KR860001369B1 - Process for preparing penicillanic acid esters - Google Patents

Abstract

Title compds. II [X=(a), (b); R1=azido, amino, 1- methoxycarbonylpropen-2-yl amino, carbobenzyloxyamino; R2=H, OH! were prepd. Thus, 424 mg chloromethyl-6-(α-azido phenylacetamido) penicillanate in 5 ml dimethylformamide was reacted with 474 mg tetrabutylammonium penicillanate-1,1-dioxide, diluted with 50 ml ethyl acetate, washed with water, concd., and chromatog. on a 40 g silica gel plate to give 320 mg 6'-(α-azidophenylacetamido) penicillanoyl oxymethyl penicillanate-1,1-dioxide.

Description

Process for producing peniclanic acid esters

Beta-lactamase, which reacts with beta-lactam antibiotics to form substances without antibacterial activity, despite the widespread use of beta-lactam antibiotics penicillins and cephalosporins to combat bacterial infections Because of the ability of microorganisms to produce enzymes, there are those belonging to the class that are inactive against resistant microorganisms. However, certain substances have the ability to inhibit beta-lactamase and can increase or enhance the antimicrobial effects of antibiotics against certain beta-lactamases, which produce microorganisms when used in combination with peniclan and cephalosporins. have.

Federal Republic of Germany Patent Publication No. 28,24,535, issued December 14, 1978, indicates that peniclanic acid sulfone is an effective beta-lactamase inhibitor. In addition, the disclosure taught that certain esters of peniclanic acid sulfone are readily hydrolyzed in vivo and have high blood levels of this beta-lactamase inhibitor. Furthermore, in UK Patent Application No. 2,044,255 and U.S. Patent No. 4,244,951, halomethyl esters of peniclanic acid sulfones are decomposed in vivo with esters that are easily hydrolyzed through a carboxyl group of an antimicrobial penicillin. A method for producing a compound that is converted to an antimicrobial peniclan and beta-lactamase inhibitor peniclanic acid sulfone is presented.

British Patent No. 2,044,255 further describes that an intermediate peniclanate chloromethyl sulfone can be prepared by coupling a chloroiodomethane and a peniclanic acid sulfone in the presence of a catalytic amount of tetrabutylammonium sulfate. In addition, this patent discloses that certain tetrabutylammonium salts of certain penicsilane-based antimicrobial agents react with alpha-haloalkylphenicylanate sulfones, with esters that can be readily hydrolyzed, to decompose in vivo to release antimicrobial penicsilanes and pennies. A report was made on compounds that are converted to silane sulfones.

The product by the preparation method of the present invention is an intermediate useful for preparing a compound having an ester that can be degraded in vivo to be converted into beta-lactam antibiotics and beta-lactamase inhibitor peniclanic acid sulfone and easily hydrolyzed. to be.

The first method of the present invention relates to a method for preparing a compound represented by the following structural formula (II).

Wherein R ₁ is azido, amino, 1-methoxycarbonylpropen-2-ylamino or carbenzyloxyamino, and R ₂ is a hydrogen atom or a hydroxy group. This method is characterized by contacting one mole of the compound of formula (B) with at least 1 mole of the following formula (C) at room temperature in a reaction inert solvent.

In each of the above formula, Y is chloro, bromo or iodo, and R ₃ is an alkyl group having 1-4 carbon atoms.

In this method, it is preferable to use acetone or dimethylformamide as the reaction inert solvent.

(여기서 R₁은 아지도, 아미노 또는 1-메톡시카르보닐프로펜-2-일아미노기이고, R₂는 수소 원자임), Y는 요오도이고, R₃은 n-부틸기인 화합물들을 제조하는 데 있다.A particularly desirable feature of this method is

Wherein R ₁ is an azido, amino or 1-methoxycarbonylpropen-2-ylamino group, R ₂ is a hydrogen atom, Y is iodo and R ₃ is an n-butyl group There is.

The second method of the present invention relates to a method for preparing a compound represented by the following structural formula (II).

In the above formula,

Wherein R ₁ is an azido, amino, 1-methoxycarbonylpropen-2-ylamino or carbenzyloxyamino group, and R ₂ is a hydrogen atom or a hydroxy group.

A feature of this process is that 1 mole of the compound of formula (D) is contacted with at least 1 mole of the compound of formula (E) at room temperature in the presence of a reaction inert solvent.

In each formula above, Y is chloro, bromo or iodo, and R ₃ is an alkyl group having 1-4 carbon atoms.

A preferred feature of this process is the use of acetone or dimethylformamide as the reaction inert solvent.

(여기서, R₁은 수소 원자이고, R₁은 아지도, 아미노 또는 1-메톡시카르보닐프로펜-2-일아미노기임), R₃가 n-부틸기, Y가 클로로인 화합물들의 제조에 있다.A particularly desirable feature of this method is

Wherein R ₁ is a hydrogen atom, R ₁ is an azido, amino or 1-methoxycarbonylpropen-2-ylamino group, R ₃ is an n-butyl group, and Y is chloro have.

이고, R₂는 앞에서 정의한 바와 같은 구조의 화합물들은 생체내에서 베타-락탐계 항생물질과 베타-락타마아제 억제제 페니실란산 술폰을 생성시키는 용이하게 가수 분해될 수 있는 에스테르 모핵을 포함한다.The first products, wherein R ₂ is as defined above and R ₁ is an azido, 1-methoxy carbonylpropen-2-ylamino or carbenzyloxyamino group, as described above, R ₁ is an amino group Intermediates useful for obtaining compounds. In addition, X

And R ₂ is a compound of the structure as defined above comprising an ester nucleus which can be readily hydrolyzed to produce beta-lactam antibiotics and beta-lactamase inhibitor peniclanate sulfone in vivo.

UK Patent Application No. 2,044,255 is a method of coupling chloroiodomethane with potassium salt of peniclanic acid sulfone in the presence of catalytic amount of tetrabutylammonium sulfate to obtain chloromethyl penicilanate sulfone, while the method of the present invention Is to use equimolar amounts of tetraalkylammonium salts of the appropriate acid in the same molar amount to provide unexpectedly high yields of condensation products.

The first method of the present invention is to contact one mole of halomethyl ester of peniclanic acid represented by the following structural formula (B) with at least one mole of the compound represented by the following structural formula (C) in a reaction inert solvent.

In each of the above formula, Y, X and R ₃ are as defined above.

The criteria for the reaction inert solvent in the first method of the present invention are similar to the method of Applicant's 1982 Patent Application No. 1221, the applicant of this application. These solvents or mixtures of these solvents should be those which dissolve the reactants without reacting to a significant extent with the reactants or products under the reaction conditions. Suitable solvents for this reaction include acetone, but various other aprotic [aprotic] solvents that are miscible with water, including ethyl acetate, acetonitrile, dimethylformamide and hexamethylphosphoamide, may also be used.

The reaction time depends on the concentration, the reaction temperature and the reactivity of the starting materials. When the reaction proceeds at a temperature of about 25 ° C., the reaction is usually completed in 30-60 minutes.

To obtain the optimum yield of product, at least 1 mole of tetraalkylammonium salt is used per mole of halomethyl ester. In addition, the use of an excess of about 10-20% of the salt does not significantly affect the quality of the product.

Upon completion of the reaction, the solvent is usually removed in vacuo and the residual product is purified by chromatography on silica gel. Tetraalkylammonium penicilanates and halomethyl penicilanate sulfones are prepared by the methods described herein.

The second process of the present invention proceeds by contacting at least 1 mole of a compound of the following structural formula (E) with 1 mole of halomethyl penicillate of the following structural fabric (D).

In each of the above formula, X, Y and R ₃ are as defined above.

This reaction proceeds in an inert solvent which dissolves the reactants without reacting to a significant extent with the reactants or products under the reaction conditions. Acetone is a suitable solvent for this reaction, but aprotic solvents that can be miscible with water, such as dimethylformamide and hexamethylphosphoramide, can also be used.

The reaction time depends on the concentration, the temperature and the reactivity of the starting materials. The reaction proceeds in the range of 0 ° C. to 60 ° C., with about 25 ° C. to 60 ° C. being preferred. The reaction time at the selected reaction temperature is about 0.5-4 hours. For convenience, this reaction can be run overnight without adversely affecting the product.

Upon completion of the reaction, the reaction solution is diluted with water and a solvent miscible with water. The organic layer is concentrated and the product is purified by column chromatography.

As pointed out above, when the compounds of the first and second methods of the present invention represented by the following structural formulas are administered to a host suffering from bacterial infection, they are easily hydrolyzed to beta-lactam antibiotics and beta-lactamase penny Silane sulfone.

(여기서, R₂는 앞에서 정의한 바와같고, R₁은 아미노)이다.In the above formula, X is

Where R ₂ is as defined above and R ₁ is amino.

Compounds having the above general formula wherein R ₂ is as defined above and R ₁ is an azido, 1-methoxycarbonylpropen-2-ylamino group or carbobenzyloxyamino group may be converted to a compound wherein R ₁ is an amino group. Useful intermediates.

Reduction of the compounds of the above structural formula wherein R ₁ is an azido group has a catalytic amount of a noble metal such as palladium (Pd / C) supported on carbon [charcoal] under an initial pressure of about 10-50 psi (0.70-3.52 kg / cm ² ). It can proceed by shaking the intermediate dissolved in a solvent such as lower alkanol and methylene chloride in the presence. Once the reduction reaction is complete, the spent catalyst is filtered off and the filtrate is concentrated to give the desired product.

In a similar way, when R ₁ is the reduction of carbonyl benzyloxy group of compounds, R ₁ is an amino group can be obtained in the product. The hydrocracking reaction can be carried out by shaking a mixture of intermediate dissolved in lower alkanols and methylene chloride with a catalytic amount of precious metal in a hydrogen atmosphere with an initial pressure of 5-50 psi (0.35-3.52 kg / cm ² ). Once the reaction is complete, the spent catalyst is filtered and evaporated to separate the product from the filtrate.

Compounds of the above formula wherein R ₁ is an amino group can be obtained by treating a solution of a compound wherein R ₁ is a 1-methoxycarbonylpropen-2-ylamino group with at least an equivalent amount of acid. If a water-insoluble reaction inert solvent such as ethyl acetate is used, at least 1-5% (v: v) of water is preferred for catalyzing the hydrolysis reaction of enimine. Suitable acids for hydrolysis reactions are organic sulfonic acids and inorganic acids. The hydrolysis product is filtered from the reaction solvent and separated into the corresponding acid addition salt.

As described above, British Patent Application No. 2,044,255 discloses the absorption of the coupled product followed by hydrolysis by coupling the halomethyl penicilanate sulfone of the present invention with various beta-lactam antibiotic substances. Produces antibiotics in vivo to increase the blood concentration and tissue concentration of peniclanic acid sulfone and beta-lactam antibiotics resulting from the hydrolysis. In addition, the above-mentioned British patent application teaches the use of products resulting from the coupling of peniclanic acid sulfones and beta-lactam antibiotics.

The following examples are given for illustrative purposes only. Nuclear magnetic resonance spectra (NMR) are measured at 60 MHz for deuterium chloroform (CDCl ₃ ), overdeuterium dimethylsulfoxide (DMSO-d ₆ ) or deuterium oxide (D ₂ O) solutions, or unless otherwise indicated, peak positions These are expressed in ppm at low magnetic fields from tetramethylsilane or 2, 2-dimethyl-2-silapentane-5-sulfonic acid sodium. As for the peak shape, the following abbreviations were used. b = wide, s = single peak, d = double peak, t = triple peak, q = quad peak, m = multiple peak.

Example 1

Iodomethyl penicillate 1, 1-dioxide.

To a solution containing 7.9 g of chloromethyl penicillate 1, 1-dioxide in 100 ml of dry acetone maintained under a nitrogen atmosphere, 21.0 g of sodium iodide was added, and the reaction mixture was subjected to overnight stirring at room temperature. The reaction mixture was concentrated in vacuo and the residue was dissolved in 150 ml of ethyl acetate and 150 ml of water. The organic layer was separated and extracted with fresh ethyl acetate. The organic extracts were combined and washed with water (1 x 50 ml) and brine (1 x 50 ml) and dried over sodium sulfate. The solvent was removed to give 10.5 g of product (melting point 100-102 ° C.).

NMR spectra (CDCl ₃ ) were 1.55 (s, 3H), 1.68 (s, 3H), 3.5 (d, 2H), 4.4 (s, 1H), 4,65 (t, 1H) and 6.0 (dd, 2H) Absorption was shown at ppm.

Example 2

6 '-(alpha-amino-p-hydroxyphenylacetamido) phenylanoyloxymethyl penicilanate 1, 1-dioxide.

A. 6 '-(alpha-carbenzyloxyamino-p-hydroxyphenylacetamido) phenylanoyloxymethyl penicilanate.

In a mixture containing 9.5 g of tetrabutylammonium 6- (alpha-carbenzyloxyamino-p-hydroxyphenylacetamido) penicilanate in 50 ml of dry acetone, iodomethyl penicillate 1, 1-dioxide 4.78 g was added and the mixture was stirred at rt for 30 min. This was concentrated in vacuo and chromatographed on 200 g of silica gel using ethyl acetate / methylene chloride (1: 1 v: v) as developing solvent to obtain 25 ml of fractions. Fractions 29-49 were combined and concentrated to give 6.5 g of the desired product of a yellow foam.

NMR spectra (DMSO-D ₆ ) are 1.42 (s, 3H), 1.52 (s, 3H), 1.6 (s, 3H), 3.1-3.9 (m, 2H), 4.5 (s, 1H), 4.58 (s, Absorbed at 1H), 5.08 (s, 2H), 4.98-5.7 (m, 4H), 5.95 (s, 2H), 5.68 (d, 2H), 7.2 (d, 2H), and 7.35 (s, 5H) ppm Indicated.

B. 6 '-(alpha-amino-p-hydroxyphenylacetamido) phenylanoyloxymethyl penicilanate 1, 1-oxide.

In a mixture containing 70 ml of methylene chloride and 70 ml of isopropanol, 6 '-(alpha-carbenzyloxyamino-p-hydroxyphenylacetamido) phenylanoyloxymethyl penicylanate 1, 6.4 g of 1-dioxide 6.5 g of% Pd / C catalyst was added and the mixture was shaken under hydrogen atmosphere for 45 minutes at an initial pressure of 50 psi (3.52 kg / cm ² ). The hydrogenation reaction was continued for 30 minutes by adding 3.0 g of catalyst. This process of adding 3.0 g of catalyst was repeated three times. The reaction solution was filtered to wash the spent catalyst with methylene chloride / isopropanol (1: 1 v: v). The filtrate and washings were combined and concentrated to almost dryness. Diethyl ether (200 ml) was added to the white suspension and stirred for 15 minutes. The solid was filtered and dried to give 4.9 g of product. The solid was dissolved in 35 ml of dimethylformamide and added dropwise to 1500 ml of fluoroform. The precipitated solid was filtered and dried to give 2.35 g of product. The filtrate was diluted with 2 l of hexane to separate the second crop (1.75 g).

NMR spectra (DMSO-D ₆ ) are 1.42 (s, 6H), 1.55 (s, 6H), 3.1-3.95 (m, 2H), 4.42 (s, 2H), 4.57 (s, 1H), 4.9-5.3 ( m, 2H), 5.4-5.75 (m, 2H), 5.95 (s, 2H), 6.82 (d, 2H), 7.35 (d, 2H) and 8.7-9.7 (m, 3H) ppm.

C. 6'-alpha-amino-p-hydroxyphenylacetamido) phenylanoyloxymethyl peniclanate 1, 1-dioxide hydrochloride.

To 35 ml of 0.1 N hydrochloric acid cooled to 0 ° C., 2.15 g of 6 ′-(alpha-amino-p-hydroxyphenylacetamido (phenicyanoyloxymethyl penicylanate 1, 1-dioxide) was added. Filtration and freeze drying gave 2.1 g of the desired product.

NMR spectra (DMSO-D ₆ ) are 1.38 (s, 6H), 1.48 (s, 6H), 3.0-3.9 (m, 2H), 4.38 (s, 1H), 4.48 (s, 1H), 4.9-5.2 ( m, 2H), 5.38-5.64 (m, 2H), 5.84 (s, 2H), 6.7 (d, 2H, 7.24 (d, 2H), 8.3-9.2 (bs, 4H) and 9.4 (d, 1H) ppm Absorption was shown in.

In a similar manner, tetramethylammonium 6- (alpha-carbenzyloxyamino) phenylacetamido (penicilanate and iodomethyl penicilanate 1, 1-dioxide as the process and starting material of AC of Example 2 Using 6 '-(alpha-aminophenylacetamido) phenylanoyloxymethyl penicillate 1, 1-dioxide hydrochloride was prepared.

Example 3

6 '-(alpha-aminophenylacetamido) phenylanoyloxymethyl peniclanate 1, 1-dioxide.

A. 6 '-(alpha-azidophenylacetamido) phenylanoyloxymethyl peniclanate 1,1-dioxide.

In a slurry containing 5.0 g of tetrabutylammonium 6- (alpha-azidophenylacetamido) pheniclanate in 75 ml of acetone under a nitrogen atmosphere, 20 ml of iodomethylphenicilanate 1,1-dioxide in 20 ml of acetone g was added and the reaction mixture was stirred at rt for 30 min. The reaction solution was concentrated to give a yellow oil. This was chromatographed on 80 g of silica gel using ethyl methylene acetate (1: 4 v: v) as the developing solvent. 75 ml fractions were collected. Fractions 2-6 were collected and concentrated in vacuo to give 4.53 g of the target compound.

NMR spectrum (CDCl ₃ ) is 1.44 (s, 3H), 1.52 (s, 3H), 1.52 (s, 3H), 1.6 (s, 3H), 1.66 (s, 3H), 3.4 (d, 2H), 4.4 (s, 1H), 4.6 (s, 1H), 5.1 (s, 1H), 5.4-5.7 (m, 2H), 5.88 (s, 2H), 7.18 (d, 1H) and 7.37 (s, 5H) ppm Absorption was shown in.

B. 6 '-(alpha-aminophenylacetamido) phenylanoyloxymethyl peniclanate 1,1-dioxide.

A mixture containing 500 ml of 6 '-(alpha-azidophenylacetamido) phenylanoyloxymethylphenylanate 1,1-dioxide and 25 mg of 10% Pd / C in 25 ml of isopropanol and 12 ml of methylene chloride was heated at 50 psi. The mixture was shaken under a hydrogen atmosphere at an initial pressure of (3.52 kg / cm 2). After 30 minutes, the reaction mixture was filtered and the filtrate was concentrated to give 362 mg of amorphous solid product.

NMR spectra (CDCl ₃ ) are 1.5 (d, 6H), 1.6 (d, 6H), 3.55 (d, 2H), 4.45 (s, 1H), 4.55 (s, 1H), 4.6-4.75 (m, 2H) , 5.5-5.7 (m, 2H), 5.9 (q, 2H), 7.4 (s, 4H) and 8.1 (d, 1H, J = 6Hz) ppm.

In a similar manner, tetrapropylammonium 6- (alpha-azido-p-hydroxyphenylacetamido) phenylanate and chloromethyl penicilanate 1,1-dioxide were used as starting materials, The process of AB was repeated to prepare 6 '-(alpha-aminophenylacetamido) phenicilaoyloxymethyl penicilanate 1,1-dioxide.

Example 4

6 '-(alpha-aminophenylacetamido) phenysilaneoiloiloxymethyl peniclanate 1,1-dioxide.

20 ml of ethyl acetate and 5 ml of methylene chloride are contained in a mixture containing 3.1 g of tetrabutylammonium 6- (alpha-aminoylphenylacetamido) pheniclanate, and 10 ml of ethyl acetate is 1,1-dioxide of iodomethyl penicillate. A mixture containing 2.0 g was added and stirred for 30 minutes at room temperature. Methylene chloride was removed in vacuo and the resulting suspension was filtered. The filtrate was treated with 25 ml of water and adjusted to pH 2.5 with 1N hydrochloric acid. The aqueous layer was left, and the organic layer was extracted with fresh water at pH 2.5. The aqueous layers were combined, saturated with salt and extracted with methylene chloride. The organic layer was separated, dried over sodium sulphate and concentrated in vacuo until the volume reached about 10 ml. The remaining solution was then added to diethyl ether with stirring, and the precipitate was filtered and dried to give 370 mg of product. The product was indistinguishable from the product isolated in Example 3B.

Tetramethylammonium 6- (alpha-amino-p-hydroxyphenylacetamido) pheniclanate and chloromethyl penicilanate 1,1-dioxide were used as starting materials. A '-(alpha-amino-p-hydroxyphenylacetamido) phenylanoylmethyl penicilanate 1,1-dioxide was prepared.

Example 5

6 '-(2,2-Dimethyl-5-oxo-4-phenyl-1-imidazolidinyl) -phenylanoyloxymethyl penicilanate 1,1-dioxide.

A solution containing 470 mg of chloromethyl penicillate 1,1-dioxide in 7 ml of ethyl acetate was added, and tetrabutylammonium 6- (2,2-dimethyl-5-oxo-4-phenyl- was added to 10 ml of ethyl acetate and 3 ml of methylene chloride. All were added at once to a solution containing 1.0 g of 1-imidazolidinyl) phenylanate and the resulting mixture was stirred at room temperature for 45 minutes. The reaction was washed in order of water and saturated brine and dried over sodium sulfate. The organic layer was chromatographed on 75 g of silica gel using ethyl acetate / hexane (1: 1 v: v) as the developing solvent and 14 ml fractions were taken every 30 seconds. Fractions 195-230 were combined and concentrated to give the desired product.

In a similar manner, 646 mg of tetrabutylammonium 6- (2,2-dimethyl-5-oxy-4- [p-hydroxyphenyl] -1-imidazolidinyl) phenylanate as starting material and iodomethyl penicila 6 '-(2,2-dimethyl-5-oxo-4- [P-hydroxyphenyl] -1-imidazolidinyl) phenylaniloxyoxymethyl penicilanate using 281 mg of nate 1,1-dioxide 1,1-dioxide was prepared.

NMR spectra (CDCl ₃ ) were 1.4-1.8 (m, 18H), 3.48 (d, 2H), 4.4-4.9 (m, 5H), 5.56 (d, 1H), 5.9 (s, 2H), 6.64 (d, 2H) and 7.18 (d, 2H) ppm.

Example 6

6 '-(alpha-azidophenylacetamido) phenylsilaneyloxymethyl peniclanate 1,1-dioxide.

To 5 ml of dry dimethylformamide, 424 mg of chloromethyl 6- (alpha-azido phenylacetamido) -peniclanate was added, followed by 474 mg of tetrabutylammonium penicilanate 1,1-dioxide, and the reaction mixture. Was stirred overnight at room temperature. The reaction mixture was diluted with 50 ml of ethyl acetate and then washed with water (3 x 15 ml) and saturated brine (1 x 15 ml). The organic layer was dried over sodium sulfate and concentrated to give a foam, which was chromatographed on 40 g of silica gel using methylene chloride / ethyl acetate (4: 1 v: v) as developing solvent and 8 ml fractions were collected every 30 seconds. Fractions 13-29 were collected and concentrated in vacuo to afford 320 mg of the desired product, which was indistinguishable from the product prepared in Example 3A.

Example 7

6 '-(alpha-aminophenylacet amido) phenylanoyloxymethyl penicilanate 1,1-dioxide p-toluene sulfonate.

A. 6'-alpha-N- [1-methoxycarbonylpropen-2-yl] aminophenyl acetamido) phenylsilaneiloxymethyl penicilanate 1,1-dioxide.

To 8125 ml of methylene chloride and 50 ml of water, 8.06 g of 6- (alpha-aminophenylacetamido) phenylanic acid brine was added and 40% tetrabutylammonium hydroxy aqueous solution was adjusted to pH 8.5. The methylene chloride layer was separated and the aqueous layer was extracted with fresh methylene chloride (2 x 30 ml). The methylene chloride layers were combined and dried over magnesium sulfate.

The reaction mixture was filtered and the filtrate was concentrated in vacuo. Chloroform (300 ml), methyl acetate (2.16 ml) and magnesium sulfate (20 g) were added to the residue and heated to reflux for 30 minutes. Magnesium sulfate was filtered and the filtrate was concentrated under reduced pressure to yield a yellow foam. The residue was treated with 150 ml of ethyl acetate to obtain a white solid, which was filtered, washed with ethyl acetate (3 × 26 ml) and diethyl ether (2 × 50 ml), dried under nitrogen atmosphere and then dried under tetrabutylammonium 6- (alpha-1). 6.5 g of -methoxycarbonylpropen-2-ylaminophenylacetamido) phenylanate was obtained.

To a solution containing 1.38 g of tetrabutylammonium in 10 ml of pure acetone, 1.04 g of iodomethyl penicillate 1,1-dioxide was added and stirred at room temperature for 10 minutes. The mixture was concentrated in vacuo and the residue was chromatographed on 75 g of silica gel using ethyl acetate / hexanes (1: 1 v: v) as developing solvent and 10 ml fractions were taken every 9 seconds. Fractions 11-19 were combined and concentrated in vacuo to afford 970 g of the desired product.

NMR spectra (CDCl ₃ ) were 1.42 (s, 3H), 1.48 (s, 3H), 1.55 (s, 3H), 1.6 (s, 3H), 1.9 (s, 3H), 3.48 (d, 2H), 3.66 (s, 3H), 4.43 (s, 1H), 4.46 (s, 1H), 4.56-4.7 (m, 2H), 5.13 (d, 1H), 5.4-5.75 (m, 2H), 5.9 (s, 2H ), 6.78 (d, 1H), 7.42 (s, 5H) and 9.38 (d, 1H) ppm.

B. 6 '-(alpha-aminophenylacetamido) phenylanoyloxymethyl penicilanate 1,1-dioxide p-toluene sulfonate.

To 346 ml of 6'-alpha-N- [1-methoxycarbonylpropenyl 2-yl] aminophenylacetamido) phenylanoyloxymethyl peniclanate 1,1-dioxide in 20 ml of ethyl acetate, 5 ml of ethyl acetate And 95 mg of P-toluenesulfonic acid hydrate in 0.5 ml of water were added. After a few seconds, the resulting precipitate was filtered, washed with ethyl acetate and dried to give 290 mg of product.

NMR spectra (DMSO-D ₆ ) are 1.38 (s, 6H), 1.5 (s, 6H), 2.3 (s, 3H), 3.05-2.9 (m, 2H), 4.4 (s, 1H), 4.5 (s, 1H), 4.95-5.3 (m, 2H), 5.35-5.7 (m, 2H), 5.9 (s, 2H), 7.08 (d, 2H), 7.55 (d, H2), 7.44 (d, 2H), 8.6 Absorption was shown at -9.0 (ds, 3H), and 9.4 (d, 1H) ppm.

Example 8

6 '-(alpha-amino-p-hydroxyphenylacetamido) phenylanoyloxymethyl penicilanate 1,1-dioxide hydrochloride.

A. 6'-alpha-N- [1-methoxycarbonylpropen-2-yl] amino-p-hydroxyphenylacetamido) phenylanoyloxymethyl penicilanate 1,1-dioxide.

To 300 ml of methylene chloride, 41.9 g of 6- (alpha-amino-p-hydroxyphenylacetamido) phenylanic acid and 50 ml of water were added and adjusted to pH 8.5 using 40% aqueous tetrabutylammonium hydroxide solution. . The mixture was placed in a separatory funnel to remove the aqueous layer, saturated with sodium sulfate, extracted with methylene chloride, the methylene chloride extracts combined, dried over sodium sulfate and concentrated to give an oil. This was triturated with acetone to crystallize to yield 44.6 g of tetrabutylammonium 6- (alpha-amino-P-hydroxyphenylacetamido) phenylanate.

The salt was added to 150 ml of methyl acetoacetate and the suspension was heated at steam bath temperature for 8 minutes. The mixture was cooled and the resulting precipitate was filtered and washed with methyl acetoacetate (3 × 25 ml) and dimethyl ether to give 49.25 g of product.

To a mixture of 47.5 g of the salt in 250 ml of dimethylformamide at 0 ° C., 18.26 g of iodomethyl penicilanate 1,1-dioxide was added to 50 ml of the same solvent with stirring for 20 minutes. 10 minutes after the addition, the reaction mixture was poured into 3 l of ethyl acetate, and the resulting precipitate was filtered. The precipitate was washed with ethyl acetate (100 ml), the washings were collected together, washed with brine (4 x 500 ml), water (4 x 500 ml) and brine (2 x 500 ml), and dried over sodium sulfate. The solvent was removed and the residue was chromatographed on 750 g of silica gel using ethyl acetate as developing solvent, and fractions 2-5 (250 ml each) were collected and concentrated to give 31.2 g of product.

NMR spectra (DMSO-D ₆ , 1H100.1 MHz) are 1.37 (s, 3H), 1.38 (s, 3H), 1.48 (s, 3H), 1.57 (s, 3H), 1.76 (s, 3H), 3.14 -3.82 (m, 2H), 3.51 (s, 3H), 4.42 (s, 1H), 4.44 (s, 1H), 4.54 (s, 1H), 5.1-5.22 (m, 1H), 5.3-5.64 (m , 3H), 5.9 (s, 2H), 6.7 (d, 2H), 7.14 (d, 2H), 9.02 (d, 1H), 9.24 (d, 1H), 9.34-9.54 (bs, 1H) ppm Indicated.

B. 6 '-(alpha-amino-p-hydroxyphenylacetamido) phenylanoyloxymethyl penicilanate 1,1-dioxide hydrochloride

6 '-(alpha-N- [1-methoxycarbonylpropen-2-yl] amino-p-hydroxyphenylacetamido) phenylanate 1,1-dioxide in 250 ml of acetone cooled to 0 ° C. To 31.1 g, 439 ml of 0.1 N hydrochloric acid was added. After stirring for 5 minutes, acetone was removed in vacuo and extracted with diethyl ether (3 × 700 ml). The aqueous layer was separated, filtered through a filter [supercell], and freeze-dried to give 23.1 g of the desired product.

NMR spectra (DMSO-D ₆ ) are 1.38 (s, 6H), 1.48 (s, 6H), 3.0-3.9 (m, 2H), 4.38 (s, 1H), 4.48 (s, 1H), 4.9-5.2 ( m, 2H), 5.35-5.64 (m, 2H), 5.87 (s, 2H), 6.7 (d, 2H), 7.24 (s, 2H), 8.3-9.2 (bs, 4H) and 9.4 (d, 1H) Absorption was shown at ppm.

Example 9

6 '-(alpha-aminophenylacetamido) phenylanoyloxymethyl penicilanate 1,1-dioxide p-toluenesulfonate.

A. Chloromethyl 6- (alpha-1-methoxycarbonylpropene) -2-ylaminophenylacetamido) pheniclanate.

To 125 ml of methylene chloride and 50 ml of water, 8.06 g of 6- (alpha-aminophenylacetamido) phenylanic acid trihydrate was added, and an aqueous 40% tetrabutylammonium hydroxide solution was adjusted to pH 8.5. The methylene chloride layer was separated and the aqueous layer was extracted with fresh methylene chloride (2 x 30 ml). The methylene chloride layers were combined and dried over magnesium sulfate.

This mixture was filtered and the filtrate was concentrated in vacuo. Chloroform (300 ml), ethyl acetoacetate (2.16 ml) and magnesium sulfate (20 g) were added to the residue and the mixture was heated to reflux for 30 minutes. Magnesium sulfate was filtered and the filtrate was concentrated under reduced pressure to obtain a yellow foam. The residue was treated with 150 ml of ethyl acetate to give a white solid material which was filtered off, washed with ethyl acetate (3 × 25 ml) and diethyl ether (2 × 50 ml), dried under nitrogen atmosphere and dried under tetrabutylammonium 6- (alpha 6.5 g of 1-methoxy carbonylpropen-2-ylaminophenyl acetamido) pheniclanate was obtained.

The compound obtained by adding 1.38 g of the tetrabutylammonium salt to 15 ml of chloroiodomethane was stirred at room temperature for 1 hour. Subsequently, the reaction solution was chromatographed on 75 g of silica gel using ethyl acetate / hexane (1: 1, v: v) as a developing solvent to obtain 50 ml of fractions. Fractions 4-6 were combined and concentrated to give 800 mg of the desired product.

NMR spectra (CDCl ₃ ) are 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 Absorption was shown at (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.

B. 6 '-(alpha-aminoylpeacetamido) phenylanoyloxymethyl penicilanate 1,1-dioxide p-toluene sulfonate.

A mixture of 496 mg of chloromethyl 6- (alpha-1-methoxycarbonylpropen-2-ylaminophenylacetamido) pheniclanate in 10 ml of acetone and 750 mg of sodium iodide was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was extracted with 40 ml of ethyl acetate. The extract was washed in the order of water (3 x 10 ml) and saturated aqueous sodium chloride solution (2 x 5 ml) and then dried over sodium sulfate. After removal of the solvent, the residual oil was triturated with petroleum ether to give a solid of iodomethyl 6- (alpha-1-methoxycarbonylpropen-2-ylamino phenylacetamido) pheniclanate.

A mixture of 509 mg of iodomethyl 6- (alpha-1-methoxycarbonylpropen-2-ylaminoacetamido) phenylanate and 474 mg of tetrabutylammonium penicillate sulfone was stirred in 10 ml of acetone for 20 minutes. The reaction mixture was concentrated to dryness and the residue was treated with 40 ml of ethyl acetate. The resulting precipitate was filtered off and the filtrate was washed with water (3 × 10 ml) and brine (2 × 5 ml). The dried organic layer was concentrated to about 20 ml and treated with 190 mg of 1 mole of P-toluenesulfonic acid and 2 drops of water in 5 ml of ethyl acetate. Stirring was continued for 3-4 minutes to form a precipitate. After stirring for 10 minutes, the desired product was filtered off and dried to give 520 mg of product.

This product was indistinguishable from that obtained in Example 7.

Example 10

Chloromethyl 6- (alpha-1-methoxycarbonylpropene-2-aminophenyl acetamido) penicilanate.

20 g of tetrabutylammonium 6- (alpha-1-methoxycarbonylpropen-2-ylaminophenylacetamido) pheniclanate was added to 400 ml of bromochloromethane at -10 ° C, and the reaction mixture was -10. The mixture was stirred for 6 hours at 0 ° C to 0 ° C and left overnight at room temperature. The mixture was concentrated in vacuo and the residue was chromatographed on 500 g of silica gel using ethyl acetate / hexane (30: 20 v: v) as eluent. Fractions containing product were combined and concentrated to give 14.4 g of foam.

This product was the same as that prepared in Example 9A.

Instead of iodochloromethane obtained in Example 1, bromochloromethane was used as a starting material to prepare the corresponding chloromethyl esters.

Claims (11)

1 mole of the compound of formula (B) is contacted with at least 1 mole of the compound of formula (C) at room temperature in a reaction inert solvent at room temperature.

In each of the above equations, X is (a)

Wherein R ₁ is azido, aminocarboxybenzyloxyamino or 1-methoxycarbonyl propen-2-ylamino and R ₂ is a hydrogen atom or hydroxy; and

Wherein R ₂ is a hydrogen atom or hydroxy, Y is selected from the group consisting of chloro, bromo and iodo, and R ₃ is alkyl having 1 to 4 carbon atoms. The method of claim 1 wherein the reaction inert solvent is selected from the group consisting of acetone and dimethylformamide. The compound of claim 1, wherein X is

Wherein R ₁ is as defined in claim 1 and R ₂ is a hydrogen atom, Y is iodo and R ₃ is an n-butyl group. The method of claim 1, wherein R ₁ is an azido group. The method according to claim 1, wherein R ₁ is an amino group. The method according to claim 1, wherein R ₁ is a methoxycarbonylpropen-2-ylamino group. 1 mole of the compound of the following formula (D) is brought into contact with at least 1 mole of the compound of the following formula (E) in a reaction inert solvent.

In each of the above equations, X is (a)

Wherein R ₁ is azido and 1-methoxycarbonylpropen-2-ylamino and R ₂ is a hydrogen atom or hydroxy; and

Wherein R ₂ is a hydrogen atom or hydroxy, Y is selected from the group consisting of chloro, bromo and iodo and R ₃ is alkyl having 1 to 4 carbon atoms. 8. The process of claim 7, wherein the reaction inert solvent is selected from acetone and dimethylformamide. 8. The compound of claim 7, wherein X is

Wherein R ₁ is as defined in claim 7 and R ₂ is a hydrogen atom, R ₃ is an n-butyl group, and Y is chloro. 8. The method of claim 7, wherein R ₁ is an azido group. 8. The method of claim 7, wherein R ₁ is a 1-methoxycarbonylpropen-2-ylamino group.