CS276966B6 - Process for preparing bis-esters of methane diol with 6'-acylaminopenicillanic acid and penicillanic acid 1,1-dioxide - Google Patents

Abstract

Esters of formula (I) and their salts are new R is H or R1; R1 is a carboxylic acyl gp. Intermediates of formula (V) are also new. (I;R=R1) are hydrolysed in vivo to form penicillanic acid, 1,1-dioxide (II) and the corresp. penicillin (III) and (II) acts as a beta-lactamase inhibitor which potentiates the antibacterial activity of (III), e.g. against S. aureus or E. coli (depending on the nature of R1). (I; R=H) is an intermediate for (I; R = R1). (I) where R is 2-phenylacetyl, 2-phenoxyacetyl, 2-amino-2-phenylacetyl or 2-amino-2-(4-hydroxyphenyl)acetyl is specifically claimed.

Description

The invention relates to novel chemical compounds having antibacterial effects. These novel antibacterial agents are methanediol bis-esters in which one hydroxy group of methanediol is esterified with a carboxy group of a 6-acylaminopenicillanic acid derivative and the other hydroxy group of methanediol is esterified with a carboxy group of penicillanic acid 1,1-dioxide.

DOS 2824535 published December 14, 1978 and Iranian patent 19601 issued June 12, 1970 disclose penicillanic acid 1,1-dioxide and its esters which are readily hydrolyzable in vitro and which are β-lactamase inhibitors. Penicillanic acid 1,1-dioxide and its esters, which are readily hydrolyzable in vivo, enhance the antibacterial activity of certain penicillin and cephalosporin compounds against certain bacteria.

Belgian Patent 74688, issued March 23, 1971, discloses: a / certainly 6'-acylaminopenicilanoyloxymethyl-6-acylaminopenicilanes; b) certain 6'-acylaminopenicilanoyloxymethyl-6-aminopenicilanes; c) 6'-aminopenicilanoyloxymethyl-6-aminopenicilanes and d) chloromethyl-6-aminopenicilanes. U.S. Pat. No. 3,850,908 discloses chloromethyl esters of certain natural, biosynthetic and semisynthetic penicillin compounds.

The antibacterial compounds of the invention are effectively absorbed from the gastrointestinal tract of mammals and converted to 6-acylaminopenicillanic acid and penicillanic acid 1,1-dioxide upon absorption.

The present invention provides novel antibacterially active compounds of formula (I)

wherein R ¹ is 2-phenylacetyl, 2-phenoxyacetyl, 2-amino-2-phenylacetyl or 2-amino-2- (4-hydroxyphenyl) acetyl.

Preferred compounds of formula I are:

6 '- (2-Phenylacetamido) penicilanoyloxymethylpenicilate 1,1-dioxide,

1,1'-dioxide 6 '- (2-phenoxyacetamido) penicilanoyloxymethylpenicilate,

6 '- (2-Amino-2-phenylacetamido) penicilanoyloxymethyl penicillanate 1,1-dioxide and 6' - (2-amino-2- (4-hydroxyphenyl) acetamido) penicilanoyloxymethylpenicilate 1,1'-dioxide.

CS 276966

The invention also provides compounds of formula III

/ 111 /

These compounds are valuable as intermediates in the preparation of the antibacterially active compounds of the invention.

In the above formulas, the broken line of attachment of substituents to the bicyclic nucleus means that the substituent is below the level of the bicyclic nucleus. Such a substituent is in the α-configuration. In contrast, a solid line attached substituent means that it is attached above the plane of the core. This configuration is called the β-configuration.

Using this system, compounds of formulas I and III are named as penicilanoyloxymethylpenicilate derivatives of formula VA in which primary and non-primary locants are used to distinguish between two ring systems:

In addition, when the disclosure relates to a compound having

A 2-amino-2 (substituted) acetamido- or 2- (substituted amino) -2- (substituted) acetamido group at the 6-position of a penicillanic acid derivative is understood to be a compound wherein said groups have the D-configuration.

According to the process of the invention, the compounds of formula (I) are prepared

I is prepared by acylating a compound of formula III with an activated derivative of the acid of formula R ² -COOH wherein R ² is as defined above followed by deprotection of amino or carboxy groups, where necessary, of R. This results in the conversion of the group R ² -CO to the group R ⁰ -CO.

This acylation reaction is suitably carried out in an inert solvent. In a typical acylation procedure, using from about 0.5 to about 3 equivalents of activated acid derivative of the formula ^R2 - COOH to a compound of formula III in an inert solvent at a temperature ranging from about -40 to about 30 ° C, preferably from about -10 to about 10 ° C. The preferred ratio of activated acid derivative to compound of formula III is 1.0: 1.0 to 1.2: 1.0. Inert solvents commonly used for this acylation reaction are: chlorinated hydrocarbons such as chloroform or dichloromethane; ethers such as diethyl ether and tetrahydrofuran; low molecular weight esters such as ethyl acetate and butyl acetate; and butyl acetate; low molecular weight aliphatic ketones such as acetone and methyl ethyl ketone? tertiary amides such as Ν, Ν-dimethylformamide and N-methylpyrrolidone? acetonitrile; water and mixtures thereof. When an aqueous solvent or water containing system is used, the pH should be maintained in the range of about 4 to about 9, preferably about 7.

An activated acid derivative of general formula R ² -COOH generally used is an acid halide such as an acid chloride. In this case, it is preferred, although not necessary, to carry out the acylation reaction in the presence of acid binders. Such suitable substances are tertiary amines such as dialkylamines, for example triethylamine, N-methylmorpholine, Ν, Ν-dimethylaniline, pyridine and the like, bicarbonate such as sodium or potassium bicarbonate. Buffer solutions such as phosphate may also be used.

Other activated acid derivatives of the formula ^R2 - COOH, which may be used are active esters such as

4-nitrophenyl and 2,4,5-trichlorophenyl ester; thioesters such as thiolmethyl and thiophenyl ester; and N-hydroxyesters such as N-hydroxysuccinimide and N-hydroxyphthalimide ester. These active esters are prepared by methods well known in the art. In many cases, these active esters may be replaced by the corresponding acid azides or imidazole or trizolamides.

Another method of activating an acid of formula R ² -COOH involves the formation of mixed anhydrides such as mixed carboxyl-carbon and mixed dicarboxylic anhydride. In the case of mixed carboxylic carbon anhydrides, the reaction of the carboxylate salt of an acid of formula R ² -COOH with a lower alkyl chloroformate, for example ethyl chloroformate, is usually used; in the case of a mixed dicarboxylate anhydride, the reaction of the carboxylate salt of an acid of formula R ² -COOH with a protected lower alkanoyl chloride, for example pivaloyl chloride, is usually employed.

In addition to the above examples, the acid of formula R ² -COOH can be activated by the action of peptide reagents by standard methods. These agents include carboimides, for example, dicyclohexylcarbodiimide, alkoxyacetylenes, for example methoxyacetylenes and ethoxyacetylene, and N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline. F

The protecting groups used to protect the amino group in compounds of the formula R ² -COOH are those commonly used during acylation of 6-aminopenicillanic acid derivatives. Particularly suitable amino protecting groups are benzyloxycarbonyl,

4-nitrobenzyloxycarbonyl and enamines formed by condensation with beta-dicarbonyl compounds such as alkyl acetone acetate. After the acylation step, the amino protecting group is removed by conventional means. When the acid of the formula R ² -COOH is activated in the form of an acid halide, for example an acid chloride, a particularly preferred method of protecting the amino group is the formation of a salt, for example the formation of a hydrochloride.

The compound of formula III may be prepared by a three-step process comprising:

and / converting 6-aminopenicillanic acid to 6- (protected amino-) penicillanic acid; b) reacting the 6- (protected amino) / penicillanic acid salt with a compound of formula VII;

(VII) and c) deprotection of the amino group. Various protecting groups may be used to protect the amino group, typical examples being benzyloxycarbonyl and 2,2,2-trichloroethoxycarbonyl. Steps a / and c) are carried out by conventional methods and step b / is carried out in a polar organic solvent at a temperature ranging from about 0 to about 80 ° C.

Alternatively, a compound of Formula III can be prepared by a four-step process comprising (i) converting 6-aminopenicillanic acid to 6- (protected amino) penicillanic acid; (ii) reacting the 6- (protected amino) penicillanic acid salt with a compound of formula X-CH ₂ -Y in which X and Y are readily cleavable groups, (iii) reacting the product of step (ii) with a compound of formula VIII; (iv) removal of the amino protecting group. Various amino protecting groups may be used to protect the amino group, typical examples are benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl and 2,2,2-trichloroethoxycarbonyl. Step (i) and (iv) are carried out in a conventional manner, step (ii) is carried out similarly to step b) described above, as well as step (iii).

Penicillanic acid 1,1-dioxide and its salts are prepared by known methods (see DOS 2824535).

Those compounds of the formula I having basic functional groups, for example the amino group in the group R, form acid addition salts and these salts are also included in the invention. Said acid addition salts are prepared by mixing a solution of a compound of formula I in a suitable solvent (e.g. water, acetone, methanol, ethanol or butanol) with a solution containing an equivalent amount of the appropriate acid. If the salt precipitates, it is collected by filtration. Alternatively, it can be obtained by solvent evaporation and, in the case of aqueous solutions, by lyophilization. Sulfates, hydrochlorides, hydrobromides, nitrates, phosphates, citrates, tartrates, pamoates, perchlorates, sulfosalicylates and 4-toluenesulfonates are particularly valuable.

Those compounds of the formula I having acidic functional groups, for example carboxy groups, in the group R ¹ form basic salts which are also included in the invention. These base salts are prepared by standard methods for penicillin compounds, for example by combining the acidic and basic components in a stoichiometric ratio in an aqueous, non-aqueous or partially aqueous medium, as preferred. It is then separated by filtration, precipitation with a false solvent and subsequent filtration, evaporation of the solvent or, in the case of aqueous solutions, freeze-drying as appropriate. The basic agents used to prepare these salts include both organic and inorganic reagents and include ammonia, organic amines, alkali metal hydroxides, carbonates, bicarbonates, hydrides and alkoxides, as well as alkaline earth metal hydroxides, carbonates, hydrides and alkoxides. Typical examples of these bases are primary amines such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine, p-toluidine and octylamine; secondary amines such as diethylamine, N-methylaniline, morpholine, pyrrolidine and piperidine; tertiary amines such as triethylamine, Ν, Ν-dimethylaniline, N-ethylpiperidine, N-methylmorpholine and 1,5-diazabicyclo [4.3.0] non-5-ene; hydroxides such as sodium hydroxide, potassium hydroxide, ammonium hydroxide and barium hydroxide; alkoxides such as sodium ethoxide and potassium ethoxide; hydrides such as calcium hydride and sodium hydride; carbonates such as potassium carbonate and sodium carbonate; and bicarbonates such as sodium bicarbonate and potassium bicarbonate.

For therapeutic use of the salts of the antibacterial agents of the invention, pharmaceutically acceptable salts are required. However, salts other than these may be used for various purposes. This may include the isolation and purification of the individual compounds and the mutual conversion of pharmaceutically acceptable salts and their salt-free derivatives.

The compounds of formula I have antibacterial activity in vivo in mammals, and this activity can be demonstrated by standard methods for penicillin compounds. For example, compounds of Formula I are administered to mice in which acute infection has been induced by intraperitoneal inoculation with a standard culture of a pathogenic bacterium. The infection rate is standardized so that mice receive a dose equal to 1 to 10 times the LD ₁₀₀ dose (LD ₁₀₀ : minimal inoculation required to 100% kill the mice). After completion of the assay, the potency of the compound is determined by comparing the number of surviving mice that received the compound of Formula I and the control. The compounds of formula I may be administered either orally (po) or subcutaneously (se).

This in vivo efficacy of the antibacterial agents of the invention is of importance for the treatment of bacterial infections in mammals, including humans, by both oral and parenteral routes of administration. These substances are valuable in the treatment of infections caused by bacteria in the human body. In general, R ¹ determines whether a given bacterium will be susceptible to a compound of formula I. A compound of formula I decomposes both after oral administration and parenteral administration to a mammal into the corresponding compound of formula VI

(VI), wherein M is a carboxylate salt-forming cation and R ¹ is as defined above, or a free acid thereof and penicillanic acid 1,1-dioxide. The penicillanic acid 1,1-dioxide then acts as a beta-lactamase inhibitor and thus increases the antibacterial activity of the compound of formula VI (or its free acid). For example, when R ¹ is 2-phenylacetyl or 2-phenoxyacetyl, they are effective in treating sensitive strains of Staphylococcus aureus; when R ¹ is D-2-amino-2-phenylacetyl, D-2-amino-2- [4-hydroxyphenyl] acetyl, 2-carboxy-2-phenylacetyl, 2-carboxy-2 (2-thienyl] acetyl, 2 -carboxy-2- [3-thienyl] acetyl, 2- [4-ethyl-2,3-dioxopiperazinocarbonylamino] -2-phenylacetyl or a group of formula II are effective in the treatment of infections caused by susceptible strains of Escherichia coli.

The above test can be used to determine how individual strains of Staphylococcus aureus or Escherichia coli are sensitive to particular compounds. Alternatively, the minimum inhibitory concentration (MIC) of a mixture of a compound of formula (VI) or a corresponding free acid thereof and a compound of formula (VIII) or a corresponding free acid thereof (1: 1) can be determined.

(VIII), wherein M is as defined above.

This minimum inhibitory concentration can be measured in the manner recommended by the International Collaborative Study on Antibiotic Sensitivity Testing (Ericcson and Sherris, Acta.Pathologica at Microbiologia Scandinav, Supp.217, Section B: 64-68 / 1971 //), which uses agar from the brain infusion. and heart (BHI) and inoculation reproducing devices. Overnight growth is diluted 100-fold and used as a standard inoculum (20,000 to 10,000 cells contained in about 0.002 ml are plated on agar surface, 20 ml BHI agar broth). Twelve-fold dilutions of the test substance are used, with an initial test drug concentration of 200 μg / ml. Individual colonies are not considered when evaluating the plates after 18 hours at 37 ° C. The sensitivity of the test organisms (MIC) is expressed as the lowest concentration of compound capable of providing complete growth inhibition when judged to the naked eye.

When the antibacterial agents of the invention or their salts are used in mammals and in particular in humans, they may be administered alone or mixed with other antibiotics and / or pharmaceutically acceptable carriers or diluents. The carriers or diluents are selected according to the intended mode of administration. For example, in the oral route of administration, the antibacterial of the invention may be used in the form of tablets, capsules, lozenges, troches, powders, syrups, elixirs, aqueous solutions and suspensions, and the like, in accordance with conventional pharmaceutical practice. The ratio of active ingredient to carrier will naturally depend on the chemical nature, solubility and stability of the active ingredient, as well as the dose contemplated. In the case of tablets for oral administration, carriers commonly used include lactose, sodium citrate and phosphoric acid salts. Various disintegrants such as starch and glidants such as magnesium stearate, sodium lauryl sulfate and talc are commonly used in the preparation of tablets. For oral administration in capsule form, lactose with high molecular weight polyethylene glycols, for example polyethylene glycol having a molecular weight of from 2,000 to 4,000, is used as the diluent. If aqueous suspensions are required for oral administration, the active ingredient is combined with emulsifying and suspending agents. If desired, certain flavor or color modifiers may be added. For parenteral administration, which includes intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile drug solutions are usually prepared and the pH of the solution is appropriately adjusted and buffered. For intravenous use, the total concentration of solutes is controlled so that the formulation is isotonic.

As mentioned above, the antibacterial compounds of the invention are suitable for administration to humans and their daily doses will not differ significantly from the clinically used penicillin antibiotics. Appropriate dosages are determined by the prescribing physician for a particular person and can be expected to vary according to the age, weight and response of the individual patient as well as the nature and extent of the patient's symptoms. The compounds of the invention will normally be administered orally at doses ranging from about 20 to about 100 mg / kg body weight / day and parenterally at doses from about 10 to about 100 mg / kg body weight / day, usually in divided doses. In some cases, it may be necessary to use a dose outside these limits.

The following examples are given for illustration only. The infrared spectra (IR) were measured in the form of potassium bromide tablets (KBr tablets) and the determined absorption bands are given in wave numbers (cm ^-1 ). Nuclear magnetic resonance spectra / NMR / were measured at 60 MHz for solutions in deuterated chloroform / CDC1 ₃ / deuterated or dimethylsulfoxide / DMSO-d _g / and peak positions are reported in ppm relative to tetramethylsilane. The following abbreviations are used for peak shapes: s-singlet, d-doublet, t-triplet, q-quartet, m-multiplet.

Example 1

6 '- (2-Phenylacetamido) penicilanoyloxymethylpenicilate 1,1-dioxide

To a stirred solution of 6.62 g of 6'-aminopenicilanoyloxymethylpenicilate 1,1-dioxide in 25 ml of chloroform was added 1.50 ml of triethylamine. The mixture was cooled to 0 ° C and a solution of 1.55 g of 2-phenylacetyl chloride in 10 ml of chloroform was added dropwise at this temperature. The resulting mixture was stirred at 0 ° C for 5 minutes and then at 25 ° C for 30 minutes. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate and water at pH 8. The ethyl acetate layer was washed with water, dried over sodium sulfate and evaporated in vacuo. The title compound is obtained.

Example 2

6 '- (2-Phenoxyacetamido) penicilanoyloxymethylpenicilate 1,1-dioxide

The title compound was prepared by acylation of 6'-aminopenicilanoyloxymethylpenicilate 1,1-dioxide with 2-phenoxyacetyl chloride as described in Example 15.

Example 3

1,1'-Dioxide 6 '- (2-amino-2-phenylacetamido) penicilanoyloxymethylpenicilate

To a stirred solution of 155.2 g of N- (1-methyl-2-ethoxycarbonylvinyl) -D-2-amino-2-phenylacetate hemihydrate (Chem.Ber., 98,789 (1965)) in 2000 ml of ethyl acetate was added 2.5 ml of N-methylmorpholine and 70 ml of isobutyl chloroformate at -15 ° C. Stir continuously for 15 minutes at -15 ° C and then add a solution of 231 g 1,1-dioxide at this temperature dropwise.

Of 6'-aminopenicilanoyloxymethylpenicilate in 100 ml of ethyl acetate over 15 minutes. Stirring is continued continuously for 1 hour at 15 ° C and then allowed to rise to room temperature. Wash with water, 0.5 M aqueous sodium bicarbonate and again with water. The ethyl acetate solution was then dried and evaporated in vacuo. The residue was dissolved in 2000 mL of 1: 1 tetrahydrofuran-water and the pH was adjusted to 2.5. The solution was stirred at pH 2.5 for one hour and then the tetrahydrofuran was evaporated in vacuo. The pH of the aqueous phase is adjusted to 8.5 and then the aqueous phase is extracted with ethyl acetate. The extracts were washed with water, dried over sodium sulfate and evaporated in vacuo. The title compound is obtained.

Physico-chemical properties of 6 '- (2-amino-2-phenylacetamido) penicilanoyloxymethylpenicilate-1,1-dioxide hydrochloride: The infrared spectrum in the form of a potassium bromide tablet shows absorption bands at 3400, 2950, 1790, 1690, 1 320 and 890 cm ¹ .

^{The 1} H nuclear magnetic resonance spectrum in perdeuterodimethylsulfoxide at 60 MHz shows absorption at 9.45 (d, 1H, J = 7Hz), 8.90 (broad s, 3H), 7.40 (broad s, 5H), 5.80 (s, 2H), 5.50 (m, 2H), 5.15 (m, 2H), 4.45 (s, 1H), 4.35 (s, 1H), 3.60 (m, 1H) , 3.00 (s, 1H), 1.40 (s, 6H), and 1.30 (s, 3H) ppm relative to the tetramethylsilane internal standard.

The decomposed proton C-NMR spectrum of perdeuterodimethylsulfoxide shows peaks at 172.406, 166.131, 165.749, 133.622, 122.649, 128.546, 69.7087, 67.1798, 63.9624, 62.2723, 60.6689,

171.931, 167.563, 127.873, 81.0634, 58.6824, 54.8879,

37.6945, 30.1372, 26.4151, 19.6717 and 17.7702 ppm relative to TMS.

Example 4

6 '- / 2-Amino-2- [4-hydroxyphenyl] acetamido / penicilanoyloxymethylpenicilate 1,1-dioxide

Following the procedure described in Example 3, the title compound was prepared from 6'-aminopenicilanoyloxymethylpenicilate 1,1-dioxide and N- (1-methyl-2-methoxycarbonylvinyl) -D-2-amino-2- (4-hydroxyphenyl) sodium acetate. the Chemical Society (London), vol. C, 1920 (1971).

Example 5

6 '- (2-Carboxy-2-phenylacetamido) penicilanoyloxymethylpenicilate 1,1-dioxide

To a stirred solution of 2.31 g of 6'-aminopenicilanoyloxymethylpenicilate 1,1-dioxide in 15 ml of ethyl acetate at 0 ° C was added 0.605 g of Ν, Ν-dimethylaniline. The temperature is maintained at 0 ° C and 30 ml of a 0.2 molar solution of phenylmalonyl chloride trimethylsilyester are added dropwise over 5 minutes. The reaction mixture was washed with water and then an equal volume of fresh water was added. The pH of the aqueous phase was adjusted to 7.0 with saturated sodium bicarbonate and the layers were separated. The organic layer was discarded and fresh ethyl acetate was added to the aqueous layer. The pH of the aqueous layer was lowered to 3.5 and the layers were separated again. The ethyl acetate layer was dried over sodium sulfate and evaporated in vacuo. The title compound is obtained.

A 0.2 molar solution of phenylmalonyl chloride trimethylsilyl ester was prepared according to Preparation A of US Patent 3862953.

Example b

6 '- / 2-carboxy-2- [3-thienyl] acetamido / penicilanoyloxymethylpenicilate 1,1-dioxide

The title compound was prepared by acylating 6'-aminopenicilanoyloxymethylpenicilate 1,1-dioxide with trimethylsilyl [3-thienyl] malonyl chloride as described in Example 5. TriCS 276966 B6 [3-thienyl] malonyl chloride methylsilyl ester was prepared according to the method of US Patent 3862933.

Example 7

6 '- [2-Carboxy-2- [2-thienyl] acetamido / penicilanoyloxymethylpenicilanoate 1,1-dioxide pH of a stirred suspension of 372 mg of 2- (2-thienyl) malonic acid in 10 ml of water and 5 ml of tetrahydrofuran is adjusted to 6 by adding saturated sodium bicarbonate solution. To the resulting solution was added 923 mg of 6'-aminopenicilanoyloxymethylpenicilate 1,1-dioxide. The mixture was cooled to about 0 ° C and 402 mg of N-ethyl-N'-3- (dimethylamino) propylcarbodiimide hydrochloride was added with stirring. Stir continuously for 5 minutes at 0 ° C and 2 hours at ° C. The pH is continuously maintained between 5.8 and 6.0. Tetrahydrofuran was evaporated in vacuo, ethyl acetate and additional water were added and the pH was raised to 8.0. Separate the layers and discard the organic layer. Fresh ethyl acetate was added and the pH was lowered to 3.0. The layers were separated again and the ethyl acetate layer was dried over sodium sulfate and evaporated in vacuo. The title compound is obtained.

Example 8

6 '- [2- [4-ethyl-2,3-dioxopiperazinocarbonylamino] -2-phenylacetamido / penicilanoyloxymethylpenicilate 1,1-dioxide

To a stirred mixture of 3.19 g of 2- (4-ethyl-2,3-dioxopiperazinocarbonylamino) -2-phenylacetic acid in 50 ml of acetone was added 1.2 ml of N-methylmorpholine. The resulting mixture was cooled to -20 ° C and a solution of 1.09 g of ethyl chloroformate in ml of acetone was added dropwise over 10 minutes. Stir continuously for 60 minutes at -20 ° C and then add a solution of 4.61 g of 6'-aminopenicilanoyloxymethylpenicilate 1,1-dioxide in 50 ml acetone at -20 ° C dropwise. Stir continuously at -20 ° C for 60 minutes, 30 minutes at ° C and 30 minutes at 25 ° C. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate and water at pH 2.5. The layers were separated and the aqueous layer was discarded. Fresh water was added and the pH was raised to 8.5. The layers were shaken and then the organic layer was separated. Fresh ethyl acetate was added and the pH was readjusted to 2.5. The layers were shaken and separated. The ethyl acetate layer was washed with water and then dried. Evaporation of the ethyl acetate layer in vacuo gave the title compound.

Example 9

The procedure of Example 22 was repeated except for the place

2- (4-ethyl-2,3-dioxopiperazinocarbonylamino) -2-phenylacetic acid used:

2- (2-oxoimidazolidinocarbonylamino) -2-phenylacetic acid,

2- (3-acetyl-2-oxoimidazolidinocarbonylamino) -2-phenylacetic acid,

2- (3-butyryl-2-oxoimidazolidinocarbonylamino) -2-phenylacetic acid,

2- (3-methylsulfonyl-2-oxoimidazolidinocarbonylamino) -2-phenylacetic acid; and

2- (3-Isopropylsulfonyl-2-oxoimidazolidinocarbonylamino) -2-phenylacetic acid. This is how:

6 '- [2- [2-Oxoimidazolidinocarbonylamino] -2-phenylacetamido / penicilanoyloxymethylpenicilate 1,1-dioxide,

6 '- [2- [3-Acetyl-2-oxoimidazolidinocarbonylamino] -2-phenylacetamido / penicilanoyloxymethylpenicilate 1,1-dioxide,

6 '- [2- [3-Butyryl-2-oxoimidazolidinocarbonylamino] -2-phenylacetamido / penicilanoyloxymethylpenicilanoate 1,1-dioxide,

6 '- [2- [3-methylsulfonyl-2-oxoimidazolidinocarbonylamido] penicilanoyloxymethylpenicilate 1,1-dioxide; and

6 '- [2- [3-Isopropylsulfonyl-2-oxoimidazolidinocarbonylamino] -2-phenylacetamido / penicilanoyloxymethylpenicillanate 1,1-dioxide. Example 10

6'-Aminopenicilanoyloxymethylpenicilate 1,1-dioxide

To a solution of 1.2 g of 6 '- (4-nitrobenzyloxycarbonylamino) penicilanoyloxymethylpenicillanate with a mixture of 30 ml of water and 50 ml of tetrahydrofuran was added 1 drop of acetic acid (the pH was lowered to 4.5). Then 1.2 g of 10% palladium on carbon was added. The mixture was shaken under a hydrogen atmosphere at a pressure of about 350 kPa for 1.5 hours. The mixture was then filtered and the residue washed with water and tetrahydrofuran. The tetrahydrofuran-water solutions, aqueous and tetrahydrofuran solutions were combined and the pH adjusted to 8.5. The resulting solution was extracted with ethyl acetate and the ethyl acetate extract was dried over sodium sulfate, and the dried solution was evaporated in vacuo. 600 mg of crude material is obtained.

The crude material is chromatographed on silica gel, eluting with 3: 1 ethyl acetate-hexane. 200 mg of the title compound was obtained (23% yield). The IR spectrum (KBr tablet) shows absorption

1783 cm ¹ . The NMR spectrum (CDCl ₃ ) shows absorption at 5.9 (s),

5.5 (m), 4.63 (m), 4.5 (s), 3.5 (d), 1.7 (s), 1.6 (s), 1.5 (s), and 1 45 / s / ppm.

Example 11

6 '- (2-Amino-2-phenylacetamido) -penicilanoyloxymethylpenicilate hydrochloride 1,1-dioxide hydrochloride

To 0.055 ml of ethyl chloroformate and 1 drop of N-methylmorpholine in 5 ml of acetone at -15 ° C was added 164 mg of N- (1-methyl-2-methoxycarbonylvinyl) -D-2-amino-2-phenylacetate in one portion. Stirring was continued for 30 minutes at -20 ° C to -20 ° C

-5 ° C and then recooled to -20 ° C. A chloroform solution of 6'-aminopenicilanoyloxymethylpenicilate-1,1-dioxide is then added to the reaction mixture. This additional mixture was stirred at room temperature for 15 minutes

-20 ° C and then allowed to warm to room temperature. Excess chloroform and water were added and the layers were separated. The organic layer was washed with water to pH 8.5 and then with saturated sodium chloride solution, then dried over sodium sulfate and evaporated in vacuo. The residue was dissolved in a mixture of 3 mL of tetrahydrofuran and 2 mL of water and the pH was adjusted to 1.5 at 0 ° C. The mixture was stirred at 0 ° C for 30 minutes and then excess ethyl acetate-diethyl ether 1: 1 and 5 mL of water were added. The layers were separated and the aqueous layer was washed twice with diethyl ether. The aqueous layer was then lyophilized to give 100 mg of the title compound.

The NMR spectrum of the product (DMSO-d ₆ / D ₂ O) shows the following absorption at 7.48 (m, 5H), 5.9 (m, 2H), 5.47 (m, 2H), 5.05 (m, 2H), 4.42 (m, 2H), 3.45 (m, 2H), 1.45 (m, 6H) and 1.36 (m, 6H) ppm using tetramethylsilane as an internal standard. The IR spectrum (KBr disk) shows absorption at 1800-1355 and 1685 cm ^-1 .

Example 12

6 '- (2-Amino-2-phenylacetamido) -penicilanoyloxymethylpenicilate 4-toluenesulfonate

To a stirred mixture of 422 mg of potassium N- (1-methyl-2-methoxycarbonylvinyl) -D-2-amino-2-phenylacetate and 2 drops of N-methylmorpholine in 10 ml of acetone under nitrogen at -20 ° C is added 0.141 ml of ethyl chloroformate . Stir for 30 minutes at -20 ° C, then allow the temperature to rise to -5 ° C with stirring. At this point, the reaction mixture was cooled to -30 ° C and 650 mg of 6'-aminopenicilanoyloxymethlylpenicilate 1,1-dioxide in chloroform was added with stirring. The temperature was allowed to rise to 0 ° C. Excess chloroform and water were added, the layers were separated and the aqueous layer was washed with chloroform. The combined chloroform solutions were washed with water to pH 8.5 and then dried with sodium sulfate. Evaporation in vacuo gave 990 mg of a solid. This solid was dissolved in 8 mL of ethyl acetate and a solution of 300 mg of 4-toluenesulfonic acid monohydrate in 3 mL of ethyl acetate was added. After 20 minutes, the ethyl acetate solution was washed with water and then evaporated in vacuo. The residue was triturated with ether and then dissolved in acetone. The acetone was evaporated and the residue was dissolved in chloroform. The chloroform was then evaporated in vacuo to give 627 mg of the title compound as a foam.

The NMR spectrum of the product (in DMSO-d6) shows absorption at 7.4 (m, 5H), 7.23 (m, 4H), 5.85 (m, 2H), 5.47 (m, 2H), 1 (m, 2H), 4.48 (S, 1H), 4.38 (S, 1H), 3.43 (m, 2H), 2.26 (s, 3H), 1.47 (m, 6H) ) and 1.37 (m, 6H) ppm using tetramethylsilane as internal standard.

Example 13 _"

6 '- (2-Amino-2-phenylacetamido) -penicilanoyloxymethylpenicilate hydrochloride 1,1-dioxide hydrochloride

To a solution of 1.36 g of 6'-aminopenicilanoyloxymethylpenicilate 1,1-dioxide in dichloromethane cooled to -35 ° C, 1.83 ml of Ν, Ν-dimethylaniline and 0.75 g of hydrochloride are added with stirring.

Of 2-amino-2-phenylacetyl chloride. Stir continuously at -20 ° C for 30 minutes and then pour the reaction mixture into a solution prepared from 0.24 g of sodium bicarbonate and 10 ml of water with stirring. Stirring is continued for 10 minutes and then the dichloromethane layer is separated. The aqueous layer was extracted with dichloromethane and the combined dichloromethane solutions were washed with saturated sodium chloride, dried over sodium sulfate and evaporated in vacuo. The residue was dissolved in about 50 mL of dichloromethane and this solution was slowly added to about 100 mL of hexane. The solid which precipitated was filtered off to give 1.37 g of the crude title product.

This product was triturated with ether and then dissolved in about 25 mL of dichloromethane. the dichloromethane solution was cooled to about -70 ° C and about 30 mL of hexane was slowly added with stirring. Stir 10 minutes. The solid was filtered to give 1.19 g of the title compound, m.p. Mp 164-170 ° C (dec.).

The NMR spectrum of the product (in DMSO-d6) shows absorption at 9.4 (d, 1H), 9.0 (broad S, 2H), 7.4 (m, 5H), 5.8 (s, 2H), 4 (m, 2H), 5.1 (broad S, 2H), 4.5 (S, 1H), 4.4 (s, 1H), 3.6 (m, 1H), 3.3 (m 1 H, 1.4 (s, 3H) and 1.3 (s, 6H) ppm using tetramethylsilane as an internal standard. The IR spectrum of the product (KBr disk) shows absorption at 3400, 2950, 1790, 1690, 1320 and 990 cm -1.

The C-NMR spectrum of the product (in DMSO-dg) shows absorption at

- ... ... ------ ---... ------ 133.622, 129.649,

67.1798, 63.9624, 30.1372, 26.4151

172.406, 171.931, 167.563, 129.015, 128.546, 127.873, 62.2723, 60.6689, 58.6824,

166.131, 165.749, 81.0634, 69.7087, 54.9879, 37.6945,

19.6717, 17.7702 using tetramethylsilane.

Example 14

1,1'-Dioxide 6 '- (2-amino-2- (4-hydroxyphenyl) acetamido) penicilanoyloxymethylpenicilate hydrochloride

To a solution of 341 mg of tetrabutylammonium 2- (1-methyl-2-methoxycarbonylvinylamino) -2- (4-hydroxyphenyl) acetate 5 ml of acetone under nitrogen was added one drop of N-methylmorpholine and then the solution was cooled to about -20 ° C. After 5 minutes, ethyl chloroformate (0.06 ml) was added and a solution of 6'-aminopenicilanoyloxymethylpenicilate-1,1-dioxide (276 mg) in a small amount of dichloromethane was added over 10 minutes at -30 ° C. The reaction mixture was allowed to warm to room temperature and the solvent was evaporated in vacuo. The residue was dissolved in a mixture of ethyl acetate and water. The layers were separated and the ethyl acetate layer was dried over sodium sulfate and evaporated in vacuo. The residue was dissolved in about 10 mL of acetone and 4 mL of water and the pH was adjusted to 1.6 with hydrochloric acid and maintained at this value until the enamine hydrolysis was complete. Acetone was removed in vacuo and the remaining aqueous phase was extracted with ether ^e. The aqueous phase is then lyophilized to yield

250 mg of the title compound.

The IR spectrum of the product shows high absorption at 1780 cm ^-1 . The NMR spectrum of the product (DMSO-dg / DgO) shows absorption at 7.08 (m, 4H), 5.92 (m, 2H), 5.5 (m, 2H), 5.07 (m, 1H),

4.97 (s, 1H), 4.5 (s, 1H), 4.33 (s, 1H), 3.47 (m, 2H), 1.50-1.38 (m, 12H) ppm.

Claims (3)

PATENT CLAIMS A process for the preparation of methanediol bis-esters with 6'-acylaminopenicillanic acid and penicillanic acid 1,1-dioxide of the formula I wherein R ¹ is 2-phenylacetyl, 2-phenoxyacetyl, 2-amino-2-phenylacetyl or 2-amino-2- (4-Hydroxyphenyl) acetyl or a pharmaceutically acceptable salt thereof, characterized in that the compound of the formula III Η E NHg = (111) acylated with a reactive carboxylic acid derivative of the formula r ² -COOH, where R ² is as defined for R 6, where all free amino groups are optionally protected, at a temperature between -40 to 30 ° C in an inert solvent and is- if necessary, the amino protecting group R ¹ is cleaved and the compound is optionally converted to its pharmaceutically acceptable salt. 2. The process of claim 1 wherein the acylating agent is 2-phenylacetic acid. 3. The process of claim 1 wherein the acylating agent is 2-phenoxyacetic acid.