CS227349B2 - Method of preparing 1,1-dioxopenicillanoyloxymethyl-6-(2-amino-2-phenylacetamide)-penicillanate - Google Patents

Description

The present invention relates to a process for the preparation of 1,1-dioxopenicilanoyloxymethyl-6- (2-amino-2-phenylacetamido) -penicillanate antibiotics of the following general formula II using the compounds of the general formula I as defined below. No. 227,345.

U.S. Pat. No. 4,234,579, issued Nov. 18, 1980, discloses penicilianic acid 1,1-dioxide and its esters, which are readily hydrolyzed in vivo, their use as antibacterial agents, and as agents for enhancing beta antibiotic activity. of the lactam type against numerous beta-lactamase producing bacteria.

U.S. Pat. No. 4,244,951, issued January 13, 1981, discloses novel antibacterially active compounds of Formula VIII below wherein penicillanic acid 1,1-dioxide is coupled to known penicillin-type antibiotics via methylenedioxy, i.e. formulas

(VIII) in which

R ^b represents the acyl group of the natural semi-synthetic penicillin.

Particularly preferred R @ ⁵ radicals are 2-amino-2-phenylacetyl and 2-amino-2- (p-hydroxyphenyl) acetyl. The compounds of formula (VIII) are prepared, for example, by reacting a salt on the carboxyl group of penicillin, such as sodium, potassium or tertiary amine, with a halomethyl ester (or related ester) of penioilanic acid 1,1-dioxide. Intermediate halomethyl esters are prepared by esterification of penicillanic acid 1,1-dioxide.

Harrison et al. in the Journal of the Chemical Society (London), Perkin I, 1772 (1976) described (a) the oxidation of 6,6-dibromopenicillanic acid with m-chloroperbenzoic acid to form a mixture of the corresponding alpha and beta-sulfoxides; 6,6-dibrompenicillanate with m-chlorpsrbensoic acid to form methyl 6,6-dibrompenicillanate-1,1-dioxide, (c) oxidizing methyl 6-alpha-chloro-penicillanate with α-chloroperbenzoic acid to form a mixture of the corresponding alpha and beta-sulfoxides and (d) oxidizing the methyl 6-bromopenicillinate with m-chloroperbenzoic acid to form a mixture of the corresponding alpha and beta-sulfoxides.

Clayton in the Journal of the Chemical Society (London), (C), 2 123 (1969) described the preparation of 6,6-dibromo- and 6,6-diiodo-penicillanic acid, (b) oxidation of 6,6-dibromo-penicillanic acid with periodate (c) hydrogenolysis of methyl 6,6-dibrompenicillanate to methyl 6-alpha-bronpenealanate; (d) hydrogenolysis of 6,6-dibrompenicillanic acid and its methyl ether to form penicillanic acid and the like; its methyl ester, and (e) hydrogenolysis of a mixture of methyl 6,6-diiodo-penicilate and methyl 6-alpha-iodo penicilate to give pure methyl-6-alpha-iodo penicillanate.

Belgian Patent Specification No. 882,028, issued September 9, 1980, describes a process for the preparation of penicillanic acid 1,1-dioxide and its esters readily hydrolyzable in vivo by oxidizing 6-halo-penicillanate or 6,6-di-halo-penicillanate to the corresponding 1,1- dioxide, followed by dehalogenation to give the desired penicillanate-1,1-dioxide.

U.S. Pat. No. 3,293,242 discloses 6- (2-azido-2-phenylecetamido) penicillanic acid and salts thereof.

Japan Kokai 78-37691 [Chem. Abstr., 89, 109466v (1978)] discloses 6,22-asido-2- (p-hydroxyphenyl) aoetamido] penicillanic acid and its reduction with hydrogen in the presence of palladium on carbon, resulting in 6- [2-amino-2- ( p-hydroxyphenyls Dacetamido] penicillanic acid.

The present invention provides a process for the preparation of 1,1-dioxopenicilanoyloxymethyl-6- (2-amino-2-phenyleoetamido) penicillanates of formula II

in which

B ¹ is hydrogen or a hydroxyl group, and pharmaceutically acceptable acid addition salts thereof, characterized in that the compound of formula I is

in which

AND? is as defined above, each of Y and Z being chlorine, bromine or iodine, or Y being hydrogen and Z is chlorine, bromine or iodine; and

4

Q is N ^ or NHCOgCHgCgH ^R, where R is hydrogen, chlorine or bromine, nitro, methyl or methoxy, is treated with hydrogen in the presence of a noble metal catalyst and an inert solvent, and the resulting product of formula II is optionally reacts with an acid to convert it into a pharmaceutically acceptable acid addition salt thereof.

The compounds of the aforementioned general formula (I) are novel and their preparation is the subject of our related Czechoslovak patent specification No. 227345. *

A particularly preferred radical for Q in the compounds of formula I above is Ny. Particularly preferred values for Y and Z are: for Y hydrogen and Z for bromine or chlorine, or for both Y and Z chlorine or bromine, especially for Y hydrogen and for Z bromine or for Y e Z bromine.

'1

Particularly preferred are those wherein Q is Ny and R is hydrogen or hydroxyl and Y and Z are bromine.

The process for the preparation of the antibiotics of the general formula II according to the invention has the advantage over the known processes that hydrogenolysis of the halogen atoms Y and Z and simultaneous reduction of the Q radical (if Q is N ^) or hydrogenolysis thereof (if Q or a hydrogenolysis thereof (when Q is NHC (CH 2 CH 2 CH 3 CH 2 R 4)) to form antibiotics of the above formula (II) in a single reaction step. The noble metal catalyst particularly preferred for the above reaction is palladium.

The novel intermediates which can be used for the preparation of the compounds of the formula I correspond to the formula IV (n & gt _;

Νη, (IV) co ₂ ch ₂ x in which Y and Z a

x are as defined above for compounds of formula I, have a value of 0, 1 or 2; and

2 is chloro, bromo, iodo or OSC (R) wherein R is (C 1 -C 6) alkyl or R (1) is chloro, bromo, iodo, nitro, (C 1 -C 3) alkyl, or alkoxy β 1 to 3 carbon atoms.

Preference is given to those intermediates of formula IV in which

Zvi

X is hydrogen and Z is chlorine or bromine, or Y and Z are each chlorine or bromine, X is chlorine, bromine or iodine and n is 0 or 2.

more preferably, those compounds of formula IV wherein n is 0, X is hydrogen and Z is bromine, or both X and Z are bromine, and X is chlorine or iodine, or is 2, X is hydrogen and Z is bromine, or both Y and Z are bromine, and X is iodine.

Most preferred are those compounds of formula IV wherein q is 0, Y and Z are bromine and X is chlorine or iodine, or a is 2, Y and Z are bromine and X is iodine.

The iodomethylsulfones of formula IV in which n is 2 and X is iodine are particularly valuable since they are very easily condensed with the salts of formula VI below to form compounds of formula I.

The compounds produced by the process of the invention are penicillanic acid derivatives corresponding to the structural formula

H

In penicillanic acid derivatives, the intermittent bond of the []] [[] substituent to the bicyclic nucleus indicates that this substituent is below the plane of the nucleus, which is referred to as a substituent having an alpha configuration. bicyclic nucleus means that this substituent is located above the plane of the nucleus and its position is referred to as the beta-configuration. in the beta configuration.

The compounds of formulas I and II are referred to herein as penicilinoyloxymethyl penicillanate derivatives. . Thus, a compound of formula (I) wherein R ¹ is hydrogen, Y and Z are bromine and Q is Ng is designated 1,1-dioxo-6,6-dibromopenicenilaloxymethyl-6- (2-azido-2- phenylaoetamido) penicillanate.

Furthermore, when referring to 2-Q-2- (R'-substituted-phenyl) acetamido or 2-amino-2- (R ¹ -substituted-phenyl) acetamido-penicillanic acid derivatives, these are always compounds in which this 2-Q-2- (R'- _su bst.fenyl) acetamido or 2-amino-2- (R-substituted phenyl) acetamido has the D-configuration.

In the compounds of formula I wherein Y is hydrogen and Z is chlorine, bromine or iodine, the Z substituent may be in the alpha configuration, in the beta configuration, or a mixture of the two isomers. All of these compounds are within the scope of the invention.

A process for the preparation of penicilinoyloxymethyl penicillanates of formula (II) by esterification, as illustrated below, is described in U.S. Pat. No. 4,244,951, issued January 13, 1981, and Dutch patent application no. No. 8,000,775, published Aug. 15, 1980, corresponding to British Patent Application No. 2,444,255.

RCHCONH

CH3, ^CH3

COOB (X) ii NHQ ¹

two stages (II)

In the above formulas, represents one of A and B are -CH, X ^c, and the second group of M, where X represents an easily odětěpitelnou group such as chloro, bromo, iodo, methylsulfonyloxy or toluenesulfonyloxy and if 'is a cation forming a salt of the carboxylic acid , for example sodium, potassium, triethylammonium or tetrabutylammonium ion, and Q ¹ represents a conventional amino function protecting group, for example benzyloxycarbonyl. As the primary product, an amino-protected derivative of formula (II) is obtained which, after removal of the protecting group (Q) by standard methods known in the art, provides the desired antibiotic active.

The above-mentioned Dutch and corresponding British application also disclose a process for the preparation of a compound of formula II wherein R ¹ is hydrogen by condensation of chloromethyl 6- (2-azido-2-phenylacetamido) penicillanate and penicillanic 1,1-dioxide salt. acid, followed by hydrogenation of the intermediate 1,1-dioxopenicilanoyloxymethyl-6- (2-azido-2-phenylaetamido) foam cilanoate.

According to processes known from the prior art, the starting 1,1-dioxopenicillanate acid corresponding to general formula IX wherein A is hydrogen, for example, dehalogenation give the corresponding sulfone 6-halo- or 6 _y 6 dihalogenpenicilanové acid. The ester of formula (IX) wherein A is CHgX ¹ is prepared from the acid by certain esterification procedures.

The following reaction Scheme A describes a preferred process for the preparation of the compounds of formula (I) of the invention and their conversion to the antibiotic active compounds of formula (II) by simultaneous hydrogenolysis of the halogens Y and Z and reduction or hydrogenolysis of the azido or NHCO 3 CH 2 by reacting a compound of formula I with hydrogen in the presence of a catalyst.

The starting halpenicillanic acids of the formula III, where M is hydrogen, are prepared, for example, from the 6-aminopenicillanic acid or the corresponding sulfoxide or sulfone by reaction with nitrous acid and halogenation or hydrogen halide of the formula YZ, where Y and Z are as defined above. a diazo compound using known methods [see, for example, Clayton et al., Jourrtal of the Chemical Society (London) (C), 2 123 (1969)].

227349 Scheme A

For esterification to prepare a compound of formula IV, the carboxylic acid of formula III is converted to a salt of the corresponding formula wherein M is a cation. A wide variety of cations can be used to prepare salts on the carboxyl group of compounds of Formula III, but commonly used salts include alkali metal salts such as sodium and potassium salts with alkaline earth metals such as calcium and barium salts, tertiary amine salts, such as trimethylamine, triethylamine, tributylamine, H-methylmorpholine and N-methylpyrrolidine, and tetraalkylammonium salts, such as tetramethylammonium, tetraethylammonium, dimethyldiisopropylammonium, tetrabutylammonium and diethyl-di-n-hexylammonium salts; tetrabutylammonium. '

The salt of formula III is reacted with a compound of the formula X ^d CH _for X 2 wherein

X has the above meaning and X has the same meaning as X or represents a better cleavable β

For example, when X is chlorine, X may be chlorine, bromine, iodine, OSOgG1, OSOgCHg, or p-CHgCgH2SOgO. Particularly preferred radicals X are iodine and OSOgCl.

The reaction between the compound of formula (X) CHgX and the salt of formula (III) is generally carried out by contacting approximately equimolar amounts of the reactants contacted in a polar organic solvent at a temperature in the range of about -10 ° C to 80 ° C, preferably 0 ° C to 60 ° C. The reaction is normally completed in a time ranging from a few hours to a few days. the desired ester of formula (ΙΪ) is isolated by known methods, such as by evaporation of the solvent and, optionally, purification of the crude product, for example by column chromatography.

Examples of suitable polar solvents which can be used in this reaction include dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, ethyl acetate, di-chloromethane, acetone and hexamethylphosphoric triamide. Optionally, an excess of a compound of formula X ² CH ₂ X, for example chloroiodomethane, may also serve as a solvent.

In the next step of the process, compounds of formula IV in which n is 0 or are oxidized to the corresponding sulfones of formula V. Although any of the oxidizing agents known in the art for oxidizing sulfides to sulfones can be used in this reaction step. however, the preferred oxidizing agents are sodium permanganate, potassium permanganate, calcium permanganate, hydrogen peroxide in the presence of certain transition metal catalysts, peracetic acid or m-chloroperbenzoic acid. The oxidation is carried out in the presence of an inert solvent, preferably at a temperature ranging from approx

-30 to 60 ° C.

Particularly preferred oxidizing agents are hydrogen peroxide in the presence of certain transition metal catalysts, potassium permanganate and m-chloroperbenzoic acid. The most preferred oxidizing agents are potassium permanganate and m-chloroperbenzoic acid.

When the compound of formula (IV) is oxidized to the corresponding compound of formula (V) using metal permanganate, the reaction is generally carried out by treating the compound of formula (IV) with about 2 to 10 mol equivalents, preferably about 1, in an inert solvent system. up to 4 mol equivalents of permanganate.

When the starting compound is a sulfoxide of formula IV in which n is 1, about half of the above amount of oxidizing agent is commonly used.

A suitable inert solvent system for this reaction is one which does not react in a harmful manner with either the starting materials or the product, usually using water. If desired, a co-solvent which is miscible with water but does not react with permanganate, such as tetrahydrofuran or acetone, may be used simultaneously. The reaction may be carried out at a temperature in the range of about -30 ° C to 60 ° C, preferably about 10 ° C to 30 ° C. When spun at room temperature, the reaction is usually practically complete in a short time, for example within 2 hours. Although the reaction may be carried out under neutral, alkaline or acidic conditions, it is preferably carried out at a pH in the range of about 4 to 9.

It is necessary to select reaction conditions in which the beta-lactam ring system of the compounds of formula IV or V does not decompose. The resulting product is isolated in a conventional manner. Usually, any excess of permanganate is decomposed with sodium bisulfite and if the product precipitates from the solvent, it is isolated by filtration. The product is separated from manganese dioxide by extraction with an organic solvent followed by evaporation of the solvent. If the product does not precipitate out of solution after completion of the reaction, it is isolated in the usual manner by solvent extraction.

When a compound of formula IV in which n is 0 is oxidized to the corresponding compound of formula V using a peroxycarboxylic acid such as m-chloroperbenzoic acid, the reaction is usually carried out by treating the compound of formula IV with about 2 to 6 mol equivalents, preferably about 2.2 mol equivalents of the oxidizing agent in an inert organic solvent.

As above, generally only half the amount of oxidizing agent is required when the sulfoxides of formula IV are used as starting materials. Preferred inert solvents are chlorinated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, ethers such as diethyl ether, tetrahydrofuran and 1,2-dimethoxyethane, and ethyl acetate. The reaction is normally carried out at a temperature of about -30 to 50 ° C, preferably about -15 to 30 ° C. At a temperature of about 0 DEG C., the reaction time is about 4 to 16 hours.

The product of formula (V) is isolated by standard methods, for example by decomposing the excess oxidizing agent with sodium bisulfite, shaking the reaction mixture between water and a water immiscible solvent, and evaporating the solvent from the washed extract. The crude product can be purified, for example, by silica gel chromatography.

When hydrogen peroxide is used to oxidize a sulfide or sulfoxide of formula IV with < 0 or 1 to the corresponding sulfone of formula V in the presence of a transition metal lysate, catalysts of this type are inorganic compounds of tungsten, molybdenum or zirconium. in which these metals are present in the highest oxidation stage. Examples of such compounds ae include tungstic acid, sodium tungsten, zirconium chloride, molybdic acid and potassium mblybate. The transition metal catalysts may be used in a wide pH range of about 3 to 9, preferably about 4 to 7.

If the oxidized compound is a sulfide of the formula IV in which n is 0, at least 2 moles of hydrogen peroxide are required for each mole of the sulfide to obtain the corresponding sulfone. However, to oxidize sulfoxides to sulfones or sulfides to sulfoxides, only 1 mole of hydrogen peroxide is required to obtain the desired product. Preferred inert solvents for hydrogen peroxide oxidation in the presence of a transition metal catalyst include lower alkanols such as methanol, ethanol β isopropanol, ethylene glycol, ethyl acetate, 1,2-dimethoxyethane, water, and mixtures of these solvents. While the oxidation can be carried out over a wide temperature range, the preferred temperature is from about 20 ° C to about 60 ° C. At this temperature, the oxidation is usually complete in about 2 hours to 2 days, for example overnight. The resulting product is then isolated and can optionally be purified by the methods described above and in the Examples.

Reaction of intermediates of formula (V) with 6- (2-Q-substituted-2-phenylacetamido) penicillanic acid salts of formula (VI) above wherein M is as defined above for compounds of formula (III) to give compounds of formula (1) Typically, the reagents are contacted in a polar organic solvent at a temperature in the range of about 0 to 80 ° C, preferably 25 to 50 ° C. The starting materials of formulas (V) and (VI) are generally used in practically equimolar amounts, but an excess of any of the reagents, for example up to 10-fold excess, may also be used. A wide variety of solvents can be used for the reaction, but relatively polar solvents that accelerate the reaction are usually preferred.

Typical useful solvents include Ν, Ν-dimethylformamide, N, 1-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, ethyl acetate, dichloromethane, acetone, and hexamethylphosphoric triamide. The reaction time varies depending on a number of factors, but is usually at a temperature of about 25 ° C for several hours, for example from 12 to 24 hours.

The compound of formula (I) is isolated by conventional means. When using a water-miscible solvent, a simple dilution of the reaction medium is usually sufficient. The product is then extracted with a water-immiscible solvent such as ethyl acetate and isolated by evaporation of the solvent. When using a water-immiscible solvent, it is usually sufficient to wash the reaction mixture with water and isolate the product by evaporating the solvent. The compounds of formula (I) may be purified by known methods such as recrystallization or chromatography, but taking into account the instability of the beta-lactam ring system.

A particularly preferred method for preparing compounds of formula I from compounds of formula III is described in the following reaction scheme:

γ z

O

(III, n = 0)

Y

O CO 3 CH 3 Cl 2 (IV, P »O, X = CI)

CH, ch ₃

COgCHi (VI)

(I) (IV, n = 0, X = 1) (V, X = I)

In the initial reaction step of this particularly preferred process, the sulfide of formula (I)

III, wherein n is 0, and Μ, Y and Z are as defined above, are reacted with a compound of formula X CHgCl wherein X is as defined above, for example, with chloroiodomethane, using the methods and reaction conditions outlined above. above for a preferred procedure using a compound of formula X CHgX.

In the second reaction step of the process, the chloromethyl ester is converted to the corresponding iodomethyl ester (IV, η = 0, X = 1), for example by reacting the starting chloromethyl ester with at least an equimolar amount of alkali metal iodide, alkaline earth iodide or ammonium iodide in the presence of an inert polar solvent. Examples of solvents suitable for this reaction include dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, methanol, ethanol, ethyl acetate, acetone, and methyl ethyl ketone. A preferred solvent is acetone. Although the reaction may be carried out successfully over a wide temperature range, a temperature of from about 0 to 50 ° C, in particular from 20 to 40 ° C, is preferred. When working in the latter temperature range, the reaction is usually complete in about 1 to 20 hours.

the desired product of formula IV wherein n is 0 and X is iodine is then isolated and purified in a known manner. For example, the solvent is evaporated and the residue is partitioned between water and a water-immiscible solvent such as ethyl acetate. Evaporation of the solvent then yields a product which can be purified if necessary, for example by chromatography on silica gel.

In a subsequent reaction step of this particularly preferred process, the iodomethyl ester of formula IV, where < = 0 and X is iodine, is oxidized to the corresponding sulfone of formula V wherein X is iodine using any of the above preferred oxidizing agents and preferred reaction conditions also described above.

The iodomethyl ester of formula V wherein X is iodine is then condensed with a compound of formula VI as described above to give the corresponding compound of formula I according to the invention.

It is necessary to use at least two moles of hydrogen peroxide per mole of starting sulfide to obtain the corresponding sulfone.

An alternative method of preparing the iodomethylsulfone of formula V wherein X is iodine is by oxidizing the chloromethyl ester of formula IV wherein n is 0 and X is chlorine, for example, to the corresponding sulfone using the oxidizing agents and reaction conditions described above, and in the subsequent conversion, for example, of chloromethylsulfone to the corresponding iodomethylsulfone of formula V by reaction with an iodine salt as described above. However, in the final reaction step, the reaction of an iodine field, such as sodium iodide in acetone, with compounds in which both Ϊ and Z are halogen atoms can result in partial dehalogenation at the 6-position of the sulfone to form a mixture containing iodomethyl-6-alpha-halopenililane The 1,1,1-dioxide and the desired 6,6-dihalogenate of formula V wherein X is iodine,

An alternative method of preparing valuable intermediates of formula I is to react a compound of formula XI with a compound of formula XII as described in the following reaction scheme:

In the formulas of this scheme, r ', M, Q, χ', Y and Z are as defined above and the reaction is carried out using the same methods and conditions as described above for the condensation reaction of compounds of formulas V and VI.

The compounds of formula I are useful intermediates for the production of valuable antibiotic active compounds of formula II described in U.S. Pat. No. 4,244,951.

Although various methods can be used to convert intermediates of formula I to antibiotics of formula II, a particularly useful and advantageous method consists in the simultaneous hydrogenolysis of the halogens of Y and Z as defined above and the reduction of the above-defined azido or benzyloxycarbonylamino groups as defined above. Q to an amino group, using hydrogen in the presence of a noble metal catalyst.

A particularly useful method of carrying out this simultaneous hydrogenolysis and reduction is to mix or shake a solution of the compound of formula I in an inert solvent under a hydrogen or hydrogen atmosphere with an inert gas diluent such as nitrogen or argon in the presence of a noble hydrogenation catalyst. metal. Suitable solvents for this hydrogenation reaction are those solvents which dissolve the starting compounds of the formula I well, but which are not subject to hydrogenation or hydrogenolysis.

Examples of such solvents include lower alkanols such as methanol, ethanol and isoprbpanol, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, low molecular weight esters such as ethyl acetate and butyl acetate, tertiary amides such as Ν, Ν -dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone, longer methylene chloride and mixtures of these solvents.

Furthermore, it is often desirable to carry out the above reaction in the presence of a sufficient amount of an acid acceptor binding one or both of the hydrogen halide formed.

Examples of suitable acid binding agents include sodium bicarbonate, calcium carbonate, sodium phosphate, potassium citrate and tertiary amines such as triethylamine,,, Ν-dimethylaniline, N-methylntorfoline, N-methylpiperidine, Ν, Ν'-dimethylpiperazine and the like.

The introduction of hydrogen gas into the reaction medium is usually carried out by carrying out the reaction in a closed vessel containing a compound of formula (I), a solvent, a catalyst and hydrogen.

The pressure inside the reaction vessel may range from about 0.1 to 10 MPa. The preferred pressure range when the gas phase is comprised of substantially pure hydrogen within the reaction vessel is about 0.2 to 0.5 MPa. The reaction with hydrogen is usually carried out at a temperature of about 0 to 60 ° C, preferably about 25 to 50 ° C. Working in a preferred temperature and pressure range, the hydrogenolysis of the halogens and the reduction of the Q moiety generally takes a few hours, for example from about 2 to 20 hours. Preferred noble metal catalysts in this hydrogenation reaction are catalysts of a known type used for this type of transformation, such as nickel, palladium, platinum and rhodium.

A particularly preferred catalyst is palladium.

I 1

The catalyst is usually present in the reaction mixture in an amount ranging from about 0.1 to 25% by weight, and preferably from about 1 to 10% by weight, based on the compound of formula I. It is often expedient to use the catalyst on an inert support. a catalyst of this type is palladium on an inert support such as activated carbon. Another suitable catalyst is palladium on calcium carbonate, wherein the calcium carbonate serves both as a noble metal carrier and as an acid binding agent.

Upon the practical completion of hydrogenolysis and reduction, the desired antibiotic of formula (II) is isolated by standard methods, for example by filtering off the catalyst, evaporating the solvent, and optionally purifying the product in a known manner such as crystallization or chromatography.

Alternatively, the product of formula (II) may be isolated in the form of a pharmaceutically acceptable acid addition salt, for example by treating the filtrate obtained after catalyst removal or the isolated free base solution with an equivalent amount of pharmaceutically acceptable acid and then removing the solvent, e.g. solid phase or evaporation. Examples of useful pharmaceutically acceptable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, succinic acid, lactic acid, tartaric acid, citric acid, gluconic acid, sugar and p- toluenesulfonová.

Attention is drawn to the fact that the hydrochlorides, hydrobromides, hydroiodides or mixtures of these salts of the compounds of formula (II) are obtained directly from the mixture after hydrogenation when only one mole equivalent of the acid-binding agent is used when starting materials of formula (I) both Y and Z are chlorine, bromine or iodine, or no acid binding agent at all when starting materials of formula I are used, wherein Y is hydrogen and Z is chlorine, bromine or iodine.

As noted above, the compounds of Formula I are valuable intermediates for the preparation of the antibacterially active compounds of Formulas II and VIII described in U.S. Patent 4,244,951 and British Patent Application 2,044,255.

The compounds of formulas II and VIII exhibit antibacterial activity in mammals in vivo, which can be demonstrated by standard methods used in penicillin-type compounds. For example, a compound of formula I is administered to mice in which an acute infection has been induced by intraperitoneal inoculation with a standardized pathogenic bacterial culture. The power of infection is standardized so that mice receive a 1 to 10-fold dose of LD ₁₀ q (LD ₁₀₀ is the minimum inoculum dose required to reliably kill 100% of control mice).

Upon completion of the assay, the efficacy of the test substance is evaluated by counting surviving mice that have been infected with bacteria and treated with a compound of formula II. The compounds of formula (II) may be administered both orally and subcutaneously.

Because of their in vivo activity, the antibacterially active compounds of Formulas II and VIII can be used to combat bacterial infections in mammals, including humans, both by oral and parenteral administration. The disclosed compounds can be used to combat infections caused by human susceptible bacteria. Usually, it is R ¹⁵ that determines whether the bacterium will be susceptible to the compound of formula (VIII). After administration to a mammal, whether orally or parenterally, the compound of formula VIII is cleaved to the corresponding compound of formula VII below (or a salt thereof) and penicillanic acid 1,1-dioxide of formula XIII below, according to the following reaction scheme ;

Penicillanic acid 1,1-dioxide acts as a beta-lactamase inhibitor and enhances the antibacterial activity of a compound of formula VII or a salt thereof. When R ^b is D-2-amino-2-phenylacetyl or D-2-amino-2- (4-hydroxyphenyl) acetyl, the compounds are useful for combating infections caused by susceptible strains of Escherichia coli and Staphyloeoccus aureus.

The in vivo test described above can be used to determine whether a particular Staphyloeoccus aureus or Escherichia coli strain is susceptible to a given compound of Formula II or VIII. Alternatively, the minimum inhibitory concentration of a mixture of equal parts of a compound of formula VII (or a salt thereof) and a compound of formula XXII (or a salt thereof) can be measured. Minimum inhibitory concentrations can be measured by the method recommended by the International Collaborative Study on Antibiotic Sensitivity Testing [Ericcson and Sherris, Acta. Phathologica et Microbiologia Scandinav, Supp. 217, section B: 64-68 (1971)] using brain-heart infusion agar and repeated inoculation devices.

One hundred-fold diluted tubes grown overnight are used as standard inoculum (20,000 to 10,000 cells in about 0.002 ml are plated onto the agar surface, each dish containing 20 ml of brain and heart infusion agar).

12-fold dilutions of the test compound are used, with an initial test compound concentration of 200 µg / ml. After cultivating the plates for 18 hours at 37 ° C, the experiment is evaluated, disregarding isolated colonies. The minimum inhibitory concentration or sensitivity of the test organism is considered to be the lowest concentration of the test substance capable of completely inhibiting the growth of the organism according to visual evaluation.

When a compound of formula (IX) or a salt thereof is used as an antibacterial agent for mammals, particularly humans, the compound may be administered either alone or mixed with other antibiotic active ingredients and / or pharmaceutically acceptable carriers or diluents. The appropriate carrier or diluent is selected taking into account the intended route of administration.

For example, if oral administration is contemplated, the antibacterially active compound of formula (II) may be used in the form of tablets, capsules, lozenges, troches, powders, syrups, elixirs, aqueous solutions and suspensions, etc., in accordance with standard pharmaceutical practice. . The ratio of active ingredient to carrier naturally depends on the chemical nature, solubility and stability of the active ingredient, as well as on the dosage contemplated.

Common carriers for the preparation of tablets for oral administration include lactose, sodium citrate and salts of phosphoric acid. Various disintegrants, such as starch, and glidants such as magnesium stearate, sodium lauryl sulfate and talc are also used to prepare the tablets. Suitable diluents for the preparation of capsules for oral administration are lactose and high molecular weight polyethylene glycols, for example polyethylene glycols having a molecular weight of from 2000 to 4000. For the preparation of aqueous suspensions for oral administration, the active ingredient is combined with emulsifiers and suspending agents, and sweetening and / or flavoring agents.

For parenteral administration, which includes intramuscular, intraperitoneal, subcutaneous and intravenous administration, sterile solutions of the active ingredient are usually prepared, the pH of which is suitably adjusted and buffered. When preparing preparations for intravenous administration, the total concentration of soluble components should be controlled so that the resulting preparation is isotonic.

The daily doses of the antibacterially active compounds of formula II and their pharmaceutically acceptable salts in human medicine will not differ significantly from those of other clinically used penicillin-type antibiotics. The definitive determination of the appropriate dose for which patient in human medicine is a matter for the attending physician. This dose can be expected to vary depending on the age, weight and response of the particular patient to the preparation as well as the nature and extent of the infection. The compounds of formula (II) will normally be used orally at doses ranging from about 20 to 100 mg per kg of patient body weight per day, and parenterally at doses ranging from about 10 to 100 mg per kg of patient body weight per day, the total dose being usually given in several sub-doses. In some cases it may be necessary to use doses outside this range.

The invention is illustrated by the following non-limiting examples, the spectra being measured in the substance, in the suspension in the nujol or KBr technique, and the position of the absorption bands necessary for identification is given in cm ^-1 . The NMfi spectra were measured at 60 MHz in solutions in deuterochloroform, deuterooxide, perdeuterodimethylsulfoxide or perdeuteroacetone, and the signal positions are expressed in ppm values over tetramethylsilane. Signal shapes are indicated by the following abbreviations:

s = sir ^ let d = doublet t = triplet q = quartet m = multiplet dd = double doublet

He did

Chloromethyl-1,6-dibromopenicilane

8.0 g (22 mol) of 6,6-dibromopenicillanic acid are stirred with 75 ml of methylene chloride, 35 ml of water are added and the pH of the mixture is adjusted to 8 with tetrabutylammonium hydroxide. The organic layer is separated and the aqueous phase is extracted with 30 ml of methylene chloride. The combined organic layers were evaporated to dryness in vacuo to give 14.2 g of the tetrabutylammonium salt of 6,6-dibromopenicillanic acid as a brownish oil. To this oily residue was added 40 ml of chloroiodomethane, the resulting mixture was stirred under nitrogen at room temperature for 3 hours, then concentrated in vacuo, allowed to stand at room temperature overnight, and then purified by chromatography on 300 g of silica gel using toluene. and ethyl acetate (95: 5 by volume) as eluent. Fractions containing less polar material were combined and evaporated to yield

5.4 g (59%) of the desired product, m.p. 105-106 ° C.

@ 1 H-NMR (CDCl3): 1.6 (s, 3H), 1.75 (s, 3H), 4.62 (s, 1H), 5.8 (dd, 2H), 82 (s, 1 H).

By repeating the above procedure, except that the chloroiodomethane always replaces an equimolar amount of bromochloromethane, diiodomethane, di (methylsulfonoxyloxy) methane, di (isobutylsulfonyloxy) methane, di (n-hexylsulfonyloxy) methane, di (benzenesulfonyloxy) methane or a compound of the formula (R ² c ₆ h ₄ Sat ₂ o) ₂ Ch ₂

in which o

R is chlorine at position 4, bromine at position 2, iodine at position 4, nitro at position 3, methyl at position 4, isopropyl at position 3, methoxy at position 4, ethoxy at position 3, or n-propoxy at position 4 , the following compounds are obtained:

bromomethyl-6,6-dibrompenicilate, iodomethyl-6,6-dibrompenicilate, methylsulfonyloxymethyl-6,6-dibrompenicilate, isobutylsulfonyloxymethyl-6,6-dibrompenicilate, n-hexyleulfonyloxymethyl-6,6-dibrompenicilate dibromosilane, benzenesulfonyloxylate R ² -C 8 H 4 -sulfonyloxymethyl-6,6-dibromophenioilanes, wherein R is as defined above for the di (substituted phenylsulfonyloxy) methane reagent.

Example 1a

Iodoethyl 6,6-dibromopenililate

To 25 mL of acetone was added 4.15 g (10.2 mmol) of chloromethyl-6,6-dibromopenicillanic acid and 7.5 g (50 mmol) of sodium iodide. The reaction mixture was stirred at room temperature overnight, then the acetone was evaporated. The dark colored residue was dissolved in 150 ml of ethyl acetate, washed three times with 25 ml each of water and 25 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solvent was evaporated in vacuo. The oily residue was purified by chromatography on 100 g of silica gel using a mixture of equal volumes of ethyl acetate and hexane as eluent, collecting 30 ml fractions. The product was eluted in fractions No. 4-6, which were combined and evaporated. 5.95 g of a colorless oily material is obtained which crystallizes on standing and melts at 67-68 ° C.

1 H-NMR (CDCl 3): 1.55 (S, 3H), 1.65 (s, 3H), 4.54 (s, 1H),

5.8 (s, 1H); 5.98 (s, 2H).

If bromomethyl-6,6-dibrompenicilate, bromomethyl-6,6-dichloropenililate, chloromethyl-6,6-dichloropenililate, chloromethyl-6-bromo-chlorpenicilBat, chloromethyl are used instead of chloromethyl 6,6-dibrompenicilate, chloromethyl 6,6-dibrompenicilate 6-chloro-6-iodopenicilanoate, chloromethyl-6-bromo-6-iodopenicilate or bromomethyl-6-bromo-6-iodopenicilate, the corresponding iodomethyl ester is obtained in each case.

Example 2

Chloromethyl-6,6-dibrompenicilane-1,1-dioxide

To a solution of 7.1 g (17.4 mmol) of chloromethyl-6,6-dibromopenicenilate in 75 mL of ethyl acetate cooled to 0 ° C was added 7.3 g (36 mmol) of m-chloroperbenzoic acid. The resulting mixture was stirred at 0 ° C under nitrogen overnight, then diluted to 150 mL with ethyl acetate and 50 mL of water was added at 0 ° C. Excess peracid is quenched by addition of sodium bisulfite, pH is adjusted from 2 to 7.5 with sodium bicarbonate, the organic layer is separated, washed with 50 ml saturated sodium bicarbonate solution, 50 ml water and 25 ml sodium chloride solution. The washed extracts were dried over magnesium sulphate, concentrated to dryness in vacuo and the residue purified by chromatography on 300 g of silica gel using toluene / hexane (9: 1 by volume) as eluent. 5.0 g (65%) of the desired dioxide are obtained in the form of a crystalline solid, m.p. 95-96 ° C.

@ 1 H-NMR (CDCl3): 1.5 (s, 3H), 1.7 Cs, 3H), 4.58 (s, 1H), 5.04 (s, 1H), Δ (dd, 2H).

H, 2.29; N, 3.18. Found: C, 24.63; H, 2.49; N, 3.31.

0.8 g of the second, more polar component, which is identified by a mixture of alpha and beta-sulfoxides of chloromethyl 6,6-dibromopenioilane in a ratio of 9i1 (according to 1 H-NMR), is isolated from the chromatography column.

Example 2A

Iodomethyl-6,6-dibrompenicilate-1,1-dioxide

To 40 ml of acetone was added 0.25 g (0.5 mmol) of iodomethyl-6,6-dibrompenicilate, the mixture was stirred until a solution was added, 0 ml of water was added, and the pH of the mixture was adjusted to pH = 10 with concentrated phosphoric acid. value 4.0. 158 mg (1 mmol) of potassium permanganate powder are added, the mixture is stirred at room temperature for 1.25 hours and then treated with 00 ml of ethyl acetate and 50 ml of water. The resulting mixture was acidified to pH 2.0 with 6N hydrochloric acid, and sodium bisulfite (pH 2.9) was added to decompose excess oxidizing agent.

The organic layer was separated, the aqueous layer was extracted with 50 mL ethyl acetate, the combined organic layers were washed three times with 25 mL each saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated. 0.29 g of a colorless oil was obtained, which was purified by chromatography on 25 g of silica gel using a mixture of 3 equal parts of ethyl acetate and hexane as eluent. Fractions of 15 ml were collected. Fractions Nos. 4 and 5 were combined and evaporated in vacuo to give 0.27 g (100%) of a colorless oily material which crystallized on standing and melted at 7 to 73 ° C.

1 H-NMR (CDCl 3, δ ppm): 1.5 (s, 3H), 1.62 (s, 3H), 4.49 (s, 1H), 5.02 (s, 1H), 5 98 (dd, 2H),

Using the above procedure, the same product is obtained using an equivalent amount of sodium permanganate or calcium permanganate instead of potassium permanganate.

Attempts to prepare iodomethyl-6,6-dibromopenicenilate-1,1-dioxide from the chloromethyl ester obtained in Example 1A resulted in the formation of iodomethyl-6-alpha-bromophenicilate-1,1-dioxide.

1 H-NMR (CDCl 3): 1.55 (s, 3H), 1.70 (s, 3H), 4.43 (s, 1H),

5.2 (d, 1H), 5.75 (dd, 1H), 6.0 (dd, 2H).

Example 3

Iodomethyl-6-bromo-6-chloro-penicillanate-1,1-dioxide

A solution of 7.6 g (17.4 mmol) of iodomethyl-6-bromo-6-chloro-penicillanate in 75 mL of ethyl acetate was cooled to 0 ° C and 7.3 g (36 mmol) of m-chloroperbenzoic acid was added. The mixture was stirred under nitrogen at 0 ° C overnight, then diluted to 150 mL with ethyl acetate and 50 mL of water was added at 0 ° C. Excess peracid was removed by addition of sodium bisulfite, basified with sodium bicarbonate from pH 2 to 7.5, the organic layer was separated and washed with 50 mL saturated sodium bicarbonate solution, 50 mL water and 25 mL sodium chloride solution. The washed extracts are dried over magnesium sulphate,

Concentrate in vacuo to dryness and purify the residue by silica gel chromatography.

Example..4

J-methyl-6,6-dichloro-pene ilahate-1,1-dioxide

To a solution of 4.09 g (0.01 mol) of iodomethyl-6,6-dichloro-penicillanate in 50 mL of acetone was added

2.5 ml (0.24 mol) of 30% hydrogen peroxide and 1 ml of 0.5M aqueous sodium tungstate solution.

The mixture was heated at reflux for 1 hour and then stirred at room temperature overnight. Evaporation of the solvent gave a crude product which was purified by silica gel chromatography.

Practically the same result is obtained when an aqueous solution of potassium molybdate or zirconium chloride is used instead of sodium tungstate in the above process.

Similarly, the title compound is obtained when methanol, ethanol, isopropanol, methyl ethyl ketone or mixtures thereof with water are used as the solvent in place of acetone and the reaction is carried out at a temperature of from 25 to 60 ° C.

Example 5

Chloromethyl-6-beta-bromopenicllenate-1,1-dioxide

To a solution of 3.52 g (8 mmol) of chloromethyl-6,6-dibromopenicilate-1,1-dioxide in 100 ml of dry benzene was added 2.32 g (8 mmol) of tri-n-butyltin hydride under nitrogen at 0 ° C. . The resulting mixture was stirred at room temperature overnight, then the solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography to give the title compound.

Alternatively, the same product is obtained by using chloro-6,6-dibromopenicenilate as starting material and the resulting sulfide, i.e. chloromethyl-6-beta-bromopenicilanate, as described in Example 2, 2A, 3 or 4 as starting material. oxidizes to the corresponding sulfone.

Example 6

Iodomethyl-6-beta-bromo-penicillanate-1,1-dioxide

A solution of 0.12 g (0.33 mmol) of chloromethyl 6-beta-bromo-penicillanate-1,1-dioxide and 0.25 g (1.66 mmol) of sodium iodide in 5 ml of acetone was stirred at room temperature for 30 hours. The resulting pale yellow suspension is evaporated to dryness, the residue is taken up in 50 ml of ethyl acetate, the solution is sequentially digested twice with 10 ml of water, 10 ml of saturated sodium chloride solution, dried over anhydrous sodium sulphate and evaporated under reduced pressure. This afforded 0.14 g of the title compound as a solid.

@ 1 H-IR (CDCl3): 1.45 (s, 3H), 1.65 (s, 3H), 4.5 (s, 1H),

4.83 (d, 1H), 5.42 (d, 1H), 6.0 (dd, 2H).

Example 7 ·

6-Alpha-Bromo-penicillanic acid 1,1-dioxide

To a mixture of 560 ml of water, 300 ml of dichloromethane and 56.0 g of 6-alpha-bromo-penicillanic acid is added 4N sodium hydroxide solution until a constant pH of 7.2 is obtained, which requires 55 ml of sodium hydroxide. The mixture was stirred at pH 7.2 for 10 minutes, then filtered, the layers were separated and the organic phase was discarded. The aqueous phase is then added rapidly with stirring to the oxidation mixture prepared as described below.

63.2 g of potassium permanganate, 1000 ml of water and 48.0 g of acetic acid are mixed in a 3-liter flask, stirred at 20 ° C for 15 minutes and then cooled to 0 ° C.

After addition of a solution of 6-alpha-bromopenicillanic acid to the oxidation mixture, the reaction mixture placed into a cooling bath at -15 C. ^At an internal temperature of bulging at 15 "C and then drops over 20 minutes at 5 ° C. Sodium metabisulfite (30.0 g) is added over 10 minutes at about 10 DEG C., the mixture is filtered after stirring for 15 minutes and the pH of the filtrate is lowered to 1.2 by addition of 170 ml of 6N hydrochloric acid. The aqueous phase was extracted with chloroform and then with ethyl acetate.

Both the chloroform and ethyl acetate extracts were dried over anhydrous. magnesium sulfate and concentrated in vacuo. From the chloroform solution, 10.0 g (16% yield) of the title compound was obtained. 57 g of an oily material are obtained from the ethyl acetate solution which gives trituration with β hexane to give a white solid. After filtration of the product, it is obtained

41.5 g (66% yield) of the title compound, melting with decomposition at 134 ° C.

Analysis calculated for: C CHH ^ BrNONOS:

30.78% C, 31.05% C,

3.23% H,

3.24% H,

25.60% Br, 25.54% Br,

N, 4.49; H, 4.66;

10.27% N 10.21% S.

Oxidation of 6-.alpha.-chloropenicillanic acid and 6-.alpha.-iodpenicillanic acid with potassium permanganate using the procedure described above gives 6-.alpha.-chloro-penicillanic acid 1,1-dioxide, respectively. 6-.alpha.-Iodopenicilanic acid 1,1-dioxide.

Example

6-beta-Chloro-penicillanic acid 1,1-dioxide

An oxidation solution is prepared consisting of 185 mg of potassium permanganate, 0.063 ml of 85% phosphoric acid and 5 ml of water. This oxidizing solution was added dropwise at a temperature of 0-5 ° C to a solution of 150 mg of sodium 6-beta-chlorophenioilate in 5 ml of water until the mixture remained permanently violet with potassium permanganate. About half of the oxidation solution prepared above is consumed.

The reaction mixture was discolored with potassium permanganate by adding solid sodium bisulfite, filtered, ethyl acetate was added to the filtrate, and the pH was adjusted to 1.8. The layers were separated, the aqueous layer was extracted with ethyl acetate, the combined ethyl acetate phases were washed with water and, after drying, evaporated in vacuo. 118 mg of the title compound are obtained.

NMR (CDCl 3): 5.82 (d, 1H), 5.24 (d, 1H), 4.53 (s, 1H), 1.62 (s, 3H), 1.50 ( s, 3H).

The above product was dissolved in tetrahydrofuran, an equal volume of water was added to the solution, the pH was adjusted to 6.8 with dilute sodium hydroxide, the tetrahydrofuran was evaporated in vacuo and the remaining aqueous solution was lyophilized. Obtained sodium salt of the title compound.

Example 9

6-beta-Bromo-penicillanic acid 1,1-dioxide

To a solution of 255 mg of sodium 6-beta-bromo-penicillanate in 5 µl of water at 0-5 ° C is added a solution prepared with 140 mg of potassium permanganate, 0.11 ml of 85% phosphoric acid and 5 µl of water. The pH is maintained between 6.0 and 6.4 during the addition. The reaction mixture was stirred at pH 6.3 for 15 minutes, then the violet-colored solution was overlaid with ethyl acetate, the pH was adjusted to 1.7 and 330 mg of sodium bisulfite was added.

After 5 min. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate solutions were washed with brine, dried (MgSO4) and evaporated in vacuo. 216 mg of the title compound are obtained as white crystals.

NMR (Deuterium Oxide, δ in ppm): 5.78 (d, 1H, J = 4Hz), 5.25 (d, 1H, J = 4Hz), 4.20 (s, 1H), 1.65 (s, 3H), and 1.46 (β, 3H).

He did

Chloromethyl-6-alpha-chloro-penicillanate

To 2.35 g (0.01 mol) of 6-alpha-chloropenilicenoic acid, in 5.0 ml of water, add 5.0 ml of 2N potassium hydroxide, then add 6.0 g of potassium bicarbonate, 0.34 g (0.001). ml) tetrabutylammonium hydrogen sulfate, 20 ml dichloromethane and 1.64 g (0.011 mol) chloromethyl chlorosulfate, and the resulting mixture was stirred at 25-30 ° C for 2 hours. The reaction mixture is filtered, the layers are separated, the organic phase is dried over sodium sulphate and evaporated to dryness. The title compound is obtained.

Example 11

Chloromethyl-6-alpha-chloro-penicillanate 1-oxide

To a solution of 8.49 g (0.03 mL) of chloromethyl 6-alpha-chloro-penicillanate in 200 mL of chloroform at 0 ° C was added a solution of 6.12 g (0.03 mol) of 3-chloroperbenzoic acid with 100 mL of stirring. chloroform. Stirring is continued for 1.5 hours at 0-5 ° C. The reaction mixture was filtered, washed with sodium bicarbonate solution and water, and dried over sodium sulfate. Evaporation of the solvent in vacuo afforded the crude title compound as a mixture of alpha and beta-sulfoxides, which may optionally be purified by silica gel chromatography.

Alternatively, the title compound can be prepared by oxidizing 6-alpha-chloropenicilic acid with one equivalent of 3-chloroperbenzoic acid in tetrahydrofuran at 0-25 ° C. This oxidation takes about 1 hour and is carried out according to the procedure described by Harrison et al. in Jour. Chem. Soc. (London), Perkin I, 1772 (1976). The resulting 6-alpha-chloro-penicillanic acid 1-oxide is then esterified as described in Example 1 to give the desired chloromethyl ester.

Using the procedure described above, the remaining 6-substituted penicillanic acid and 6,6-dihalo-penicillanic acid esters of Examples 1a, A are converted to the corresponding 1-oxides.

The same compound is obtained by reacting 0.1 mol of chloromethyl 6-alpha-chlorophenilate in 150 ml of isopropanol containing 0.8 ml of 0.5M sodium tungstate or an equivalent amount of potassium molybdate, with 0.1 mol of 30% hydrogen peroxide. The peroxide was slowly added to the remaining reagents at 60 ° C, then allowed to cool overnight with stirring. The product is isolated as described above.

Example 12

Chloromethyl-6-alpha-chlorpenicilenate-1,1-dioxide

To a solution of 2.83 g (0.01 mol) of chloromethyl 6-alpha-chloro-penicillanate in 50 ml of chloroform was added 4.32 g (0.025 mol) of m-chloroperbenzoic acid and the mixture was stirred at room temperature under nitrogen for 36 hours. The solvent was evaporated in vacuo, the residue was partitioned between ethyl acetate and water, pH 6.0, and sodium bisulfite was added until a negative peroxide test was performed. The pH is adjusted to 8.0, the layers are separated, the organic phase is washed with brine, dried over sodium sulfate and evaporated to dryness in vacuo to give the title compound.

Alternatively, the title compound obtained by oxidation of the same starting material in methanol or of ethanol or ethanol containing a catalytic amount of sodium tungstate by the addition of two molar equivalents of hydrogen peroxide at a temperature of 20-60 C. ^In

Example 13

1,1-dioxo-6,6-dibrompenicilanoyloxymethyl-6- (D-2-azido-2-phenylacetamido) penicileate

To a mixture of 0.232 g (0.37 mmol) of tetrabutylammonium 6- (D-2-azido-2-phenylecetamido) penicillanate and 10 ml of acetone was added 0.20 g (0.37 mmol) of iodomethyl-6,6-dibrompenicilate- The mixture was stirred at room temperature for 30 minutes and an additional 50 mg of tetrabutylammonium 6- (D-2-azido-2-phenylacetamido) penicillanate was added and stirring was continued for 30 minutes. The reaction mixture is concentrated to dryness and the residue is applied to a column of 50 g of silica gel, eluting with a mixture of equal volumes of ethyl acetate and hexane, collecting 7 ml fractions. Fractions No. 17-24 are combined and evaporated in vacuo to give 0.14 g (49%) of the desired product as a yellowish oil.

1 H-NMR (CDCl 3, δ S in ppm): 1.4 (s, 3H), 1.5 (s, 3H), 1.59 (s, 3H), 1.62 (s, 3H), 4 4 (s, 1 H), 4.5 (s, 1 H), 4.97 (s, 1 H), 5.04 (s, 1 H), 5.4-5.70 (m, 2 H), 85 (s, 2H); 7.05 (d, 1H); 7.35 (s, 5H).

XC, (in substance): 1810, 1775 cm @ -1.

The starting tetrabutylammonium-6- (D-2-ezido-2-phenylacetamido) penicillanate was prepared as follows:

1 g of sodium (D-2-azido-2-phenylacetamido) -pentilicate, 50 ml of ethyl acetate and ml of water are mixed and the pH is adjusted to 2.0 with 2N hydrochloric acid. The organic layer is separated, washed with 10 ml of chloride solution NaHCO 3 and the solvent was evaporated in vacuo. The foamy residue was dissolved in 30 ml of methylene chloride, 15 ml of water was added, and then a 40% solution of tetrabutylammonium hydroxide was added until the pH of the aqueous phase rose to 8.0.

The organic layer was separated and the aqueous layer was extracted twice with 20 ml of methylene chloride each time. The combined extracts were dried over sodium sulfate and concentrated to dryness. The hard gum residue was triturated twice with 10 ml of ethyl acetate and twice with 10 ml of ethyl ether each time and the resulting off-white solid was air dried. 1.25 g of the desired tetrabutylammonium salt is obtained.

Example 14

1,1-dioxo-6,6-dibrompenicilanoyloxymethyl-6- [D-2-benzyloxycarbonylamino-2- (p-hydroxyoxyphenyl) aceteraido] penicillanate

To a mixture of 101.3 g (0.25 mol) of 6- [D-2-benzyloxycarbonylamino-2- (p-hydroxyphenylacetamido penicillanic acid), 250 ml of water, 500 ml of methylene chloride and 84.8 g (0.25 mol) of tetrebutylammonium- of hydrogen sulphate, cooled to 5 ° C, 125 ml 2N sodium hydroxide was added while maintaining the temperature at 5-10 ° C. The organic phase was separated and the aqueous phase was extracted with methylene chloride, the combined organic layers were dried over sodium sulfate and the solvent was evaporated in vacuo. The residue was dissolved in 1000 ml of ethyl acetate, evaporated in vacuo to a volume of about 300 ml and left in a refrigerator overnight. filtered and dried in vacuo.

To 74.1 g (0.10 mol) of tetrabutylammonium-6- [D-2-benzyloxycarbonylamino-2- (p-hydroxyphenyl) acetamido] penicillanate in 1000 ml of methyl ethyl ketone was added 49.8 g (0.10 mol) of methylsulfonyloxymethyl _T 6,6-dibromopenicillanate 1,1-dioxide and the resulting mixture was stirred for 1 hour at 50 ° C. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate and water. The aqueous layer was separated, washed with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the ethyl acetate in vacuo gave the title compound.

Example 15

1,1-dioxo-6-beta-bromopenicilanoyloxymethyl-6- (D-2-azido-2-phenylacetamido) penicillanate

To a mixture of 0.152 g (0.25 mmol) of tetrabutylammonium (D-2-azido-2-phenylacetamido) penicillanate and 5.0 ml of acetone was added 0.14 g (0.25 mmol) of iodomethyl-6-beta-bromopenicilane- 1,1-dioxide. The resulting colorless mixture was stirred at room temperature for 30 minutes, then the solvent was evaporated in vacuo and the residue was chromatographed on a 25 g silica gel column eluting with a mixture of equal volumes of ethyl acetate and hexane. Fractions of 6 ml are collected at intervals of about 30 seconds. Fractions 13-17 were combined and concentrated in vacuo to give 0.125 g of the desired product as a foam.

¹ H-NMR (CDCl 3, hodnoty5 in ppm): 1.4 Cs, 3H), 1.5 (s, 3H), 1.6 (s, 3H), 1.65 (s, 3H), 4 42 (s, 1H), 4.5 (s, 1H), 4.75 (d, 1H), 5.07 (s, 1H), 5.3 (d, 1H), 5.4-5, 75 (m, 2H), 5.85 (broad s, 2H), 7.1 (d, 1H),

7.35 (a, 5H).

16 (in substance): 1800, 1775 cm -1.

Example 16, 1-Dioxo-6-alpha-bromo-penicilanoyloxymethyl-6- (D-2-azido-2-phenylacetamido) penicillanate

A mixture of 0.308 g (0.5 mmol) of tetrabutylammonium (D-2-azido-2-phenylacetamido) penicillanate,

0.219 g (0.485 mmol) of iodomethyl-6-alpha-bromopenicilate-1,1-dioxide and 1.0 ml of acetone are stirred at room temperature for 30 minutes, then the solvent is evaporated off under vacuum and the residue is chromatographed on a 50 g silica gel column using a mixture. equal volumes of ethyl acetate and hexane as eluent. The product containing fractions were collected and the solvent was evaporated in vacuo to give 0.125 g (38%) of the title compound as an oil.

1 H-NMR (CDCl 3): δ 43 Cs, 3H), 1.5 (s, 3H), 1.6 (s, 3H), 1.66 (s, 3H), 4, 4 Cs, 2H), 4.64 (s, 1H), 5.05 Cs,

1H), 5.1 (dd, 1H), 5.4 to 5.7 (m, 2H), 5/85 (s, 2H), 7.08 (d, 1H), 7.35 (s, 5H).

IR (neat): 1795, 1775 cm ^- '.

Example 17

1,1-dioxopenicilanoyloxymethyl-6- (D-amino-2-phenyl-acetamido) foaming anilate

A mixture of 1.2 g * 5% palladium on calcium carbonate and 30 ml of a mixture of equal volumes of isopropanol and methylene chloride was hydrogenated at 50 psi for 30 minutes and then treated with 0.25 g (0.32 mmol) of 1,1-8 g (0.32 mmol). dioxo-6,6-dibrompenicilanoyloxyniethyl-6- (D-2-azido-2-phenylacetamido) penicillanate dissolved in 3 mL of methylene chloride. The resulting mixture was hydrogenated at 50 psi for 1 hour, then the catalyst was filtered off and washed with 30 ml of a mixture of equal parts of isopropanol and methylene chloride. Concentration of the filtrate in vacuo afforded a reddish brown solid which was triturated with 15 ml of ethyl ether, filtered, washed with 10 ml of ether and air-dried to give 0.195 g of the desired product.

¹ H-NMR (CDCl d in ppm): 1.5 (d, 6H), 1.6 (d, 6H), 3.55 (d, 2H1, 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), 8.1- (a, 1H).

Example 18

1,1-dioxopenicilenoyloxymethyl-6- (D-2-amino-2-phenyl8-acetamido) penieilbnát-hydrobromide

A mixture of 0.125 g (0.17 mmol) of 1,1-dioxo-6-alpha-bromobenzicilanoyloxymethyl-6- (D-2-azido-2-phenyl aoetamido) penicillanate, 10 mL of methylene chloride, 10 mL of isopropanol and 0.35 g of 10 % palladium on carbon was hydrogenated at 50 psi for 75 minutes. The catalyst was filtered off and the filtrate was evaporated in vacuo to an off-white solid which, after trituration with ethyl ether, filtering, washing with ether and drying under nitrogen, afforded 78 mg of the title compound.

K 1

The IC spectrum and the 1 H-NMR spectrum of the product, measured in perdeuterodimethylsulfoxide, are identical to those of an authentic sample.

One hour of hydrogenation of 100 mg of 1,1-dioxo-6-beta-bromopenicilanoyloxymethyl-6- (D-2-ezido-2-phenylacetamido) penicillanate using the above procedure afforded 68 mg of the same product.

Claims (4)

SUBJECT OF THE INVENTION A process for the preparation of 1,1-dioxopenicilanoyloxymethyl-6- (2-amino-2-phenylacetamido) penicillanates of the general formula II in which: R ¹ represents hydrogen or hydroxyl, and their pharmaceutically acceptable acid addition salts, characterized in that a compound of formula I (I) wherein R ¹ has the above meaning, each of X and Z represents chlorine, bromine or iodine, or Y is hydrogen and Z represents chlorine, bromine or iodine and <2 represents a group or NHCOgCHgCgH ^ R ^ wherein R ^ is hydrogen, chlorine or bromine, nitro, methyl or methoxy, are treated with hydrogen in the presence of noble metal catalysts and in the presence of an inert solvent, and the resulting product of formula (II) is optionally converted into its pharmaceutically acceptable acid addition salt by reaction with an acid. 2. A process according to claim 6, wherein Q is Nj or NHCO3CHgCgHg, each of Ϊ and Z is chlorine or bromine, or Y is hydrogen and Z is chlorine or bromine; and as a noble metal palladium catalyst. 3. The process of claim 2, wherein Q is N, each of Y and Z is bromine or Y is hydrogen and Z is 1 is bromo and R is as defined above. 4. A method according to any one of claims 1 to 3, characterized in that the starting material is used in which R ¹ is hydrogen and the other substituents are as defined above.