DK147513B - ANALOGY PROCEDURE FOR THE MANUFACTURE OF CEFUROXIMESTERS - Google Patents

Description

147513 i

The present invention relates to an analogous process for the preparation of novel cefuroxime esters of the general formula I shown in the preamble of claim 1, wherein R and R have the same meanings stated, i.e. esters of (6R, 7R) -3-carbamoylloxymethyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylic acid (i.e. isomer), which has the adopted name of cefuroxime. The process according to the invention is characterized by the characterizing part of claim 1.

Cefuroxime disclosed in British Pat.

1,453,049 is a valuable broad-spectrum antibiotic characterized by high activity against a wide variety of gram-positive and gram-negative microorganisms, which is enhanced by the very high stability of the compound against β-lactamases produced by a variety of gram-negative microorganisms. In addition, the compound is stable in the body due to its resistance to the action of mammalian esterases and it provides high serum levels after parenteral administration (e.g. in the form of the sodium salt) to humans and animals while exhibiting a low serum binding.

DK patent application No. 4432/74 discloses an analogous process for the preparation of various cephalosporin compounds, including cefuroxime, and non-toxic salts, biologically acceptable esters, 1-oxides or solvates thereof. The mention of esters in the specification is general, there is no example of making any such ester and not naming any particular ester. On the whole, on the priority day of the present invention, not a single cefuroxime ester is specifically described; however, this information should be supplemented by the fact that DK patent applications Nos. 637/77 and 638/77 disclose the preparation of cefuroxime esters other than the present ones, but these applications were not publicly available on the priority date of the present invention.

Cefuroxime and its salts, for example, alkali metal salts such as the sodium salt, are primarily valuable as antibiotics for injection as they are poorly absorbed from the gastrointestinal tract and are therefore present only in sera and urine at low concentrations after oral administration. Therefore, extensive studies of the results of various cefuroxime derivatives have been conducted by oral route, as the development of derivatives absorbed from the digestive tract and which, after oral administration, is converted to the parent antibiotic in the body's sera, would further extend the valuable therapeutic potential of cefuroxime, ia. a. because patients using oral preparations will then be able to maintain treatment with cefuroxime in a hospital with injection preparations.

It is known from the literature on β-lactam antibiotics that absorption from the digestive tract after oral administration of certain penicillin and cephalosporin antibiotics can be improved (compared to the parent antibiotic) by converting the free 3-carboxy group in the case of penicillin compounds or the free 4-carboxy group in the case of cephalosporin compounds, to certain esterified carboxy groups. Thus, for example, penicillin G can be converted to its acetoxymethyl ester to provide a compound with improved digestive tract absorption after oral administration compared to penicillin G itself.

It is believed that the presence of an appropriate esterification group enhances the absorption of the parent antibiotic from the digestive tract, the esterification group being hydrolyzed after absorption by the presence of enzymes present in, for example, serum and body tissue, thereby forming the antibiotically active parent acid. It will be appreciated that the exact nature of the esterification group is critical as it is necessary for the ester to be sufficiently stable to allow it to reach the site of absorption without undergoing significant degradation, e.g. in the stomach, while, on the other hand, it must be sufficiently sensitive to be converted to the antibiotic active parent acid within a short time of absorption of the ester.

In addition, the degree to which the particular ester group increases the oral absorption of the β-lactam antibiotic is random and unpredictable and depends on the nature of the selected parent acid. For example, an esterification group which has been shown to be effective in improving the utility of a penicillin antibiotic need not necessarily confer similar benefits to an antibiotic of the cephalosporin series, and a lack of consistency has been found within each of these particular ranges of lactam antibiotics.

3 147513

Surprisingly, it has now been found that cefuroxime can be esterified on the 4-carboxyl group with an ester group -O.CH (R 2) .O.CO.OR 2 ·, wherein R 2 and R 2 have the meanings given for the introduction of claim 1 of high absorption level esters from the gastrointestinal tract, esters which are rapidly degraded in the organism to form the parent antibiotic cefuroxime active in the organism. This is evident from the experiments described below.

Measurement of the amount of a given cephalosporin derivative, in this case cefuroxime, recovered in the urine after oral administration in rats thereof, in the case of cefuroxime or esters thereof, experience shows in good terms a good indication of the suitability of compounds as an orally administered antibiotic to humans. As the ester group is cleaved by esterases in the intestine, it is the recovery in the urine of cefuroxime, the antibiotic-active substance, that is measured. The table below shows the percent recovery values in the urine of cefuroxime after administration in the rats, partly of the four cefuroxime esters prepared according to the examples below, and partly of cefuroxime:

Compound% recovery

According to Example 1 8.3

According to Example 2 8.0

According to Example 3 14.0

According to Example 4 6.0

Cefuroxime <2

It is seen that cefuroxime is practically not absorbed in the gastrointestinal tract, while the tested esters are absorbed to a much greater extent.

In general, such test results are confirmed with the recovery of orally administered cephalosporin derivatives in the urine in human trials, but not in absolute quantitative terms. It usually turns out that the pharmacokinetics of such compounds are so much different in humans than in rats that the oral absorption as measured by% recovery in urine is much higher in humans than in rats.

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In other words, the tests show that the esters in question represent human orally absorbable cefuroxime derivatives in contrast to the free acid or salts of this antibiotic.

The esters of general formula I have acceptable stability as evidenced by their low in vitro antibacterial activity compared to cefuroxime; this shows that a large proportion of ester remains unchanged throughout the performance of the in vitro tests. The esters, on the other hand, are highly sensitive to esterase hydrolysis leading to the formation of cefuroxime, which is shown, for example, in in vitro tests using esterases derived from rat liver, human liver or human serum.

Compounds of formula I, wherein is an alkyl group 2 having 1-3 carbon atoms and R is a hydrogen atom or a methyl group, have been found to provide particularly good absorption of cefuroxime, as evidenced by animal experiments, which is why it is particularly convenient to proceed according to the invention. 2nd

Particularly conveniently, according to the invention, 1- (ethoxycarbonyloxy) -ethyl- (6R, 7R) -3-carbamoyloxymethyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph-3- is prepared. em-4-carboxylate, which partly gives good recovery in rat urine after oral administration, which shows good absorption in the gastrointestinal tract and is stable in vitro.

Esters of general formula I can be used to treat various diseases caused by pathogenic bacteria in humans and animals, such as respiratory and urinary tract infections.

If the compounds of formula I are prepared by reacting cefuroxime, a salt thereof, for example, an alkali metal salt such as the sodium or potassium salt or an onium salt, for example an ammonium salt such as a quaternary ammonium salt, or a corresponding 1-oxide, with a halogen ester having the one of claim 1 Formula 1 2 II wherein R and R and the asterisk have the indicated meanings and X is halogen such as chlorine, bromine or iodine, and reduction of any 1-oxide formed, for example, by treatment with acetyl chloride and potassium iodide, the reaction is conveniently carried out in a solution in an inert organic solvent, e.g., an N, N-disubstituted amide such as Ν, Ν-dimethylformamide or N, N-dimethylacetamide, a ketone such as acetone, a sulfoxide such as dimethylsulfoxide, a nitrile such as acetonitrile or hexamethylphosphoric acid , at a temperature of -50 ° to + 150 ° C, e.g. -10 ° to + 50 ° C, preferably between 0 ° C and room temperature. When a cefuroxime salt, such as the potassium salt, is used as the starting material and the reaction is carried out in a nitrile solvent, a crown ether such as 18-crown-6 can be used if desired. When the free acid is used as the starting material, the reaction can advantageously be carried out in the presence of a base, for example a weak inorganic base such as sodium carbonate or potassium carbonate; it is convenient to add the base to the cefuroxime-containing reaction system before adding the halogen ester of formula II. The use of potassium carbonate as a base in connection with a compound of formula II wherein X is bromine or iodine has been found to be advantageous since the formation of a ceph-2 em ester product under these conditions is kept to a minimum. It is convenient to use substantially equivalent amounts of cefuroxime and base, e.g. 0.5 mole of a diacid base such as potassium carbonate per mol of cefuroxime. The halogen ester II is suitably used in a small excess, for example in an amount of 1-1.5 moles per ml. mol of cefuroxime.

The course of the reaction can be readily monitored by TLC as the process involves the conversion of a polar acid or polar salt as a starting material into a neutral ester product.

When esters of formula I are prepared by acylating a compound of formula III shown in claim 1 wherein R and R have the meanings given above, or an acid addition salt or N-silyl derivative thereof, with an acylating agent corresponding to (Z) -2 For example, - (fur-2-yl) -2-methoxyiminoacetic acid, for example an acid halide, acid anhydride or carbodiimide, can be used in the manner described in British Patent Specification No. 1,453,049.

Starting materials of formula III can be prepared in conventional manner, for example, using the technique described in U.S. Patent Nos. 3,905,963 and British Patent Nos. 1,041,985 and 1,350,772.

The esters of formula I can also be prepared by in situ carbamoylation of a compound of the general formula 2 shown in claim 1 wherein R and R have the above meanings, in conventional manner, e.g. in the manner described in British Patent Specification No. 1,453,049. For example, carbamoylation may be carried out using a suitable isocyanate or cyanoic acid.

Starting materials of formula IV can be prepared in situ by esterification of the corresponding 4-carboxylic acid or a salt thereof, e.g., an alkali metal salt such as the sodium salt or potassium salt, with a halogen ester of formula II, as described above except that a temperature is preferably used. in the range -100 ° C to + 150 ° C, preferably between -70 ° C and 0 ° C.

If the desired ester product is significantly contaminated with the corresponding ceph-2 em isomer, the product can be oxidized, for example, by treatment with a peracid such as metaperiodic acid, peracetic acid, monoperphthalic acid or m-chloroperbenzoic acid or with t-butyl hypochlorite in the presence of a weak base such as pyridine to form the ceph-3-em-1-oxide ester, which can then be reduced, for example, by treatment with acetyl chloride and potassium iodide, to form substantially pure ceph-3-em ester.

The individual diastereoisomers can be isolated from the isomeric mixture by crystallization.

The process according to the invention is illustrated in the following by means of some examples. Melting points

V

was tuned in a Mettler apparatus and has the form (Mv) where x is the heating rate (in ° C per minute) and y is the insertion temperature. The Ν, Ν-dimethylformamide used was dried by passing through acidic alumina. Organic solutions were dried over anhydrous magnesium sulfate. TLC (thin layer chromatography) plates were developed in chloroform / methanol / formic acid (45: 8: 1) and the compounds were placed under ultraviolet light at 254 nm and exposed to iodine vapor. or by spraying with ninhydrin and heating to 120 ° C. Prior to the examples, preparation of some starting materials is described.

Starting material 1 Iodomethyl-methyl carbonate

A solution of 7.07 g (56.75 mmol) of chloromethyl methyl carbonate in 5 ml of acetone was treated with a solution of 8.51 g (56.75 mmol) of sodium iodide in 30 ml of acetone. The resulting suspension was stirred at 22 ° C for 2 1/4 hours and then evaporated under vacuum to a solid. This solid is partitioned between 75 ml of ether and 75 ml of water. The aqueous phase was extracted with an additional 2 x 75 ml of ether and the combined organic extracts were washed successively with 3 x 75 ml of water, 50 ml of aqueous sodium metabisulphite and 100 ml of saturated brine. The solution was dried and evaporated in vacuo to give 6.45 g of the title ester.

Starting material 2 (R, S) -1-Chloroethyl chloroformate 100 ml of ethyl chloroformate was treated with chlorine at room temperature for 5 hours and the reaction mixture was allowed to stand for 5 days. Distillation of the mixture at atmospheric pressure gave the title ester in an amount of 71.8 g with b.p. 120-130 ° C.

Starting material 3 (R, S) -1-Chlorethyl-methyl carbonate 10.0 g (70 mmol) (R, S) -1-chloroethyl chloroformate and 25 ml of methanol were stirred together for 1 hour; initially the reaction was exothermic but the reaction mixture cooled to ca. 20 ° C. The excess methanol was removed in vacuo to give 11.37 g of the title compound.

Starting material 4 (R, S) -1-Chloroethyl isopropyl carbonate 10.14 g (71 mmol) (R, S) -1-Chloroethyl Chloroformate was refluxed with 35 moles of propan-2-ol for 30 minutes and added 8 drops of triethylamine and the reflux is continued for 20 minutes. The solution was quickly darkened and distilled to form two fractions: i) Fraction 1, bp. 80-90 ° C / 760 mm Hg (30 ml) ii) Fraction 2, bp. 60-70 ° C / 15 mm Hg (5.93 g), which was the title ester.

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Starting material 5 Ethyl ethyl ethyl carbonate

To a solution of 21.3 g of hydrochloric acid ethyl ester and 11.7 ml of ethanol in 150 ml of ether, stirred under dry nitrogen at -10 ° C, 16 ml of anhydrous pyridine in 25 ml of ether were added dropwise over 35 minutes. During the addition, the temperature rose to 2 ° C and a white solid precipitated from the solution. The mixture was stirred for an additional hour and the temperature rose to 15 ° C. 100 ml of water was added and the aqueous layer was separated and extracted with 100 ml of ether. The combined organic layers were washed successively with 2 x 50 ml of 2N hydrochloric acid, 50 ml of water, 2 x 50 ml of aqueous sodium bicarbonate solution, 2 x 50 ml of water and 50 ml of saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting liquid was distilled at atmospheric pressure to give 15.57 g of the title carbonate of boiling point 116-117 ° C.

Starting material 6 1-Bromomethylethyl carbonate

Hydrogen bromide gas was introduced into 15.41 g of ethyl ethyl carbonate containing a few mg of t-butylhydroquinine, cooled to -15 ° C until slightly more than one molar equivalent (11 g) was added. The liquid was rinsed with nitrogen and then distilled under reduced pressure. to give 24.27 g of the bromomethyl carbonate with b.p. 89-91 ° C / 33 mm Hg.

Starting material 7

Potassium (6R, 7R) -7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -3-hydroxymethylceph-3-em-4-carboxylate 4.57 g (6R, 7R) -7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -3-hydroxymethyl-ceph-3-em-4-carboxylic acid was dissolved in hot ethanol and the solution clarified by filtration through diatomaceous earth. The solution was allowed to cool to 20 ° C and a semi-molar solution of potassium acetate in ethanol (24 mL) was added dropwise, adding dropwise to the stirred solution over 10 minutes. A white solid crystallized and the mixture was cooled in the refrigerator for 30 minutes. The resulting solid was filtered off, washed with 3 x 20 ml cold ethanol and 2 x 20 ml ether and dried under vacuum over phosphorus pentoxide to give 4.80 g of the title compound with [α] = + 66 ° (c = 1,006 i

1 Q. V

water), xmax (water) 275 nm, E ^ cm 378.

Starting material 8 (6R, 7S) -7- (Ten-2-yl) -acetamido-3-trichloroacetylcarbamoyloxymethylceph-3-em-4-carboxylic acid

To a stirred suspension of 10.52 g (6R, 7S) -3-hydroxymethyl-7- (thien-2-yl) -acetamidoceph-3-em-4-carboxylic acid in 70 ml of ethyl acetate, cooled in ice, was added. there are 4.3 ml of trichloroacetyl isocyanate. After 30 minutes, 250 ml of petroleum ether was added dropwise and the resulting solid filtered off, washed with petroleum ether and dried under vacuum to give the trichloroacetyl carbamate as a yellow solid in an amount of 16.27 g, [α] 22 = 75 ° (c = 0.772 in DMSO), Xmax

1% D

(ethanol) 236.5 nm, E cm = 253.

Starting material 9 (R and S) -1- (Ethoxycarbonyloxy) -ethyl- (6R, 7S) -7- (thien-2-yl) -acetamido ~ 3-trichloroacetylcarbamoyloxymethyl-ceph-3-em-4-carboxylate To a solution of 16.15 g of starting material 8 in 150 ml of anhydrous Ν, Ν-dimethylformamide was added to powdered potassium carbonate (2.07 g, dried over <RTIgt; vacuum ”) and the mixture was stirred for 1 hour until almost all of the solid was dissolved. The solution was cooled to 1 ° C and 7.88 g of 1-bromoethyl ethyl carbonate were added and the solution was stirred in nitrogen for 1 hour. An additional 3.94 g of 1-bromomethylethyl carbonate was added and the ice bath was removed. Stirring was continued for an additional 1 hour and 20 minutes during which time the temperature rose to 20 ° C and a solid emerged from the solution. The reaction mixture was poured into ice and 2N hydrochloric acid (250 ml) and extracted with 3 x 250 ml ethyl acetate.

The combined organic phases were washed with 3 x 100 ml of 2N hydrochloric acid and the aqueous phases were combined and extracted with 100 ml of ethyl acetate. The combined organic extracts were washed successively with 100 ml of water, 2 x 100 ml of saturated aqueous sodium bicarbonate solution, 2 x 100 ml of water and 2 x 100 ml of saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to ca. 100 ml. 2.08 g of a solid was crystallized and filtered off, and the filtrate was added dropwise to 700 ml of stirred light petrol to precipitate a solid; it was triturated with petroleum ether and then with isopropyl ether to give an amorphous solid which was filtered off and dried in vacuo to give 2 of 11.37 g of the title compound.

80 °, [α] D = + 50 ° (c = 0.844 in dioxane).

Starting material 10 (R and S) -1- (Ethoxycarbonyloxy) ethyl (6R, 7R) -7-amino-3-trichloroacetylcarbamoyloxymethylceph-3-em-4-carboxylate 8.33 g of powdered phosphorus pentachloride was dissolved in 100 ml of anhydrous dichloromethane under dry nitrogen. The solution was cooled to 3 ° C and 3.23 ml of anhydrous pyridine was added, raising the temperature to 13 ° C. The resulting suspension was stirred under nitrogen for 15 minutes while the temperature dropped to 4 ° C and then 11.20 g of starting material 9 was added portionwise over 5 minutes. The resulting solution was stirred at 2-4 ° C for 1.5 hours and then transferred under nitrogen to a mixture of 17 ml of methanol and 33 ml of dichloromethane, cooled to -40 ° C, keeping the temperature below -20 ° C. The solution was stirred under nitrogen for a further 30 minutes and the temperature rose to -3 ° C. Water (50 ml) was added and stirring was continued for 30 minutes at 15 ° C. The aqueous layer was separated and extracted with 2 x 100 ml of dichloromethane and the combined organic layers were washed successively with 100 ml of saturated aqueous sodium bicarbonate solution, 100 ml of water and 100 ml of saturated brine, dried over magnesium sulfate, treated with charcoal, filtered and concentrated in vacuo to ca. . 40 ml. The solution was added dropwise to 400 ml of stirred isopropyl ether to precipitate a solid which was filtered off and dried in vacuo to yield 5.273 g of the title compound. M + 96 °, [α] D = + 28 ° (c = 0.938 in chloroform).

Starting material 11 (R and S) -1- (Ethoxycarbonyloxy) -ethyl- (6R, 7R) -7-amino-3-carbamoylloxyceph-3-em-4-carboxylate

To a solution of starting material 10 in 40 ml of methanol was added a solution of 0.816 g of sodium formate in 10 ml of water. A gum formed which did not dissolve when an additional 10 ml of methanol was added. The solution was stirred for 2 hours at 20 ° C, charcoal was added and the solution was filtered through diatomaceous earth. Most of the methanol was removed on a rotary evaporator and the resulting mixture was partitioned between 30 ml of saturated aqueous sodium bicarbonate solution and 2 x 100 ml of ethyl acetate. The combined organic phases were washed successively with 2 x 50 ml water and 50 ml saturated brine, dried over magnesium sulfate and concentrated to ca. 20 ml. The solution was added dropwise to 250 ml of stirred petroleum ether to precipitate a yellow solid which was filtered off, washed with light petrol and dried under vacuum. There was thus obtained 1.49 g of the title compound, mL 80 ° [α 3 = + 31 ° (c = 0.860 in dioxane).

65 JD

Example 1

Methoxycarbonyloxymethyl- (6R, 7R) -3-carbamoyloxymethyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylate 0.93 g (4, 3 mmol) iodomethyl-methyl carbonate in 3 ml of N, N-dimethylformamide was added to a solution of 1.00 g (2.2 mmol) of potassium (6R, 7R) -3-carbamoyloxymethyl-7 - ((Z) - 2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylate in 10 ml of Ν, Ν-dimethylformamide and the solution was stirred at 22 ° C for 45 minutes (TLC showed essentially complete reaction after 30 minutes).

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The above solution was partitioned between 80 ml of ethyl acetate and 80 ml of 2N hydrochloric acid and the aqueous phase was re-extracted with ethyl acetate (2 x 100 ml). The combined organic extracts were then washed in the above order with 100 ml of water, 2 x 75 ml of 3% sodium bicarbonate solution, 75 ml of water, 50 ml of aqueous sodium metabisulphite, 50 ml of water, 4 x 50 ml of 2N hydrochloric acid, 50 ml of water and 50 ml. ml of saturated saline. The solution was dried and evaporated in vacuo to a foam of 1.19 g. This foam was triturated with 50 ml of anhydrous ether; the obtained solid was filtered off and washed with 2 x 20 ml of anhydrous ether and dried under vacuum to give 0.93 g of the title ester, m.p. (Mg0) 100 ° C. [algQ = + 41 ° (c = ° '71 'DMS0) ·

Example 2 (R and S) -1- (Ethoxycarbonyloxy) -ethyl- (6R, 7R) -3-carbamoyloxymethyl-7- [C 2) -2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph 3-em-4-carboxylate a) (R, S) -1-Iodoethyl-ethyl carbonate

A solution of 13.14 g (86.4 mmol) of (R, S) -1-chloroethyl-ethyl carbonate and 14.8 g (99 mmol) of sodium iodide in 100 ml of acetone was refluxed for 35 minutes. The acetone was removed under vacuum and the residue partitioned between 150 ml ether and 150 ml water.

The organic phase was separated and washed in the order of water, aqueous sodium metabisulphite solution, water (3 times) and saturated brine, then dried. The ether was removed in vacuo to give the title ester as title.

b) (R and S) -1- (Ethoxycarbonyloxy) -ethyl- (6R, 7R) -3-carbamoyloxymethyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph 3-em-4-carboxy-2 lat and its Δ-isomer

The product of Example 2 (a) was immediately dissolved in 20 ml of Ν, Ν-dimethylformamide and added to a solution of 8.58 g (18.5 mmol) of potassium (6R, 7R) -3-carbamoyloxymethyl-7 - [( Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylate in 50 ml of Ν, Ν-dimethylformamide. The reaction mixture was stirred at 25 ° C for 1 hour and then partitioned between 150 ml of ethyl acetate and 200 ml of 2N hydrochloric acid. The aqueous layer was extracted with an additional 3 x 100 ml of ethyl acetate and the combined organic extracts were washed in that order with 2 x 200 ml of water, 200 ml of 3% aqueous sodium bicarbonate solution, 3 x 200 ml of water and 200 ml of saturated brine and dried. 13 147513 and the solvent removed in vacuo to give a glass in an amount of 5.64g. Trituration of this glass with ether gave 5.51 g of the title compound in the form of 2 a gel (containing about 20% of the Δ isomer).

c) (R and S) -1- (Ethoxycarbonyloxy) -ethyl- (1S, 6R, 7R) -3-carbamoyloxymethyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido ] -ceph-3-em-4-carboxylate, 1-oxide

A solution of 1.985 g (3.65 mmol) of the product obtained in Example 2 b) in 40 ml of dry dichloromethane was treated with a solution of 0.8 g (465 mmol) of m-chloroperbenzoic acid in 40 ml of dichloromethane to give an instant gelatinous precipitation. The reaction mixture was stirred at 21 ° C for 45 minutes and the solvent removed in vacuo to give a solid. Trituration of the solid with 2 x 100 ml ether gave 1.47 g of the title ester sulfoxide which was decomposed without melting at & at ca. 200 C, Xmax (ethanol) 275.5, nm (E + cm = 356).

d) (R and S) -1- (Ethoxycarbonyloxy) -ethyl- (6R, 7R) -3-carbamoyloxymethyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph- 3-em-4-Karb-oxylat_

A solution of 1.18 g (2.12 mmol) of the product obtained in Example 2 (c) in 20 ml of Ν, Ν-dimethylformamide was cooled to -10 ° C and treated with 1.38 g (8.3 mmol) of potassium iodide. followed by 0.31 ml (0.34 g, 4.35 mmol) of acetyl chloride. The reaction mixture was stirred at -10 ° C for 30 minutes and then allowed to warm over the next 45 minutes at which time TLC showed that the sulfoxide starting material had disappeared.

The reaction mixture was partitioned between 80 ml of ethyl acetate and 80 ml of 2N hydrochloric acid and the aqueous solution was extracted with an additional 80 ml of ethyl acetate. The combined organic extracts were washed in the above order with sodium metabisulphite solution, water and saturated brine and then dried and the solvent removed under vacuum to give 1.35 g of a foam which, upon trituration with 30 ml ether, yielded 1.00 g of the title compound. indicated esters with m.p. Mgq = 103 ° C, [α] D = + 12.8 ° (c = 1.09, DMSO).

Example 3 (R and S) -1- (Methoxycarbonyloxy) -ethyl- (6R, 7R) -3-carbamoyloxymethyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] - ceph-3-em-4-carboxylate A. (R and S) -1- (Methoxycarbonyloxy) -ethyl- (1S, 6R, 7R) -3-carbamoyloxy-methyl-7 - [(Z) -2- (fur) -2-yl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylate, 1-oxide

Method 1 a) (R and S) -1- (Methoxycarbonyloxy) -ethyl- (6R, 7R) -3-carbamoyloxymethyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido ] -ceph-3-em-2 4-carboxylate and its Δ-isomer

A solution of 11.37 g (R, S) -1-chloroethyl methyl carbonate in 10 ml of acetone was treated with a solution of 17.0 g (113 mmol) of sodium iodide in 50 ml of acetone. A precipitate was formed immediately and after stirring for 5 minutes the mixture was evaporated under vacuum to dryness. The residue was partitioned between 150 ml ether and 100 ml water and the aqueous phase was re-extracted with 3 x 50 ml ether.

The combined organic extracts were washed in the above order with 100 ml of water, 75 ml of sodium metabisulfite solution, 75 ml of water and 70 ml of saturated brine, and dried and evaporated under vacuum to dryness to give 5.5 g (R, S) -1-iodoethyl methyl carbonate as a solid.

A solution of 5.50 g (24 mmol) of (R, S) -1-iodoethylmethyl carbonate in 5 ml of Ν, Ν-dimethylformamide was added to a solution of 4.0 g (8.6 mmol) of potassium (6R, 7R) -3-carbamoyloxymethyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylate in 15 ml of N, N-dimethylformamide. The reaction mixture was stirred at 22 ° C for 4 hours and then allowed to stand overnight.

The mixture was then partitioned between 75 ml of ethyl acetate and 75 ml of 2N hydrochloric acid.

The aqueous phase was extracted with an additional 3 x 50 ml of ethyl acetate and the combined organic extracts were washed in the order of 50 ml of water, 2 x 50 ml of 3% sodium bicarbonate solution, 2 x 50 ml of water and 50 ml of saturated brine and dried. evaporated under vacuum to dryness. Trituration of the 3.8 g of residue with 100 ml of diisopropyl ether gave a solid which was filtered off and dried under vacuum to give 2.7 g of the title ester; mp. MgQ <70 ° C (dec.), [Α] ~ 2 = + 183 ° (c = 0.84, DMSO), Amax (ethanol) = 281 ran (E,% = 278) with an inflection at 260 nm (E = cm = 219).

b) (R and S) -1- (Methoxycarbonyloxy) -ethyl- (1S, 6R, 7R) -3-carbamoyloxy-methyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido ] -ceph-3-em-4-carboxylate, 1-oxide

A solution of 2.59 g (4.92 mmol) of the product obtained in Example 3 a) in 20 ml of dichloromethane was treated with 1.06 g (6.14 mmol) of m-chloroperbenzoic acid. The reaction mixture was stirred for 1 hour at 21 ° C and then diluted with 20 ml of anhydrous ether. The resulting solid was filtered off and washed with ether and dried in vacuo to give the title ester sulfoxide.

The filtrate was evaporated to dryness and the residue was triturated with 100 ml of anhydrous ether and the resulting solid treated in a similar manner to that described above to give a further yield of the title ester sulfoxide. The two portions of sulfoxide ester were combined to give 2.26 g of the product, m.p. Mg = 165 ° C, [α] 22 = + 44.7 ° (c = 0.91, DMSO).

Method ii a) Potassium (IS, 6R, 7R) -3-carbamoyloxymethyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] ceph-3-em-4-carboxylate, 1-oxyd_

A solution of 0.216 g (2.2 mmol) of potassium acetate in 15 ml of ethanol was added to a solution of 0.88 g (2 mmol) (1S, 6R, 7R) - 3-carbamoyloxymethyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] ceph-3-em-4-carboxylic acid, 1-oxide in 15 ml of dry Ν, Ν-dimethylformamide and an additional 10 ml of ethanol was added.

The resulting suspension was cooled and the solid filtered and dried to give the title salt as 0.946 g (86%) of DMF solvate, Amax (pH 6 buffer) 263 nm (E? -0 = 312) with an inflection at 280 nm (E? -0 = 278).

1 cm 1 cm b) (R and S) -1- (Methoxycarbonyloxy) -ethyl- (1S, 6R, 7R) -3-carbamoyloxymethyl-7 - [(Z) -2- (fur-2-yl) 2-Methoxyiminoacetamido] -ceph-3-em-4-carboxylate, 1-oxide 1.07 g (7.7 mmol) (R, S) -1-chloroethyl methyl carbonate in 5 ml of Ν, Ν-dimethylformamide was added to 40 ° C heated suspension of 2.76 g (5 mmol) of potassium (1S, 6R, 7R) -3-carbamoyloxymethyl-7- [(7,) - 2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylate, 1-oxide, Ν, Ν-dimethylformamide solvate in 45 ml of dry Ν, Ν-dimethylformamide.

16 147513

After 2 1/4 hours, the reaction mixture was poured into 100 ml of 2N hydrochloric acid and 100 ml of ethyl acetate. The aqueous layer and solid were extracted with ethyl acetate (2 x 100 ml) and the organic solutions were combined and washed in the order of 3 x 100 ml 2N hydrochloric acid, 100 ml water, 2 x 100 ml saturated aqueous sodium bicarbonate, 100 ml water and 2 x 100 ml of saturated saline. The solution was treated with charcoal and then dried (magnesium sulfate) and evaporated to a yellow solid (0.64 g). Trituration of this material with 21 ° ether gave 0.06 g of the title / sulfoxide ester, [α] D = + 40 ° (c = 0.58 in DMSO), Amax (CHCl CH) = 277.5 nm (E ^% = 289).

B. (R and S) -1- (Methoxycarbonyloxy) -ethyl- (6R, 7R) -3-carbamoyloxy-methyl-7 - [(Z) -2- (fur-2-yl) ) -2-Methoxyiminoacetamido] -ceph-3-em-4-carboxylate

A cooled solution of 2.12 g (3.9 mmol) (R and S) -1- (methoxy-carbonyloxy) -ethyl- (1S, 6R, 7R) -3-carbamoyloxymethyl-7 - ((Z) - 2 - (fur-2-yl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylate, 1-oxide in 10 ml of Ν, Ν-dimethylformamide was treated in the above order with 2.59 g (15.6 mmol) potassium iodide and 0.55 ml of acetyl chloride, and the mixture is stirred at about 4 ° C for 1 hour, then partitioned between 60 ml of ethyl acetate and 60 ml of 2N hydrochloric acid, the aqueous phase is extracted with 3 x 40 ml of ethyl acetate and the combined organic extracts are washed the above order with 40 ml of water, 40 ml of 3% aqueous sodium bicarbonate solution, 40 ml of water, 50 ml of aqueous sodium bisulfite, 40 ml of water and 50 ml of saturated brine, The organic solution was dried and evaporated to dryness under vacuum.

Trituration of the residue on 2.1 g with 50 ml of diisopropyl ether gave a solid which was filtered off, washed with additional diisopropyl ether and dried under vacuum.

This 1.99 g solid was stirred with 20 ml of anhydrous ether for 2 hours, then filtered, washed with additional ether, filtered off and dried in vacuo to give 1.6 g of the title ester, m.p. Mg = 121 ° C (dec.), [Α] D = + 11.8 ° (c = 0.91, DMSO).

1475 13 17

Example 4 (R and S) -1- (Isopropoxycarbonyloxy) -ethyl- (6R, 7R) -3-carbamoyloxy-methyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] - ceph-3-em-4-carboxylate (a) (R and S) -1- (Isopropoxycarbonyloxy) -ethyl- (6R, 7R) -3-carbamoyloxymethyl-7 - [(Z) -2- (fur-2) -yl) -2-methoxyiminoacetamido] -ceph-3-em-2,4-carboxylate and its Δ-isomer

A solution of 1.0 g (6 mmol) of (R, S) -1-chloroethyl isopropyl carbonate in 5 ml of acetone was stirred with a solution of 1.50 g (10 mmol) of sodium iodide in 20 ml of acetone for 4 hours.

Then the mixture was evaporated to dryness in vacuo and the residue was added to a solution of 2.50 g (5.4 mmol) of potassium (6R, 7R) -3-carbamoyloxymethyl-7 - [(Z) -2- (fur-2) yl) -2-Methoxyimino-acetamido] -ceph-3-em-4-carboxylate in 20 ml of Ν, Ν-dimethylformamide and stirred for 2 hours. Additional portions of 1.0 g, 1.0 g and 1.5 g (6, 6 and 9 mmol) of (R, S) -1-chloroethyl isopropyl carbonate were added after 0, 16 and 22 hours and the reaction mixture was stirred for an additional 16 hours. at which time the reaction was substantially complete (by TLC). The reaction mixture was partitioned between 70 ml of ethyl acetate and 80 ml of 2N hydrochloric acid. The aqueous phase was extracted with ethyl acetate (3 x 40 ml) and the combined organic extracts were washed in the above order with 2 x 50 ml water, 50 ml aqueous sodium bicarbonate solution, 50 ml water and 50 ml saturated brine, and dried and evaporated under vacuum to dryness. . Trituration of the residue with 50 ml of diisopropyl ether gave a mixture of the two titled esters. This mixture had the following physical properties: λ max (ethanol) = 277.5 nm (E .. = 303).

j. if b) (R and S) -1- (Isopropoxycarbonyloxy) -ethyl- (1S, 6R, 7R) -3-carbamoylloxymethyl-7 - [(Z) -2- (fur-2-yl) -2- methoxyiminoacetamido] -ceph-3-em-4-carboxylate, 1-oxide

A solution of 1.9 g (3.43 mmol) of the product obtained in Example 4 a) in 20 ml of dichloromethane was treated with 0.74 g (4.3 mmol) of m-chloroperbenzoic acid.

The mixture was stirred at 22 ° C for 1 hour and then evaporated under vacuum to dryness. Trituration of the residue with 80 ml of anhydrous ether gave a solid which was filtered off, washed (with anhydrous ether) and dried in vacuo to give 1.50 g 3 of the title ester sulfoxide with m.p. = 147513 18 176 ° (decomposition), [α] 22 = + 55.4 ° (c = 1.0, DMSO).

c) (R and S) -1- (Isopropoxycarbonyloxy) -ethyl- (6R, 7R) -3-carbamoyl-oxymethyl-7- [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] - ceph-3-em-4-carboxylate

One to approx. 4 ° C cooled solution of 1.37 g (2.4 mmol) of the product obtained in Example 4 b) in 20 ml of Ν, Ν-dimethylformamide was treated with 1.60 g (9.64 mmol) of potassium iodide and 0.34 ml of acetyl chloride and the reaction mixture was stirred at 4 ° C for 1 hour.

The mixture was then partitioned between 70 ml of ethyl acetate and 80 ml of 2N hydrochloric acid.

The aqueous phase was extracted with 3 x 50 ml of ethyl acetate and the combined organic extracts were washed in the order of 2 x 50 ml of water, 50 ml of aqueous sodium metabisulphite solution, 50 ml of water and 50 ml of saturated brine, and dried and evaporated to dryness under vacuum. The resulting residue was triturated with 100 ml of anhydrous ether, filtered off and dried in vacuo to give 0.86 g of the title ester, m.p. = 109 ° C (dec.), Fa] D = + 18.2 ° (c = 1.0, DMSO).

Example 5 (R and S) -1- (Ethoxycarbonyloxy) -ethyl- (6R, 7R) -3-carbamoyloxymethyl-7 - [(Z) -2-fur-2-yl) -2-methoxyiminoacetamido] -ceph-3 -em-4-carboxy- lat_

To a stirred suspension of 2.10 g of starting material 7 in 50 ml of anhydrous Ν, Ν-dimethylformamide, cooled to -4 ° C, was added 1.28 g of 1-bromomethylethyl carbonate. An additional Ν, Ν-dimethylformamide, 30 ml, was added after 20 minutes and an additional 20 ml portion after 50 minutes. The suspension was stirred for a total of 1-5 hours at -4 ° C to + 2 ° C, then 1.72 ml of trichloroacetyl isocyanate was added, causing the temperature to rise to 8 ° C. The resulting clear solution was stirred for an additional 10 minutes and then poured onto ice. Saturated aqueous sodium bicarbonate solution (100 mL) and ethyl acetate (250 mL) were added and the aqueous layer was separated and extracted with ethyl acetate (2 x 250 mL). The combined organic layers were washed successively with 2 x 100 ml water, 3 x 100 ml hydrochloric acid, 2 x 100 ml water and 100 ml saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to ca. 50 ml. The solution was added dropwise to 250 ml of petroleum ether and the precipitated solid was filtered off, washed with 3 x 50 ml of gasoline and dried under vacuum. The crude product, 1.435 g, was chromatographed on 150 g of silica gel eluting with a mixture of dichloromethane and ethyl acetate, first in a ratio of 3: 1 and in an amount of approx. 1 liter, and then in a 3: 2 ratio.

The relevant fractions were combined and evaporated to give a foam which was dissolved in 25 ml of ethyl acetate and added dropwise to 250 ml of stirred n-hexane. The resulting solid was filtered off and dried under reduced pressure to give 0.790 g of a mixture which was found by HPLC to contain the title compound.

[α] D = + 105 ° (c = 1.036 in ethanol), xmax (ethanol) 275 nm, 1 S; 380th

lem

Example 6 (R and S) -1- (Ethoxycarbonyloxy) -ethyl- (6R, 7R) -7- [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -3-trichloroacetylcarbamoyloxymethyl ceph-3-em-4-carboxylate

To a suspension of 2.10 g of starting material 7 in 100 ml of anhydrous Ν, Ν-dimethylformamide, stirred at -2 ° C, was added 1.28 g of 1-bromomethylethyl carbonate. A solution was formed as the mixture was stirred for 2 hours at -2 ° C to + 4 ° C. Trichloroacetyl isocyanate (1.72 ml) was added, increasing the temperature to 6 ° C and stirring for a further 15 minutes during which time the temperature dropped to 0 ° C. The solution was poured into ice and 2N hydrochloric acid (250 ml) and extracted with 2 x 200 ml of ethyl acetate. The combined organic extracts were washed successively with 2 x 100 ml of 2N hydrochloric acid and the aqueous layers were combined and extracted with 50 ml of ethyl acetate. The combined organic phases were then washed with 100 ml of water, 2 x 100 ml of saturated aqueous sodium bicarbonate solution and 100 ml of water in that order and the alkaline extracts were extracted with 100 ml of ethyl acetate. The combined organic phases were washed with 2 x 60 ml of saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to ca. 30 ml. The solution was added dropwise to 250 ml of stirred gasoline and the precipitated white solid was filtered off, washed with gasoline and dried in vacuo to give a mixture in an amount of 1.848 g, which mixture was found by HPLC to contain the title [α] D = + 62.2 ° (c = 0.965

1% D

nol), xmax (ethanol) 274 nm, E ^ cm 318.

Example 7 (R and S) -1- (Ethoxycarbonyloxy) -ethyl- (6R, 7R) -3-carbamoyloxy-methyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] - ceph-3-em-4-carboxylate

A solution of 200 mg of the product of Example 6 in 6 ml of methanol was stirred with 100 zinc dust for 6.5 hours. The solution was filtered through diatomaceous earth and the filter pad was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and added dropwise to petroleum ether to precipitate a solid which was filtered off and dried under reduced pressure to give 104 mg of a mixture which was found by HPLC to contain the title compound with Xmax (ethanol) 277 nm, E? -0 = 365.

lem

Example 8 (R and S) -1- (Ethoxycarbonyloxy) -ethyl-6R, 7R) -7 - [(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] -3-carbamoyloxymethylceph-3-em -4-carboxylate

To a solution of 1.37 g of starting material 11 and 0.60 g of (Z) -2- (fur-2-yl) -2-methoxyiminoacetic acid in 25 ml of anhydrous dichloromethane was added 0.825 g of dicyclohexylcarbodiimide and 12 mg of p-dimethylaminopyridine. The resulting suspension was stirred for 55 minutes, then 2 drops of glacial acetic acid were added. The solid was filtered off and the filtrate was concentrated and chromatographed on 200 g of silica gel eluting with a 3: 2 mixture of dichloromethane and ethyl acetate. The relevant fractions were combined and concentrated, filtering a solid and the filtrate, ca. 20 ml, was added dropwise to 200 ml of stirred petroleum ether. The resulting precipitate was filtered off, washed with gasoline and dried in vacuo to give 1.03 g of the title compound. M + g 93 ° [α] + = + 59 ° (c = 0.982 in chloroform).

Claims (2)

1475 13 1. Analogous process for preparing cefuroxime esters of the general formula. Η HJ — C.CO.NH — ZZ / 'N 1 tt i_N Λ-CHo.0.C0.NH_ \ V 1 l OCH, 0 TJ Ixi CO.O.CH.O.CO.OR i2 1. where R is an alkyl group of 1-6 carbon atoms, R is hydrogen or an alkyl group of 1-6 carbon atoms and the asterisk indicates an asymmetric carbon atom when R is different from hydrogen, characterized by a) reacting cefuroxime, (6R, 7R) -3- carbamoyloxymethyl-7 - [(Z) - 2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylic acid, a salt thereof or a corresponding 1-oxide, with a halogen ester of formula x 1 X.CH.O.CO.OR II i2 1 2 wherein R and R have the above meanings and X is halogen, whereby, if a 1-oxide is formed, the resulting product is reduced, or b) acylates a compound of the formula H Ss y - | --γ '"-i ^ ch2ocohh2 m • x 1 CO.O.CHO.CO.OR i2