JPH0446958B2 - - Google Patents

Description

[Detailed description of the invention]

Despite the widespread use and accepted efficacy of penicillins and cephalosporins (beta-laclam antibiotics) against bacterial infections, certain members of the group are not active against resistant microorganisms. This is because the microorganism is capable of producing the enzyme beta-lactamase, which reacts with beta-lactam antibiotics and converts them into products with no antibacterial activity. However, certain substances have the ability to inhibit beta-lactamases, and when used with penicillins or cephalosporins, certain beta-lactamase
Promotes antibacterial effectiveness of antibiotics against lactamase-producing microorganisms. West German Published Patent No. 2,824,535, published December 14, 1978, teaches that penicillanate sulfone is an effective beta-lactamase inhibitor as described above. Furthermore, the above application states that certain penicillanic acid sulfone esters are
It is shown that it is quickly hydrolyzed in the body, giving high blood levels of this beta-lactamase inhibitor. Furthermore, British Patent Application No. 2,044,255 and U.S. Patent No. 4,244,951 also show that the halomethyl ester of penicillanic acid sulfone is bonded to the carboxyl group of antibacterial penicillin, creating an ester compound that is easily hydrolyzed. It has been shown to form and degrade in vivo to the antibacterial penicillin and beta-lactamase inhibitor penicillanate sulfone. British Patent Application No. 2,044,255 further shows that the intermediate chloromethylpenicillanate sulfone can be obtained by combining the potassium salt of penicillanate sulfone with chloroiodomethane in the presence of a catalytic amount of tetrabutylammonium sulfate. There is. In addition, the tetrabutylammonium salt of certain penicillane antibacterial agents is combined with alpha-haloalkylpenicillanate sulfones to yield an easily hydrolyzed ester compound that is converted to antibacterial penicillins and penicillanate sulfones in vivo. It has been reported that it disintegrates. The present invention relates to a compound having the following structural formula and a method for producing the same.

[Formula] is. In the formula, R ₂ is hydrogen or hydroxy, R ₁
is 1-methoxycarbonylpropen-2-ylamino. In this compound, R ₃ has 1 to 4 carbon atoms.
A compound with the following structural formula that is an alkyl of It is obtained by reacting at least 1 mole of iodochloromethane or bromochloromethane at about -20°C to 25°C. A preferred embodiment of the claimed process is to use an excess of bromochloromethane. The products of the present process are useful intermediates in the synthesis of hydrolyzable ester compounds that decompose in vivo to beta-lactam antibiotics and the beta-lactamase inhibitor penicillanate sulfone. That is, the synthesis of an ester compound of the following formula. In the formula, X is

[Formula] In the formula, R ₁ ' is azide, amino, 1-methoxycarbonylpropen-2-ylamino or carbobenzyloxyamino, R ₂ is hydrogen or hydroxy, and these are the following where Y is chloro, bromo or iodo. 1 mole of a compound with a structural formula like It is obtained by reacting at least 1 mol of a compound having the following structural formula, in which R _{3 is} alkyl having 1 to 4 carbon atoms, in a reactive solvent at room temperature. A preferred embodiment of this step is to use acetone or dimethylformamide as a reaction-inert solvent. In a particularly favorable embodiment of this step, R ₂ is hydrogen,
R ₃ is n-butyl, Y is chloro, and R ₁ ' is azide, amino or 1-methoxycarbonylpropene-
This is the synthesis of a compound with a structural formula of 2-ylamino. Compounds in which R ₁ ' is azide, 1-methoxycarbonylpropen-2-ylamino, or carbobenzyloxyamino are useful intermediates for compounds in which R ₁ ' is amino, as the processes described herein demonstrate. While British Patent No. 2,044,255 teaches the combination of chloroiodomethane and the potassium salt of penicillanic acid sulfone in the presence of a catalytic amount of tetrabutylammonium sulfate, the method of the present invention teaches that an equal amount of a suitable By using the tetraalkylammonium salt of the acid and the necessary halide, the condensation product was obtained in unexpectedly high yield. The method of the present invention has the following structural formula (wherein R,
1 mole of a tetraalkylammonium salt (n and R ₃ defined previously); This is easily carried out by reacting at least 1 mole of chloroiodomethane or bromochloromethane to give the corresponding chloromethyl ester. Optimal yields require the use of at least equal moles of bromochloromethane or chloroiodomethane for each mole of tetraalkylammonium salt used. In the best case, it is desirable to use a 1- to 2-fold stoichiometric excess of chloroiodomethane or bromochloromethane. In fact, chloroiodomethane or bromochloromethane can be used both as a reactant and as a solvent, although other reaction-inert solvents can be used together with chloroiodomethane or bromochloromethane. . When the reaction is carried out in a reaction-inert solvent, the solvent must substantially dissolve the reactants or products without any reaction with them under the reaction conditions. It is desirable that the solvent has a boiling point and melting point that match the reaction temperature. Such solvents or mixtures thereof include halogenated hydrocarbons such as chloroform carbon tetrachloride and hexachloroethane, and aromatic solvents such as toluene and xylene. The reaction time essentially depends on the concentration of the starting materials; the reaction temperature and the reactivity. The reaction is heated from about -20℃ to approx.
When carried out at 25°C, the reaction time for product formation is approximately 18-0.5 hours. Once the reaction has ended, the product can be isolated by chromatography on a silica gel column. As previously indicated, the products of this process are described in British Patent Application No. 2,044,255 and U.S. Patent No. 4,244,
No. 951, it degrades in vivo to beta-lactam antibiotics and the beta-lactamase inhibitor penicillanate sulfone. It is a useful intermediate in the synthesis of ester compounds that are easily hydrolyzed. The starting materials for the processes described above are either commercially available or synthesized by methods known in the literature or described herein. The following structural formula

[Formula] When the compound is administered to a host suffering from a bacterial infection, it is rapidly hydrolyzed to a beta-lactam antibiotic and a beta-lactamase inhibitor penicillanate sulfone. In the above structural formula of the compound used in these steps, R ₂ is as defined, R ₁ ' is azide, 1
Compounds with -methoxycarbonylpropen-2-ylamino or carbobenzyloxyamino are useful intermediates, and they can be converted to compounds in which R ₁ ' is amino. Reduction of compounds with the above structure in which R ₁ ' is azide can be carried out by dissolving the intermediate in a suitable solvent such as a lower alkanol and methylene chloride, and in the presence of a catalytic amount of a noble metal such as palladium on carbon. This is done by shaking at an initial pressure of about 10-50 psi in a hydrogen atmosphere. When the reduction is complete, the used catalyst is removed and the liquid is concentrated to obtain the desired product. Similarly, the compound in this step in which R ₁ ' is carbobenzyloxyamino can be reduced to the product in which R ₁ ' is amino. The hydrogenation reaction is carried out in a hydrogen atmosphere at an initial pressure of about 10 − in the presence of a lower alkaline nol, an intermediate dissolved in methylene chloride, and a catalytic amount of a noble metal.
This can be easily done by shaking at 50 psi. When the reaction is completed, the catalyst is removed and the product is isolated by distilling off the liquid under reduced pressure. R ₁ ' is 1-methoxycarbonylpropene-2-
From a compound which is ylamino, a compound having the above structure in which R ₁ ' is amino can be obtained by adding at least an equal amount of acid to a solution of the former. If a non-aqueous reaction-inert solvent such as ethyl acetate is used,
It is desirable that at least 1-5% (volume:volume) water be present in the above solvent to facilitate hydrolysis of the enimine. Acids suitable for hydrolysis include inorganic mineral acids as well as organic sulfonic acids. The hydrolysis product is isolated as the addition salt of the corresponding acid from the reaction solvent by filtration. As mentioned above, UK Patent Application No. 2,044,255
No. is the product of the claimed process. In vivo, halomethylpenicillanate sulfones are condensed with various beta-lactam antibiotics and absorption and subsequent hydrolysis of the condensed compounds result in high blood and cellular concentrations of penicillanate sulfones and beta-lactam antibiotics. It is shown to provide an antibacterial reagent. Furthermore, the just-mentioned British patent application also describes the use of products obtained by condensation of penicillanic acid sulfone and beta-lactam antibiotics. The following example is provided solely for later illustration. Nuclear magnetic resonance spectrum (NMR) is 60MHz
Deuterated chloroform (CDCl ₃ ), perdeuterated dimethyl sulfoxide (DMSO-d ₆ )
Alternatively, it can be used as heavy water (D ₂ O) or other solutions, and the peak position is 1/1 million times lower than the downfield from tetramethylsilane or sodium 2,2-dimethyl-2-silapentane-5-sulfonate.
Expressed in units (ppm). The following abbreviations were used as peak shapes: b, broad; s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet. Reference example 1 Add 806 to 125ml of methylene chloride and 50ml of water.
g of 6-(alpha-aminophenyl acetamido)penicillanic acid trihydrate is added, and the pH is adjusted to 8.5 by adding 40% aqueous tetrabutylammonium hydroxide solution. Separate the methylene chloride layer and extract the aqueous layer with fresh methylene chloride (2 x 30 ml). Combine the methylene chloride layer,
Dry with magnesium sulfate. filtrate and concentrate under vacuum. Chloroform (300 ml), methyl acetoacetate (2.16 ml) and magnesium sulfate (20 g) were added to the residue, and the mixture was heated under reflux for 30 minutes. Remove magnesium sulfate,
Concentrate the liquid under reduced pressure to obtain a yellow foamy substance. Adding 150 ml of ethyl acetate to the residue gives white crystals, which are collected, washed with ethyl acetate (3 x 25 ml) and diethyl ether (2 x 50 ml), and dried under a nitrogen atmosphere to give 6.5 g of tetrabutyl. Ammonium 6-(alpha-1-methoxycarbonylpropen-2-ylaminophenyl acetamide)penicilanade is obtained. Example 1 Chloromethyl 6-(alpha-1-methoxycarbonylpropen-2-ylaminophenyl acetamide)penicilanato 8.06 in 125 ml methylene chloride and 50 ml water
By adding g of 6-(alpha-aminophenylacetamido)penicillanic acid trihydrate and adding 40% aqueous tetrabutylammonium hydroxide solution.
Adjust pH to 8.5. Separate the methylene chloride layer and extract the aqueous layer with fresh methylene chloride (2 x 30 ml). Combine the methylene chloride layers and dry with magnesium sulfate. The mixture is filtered and the liquid is concentrated under vacuum. Add chloroform (300 ml), ethyl acetoacetate (2.16 ml) and magnesium sulfate (20 g) to the residue,
The mixture is heated to reflux for 30 minutes. The magnesium sulfate was removed and the liquid was concentrated under reduced pressure to obtain a yellow foam. When ethyl acetate is added to the residue, it becomes a white solid, which is taken out and ethyl acetate (3 x 25 ml)
and diethyl ether (2 x 50 ml) and drying under a nitrogen atmosphere to obtain 6.5 g of tetrabutylammonium 6-(alpha-1-methoxycarbonylpropen-2-ylaminophenyl acetamide) penicillanate. 1.38 g of tetrabutylammonium salt is added to 15 ml of chloroiodomethane and the mixture is stirred for 1 hour at room temperature. The reaction was then transferred onto 75 g of silica gel in ethyl acetate/hexane (1:1 vol/vol).
Perform chromatography using this as the eluent and take fractions of 50ml each. Combine fractions 4-6 and concentrate
Obtain 800 mg of desired product. NMR spectrum (CDCl ₃ ) is 1.5 (s, 3H),
1.57 (s, 3H), 1.9 (s, 3H), 3.65 (s, 3H),
4.4 (s, 1H), 4.65 (s, 1H), 5.12 (d, 1H),
5.42−5.7 (m, 2H), 5.75 (dd, 2H), 6.8 (d,
1H), 7,4 (s, 5H) and 9.35 (d, 1H) ppm. Reference example 2 6′-(alpha-aminophenyl acetamide)
Penicilanoyloxymethylpenicilanato 1,1-dioxide p-toluenesulfonate 496 mg of chloromethyl 6-(alpha-1-methoxycarbonylpropene-2-ylaminophenyl acetamide) penicilanato and 750 mg of sodium iodide in 10 ml of The mixture in acetone is stirred at room temperature overnight. The solvent is removed under vacuum and the residue is extracted with 40 ml of ethyl acetate. Add the extract to water (3
x 10 ml), saturated aqueous sodium chloride solution (2 x 5 ml)
Wash and dry with sodium sulfate. Petroleum ether was added to the remaining oil (700 mg) after the solvent was distilled off, and the vessel wall was rubbed to obtain iodomemel 6-(alpha-1-methoxycarbonylpropen-2-ylaminophenyl acetamide) penicillanate as a solid. A mixture of 590 mg of iodomethyl 6-(alpha-1-methoxycarbonylpropen-2-ylaminoacetamide) penicilanato and 474 mg of tetrabutylammonium penicilanato sulfone.
Stir in 10 ml of acetone for 20 minutes. The reaction mixture is concentrated to dryness and 40 ml of ethyl acetate is added to the residue. Remove the resulting precipitate, and add water (3 x 10ml) to the liquid.
and saline (2 x 5 ml). The dried organic layer is concentrated to about 20 ml and 5 ml of ethyl acetate containing 190 mg of p-toluenesulfonic acid monohydrate and 2 drops of water is added. After stirring for 3-4 minutes, a precipitate forms. After stirring for 10 minutes, remove and dry the desired product, 520 mg. Example 2 Chloromethyl 6-(alpha-1-methoxycarbonylpropen-2-ylaminophenyl acetamide)penicilanato 20 g of tetrabutylammonium 6-(alpha-1-
Methoxycarbonylpropen-2-ylaminophenyl acetamido)penicilanato is added and the reaction mixture is stirred at -10 to 0°C for 6 hours and then left at room temperature overnight. The mixture is concentrated under vacuum and the residue is chromatographed on 500 g of silica gel using ethyl acetate-hexane (80:20 vol:vol) as eluent. Combine and concentrate the fractions containing the product.
Obtain 14.4 g of foamy material. The product is essentially the same as the compound synthesized in Example 1.

Claims (1)

[Claims] 1 1 mole formula: at least 1 mole of a solvent selected from bromochloromethane and iodochloromethane and about -20
A formula characterized by allowing the reaction to occur at temperatures between ℃ and approximately 25℃. A method for producing the compound. [In each of the above formulas, R is [Formula], R ₂ is hydrogen or hydroxy; R ₁ is 1-
It is methoxycarbonylpropen-2-ylamino; R ₃ is alkyl having 1 to 4 carbon atoms. 2. The method of claim 1, wherein R ₂ is hydrogen and R ₃ is n-butyl. 3. The method of claim 2, wherein the reaction is carried out in the presence of excess bromochloromethane. 4 formula (wherein R is [formula]; R ₂ is hydrogen or hydroxy; R ₁ is 1-
methoxycarbonylpropen-2-ylamino).