formula]), 7.60 (2H, bs, H ₂ N-), 8.24 (1H, s,

[Formula]) (2) 2-(2-aminothiazol-4-yl)thioglyoxylic acid-s-methyl ester 10.1g
and sodium carbonate 10.6 in 80 ml of water under ice cooling.
g and stirred at the same temperature for 1 hour. Next, the reaction solution was adjusted to pH 2.5 with 6N hydrochloric acid under ice cooling. If the precipitated crystals are collected by filtration, washed with water, and then dried, 2-(2-aminothiazol-4-yl)glyoxylic acid 6.2 having a melting point of 200°C or higher is obtained.
g (yield 67.8%). IR (KBr) cm ^-1 :〓:C=O1660 NMR ( _d6 -DMSO) δ value: 8.11 (1H, s,

【formula】), 7.50~8.30 (2H, bs,

[Formula]) Example 2 2-Amino-4-chloroacetylthiazole・
7.8 g of bromohydrohydride/1 ethanol adduct in 50 g of water
ml, and 2.3 g of sodium hydrogen carbonate was gradually added over 15 minutes while stirring at 20°C. If the precipitated crystals are collected by filtration, washed with 10 ml of water, and then dried in vacuum, 2-amino-
4-chloroacetylthiazole 4.5g (yield 98.8
%). IR (KBr) cm ^-1 :〓C=O1675, 1600 NMR ( _d6 -DMSO) δ value: 5.00 (2H, s,

[Formula]), 7.47 (2H, bs, H ₂ N-), 7.80 (1H, s,

[Formula]) Example 3 (1) A mixture of 40.8 g of acetic anhydride and 18.4 g of formic acid was
Stir for 1 hour at 40-45°C. To this solution, 20.2 g of 2-(2-aminothiazol-4-yl)thioglyoxylic acid-s-methyl ester was added under water cooling.
After adding, stir at 25°C for 1 hour. Then,
After adding 160 ml of water dropwise to this reaction solution under ice cooling,
Stir for 30 minutes under water cooling, and filter the precipitated crystals. If this crystal is washed successively with water and acetone and then dried, it will show a melting point of 230°C or higher.
21.9 g (yield 94.4%) of -formylamitiazol-4-yl)thioglyoxylic acid-s-methyl ester are obtained. IR (KBr) cm ^-1 :〓C=O1690, 1670, 1650 (2) 2-(2-formylaminothiazole-4-
Suspend 23 g of s-methyl thioglyoxylate in 200 ml of water, and add to this under water cooling.
125 ml of 2N aqueous sodium hydroxide solution was added dropwise over 30 minutes, followed by stirring at room temperature for 1 hour. After the reaction is complete, the reaction solution is diluted with 6N hydrochloric acid under ice cooling.
Adjust to 2.5. If the precipitated crystals are collected by filtration, washed successively with water and acetone, and then dried, 16.2 g of 2-(2-formylaminothiazol-4-yl)luglyoxylic acid having a melting point of 210°C or higher is obtained.
(yield 81.6%). IR (KBr) cm ^-1 :〓:C=O1660 NMR ( _d6 -DMSO) δ value: 8.31 (1H, s,

[Formula] or

【formula】), 8.60 (1H, s,

[Formula] or

【formula】), 12.8 (1H, bs,

【formula】)

Claims (1)

[Claims] 1. General formula [] [In the formula, X ¹ represents a halogen atom, and R ¹ represents an optionally protected amino group. ] A compound represented by the general formula [ ] or a salt thereof is reacted with a dialkyl sulfoxide or a dialkyl sulfoxide, and the compound represented by the general formula [] [In the formula, R ¹ has the same meaning as described above, and R ²
represents an alkyl group or an aralkyl group. ] A compound represented by the general formula [ ] or a salt thereof is obtained, the amino group is protected if desired, and then hydrolyzed. [In the formula, R ¹ has the same meaning as described above. ] 2-(2-aminothiazole-4-
method for producing glyoxylic acid derivatives or salts thereof. 2-(2-aminothiazol-4-yl) according to claim 1, wherein 2 X ¹ is a chlorine atom
A method for producing a glyoxylic acid derivative or a salt thereof. 2- according to claim 1 or 2, wherein 3 R ¹ is an amino group or a formylamino group.
A method for producing a (2-aminothiazol-4-yl)glyoxylic acid derivative or a salt thereof. 4 2-(2-
A method for producing an aminothiazol-4-yl)glyoxylic acid derivative or a salt thereof.