PL151670B1 - Method for manufacturing semisynthetic cephalosporins - Google Patents

Description

RZECZPOSPOLITA PATENT DESCRIPTION 151 670

POLAND

OFFICE

PATENT

RP

Additional patent to patent no - Int. Cl. ⁵ C07D 501/06

Reported: 87 03 19 (P. 264721)

Precedence - cnrnsii

Application announced: 88 10 27

Patent description published: 1991 02 28

Creators of the invention: Irena Oszczapowicz, Edward Żukowski, Jacek Kulak, Adam Sikora, Teresa Gumiężna, Barbara Sitek

Entitled by the patent: Biotechnology Research and Development Center, Warsaw (Poland)

Method of obtaining semisynthetic cephalosporins

The subject of the invention is a process for the preparation of semi-synthetic cephalosporins of the general formula I, where Ri represents an alkyl group containing up to five carbon atoms, a substituted or unsubstituted aryl or aralkyl, or a heterocyclic system containing such heteroatoms as sulfur, oxygen, nitrogen, preferably furyl, thienyl, thiazole, pyran, unsubstituted or substituted, for example, with groups such as halogen, alkyl, alkoxy, acyl, where the alkyl group contains a maximum of five carbon atoms, R2 is hydrogen, an alkyl group containing up to five carbon atoms, an optionally substituted carboxyl group, preferably a carboxymethyl group, carboxyisopropyl, cycloalkyl or alkenyl group with up to seven carbon atoms or alkoxycarbonylalkyl group in which alkyl and alkoxy contain up to five carbon atoms, R3 is hydrogen, halogen, hydroxyl, alkyl, alkoxy, containing up to four carbon atoms, hydroxymeth 1, halomethyl, acyloxymethyl, carbamoyloxymethyl, vinyl, 1-pyridinomethyl, [2,3- (1,3-propenyl)] -1-methylpyridinium, -CH2-S-R3 group, where R5 is a substituted or unsubstituted heterocyclic system containing such heteroatoms such as sulfur, nitrogen, preferably 1-methyl-lH-tetrazole, substituted or unsubstituted triazole, thiadiazole, thiazole, triazine, preferably 4-carboxymethyl-3-methyl-1,3-thiazole, 2,5-dihydro-6-hydroxy -2-methyl-5-oxo-1,2,4-triazine, 2,5-dihydro-6-hydroxy-2-methyl-5-oxylane-1,2,4-triazine or the group CH = CH-S-R6 where R6 is preferably 1,5,6-trihydro-4-formyl-1,2,4-triazine, R4 is hydrogen, a tertiary amine, preferably trimethylamine, triethylamine, tributylamine, N-methylpyrrolidine, N-methylpiperidine, N-ethylpiperidine, N -methylmorpholine, N, N-dimethylaniline, trimethylsilyl, alkyl containing up to five carbon atoms, substituted or unsubstituted aryl, or aralkyl, cycloalkyl, acylalkyl, acyloxyalkyl in which a 1kyl has a maximum of six carbon atoms, preferably acetylmethyl, acetyloxymethyl, acetyloxyethyl, pivaloyloxymethyl, 2-methoxy-2-methylpropionyloxyethyl, 2-methoxy-2-propionyloxyethyl.

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Compounds of the general formula I, in which R1-R4 have the meaning given above, especially those having a 2-alkoxyimino (-NOR2) group in the Z (syn) configuration in the side chain, are characterized by a very strong antibacterial activity against many Gram-positive and Gram-positive microorganisms. negative. Moreover, due to the presence of the 2-alkoxyimino (-NOR2) group in the side chain, the compounds of the general formula I show very high resistance to the action of J-lactamases produced by gram-negative microorganisms.

Many compounds of general formula I have found wide application in the treatment of infectious diseases.

The known methods for the preparation of cephalosporins of the general formula I, in which R1-R4 have been defined above, mainly consist in acylating the free acids, salts or esters of Ίaminocephalosporanic acid or its derivatives substituted in the 3-position, with active derivatives of the acids of general formula 4, in which R1 and R2 have been defined above. Chlorides and mixed anhydrides are mainly used as active compounds mentioned.

Depending on the type of the 7-aminocephalosporanic acid derivative used, the type of active acid of the general formula 4 and the reaction conditions, the yield of the obtained cephalosporin of the general formula 1 ranges from 40 to 87% (Polish patent specifications Nos. 98 962, 101 031 , 102925, application P176 681, BUP 12/75, patents: BE 817304, BE 852 427, BE 866422, USA 4 180 658, EP37 380, J5 8 167 593 A). The acylating agent is also Ν, Ν-dicyclohexylcarbodiimide, with the reaction efficiency ranging from 31 to 75% (Polish patent description 98 962, patents: DT 2 204 108 A, DT 2 223 375 A, NL 7 606 614 and GB 2 029 823).

A completely different, known method for the preparation of compounds of general formula 1 is the reaction of acids of general formula 4 with esters of 7-isocyanatiocephalosporanic acids, presented in various ways in position 3 (Polish Patent Nos. 102925, 101 031).

There is also a known method of using esters of mercaptoalkylcarboxylic acids for the synthesis of cefamandol, i.e. cephalosporins with structure and physicochemical properties substantially different from the compounds of the general formula 1, being the subject of the invention (Polish patent application P 260 837, BUP 9/88).

According to the invention, the process for the preparation of cephalosporins of general formula 1 in which R1-R4 are as defined previously consists in reacting compounds of general formula 2 in which R3 and R4 are as previously defined, and R7 is hydrogen, trimethylsilyl or R7NH is HCl. NH2, with new reactive compounds of general formula 3, where R1 and R2 are as previously defined, Rs is an alkyl of up to three carbon atoms, and Rg is hydrogen, methyl, ethyl, acetylmethyl or ethoxycarbonyl, in organic solvents at a temperature -60 ° C to + 60 ° C, then the compounds of general formula I, in which R1-R4 are as defined above, are isolated as end products in the form of esters, free acids or salts.

As organic solvents in the process of the invention, preferably acetonitrile, halogenated aliphatic hydrocarbons such as methylene chloride, ethylene chloride, ethyl chloride, chloroform, cyclic ethers such as dioxane, tetrahydrofuran, aliphatic esters such as ethyl acetate, butyl acetate, Ν, Ν-dimethylformamide, N, N-dimethylacetamide, Ν, Ν-dimethylsulfoxide or mixtures of these solvents.

The reaction to prepare compounds of general formula I, wherein R1-R4 are as previously defined, is carried out for 1-70 hours, preferably 2-24 hours.

In the process of the invention, esters of general formula 3, wherein R 1, R 2, Re and R 9 have been defined above, are used as new reactive compounds for acylating compounds of general formula II.

The above method is a new, original method for the preparation of cephalosporins of the general formula I, in which R1-R4 are given above. The new compounds of the general formula III are obtained by reacting the active derivatives of the acids of the general formula IV, especially those having a 2-alkoxyimino (-NOR2) group with the Z (syn) configuration, in which R1 and R2 are as previously defined, with alkyl esters mercaptoalkyl carboxylic acids of general formula 5,

151 670 where Re and Ra are as previously defined, or by reaction of acids or salts of acids of general formula 4, where Ri and R2 are as previously defined, with compounds of general formula 5, where Re and R9 are as previously defined, in the presence of N, N-dicyclohexylcarbodiimide, in organic solvents at a temperature of -40 ° C to + 40 ° C, optionally in the presence of tertiary amines, whereafter compounds of general formula 3, where R1, R2, Re and R9 are as previously defined , are used in crude form for further syntheses or the compounds mentioned are purified and isolated.

Chlorides, bromides, azides, symmetric anhydrides or mixed anhydrides are used as active derivatives of acids of general formula IV, where R 1 and R 2 are as previously defined. Compounds of general formula V, in which Re and R9 are as defined above, are preferably mercaptoacetic acid ethyl ester, 2-mercaptopropionic acid ethyl ester, 2-mercaptosuccinic acid diethyl ester, 2-mercaptoacetyl acetic acid ethyl ester.

As solvents for the synthesis of new compounds of general formula 3, where R1, R2, Re and R9 are as previously defined, preferably acetonitrile, halogenated aliphatic hydrocarbons such as methylene chloride, ethylene chloride, ethyl chloride, chloroform, cyclic ethers such as such as dioxane, tetrahydrofuran, Ν, Ν-dimethylformamide, N, N-dimethylacetamide, Ν, Ν-dimethylsulfoxide, or mixtures of these solvents. The reactions to prepare compounds of general formula 3, wherein R 1, R 2, Re and R 9 are as previously defined, are preferably carried out for 1-24 hours.

As optional tertiary amines in the synthesis of compounds of general formula III, where R1, R2, Re and R9 are as defined above, preferably trimethylamine, triethylamine, tributylamine, N-methylpyrrolidine, N-methylpiperidine, N-ethylpiperidine, N-methylmorpholine, Ν, Ν-dimethylaniline. The obtained cephalosporins of the general formula I, where R1-R4 are defined above, are isolated in the form of esters, free acids or also salts. The resulting cephalosporins can be reacted at the 3-position of the cephalosporan system to give the final derivatives of the general formula I, where R1-R4 have been defined previously.

As is known in the process of preparation of semisynthetic cephalosporins of the general formula I, substituent synthesis or substitution reactions are known and used, both in the 7-position and the 3-position of the cephalosporan system, which acylation method at the 7-position is included in the process of the present invention. Accordingly, the known 3-substituent exchange reactions can be performed both before and after the acylation reaction. If the acylation is carried out after prior substitution of the 3-substituent, the target compound of general formula 1 is obtained.

On the other hand, when acylation occurs before the substitution of the 3-position substituent, an intermediate is obtained for which further reactions are required at the 3-position of the cephalosporan system, leading to the target compound of general formula 1. All 3-group exchange reactions may take place in known method only in the scope of R3 substituents, e.g. replacement of the 3-acetoxymethyl group with the 3-hydroxymethyl group by enzymatic or alkaline hydrolysis, replacement of the 3-hydroxymethyl group with the 3-carbamoyloxymethyl group by the action of an isocyanate (Examples XV, XVI and XVIII) and others. The compounds of general formula I obtained in this way are isolated in the form of esters, free acids or salts.

The method according to the invention has a number of significant advantages. The preparation of compounds of general formula 1 using esters of general formula 3, where R1-R9 are as previously defined, is carried out in the process of the invention under relatively mild conditions previously indicated, i.e. optimum reaction temperature around 0 ° C, slight excess of acylating agent , the use of inert solvents, and the yields of the final cephalosporins are close to the yields of synthesis of these compounds by known methods and amount to 55-80%.

An important advantage of the discussed method is the fact that during the synthesis of compounds of the general formula 1, where R1-R4 have been defined previously, the Z (syn) configuration of the 2alkoxyimino group does not change, which is very important for maintaining the high antimicrobial activity of the compounds according to the invention. Another significant advantage of the preparation of cephalosporins of the general formula I, where R1-R4 are as defined above, is the high purity of the compounds in question, equal to the purity of analogous cephalosporins obtained by known methods. Jed4

The new, highly reactive compounds of general formula 3 for acylating compounds of general formula 2 to give cephalosporins of general formula 1 in which R 1 -R 9 are as defined above are prepared under the mild conditions indicated above, while the yields of the discussed esters are relatively high and amount to 60-90%. It is very important that the compounds of general formula III obtained do not require thorough purification and can be used for further syntheses immediately after the reaction.

The following examples illustrate the invention.

Example I. To a solution of 9.37 g (0.05 mol) of 2- (Z-methoxyimino) -2- (2-furyl) -acetic acid chloride in 60 ml of tetrahydrofuran, under nitrogen atmosphere and at -25 ° C, 6, 6 g (0.05 mol) of 2-mercaptoacetic acid ethyl ester and stirred. Then, after completion of the reaction, the obtained solution is added to a mixture of 400 ml of water and 100 ml of methylene chloride, cooled to 0-5 ° C, and the pH is adjusted to about 6.0. After separating the layers, the aqueous layer was extracted 3 more times with 50 ml of methylene chloride, then the combined organic extracts were washed with brine solution (2 X 30 ml), then dried, decolorized with activated carbon and concentrated in vacuo. The residue obtained is washed with 2 X 30 ml of petroleum ether and evaporated again. 12.1 g of [2- (Z-methoxyimino) -2- (2-furyl) -acetylthio] -acetic acid ethyl ester were obtained, representing 85% of theory.

IR (film) - 1720 cm ^-1 (group C = O ester); 3080-3020 cm ¹ ; 995-930 cm ¹ ; 890-875 cm ¹ '-CH-furan ring /; 750-720 cm ¹ .

¹ H NMR / DMSO-d6,? (Ppm) -1.22, 3H, t, J = 7.0 (-CH ₂ -CH ₃ ); 4.05, 3H, s, (= NOCH ₃ ); 3.85-4.1.2H, q, J = 7.0 (-CH ₂ CH ₃ ); and 2H, -S-CH ₂ -CO-; 6.58 (1H), 6.69 (1H), 7.8 (1H), furan ring protons.

Example II. Proceeding analogously to Example 1, but using 2.0 g (0.01 mol) of 2- (Z-methoxyimino) -2- (2-thienyl) -acetic acid chloride, 2.3 g of ethyl ester of the acid [2- ( Z-methoxyimino) -2- (2-thienyl) -acetylthio] -acetic acid, 76% of theory.

IR (film) - 1715 cm ¹ (group C = O ester); 3090-3015 cm ¹ ~; 930-920 cm ¹ -CH-thiophene ring /; 850-840 cm ¹ .

¹ H NMR / DMSO-d ₆ ,? (Ppm) -1.25, 3H, t, J = 7.0 (-CH ₂ -CH ₃ ); 3.98, 3H, s, (= NOCH ₃ ); 3.82-4.15.2H, q, J = 7.0 (-CH ₂ CH ₃ ); and 2H, -S-CH ₂ -CO-; 7.05 (1H), 7.32 (2H), thiophene ring protons.

Example III. To a solution of 2.8 g (0.0166 mol) of 2- (Z-methoxyimino) -2- (2-furyl) acetic acid in 100 ml of methylene chloride is added, at 0-5 ° C, 2.12 g (0 0.0177 mol) of 2-mercaptoacetic acid ethyl ester, then 0.1 ml of N-methylmorpholine and 3.8 g (0.0184 mol) of Ν, Ν-dicyclohexylcarbodiimide and stirred at the indicated temperature. After completion of the reaction, the separated precipitate is filtered off, and the filtrate is added to 250 ml of water cooled to 0-5 ° C, adjusted to a pH of about 6.0 and the layers are separated. The aqueous layer was extracted with an additional 30 mL of methylene chloride, then the combined organic extracts were washed with brine solution (2 X 20 mL), dried and concentrated in vacuo. The residue obtained is washed with 2 X 20 ml of petroleum ether and evaporated again. 3.9 g of [2- (Z-methoxyimino) -2- (2-furyl) -acetylthio] -acetic acid ethyl ester were obtained, representing 77.5% of theory.

IR and NMR spectra identical to example 1.

Example IV. 12.2 g (0.06 mol) of N, N-bis- (trimethylsilyl) acetamide are added to a suspension of 5.4 g (0.02 mol) of 7-aminocephalosporanic acid in 80 ml of acetonitrile and stirred until dissolved. Then it is cooled to 0-5 ° C and 8.0 g (0.028 mol) of [2- (Z-methoxyimino) -2- (2-furyl) -acetylthio] -acetic acid ethyl ester in 60 ml of acetonitrile are added to the solution. containing 2 g of N, N-bis (trimethylsilyl) acetamide and stirred at the stated temperature. After the reaction is completed, the resulting solution is added to a mixture of 900 ml of water and 200 ml of methylene chloride, cooled to 0-5 ° C. After separating the layers, the aqueous layer is extracted 3 more times with 100 ml of methylene chloride each. The combined organic extracts are washed with brine solution (2 x 60 ml) then dried, decolorized with activated carbon and concentrated. The residue is suspended in 120 ml of anhydrous diethyl ether, 20 ml of petroleum ether are added, the mixture is stirred for 10 minutes, and then the separated precipitate is filtered and dried. 6.1 g of 7- [2- (Z-methoxyimino) -2 151 670 5 (2-furyl) -acetamido] -3- (acetoxymethyl) -cephem-3-carboxylic acid-4 were obtained, which is 72% of theory. .

IR (KBr) - 1650cm ^-1 (C = O; -NHCO-); 1705cm ¹ (C = O; -COOH), 1720cm ¹ '(C = O; -CHzOCO-); 1770 cm ¹ (C = O; β-lactam).

¹ H NMR / DMSO-de, <5 (ppm) -2.08, 3H, s (COCH3); 3.60, 2H, s, _(-S-CH2) -; 3.94, 3H, s, (= NOCH3); 4.74, 5.08, 2d, J = 12.7, (-CH2OCO-); 5.23, 1H, d, J = 4.7 (C-6); 5.88, 1H, dd, J = 4.7; J = 7.5 (C-7); 6.71.2H, 7.87.1H, the protons of the furan ring; 9.88, 1H, d, J = 7.5 (-NHCO-).

Example 5: 7- [2- (Z-methoxyimino) -2- (2-furyl) -acetamido] -3- (acetoxymethyl) -cephem-3-carboxylic acid-4, obtained in Example 3, is suspended in 80 ml of anhydrous methylene chloride and 4 ml of a 25% solution of 2-ethylcaproic acid sodium in methyl alcohol are added. 100 ml of anhydrous diethyl ether are then slowly added dropwise to the solution obtained with vigorous stirring. The separated precipitate is filtered, washed with diethyl ether and dried. 2.9 g of sodium salt of 7- [2- (Z-methoxyimino) -2- (2-furyl) -acetamido] -3 (acetoxymethyl) -cephem-3-carboxylic acid-4 were obtained, which is 92.0% theoretical capacity.

IR (KBr) - 1600 cm ^-1 (C = O; -COONa); 1670 cm ^1- (C = O; -NH-CO-), 1725 cm ¹ '(C = O; -CH2OCO-); 1770 cm ¹ '(C = O; β-lactam). ¹ H NMR / DMSO-d _6, <5 (ppm) -2,02,3H, s (COCH3); 3,43,2H, d, J = 9.8 _(-S-CH2); 3.89, 3H, s, (= NOCH3); 4.78, 5.03 2H, 2d, J = 12.2, (-CH2OCO-); 5.14.1H, d J = 4.7 (C-6); 5.72.1H, dd, J = 4.7; J = 8.0 (C-7); 6.70, 2H, 7.85, 1H, the protons of the furan ring; 9.77, 1H, d, J = 8.0 (-NHCO-).

Example VI. 25.4 g (0.125 mol) of N, N-bis (trimethylsilyl) acetamide are added to a suspension of 5.75 g (0.025 mol) of 3-hydroxyxymethyl-7-aminocephalosporanic acid in 100 ml of acetonitrile and stirred until dissolved. The obtained solution of 3-trimethylsilyloxymethyl-7- (N-trimethylsilyl) -aminocephalosporanic acid, cooled to 0-5 ° C, was added to a solution of 10.1 g (0.035 mol) of [2- (Z-methoxyimino) acid ethyl ester ) 2- (2-furyl) acetylthio] acetic acid in 80 ml of acetonitrile containing 3 g of N, N-bis- (trimethylsilyl) acetamide and stirring at the indicated temperature. After the reaction is completed, the resulting solution is added to a cooled to 0-5 ° C mixture of 1000 ml of water and 300 ml of ethyl acetate. After separation of the layers, the aqueous layer was extracted with 3 × 100 ml of ethyl acetate. The combined acetate extracts are washed with brine solution (2 x 60 ml) then dried, decolorized with activated charcoal and concentrated. 6.5 g of 7- [2- (Z-methoxyimino) -2- (2-furyl) acetamido] -3- (hydroxymethyl) -cephem-3-carboxylic acid-4 are obtained, which is 68.3% of theory. .

IR (KBr) - 1680 cm ^-1 (C = O; -NH-CO-); 1725 cm ¹ '(C = O; -COOH), 1760 cm ¹ ' (C = O; / 5-lactam).

¹ H NMR / DMSO-d _6, <5 (ppm) 3.60, 2H, s, (-S-CH2-); 3.91, 3H, s, (= NOCH ₃ ); 4.27, 2H, s, (-CH2OH); 5.10, 1H, d, J = 4.7 (C-6); 5.78, 1H, dd, J = 4.7; J = 7.5 (C-7); 6.62, 2H, 7.85, 1H, furan ring protons; 9.82, 1H, d, J = 7.5 (-NHCO-).

¹³ C NMR (DMSO-d ₆ ) 163.35, 163.08, 161.51, the groups C = O (n-lactam), -COOH and -NHCO-; 145.26 -C = N-; 144.77, 142.44 - C-2 and C-5 of the furan ring; 131.28, 123.26 - C-3 and C-4 of the Cephemic system; 112.81,111.88 - C-3 and C-4 of the furan ring; 62.19 - OCH3; 59.71 - CH2OH; 58.46, 57.38 - C-6, C-7 of the Cephemic system; 25, 52 - SCH2-.

Example VII. 1 g of 7- [2- (Z-methoxyimino) -2- (2-furyl) -acetamido] -3- (hydroxymethyl) -cephem-3-carboxylic-4-acid is dissolved in 15 ml of anhydrous acetone, 2.4 ml are added 12.5% acetone solution of the sodium salt of 2-ethylcaproic acid and stirred for one hour at 3-5 ° C. The separated precipitate is filtered, washed with anhydrous acetone and dried. 1 g of the sodium salt of 7- [2- (Z-methoxyimino) -2- (2-furyl) -acetamido] -3- (hydroxymethyl) -cephem-3-carboxylic acid-4 is obtained, which is 95.0% of the yield. theoretical.

IR (KBr) - 1600 cm ^-1 (C = O; -COONa); 1665 cm ¹ '(C = O; -NHCO-); 1760 cm ¹ '(C = O; β-lactam).

Example VIII. Proceeding analogously to Example 3, but using 0.01 mole of 7-aminocephalosporanic acid and 0.013 mole of [2- (Z-methoxyimino) -2- (2-thienyl) -acetylthio] -acetic acid ethyl ester, 0.062 moles of 7- [ 2- (Z-methoxyimino) -2- (2-thienyl) acetamido] -3- (acetoxymethyl) -cefem-3-carboxylic acid, 62.0% of theory.

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IR (KBr) - 1655 cm ^-1 (C = O; -NH-CO-); 1705 cm ¹ '(C = O; -COOH), 1725 cm ¹ ' (C = O; -CH2OCO-); 1770 cm ¹ '(C = O; β-lactam).

¹ H NMR / DMSO-d, δ (ppm) -2,06,3H, s (COCH3); 3,48,3,72,2H, d, J = 18, (-SCH _2); 3.92 3H, s, (= NOCH3); 4.73.5.06.2H, 2d, J = 13, (-CH2OCO-); 5.24, 1H, d, J = 4.7 (C-6); 5.78, 1H, d, J = 4.7, (C-7); 7.8-7.1, 3H, thiophene ring protons; 9.87, IH, (-NHCO-).

Example IX. Proceeding analogously to Example 1, but using 0.02 mole of 3 - [(1-methyl-1H-tetrazolyl-5) -thiomethyl] -7-aminocephalosporanic acid and 0.028 mole of [2- (Z-methoxyimimo) - acid ethyl ester 9.5 g of an oily residue are obtained with 2- (2-furyl) acetylthio] acetic acid, to which are added 2 x 30 ml of petroleum ether and evaporated in vacuo. 7.1 g of 7- [2- (Z-methoxyimimo) -2- (2-furyl) -acetamido] -3 - [(1-methyl-1H-tetrazolyl-5-) thiomethyl] -cephem-3- [beta] acid are obtained. carboxylic acid-4, 72.6% of theory.

IR (KBr) - 1675 cm ^-1 (C = O; -NH-CO-); 1710 cm ¹ (C = O; -COOH), 1765 cm ¹ (C = O; β-lactam).

¹ H NMR / DMSO-de, <5 (ppm) -3.67, 2H, (-SCH ₂ -, C-2); 3.88, 3H, s, 3.95, 3H, s, (-NCH ₃ i = NOCH ₃ ); 4.1-4.5.2H, m, (-SCH ₂ - from the side chain at C-3); 5.01, 1H, dd, J = 4.7, J = 8.0 (C-7); 5.69, 1H, d, J = 4.7 (C-6); 6.58, 2H, 7.81, 1H, furan ring protons; 9.6, 1H, d, J = 8.0 (-NHCO-).

Example 10 To a solution of 6.56 g (0.035 mol) of 2- (Z-methoxyimimim) -2- (2-furyl) -acetic acid chloride in 45 ml of tetrahydrofuran at -20 ° C under nitrogen atmosphere 4.8 g are added. (0.04 mol) 2-mercaptoacetic acid ethyl ester and stirred. To the obtained solution of [2- (Z-methoxyimimo) -2- (2-furyl) -acetylthio] -acetic acid ethyl ester at 0-5 ° C is added a solution of 7- (N-trimethylsilyl) -aminocephalosporanic acid trimethylsilyl ester in 110 ml of tetrahydrofuran obtained by the action of 8.1 g (0.03 mol) of 7-aminocephalosporanic acid and 18.3 g (0.09 mol) of N, N-bis- (trimethylsilyl) -acetamide and stirred at the specified temperature . After completion of the reaction, the procedure continued as in Example IV. 8.1 g of 7- [2- (Z-methoxyimimo) -2- (2-furyl-acetamido] -3- (acetoxymethyl) cephem-3-carboxylic acid-4-acid are obtained, which is 63.8% of theory. The IR and NMR spectra are identical to the product obtained in Example III.

EXAMPLE 11 By following the same procedure as in Example 1, but using 3.63 g (0.02 mol) of 2- (Z-methoxyimimimo) -2-phenylacetic acid chloride 4.7 g of the acid ethyl ester [2- (Z- methoxyimimimo) -2- (phenyl) -acetylthio] -acetic acid, 79% of theory.

IR (movie) - 1720 cm ^-1 (group C = 0, ester); 3050 cm ¹ ', -1900-1690 cm ¹ ', 770-735 cm ¹ ', 705-690 cm' ¹ (-CH-phenyl ring).

Example XII. Proceeding analogously to Example 1, but using 3.63 g (0.02 mol) of 2- (Z-methoxyimimimo) -2-phenylacetic acid chloride and 3.35 g (0.025 mol) of 2-mercaptopropionic acid ethyl ester, 4 . 5 g of [2- (Z-methoxyimimo) 2- (phenyl) -2-propionylthio] -acetic acid ethyl ester, 72.5% of theory.

IR (film) - I7l5cm ^-1 (group C = 0, ester); 3040cm ¹ ', -1880-1660cm ¹ ', 770-730cm ¹ ', 710-690cm ¹ (-CH-phenyl ring).

Example XIII. Proceeding analogously to Example 4, but using 5.4 g (0.02 mol) of 7-aminocephalosporanic acid and 8.9 g (0.03 mol) of ethyl ester of [2- (Z-methoxyimimo) -2- (phenyl) ) -acetylthio] -acetic acid, 6.6 g of 7- [2- (Z-methoxyimimo) -2-phenylacetamido] -3 - [(acetoxymethyl) -cephem-3-carboxylic acid-4 were obtained, which is 76.2% theoretical capacity.

IR (KBr) - 1660 cm ^-1 (C = O; -NH-CO-); 1710 cm ¹ (C = O; -COOH), 1740 cm ¹ '(C = O; -CH2OCO-); 1780 cm ¹ '(C = O; β-lactam).

¹ H NMR / DMSO-d _6, <5 (ppm) -2.1, 3H, s (COCH3); 3.6, 2H, q, J = 18, (-SCH _2); 3.99, 3H, s, (= NOCH3); 4.66, 4.93, q, J = 13, (-CH2OCO-); 5.26, 1H, d, J = 5 (C-6); 5.89, 1H, dd, J = 5, J = 8, (C-7); 7.3-7.9, 5H, m, phenyl ring protons; 9.76, 1H, d, J = 8 (-NHCO-).

Example XIV. Proceeding analogously to Example 4, but using 5.4 g (0.02 mol) of 7-aminocephalosporanic acid and 9.3 g (0.03 mol) of [2- (Z-methoxyimimo) 2- (phenyl) ethyl ester -2-propionylthio] -acetic acid, 5.9 g of 7- [2- (Z-methoxyimimo) -2-phenylacetamido] -3- (acetoxymethyl) -cephem-3-carboxylic acid-4 is obtained, which is 68.3% theoretical capacity. IR and NMR spectra identical to example XIII.

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Example XV. 5.35 g (0.014 mol) of 7- [2- (Z-methoxyimimo) -2- (2-furyl) -acetamido] 3- (hydroxymethyl) -cephem-3-carboxylic acid-4 are dissolved in 45 cm ^{3 of} anhydrous tetrahydrofuran and cooled to -40 ° C. Then a solution of 2.0 cm ³ of chlorosulfonyl isocyanate in 7.5 dm ³ of tetrahydrofuran and stirred for 1 hour at the specified temperature. After completion of the reaction, 11 cm ^{3 of} water are gradually added, the mixture is stirred at 0-5 ° C, about 45 cm ^{3 of a} saturated Na 2 CO ³ solution are added dropwise to pH 6.0, stirred for 15 minutes, then 50 cm ³ of ethyl acetate are added and Mixing for 10 minutes separates the layers. After acidification to pH 2.0, the aqueous layer is extracted with 2 × 40 cm ³ of ethyl acetate. After decolorizing with active charcoal, the acetate extracts are concentrated, and the separated precipitate is filtered, washed with water, ethyl acetate 2 × 20 cm ³ and dried. 4.45 g of 7- [2- (Z-methoxyimimo) -2- (2-furyl) -acetamido] 3- (carbamoyloxymethyl) -cephem-3-carboxylic acid-4 is obtained, 75% of theory.

IR (nujol) - 1655 cm ^-1 (C = O; -NHCO-); 1728 cm ¹ , 1715 cm ¹ (C = O; -OCONH ₂ ), 1700 cm ¹ (C = O; COOH); 1760 cm ¹ (C = O; / J-lactam).

¹ H NMR / DMSO-de, <5 (ppm) -3,56,2H, m, (-SCH _2); 3.91, 3H, s, (= NOCH ₃ ); 4.61, 4.94, 2H, q, J = 13 (-CH2OCO-); 5.2, 1H, d, J = 5, (C-6); 5.8, 1H, dd, J = 5, J = 8 (C-7); 6.58, 2H, s, (= CONH2); 6.6.6.75 2H, 7.85.1 H, (furan ring protons); 9.75, 1H, d, J - 8 (-NHCO-).

Example XVI. By proceeding analogously to Example 15, but using 7- [2- (Z-methoxyimimim) -2- (2-thienyl) -acetamido] -3- (hydroxymethyl) -cephem-3-carboxylic acid-4, 7- [2 - (Z-methoxyimimo) -2- (2-thienyl) -acetamido] -3- (carbamoyloxymethyl) -cephem-3-carboxylic-4 in 69.0% of theory.

IR (KBr) - 1655 cm &lt; ¹ &gt; (C = O; -NHCO-); 1710 cm ¹ '(C = O; -OCONH ₂ ), 1720 cm ¹ (C = O; COOH); 1760 cm ¹ (C = O; / J-lactam).

¹ H NMR / DMSO-de, <5 (ppm) -3,58,2H, m (-SCH ₂ -); 3.92, 3H, s, (= NOCH ₃ ); 4.64, 4.99, 2H, q, (-CH2OCO-); 5.25, 1H, d, J = 5, C-6); 5.87, 1H, dd, J = 5, J = 8, (C-7); 7.71, 1H, and 7.3 to 7.1,2H-protons of the thiophene ring; 9.8, 1H, d, J = 8 (-NHCO-).

Example XVII. 5.46 g (0.02 mol) of 3-carbamoyl-7-aminocephalosporanic acid are suspended in 950 cm ^{3 of} anhydrous methylene chloride, 85 cm ^{3 of} hexamethylenedisisalate are added and heated in a water bath for 18 hours. After filtration, the solution is evaporated with methylene chloride, the residue is dissolved in 100 cm ^{3 of} acetonitrile and 2 cm ³ heksametylenodisilazanu. The resulting solution is cooled to 5-10 ° C, a solution of 8.0 g (0.028 mol) of [2- (Z-methoxyimimo) -2- (2-furyl) -acetylthio] -acetic acid ethyl ester in 60 cm ^{3 of} acetonitrile is added. and stirred at the specified temperature. After completion of the reaction, the obtained solution is added to a mixture of 800 cm ^{3 of} water and 250 cm ³ of ethyl acetate, cooled to a temperature of 12-15 ° C, and stirred for 10 minutes at a pH value of 2.0. After separating the layers, the aqueous layer is extracted with 2 × 100 cm ³ of ethyl acetate. The combined ethyl acetate extracts were washed with brine (2 x 50 cm ^3), decolorized with activated carbon and concentrated to a volume of about 40 ^cm3. The 7- [2- (Z-methoxyimimimo) -2- (2-furyl) -acetamido] -3- (carbamoyloxymethyl) -cephem-3-carboxylic acid-4-acid precipitate isolated is filtered, washed with water and ethyl acetate (2 X 20 cm ³ ) and dried. IR and NMR spectra identical to example XV.

Example XVIII. To a solution of 4.95 g (0.01 mol) of 7- [2- (Z-methoxyimimo) -2- (2-furyl) -acetamido] -3- (hydroxymethyl) -cephem-3-carboxylic acid pivaloyloxymethyl ester-4 is added 1.85 g (0.015 mol) of acetyl bromide and 1.2 g (0.015 mol) of pyridine are combined and stirred for 1.5 hours. After the reaction solution was evaporated to dryness and to the residue was added 150 cm ^{3 of} a mixture of sodium bicarbonate and 150 cm ³ of ethyl acetate. After stirring for 10 minutes, the layers are separated and the organic layer is washed successively with 1N sodium bicarbonate solution, 1N hydrochloric acid and saturated brine. After decolorization with activated charcoal, the solution was evaporated and the residue was triturated with petroleum ether to give 4.1 g of 7- [2- (Z-methoxyimimo) -2- (2-furyl) -acetamido] -3- (acetoxymethyl) acid pivaloyloxymethyl ester - cephem-3-carboxylic acid-4, 76% of theory.

151 670

IR (KBr) - 1660 cm ^-1 (C = O; -NHCO-); 1725cm ¹ '(C = O; -CH ₂ OCO-), 1740 cm ¹ (C = O; -COOCHa); 1770 cm ¹ '(C = O; β-lactam).

¹ H NMR / DMSO-d6,? (Ppm) -1.2,9H, m [-C (CH ₃ ) ₃ ]; 2.1, 3H, s (-COCH ₃ ); 4.0, 3H, s, (NOCHs); 4.8; 5.12, 2H, q, J = 13 (-CH ₂ OCO-); 5.2, 1H, d, J = 5, C-6); 5.5-5.7, 2H, m, (-OCH2O-); 5.9, 1H, dd, J = 5, J = 8, (C-7); 6.7, 2H, 7.9, IH- protons of the furan ring; 9.8, 1H, d, J = 8 (-NHCO-). .

Claims (2)

Patent claims 1. A method for the preparation of semi-synthetic cephalosporins of the general formula I, where R1 is an alkyl group containing up to five carbon atoms, a substituted or unsubstituted aryl or aralkyl or a heterocyclic system containing such heteroatoms as sulfur, oxygen, nitrogen, preferably furyl, thienyl, thiazole, pyran , unsubstituted or substituted with groups such as halogen, alkyl, alkoxy, acyl, where the alkyl group contains a maximum of five carbon atoms, R2 is hydrogen, an alkyl group containing a maximum of five carbon atoms, an optionally substituted carboxyl group, preferably a carboxymethyl group, a 1-carboxyisopropyl group, cycloalkyl or alkenyl containing up to seven carbon atoms or alkoxycarbonylalkyl group in which alkyl and alkoxy contain up to five carbon atoms, R ₃ is hydrogen, halogen, hydroxyl, alkyl, alkoxy, containing up to four carbon atoms, hydroxymethyl, halomethyl, acyloxymeth yl, carbamoyloxymethyl, vinyl, 1-pyridinylmethyl, [2,3 / 1,3-propenyl] -1-methylpyridinium, -CH2-S-R5 group, where R5 is a substituted or unsubstituted heterocyclic system containing heteroatoms such as sulfur, nitrogen, preferably 1-methyl-1H-tetrazole, substituted or unsubstituted triazole, thiadiazole, thiazole, triazine, preferably 4-carboxymethyl-3-methyl-1,3-thiazole, 2,5-dihydro-6-hydroxy-2-methyl-5-oxo -1,2,4-triazine, 2,5-dihydro-6-hydroxy-2-methyl-5-oxylane-1,2,4-triazine or the group -CH = CH-SR6, where R6 is preferably 1,5,6 -trihydro-4-formyl-1,2,4-triazine, R4 is hydrogen, tertiary amine, preferably trimethylamine, triethylamine, tributylamine, N-methylpyrrolidine, N-methylpiperidine, N-ethylpiperidine, N-methylmorpholine, Ν, Ν-dimethylsilyl,-dimethylsilyl containing up to five carbon atoms, substituted or unsubstituted aryl, or aralkyl, cycloalkyl, acylalkyl, acyloxyalkyl in which the alkyl has a maximum of six carbon atoms, preferably acetylmethyl, acetyloxymethyl, acetyloxyethyl, pivaloyloxymethyl, 2-methoxy-2-methylpropionyloxymethyl, 2-methoxy-2-propionyloxyethyl, characterized in that compounds of general formula 2, where R ₃ and R 4 are as defined above, and R 7 is hydrogen, trimethylsilyl or R7NH- represents the HCHNHa group, is reacted with new reactive compounds of general formula 3, where R1 and R2 are as defined above, Re is an alkyl containing up to three carbon atoms, and Rg is hydrogen, methyl, ethyl, acetylmethyl or ethoxycarbonyl , in organic solvents at temperatures down to -60 ° C to + 60 ° C, whereupon compounds of general formula I, where R1-R4 are defined above, are isolated as end products in the form of esters, free acids or salts. 2. The method according to p. A process as claimed in claim 1, characterized in that acetonitrile, halogen derivatives of aliphatic hydrocarbons such as methylene chloride, ethylene chloride, ethyl chloride, chloroform, cyclic ethers such as dioxane, tetrahydrofuran, aliphatic esters such as ethyl acetate, butyl acetate, are preferably used as organic solvents, Ν, Ν-dimethylformamide, N, N-dimethylacetamide, Ν, Ν-dimethylsulfoxide or mixtures of these solvents. 151 670 kr «tó * r 1 Rf- NH η / -R ₃ COORm LJ ^ ó-in 1 R _r C-CO-S-CH-COOR ₈ JI 'iWR _t Rg bits 3 fU-C-COOH AND NORj, balls M. HS-CH-C00R ₈ r ₉ UJtÓW 5