SU520050A3 - The method of obtaining derivatives of penicillin or cephalosporin - Google Patents

Description

OBTAINING DERIVATIVES OF PENICILLIN OR

(54) METHOD

CEFALOSPORINA

one

The invention relates to the field of obtaining new derivatives - penicillin or cephalosporin, which have interesting biological activity and can be used in the pharmaceutical industry.

There is a known method in the literature for obtaining derivatives of 7-substituted aminocephalosporanic acid by reacting 7-isocyanatocephalosporanic acid in which the carboxyl group is blocked with a carboxylic acid, followed by removal of the protective group and isolation of products in a known manner.

A method for preparing penicillin or cephalosporin derivatives of the general formula based on the known reaction is proposed.

R, R,

N

CK-CO-IJH-Q

one

R,

where Q is the remainder of the general formulas

l

SNS

with he

in which X is a hydrogen atom, a hydroxyl group or a lower alkanoyloxy group, or a CH2X group and a carboxyl group are linked together to form either the lactone group —CO — OCH2, or the lactam group CO — NH — CH—;

RI is lower alkyl or aryl, which may have one or more substituents selected from the group including chlorine, fluorine, lower alkyl, nitro or amino group,

preferably 2,6-dichlorophenyl, or Ri-goig-alkyl;

R2 is hydrogen lower alkyl, carboxyl group, lower alkoxycarbonyl group, or carboxyl group, converted to

alkali metal or alkaline earth metal or amine salt, cyano, carbamyl, amino group, chlorine atom;

Ks - hydrogen atom, halogen, cyano, amino, lower aralkoxycarbonylamino group, lower alkyl, carboxyl group, pisca alkoxycarbonyl, aryloxycarbonyl, lower aralkoxycarbonyl group, carbamoyl group, which can be replaced by lower alkyl, freqcarbonyl group, lower aralkoxycarbonyl group;

or their salts with w, alkaline or alkaline earth metals or aminamn, or their esters or amides.

The method consists in that 6-isocyanatopenicillanic acid or 7-isocyanatocephalosporanic acid of the general formula

O CN-Q,

in which Q has the above meanings, and the carboxyl or hydroxy group present in Q is protected, is reacted with an acid of the general formula

R. RZ

K / N

About CH-Кз

soon

in which Ri, R2 and Kz are as defined above.

This reaction is preferably carried out in an inert organic solvent, for example toluene, dichloromethane, benzonitrile. If desired, a small amount of base, which is the substituted imidazole, can be used as a catalyst in this reaction.

In the compounds obtained with this, the protecting groups, which are usually a di- or trialkylsilyl group, are optionally cleaved off, for example by hydrolysis, and the resulting acid is transferred, if necessary, to the corresponding salt or ester or amide.

Lower alkyl everywhere means alkyl containing not more than 4 carbon atoms.

Example 1. Preparation of sodium salt of (2,5-dichlorophenyl) -isoxazol-5-yl - acetamido} -penicillanic acid.

A 250 ml flask with three necks is supplied with a thermometer, a good cooler and a dropping funnel. The reaction is carried out in nitrogen. 220 ml of dichloromethane and 2.72 g (10 mmol) of 3- (2,6-dichlorophenyl) -isoxazole-5 acetic acid are introduced into the flask. After adding 0.13 ml of N-vinylimidazole (catalyst), a solution of 3.14 g (10 mmol) of trimethylsnlyl-6-isocyanatopenicillanate in dichloromethane is added dropwise to the stirred solution at a temperature of 20 ° C. After 23 hours, the reaction is complete and the isocyanate is converted to the desired product with a yield of about 70%. The reaction mixture is poured into ice water, where the pH is maintained.

equal to 7 and subjected to extraction twice with simple diethyl ether. The aqueous layer is acidified to a pH value of 4 and extracted three times with diethyl ethyl ether. The desired product is completely separated from the aqueous layer. The collected organic layers are washed with a small amount of ice water and then dried over anhydrous magnesium sulphate, filtered and evaporated several times under vacuum at 0 ° C.

A solution of sodium a-ethyl carbonate in ethyl acetic acid is added dropwise to the concentrated solution. The colorless precipitate that forms is collected on a filter, washed with diethyl ether and dried in vacuo. The yield is 2.81 g (57%).

Analysis of the PMR spectra of the product, dissolved in hexadeuterodimethylsulfonic oxide 60 Me, b-VRNA, ppm, internal standard-tetramethiellane):

Nmultiylet at 8.95

(0.7 proton)

 SbN around 7.5 (3 protons)

isoxazolyl-H6,50 (proton)

-SPA-Cr-H 3.99 (3 protons) Sat-N and Sat-Nmultiplet between 5.50

and 5.30 (2 protons) Cz- (CH3) 21.62 and 1.52 (doublet

6 protons)

Partial analysis by IR spectra (in KBG disk, size), 3365Н

° 1750С O r-lactam

1700C O amide

1610С About carboxylate

and he

1505NH deformation

1600C O aromatic

1330 Isoxazolyl ring

788 1C-C1 increasing with

755 Jibratsi

5 Example 2. Preparation of (2,6-dichlorophenpl) -4-carboxyisoxazol-5-yl-acetamndo} -penicillanic acid.

In a flask with three necklets, equipped with a gaseous tube, a thermometer and a dropping funnel, 314 mg (1 mmol) of trimethylsnlyl-6-isocyanatopenicillanate and 316 mg (1 mmol) of 3- (2,6-dichlorophenyl) -4-carboxyisoxazole-5- are mixed Iluacetic acid prepared by the reaction of 3- (2,6-dichlorophenyl) -45; carboxy-5-methylisoxazole formed by the addition in polar opposite positions of 1,3,2,6-dichlorfeiylbenzonitriloxy and trimethylsilyl-2-butynolone with two equivalents of n-butyl lithium and one equivalent of tetramethylethylenediamine in toluene followed by the introduction of CO2, dissolved in 25 ml benzonitrile.

A solution of 145 mg (1.1 mmol) of N-methylbenzimidazole is added dropwise to this mixture.

in 5 ml of benzonitrile. There is a direct formation of carbon dioxide. After 2 hours, the removal of carbon dioxide is stopped and the reaction mixture is then poured into a mixture of 30 ml of water and 50 ml of diethyl ether, cooled with ice, and the pH value is 7. The aqueous solution is extracted twice with 50 ml of diethyl ether.

After addition of 50 ml of diethyl ether and 10 ml of ethyl acetate, the pH value is 4. The layers are separated and the aqueous layer is extracted twice more with 50 diethyl ether.

The combined organic layers are washed with ice water and dried over magnesium sulfate. After removal of the solvent, 136 mg of a solid with a faint yellow tint is obtained, which has been purified.

Example 3. Preparation of the sodium salt of (2,4,6-trimethylphenyl-isoxazole - 5 -yl 1-acetamido) -penicilliaic acid.

Basically, as described in Example 1, 1, 23 g (5 mmol) of 3- (2,4,6-trimethylphenyl) -isoxazol-5-yl-acetic acid reacted with 1.57 g (5 mmol) of trimethylsilyl-6-isocyanatocenicillanate in 25 ml of drained dichloromethane in the presence of about 0.05 ml of N-vinylimidazole (as a catalyst).

The reaction ends after 6.5 hours. In accordance with thin layer chromatography, the isocyanate is converted to the desired product in a yield of about 60%. The reaction product is treated in the usual way. At a pH of 4.5, penicillin is extracted from water by means of ethyl ether. The ether solution is washed with a small volume of ice water, treated with activated or vegetable or animal charcoal, dried over anhydrous magnesium sulphate and the concentration is increased several times under vacuum at 0 ° C.

A solution of α-ethylcapronate Iastri in diethyl ether is added dropwise to a concentrated solution.

The resulting colorless precipitate is collected by filtration and re-washed with cold diethyl ether. After BbicyujHBaHHH in vacuo, the weight of the product is 0.8 g. Thin layer chromatography, IR and PMR spectra indicate good purity of the product.

Example 4. Preparation of the sodium salt of (2,6-dichlorophenyl) -4-lethylisoxazole - 5nl1-acetamido} -peiollaic acid.

A solution of approximately 1 mmol of trimethylsilyl-7-isocyanate desacetoxycephalosnoranate in 2 ml of toluene is added to 286 mg (1 mmol) of 3- (2,6-dichlorfeiyl) -4-methylisoxazole-5-yl-acetic acid, partially dissolved in 10 ml of dried toluene. The introduction of approximately 0.1 mmol of 1-isopropylbenzimidazole (as a catalyst) causes the onset of a medlene reaction (which lasted 24 hours at room temperature).

When no more carbon dioxide emissions are observed in the dried stream of nitrogen passing over the surface of the stirred reaction mixture, the contents of flask 5 are poured into a well-mixed mixture of ice water and diethyl ether. The OH value is adjusted to 6.8, the layers are separated, and the aqueous layer is extracted twice with diethyl ether. The combined organic layers are washed twice with ice water. The organic layer was decanted and the combined water layers (70 ml) at a pH value of 2.3 removed 80 ml of a mixture (2: 1) of 15 ethylethyne simple Efnr and ethyl ester of acetic acid. This extract is washed twice with 5 ml of ice water. Sushat over anhydrous magnesium sulphate, filter and completely evaporate in vacuo. The residual oil is slightly yellow and hardens when it is stirred in dry diethyl ether. The ether is decanted and the solid is again mixed twice with ether. The almost colorless solid 5 is dried under vacuum to constant weight. The yield was 290 mg. The resulting product is purified by thin layer chromatography, which shows the presence of only one sulfur-containing compound. The expected structure was confirmed by IR and PMR spectra. The PMR spectrum indicated that the product obtained was about 82% pure because it contained 1 mole of the starting acetic acid and 2.5 moles of diethyl ether 5 (possibly crystalline bound) and 5 mmol of the desired product.

Example 5. Preparation of the salt of cyclohexnlamine 6- {a-chloro-3- (2.4,6-trimetnlphenylUisoxazole-5-nl-acetamido} - penicillanic acid 0.

A solution of 700 mg of trnmethylsilyl-b-isoacetate nanopenicillate in 10 ml of dried dichloromethane over 25 minutes is added dropwise to a solution of 700 mg of 1-chloro-1-HZ- (2.4,6-trimethyl 5 feinl) -isoxazol-5-yl-acetic acid and about 0.03 ml of N-vinylimndazole (as a catalyst) in 25 ml of dried dichloromethane.

The reaction mixture was added for 4 hours. Then hydrolyzed by the introduction of about 0.2 ml of ethanol at a temperature of 0 ° C. The reaction mixture is poured into a burying mixed mixture of simple diethyl ether and ice water, which has a pH of 7. After separation of the layers, the water layer is extracted once more with simple ethyl ethyl alcohol and then acidified to a pH of 3.5. The desired compound is completely removed from the aqueous layer by double extraction with diethyl ether. These extracts were combined, washed with a small volume of ice water, dried over anhydrous magnesium sulphate and evaporated in vacuo. The residual oil is dissolved in 5 ml of acetone-a. Diluted solution

cyclohexylamine in diethyl ether is added slowly so that there is no increase in temperature of the precipitate. The colorless solid is collected on a filter, washed with cold diethyl ether and dried in vacuo. The yield was 250 g

The authenticity of the obtained product is confirmed by the PMR spectrum and the IR spectrum (KBr disk, 1775 p-lactam, 1680 C O ppm 1390 and 1450 isoxazole ring). The purity of the obtained product is 85%.

Example 6. Preparation of sodium salt 6 (3- (2, b-dichlopphenyl) -4-methylisoxazole-5il1-acetamido} -penicillanic acid.

Basically, as described in Example 11, with 286 mg (1 mmol) of 3- (2,6-dichloro) phenyl-4-methylisoxazol-5-yl-acetic acid, 314 mg (I mmol) of trimethylsilyl-6-isocyanatopenicillate in 10 react ml of dry toluene in the presence of about 0.01 ml of N-isopropylbenzimidazole (as a catalyst). The reaction mixture is mixed overnight at 15 ° C. In accordance with thin-layer chromatography, the isocyanate is converted into a fired product. The reaction product is treated in the usual way.

At a pH of 3.8, penicillin removes -13 of the aqueous layer by extracting three times with iO ml of diethyl ether. The combined extracts are washed with ice water, sutured over anhydrous magnesium sulphate, filtered and evaporated in vacuo to a volume of 3 ml of Trimeono. The addition of a solution of ethyl {apronate sodium in diethyl ether trihydrates to a colorless precipitate, (which is collected on a filter, washed with hot diethyl ether, and dried in vasum to constant weight. Poolly KT is ground to powder in a small cold dried acetone. The yield is 300 mg.

The test of the obtained product is fine: with a loynoy komatografny, on the IR spectrum,: spectrum of PMR, confirms the necessary: structure. The product is only slightly contaminated with 1 very small amount of acetone and sodium sodium tacylcapronate.

Example 7. Preparation of cyclohexlamine salt 6 - Ggu-methyl-GZ- (2.4,6-trimethylphenyl): zoxazol-6-yl-acetamido} - penicillanic acid;

Basically, as described in Example 5, the reactivity of equimolar amounts of trimethylsilyl-isocyanatopenicillapate and 1-methyl-1- 32, 4, b-trimethyl) -phenylisoxazol-5-yl-acetic acid is carried out in the presence of a small amount of N-viii or imidazole. The solvent is dried dichloromethane. The naked transformation occurs during

hour stirring at room temperature. The reaction mixture is processed in the usual way. During the separation, penicillin is extracted at a pH of 4 with diethyl

simple ether and get it as a salt of cyclohexylamine.

When using thin layer chromatography, IR spectrum (intensive absorption of | 3-lactamcarbonyl) at 1778 cm- (KBr discs) and the PMR spectrum confirm the expected structure of the obtained product and show its good state of purity.

Example 8. Preparation of sodium salt

, - (2,4, b-trimethyl) -phenyl-4 - methylisoxazol-5-yl - acetamido} - desacetoxycephalosporanic acid.

Basically, as described in Example 5, the reaction is carried out between 1.8 g (5 mmol) of 3- (2,4,6-trimethyl) -phenyl 4-methylisoxazole-5-yl-acetic acid, dissolved in 25 ml of dried dichloromethane, and 5 , 04 mmol of trimethylsilyl - 7 - isocyanatodesacetoxycephalosporanate, dissolved in 9 ml of toluene, in the presence of about 0.05 ml of N-vinylimidazole (as a catalyst).

The addition of the isocyanate solution in toluene is carried out for approximately 20 minutes. The release of carbon dioxide is noted after 5 minutes. After 7.5 hours of additional mixing, the reaction is interrupted, since thin-layer chromatography of the reaction mixture shows an isocyanate conversion of about 80% in the desired direction and the evolution of carbon dioxide almost ceased. The reaction mixture is treated in the usual way. Nefalosporin is extracted at a pH value of 4.5 using a mixture (9: 1) of diethyl ether and ethyl ether acetic acid. The combined extracts are washed with ice water, dried over anhydrous magnesium sulphate, filtered, and evaporated completely in vacuo. Residual oil

dissolved in diethyl ether.

Adding a portion of the calculated amount of α-ethylcapronate dissolved in diethyl ether gives a precipitate which is collected on a filter and

washed with a small amount of cold diethyl ether and dried in vacuo. Sodium ethyl ethyl capronate is again added to the combined filters. The solid precipitate obtained a second time is treated in the same manner as the first. For the third and last time, a precipitate is obtained by adding dissolved sodium a-ethylcapronate, until a further increase in the resulting precipitate occurs. Material received in

the third time, being pure, as indicated by thin layer chromatography, is crystallized from acetone. Such materials are combined together, their solution in acetone. The solution in acetone is slightly evaporated in vacuo and subsequently

seed crystals.

After the crystallization subsided, the flask was placed in an ice chamber. The next day, the crystals are collected by filtration, washed with cold acetone and diethyl ether and dried in vacuo to constant weight. The yield is 1.7 g.

The expected structure was confirmed by the IR spectrum and the PMR spectrum. In accordance with the PMR spectrum and thin layer chromatography, the resulting product is contaminated with only a small amount of acetone and a small amount of urea ML-dyzapopetotocetsefalosporanovoy acid.

Example 9. Preparation of (2,6-dichlorophenyl-4-carbamylisoxazol-5-yl-acetamido) -penicillanic acid.

600 mg (2 mmol) of 3- (2,6-dichlorophenyl) -4carbamylisoxazol-5-yl-acetic acid and 630 mg (2 mmol) of trimethylsilyl-5-nzonyanatopenicillayate are dissolved in a mixture of 15 ml of dried benzonitrile and 15 ml of dried tetrahydrofuran and directly with 15 ml of dried tetrahydrofuran and directly with 15 ml of dried benzonitrile and 15 ml of dried tetrahydrofuran and directly of 15 ml of dried tetrahydrofuran and then directly mixed im adding about 0.02 ml of N-methylimndazole. The carbon dioxide release decreased exactly after three hours of stirring at room temperature. Thin layer chromatography of the reaction mixture showed good isocyanate conversion. The reaction mixture is poured into a well-mixed ice-cooled mixture of 30 ml of water, 20 ml of diethyl ether and 20 ml of ethyl acetate. The NaOH solution is added until the pH reaches 8.5. The layers are separated and the AQUATIC layer is purified by extrusion with diethyl ether. The organic layers are poured and the aqueous layer at pH 3.0 is extracted with a mixture (1: 1) of diethyl ether and ethyl acetate. The combined extracts were washed with ice water, dried over anhydrous magnesium sulphate, filtered and completely evaporated in vacuo.

The resulting solid precipitate, c.low yellow (1.1 g), is subjected to the IR spectrum test and the PMR spectrum. The product contained the desired penicillin, however, also small amounts of U, N-dipenicillanic acid urea and the starting carboxylic acid. To obtain a cleaner sample, the crude product is re-extracted with cold dried diethyl ether, which dissolves the urea. The esterified extract is mixed with ice water having a pH of 7. Most of the starting carboxylic acid is removed from the aqueous layer at a pH of 4.5. The aqueous layer is re-subjected to extraction at a pH value of 4.5-3.5 with a mixture of a large amount of diethyl ether and a small, but gradually increasing amount of ethyl ester of acetic acid. The extracts, free from the starting carboxylic acid, urea and decomposition products, are combined and, after the usual treatment, are completely evaporated in vacuo. The resulting colorless solid was dried to constant weight (350 mg).

According to the results of thin-layer chromatography, the IR spectrum and the PMR spectrum of the final product was clean, however, a small residual quantity of ethyl acetate and diethyl ether was present.

Example 10. Preparation of the sodium salt of (2,6-dichloro-phenl) -4-cnanoisoxazole - 6Il-acetamido) - peiciclaic acid.

297 mg (1 mmol) of 3- (2,6-dichlorophenyl) -4-cyanoisoxazol-5-yl-acetic acid, 314 mg (1 mmol) of trimethylsilyl-6-isocyanatopenicillanate and a small amount of N-isopropyl-benzimidazole is dissolved in 5 ml of dry dichloromethane. As shown by thin layer chromatography, good isocyanate conversion is achieved after 3 hours of conducting the reaction at room temperature. The reaction product is treated in the usual way. A solution of penicillin in water is purified by extraction with diethyl ether at pH 7.0 and 4.5. Penicillium is removed from water by extraction with diethyl ether at a constant pH of 3.3.

The esterified extract was washed with ice water, dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo. The residual oil is dissolved in about 3 ml of dried ethyl acetate, followed by the addition of about 0.6 mmol of sodium a-ethylcapronate dissolved in a small volume of ethyl acetate. Adding dried diethyl ether resulted in

Slowly stain the precipitate, which is collected by filtration, washed with cold diethyl ether and dried under vacuum to constant weight. The yield is 180 mg. Example I. Preparation of the sodium salt of (1) -adamantylisoxazol-5-yl-acetamndo} -penicillanic acid.

Basically, as described in Example 5, a solution of 780 mg (2.5 mmol) of trimethylsilyl-6-isocyanatonenicillate in 10 ml of dried dichloromethane is added but dropwise to a solution of 650 mg (2.5 mmol) of 3- (1) -adamantylisoxazole 5 α-l-acetic acid and about 0.02 ml of N-BH nilimidazole in 20 ml of dried dichloromethane. The transformation was completed in 2.5 hours of stirring at room temperature, as indicated by the termination of carbon dioxide released. Thin layer chromatography indicates a good conversion of isocyanate to the desired penicillanic acid. The reaction product is treated as usual. In the separation, the penicillan compound is extracted with nz water by extraction twice with diethyl ether,

carried out the first time at pH 5.5 and the second at pH 4.0. The extracts are separately washed with ice and water, dried over anhydrous magnesium sulphide, filtered and completely evaporated in vacuo. The output is 700 and 300 mg, respectively.

eleven

Both products showed good IR spectrum and, as shown by thin layer chromatography, had only one penicillin-containing material. Since the sample obtained by extraction at a pH value of 5.5 is contaminated with the starting acetic acid derivative, it is dissolved in ether with the subsequent addition of sodium a-ethylcapronate. The resulting sodium salt (360 mg) is the pure product with the exception of the presence of a pebolic amount of residual G ethyl sodium.

As shown by the PMR spectrum, the second product is pure, with the exception of the presence of small amounts of diethyl ether (about 4.0 wt.%).

Example 2. Preparation of 6- (a - ("- pitrobenzyloxycarbonylamino) -GZ- (2,6 - dichlorophenyl) -isoxazol-6-yl-acetamichChO} - pyiicillanic acid.

2.33 g (5 mmol) 1 - fl-nitrobenzyloxycarbonylamino) -1-ГЗ- (2,6-dichlorophenyl) - isoxazol-6-yl-acetic acid 1.57 g (5 mmol) tpimetilsilid-5-isocyanatopenipylate and 0.1 ml N-vinylimidazole (as a catalyst) is dissolved in 50 ml of dried dichloromethane. After 3 hours of stirring in nitrogen at room temperature, the conversion is complete. According to thin layer chromatography, the isocyanate is minced to 70% in the desired product. The reaction product is cooled to 0 ° C, followed by the addition of a few ml of cooled acetone containing sufficient amounts to hydrolyze the silylether. The mixture is then completely evaporated under vacuum in the cold. The residue is dissolved in 75 ml of a cold mixture (1: 1) of diethyl ether and ethyl acetate. Since a penicillin-containing material is used to prepare the compound of Example 14, it is not the product in the substantially pure state that is separated out to separate it, but the desired product as much as possible. Therefore, the solution is combined with 70 ml of ice water having a pH of 7. The well-stirred mixture is acidified to a pH of 5.8 and transferred to a separatory funnel. In one layer it is lowered and separated because it contains N.N-dipenicillanic acid urea and some amount of the desired product.

The organic layer is sequentially washed twice with weakly acidified ice water and once with a neutral amount of water. The organic layer, completely freed from urea and catalyst, is dried over anhydrous magnesium sulphate, filtered and completely evaporated in the cold.

The residue is in vacuum to constant weight. The yield is 3.4 g of a slightly yellow crystalline solid. Thin layer chromatography of the obtained product showed the presence of only the desired penicillin-containing compound and the outcome12

NOIs amino acids in a ratio of about 2: 1. This is confirmed by the PMR spectrum, which also reveals the presence of ethyl acetate and a small amount of water. The calculated content of the desired penicillin in the raw product was from 2.2 to 2.4 g.

Example 13. Preparation of 6- {a-amino-310 (2,6-dichlorophenyl) -isoxazol-5-yl-acetamido} -pennicenanoic acid.

3.0 g of the crude product obtained in Example 12, containing about 2 g of 6- {a- (pnitrobenzloxycarbonylamino) (2.6 - di5-chlorophenyl) -isoxazol-6-yl-acetamido-penicillanic acid, dissolved in 100 ml of ethyl ether acetic acid is mixed with 25 ml of water. By adding dilute sodium hydroxide, the pH value of the mixture takes the value 7. After the introduction of 1.5 g of Pd - C 10%, hydrogen was continuously passed. Thin layer chromatography showed that the reduction was complete after 135 minutes of stirring at room temperature.

5 Over a period of 10 minutes, nitrogen was passed through the reaction mixture, water was added and the pH reached 4.7. The contents of the funnel are transferred to a separatory funnel. The mixture penetrates the clear ethyl acetate layer.

0 acid and the aqueous layer from the emulsion layer are separated. The aqueous layer is removed and removed. Then the layer of the emulsion is subjected to centrifugation. The resulting layers are separated. The ethyl acetate layer combines

5 with the first ethyl acetate extract. The aqueous layers are also combined and once again subjected to extraction with ethyl acetate. The aqueous layer is drained. The remaining catalyst is removed from the collected acetic acid ethyl ester extracts by filtration. The colored filtrate is evaporated at 0 ° C under vacuum to a volume of 25 ml. 100 ml of ice water are added and

5 The mixture has a pH of 7.0. The layers are separated and the colored organic layer is drained. A solution of the desired compound in water is purified by extraction twice with a mixture (1: 1) of ethyl acetate and

0 diethyl ether. The resulting nearly colorless solution in water is acidified to a pH of 4.7 and is subjected to extraction twice with an excess volume of ethyl acetate. Water layer

Claims (3)

5 is poured off and the combined layers of ethyl acetate are washed twice with a small amount of glacial acid. Thin layer chromatography showed one oblong (compound represented by D, L0 mixture) gray positive spot. After complete evaporation of the extract, a colored solid was obtained. The yield is 650 mg of material. An IR spectrum is obtained from the obtained product and the PMR spectrum is found to have obtained (i: 1) the desired penicillin and ethyl acetate, possibly contaminated with a small amount of 3- (2,6-dichlorophenyl) -isoxazole derivatives. Example 14. Obtaining the sodium salt of (4-nitro) -phenylisoxazol-5-yl-acetamido) -penicillanic acid. The reaction is carried out in the usual manner with 166 mg) (0.67 mmol) of 3- (4-nitrophenyl) isoxazol-5-yl-acetic acid. 210 microns (0.67 mmol) of trimethylsilyl-8-isocyanatopenicillanate and traces of N-isopropylbenzimidazole. The solvent is benzonitrile (5 ml). The reaction is complete after 5 hours of stirring at room temperature. The contents of the flask are poured into a cold ice well-mixed mixture of 25 ml of water, 20 ml of diethyl ether, and 25 ml of ethyl acetate. By adding dilute NaOH, the acidic mixture (pH 3.0) is neutralized to a pH value of 7 and the layers are separated. The organic layer is poured and the aqueous layer is purified by extracting once with 40 ml of a mixture (1: 1) of ether and ethyl acetate. 30 ml of a mixture (1: 1) of a mixture of ether and ethyl acetate are mixed with the aqueous layer and the pH is lowered to 3.5. The layers are separated and the aqueous layer is again subjected to extraction with 50 ml of the same solvent mixture. The combined organic layers are washed twice with a small volume of ice water, then dried over anhydrous magnesium sulphate, filtered and completely evaporated in vacuo. The resulting yellowish dough is ground to powder with dry diethyl ether. The obtained partially crystalline solid is collected by filtration and then re-mixed in ether. After vacuum drying, the resulting product weighs 73 mg. Examination of the product by thin layer chromatography and PMR spectromethod shows that the desired penicillanic acid contains 5-6 moles of water per 1 mole of the compound and a small amount of diethyl ether, however, it was virtually pure in other respects. The collected ether-containing filtrate and the washings were completely evaporated. The residue is dissolved in 3 ml of a dried mixture (1: 1) of ether and ethyl acetate and then treated in the cold with a dilute solution of sodium a-ethylcapronate in ether. The precipitated sodium salt of the desired penicillanic acid is collected by filtration and re-washed with dried ether. After experiencing the usual way. Apart from the remaining water (which is much less than in the case of unbound penicillanic acid), the purity of the sodium salt is 80-85%, since it contained about 5 wt. % decomposition products and 10-15 wt. % a-ethyl capronate sodium. Example 15. Preparation of 6- {3-methylisoxazol-5-yl-acetamido} - penicillic acid CHj-C - CH g1 H andA. c-CH-c-ii-cc with II 1 CN -C: GN mainly as described in Example 11, 282 mg (2 mmol). Z-methylisoxazol-5-yl-acetic acid was reacted with 628 mg (2 mmol) trimethylsilyl-6-isocyanate penicillinate in 10 ml of dry dichloromethane in the presence of three drops of N-isopropylbenzimidazole (catalyst). After conventional treatment of the reaction mixture, a slightly colored product of high purity was obtained according to TLC, IR and PMR spectra. Analysis of the PIR spectrum of the product dissolved in hexadeutero dimethyl sulfoxide with some D2O (60 MeS-value per ppm of parts per million; tetramethylsilane as internal ethanol): Isoxazolyl C4-H 6.22 Cz-H and Sb-H5.50 (2 proton) Cr-P4.32 SNg-CO-3.82 (2 protons) Isoxazolyl -CH3 2.23 Cz-CH3 / 21.65 and 1.52 Private analysis of the IR spectrum of the final product (in KBr value), ± 3500OK carboxyl 3350NH 1780C O p-lactam 1740C 0 carboxyl 1670O O amide 1380-1430 absorber, characteristic of isoxazole. Invention 1. Method for producing derivatives of penicillin or cephalosporin boiling the formula R, R2 CH-CO-NH-Q wherein Q - residue of the general formulas But ... H in which X - hydrogen, hydroxyl or lower alkanoyloxy, or a group - CHjX and carboxyl group vme15 ste form lactone group -CO-OCH2-, or lactam group -CO-NH-CHg; .RI is lower alkyl or aryl, which may have one or more substituents selected from the group including chlorine, fluorine, lower alkyl, nitro or amino group, or R is greg-alkyl; R2 is hydrogen, lower alkyl, a carboxyl group, a lower alkoxycarbonyl group or a carboxyl group transformed into a salt of the silk or sh, earth metal or amine, cyano, carbamyl, amino, chlorine atom; Rs is a hydrogen, halogen, cyano, amipO-, lower aralkoxycarbonylamino group, lower alkyl, carboxyl group esterified with lower alkyl, aryl or aralkyl, or a carbamyl group that may be mixed at the nitrogen atom by lower alkyl or phenyl. or their salts with bacterium or w, tree-earth metals or amines, or their; firs or their amides, distinguished by the fact that, 6-isocyanatopenicillanic or 7 isocyanatocephalosporanic acid of the formula; 20050 sixteen O CN-Q, in which Q is as defined above, and the carboxyl or hydroxy group present in Q is protected, is reacted with an acid of the general formula R, RZ And 1. l about CH-Rj COOU in which RI, Ra and Rs are as defined above, followed by isolation of the desired products or cleavage of the protective groups, if any, or by transferring the compounds to salt or ether or amide by known methods. 2. A method according to claim 1, wherein the isocyanate is reacted with an acid in the presence of a small amount of a base, for example, a substituted imidazole, as a catalyst. 3. Method according to paragraphs. 1 and 2, characterized in that the process is carried out in an organic solvent medium.