CS228948B2 - Method of preparing penicillanoyloxymethyl derivatives of 1,1-dioxide of penicillanic acid - Google Patents

Description

The invention relates to a process for the preparation of penicillanic acid esters, in particular to a process for the preparation of certain penicillanic acid 1,1-dioxide peinicilinoxymethyl derivatives.

Despite the widespread adoption and widespread use of β-lactam antibiotics of the penicillin and cephalosporin type to combat bacterial infections, there are some compounds in this class of substances that are not effective against resistant microorganisms because these organisms are capable of producing the β-lactamase enzyme that reacts with (3- lactam antibiotic to produce products devoid of antibacterial activity. * certain compounds are not able to inhibit .beta.-lactamases, and when used in combination with a penicillin or cephalosporin can increase _Λ sewn antibacterial effectiveness of the antibiotic against certain micro- organisms producing / J-lactamase.

DOS No. 2,824,535, published December 14, 1978, states that penicillanic acid sulfone is such a potent inhibitor / lactamase. In addition, it is described in this publication that certain penicillanic acid sulfone esters readily hydrolyze in vivo, resulting in the presence of high amounts of this O-lactamase inhibitor in the blood. Further, in British Patent Application Publication No. 2,044,255 and in U.S. Pat

R 3 represents an n-butyl group and n has the value 2, and in which R represents a radical of the formula

9 ~ 7?

R,

CHCONHI wherein n is an integer of 0 or 2 and R represents a hydrogen atom, a radical of formula or a radical of formula

in which

R 2 represents a hydrogen atom or a hydroxyl group and

R 1 is azido, amino, 1-methoxycarbonylpropen-2-ylamino or benzyloxycarbonylamino, characterized in that 1 mole of a compound of formula II wherein:

R2 represents a hydrogen atom, n is 0,

R3 is n-butyl and

R 1 is azido, amino or 1-methoxycarbonylpropen-2-ylamino.

The compounds of formula (I) above are useful intermediates for the preparation of compounds with readily hydrolyzable esters that are cleaved in vivo into β-lactam type antibiotics and penicillanic acid sulfone, acting as a β-lactamase inhibitor.

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of penicilinoyloxymethyl derivatives of penicillanic acid 1,1-dioxide of formula III

in which

X is a radical of formula

in which

R3 is alkyl having 1 to 4 carbon atoms, is reacted with at least 1 mole or jodchlormethanu bromchlonmethanu at from about --20 DEG C. to 25 ^Q C. with the proviso that if n is 2, then R is hydrogen.

A preferred embodiment of this process consists in the use of bromochloromethane, in accordance with a particular embodiment, in a preferred embodiment, those compounds of formula (I) in which R is an atom are produced.

in which

R 1 is azido, amino, 1-methoxycarbonylpropen-2-ylamino or benzyloxycarboinylamino; and

R2 represents a hydrogen atom or a hydroxyl group, characterized in that 1 mol of the compound of the general formula (VI) is present

in which

Y is chlorine, bromine or iodine, reacted with at least 1 mole of the compound of formula VII

in which

R 3 is C 1 -C 4 alkyl, in an inert solvent at room temperature.

According to a preferred embodiment of this process, acetone or dl-methylformamide is used as the inert solvent.

According to a particularly preferred embodiment of the process according to the invention, the compounds are produced wherein X is the radical of the formula

where

R 1 is azido, amino or 1-methoxycarbonylpropen-2-ylamino; and

R2 represents a hydrogen atom using starting materials in which R3 represents an n-butyl group and Y represents a chlorine atom.

Those products of formula III in which R 2 is as defined above and R 1 is azido, 1-methoxycarbonylpropen-2-ylamino or benzyloxycarbonylamino are useful intermediates for the preparation of those compounds wherein R 1 is amino, such as after. written below. In addition, compounds of the above structure wherein X is a radical of formula

WHAT

Z \ CH N \

CH kde

R 5 is as hereinbefore defined, containing an easily hydrolyzable ester moiety, so that in vivo they provide an β-lactam type antibiotic and a penicillanic acid sulfone acting as an β-lactamase inhibitor.

While British Patent Application No. 2,044,255 describes the condensation of chloroiodomethane with the potassium salt of penicillanic acid sulfone in the presence of a catalytic amount of tetrabutylammonium sulfate, resulting in the formation of the chloromethyl penicillanate sulfone, equimolar amounts of tetraalkylammonium salt of the corresponding acid and corresponding halide and unexpectedly higher yields of the desired products are achieved.

The process according to the invention is carried out by contacting 1 mole of a halomethylpenitililate of formula (VI) with at least 1 mole of a compound of formula (VII).

This reaction is carried out in an inert solvent which is intended to dissolve the reactants without reacting substantially with them or the reaction product under the reaction conditions. Acetone is the preferred solvent for this reaction, although other highly polar, water miscible aprotic solvents such as dimethylformamide and bsxamethylphosphoric amide may also be used.

The reaction time depends on the concentration, the reaction temperature and the reactivity of the starting materials. The reaction is generally carried out at a temperature in the range of from 0 to 60 ° C, preferably from about 25 to 60 ° C. Working at a preferred temperature range, the reaction time is about 0.5 to 4 hours. Often, the reaction is expediently allowed to proceed overnight without any detrimental effect on the reaction product.

After completion of the reaction, the reaction mixture is diluted with water and a water-immiscible solvent, the organic phase is concentrated and the product is purified by column chromatography.

Compounds of formula III wherein X is a radical of formula

CHCOHHI * 1 where

R2 is as defined above and

R1 is an amino group and, when administered to an animal suffering from a bacterial infection, easily hydrolyzes to a β-lactam antibiotic and a penicillanic acid sulfone acting as an β-lactamase inhibitor.

Those compounds of formula III wherein R 2 is as defined above and R 1 is azido, 1-methoxycarbonylpropem-2-ylamino or benzyloxycarbonylamino are useful intermediates.

CH, products which can be converted to the corresponding compounds wherein R 1 is amino.

The reduction of those compounds of formula III in which R1 is an azido group may be accomplished by dissolving the corresponding intermediate in a suitable solvent or solvents such as lower alkanol or methylene chloride and shaking in the presence of a catalytic amount of a noble metal such as palladium on coal, under a hydrogen atmosphere at an initial pressure of about 0.07 to 0.35 MPa. After completion of the reduction, the spent catalyst is filtered off and the filtrate is concentrated to give the desired product.

Similarly, those compounds of formula III wherein R 1 is benzyloxycarbonylamino can be reduced to the corresponding compounds wherein R 1 is amino. The hydrogenolytic reaction can be easily accomplished by shaking a mixture of the intermediate dissolved in a lower alkanol and methylene chloride and a catalytic amount of a noble metal in a hydrogen-containing amount of a noble metal under an atmosphere of hydrogen at an initial pressure of 0.035 to 0.35 MPa. After completion of the reaction, the catalyst is filtered off and the product is isolated from the filtrate by evaporation.

Compounds of formula III wherein R 1 is amino can be obtained from those wherein R 1 is 1-methoxycarbonylpropan-2-ylamino by treating a solution of this starting material with at least an equivalent amount of acid. If a non-aqueous inert solvent such as ethyl acetate is used, it is preferred that the solvent contains at least 1 to 5% (v / v water) to facilitate the hydrolysis of the enimine. The hydrolysis product is isolated as the corresponding acid addition salt by filtration from the reaction solvent.

The aforementioned British Patent Application No. 2,044,255 also describes a method of using products obtained by condensation of a penicillanic acid sulfone with a β-lactam type antibiotic.

The invention is illustrated by the following non-limiting examples. All NMR spectra in these examples were measured at 60 MHz in solutions in deuterochloroform, perdeuterodimethylsulfoxide or deuterium oxide, or in any other solvent, which is always adjusted, and the signal positions are expressed in ppm relative to tetramethylsilane or 2,2-dimethyl-2-silapentane. -5-sulfonate. Signal shapes are indicated by the following abbreviations:

w - wide signal s = singlet d = doublet t = triplet q = quartet m = multiplet

Example 1

6‘- (α-azidophenylphenylacetamido} peniicilanoyloxymethyl-penicillanate-1,1-dioxide

To 5 ml of dry dimethylformamide was added 424 mg of chloromethyl 6- (α-azidophenylacetamido) penicillanate followed by 474 mg of tetrabutylammonium penicillanate-1,1-dioxide, the resulting mixture was stirred at room temperature overnight. ethyl acetate and then washed three times with 15 ml of water each time and once with 15 ml of saturated sodium chloride solution.

The organic phase is dried over sodium sulphate and concentrated to a foamy residue which is chromatographed on silica gel (40 g) using methylene chloride / ethyl acetate (4: 1 v / v) as the eluent, collecting 8 ml fractions, and Fractions 13-29 are combined and concentrated in vacuo to give 320 mg of the desired product.

NMR (CDCl3):

1.44 (s, 3H);

1.52 (s, 3HJ,

1.6 (s, 4H),

1.66 (s, 3Hj,

3.4 (d, 2Ή)

4.4 (s. 1H).

4.46 (s, 1H,

4.6 (t, 1 H),

5.1 (s, 1 H),

5.4 to 5.7 (m, 2H);

5.88 (s, 2H).

7.18 (d, 1H)

7.37 ppm (s, 5H).

Example 2

The following compounds were prepared as described in Example 1 using the appropriate chloromethyl-6-substituted penicillanate and tetraalkylammonium penicillanate-1,1-dioxide as starting materials:

6‘- (ω-azido-p-hydroxyphenylacetamido) penicilanoyloxymethyl-penicillanate-1,1-dioxide,

6 ‘- (α-benzyloxycarbonylaminophenylacetamido) penicilanoyloxymethyl-penicillanate-1,1-dioxide,

6 ‘- (α-benzyloxycarbonylamino-β-hydroxyphenylacetamido) penicilanoyloxymethyl-penicillanate-1,1-dioxide,

6‘- (α-aminophenylacetamido} penicilanoyloxymethyl-penicillanate-1'-dioxide

6‘- (α-amino-β-hydroxyphenylacetamido) penicilanoyloxymethyl-penicillanate-1,1-dioxide,

6‘- (2,2-idimethyl-5-oxo-4-phenyl-1-imidazolidinyl] penicilanoyloxymethyl-penicillanate-1,1-dioxide; and

6- (2,2-Dimethyl-5-oxo-4- [p-hydroxyphenyl] -1-imidazolidimyl) penicillanoyloxymethyl penicillanate-1,1-dioxide.

Example 3

6‘- (ar-aminophenylacetamido) penicilanoyloxymethyl-penicillanate-1,1-dioxide-p-toluenesulfonate

A. Chloromethyl-6- (α-1-methoxycarbonylpropen-2-ylaminophenylacetamido) penicillanate

To 125 ml of methylene chloride and 50 ml of water was added 8.06 g of 6- (α-aminophenylacetamido) foaming trihydrate, a new acid, and the pH was adjusted to 8.5 by addition of a 40% aqueous tetrabutylammonium hydroxide solution. The methylene chloride layer was separated and the aqueous layer was extracted twice with 30 ml of fresh methylene chloride each time. The methylene chloride layers were combined and dried over magnesium sulfate.

The mixture was filtered and the filtrate was concentrated in vacuo. 300 ml of chloroform, 2.16 ml of ethyl acetate and 20 g of magnesium sulphate were added to the residue, the mixture was heated under reflux for 30 minutes, then the magnesium sulphate was filtered off and the filtrate was concentrated under reduced pressure to a yellow foam. Trituration of this residue with 150 ml of ethyl acetate gave a white solid, which was filtered off, washed three times with 25 ml of ethyl acetate and twice with 50 ml of diethyl ether each time and dried under nitrogen. It is obtained

6.5 g of tetrabutylammonium-6- (α-1-methoxycarbonylp, ropen-2-ylaminophenylacetamido) penicillanate.

1.38 g of the tetrabutylammonium salt prepared above was added to 15 ml of chloroiodomethane and the resulting mixture was stirred at room temperature for 1 hour. The reaction solution is chromatographed on 75 g of silica gel using a mixture of equal volumes of ethyl acetate and hexane as the eluent, collecting 50 ml fractions. Fractions 4-6 were combined and concentrated to give 800 mg of the desired product.

NMR (CDCl3):

1.5 (s, 3H).

1.57 (s, 3H);

1.9 (s, 3H);

ID

3.65 (s. 3H);

4.4 (s. 1H).

4.65 (s, 1 H),

5.12 (b, 1H),

5.42 to 5.7 (m, 2H),

5.75 (double d, 2H),

6.8 (d, 1 H),

7.4 (s, 5H);

9.35 (d, 1 H) ppm.

B. 6‘- (α-aminophenylacetamido) penicilanoyloxymethyl-penicillanate-11,1-dioxide-p-toluenesulfonate

A mixture of 496 mg of chloromethyl 6- (α-1-methoxycarbonylpropen-2-ylaminophenylacetamido-iodicenoate) and 750 mg of sodium iodide in 10 ml of acetone is stirred at room temperature overnight, then the solvent is evaporated in vacuo and the residue is extracted with 40 ml of ethyl acetate. The extract was washed successively with water (3.times.10 ml) and brine (2.times.5 ml) and dried over Na2 SO4. -1-methoxycarbomylpropen-2-ylamino-phenylacetamido penicillanate.

A mixture of 590 mg of iodomethyl-6- (N-1-methoxycarbonylpropen-2-ylaminoacetamido-jpenicillanate) and 474 mg of tetrabutylammonium penicillanate sulfone was stirred in 10 ml of acetone for 20 minutes, and the reaction mixture was concentrated to dryness. The precipitate is filtered off and the filtrate is washed three times with 10 ml of water and twice with 5 ml of sodium chloride solution each time, the organic phase is dried, concentrated to a volume of ca. After stirring for 3 to 4 minutes, a precipitate formed which was filtered off and dried after stirring for 10 minutes.

520 mg of the expected product are obtained. NMR (perdeuterodimethylsulfoxide):

1.38 (s, 6H);

1.5 (s. 6H),

2.3 (s, 3H),

3.05 a, 3.9 (m, 2H),

4.4 (s, 1 H),

4.5 (s, 1 H),

4.95 to 5.3 (m, 2H),

5.35 to 5.7 (m, 2H);

5.9 (s, 2H).

7.08 (d, 2H),

7.55 (d, 2 H),

7.44 (d, 2H).

8.6 to 9.0 (broad s, 3HJ and

9.4 ppm (d, 1 H).

Claims (2)

SUBJECT OF THE INVENTION A process for the preparation of penicilanoyloxymethyldeirivates of penicillanic acid 1,1-dioxide of formula III R @ 2 is hydrogen or hydroxy, characterized in that 1 molar part of the compound of formula (VI): X is a radical of the formula ρ ^ζζ -CHCONH or ^CO \ HN-f-CH * where R 1 is azido, amino, 1-methoxycarbonylpropen-2-ylamino or benzyloxycarbonylamino and wherein: X is as defined above and Y is chlorine, bromine or iodine, reacted with at least 1 molar part of the compound of formula VII R3 is alkyl having 1 to 4 carbon atoms in an inert solvent at 0 to 60 ^Q C. 2. The process according to claim 1, wherein the inert solvent is acetone or dimethylformamide.