CS228947B2

CS228947B2 - Method of preparing penicillanoyloxymethyl derivatives of 1,1-dioxide of penicillanic acid

Info

Publication number: CS228947B2
Application number: CS831991A
Authority: CS
Inventors: Vytautas J Jasys
Original assignee: Pfizer
Priority date: 1981-03-23
Filing date: 1983-03-23
Publication date: 1984-05-14
Also published as: CS228948B2

Description

CZECHOSLOVAK SOCIALIST REPUBLIC (19) DESCRIPTION OF THE INVENTION <PATENT .228947 ^ (11) (S2) (22) Registered 23 03 82 (21) (PV 1991-83) (32) (31) (33) Priority from 23 03 81 (246482) United States (51) Int. Cl.3 C 07 D 499/80 C 07 D 499/32 C 07 D 499/52 // A B1 K 31/43 OFFICE AND DISCOVERY OFFICE (40) Published 15 09 83 (45) Published 15 08 86 (72 )

The inventor of JASYS VYTAUTAS JOHN, NEW LONDON, CONNECTICUT (73)

The proprietor of the PFIZER INC, NEW YORK, NEW YORK patent (54) The process for producing the panicilanoyloxymethyl derivative of the penicillanic acid 1,1-dioxide 1 of U.S. Pat. No. 4,244,951 also discloses that the halomethyl esters of sulfonupenicillanic acid may be to condense with the carboxyl group of the antibacterially active penicillin to form compounds with these readily hydrolyzable esters, which compounds are cleaved in vivo by the β-lactamase-acting penicillins and sulfonpenicillanic acid-acting antiseptic agents. It is further disclosed in the British patent application that the intermediate chloromethyl-pinic-lane sulfone can be prepared by condensation of the potassium salt of the penicillanic acid sulfone with chloroiodomethane in the presence of a catalytic amount of metabutylammonium sulphate. In addition, the tetrabutyl-ammonium salts of certain penicillanic acid-type antibacterial agents can be condensed with α-haloalkyl-penicillanate sulfones to form readily hydrolysable esters which in vivo cleave into anti-bacterially active penicillins and sulfone. peni-cilanic acid.

In our related Czechoslovak Patent Publication No. 228 920, a process for the preparation of compounds of Formula I is described and protected.

The invention relates to a process for the preparation of esterupenicillanic acid, in particular to a process for the production of certain penicillanyloxymethyl derivatives of penicillanic acid 1,1-dioxide. Despite the widespread acceptance and widespread use of β-lactam antibiotics penicillan acephalosporin type to combat bacterial infections, there are some compounds in this class of compounds that are not effective against resistant microorganisms since these organisms are capable of producing enzyme / Hactamase , which reacts with a β-lactam antibiotic to produce products that do not exhibit antibacterial activity. However, certain compounds are capable of inhibiting Hactamase and, when used in combination with penicillin or cephalosporin, may increase the antibacterial activity of the antibiotic to certain β-lactamase producing microorganisms. In U.S. Pat. No. 2,824,535, issued Dec. 14, 1978, the penicillanic acid sulfone is said to be such an effective .beta.-lactamase inhibitor. In addition, it has been described in this publication that certain sulfonupenicillanic acid esters are readily hydrolyzed in vivo, resulting in the presence of high levels of this β-lactase inhibitor in the blood. Furthermore, in British Patent Application No. 2,044,255 and in US-228947 3, 4, 228947

is hydrogen, R 3 is n-butyl, and n is 2, and wherein R is CHCONH-

Wherein n is a number of 0 or 2 and R is a hydrogen atom, the remainder is a formula or a radical of the formula

CO CH. wherein R 2 represents a hydrogen atom or a hydroxyl group and

R 1 is azido, amino, 1-methoxycarbonylpropen-2-ylamino or benzyloxycarbonylamino, wherein 1 mole of the compound of formula II wherein R 2 is hydrogen, n is 0,

R 5 is n-butyl and

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

The compounds of the above general formula I are useful intermediates for the preparation of compounds with readily hydrolysable esters which are cleaved in vivo to form antibiotics (3-lactam type and peni-cilanyl sulfone acting as an inhibitor of β-lactamase).

It is an object of the present invention to provide a process for the preparation of penicilinoyloxymethyl derivatives of penicillanic acid 1,1-dioxide, general formula III

In which X represents the remainder of the formula

or

CHCQNH

Wherein R 3 is an alkyl group having 1 to 4 carbon atoms, it is reacted with at least 1 mol of iodochloromethane or bromochloromethane at a temperature of about -20 ° C to 25 ° C with the restriction that when n is 2 then R is hydrogen . A preferred embodiment of this process consists in the use of bromochloromethane, in accordance with a particularly preferred embodiment, the compounds of the above formula (I) in which R is a

1 / CH N ~

Ct-L in which

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

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

in which

Y is chloro, bromo or iodo, not reacted with at least 1 mole of the compound of formula V

wherein R 3 is an alkyl group having 1 to 4 carbon atoms, in an inert solvent at room temperature. According to a preferred embodiment of this process, acetone or dimethylformamide is used as inert solvent.

A particularly preferred embodiment of the process according to the invention consists in the preparation of those compounds in which X represents a radical of formula CHCONH- wherein R2 represents a hydrogen atom, Y represents an iodine atom, R3 represents an n-butyl group and

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

Those products of formula (III) wherein R 2 is as defined above and R 1 is an azido, 1-methoxycarbonyl-prop-2-ylamino or benzyloxycarbonylamino are useful intermediates for the preparation of those compounds in which R 1 represents an amino group as defined above written below. Furthermore, the compounds of the aforementioned structure in which X represents the remainder of formula 220947 6

wherein R 2 is as defined above, contains an easily hydrolysable ester moiety, such that in vivo they provide a β-lactam antibiotic and a penicillanic acid sulfone acting as an β-lactamase inhibitor.

While British Patent Application No. 044,255 discloses the condensation of chloroiodomethane with the potassium salt of the penicillanic acid sulfone in the presence of catalytic amounts of tetrabutylammonium sulfate to produce the chloromethyl-penicillan sulfone, equimolar amounts of tetraalkyl-ammonium are used in the present invention. salts of the corresponding acid and the deprotecting halide, yielding unexpectedly higher yields of the desired products.

The process of the present invention is carried out by contacting 1 mol of the pence-cilanyl sulfone halomethyl ester of the formula IV with at least 1 mole of the compound of formula V in an inert solvent. The inert solvent is to dissolve the reactants without, with or without the reaction product reacted to some significant extent under the reaction conditions. The boiling temperature and the freezing point of the solvent are preferably in accordance with the reaction temperature. A preferred solvent for the described reaction is acetone, although a wide range of other water-miscible aprotic solvents, including ethyl acetate, acetonitrile, dimethylformamide and hexamethylphosphoric triamide, may also be used for this purpose.

The reaction time depends on the concentration, the reaction temperature and the reactivity of the starting materials. When the reaction is carried out at a preferred temperature of about 25 ° C, the reaction is usually complete in 30 to 60 minutes.

At least 1 mole of tetraalkylammonium salt is used for each mole of halomethyl ester to achieve optimum product yield. In addition, up to 10% excess salt can be used without significantly affecting the quality of the resulting product.

After completion of the reaction, the solvent is evaporated off, usually under vacuum, and the remaining product is purified by chromatography on silica gel.

The tetraalkylammonium salts of penicillanic acids 228947 selin and halomethyl-peniclane sulfones are prepared as described herein.

Compounds of formula III wherein X is a radical of formula

wherein R 2 is as defined above and a

R 1 is amino, is readily hydrolysed to the β-lactam antibiotic and to the penicillanic acid sulfone acting as an inhibitor (S-lactamase) when applied to an animal suffering from bacterial infection.

Those compounds of formula (III) wherein R 5 is as defined above and R 1 is azido, 1-methoxycarbonylprop-2-ylamino or benzyloxycarbonylamino are useful intermediates which can be converted into the corresponding compounds in which wherein R 1 is an amino group.

Reduction of those compounds of the above general formula (III) wherein R 1 is azido 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 to an angle, in a hydrogen atmosphere at an initial pressure of about 0.07 to 0.35 MPa. After the reduction is complete, the spent catalyst is filtered off and the filtrate is concentrated to give the desired product.

Similarly, those compounds of general formula III wherein R 1 is benzyloxycarbonylamino can be reduced to the corresponding compounds wherein R 1 is an amino group. The hydrogenolysis reaction is readily accomplished by shaking the mixture of the lower alkanol-methylene chloride intermediate product and the noble metal catalyst in a hydrogen atmosphere 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 filtered off. isolated from the filtrate by evaporation.

Compounds of the above general formula (III) wherein R 1 is amino may be obtained from those compounds wherein R 1 is 1-methoxycarbonylpropen-2-ylamino by treating at least equivalent amounts of the starting material. acid. When using a non-aqueous inert solvent such as ethyl acetate, it is preferred that the solvent contains at least 1 to 5% (by volume / volume) of water, thereby facilitating hydrolysis of the solvent. Acids suitable for this hydrolysis include inorganic mineral acids as well as organic sulfonic acids. The hydrolysis product is isolated in the form of the corresponding acid addition salt by filtration from the reaction solvent. British patent application no. No. 2,044,255 also discloses a method of using products obtained by condensation of a penic-lactic acid sulfone with an antibiotic β-lactam type.

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, optionally in another solvent, and the signal positions are expressed in ppm values of prototetramethylsilane or 2,2-dimethyl- 2-silane-pentane-5-sulfonate. Signal shapes are denoted by the following abbreviations: w = broad signal s - singlet d = - dublet t - triplet q = quartet m = multiplet. Example 1 6 '- (n-amino-β-hydroxyphenylacetamido) -pentlanoyloxymethyl-penicillanate-1,1-dioxide A. 6'- (α-benzyloxycarbonylamino-β-hydroxyphenylacetamido) penicilinoxyloxymethyl-penicillanate 1,1-dioxide To 9.5 g of tetrabutylammonium-6- (α-benzyloxycarbonylamino-β-hydroxyphenylacetamide to 25 ml of acetone in 50 ml of dry acetone is added 4.78 g of iodomethyl-penicillanate-1,1-dioxide, the reaction mixture was stirred at room temperature for 30 minutes and then concentrated in vacuo. The residue was chromatographed on 200 g of silica gel using a mixture of equal volumes of ethyl acetate and methylene chloride as the eluent, collecting 25 ml fractions. to 49 are combined and concentrated to give 6.5 g of the desired product as a yellow foam NMR (CDCl3): 1.42 (s, 3H, 1.52 (s, 3H), 1.6 (s) (3H), 3.1-3.9 (m, 2H), 4.45 (s, 1H, 4.58 (s, 1H), 5.08 (s, 2H), 4.98-5.7 (m). , 4H), 5.95 (s, 2H), 6.68 (d, 2H), 7.2 (d, 2H) and 7.35 ppm (s, 5H) 228947 10 B. 6'- (α-amino-β-hydroxyphenylacetamido) -penicilanoyloxymethyl-penicillanate-1,1-dioxide To 6.4 g of 6 '- (α-benzyloxycarbonylamino) - hydroxyphenylacetamido) penicillanyloxymethyl-penicillanate-1,1-dioxide in 70 ml of methylene chloride and 70 ml of isopropanol are added 6.5 g of 10% palladium on carbon and the mixture is shaken for 45 min under hydrogen pressure at initial pressure 0.35 MPa, then an additional 3.0 g of catalyst was added and the hydrogenation was continued for 30 minutes. This addition of 3.0 g of catalyst was repeated three times. The reaction mixture was filtered, the spent catalyst was washed with a mixture of equal volumes of methylene chloride and isopropanol, the filtrate was combined with washings and concentrated to near dryness. To the resulting white suspension was added 200 mL of diethyl ether and stirred for 15 minutes. The solids were filtered and dried to give 4.9 g of product, which was dissolved in 35 ml of dimethylformamide and added dropwise to 1500 ml of chloroform. The precipitated solid was filtered and dried (2.35 g). A second crop of 1.75 g was obtained by diluting the filtrate with 2 L of hexane. NMR (DMSO-d6): 1.42 (s, 6H), 1.55 (s, 6H), 3.1-3.95 (m, 2H), 4.42 (s, 1H), 4.57 (s, 1H), 4.9-5.3 (m, 2H); 5.4-5.75 (m, 2H); 5.95 (s, 2H); 6.82 (d, 2H); 7.35 (d, 2H); 2H) and 8.7 to 9.7 ppm (m, 3H, C. 6'- (α-amino-β-hydroxyphenylacetamide to penicilinoyloxymethyl-penicillanate-1,1-dioxide hydrochloride To 35 mL of 0.1 N acid) hydrochloric acid, cooled to 0 [deg.] C., is added 2.15 g of 6 '-( N-amino-p-hydroxyphenylacetamido) penicilino-yloxymethyl-penicillanate-1,1-dioxide, the resulting solution is filtered and freeze-dried. to give 2.1 g of the desired product NMR (CDCl3): 1.38 (s, 6H), 1.48 (s, 6H), 3.0-3.9 (m, 2H), 4.38 (s, 1H) 4.48 (s, 1H); 4.9-5.2 (m, 2Ή); 5.38-5.64 (m, 2H); 5.84 (s, 2H); 6.7 (d, 2H); 24 (d, 2H, 8.3-9.2 (broad s, 4H) and 9.4 ppm (d, 1H).

Analogous to the procedures described above, 6 '- (α-aminophenylacetamate) is obtained by using tetramethylammonium-6- (α-benzyloxycarbonylamino-phenylacetamido-penicillanate and iodomethyl-pemulcianil-1,1-dioxide as starting material). 1,1-Dioxide Hydrochloride Example 2 6 '- (N-aminophenylacetamidopenicilanoyl-oxymethylpenicilane-1,1-dioxide A. 6'- (N-azidophenylacetamido] penicillanyloxymethylpinicilane-1,1-dioxide K a suspension of 5.0 g of tetrabutylammonium-6 - ((- azidophenylacetamido) penicillanate in 75 ml of acetone was added under a nitrogen atmosphere 3.0 g of iodomethylpenicilane-1,1-dioxide in 20 ml of acetone and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was concentrated to a yellow oily residue which was chromatographed on 80 g of silica gel using an ethyl acetate / methylene chloride mixture (1: 4 v / v) as the eluting agent, collecting 75 ml fractions. 2 to 6 are combined and concentrated in vacuo to give 4.53 g of the desired compound. NMR (CDCl3): 1.44 (s, 3H), 1.52 (s, 3H), 1.6 (s, 3H), 1.66 (s, 3H). 3.4 (d, 2H), 4.4 (s, 1H), 4.46 (s, 1H), 4.6 (t, 1H), 5.1 (s, 1H), 5.4-5.7 (m, 2H); ), 5.88 (s, 2H), 7.18 (d, 1IT) and 7.37 ppm (s, 5H). B. 6 '- (α-aminophenylacetamido jpenicilaneyloxyimethylpenicilane-1,1-dioxide)

A mixture of 500 mg of 6'- (n-azidophenylacetamido) -penicilanoyloxymethyl-peinicilane-1,1-dioxide and 500 mg of 10% palladium on carbon in 23 ml of isopropanol and 12 ml of methylene chloride is shaken under a hydrogen atmosphere at room temperature under initial pressure 0.35 MPa. After 30 min, the reaction mixture was filtered and the filtrate concentrated to give 362 mg of the desired product as an amorphous solid. NMR (CDCl3): 1.5 (d, 6H), 1.6 (d, 8H), 3.55 (d, 2H), 4.45 (s, 1 H), 4.55 (s, 1 H), 228947 11 4.6 to 4.75 (m, 2 H), 5.5 to 5.7 (m, 2 H), 5.9 (q, 2 H) , 7.4 (s, 4H) and 8.1 (d, 1H, 1 = 6 Hz) ppm.

In an analogous manner, 6'- (α- azido-β-hydroxyphenylacetamido-penicillanate and chloromethyl-penicillanate-1,1-dioxide as the starting material of the procedures described in this example are used). EXAMPLE 3 6 '- (α-Aminophenylacetamido) penicilinoate 1-oxymethyl-penicillanate-1,1-dioxide To 3.1 g of tetrabutylammonium-6- (α-aminophenoxy) penicillanate-1,1-dioxide. iodomethyl-penicillanate in 20 ml of ethyl acetate and 5 ml of methylene chloride was added 2.0 g of iodomethyl-penicillanate 1,1-dioxide in 10-ethyl acetate and the reaction mixture was stirred at room temperature for 30 minutes. Water (25 ml) was added to the filtrate and the pH was adjusted to 2.5 with 1N hydrochloric acid, the aqueous layer was re-extracted with fresh water (pH 2.5) and the aqueous layers were combined and saturated. with sodium chloride and extracted with methylene chloride The mixture is separated, dried over sodium sulfate and concentrated in vacuo to a volume of about 10 ml. The remaining solution was stirred into diethyl ether, the precipitate formed was filtered off and dried. 370 ml of product are obtained which does not differ from the product prepared in paragraph B of Example 2.

In an analogous manner to this example, 6 '- (α-amino--) is prepared using tetramethylammonium 6- (α-amino-β-hydroxyphenylacetamido) penicillin and chloromethyl-penicillanate-1,1-dioxides as starting materials. p-oxyphenylacetamido) penicillanyloxymethyl-penicillanate 1,1-dioxide. Example 4 6'- (2,2-Dimethyl-5-oxo-4-phenyl-1-imidazolidinyl) penicilinoxymethylmethyl-peniciline-1,1-dioxide To a solution of 1.0 g of tetrabutylammonium-6- (2 Of 2-dimethyl-5-oxo-4-phenyl-1-imidazolidinyl) pentanilate in 10 ml of ethyl acetate and 3 ml of methylene chloride are added in one portion to a solution of 470 ml of chloromethyl-penicillan-1,1-dioxide in 7 ml of ethyl acetate and the resulting mixture was stirred at room temperature for 45 minutes. The reaction mixture is washed successively with water and saturated sodium chloride solution, dried over sodium sulphate and the organic phase is chromatographed on 75 g of silica gel using a mixture of equal volumes of ethyl acetate and hexane as eluent, and 12 fractions are collected every 30 seconds. 14 ml. Fractions 195 to 230 were concentrated to give the desired product.

By an analogous procedure using 646 mg of tetrabutylammonium-6- (2,2-dimethyl-5-oxo-4- [p-hydroxyphenyl] -1-imidazinyl) penicillanate and 281 mg of iodomethylpentanilenate, of 1-dioxide, 210 mg of 6 '-( 2,2-dimethyl-5-oxo-4- [p-hydroxyphenyl] -1-imidazolidines] penicilinoxymethylmethyl-peniciline-1,1-dloxide was prepared. NMR (CDCl3): 1.4-1.8 (m, 18H), 3.48 (d, 2H), 4.4-4.9 (m, 5H), 5.56 (d, 1H), 5.9 (s). (2H), 6.64 (d, 2H) and 7.18 ppm (d, 2H) Example 5 6'- (α-aminophenylacetamido) penicilinoyl-oxymethyl-penicillanate 1,1-dioxide p-toluenesulfonate A. 6'- (α-N- [1-methoxycarbonylpropen-2-yl] aminophenylacetamido) penicillanyloxymethyl-penicillanate 1,1-dioxide

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

The mixture was filtered and the filtrate concentrated in vacuo. Chloroform (300 ml), methyl acetate (2.16 ml) and magnesium magnesium sulfate (20 ml) were added to the residue, and the mixture was heated to reflux for 30 minutes. The magnesium sulphate is filtered off and the filtrate is concentrated to a yellow foamy residue which, after trituration with 150 ml of ethyl acetate, yields a white solid which is washed three times with 25 ml of ethyl acetate each time and twice with 50 ml of diethyl ether each time and dried under nitrogen. 6.5 g of tetrabutylammonium-6- (al-methoxycarbonylpropen-2-ylaminophenylacetamido) penicillanate are obtained. To 1.38 g of the tetrabutylammonium salt prepared above in 10 ml of dry acetone was added 1.04 g of iodomethyl-penicillanate-1,1-dioxide and stirred for 10 minutes at room temperature. The reaction mixture was concentrated in vacuo and the residue was chromatographed on 75 g of silica gel using a mixture of equal volumes of ethyl acetate and hexane as eluent, taking 10 ml fractions every 9 minutes. Fractions # 11 to 19 were combined with 228947 13 and concentrated in vacuo. 970 mg of the desired product is obtained. NMR (CDCl3): 1.42 (s, 3H), 1.48 (s, 3H), 1.55 (s, 3H), 1.6 (s, 3H), 1.9 (s, 3H), 3.48 (d, 2H), 3 , 66 (s, 3H), 4.43 (s, 1H), 4.46 (s, 1H), 4.56-4.7 (m, 2H), 5.13 (d, 1H), 5.4-5.75 ( m, 2H), 5.9 (s, 2H), 6.78 (d, 1H), 7.42 (s, 5H) and 9.38 ppm (d, 1H). B. 6'- (n-aminophenylacetamido) penicillanyloxymethylpenicilane-1,1-dioxide-p-toluenesulfonate K 346 mg 6 '- («- N- [1-methoxycarbonylpro-pen-2-yl] aminophenylacetamido) ) penicillanyl oxymethylpenicilane-1,1-dioxide in 20 ml of ethyl acetate is added 95 mg of p-toluenesulfonic acid hydrate in 5 ml of ethyl acetate and 0.5 ml of water. After a few minutes, the precipitate formed is filtered off and dried with ethyl acetate. 290 mg of the desired product are obtained. NMR (DMSO-d6: 1.38 (s, 6H); 1.5 (s, 6H); 2.3 (s, 3H); 3.05-3.9 (m, 2H); 4.4 (s, 1H); 1H), 4.95-5.3 (m, 2H), 5.35 and 5.7 (m, 2H), 5.9 (s, 2H), 7.08 (d, 2H), 7.55 (d, 2H), 7.44 (d, 2H), 8.6-9.0 (broad s, 3H) and 9.4 ppm (d, 1H) Example 6 6'- (α-amino-β-droxyphenyl acetamido) ) -penicilanoyloxymethyl-penicillanate-1,1-dioxide hydrochloride A. 6'- (N '- [1-methoxycarbonylpropen-2-yl] amino-β-hydroxyphenylacetamido] peni-cilanoyloxymethyl-penicillanate-1, 1-Dioxide 41.9 g of 6- (n-amino-β-hydroxyphenylacetic amidepenicilic acid and 50 ml of water are added to 300 ml of methylene chloride and adjusted to pH 8.5 with 40% aqueous tetrabutylammonium hydroxide). The reaction was poured into a separatory funnel, the aqueous layer was separated, saturated with sodium sulfate and extracted with methylene chloride, and the methylene chloride was combined, dried over sodium sulfate, and concentrated to an oily residue which was triturated with acetone. It is obtained 44.6 grams of tetrabutylammonium-6- (n-amino-p-hydroxyphenylacetamido) penicillanate.

The above salt was added to 150 methyl acetate and the suspension was heated on a steam bath for 8 minutes. The resulting mixture is allowed to cool, the precipitate formed is filtered off, washed with methyl acetate (3 x 25 ml) and diethyl ether (3.times.25 g). 18.26 g of iodomethyl-peniciline-1,1-dioxide in 50 ml of the same solvent were added to 47.5 g of the above salt in 250 ml of dimethylformamide with stirring over 20 minutes. 10 minutes after the addition was complete, the reaction mixture was poured into 3 liters of ethyl acetate and the precipitate formed was filtered off. The precipitate is washed with 100 ml of ethyl acetate, the washings are combined with the filtrate, washed successively four times with 500 ml of sodium chloride solution, four times with 500 ml of each solution and twice with 500 ml of sodium chloride solution each time, dried sodium sulfate and the solvent were evaporated. The residue is chromatographed on 750 g of silica gel using ethyl acetate as eluent. 250 ml collections are collected. Fractions # 2 to 5 are combined and concentrated to give 31.2 g of product. NMR (CDCl3, 1H 100.1MHz): 1.37 (s, 3H), 1.38 (s, 3H), 1.48 (s, 3H), 1.57 (s, 3H), 1.76 (s, 3H) 3.14-3.82 (m, 2H); 3.51 (s, 3H); 4.42 (s, 1H); 4.44 (s, 1H); 4.54 (s, 1H); 1 to 5.22 (m, 1H), 5.3 to 5.64 (m, 3H), 5.9 (s, 2H), 6.7 (d, 2H), 7.14 (d, 2H), 9 .Delta. (D, 1H), 9.24 (d, 1H), 9.34 to 9.54 ppm (broad s, 1H). B. 6'- (α-penicilinoyloxymethylpenic-lane-1,1-diamino-p-hydroxyphenylacetamido) oxide hydrochloride oxide hydrochloride To a solution of 31.1 g of 6 '- (α- [1-methoxycarbonylpropene-2) -yl] amino-β-hydroxyphenylacetamido) penicillanate 1,1-dioxide in 250 ml a-

Claims

228947 15 cetone, cooled to 0 ° C, was added 439 ml of 0.1 N hydrochloric acid. Stirring for 3 minutes, the acetone was evaporated in a vacuum and the aqueous residue was extracted three times with 700 ml of diethyl ether each time. The aqueous layer was separated, filtered through celite, and 23.1 g of the desired product were obtained by lyophilization. NMR (penduterodimethylsulfoxide): 1.38 (s, 6H), 16 1.48 (s, 6H), 3.0-3.9 (m, 2H), 4.38 (s, 1H), 4.48 (s, 1H) 4.9, 5.2 (m, 2H), 5.35 to 5.64 (m, 2H), 5.87 (s, 2H), 6.7 (d, 2H), 7.24. (d, 2H), 8.3-9.2 (broad s, 4H), and 9.4 ppm (d, 1H). the object of inventing

A process for the preparation of penieilanoyloxymethyl derivatives of penicillanic acid 1,1-dioxide of the general formula IIIl, characterized in that with 1 molar part of the compound of the general formula IV

wherein X is the formula

CHCONH- H * CH: Ls. In CCL 3, wherein Y is chlorine, bromine or iodine, it is not reacted with at least 1 molar portion of the compound of formula V or

xc CH - HH CH, wherein R 1 is azido, amino, 1-methoxycarbonylpropen-2-ylamino or benzyloxycarbonylamino and R 2 is hydrogen or hydroxy-

wherein X is as defined above and R 3 is an alkyl group having 1 to 4 carbon atoms in an inert solvent at room temperature.

2. The process of claim 1 wherein the inert solvent is acetone or dimethylformamide. Severografia, n. P., Závod 7, Most Price 2,40 Kcs