CS236895B2 - Process for the production of antibacterially active 1,1-alkanediol dicarboxylates - Google Patents

Abstract

The invention describes a process for the preparation of new chemical compounds valuable as antibacterial agents. The invention particularly relates to a process for the preparation of monoesters and diesters of certain 1,1-alkanediol dicarboxylates in which the carboxyl group of penicillin or/and the carboxyl group of certain β-lactamase inhibitors present is esterified. It is known from U.S. Patent No. 4,234,579 that 1,1-dioxide of penicillanic acid (sulbactam) is an effective β-lactamase inhibitor and antibacterial agent. U.S. Patent No. 4,244,951 describes bis-esters of the general formula IX below in which sulbactam is linked to known antibacterially active penicillins via methanediol.

Description

In the above general formula, R 1 represents certain acyl residues contained in the known antibacterially active penicillins. For example, R 1 may be 2-amino-2-phenylacetyl or 2-amino-2- (p-hydroxyphenyl) acetyl.

U.S. Patent 4,342,772, issued Aug. 3, 1982, discloses analogous compounds in which penicillins and β-lactamase inhibitors, such as penicillanic acid 1,1-dioxide, clavulanic acid, and 6/3-halopenicillanic acids are together. linked via 1,1-alkanediol groups.

Further disclosed are compounds of the above formula IX wherein R 1 is a radical of formula

RjtCOO θ- CHCO-NH _Z wherein R Z represents certain alkyl or alkoxy groups.

Ampicillin, i.e. 6- [D- (2-amino-2-phenylacetamido) -penicillanic acid, is disclosed in U.S. Patent No. 2,985,648. Amoxicillin, i.e. 6- [D- (2-amino-2-) p-hydroxyphenyl / acetamido] penicillanic acid is known from U.S. Pat.

No. 192,198 and U.S. Re-U. S. Patent No. 28,744. 2,985,648, 3,520,876 a

No. 053,360 discloses amoxicillin p-acyl derivatives.

2- (3-Acetoxymethyl-2α-ethylpenam-3 H -carboxylic acid 1,1-dioxide) is disclosed as a useful β-lactamase inhibitor in U.S. Pat. No. 4,256,733.

2- (3-Chloromethyl-2H-methylpenam-3α-carboxylic acid 1,1-dioxide) is described as a β-lactamase inhibitor in British Patent Application No. 2,070,592.

Bis-esters of 1,1-alkanedioles with 6-3-hydroxymethylpenicillanic acid 1,1-dioxide are described in U.S. Pat. No. 4,342,768. The corresponding 6α-hydroxymethylpenicillanic acid 1,1-dioxide derivatives and inhibitors (3) are also described. 6-aminoalkylpenicillanic acid 1,1-dioxide lactamases.

The present invention provides a process for the preparation of antibacterially active compounds of the formula I and certain intermediates for their preparation. The antibacterially active compounds of formula I are effectively absorbed from the gastrointestinal tract of a mammal and are then rapidly converted to the penicillin component R _P COOH and / or to the β-lactamase R _B COOH inhibitor component or salts thereof.

The present invention provides a process for the preparation of compounds of formula I

RCOCH2OC = O

II \

O A

RÚCOCHžjnOC ^ O

II o

(i) in which:

A is C 1 -C 8 alkylene, isopropylidene, cyclohexylene or phenylene, n is 0 or 1,

R ¹ and R ¹ are different and R is a radical RP or RB, where n is 0, R ¹ is hydrogen, C 1 -C 4 alkyl, benzyl, CH 2 Cl 2, CH 2 I or tetrabutylammonium, and If n is 1, R ¹ represents a radical R or _B RP

R _P represents a radical of formula

where

R ² represents hydrogen,

where

Q ¹ is hydrogen, amino, N 3, benzyloxycarbonylamino, 4-nitrobenzyloxycarbonylamino or 1-methyl-2-methoxycarbonylvinylamino, and

R ⁴ is hydrogen, hydroxyl, C 2 -C 7 alkanoyloxy, C 2 -C 7 alkoxycarbonyloxy or the radical of formula R ⁵ C ⁶ H ⁴ COO wherein R ⁵ is hydrogen, C 1 -C 6 alkyl, alkoxy 1-4 carbon atoms, fluorine, chlorine or bromine, or cyano; and

R _b represents a radical of formula

where

X ¹ represents a hydrogen atom, CH 2 OH, CH 2 NH 2 or CH 2 NHCOOCH 2 C 6 H 5, and pharmaceutically acceptable cationic salts or acid addition salts thereof, characterized in that the compounds of the general formulas:

RCOOCH2X a

MOC = O

A /

RifCOCH2 CnO4 OO

wherein n, A, R, and R ¹ are as defined above, M represents a carboxyl salt-forming cation, and

X represents a leaving group, reacts in the presence of a polar organic solvent, preferably,, Ν-dimethylformamide, ethyl acetate, dichloromethane or acetone, at a temperature of from 0 to 80 ° C, preferably from 25 to 50 ° C, and then in that R @ ¹ or R @ ¹ contains a substituent selected from the group consisting of azido, benzyloxycarbonylamino or 1-methyl-2-methoxycarbonylvinylamino, it converts the substituent into amino in a manner known per se. and optionally converting the resulting product into a pharmaceutically acceptable cationic salt or acid addition salt.

Pharmaceutically active compounds of the formula I and their salts are those in which, even if n is 0, R @ ^{1 represents a} C1 -C4 alkyl or hydrogen atom, or an alkali metal salt thereof, preferably a sodium salt and potassium, and

b) when n is 1, one of R and R ^{1 is} R _B and the other one is R _P , where R ² and R ⁴ are as defined above and Q ¹ is hydrogen or amino.

Particularly preferred antibacterial agents of this type are those in which n = 0 and R ¹ is hydrogen or a cationic salt or acid addition salts, and those in which n = 1 and R ² is a radical of formula

CHCO i.e. compounds of the following formulas II and III in which R ¹ is hydrogen, and compounds having the following general formula IV

O

II

R _b COCH2OC — O \

A — COOR ¹ (II) o

II

A — COOR ¹ (III)

Particularly preferred are those compounds of formula I wherein A is (CH2), (CH3) 2C, 1,4-cyclohexylene, or phenylene, wherein m is 1-8.

Even more preferred residues in meaning

3-β 8 9 8 of the symbol A are (CH 2) 2, (CH 2) 3, (CH 2) 4, (CH 2 is, C (CH 3) 2, 1,4-phenylene and trans-1,4-cyclohexylene.

Particularly preferred carboxylic acids of formula R _B COOH from which the compounds of the invention are derived are the 1,1-dioxoacids of formula X

COOH fXI in which

X ¹ is as defined above.

Particularly preferred radicals R @ _B are radicals derived from carboxylic acids of the formula X in which X @ ¹ represents a hydrogen atom or a group

CH 2 OH, and especially wherein X ¹ is hydrogen, i.e., residues derived from penicillanic acid 1,1-dioxide.

The invention also relates to compounds of formula IV and the following formula VI

(VI) wherein

R ² represents a radical of formula

4-R ⁴ C ⁶ H ⁴ CH (Q ¹ ) CO.

Particularly preferred radicals R @ ⁴ are hydrogen, hydroxy, acetoxy, tert-butylcarbonyloxy or isobutoxycarbonyloxy.

Particularly preferred radicals Q ¹ in the above-mentioned compounds containing this radical are hydrogen, amino, N 3, benzyloxycarbonylamino and 1-methyl-2-methoxycarbonylvinylamino, with hydrogen and amino being particularly preferred. preferred antibacterial agents produced by the process of the invention.

Other particularly preferred compounds correspond to formulas C and VII

O

238895 where

R 1 represents a hydrogen atom, a C 1 -C 4 alkyl group, a benzyl group, a CH 2 Cl group, a CH 2 group, or a salt-forming cation with a carboxyl group.

Particularly preferred cations are tetrabutylammonium or an alkali metal cation. Preferred alkali metal cations are sodium and potassium cations.

The compounds produced by the process of the invention are valuable as intermediates or as active jerecursors of the respective penicillin or β-lactamase inhibitor contained in the compound of the invention. For example, compounds of the formula V wherein A is as defined above and R ¹ represents an alkyl group having 1 to 4 carbon atoms, hydrogen, or a pharmaceutically acceptable cation are valuable prodrugs preparation sulbactam; a compound of formula VI wherein R ² is a radical of formula

4-R ⁴ C ⁶ H ⁴ CH (Q ¹ ) CO,

R ¹ represents a hydrogen atom or a hydroxyl group, Q ¹ represents an amino group, A is as defined above and R ¹ represents an alkyl group having 1 to 4 carbon atoms or a hydrogen atom, or a pharmaceutically acceptable cationic salt or acid addition salt thereof is useful ; ampicillin precursors (R ⁴ = H 3 or amoxicillin (R ⁴ = OH). Those compounds of formulas V and VI wherein R ¹ is, for example, CH 2 Cl 2, benzyl or tetrabutylammonium, and compounds of formula VI wherein Q ¹ has another meaning also hydrogen or amino is useful as intermediates.

Similarly, those compounds produced by the process of the invention containing both R _b and R _p residues are valuable either as intermediates or as anti-bacterial agents that are effectively absorbed in the gastrointestinal tract of a mammal where they are rapidly converted to practically equimolar amounts of penicillin and β-lactamase inhibitor. which form the components of these compounds. Those compounds of formula I, which contain a free amino group at one or both radicals R _P and R _B as defined above, can form acid addition salts with acids. Such salts with pharmaceutically acceptable acids are within the scope of the invention. Examples of suitable acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, citric acid, malic acid, tartaric acid, maleic acid, fumaric acid, gluconic acid, sugar acid, benzenesulfonic acid, p-toluenesulfonic acid, p-chlorobenzenesulfonic acid and 2-naphthalenesulfonic acid.

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

In penicillanic acid derivatives, the intermittent bonding (....) of the substituent to the bicyclic nucleus indicates that the substituent is below the plane of the nucleus. Such a substituent is designated as having the α-configuration. In contrast, the increased bond (Jtf) of a substituent to a bicyclic nucleus means that the substituent is located above the plane of the nucleus and is referred to as the β-configuration. Binding of a substituent to the bicyclic nucleus, taken by a normal solid line (-), means that the substituent may be in both the οί-configuration and the β-configuration.

The compounds corresponding to formulas (I) to (IX) are named as dicarboxylic acid diesters of formula (I)

HOOC- A-COOH in which

A is as defined above.

For example, a compound of formula VIII below wherein R ¹ is hydrogen, Q ¹ is amino, and A is [CH 2] 2 is referred to as 6- (2-amino-2-phenylacetamido-penticilanoyloxymethyl-1,1- a compound of formula VIII wherein R ⁴ is hydroxy, A is a residue (CH 3 Cl 2 and Q ¹ is an azidoscine) is designated 6- [2-azido-2- (p-hydroxyphenyl Jacetamido) penicilanoyloxymethyl-1,1,1-dioxidenicilanoyloxymethyl succinate -dioxopenicilanoyloxymethyl dimethyl malonate and a compound of formula V wherein R ¹ is benzyl and A is (CH 2) 3 is referred to as benzyl 1,1-dioxopenicilanoyloxymethyl glutarate.

It should further be noted that wherever there are references to compounds containing the penicillin residue R _P as defined above, where R ² is a substituent of the formula

wherein R ⁴ and Q ¹ are as defined above, with the proviso that Q ^{1 is} not hydrogen, unless specifically stated in any case, it is always a compound in which this substituent has a D-configuration.

The compounds of formula I can be prepared in accordance with the invention by a variety of methods known in the art for the synthesis of esters. However, a preferred process is to prepare a salt by condensation of a carboxylic acid salt with a halomethyl ester, wherein the halogen is a leaving group X. Preferred radicals X are chlorine, bromine, iodine, methanesulfonyloxy and p-toluenesulfonyloxy. For example, the following are two general methods of preparation in case n is 1, R is R _p , R ¹ is R _b , R _P is formula

Q ¹ is N 3, C 6 H 8 CH 3 OOCONH, P-NO 2 C 6 H 4 OCONH or

R _b represents a radical of formula

M represents a salt-forming cation on the carboxyl group, preferably sodium, potassium or tetrabutylammonium,

X is as defined above.

1.

RpCOOCH2X +

MOCO \ MX

A ->

/

R _b COCH2OCO

II o

(II ‘)

- (VIII ¹ j - (VIII, Q ⁴ = NH 2) where

236O 9 S

2.

RpCOOCHzOCO \

A 4- R b COOCH 2 ->

of

MOCO (III ‘) (XIII) —MX

-> (VIII *) - (VIII, Q ¹ = NH 2)

In each of the reactions shown above, to the compound of Formula VIII ^1, protected at the amino group, the respective carboxylate salt and halomethyl are contacted in about equimolar amounts in the presence of a polar organic solvent at from about 0 to 80 ° C, preferably from 25 to 50 ° C. Although, as mentioned above, roughly equimolar amounts of reactants are used, it is also possible to use an excess of either the carboxylic acid salt or the halomethyl ester, up to a ten-fold molar excess. A wide variety of solvents can be used for this reaction, but it is usually preferred to use a relatively polar organic solvent to minimize the reaction time. Typical useful solvents include Ν, Ν-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, ethyl acetate, dichloromethane, acetone, and hexamethylphosphoric triamide. The time required to complete the reaction virtually varies depending on a number of factors, such as the nature of the reactants, the reaction temperature, and the solvent. Typically, however, reaction times ranging from about 10 minutes to 24 hours are used at about 25 ° C.

The resulting desired amino-protected compound of formula (VIII) is then isolated in a manner known per se. For example, the reaction mixture is taken up in a water-immiscible solvent such as ethyl acetate, chloroform or dichloromethane, the organic solution is washed with water and brine, and dried. Evaporation of the solvent yields an intermediate of formula (VIII) which may optionally be purified, for example by chromatography on silica gel.

The cleavage of the amino function of the intermediate of formula (VIII ⁾ is carried out by methods known per se [see, for example, Gross et al., "The Peptides, Analysis, Synthesis, Biology", Academic Press, New York, NY, Vol. 3, 19811, but bearing in mind the lability of the β-lactam ring and ester linkages. For example, when Q ¹ is L-methyl-2-methoxykarbonylvinylaminoskupmu may be protecting group (l-Methyl-2-methoxykarbonylvinylovou group] cleaved by simply reacting the formula VIII compound ¹ with one equivalent of a strong aqueous acid such as hydrochloric acid in an inert solvent at a temperature in the range of from -10 to 30 [deg.] C. According to a typical embodiment, the intermediate enamine is treated with one equivalent of hydrochloric acid in aqueous acetone, and the reaction is usually completed in a short time, for example within 1 hour. then evaporated in vacuo and the acetoacetate methyl-N, a byproduct, was removed by extraction with ether. the resulting compound of formula VIII (Q ^l - NH) was then recovered by lyophilization as its hydrochloride.

Intermediate compounds of formula VIII wherein Q ¹ is azido or benzyloxycarbonylamino can then be converted to the corresponding amino compound (VIII, Q ¹ = NH 2) by subjecting this intermediate of formula VIII to conventional catalytic hydrogenolysis. This intermediate is stirred or shaken under a hydrogen atmosphere or optionally in a mixture of hydrogen with an inert diluent such as nitrogen or argon in the presence of a catalytic amount of a hydrogenolysis reaction catalyst. Suitable solvents for this hydrogenolysis are lower alkanols such as methanol and isopropanol, ethers such as tetrahydrofuran and dioxane, low molecular weight esters such as ethyl acetate and butyl acetate, chlorinated hydrocarbons such as dichloromethane and chloroform, water and mixtures of these solvents. Typically, solvents and conditions under which the starting material is soluble are chosen. The hydrogenolysis is generally carried out at a temperature in the range of from 0 to 60 ° C, at a pressure of from 1 to 10 bar, preferably at a pressure of from 3 to 4 bar. In the hydrogenolytic reaction, catalysts known to be suitable for this type of transformation are used as catalysts. Typical examples are nickel and noble metals such as palladium, platinum and rhodium. The catalyst is usually used in an amount of from 0.5 to 5.0, preferably about 1.0 times the weight of the intermediate of formula VIII. It is often expedient to apply the catalyst to an inert support. A particularly suitable catalyst is palladium on an inert support such as coal.

objako sloučeVIII invention, in the compounds of Sahu kteZbývajici penicillin radical R _P, compounds of Formula III, VI, VII or REM R is a residue ^of formula

C6H5OCH2CO or

Q?

where Q ¹ represents a hydrogen atom and which do not contain an amino group in the radical R _B , are prepared, for example, by the same methods as above, except that the final reaction step of the deprotection of the amino function is obviously not necessary.

Intermediates of formula (II) may be obtained, for example, by the method illustrated below.

—MX

C6H5CH2OCO-A-COOM + R _B COzCH2X (XVII) (XIII)

C6H5CH2OCO \ H2

A - + / catalyst

RbCOOCH2OCO (II, R1 = C6H6CH2)

HOOC \ M ⁺

A Z

RbCOOCH2OCO (II, R1 = H)

Mooc \ -MX ² A / R _B ² XCH2X COOCH2OCO (II ')

XCH2OCO \

AND

OF

RbCOOCHžOCO (II ')

In the formulas shown in this scheme, A, Β, M and X are as defined above and X ² is X or a more easily cleavable group than X, for example when X is chlorine, X ^{2 can} be chlorine, bromine, iodine , chlorosulfonyloxy, methanesulfonyloxy or p-toluenesulfonyloxy. Particularly preferred radicals represented by X ² are bromine and iodine.

The first reaction step in the above reaction scheme wherein the benzyl polyester salt is reacted with 1,1-dioxopenicillanic acid halomethyl ester to give compounds of formula II wherein R 1 is benzyl is carried out as described above for the preparation of intermediates of general formula I of formula VIII.

Selective cleavage of the benzyl group is usually accomplished by catalytic hydrogenolysis using the same methods and conditions as described above for the conversion of compounds of formula VIII wherein Q ¹ is azido or benzyloxycarbonylamino to the corresponding compounds of formula VIII of the invention wherein Q ¹ is amino . A particularly preferred process consists in using palladium on carbon as the catalyst and tetrahydrofuran or ethyl acetate as the solvent, and operating at a pressure of 0.3 to 0.4 MPa. The carboxylic acid of formula II wherein R 1 is hydrogen can then be isolated by standard methods or conveniently reacted with an appropriate base to form the corresponding salt of formula II 'wherein M is a salt-forming cation as defined above on the carboxyl group. A preferred method for obtaining the sodium or potassium salts of formula (II ') is to use the sodium or potassium salt of 2-ethylhexanoic acid as the base. Usually, the carboxylic acid of formula II is dissolved in ethyl acetate, an equimolar amount of sodium (or potassium) 2-ethylhexanoate is added with stirring, the precipitated salt of formula ΙΓ is filtered off and washed.

Salts of formula II ‘in which M is a tetrabutylammonium radical can be obtained from the corresponding acid or its sodium or potassium salt. Thus, for example, the carboxylic acids of the general formula II are usually reacted with an equimolar amount of tetrabutylammonium hydroxide in the presence of a water-immiscible organic solvent, preferably chloroform. The solvent layer was separated and the product was isolated by evaporation of the solvent.

The intermediates of formula (II ') are obtained by eliminating the elements of compound MX ( ²⁾ in the reaction of the corresponding compounds of formula (II') and formula (XCH ² X ²⁾ wherein Μ, X and X ² are as defined above. This reaction is carried out under the same conditions and methods described above for the preparation of intermediates of formula VIII.

Intermediates of formula III can be obtained using the same methods and conditions as described above for the preparation of intermediates of formula II, but using analogous penicillin derivatives of the general formula RpCOOCr x X instead of compounds of the formula R _D COOCH 2 X as illustrated in the following reaction scheme.

—MX

C6H5CH2OCO-A-COOM + R _P CO2CH2X (XVII j (XII)

H2

- RpCOžCHžOCO CO2CH2C6H5-A (III, R ¹ = CH 2 CeH5) catalyst

23B895

M +

- R _P CO2'CH2OCO — A — COOH ->

(III, R 1 = H, Q ¹ / NH ² ) —MX ²

-> RpCOžCHsOCO-A-COOM (III, R = M, Q NHZ) XCH; X ² -> RpCOžCHžOCO COOCHzX-A (III, R = CHaX Q ¹ NHžj

In the formulas shown in this scheme, A, Μ, X, X ^2, and R _{P are} as defined above. The amine protecting group may be cleaved as described above to convert the intermediate compounds of formula VIII to amino compounds of the same formula.

Those compounds in which ^R4 is as defined above, acyloxy or alkoxycarbonyloxy group may be prepared using the appropriate p-hydroxyaniline or p-acylamoxicilinu alkoxykarbonylamoxicilinu prepared for example by acylation of 6-aminopenicillanic acid, the appropriate acid of the formula ^{R O> _? HC00H} ť

in which

Q ¹ is as defined above and

R ⁴ is formyloxy, alkanoyloxy or alkoxycarbonyloxy, or a carboxyl-activated derivative thereof, by the methods described in U.S. Patent 4,053,369. Alternatively, intermediates of formula VIII * and their precursors of formulas VI and XIII, wherein R ⁴ is OH, prepared as described above and the intermediate of formula VIII 'in which R ⁴ is hydroxy, acyl or alkoxycarbonyl then give the corresponding compound of formula VIII wherein R ⁴ is formyloxy, alkylcarbonyloxy or alkoxycarbonyloxy.

Acylation or alkoxycarbonylation of an intermediate of formula (VIII ⁾ wherein R ⁴ is hydroxy and Q ¹ is as defined above may be accomplished, for example, by reaction of the above compound of formula (VIII ⁾ with an appropriate acid chloride, acid anhydride or mixed anhydride. The reaction is usually carried out in the presence of an inert solvent system. According to a typical embodiment, 0.5 to 2.0 molar equivalents, preferably about 1 mol equivalents of the respective acid chloride or acid anhydride, are contacted with an initial compound of formula VIII wherein R ⁴ is hydroxy in an inert a solvent, in the presence of a tertiary amine, at a temperature ranging from -10 to 30 ° C. Inert solvents which can be used in this acylation are chlorinated hydrocarbons such as chloroform and dichloromethane, ethers such as diethyl ether and tetrahydrofuran, low molecular weight esters such as ethyl 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, and mixtures of these solvents. The tertiary amine is usually used in an amount equivalent to that of the starting chloride or acid anhydride. Typical useful tertiary amines are triethylamine, tributylamine, diisopropylethylamine, pyridine and 4-dimethylaminopyridine.

In addition, the compounds of formulas II to VI in the form of free carboxylic acids and in the form of salts wherein R ¹ is hydrogen or an alkali metal cation such as sodium or potassium are useful intermediates for the production of antibacterially active compounds of formula I wherein n has a value of 1, are also useful precursors of β-lactamase inhibitors of the formula R _B COOH or a penicillin of the formula R _P COOH, in which R _B and R _P are as defined above. Particularly preferred β-lactamase inhibitors are compounds of formula V wherein R ¹ is hydrogen, sodium or potassium, and A and R ¹ are as defined above, which are useful precursors of penicillanic acid 1,1-dioxide (sulbactam).

Similarly, penicillin derivatives of formula VI wherein R ¹ is hydrogen, sodium or potassium and R ² is 2,6- (CH ² O) 2 C ³ H ³ CO, C ⁶ H ⁵ OCH 2 CO or 4-R ⁴ -C ⁶ H ⁴ CH (NH 2) CO, and pharmaceutically acceptable addition salts of such compounds in which R ² has the latter meaning, are useful precursors of the corresponding penicillins. Particularly preferred compounds are those compounds of formula VI wherein R ² represents a radical of formula

NH _2, and especially those in which R ⁴ is hydrogen or hydroxy, which are useful precursors of the well known antibacterial agents ampicillin and amoxicillin.

The compounds of formula I which contain a free amino group may form acid addition salts, which salts are also within the scope of the invention. Said acid addition salts are prepared by standard methods known in penicillin chemistry, for example by mixing a solution of a compound of formula I in a suitable solvent, for example water, ethyl acetate, acetone, methanol, ethanol or butanol, with a solution containing the stoichiometric equivalent of acid. If the salt precipitates, it is isolated by filtration. Alternatively, the salt may be isolated by evaporation of the solvent or, in the case of aqueous solutions, by lyophilization. Of particular interest are salts with sulfuric, hydrochloric, hydrobromic, nitric, phosphoric, citric, tartaric, pamoic, perchloric, sulfosalicylic, benzenesulfonic, 4-toluenesulfonic and 2-naphthalenesulfonic acids.

The compounds of the formula I and their salts can be purified by methods customary in penicillin chemistry, for example by recrystallization or chromatography, taking into account the instability of the [beta] -lactam ring system and the ester linkages.

As mentioned above in the description of the prior art, numerous β-lactamase inhibitors used as starting materials for the synthesis of the compounds of the invention are known in the art. 6'-Hydroxymethylpenicillanic acid 1,1-dioxide is prepared by reacting benzyl 6,6-dibromopenicenilate with tert-butyllithium or tert-butylmagnesium chloride in an inert solvent at a temperature of from -70 to -20 ° C. The resulting enolate is then treated with formaldehyde and the resulting mixture of isomeric benzyl 6-bromo-6-hydroxymethylpenicilanes is isolated. This mixture is oxidized to the corresponding 1,1-dioxide, for example using an organic peracid such as m-chloroperbenzoic acid. The isolated sulfone is hydrogenated in the presence of palladium to a calcium carbonate catalyst to provide the desired sulfone of 6α-hydroxymethylpenicillanic acid.

As mentioned above, 6/3-hydroxymethylpenicanoic acid sulfone is disclosed in U.S. Patent 4,342,768 issued August 3, 1982.

A preferred process for preparing 7-aminomethyl- and 6- (1-amino) ethylpenicillanic acid 1,1-dioxide is also starting from benzyl 6,6-dibromopenicenilanes. This starting material is reacted briefly with 1 mol equivalent of methyl magnesium bromide in an ether solvent at a temperature of from -100 to -50 ° C. The resulting Grignard reagent is contacted with about 0.5 mol equivalents of benzyloxycarboxamidomethyl acetate or 1-benzyloxycarboxamidoethyl acetate at the above temperature for about 0.5 to 2 hours to give a mixture of epimers such as benzyl 6-bromo-6-benzyloxycarbonylaminomethylpenicilate. This mixture is reacted in the next step or separated by column chromatography. In the next reaction step, the bromine atom is cleaved, for example by halogenolysis with tri-n-butyltin hydride, optionally in the presence of a small amount of free radical initiator, preferably 2,2'-azobisisobutyronitrile, in a hydrocarbon solvent such as benzene or toluene at 60 to Mp 100 ° C. The 6β-benzyloxycarbonylaminomethylpenicillanic acid ester is then isolated by crystallization (optionally using a mixture of epimers as starting material) and the 6α-epimer is obtained by evaporating the mother liquor and chromatographing the residue. The epimeric sulfides are then oxidized to sulfones, for example as described above for 6-hydroxymethylpenicilanes and the benzyl protecting groups are removed by standard hydrogenolytic methods.

When the therapeutic application of a salt of an antibacterially active compound of the invention is contemplated, a pharmaceutically acceptable salt is required, but non-pharmaceutically acceptable salts can be used for a number of purposes, including isolation and purification of certain compounds, as well as converting pharmaceutically acceptable salts into the corresponding compounds which are not in the form of salts.

Compounds of formula I according to the invention wherein n is 1, one of R and R ¹ is R _B and the other of R _P as defined above, R ² is 2,6-dimethoxybenzoyl, phenoxyacetyl group or a 4-R ⁴ C6HdCHCO, Pril

NH2 appropriate carboxylic acid, the lower alkyl esters and alkali metal salts of Formula II or V, as well as carboxylic acids, lower alkyl esters and alkali metal salts of formula VI wherein R ² is 2,6-dimethoxybenzoyl, phenoxyacetyl or the radical of formula 4-R ⁴ C ⁶ H ¹ CHCO, as well as the acid addition salts of those compounds containing a free amino group, generally exhibit antibacterial activity in mammals in vivo. This activity can be demonstrated by standard methods used with penicillin type compounds. For example, the aforementioned compound of formula I, II, V or VI 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 1 to 10 times the LD10 dose (the minimum inoculum dose required to reliably kill 100% of the control mice). Upon completion of the assay, the efficacy of the test substance is evaluated by counting the surviving mice that have been infected with bacteria and treated with the compound of the invention. The antibacterially active compounds of the formula I as well as the carboxylic acids, esters and salts with the alkali metals of the formulas II, V and VI are:

23S893

Z1 can be administered either orally or subcutaneously.

Because of the in vivo activity of the antibacterially active compounds of the invention, these compounds can be used to combat bacterial infections in mammals, including humans, by both oral and parenteral routes of administration. The disclosed compounds can be used to combat infections caused by human susceptible bacteria.

A compound of the invention, for example, one of the compounds of formula VIII wherein Q ¹ is amino and R ^{4 is} not hydrogen, is cleaved to 6-β-amino-2- (4-hydroxyphenyl) after oral or parenteral administration to a mammal. acetamido] penicillanic acid (amoxicillin) and penicillanic acid 1,1-dioxide (sulbactam). Sulbactam then acts as an inhibitor of β-lactamase and increases the antibakierial activity of amoxicillin. Similarly, a compound of formula VIII wherein R ⁴ is hydrogen is cleaved to 6- (2-amino-2-phenylaeetamido) penicillanic acid (ampicillin) and sulbactam. Antibacterial compounds of formula I can therefore be used for combating bacteria sensitive to roughly equimolar mixture of penicillin, R _p COOH and RbCOOH, for example a mixture of amoxicillin and sulbactam for the compound of formula VIII, wherein Q ¹ is amino and R ⁴ represents a hydroxyl group or ampicillin and sulbactam when odpovídadjící compound wherein R ⁴ is hydrogen. Examples of such bacteria include susceptible strains of Escherichia coli and Staphylococ cus anreus.

The carboxylic acids of the formula II, in particular those corresponding to the general formula

their alkyl esters having 1 to 4 carbon atoms in the alkyl moiety, and alkali metal salts, especially sodium and potassium salts, are useful as orally or parenterally applicable sulbactam precursors and can therefore be used therapeutically as β-lactamase inhibitors, such as described for sulbactam in U.S. Pat. No. 4,234,579.

Antibacterially active carboxylic acids, esters and salts of the general formula VI as defined above, in particular substances corresponding to the general formula XX

-Ά-COOH their C 1 -C 4 alkyl esters, and their pharmaceutically acceptable acid addition salts and cationic salts, are useful as orally and parenterally applicable precursors of amoxicillin (when R ^{4 is} other than hydrogen) and ampicillin ( when R ^{4 is} hydrogen).

Examples of pharmaceutically acceptable acid addition salts of the compounds of formula (I) having a free amino group in Q ¹ or X ¹ include hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, succinic, lactic, tartaric, citric, gluconic, sugar salts. , benzenesulfonic, p-toluenesulfonic, p-chlorobenzenesulfonic and 2-naphthalenesulfonic.

Examples of pharmaceutically acceptable cationic carboxylic acid salts of formulas II, III, V or VI include alkali metal salts such as sodium and potassium salts, as well as ammonium salts and salts with pharmaceutically acceptable amines such as N-methylglucamine, N, N-dibenzylethylenediamine, ethanolamine and procaine.

The above precursors of formulas II and III in which R @ ¹ represents a C1 -C4 alkyl group or hydrogen, and their pharmaceutically acceptable salts, can also be applied as a physical mixture of the two compounds, the weight ratio of the components in such mixture being ranging from about 1: 3 to 3: 1. These compositions, after oral or parenteral administration to a mammal, also cleave into mixtures of β-lactamase (R _B COOH) and penicillin (R _P COOH) inhibitors.

The in vivo test described above can be used to determine whether the respective strain of Escherichia coli or Staphylococcus aureus is sensitive to a given compound or mixture.

Alternatively, for example, the minimum inhibitory concentration of a mixture of equal parts of amoxicillin and sulbactam or ampicillin and sulbactam can be measured. Minimum inhibitory concentrations can be measured by the procedure recommended by the International Collaborative Study of Antibiotic Sensitivity Testing [Ericcson and Sherris, Acta. Pathologica et Microbiologia Scandinav, Supp. 217, section B: 64-68 (1971)], using brain-heart infusion agar and re-inoculation equipment, using 100-fold diluted contents of overnight culture tubes as standard inoculum. 000 to 10,000 cells (about 0.002 ml, each dish containing 20 ml brain and heart infusion agar) using 12-fold dilutions of the test compound with an initial test compound concentration of 200 µg / ml. The lowest 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 the antibacterially active compounds of the invention or their salts are used in mammals, particularly humans, the compound may be administered either alone or mixed with other antibiotic active substances 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 agent 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 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 the dosage contemplated.

Common carriers for the preparation of tablets for oral administration 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 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 from 2000 to 4000. For the preparation of aqueous suspensions for oral administration, the active ingredient is combined with emulsifiers and suspending agents, with the addition of sweeteners. 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.

As mentioned above, the antibacterially active compounds of the present invention are used in human medicine and their daily dosage 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 the invention 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 usually being administered 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. To measure NMR spectra, solutions in deuterated chloroform (CDCl3) or deuterated dimethylsulfoxide (DMSO-d6) are used, and signal positions are expressed in ppm values over tetramethylsilane. Signal shapes are indicated by the following abbreviations:

s = singlet d = doublet t = triplet q = quartet m = multiplet dd = double doublet ss - wide singlet

Example 1

Monobenzyl esters of dicarboxylic acids

A. Trans-1,4-cyclohexanedicarboxylic acid monobenzyl ester

To a solution of 1.0 g (2.8 mmol) of dibenzyl trans-1,4-cyclohexanedicarboxylate in 20 ml of warm tert-butanol is added a solution of 1.9 g of potassium hydroxide in 10 ml of tert-butanol. After stirring overnight at room temperature, the cloudy reaction mixture was freed from solvent by evaporation, the residue was taken up in water and acidified first to pH 5.3 and after 30 minutes to pH 5.25. Acidification is carried out with dilute hydrochloric acid. The precipitated solid product is filtered off, redissolved in dilute sodium bicarbonate solution and the pH is

236893 resets to 5.25 to precipitate the purified monoester.

@ 1 H-NMR (DMSO-d6, .delta. in ppm): 1.1-2.3 (m, (10H), 5.1 (s, 1H), 7.35 (s, 5H). terephthalate

To a warm solution of 10 g of dibenzyl terephthalate in 200 ml of t-butanol is added a solution of 1.9 g of potassium hydroxide in 103 ml of t-butanol and 10 ml of water. The resulting mixture was stirred at room temperature for 60 hours, then the solvent was evaporated in vacuo, the residue was taken up in water, acidified to pH 5.3 and worked up analogously to Part A. The desired monoester melting at 178% was obtained in 56% yield. Deň: 32 ° C.

1 H-NMR (DMSO, δ in ppm): 5.3 js, 2H, 7.4 js, 5H), 8.1 (s, 4H).

IR: absorption maxima at 1690 and 1710 cm ^1st

g of dibenzyl terephthalate in 225 ml of benzyl alcohol containing an equimolar amount of potassium hydroxide is saponified by stirring overnight at room temperature. After trituration with ethyl ether, the monobenzyl terephthalate potassium salt was obtained in 75% yield.

Example 2

Cis-1,2-Cyclohexanedicarboxylic acid monobenzyl ester

To a solution of cis-1,2-cyclohexanedicarboxylic anhydride [0.10 mol] in 200 ml of toluene was added dropwise a solution of 10.8 g (0.10 mol of benzyl alcohol in 50 ml of toluene) dropwise. The reaction mixture was heated to 60 ° C for 1 hour, the solvent was evaporated to a small volume, the residue was cooled and the precipitated solid monoester was filtered off.

Alternatively, the reaction mixture in toluene is treated with an equimolar amount of ethanolic potassium hydroxide solution to give the monobenzyl ester potassium salt. The sodium salt is obtained in an analogous manner using methanolic sodium hydroxide solution.

The above-described dicarboxylic anhydrides yield the corresponding monobenzyl esters or their sodium or potassium salts:

succinic anhydride glutaric anhydride (refluxing in toluene overnight) cis-1,2-cyclohutanedioic anhydride violet anhydride 1,2-naphthalenedicarboxylic acid anhydride

3,4-furamic acid

2,3-pyridinedicarboxylic acid

2,3-pyrazinedicarboxylic acid.

Example 3

Benzyl 1,1-dioxopenicilanoyloxymethyl succinate ^Γ .

To a mixture of 9.2 g (0.044 mol) of benzyl succinic acid, 200 ml of chloroform and 25 ml of water was added, with vigorous stirring, a 40% aqueous solution of tetrabutylammonium hydroxide up to pH 8.5. The chloroform layer was separated and the aqueous layer was extracted once with 100 ml of chloroform. The combined chloroform phases are dried over sodium sulphate and concentrated to an oily residue in vacuo, treated with 200 ml of toluene and added with 16.2 g (0.044 mol) of iodomethyl-penicillanate-1,1-dioxide. The resulting filtrate was washed once with 100 ml of saturated sodium bicarbonate solution, once with 100 ml of water and once with 100 ml of sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Concentrate in vacuo to an oily residue which is chromatographed on 1 kg of silica gel using a mixture of equal volumes of ethyl acetate and hexane. 8.5 g (43%) of a white solid are obtained.

1 H-NMR (CDCl 3, δ in ppm): 1.45 (s, 3H), 1.63 (s, 3H), 2.77 (s, 4H), 3.47 (d, 2H), 4.43 (s, 1H), 4.62 (t, 1H), 5.17 (s, 2H), 5.84 (AB quartet, 2H), 7.4 (s, 5H).

The following compounds are also prepared in an analogous manner from the corresponding monobenzyl ester:

(a) Benzyl 1,1-dioxopenicilanoyloxymethyl glutarate

The product resulted in a yield of 61%.

@ 1 H-NMR (CDCl3, .delta. in ppm): 1.42 (s, 3Hj, 1.6 (s, 3H), 1.8-2.2 (m, 2H), 2.28-2.68 (m 4H1, 3.45 (d, 2H), 4.4 (s, 1H), 4.6 (t, 1H), 5.14 (s, 1H), 5.8 (AB quartet, 2H), 7 37 (s, 5H).

b j Benzyl 1,1-dioxopenicilanoyloxymethyl adipate

The product resulted in a yield of 47%.

¹ H-NMR (CDCl 3, δ in ppm), 1.46 (s, 3H), 1.63 (s, 3H), 1.53-1.86 (m, 4H), 2.22-2, Δ (m, 4Hj, 3.46 (d, 2H), 4.42 (s, 1H), 4.6 (t, 1H), 5.13 (s, 2H), 5.82 (AB quartet, 2H) 7.33 (s, 5H).

238193 c) Benzyl 1,1-dioxopenililanoyloxymethyl dimethyl malonate

The product resulted in a yield of 73.8%.

⁴ H-NMR (CDCl 3, δ in ppm): 1.4 (s, 3H), 1.53 (s, 9H), 3.45 (d, 2H), 4.4 (s, 1H), 4, 56 (t, 1H), 5.22 (s, 2H), 5.78 (AB quartet, 2H), 7.35 (s, 5H).

d J Benzyl-1,1-dioxopenicilanoyloxymethyl malonate

The product resulted in a yield of 45%.

1 H-NMR (CDCl 3, δ in ppmj: 1.43 (s, 3H), 1.6 (s, 3H), 3.46 (d, 2H, 3.53 (s, 2H), 4.42 (s) s, 1H), 4.6 (t, 1H), 5.2 (s, 2, H), 5.85 (AB quartet, 2H), 7.39 (s, 5H).

IR (Nujol): 1795, 1790 ^cm-first

e) Benzyl-1,1-dioxopenicllanoyloxymethylsebacate

The product resulted in an oily form in a yield of 51%.

⁴ H-NMR (CDCl 3, δ in ppm): 1.2-1.9 (m, 18H), 2.1-2.5 (m, 4H), 3.4 (d, 2H), 4, 4 (s, 1 H), 4.6 (t, 1 H), 5.1 (s, 2 H), 5.8 (q, 2 H),

7.3 (s, 5H).

f) Analogously, the remaining monobenzyl esters of Examples 1 and 2 are converted to the corresponding compounds of formula

C _e H _£ ^ CH OC = 0 wherein A is as defined for the starting monobenzyl.

Example 4

Sodium 1,1-dioxopenicilanoyloxymethyl succinate

To a suspension of 4 g of 10% (w / w) palladium on carbon in tetrahydrofuran was added a solution of 8.4 g (0.019 mol) of benzyl 1,1-dloxopenicilanoyloxymethyl succinate in 75 ml of tetrahydrofuran, and the mixture was shaken in a hydrogenation apparatus under hydrogen pressure. 0.352

MPa. After 30 minutes, the catalyst is removed by filtration through a filter aid, the filter cake is washed with 75 ml of tetrahydrofuran, the combined filtrates are concentrated in vacuo and the residue is taken up in 75 ml of ethyl acetate. To the resulting solution was added 3.07 g (0.019 mol) of sodium 2-ethylhexanoate with stirring. After 15 minutes, the precipitate formed is filtered off, washed with diethyl ether and dried under nitrogen to give

6.8 g (95%) of a white solid.

The following sodium salts were prepared in an analogous manner, except that in cases where no precipitate formed upon addition of sodium 2-ethylhexanoate, precipitation was accomplished by addition of ether.

(a) Sodium 1,1-dioxopenicilanoyloxymethyl glutarate

The product resulted in 93% yield.

1 H-NMR (D 6, δ in ppm): 1.48 (s, 3H), 1.63 (s, 3H), 1.6-2.7 (m, 6H), 3.22-3.98 ( m, 2H), 4.68 (s, 1H), 4.8-5.13 (m, 1H), 5.86 (AB quartet, 2H).

b) Sodium 1,1-dioxopenicilanoyloxymethyl adipate

The product resulted in a yield of 79%.

¹ H-NMR (D 2 O, δ in ppm): 1.46 (s, 3H), 1.63 (s, 3H), 1.44-1.8 (m, 4H), 2.1 to 2, Δ (m, 4H), 3.1-3.96 (m, 2H), 4.56-4.76 (signal for HOD, covering C3-H), 5.0 to 5.16 (m, 1H) 5.92 (AB quartet, 2H).

c) Sodium 1,1-dioxopenilcilanoyloxymethyl dimethyl dimethyl malonate

The product resulted in a yield of 94.5% (recrystallization from ethyl acetate / hexane gave needle-like crystals).

@ ¹ H-NMR (D2 O, .delta. In ppm): 1.33 (s, 6H), 1.44 (s, 3H), 1.58 (s, 3H), 3.16-3.9 (m, 2H), 4.65 (s, 1H), 4.93-5.1 (m, 1H), 5.93 (AB quartet, 2H).

IR (nujol): 1780 cm ^1st

. d) Sodium 1,1-dioxopenicilanoyloxymethyl malonate

The product resulted in a yield of 88%.

@ ⁴ H-NMR (D2 O, .delta. In ppm): 1.45 (s, 3H), 1.6 (s, 3H), 3.2-3.93 (m, 2H), 4.66 (s, 1H), 4.96-5.13 (m, 1H), 5.88 (AB quartet, 2H).

It has been found that the hydrogen atoms in the CH2 group in the malonate residue are exchanged with D2Q,

236893

e) Sodium 1,1-dioxopenicilanoyloxymethyl sebacate

The product resulted in 80% yield.

@ ⁴ H-NMR (D2 O, .delta. In ppm): 1.2-1.7 (m, 18H), 2.15 (t, 1H), 2.45 (t, 2H), 3.45 (d, 1H), 3.65-3.75 (dd, 1H), 4.75 (s, 1H), 5.15-5.25 (m, 1H), 5.8-6.0 (dd, 2H) .

IR (KBr): 1570, 1770, 1800 cm -1

f) The remaining benzyl esters prepared in Example 3 were hydrogenated and converted to the corresponding sodium salts as described above. The corresponding potassium salts are obtained by using potassium 2-ethylhexanoate in the above procedure.

Example 5

A. Chloromethyl 6- [D- (2- (1-methyl-2-methoxycarbonylvinylamino) -2-phenylacetamido)] penicillanate

To 42.9 g (0.062 mol) of tetrabutylammonium 6- [D- (2- (1-methyl-2-methoxycarbonylvinylamino) -2-phenylacetamido)] penicillanate was added 500 ml of chloroiodomethane, the mixture was stirred at room temperature for 1 hour. then thicken. The residue is chromatographed on 1 kg of silica gel, eluting with a mixture of ethyl acetate and hexane (80:20 by volume), collecting 75 ml fractions. Fractions 5-13 were combined and evaporated to dryness to give a yellow oil which was re-chromatographed. Elution with a mixture of equal volumes of the above solvents afforded 30.6 g (80 percent) of the desired chloromethyl ester as a foam.

⁴ H-NMR (CDCl 3, δ in ppm): 1.5 (s, 3H), 1.57 (s, 3H), 1.9 (s, 3H), 3.65 (s, 3H), 4 4 (s, 1H), 4.65 (s, 1H), 5.12 (d, 1H), 5.42-5.7 (m, 2H), 5.75 (double d, 2H, 6.8) (d, 1H), 7.4 (s, 5H), 9.35 (d, 1H).

B. Iodomethyl-6- [D- (2- (1-methyl-2-methoxycarbonylvinylamino) -2-phenylacetamido)] penicillanate

4.96 g (10 mmol) of the above chloromethyl ester are mixed with 7.5 g (50 mmol) of sodium iodide in 50 ml of acetone, stirred overnight and then concentrated to dryness. The residue is taken up in 150 ml of ethyl acetate, the solution is washed three times with 50 ml of water each time and once with 50 ml of sodium chloride solution, dried over sodium sulfate and concentrated. 6.0 g of product are obtained in the form of a pale yellow foam. Trituration of this material with petroleum ether gave 5.2 g (89%) of a pale yellow solid.

C. When tetrabutylammonium-6- [D- (2- / 1-methyl-2-methoxycarbonylvinylamino) -2- (4-hydroxyphenyl) acetamido] penicillanate is used as the starting material in the above reactions, with cosolvent as the starting material in Part A, dimethylformamide is used to give the iodomethyl ester of the corresponding amine derivative of amoxicillin.

Example 1 a d 6

1,1-dioxopenicilanoyloxymethyl-6- [D- (2- (1-methyl-2-methoxycarbonylvinylamino) -2-phenylacetamido)] penicilanoyloxymethyl-trans-1,4-cyclohexanedicarboxylate

A mixture of 2.33 g (3.97 mmol) of sodium-1,1-dioxopenicilanoyloxymethyl-trans-1,4-cyclohexanedicarboxylate, 1.72 g (3.97 mmol) of iodomethyl-6- [D- (2- / 1- of methyl 2-methoxycarbonylvinylamino (2-phenylacetamido) -penicillanate and 40 ml of dimethylformamide are stirred at room temperature for 5 minutes. The reaction mixture was diluted with ethyl acetate, washed three times with a small amount of water and once with brine, dried over sodium sulfate, and the solvent was evaporated in vacuo. The residue was chromatographed on a silica gel column using a 7: 3 mixture of ethyl acetate and hexane as eluent. 1.4 g (40%) of the desired enamine are obtained.

@ ¹ H-NMR (CDCl3 .delta. in ppm): 1.3-2.4 (m, 16H), 3.3-3.7 (m, 5H), 4.3-4.4 (s, 2H) ), 4.5-4.7 (m, 2H), 5.0-5.2 (d, 1H), 5.3-5.4 (m, 2H), 5.5-5.9 (m 4H), 6.5-6.8 (d, 1H), 7.3 (s, 5H).

IR (KBr): 1600, 1760, 1800 ^cm-first Example 7

1,1-dioxopenicilanoyloxymethyl-6- [D- (2-amino-2-phenylacetamido)] penicilanoyloxymethyl-trans-1,4-cyclohexanedicarboxylate hydrochloride

To a solution of 1.4 g (1.61 mmol) of 1,1-dioxopenicilanoyloxymethyl-6- [D- (2- (1-methyl-2-methoxycarbonylvinylamino) -2-phenylacetamido)] penicilanoyloxymethyl-trans-1,4 -cyclohexanedicarboxylate in 150 ml of acetone is added 20 ml of 0.1N hydrochloric acid, the solution is stirred for 5 minutes and the solvent is evaporated off under vacuum. The residue is diluted with water and the aqueous phase is washed twice with a mixture of equal parts of ethyl ether and ethyl acetate. The aqueous phase is filtered and lyophilized. This afforded 634 mg (48 percent) of the title compound, melting at 155-170 ° C with decomposition.

@ ⁴ H-NMR (DMSO-d6 with D2O exchange, .delta. In ppm): 1.25-1.5 (m, 16H), 1.85-1.95 (m, 4H), 2.35-2, Δ (m, 2H), 3.3 (dd, 1H), 3.7 (dd, 1H), 4.4 (s, 1H), 4.55 (s, 1H), 5.1 (s,

1H), 5.2 (q, 1H), 5.45 (d, 1H), 5.5-5.65 (q, 1H), 5.7-5.95 (m, 4H), 7.4- 7.6 (m, 5H), 8.85 (bs, 3H), 9.45 (d, 1H).

IR (KBr): 1690, 1760, 1800 cm @ ^-1 . Example 8

Benzyl chloromethyl sebacate

To a mixture of monobenzyl sebacate (48.67 g, 0.155 mol), sodium bicarbonate (26.04 g, 0.310 mol), water (200 ml) and tetrabutylammonium hydrogen sulphate (52.55 g, 0.155 mol) was added chloroform (100 ml). After shaking, the organic layer is separated, the aqueous phase is re-extracted with chloroform and the combined chloroform layers are dried over sodium sulfate. The residue is taken up in 50 ml of bromochloromethane, stirred overnight at room temperature, concentrated in vacuo, stirred with ethyl acetate, filtered and the filtrate concentrated in vacuo. The residual crude product was purified by silica gel column chromatography to give 2 g of purified monoester as an oil.

@ ⁴ H-NMR (CDCl3, .delta. In ppm): 1.1-

1.9 (m, 12H), 2.2-2.5 (m, 4H), 5.0 (s, 2H), 5.6 (s, 2H), 7.3 (s, 5H).

EXAMPLE 9 1,1-dioxopenicilanoyloxymethyl-6- [D- (2- (1-methyl-2-methoxycarbonylvinylamino) -2-phenylacetamido)] penicilanoyloxymethyl sebacate

To a solution of 0.59 g (1.0 mmol) of iodomethyl-6- [D- (2- (1-methyl-2-methoxycarbonylvinylamino) -2-phenylacetamido) -penicillanate in 10 ml of dimethylformamide is added 0.47 g [1, 0 mmol) of sodium 1,1-dioxopenicilanoyloxymethyl sebacate and the mixture is stirred until complete dissolution. The reaction mixture was flash chromatographed on a silica gel column (23 cm) eluting with ethyl acetate: hexane (7: 3). 200 mg (22%) of the desired enamine are obtained.

¹ H-NMR (CDCl 3, δ in ppm): 1.2-1.8 (m, 24H), 1.9 (s, 3H), 2.2-2.6 (m, 4H), 3, 4 to 3.8 (m, 5H), 4.4 (s, 2H), 4.6-4.7 (m, 2H), 5.2 (d, 1H), 5.3 (s, 1H) 5.6-6.0 (m, 4H).

6.9 (d, 1H); 7.3 (s, 5H).

Example 10 1,1-dioxopenicilanoyloxymethyl-6- [D- (2-amino-2-phenylacetamido)] penicilanoyloxymethyl sebacate hydrochloride

To a solution of 200 mg (0.22 mmol) of penicilanoyloxymethyl-6- [D- (2- / 1-methyl-2-methoxycarbonylvinylamino) -2-phenylacetamido) -penicilanoyloxymethyl sebacate in 25 mL of acetone was added 3.2 mL of 0.1 After stirring for a few minutes, an additional 1.0 ml of hydrochloric acid was added and stirring was continued for one minute. The acetone is evaporated, the residue is diluted with water and washed twice with a mixture of equal parts of ethyl ether and ethyl acetate. The aqueous layer was filtered and lyophilized to give 110 mg (59%) of the product.

1 H-NMR (DMSO-d 6 + exchange with D 2 O, δ ppm): 1.2-1.6 (m, 24H), 2.4 (q, 4H),

3.3 (d, 1H), 3.65-3.75 (dd, 1H), 4.4 (s, 1H), 4.55 (s, 1H), 5.05 (s, 1H), 5 2 (q, 1H), 5.45 (d, 1H), 5.55-5.65 (m, 1H), 5.7-5.9 (m, 4H), 7.35-7.55 (m, 5H), 8.65 (bs, 3H), 9.45 (d, 1H).

Example 11 1,1-dioxopenicilanoyloxymethyl-6- [D- (2-amino-2-phenylacetamido)] penicilanoyloxymethyl terephthalate hydrochloride

A. 1,1-dioxopenicilanoyloxymethyl-6- [D- (2- (1-methyl-2-methoxycarbonylvinylamino) -2-phenylacetamido)] pentyl ayloxymethyl terephthalate

To a solution of 0.59 g (1 mmol) of iodomethyl-6- [D- (2- (1-methyl-2-methoxycarbonylvinylamino) -2-phenylacetamido) -penicillanate in 10 ml of dimethylformamide is added 0.48 g (1.1 mmol) of sodium 1,1-dioxopenicilanoyloxymethyl terephthalate and the mixture is stirred until a solution is obtained which is diluted with ethyl acetate and washed three times with a small amount of water, once with brine and dried over sodium sulfate. The solvent was evaporated in vacuo, the residue was taken up in a small amount of ethyl acetate and purified by chromatography on silica gel using a 6: 4 mixture of ethyl acetate and hexane as eluent. Evaporation of the product-containing fractions gave 0.3 g (23%) of the enamine protected compound.

⁴ H-NMR (CDCl 3, δ in ppm): 1.1-1.5 (m, 12H), 1.7 (s, 3H), 3.3-3.6 (m, 5H), 4 (s, 2H), 4.4-4.6 (m, 2H), 5.1 (d, 1H), 5.4 (s, 1H), 5.8-6.1 (m, 4H) 6.9 (d, 1H), 7.2 (s, 5H), 8.0 (s, 4H).

Β. To a solution of 0.3 g (0.35 mol) of the above enamine-protected product in 25 ml of acetone was added 4.5 ml of 0.1 N hydrochloric acid with stirring, the resulting mixture was stirred for a few minutes, then the solvent was evaporated. the residue was partitioned between water and ethyl ether. The aqueous phase was washed with a mixture of equal parts of ethyl 33 ether and ethyl acetate, filtered and the filtrate was lyophilized. This afforded 222 mg (78%) of the title hydrochloride.

⁴ H-NMR (dimethylsulfoxide-β-D / O, δ ppm): 1.25-1.4 (d, 6H), 1.4-1.5 (d, 6H), 3.2-3 3 (d, 1H), 3.65-3.75 (dd, 1H), 4.45 (s, 1H), 4.6 (s, 1H), 5.1 (s, 1H), 5.2 (d, 1H), 5.45-5.5 (d, 1H), 5.55-5.65 (m, 1H), 6.0-6.4 (m, 4H), 7.35-7, 55 (m, 5H), 8.15 (s, 4H), 8.85 (bs, 3H), 9.45 (d, 1H).

IR (KBr): 1690, 1740, 1800 cm ^1st Example 12

1,1-dioxopenicilanoyloxymethyl-6- [D- (2-amino-2-phenylacetamido)] pentyllanoyloxymethyl isophthalate hydrochloride

A. 1,1-dioxopenicilanoyloxymethyl-6- [D- (2- (1-methyl-2-methoxycarbonylvinylamino) -2-phenylacetamido)] -penicilanoyloxymethyl isophthalate

To a solution of 0.59 (110 mmol) of iodomethyl-6- [D- (2- (1-methyl-2-methoxycarbonylvinylamino) -2-phenylacetamido) -penicillanate in 10 ml of dimethylformamide was added 0.43 g (1.0 mmol). of sodium 1,1,1-dioxopenicilanoyloxymethyl isophthalate and the mixture is stirred at room temperature until complete dissolution. After working up the reaction mixture as described in Part A of the preceding example, 200 mg (23%) of the desired enamine is obtained.

@ ¹ H-NMR (CDCl3, .delta. In ppm): 1.3-1.6 (m, 12H), 1.85 (s, 3H), 3.6 (s, 3Hj, 3.4-3.55) (m, 2H), 4.45 (s, 2H), 4.6-4.7 (m, 2H), 5.2 (d, 1H), 5.4-5.7 (m, 2H, 5) 9-6.2 (m, 4H), 6.9 (bd, 1H), 7.3 (s, 5H), 7.5-7.7 (m, 1H),

8.1- 8.4 (m, 2H), 8.7 (bs, 1H), 9.4 (d, 1H).

B. The enamine protecting group was removed as described in Part B of the preceding example and the hydrochloride was prepared. The yield of the product is 94%.

⁴ H-NMR (dimethylsulfoxide D 2 O, d-ppm): 1.3 (d, 6Hj, 1.5 (d, 6Hj, 3.7) (dd, 1H), 3.3 (d, 1H), 4.5 (s, 1H), 4.65 (s, 1H), 5.1 (s, 1H), 5.2 (d, 1H), 5.45 (d, 1H), 5.55-5.65 (m) 1H, 6.0-6.2 (m, 4H), 7.35-7.55 (m, 5H), 7.0 (t, 1H), 8.25-8.35 (m, 2H), 8.48 (t, 1H), 8.85 (bs, 3H), 9.45 (d, 1H).

IR (KBr): 1750—1800 cm ¹ (wide)

Example 13

6- [D- (2-amino-2-phenylacetamido)] penicilanoyloxymethyl-l, l-dioxopenicillanoyloxymethyl succinate hydrochloride [VIII, R ⁴ = H, Q 1 = NH 2, A = (CH) z]

To a solution of 5.9 g (0.01 mol) of iodomethyl-6- [D- (2- (1-methyl-2-methoxycarbonylvinylamino) -2-phenylacetamido)) penicillanate in 30 ml of dimethylformamide was added with stirring 5.5 g. (0.014 mol) of sodium 1,1-dioxopenicilanoyloxymethyl succinate. After 20 minutes, ethyl acetate (150 ml) was added, the mixture was washed with water (3.times.50 ml), brine (50 ml), water (2.times.50 ml), brine (50 ml), dried (Na2 SO4) and concentrated. 6.3 g of yellow bovine product are obtained, which is dissolved in 80 ml of acetone and hydrolysed by stirring for 15 minutes with 80 ml of 0.1N hydrochloric acid. The acetone is evaporated in vacuo and the aqueous residue is extracted successively with 50 ml of ethyl acetate, 75 ml of a mixture of equal parts of ethyl acetate and ethyl ether, and again with 50 ml of ethyl acetate. The aqueous phase is filtered to a clear solution, from which 2.95 g of solid material is obtained by lyophilization, which gives 0.26 g (3%) of pure hydrochloride by chromatography on Sephadex LH-20 (water) ion exchanger.

1 H-NMR (DMSO-d 6, δ S values in ppm): 1.4 (s, 6H), 1.52 (s, 6H), 2.7 (s, 4H), 3.1-3.95 ( m, 2H), 4.4 (s, 1H), 4.52 (s, 1H), 5.0-5.28 (m, 2H), 5.3-5.68 (m, 2H), 5 , 68-6.0 (m, 4H), 7.43 (bs, 5H).

IR (nujol) 1810-1730 cm ^-1 (broad band).

a) 6- [D- (2-amino-2-phenylacetamido)] penicilanoyloxymethyl-l, l-dioxopenlcilanoyloxymethyl glutarate hydrochloride [VIII, R ⁴ - H, Q ¹ = NH 2, A = (CH2) 3j

In a similar manner, 2.94 g (5 mmol) of the same methyl-methoxycarbonylvinyl amine derivative protected ampicillin iodomethyl ester and 3.0 g (7.5 mmol) of sodium 1,1-dioxopenicilanoyloxymethyl glutarate were stirred in 20 ml of dimethylformamide for 5 minutes. Ethyl acetate (150 ml) was added to the reaction mixture, washed with water (3 x 50 ml) and brine (50 ml), dried over sodium sulfate and evaporated to dryness in vacuo. The residue was purified by chromatography on 100 g of silica gel using methylene chloride / ethyl acetate (60 to 40 by volume) as eluent, fractions being collected every 60 sec. Fractions 16-24 were combined and the solvent was evaporated, yielding 1.8 g of a bovine material which was dissolved in 30 ml of acetone. To the solution is added 21.5 ml of 0.1N hydrochloric acid, the mixture is stirred for 20 minutes, then the acetone is evaporated under reduced pressure and the aqueous phase is extracted first with 30 ml of ethyl ether and then with a mixture of equal parts of ethyl acetate and ethyl ether.

The 236898 layer was filtered through diatomaceous earth and the filtrate was lyophilized. 1.45 g (37 percent) of the desired hydrochloride is obtained.

@ ⁴ H-NMR (DMSO-d6, .delta. In ppm): 1.4 (s, 6H), 1.52 (s, 6H), 1.5-2.0 (m, 2H), 2.2- 2.5 (m, 4H), 3.06-3.9 (m, 2H), 4.38 (s, 1H), 4.5 (s, 1H), 5.03-5.26 (m, 2H), 5.33-5.63 (m, 2H), 5.63-5.93 (m, 4H), 7.43 (bs, 5H).

IR (nujol): 1815 - 1730 cm ^-1 .

The following compounds are also obtained as described above:

b) 6- [D- (2-amino-2-phenylacetamido) penicilanoyloxymethyl-1,1-dioxopenicillanoyloxymethyl adipate hydrochloride [VIII, R ⁴ = H, Q ¹ = NHZ, A == (CH2J4]

Purification by ion exchange chromatography yields a product with a purity of 95% (by HPLC).

@ ⁴ H-NMR (DMSO-d6, .delta. In ppm): 1.4 (s, 6Hj, 1.5 (s, 6Hj, both singlets at the top of the 4Hj multiplet, 2.2-2.6) m, 4Hj, 3.06-3.93 (m, 2H), 4.4 (s, 1H), 4.53 (s, 1H, 5.06-5.26 (m, 2Hj, 5.36-8) 5.96 (m, 6H), 7.46 (bs, 5H).

IR (nujol: 1815-1725 cm -1 ⁾ .

cj 6- [D- (2-amino-2-phenylacetamido j] penicllanoyloxymethyl-1,1-dioxopenicillanoyloxymethyl dimethylmalonate hydrochloride [VIII, R ⁴ = H, Q ¹ = NH 2, A = (CH3jsC] was obtained in a yield of 76%.

@ ¹ H-NMR (250 MHz, DMSO-d6, .delta. In ppm): 1.341 (s, 6H), 1.366 (s, 6H), 1.48 (s, 6H), 3.0-3.9 (m) 2H, 4.41 (s, 1H), 4.53 (s, 1H), 5.116 (bs, 1H, 5.2 (bs, 1H), 5.46 (s, 1H), 5.55-5 65 (m, 1H), 5.7-6.0 (m, 4H), 7.33-7.64 (m, 5H), 8.88 (bs, 3H), 9.45 (d, 1H).

IR (nujolj: 1815 - 1770 cm -1 ⁾ .

dJ 6- [D- (2-Amino-2-phenylacetamido)] penicilanoyloxymethyl-1,1-dioxopenicilanoyloxymethyl malonate hydrochloride [VIII, R ⁴ = H, Q ¹ = NH 2, A = CH 2] The product resulted in 80% yield. .

⁴ H-NMR (dimethylsulfoxide, δ ppm): 1.33 (s, 6H), 1.46 (s, 6H), 3.0-3.9 (m, 2Hj, 3.73 (s, 2Hj) 4.36 (s, 1H), 4.46 (s, 1H), 5.0-5.25 (m, 2H), 5.3-5.96 (m, 6H),

7.4 (bs, 5HJ).

Example 14

6- [D- (2-amino-2-phenylacetamido) j penicilanoyloxymethyl-1,1-dioxopenicillanoyloxymethyl glutarate hydrochloride (VIII, R ⁴ = H, Q ¹ = NH 2, A = (CH2) 3j

A. 6- [D- (2-Azido-2-phenylacetamido)] penicilanoyloxymethyl-1,1-dioxopenicilanoyloxymethyl glutarate

To a mixture of 1.18 g (0.0023 mol) of iodomethyl-6- [D- (2-azido-2-phenylacetamido)] penicillanate and 1.2 g (0.003 mol) of sodium -1,1-dioxopenicilanoyloxymethyl glutarate is added 15 ml. After one hour, an additional 1.0 g of sodium salt is added, the solution is stirred for a further 30 minutes, then diluted with 100 ml of ethyl acetate, washed twice with 30 ml each of sodium chloride solution, twice with 100 ml of ethyl acetate. 30 ml of water and once with 30 ml of sodium chloride solution, dried over sodium sulphate and concentrated in vacuo to a foamy residue. Chromatography on 100 g of silica gel using a 7: 3 mixture of ethyl acetate and hexane gave 0.72 g ( 43%) of the purified azidoderivative.

@ ¹ H-NMR (CDCl3, .delta. In ppm): 1.41 (s, 3Hj, 1.5 (s, 3Hj, 1.6 (s, 3Hj, 1.63 (s, 3H)), 1.77- 2.23 (m, 2H), 2.26-2.66 (m, 4H), 3.42 (d, 2H), 4.38 (s, 1H), 4.43 (s, 1H), 4.58 (t, 1H), 5.06 (s, 1H), 5.4-5.9 (m, 6H), 7.1 (d, 1H), 7.33 (s, 5H).

B. The azide derivative prepared above was dissolved in 15 ml of dichloromethane and 15 ml of isopropanol, 0.5 g of 10% palladium on carbon was added and the mixture was hydrogenated under 50 psi of hydrogen for 45 minutes. After the addition of an additional 0.25 g of catalyst, the hydrogenation was continued for a further 30 minutes, then the catalyst was filtered off, washed with a mixture of dichloromethane and isopropanol, and the filtrate was concentrated in vacuo. About 3 ml of a suspension is obtained, from which a precipitate is formed after the addition of 30 ml of diethyl ether. After stirring for 5 minutes and filtration, 0.24 g (35%) of the free base is obtained, from which 0.21 g is dissolved in 2.8 ml of 0.1N hydrochloric acid and the solution is filtered through diatomaceous earth. Lyophilization of the filtrate gave 0.14 g of hydrochloride.

A free base sample is used for the assay

NMR spectra.

@ ¹ H-NMR (DMSO-d6, .delta. In ppm): 1.38 (s, 3H), 1.43 (s, 3H), 1.5 (s, 3Hj, 1.6 (s, 3Hj, 1H)); 65-2.0 (m, 2H), 2.25-2.6 (m, 4H), (partially covered by DMSO), 3.1-3.9 (m, 2H), 4.43 (s, 1H), 4.5 (bs, 2H), 5.03-5.2 (m, 1H), 5.36-5.6 (m, 2H), 5.6-5.9 (m, 4H), 7.26 (bs, 5H).

Example 15

6- [D- (2-Amino-2-phenylacetamido)] penicilanoyloxymethyl-1,1-dioxopenicilanoyloxymethyl adipate hydrochloride

A. Using the procedure of Example 13, using sodium 1,1,1-dioxopenicilanoyloxymethyl adipate instead of sodium 1,1,1-dioxopenicilanoyloxymethyl glutarate, yielding 6- [D- (2-azido-2-phenylacetamido)] in 37.7% yield. penícilanoyloxymethyl-1,1-dioxopenicilanoyloxymethyl adipate.

¹ H-NMR (CDCl 3, δ in ppm): 1.45 (s, 3H), 1.55 (s, 3H), 1.63 (s, 3H), 1.68 (s, 3H) (previous singlets are found at the multiplet peak for 4H), 2.2-2.6 (m, 4H), 3.48 (d, 2H, 4.43 (s, 1H), 4.48 (s, 1H), 4 65 (t, 1H), 5.12 (s, 1H), 5.5-5.95 (m, 6H), 7.15 (d, 1H), 7.38 (s, 5H).

B. The title compound as the free base is obtained by hydrogenating the azido compound prepared in paragraph A using the procedure described in Part B of Example 13. This base, also following the procedure described in Part B of Example 13, is converted to the hydrochloride which is identical to the compound. obtained in part b) of Example 13.

Example 16

6- [D- (2-Amino-2-phenylacetamido}] penicilanoyloxymethyl-1,1-dioxopenicilanoyloxymethyl-dimethylmalonate-p-toluenesulfonate

A. 6- [D- (2- (1-Methyl-2-methoxycarbonylvinylamino) -2-phenylacetamido)] penicllanoyloxymethyl-1,1-dioxopenicllanoyloxyniethyl-diinethylmalonate

To 4.0 g (0.01 mol) of sodium 1,1-dioxopenicilanoyloxymethyl-dimethyl malonate and 6.0 g (0.01 mol) of odomethyl 6- [D- (2- / 1-methyl-2-methoxycarbonylvinylamino)] (2-Phenylacetamido) -penicillanate was added 40 mL of dimethylformamide and stirred at room temperature for 30 minutes. The reaction mixture is poured into 300 ml of ethyl acetate, washed four times with 100 ml of water and once with 100 ml of brine, dried over sodium sulfate and concentrated in vacuo. 9.3 g of a foam are obtained, which is purified by chromatography on 300 g of silica gel, eluting with a 60:40 mixture of ethyl acetate and hexane, collecting 25 ml fractions. Fractions 39-65 were combined and evaporated in vacuo to give 4.3 g (51%) of a reddish brown foam.

Ή-NMR (CDCl 3, δ in ppm): 1.43 (s, 3H), 1.46 (s, 9H), 1.53 (s, 3H), 1.6 (s, 3H),

1.9 (s, 3H), 3.42 (d, 2H), 3.63 (s, 3H), 4.4 (s, 1H), 4.42 (s, 1H), 4.53-4 57 (m, 2H), 5.06 (d, 1H), 5.35-5.93 (m, 6H), 6.73 (d, 1H), 7.33 (s, 5H), 4 (d, 1 H).

B. 0.836 g (1 mmol) of the enamine prepared in Part A was added to 30 ml of ethyl acetate and stirred until it became a solution. A solution of 0.19 g (1 mmol) of p-toluenesulfonic acid hydrate in 5 ml of ethyl acetate was added, the mixture was stirred for 15 minutes, then the solvent was evaporated. The hard gum residue was triturated with 150 mL of ethyl ether, stirred overnight, then filtered, washed with ethyl ether and air dried. 0.84 g (92%) of the corresponding p-toluenesulfonic acid salt is obtained.

1 H-NMR (DMSO-d 6, δ ppm): 1.4 (s, 12H), 1.5 (s, 6H), 2.3 (s, 3H), 3.1-3.9 (m 2H, 4.36 (s, 1H), 4.5 (s, 1H), 5.0-5.25 (m, 2H), 5.33-6.0 (m, 6H), 7, Δ (d, 2H), 7.3-7.63 (m, 7H).

Example 17

6,3-Bromo-penicilanoyloxymethyl-6- [D- (2-amino-2-phenylacetamido)] penicilanoyloxymethyl glutarate

A. Iodomethyl-6S-bromopenicilaneate

To a solution of 0.96 g (3 mmol) of potassium 6 (3-bromo-penicillanate) and 1.80 g (18 mmol) of potassium bicarbonate in 9 ml of water and 9 ml of ethyl acetate is added 0.10 g (0.3 mmol) of tetrabutylammonium- hydrogen chloride and then 0.45 g (4.5 mmol) of chloromethyl chlorosulfonate. The reaction mixture is stirred for 1.5 hours, then the organic phase is separated, the aqueous phase is extracted with ethyl acetate, the combined organic layers are washed with water, dried and concentrated. The crude product was purified by silica gel chromatography eluting with petroleum ether / ethyl acetate (9: 1) to give chloromethyl 6 (3-bromo-penicillanate) as an almost colorless oil.

To a solution of this chloromethyl ester (0.82 g, 2.5 mmol) in acetone (5 mL) was added sodium iodide (0.75 g, 5 mmol) and stirred for 24 h. The precipitated salt is filtered off, the filtrate is evaporated in vacuo and the oily residue is taken up in ethyl acetate. The solution was washed with water, dried over magnesium sulfate, concentrated to a small volume and purified in the same manner as the above chloromethyl ester. The desired iodomethyl ester was obtained as a yellow oil.

Ή-NMR (CDCl 3, δ ppm): 1.55 (s, 3H), 1.69 (s, 3H), 4.5 (s, 1H), 5.34 and 5.57 (2d, I = 4 Hz, 2H), 5.97 (ABq, J = 5 Hz, 2H).

B. N -brompenicilanoyloxymethyl-B- [D- (2- (2-methyl-2-methoxycarbonylvinylammonio) -2-phenylacetamido]] penicilanoyloxymethyl glutarate

To a solution of 832 mg (1 mmol) of tetrabutylammonium 6- [D- (2-methyl-2-methoxycarbonylamino) -2-phenylacetamido] penicilanoyloxymethyl glutarate in 3 ml of ethyl acetate and 3 ml of dichloromethane is added a solution of 430 mg (1 mmol). After stirring for a few minutes, the dichloromethane is evaporated from the resulting suspension, the precipitated salt is filtered off and the filtrate is washed with 5 ml of water, 10 ml of fresh water are added to the organic phase and the pH is adjusted with 1N hydrochloric acid. The aqueous phase was separated and lyophilized to give the title compound as the hydrochloride.

Example 18

When used in procedures described below in Preparations A and B or in Part A of the preceding Example is always the appropriate starting compound of formula R _B COOH or a sodium or potassium salt obtained in a similar manner the corresponding compounds of formula

R _b COOCH 2 Cl or R _B COOCH 21 wherein

R _B is as defined below.

compound R _B COOH or a salt thereof prepared according to the procedure of

according to U.S. Pat. No. 4,342,768

preparation

Example 19

Crystalline acids of formula V wherein R ¹ = H

A. 1,1-dioxopenicilanoyloxymethyl-glutaric acid

Benzyl 1,1-dioxopenicilanoyloxymethylglutarate in ethyl acetate is subjected to hydrogenolysis in the presence of 10% palladium on carbon catalyst. After evaporation of the ethyl acetate from the filtrate, the oily residue is taken up with isopropanol, the mixture is stirred at 22 ° C for 60 minutes and then left to stand at 50 ° C overnight. The resulting solid was taken up with isopropanol, washed with cold isopropanol and then with hexane after filtration. The resulting crystalline 1,1-dioxopenicilanoyloxymethylglutaric acid was dried under vacuum at room temperature. The product melting at 76-78 ° C resulted in 63% yield.

B. 1,1-dioxopenicilanoyloxymethyl-dimethylmalonic acid

To a solution of 10 g of sodium 1,1-dioxopenicilanoyloxymethyl dimethyl malonate in 100 ml of ethyl acetate was added 23 ml of 1N hydrochloric acid in 50 ml of water. The mixture was stirred, then allowed to stand, the organic layer was separated, dried, the solvent was evaporated in vacuo and the residue chromatographed on 400 g of silica gel using a mixture of equal parts of ethyl acetate and acetone as eluent. The product-containing fractions were combined, the solvent was evaporated, the viscous oily residue was dissolved in ethyl ether, the solution was freed from insoluble matter by filtration, and the filtrate was evaporated to an oily residue which was crystallized by scratching the vessel walls. 7.2 g of white crystalline product are obtained, m.p. 121-123 ° C.

Analysis: Calculated for C 11 H 18 O 5 NS

H, 5.07; N, 3.71. found

H, 5.19; N, 3.65. Preparation A

Chloromethyl-penicillanate-1,1-dioxide

To a mixture of 4.66 g of penicillanic acid 1,1-dioxide, 50 ml of dichloromethane and 35 ml of water was added 40% aqueous tetrabutylammonium hydroxide until pH 6.0. The dichloromethane layer was separated and the aqueous phase was extracted twice with 50 ml of fresh dichloromethane each. The organic layers were combined, dried over sodium sulfate and concentrated. 10.1 g of tetrabutylammonium salt of penicillanic acid 1,1-dioxide are obtained.

The tetrabutylammonium penicillanate-1,1-dioxide obtained above was added to 50 ml of chloroiodomethane and the reaction mixture was stirred at room temperature overnight. The resulting mixture was concentrated to half volume in vacuo and chromatographed on 200 g of silica gel using ethyl acetate / hexane as eluent. A 12 ml fraction is collected every 30 seconds. Fractions 41-73 were combined and concentrated to dryness to give 3.2 g of the title compound.

NMR (CDCl3, δ ppm): 1.5 (s, 3H), 1.66 (s, 3H), 3.42 (d, 2H), 4.38 (s, 1H), 4.6 (t , 1H), and 5.7 (dd, 2H).

Preparation

Iodomethyl-penicillanate-1,1-dioxide

To a solution of 7.9 g of chloromethyl-penicillanate-1,1-dioxide in 100 ml of dry acetone was added 21.0 g of sodium iodide under nitrogen, the reaction mixture was stirred at room temperature overnight, then concentrated in vacuo and the residue was concentrated. Dissolve in 150 mL of ethyl acetate and 150 mL of water. The organic layer was separated and the aqueous layer was extracted with fresh ethyl acetate. The organics were combined, washed once with 500 ml of water and once with 50 ml of brine, dried over sodium sulfate and the solvent was evaporated. 10.5 g of the title product are obtained, m.p. 100-102 ° C.

NMR (CDCl3, δ in ppm): 1.55 (s, 3H), 1.68 (s, 3Hj, 3.5 (d, 2H), 4.4 (s, 1H), 4.65 (t, 1H, 6.0 (dd, 2H).

Preparation C

Chloromethyl-6- [D- (2-azido-2-phenylacetamido) -penicillanate

A solution of 12.0 g (0.03 mol) of 6- [D- (2-azido-2-phenylacetamido) penicillanic acid sodium salt in 25 ml of water was treated with 100 ml of methylene chloride and 10.17 g (0.03 mol). j tetrabutylammonium hydrogen sulphate.

The mixture having a pH of 3.0 is adjusted to pH 7.5 with sodium bicarbonate, the organic layer is separated and the aqueous layer is extracted twice with 100 ml of methylene chloride each time. The combined organic phases were dried over sodium sulfate and the solvent was evaporated. The solid residue was triturated with 300 ml of ethyl acetate, the mixture was filtered, the filter cake was washed first with ethyl acetate and then with ethyl ether, and dried under nitrogen. 16.5 g (89%) of the tetrabutylammonium salt are obtained.

12.32 g (0.02 mol) of the above salt are mixed with 70 ml of chloroiodomethane and the mixture is stirred at room temperature overnight. The reaction mixture is concentrated to dryness and the residue is purified by chromatography on 600 g of silica gel, eluting with a mixture of equal volumes of ethyl acetate and hexane. 8.1 (95% of the desired chloromethyl ester) are obtained in the form of a yellowish viscous oil.

Chloromethyl 6- [2-azido-2- (p-hydroxyphenyl) acetamido] penicillanate was prepared in an analogous manner.

Preparation D

Iodomethyl-6- [D- (2-azido-2-phenylacetamido)] -penicillanate

1.27 g (3 mmol) of chloromethyl 6- [D- (2-azido-2-phenylacetamido) -penicillanate, 20 ml of acetone and 2.25 g (15 mmol) of sodium iodide are mixed in a sealed flask. After stirring overnight at room temperature, the resulting suspension was concentrated, the residue was taken up in 100 ml of ethyl acetate, washed three times with 30 ml of water and once with 30 ml of brine, dried over sodium sulfate and concentrated in vacuo. The light yellow foam residue was purified by chromatography on 75 g of silica gel, eluting with a mixture of equal volumes of ethyl acetate and hexane. Fractions of 20 ml are collected. Fractions 11-15 were combined and concentrated in vacuo to give 1.18 g (76%) of the desired product as a pale yellow resin.

Preparation

6α-Hydroxymethylpenicillanic acid sulfone

A. Benzyl 6-bromo-6-hydroxymethylpenicilate

A solution of 44.9 g of benzyl-6,6-dibromopenicilane in 600 ml of dry tetrahydrofuran is cooled to -78 ° C and 56.4 ° C is added dropwise in an inert atmosphere with vigorous stirring and maintaining the temperature at -60 ° C. ml of tert-butyl magnesium chloride. After stirring for 30 minutes at -78 ° C, formaldehyde gas was added to the resulting solution in a stream of nitrogen until 5 moles of formaldehyde were introduced into the mixture. The reaction was quenched at -78 ° C by dropwise addition of 5.7 mL of acetic acid over 25 minutes. The reaction solution was allowed to warm to room temperature and concentrated in vacuo. 200 ml of water and 200 ml of ethyl acetate were added to the residue, the organic layer was separated and the aqueous layer was extracted again with ethyl acetate. The organic phases are combined, washed successively with 200 ml of water, 200 ml of 5% aqueous sodium hydrogen carbonate solution and 200 ml of water, and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave 38.2 g of the desired product, epimeric to C6.

B. Benzyl-6-bromo-6-hydroxymethylpenicilate sulfone

To a solution of 500 mg of benzyl 6-bromo-6-hydroxymethylpenicilate in 30 ml of ice-cooled methylene chloride at 0-5 ° C was added portionwise 633 mg of 85% m-chloroperbenzoic acid over 20 minutes. The reaction mixture was allowed to warm to room temperature, stirred for about 40 hours, then the solvent was evaporated in vacuo and the residue was stirred with water and ethyl acetate. The pH of the mixture is adjusted to 7.4 with saturated sodium bicarbonate solution, the organic phase is separated and 30 ml of fresh water are added. The pH of the mixture was adjusted to 8.2 with saturated sodium bicarbonate solution, the ethyl acetate layer was separated and washed with saturated sodium bicarbonate solution and brine. The ethyl acetate layer was separated, dried over magnesium sulfate and evaporated to an oily residue which was obtained in a yield of 500 mg.

C. 6'-Hydroxymethylpenicillanic acid sulfone

A suspension of 500 mg of 5% palladium on carbon and 500 mg of benzyl-6-bromo-6-hydroxymethylpenicilate sulfone in 200 ml of 50% aqueous methanol was shaken for 20 minutes under hydrogen at an initial pressure of 0.34 MPa, then an additional 500 mg was added. of fresh catalyst and the hydrogen pressure is adjusted to 0.36 MPa. After shaking for 1 hour, the catalyst was filtered off and the methanol was evaporated in vacuo. The pH of the remaining solution was adjusted to 8.0 and the solution was extracted with ethyl acetate. The aqueous layer was acidified to pH 2 (using 6N hydrochloric acid) and the product was extracted with ethyl acetate. After evaporation of the solvent, 100 mg of the desired product is obtained which, after crystallization from a mixture of chloroform and ethyl acetate, containing a drop of dimethylsulfoxide, melts with decomposition at 211-212 ° C.

NMR (100 MHz, DHSO-d6, δ in ppm): 4.93 (d, 1H, J = 2Hz), 4.27 (s, 1H), 3.76 (m, 3H), 1.5 ( s, 3H), 1.4 (s, 3H).

Claims (6)

A process for the preparation of antibacterially active 1,1-alkanediol dicarboxylates of the general formula I RCOCH ₂ OC = O II \ O A R ¹ (COCH 2) _th OC = O II o (i) in which: A is C 1 -C 8 alkylene, isopropylidene, cyclohexylene or phenylene, n is 0 or 1, R ¹ and R ¹ are different and R is a radical RP or RB, where n is 0, R ¹ is hydrogen, C 1 -C 4 alkyl, benzyl, CH 2 Cl 2, CH 2 I or tetrabutylammonium, and If n is 1, R ¹ represents a radical R or _B RP R _P represents a radical of formula wherein R ² represents H, OCH ₃ C8H5OCH2CO or wherein Q ¹ is hydrogen, amino, N 3, benzyloxycarbonylamino, 4-nitrobenzyloxycarbonylamino or 1-methyl-2-methoxycarbonylvinylamino and R ⁴ is hydrogen, hydroxyl, C 2 -C 7 alkanoyloxy, C 2 -C 7 alkoxycarbonyloxy or the radical of formula R ⁵ C ⁶ H ⁴ COO wherein R ⁵ is hydrogen, C 1 -C 4 alkyl, alkoxy C 1 -C 4, fluoro, chloro or bromo or cyano; and R _b represents a radical of formula wherein X ¹ represents a hydrogen atom, CH 2 OH, GH 2 NH 2 or CH 2 NHCOOCH 2 C 6 H 5, and pharmaceutically acceptable cationic salts or acid addition salts thereof, characterized in that the compounds of the formulas: RCOOCH2X a MOC = O \ A / R 1 (COCH ₂ ) _n OC = O o wherein n, A, R and R ⁴ are as defined above, M represents a salt-forming cation with a carboxyl group and X represents a leaving group, reacts with one another in the presence of a polar organic solvent, preferably Ν, form-dimethylformamide, ethyl acetate, dichloromethane or acetone, at a temperature of from 0 to 80 ° C, preferably from 25 to 50 ° C. wherein R @ ¹ or R @ ¹ contains a substituent selected from the group consisting of azido, benzyloxycarbonylamino or 1-methyl-2-methoxycarbonylvinylamino, converting this substituent to an amino group, and optionally converting the resulting product into a pharmaceutically acceptable cationic salt or acid addition salt. 2. A process according to claim 1, wherein the corresponding starting materials are used to form compounds of formula (I) wherein n is 0, R < ¹ > is hydrogen, (C1-C4) alkyl, sodium, potassium or the tetrabutylammonium residue and the remaining general symbols are as defined in point 1. 3. The method according to claim 1, characterized by applying the appropriate starting materials to give compounds of formula I wherein n is 1, one of R and R ¹ represents a radical R _fi and the second radical R _P and A is as defined above. 4. A method according to claim 2 or 3, characterized in that using the corresponding starting materials to give compounds of formula I in which R ² represents a radical of formula O, ¹ where R ⁴ and Q ¹ are as defined above and R _b is a radical of the formula and the remaining general symbols are as defined above. 5. The process of claim 4, wherein the corresponding starting materials are used to form the compounds of claim 4, wherein R < ⁴ > represents a hydrogen atom or a hydroxyl group and the remaining general symbols are as defined above. 6. A process according to claim 5, wherein the corresponding starting materials are used to produce the compounds according to claim 5, wherein R < ⁴ > is hydrogen and the remaining general symbols are as defined above.