JPH0433792B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Field of Application] The present invention relates to 2-aminothiazole derivatives, more specifically, the following general formula: [In the formula, R ¹ represents a lower alkyl group. ] It is related with the 2-aminothiazole derivative (syn isomer) represented by these. [Prior Art] The present inventors have already developed the general formula [In the formula, R ¹ has the same meaning as above, R ² is a hydrogen atom or a carboxyl protecting group, and R ³ is an optionally substituted heterocyclic group that has a carbon-nitrogen bond with the exomethylene group at the 3-position shows. ] We discovered that cephalosporin (syn isomer) and its salts represented by
-99592, 59-93085, 59-193893, same
60-4191, 60-6694). [Problems to be Solved by the Present Invention] The object of the present invention is to provide a cephalosporin (synisomer) of the general formula [] having an excellent antibacterial spectrum or a useful intermediate of a salt thereof, the cephalosporin of the general formula [I]. The purpose of the present invention is to provide a new compound (syn isomer). [Means for Solving the Problems] As a result of intensive research to achieve the above object, the present inventors found that a 2-aminothiazole derivative (synisomer) represented by the general formula [I] having a free amino group body) in the presence of boron trifluoride or its complex compound to give the general formula [In the formula, R ² and R ³ have the same meanings as above. ] It was discovered that cephalosporin (syn isomer) of the general formula [] or its salt could be easily obtained in high yield by reacting with the compound [], and the present invention was completed based on this discovery. It is. The present invention will be explained in detail below. The lower alkyl group of R ¹ in general formula [I] refers to straight chain or branched C _1-5 alkyl, for example,
Methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, sec.-butyl, tert.-
Meaning butyl, pentyl, etc. Next, a method for producing the compound of general formula [I] will be explained. This compound can be produced, for example, according to the production method shown below. [In the formula, R ¹ has the same meaning as above, and X represents a halogen atom, which may be a syn or anti isomer or a mixture thereof. (1) Production of compound of general formula [V] The nitroso form of general formula [V] can be obtained by reacting the compound of general formula [] with a nitrosating agent. This reaction is usually carried out in a solvent, and the solvents used include, for example, water, acetic acid, benzene,
Examples include solvents that are inert to the reaction, such as methanol, ethanol, and tetrahydrofuran. Moreover, two or more kinds of these solvents can also be used as a mixture. Next, preferred nitrosating agents used in this reaction include nitrous acid and its derivatives, such as nitrosyl halides such as nitrosyl chloride and nitrosyl bromide; alkali metal salts of nitrite such as sodium nitrite and potassium nitrite; Examples include alkyl nitrites such as butyl nitrite and bentyl nitrite. When using a salt of nitrous acid as a nitrosating agent, the reaction is preferably carried out in the presence of an inorganic or organic acid such as hydrochloric acid, sulfuric acid, formic acid, or acetic acid. Furthermore, when a nitrous acid alkyl ester is used as a nitrosating agent, it is preferably carried out in the presence of a strong base such as an alkali metal alkoxide. This nitrosation reaction is carried out at 0°C to 30°C for 10 minutes to
Complete in 10 hours. (2) Production of compound of general formula [] The compound of general formula [] can be obtained by reacting the compound of general formula [V] with an alkylating agent. This alkylation reaction can be carried out according to a conventional method, and is usually completed in 5 minutes to 10 hours at -20 to 60°C. The solvent used here may be any solvent as long as it does not adversely affect the reaction, such as tetrahydrofuran, dioxane, methanol, ethanol, chloroform, methylene chloride, ethyl acetate, butyl acetate, N,N-dimethylformamide, N , N-dimethylacetamide,
Examples include water. Moreover, two or more kinds of these solvents can also be used as a mixture. The alkylating agents used include, for example, lower alkyl halides such as methyl iodide, methyl bromide, ethyl iodide, and ethyl bromide, dimethyl sulfate, diethyl sulfate, diazomethane, diazoethane, or p-toluenesulfonic acid. Examples include methyl. When a compound other than diazomethane or diazoethane is used as an alkylating agent, it is usually an alkali metal carbonate such as sodium carbonate or potassium carbonate, an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, triethylamine,
The reaction is preferably carried out in the presence of a base such as pyridine. (3) Production of compound of general formula [] The halogen compound of general formula [] can be obtained by reacting the compound of general formula [] with a halogenating agent. This reaction is usually carried out in a solvent, and the solvents used include halogenated hydrocarbons such as methylene chloride and chloroform; organic acids such as acetic acid and propionic acid; and ethers such as tetrahydrofuran and dioxane, which adversely affect the reaction. Examples include solvents that do not give Moreover, two or more kinds of these solvents can also be used as a mixture. This halogenation reaction is usually completed at 0 to 50°C in 30 minutes to 24 hours. The halogenating agents used include halogens such as bromine and chlorine; sulfuryl halides such as sulfuryl chloride; hypohalous acids or salts thereof such as hypochlorous acid, hypobromous acid, and sodium hypochlorite; N - N- such as bromosuccinimide, N-chlorosuccinimide, N-bromophthalimide, etc.
Halogenated imide compounds; perbromide compounds such as pyridinium hydrobromide perbromide and 2-carboxyethyl triphenylphosphonium perbromide; and the like. (4) Production of compound of general formula [I] The compound of general formula [I] can be obtained by subjecting the compound of general formula [] to a ring-closing reaction with thiourea. This ring-closing reaction is usually carried out in a solvent, and any solvent may be used as long as it does not adversely affect the reaction. For example, water, methanol, ethanol, acetone, tetrahydrofuran, dioxane, N,N- Examples include dimethylformamide, N,N-dimethylacetamide, and N-methylpyridone. Moreover, two or more kinds of these solvents can also be used as a mixture. In addition, in this reaction, the reaction may proceed smoothly if a deoxidizing agent is added, and the deoxidizing agents used include, for example, alkali metal hydroxide, alkali metal hydrogen carbonate, triethylamine, pyridine, N , N-dimethylaniline, and other inorganic or organic bases. The reaction time is usually 1 to 48 hours, preferably 1 to 48 hours.
It is 10 hours. This ring-closing reaction is carried out in the range of 0 to 100°C,
Thiourea is usually used in an amount of 1 to several times the amount of the compound of general formula []. As described above, the syn isomer of the thiazole compound of general formula [I] can be selectively obtained in high yield and at low cost. [Example] Next, the present invention will be described with reference to Examples and Reference Examples, but the present invention is not limited thereto. Example 1 (1) 10.1 g of acetoacetamide was dissolved in 35 ml of water, and 6.9 g of sodium nitrite was added under ice cooling.
Add 25 ml of 4N sulfuric acid dropwise over 30 minutes while stirring at 0-5°C. After dropping, react at the same temperature for 30 minutes, then PH with saturated sodium bicarbonate aqueous solution.
Adjust to 6.0. After removing the insoluble matter, water was distilled off under reduced pressure,
Add 20 ml of ethyl acetate to the resulting residue and collect the precipitated crystals to obtain 8.6 g of 2-hydroxyimino-3-oxobutyric acid amide with a melting point of 96-97°C.
(yield 66.2%). IR (KBr) cm ^-1 ; ν _c=p 1670 NMR (d ₆ −DMSO) δ value; 2.26 (3H, s, CH ₃ CO−), 7.46 (1H, bs,

【formula】), 7.62 (1H, bs,

[Formula]), 12.60 (1H, s, = N ~ OH ) (2) 6.5 g of 2-hydroxyimino-3-oxobutyric acid amide and 5.6 g of anhydrous sodium carbonate were heated at 20°C.
Dissolve in 20ml of water. Furthermore, dimethyl sulfate
Add 6.6g at 20-25°C and stir at the same temperature for 2 hours. Next, collect the precipitate, add 100ml of methanol to the obtained precipitate, and heat at 40-50℃ for 30 minutes.
Stir for a minute. Then, after removing the insoluble matter,
The solvent is distilled off under reduced pressure, and 20 ml of ethanol is added to the resulting residue to collect crystals, and the melting point is
2-(syn)-methoxyimino-3 at 156-157℃
- Obtain 5.2 g (yield 72.2%) of oxobutyric acid amide. IR (KBr) cm ^-1 ; ν _c=p 1700, 1670 NMR (d ₆ −DMSO) δ value; 2.26 (3H, s, CH ₃ CO−), 3.96 (3H, s, −OCH ₃ ), 7.46 ( 1H, bs,

【formula】), 7.58 (1H, bs,

[Formula]) (3) 7.2 g of 2-(syn)-methoxyimino-3-oxobutyric acid amide is suspended in 36 ml of tetrahydrofuran, and 0.8 g of bromine is added under stirring at 40°C.
After confirming that the coloring caused by bromine has disappeared, 25
At ~30°C, add a further 7.2 g of bromine with stirring.
After reacting at the same temperature for 1 hour, the solvent was distilled off under reduced pressure. Add 50 ml of ethyl acetate and 20 ml of water to the resulting residue, adjust the pH to 6.0 with a saturated aqueous sodium bicarbonate solution, and then separate the organic layer and wash with 20 ml of saturated brine. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. 20 ml of a mixed solvent of diisopropyl ether and ethyl acetate (1:1) is added to the resulting residue to collect crystals, resulting in 4.
-promo-2-(syn)-methoxyimino-3-
9.2 g (yield 82.1%) of oxobutyric acid amide is obtained. IR (KBr) cm ^-1 ; ν _c=p 1715, 1660 NMR (d ₆ −DMSO) δ value; 4.02 (3H, s, −OCH ₃ ), 4.58 (2H, s, BrCH ₂ CO−), 7.72 ( 2H, bs, -CONH ₂ ) (4) 4-bromo-2-(syn)-methoxyimino-
4.5g of 3-oxobutyric acid amide and 13.5g of ethanol
ml, add 1.5 g of thiourea, and add 20 to 30 g of thiourea.
Incubate at ℃ for 1 hour. Collect the precipitated crystals, wash them with ethanol, suspend them in 25 ml of water, and adjust the pH to 6.0 with a saturated aqueous sodium bicarbonate solution.
Next, the crystals were collected and mixed with water-methanol (1:
If recrystallized with 15 ml of the mixed solvent of 1), the melting point will be 208.
2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid amide at ~209°C
Obtain 2.9 g (yield 71.8%). IR (KBr) cm ^-1 ; ν _c=p 1665 NMR (d ₆ -DMSO) δ value; 3.84 (3H, s, -OCH ₃ ), 6.75 (1H, s,

[Formula]), 7.26 (2H, bs, −NH ₂ ), 7.61 (1H, bs,

【formula】), 7.91 (1H, bs,

[Formula]) Example 2 2-(2-aminothiazol-4-yl)-2
-(Syn)-methoxyiminoacetic acid amide 10.0g,
Add to a mixed solvent of 20 ml of sulfolane and 20 ml of anhydrous methylene chloride containing 10.2 g of boron trifluoride. After reacting for 1 hour at room temperature, the crystals are collected. Then,
The crystals were suspended in 100 ml of ethyl acetate, stirred for 1 hour, and then collected. Wash twice with 20 ml of ethyl acetate,
After drying, 14.1 g of crystals are obtained. IR (KBr) cm ^-1 ; 1680, 1650, 1620, 1200~
1000 Reference example 1 Pivaloyloxymethyl = 7-amino-3-
(5-methyl-1,2,3,4-tetrazole-
Dissolve 4.10 g of 2-yl)methyl-Δ ³ -cephem-4-carboxylate in 41 ml of ethyl acetate,
Add 3.36 g of the crystals obtained in Example 2 and react at room temperature for 3 hours. Next, add 41 ml of water to the reaction solution, and adjust the pH to 4.5 with sodium hydrogen carbonate. The organic layer is separated, washed with 20 ml of water, and then dried over anhydrous magnesium sulfate. Then, 2.4 g of mesitylene sulfonic acid dihydrate was added and reacted for 1 hour at room temperature. The obtained crystals are collected and washed with 5 ml of ethyl acetate to give pivaloyloxymethyl 7-[2-(2-aminothiazol-4-yl)-2-, which has a melting point of 218-220°C (decomposition). (syn)-methoxyiminoacetamide]-3-[(5-methyl-1,
2,3,4-tetrazol-2-yl)methyl]
7.18 g (yield 90.5%) of mesitylene sulfonate of -Δ ³ -cephem-4-carboxylate is obtained. Reference example 2 2-(2-aminothiazol-4-yl)-2-
6.0 g of (syn)-methoxyiminoacetic acid amide was suspended in 13 ml of anhydrous methylene chloride, and 10.3 ml of a mixed solution of sulfolane-anhydrous methylene chloride (1:1) containing 2.72 g of boron trifluoride was added at 15 to 20°C. 10 at the same temperature
Let it react for a minute. Then, pivaloyloxymethyl=7-amino-3-(5-methyl-1,2,3,
Add 13 ml of anhydrous methylene chloride solution containing 4.10 g of 4-tetrazol-2-yl)methyl-Δ ³ -cephem-4-carboxylate and heat at 30 to 35°C for 2 hours.
Incubate for 30 minutes. Then, the reaction solution was introduced into 15 ml of ice water, and the pH was adjusted to 5.5 with a saturated aqueous sodium bicarbonate solution.
Adjust to. Then, after removing insoluble materials, the organic layer is separated, washed with 15 ml of saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 60 ml of ethyl acetate was added to the resulting residue to dissolve it, then 2.36 g of mesitylene sulfonic acid dihydrate was added and stirred for 30 minutes to remove the precipitated crystals. , pivaloyloxymethyl 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-(5-methyl) with a melting point of 218-220°C (decomposed) -1,2,3,4-
6.37 g (yield: 80.2%) of mesitylene sulfonate of methyl-Δ ³ -cephem-4-carboxylate (tetrazol-2-yl) is obtained. IR (KBr) cm ^-1 ; ν _c=p 1782, 1745, 1680

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ represents a lower alkyl group. ] A 2-aminothiazole derivative (syn isomer) represented by: