SU1500163A3 - Method of producing carboxyalenamidocephalosporins or their esters or their salts with alkaline metals - Google Patents

Abstract

Cephems and analogues of formula (I) are new. R = aryl or heterocyclyl; R1 = H or halogen; R2 = single bond, alkylene, oxa-alkylene or thia-alkylene- R3, R6 = H, salt-forming atom or gp. or ester-forming gp.; R4 = H or MeO; R5 = H or a 3-substituent as found in cephalosporins; X = O, S or SO. Provided that when R2 = thia-alkylene, then R1 = halogen. - Intermediates of formula (II) are new.

Description

R30-C (0) -Kt-CR CHT-C (0) -NH-CR -C (0) -lil-CH-X-CHfe-CR. (0) ORtf,

where or C1; R5; simple bond, n-or amino group of thiazolyl; X - oxygen: iso-C -C, -alkylene, thiomethylene; RJ is independently H, alkali metal, lower n- or iso-alkyl or phenylalkyl, n- or iso-alkenyl, phenylalkyl, lower alkanoyloxymethyl, diphenylmethyl, benzyl (it may be substituted with CHj, NOa, OCHj); R - H, OCHj; R, - H, Cl, CRj (OH may be substituted with OCH3, CHjC (O), carbamoyloxy), vinyl, (it may be substituted with CN, C (0) OH, tert-butoxycarbonyl, CFj), OH, methanesulfonyloxy, vinyl thio group, CH —S — Rj with Rj — CHi, CFiH,, triazolyl, methyl tetrazolyl, thiadiazolyl (it may be substituted by CH, NHj., t-butoxycarbonylamino, aminomethyl, t-butoxycarbonylaminomethyl); R-, tienyl, substituted NHj, tert-butoxycarbonylamino - or benzyloxycarbonylamino isoxazolyl or thiadiazolyl; thiazolyl (it may be substituted by NHj, tert-butoxycarbonyl, benzyloxycarbonyl, methylbenzyloxycarbonyl, formyl, chloroacetyl, tert-butyldimethylsilyl, p-nitrobenzyl), HC1 salt or CFjCOOH

 sulphonyl, and when R is thiomethyl, then R4 is C1, and the carboxy and amine groups in the carboxyalkene amido moiety are in the cis position, their esters, or alkali salts, which can be used in medicine in as antibiotics. The goal is to create new active and low toxic substances of the specified class. Their synthesis is carried out by condensation of cephalosporin unsubstituted by NHj with the corresponding acid (1.1–2 mol) or its pu-I ak, a solvent-based derivative in 3–36 volumes of solvent. CHCl,, dimethoxyethane, dimethyl acetamide, dioxane, ethyl acetate, ethylene chloride, methyl isobutyl ketone, tetrahydrofuran, toluene or water are used as the latter. Condensation is carried out either in the absence of a condensing agent and a base, or in the presence of 0-2.5 mol of one of the substances - carbonyldiimidazole, cyanuric chloride or its complex with pyridine, dicyclohexylcarbodiimide, bromo-anhydride of diethoxyphosphonic acid, ethyl ethoxydehydrochnennolinenine one, ethnone oxidine acid, ethyl acetate, and hydrochloride; X - oxygen,

 sulphonyl, moreover, when R is thiomethylene, then R4 is C1, and the carboxy and amido groups in the carboxyalkenamido radical are in the cis position, their esters, or alkali salts, which can be used in medicine as antibiotics . The goal is to create new active and low-toxic substances of the specified class. Their synthesis is carried out by condensation of cephalosporin unsubstituted by NHj with the corresponding acid (1.1–2 mol) or its pu-I ak, a solvent-based derivative in 3–36 volumes of solvent. CHCl,, dimethoxyethane, dimethyl acetamide, dioxane, ethyl acetate, ethylene chloride, methyl isobutyl ketone, tetrahydrofuran, toluene or water are used as the latter. Condensation is carried out either in the absence of a condensing agent and a base, or in the presence of 0-2.5 moles of one of the substances carbonyldiimidazole, cyanuric chloride or its complex with pyridine, dicyclohexylcarbodiimide, bromo-anhydride of diethoxyphosphonic acid, ethyl ethoxyhydrohydhnnnnoline

(Y)

SP

O5

oo

s

benztriazole, oxalic acid chloride, POCl3, SOCla, CFjC (0) 0, (CH5) SiCl or Vilsmeier reagent and up to 6 mol of base - dimethylaniline, lutidine, methylmorpholine, picoline, pyridine or triethylamine at a temperature of from (-50) С to room temperature (15 min - 15 h). When necessary, the amino-protecting and / or carboxy group substituents (E3, RS. Re and RT) in 3.9-41 volumes are removed in the substance. required solvent - anisole,,, CHjNO, tetrahydrofuran, toluene or water 15

The invention relates to a method for producing new antibiotics of the cephalosporic series, namely, carboxyl alkenamido cephalosporins or their esters, or their salts with alkali metals, which can be used as antibacterial agents in medicine.

The aim of the invention is the creation of new antibiotics of the cephalosporin series, possessing higher antimicrobial activity with low toxicity.

In tab. 1-4 show the techniques and modes for the preparation of esters of various formulas. Tables 5–8 show the methods and modes for the preparation of free acids or their Na-salts according to different schemes (Na-salt is a neutralization product with a convenient aqueous solution of NaHCO (2 eq. And the resulting solution is passed through a column with an adsorbent and lyophilized with obtaining sodium salt as a solid (MIC is the minimum inhibitory concentration against E. coli EC-14, mg / ml). Table 9 shows the methods and modes for the preparation of pharmaceutically acceptable esters of a specific formula. chemical characteristics and methods of obtaining complex esters of various formulas. The physico-chemical characteristics and methods for the preparation of carboxylic acids or their Na-salts of various formulas are shown in Tables 14 to 17. Table 18 gives the physico-chemical characteristics and methods for the preparation of pharmaceutical esters of a specific formula.

by treating it with 3–18 mol of the substance — AlClj, HClj of methyl-N-methyldithiocarbamate, KAHCO3, tin chloride, TiCl, and zinc or triphenylphosphine complex palladium at 0–30 ° C. When one of Rj and Rg is hydrogen, The substance is neutralized with 1 mole or more of base at room temperature to obtain alkali salts. New antibiotics are in some cases 8 times more active than the known ones with low toxicity. 19 tab.

0

j

G

five

0

five

In tab. 1-18, the following abbreviations have been accepted: Q NHJ, -amine with the core of formula (II) core having Ry, Rg, etc .; Q CO is the side chain of acyl in the 7-position of the cephalosporin - the residue of an acid of formula (III); structure: Ac - acetyl; Me is methyl; Et is ethyl; t-Bu is t-butyl; MEM is methoxistoxymethyl; MS is methanesulfonyl; EEDH - 2-ETOXI-1-ETHIL-1,2-dihydroquinolin; TFA - trifluoroacetic acid; BOC - benzyloxycarbonyl; VZL - benzyl; VN or DFM -. diphenylmethyl; TBA is tert-butoxycarbonyl; DHM - dichloromethane; HLF - chloroform; DCC - dicyclohexylcarbodiimide; MBP -. p-oxybenzyl; MP - 4-methylpentan-2-one; yes - lyoxane; pNB - para-nitrobenzyl; DMA. - dimethylacetamide; LOM - acetoxymethyl; POM - pivaloyloxymethyl.

Example 1, (getting sodium salt).

1. Solution of carboxylic acid,

(1 g) in aqueous 0.5% acidic sodium carbonate- (6 ml) is adjusted to pH = 7 with hydrochloric acid, washed with ethyl acetate, desalted, and poured into a 10 ml vial. This solution is lyophilized and the sodium salt is obtained as a powder.

2. Similarly, aqueous sodium carbonate is added to a suspension of carboxylic acid (I) (1 g) in water so that the solution is pH-adjusted to 6.5. The solution was desalted and poured into ampoules with a capacity of 10 ml, then lyophilized, and the sodium salt was obtained. .

515001

3. The sodium salt (1 g), obtained under sterile conditions, is dissolved in sterile water (4 g) and twice a day orally or intravenously injected into the body of a patient suffering from an infectious disease, Staphylococcus aureus, in order to treat this disease

4. Carboxylic acids are dissolved in water in acidic sodium carbonate and analyzed as sodium salt on

MTS standard chemotherapy

B.-C-CO

 II (111)

CRi

R

4-L

Soyab

(P)

1, in a mixture of dichloromethane (10 volumes), 2-ethoxy-1-ethoxycarboxy-1-1,2-dihydroquinoline (1.1 equivalents), H, and -dicyclohexylcarbodiimide (1.1 equivalents), pyridine (1.5 equivalents) and carboxylic acid (III)

(1.1 equivalent) is stirred for 1-6 -h at a temperature from 0 s to room temperature,

2, In a mixture of ethyl acetate (10 volumes), di-2-pyridyl disulfide (1.1 equivalents), triphenylphosphine (1.1 equivalents) and carboxylic acid (lil) (1.1 equivalents) are stirred for 2-6 hours at temperature from 10 to 50 ° C

3, In a mixture of dichloromethane (3 volumes), 1,3,5-tripyridine triazine trichloride (4 equivalents) and carboxylic acid (III) (1.1 equivalents) is stirred for 1-5 hours at a temperature from -10 to 10 C.

4, In a mixture of carbon tetrachloride (, 30 volumes), 4-methyl morpholine (1.5 equivalents), tris-diethyl aminophosphine (1.1 equivalents) and carbonic acid (III) (1.1 equivalents) maintained at temperature

from -20 to 10 s for 1-5 hours,

. 5. In a mixture of chloroform (10 volumes) and dimethoxyethane (10 volumes), triethylamine (1.5 mol) and mixed carboxylic anhydride (III and isobutoximonic acid, they are stirred at a temperature of from -5 to 30 minutes — 6 h

3 6 Japanese Society of Chemotherapy with obtaining values of 3.1-0.2 µg / ml. against Streptococcus pyogenes C-203 and 0.8-0.025 μg / ml against Escherichia coli N.

PRI me R 2 (amidation). The 7-beta-amino compound (II) (1 equivalent) is treated with a carboxylic acid corresponding to the 7-beta-side chain (III) or its active pro-. izvudnye MuI in the amide (I) scheme

u

I-c-X

CRi ri

f, G COORfi SOOKz (I)

five

five

ABOUT

Q f

Q

6, In a mixture of ethyl acetate (10 volumes), 1, 2-dyuO1Oretan (10 volumes), 4-metsh1morfolin (1.5 equivalents)

and symmetric carboxylic anhydride (III) (1.1 equivalent) is heated under reflux for 10 minutes to 2 hours,

7, In a mixture of dichloromethane (10 volumes), pyridine (1.5 equivalents) and mixed carboxylic anhydride (III) and methanesulfonic acid (1.1 equivalents) are stirred for 1-3 hours At a temperature from to room temperature,

8, In a mixture of ethyl acetate (10 volumes), pyridine (1.5 equivalents)

and mixed acid anhydride of diethylphosphate and carboxylic acid (III) (1.5 equivalents) is stirred at a temperature from 0 to for 1-5 hours.

9, In a mixture of ethyl acetate (10 volumes), dichloromethane (10 volumes), N-methylmorpholine (1 equivalent) and mixed carboxylic anhydride (III) and dichlorophosphoric acid (1.1 equivalent) are stirred for 1-3 h at temperature from to room temperature.

10, In a mixture of lutidine (1.5 equivalents), -dichloromethane (10 volumes) and mixed anhydride (1.1 to 2 equivalents) of carboxylic acid (III) and monochlorophosphoric acid dimethylamide are stirred for 1-4 hours at a temperature from 0 to ,

11. In a mixture of dichloromethane (5 volumes), trifluoroacetic anhydride (1.5 equivalents), pyridine

(3 equivalents) and carboxylic acid (III) (1.5 equivalents) is stirred for 1-5 hours at a temperature from 0 to room temperature

12. In a mixture of dichloromethane (10 volumes), acid diethyl phosphate bromide (1.2 equivalents), 4-methylmorpholine (2.5 equivalents) and carboxylic acid (III) (1.2 equivalents) are stirred for 1-3 h at a temperature from C to room temperature.

13. The amine (II) comprising the carboxyl at the 4-position of the cephem ring is dissolved in an aqueous (10 volumes) acidic sodium carbonate (2.5 equivalents). The solution of carboxylic acid (III) (1.1 equivalent) is added dropwise to the solution. The mixture is kept at a temperature of from to room temperature, for 30 minutes - 2 hours.

14. Amine (II), including carboxyl in the .4-position of the cephem ring, is treated with trimethylsilyl chloride

and triethylamine (1.2 equivalents each), then treated with pyridine (4 equivalents) and carboxylic acid chloride (III) (1.1 equivalents) for 30 minutes to 2 hours. The resulting silyl ester is hydrolyzed with acid.

15.-In a solution of picoline (4 equivalents) and carboxylic acid chloride (III) (1.2 equivalents) in dichloromethane (20 volumes) are stirred at a temperature from 0 to 2 hours for 30 minutes.

16. mixtures of dimethylformamide

(2 volumes) and ethyl acetate (10 volumes are mixed with triethylamine (1.1 equivalents) and carboxylic acid chloride (III) (1.1 equivalents) at 0-20 ° C for 30 minutes - 3 hours.

17. In a mixture of dichloromethane (30 volumes), cyanuric acid chloride (1.1 equivalents), pyridine (4 equivalents) and carboxylic acid (III) (1.1 equivalents) is stirred for 5 minutes to 2 hours at a temperature of - 30 С to 10 С.

18. In a mixture of dichloromethane (3 volumes), phosphorus oxychloride (1.1 equivalents), triethylamine (1.5 equivalents) and carboxylic acid (III) (1.1 equivalents) is stirred for

20 min - 2 h at a temperature of from -10 to 10 s.

19. The amine (II) is treated with trimethylsilyl chloride and an acid acceptor, and the corresponding N-trimethylsilyl compound is obtained. This compound is treated with phosphorus oxychloride (1.5 equivalents), carboxylic acid (III) (1.2 equivalents) and dimethylaniline (4 equivalents) in dichloromethane

(5 hours) within 30 minutes - 2 hours at a temperature from 0 s to room temperature.

20. In a mixture of dichloromethane (8 volumes), thionyl chloride (1.5 equivalents), pyridine (2.5 equivalents) and carboxylic acid. (III) (equivalent) is stirred for

1-5 hours at a temperature of -30 to

21. In a mixture of chloroform (3 volumes), toluene (1 o volume), picoline (2 equivalents), oxalyl chloride (1 equivalent) and carboxylic acid (III) (1.1 equivalents) are stirred for 10 minutes - 2 hours at a temperature of -50 to 10 ° C.

 22. In a mixture of dichloromethane (20 volumes), pyridine (3 equivalents) and carboxylic acid (III) benzotriazolyl ester (3 equivalents) is stirred for 5-30 hours at 10-55 C.

23.In a mixture of dichloromethane (20 volumes), 1-ethoxycarbonyl-1,2-dihydroquinoline (2.5 equivalents) and 2-ethoxycarboxylic acid (III) (2. equivalents) is stirred at room temperature for 1- 15h

24. In a mixture of dioxane (10 volumes) and phthalimide ester of carboxylic acid (III) (2 equivalents) is stirred for 2-8 hours at 10-50 C.

25. In a mixture of methyl isobutyl ketone (10 volumes) and succinimide carboxylic acid ester (III) (1.3 equivalents), the mixture is stirred for 2-9 hours at.

26. In a mixture of carbonyldiimidazole (1.1 equiv.), Tetrahydrofuran (10 volumes), dimethylacetamide (5 volumes) and carboxylic acid (III). (1.1 equivalent) is stirred for 1-5 hours at a temperature from 0 to room temperature.

27. In a mixture of dimethylformamide

(5 volumes), dimethylaniline (1.3 eBivalent), carboxylic acid (III) and Vilsmeier's reagent, obtained from dimethylformamide (1.1 equivalents), are stirred at room temperature for 1-5 hours.

28. In a mixture of dichloromethane (10 volumes), dimethylformamide (5 volumes), N, N -dicyclohexylcarbodiimide (1.1 equivalents), picoline (1.2 equivalents) and carboxylic acid (III) (1.1 equivalents) are heated in for 2-24 hours

29, To a solution of diphenylmethyl ester of 7-amino-3- (1-methyl-15 from 70 to 90%. 5-tetrazolyl) thiomethyl-3-cephem-4-car- 2. In a solution of tert-butyl, benzoic acid in dichloromethane zyl, para-methylbenzyl, pa- (50 hours), containing 2- (2-benzshüxira-methoxybenzyl or diphenylcarbonimido-4-thiazolyl) -4-benzyloxymethyl ester in a mixture of carbonyl-2 - butenoic acid (1 eq - 20 dichloromethane (5-9 h) and anisole (2 - vivalent), N, N - dicyclohexyl carbodiimide (1 equivalent) is injected. After stirring for 2 hours at room temperature, the mixture is centered. The residue was stirred

8 h) alumina, tetrachloride tetrachloride or titanium tetrachloride (3 to 12 equivalents) are introduced at a temperature of from -10 to 25 10 ° C, the mixture is stirred for ethyl acetate, filtered to remove 1-24 h. The mixture is washed with a diluted solid and purified in chromate hydrochloric acid and water, by a graph graph. The result is (2-benzyloxycarbonyl-4-thiazolyl) -4-benzyloxycarbonyl-2-butenoylamino-3- (1-methyl-5-tetrazolyl) thiomethyl-3-cephem-4-carboxylic acid complex diphenylmethyl ester. Yield 90%.

30 "In a solution of 7-amino-3-pyridinomethyl-3-cephem-4-carboxylic acid hydrochloride hydrochloride in a mixture of water (10 hours) and dioxane (15 hours), sodium carbonate is added at 0 ° C.

(2 equivalents), 2- (2-benzyloxycardo O 90% formic acid (5-6 hours) bonylamino-4-thiazolyl) -4-benzyloxy- and anisole (2-3 hours). A mixture of stirring-carbonyl-2-butenoic acid (l, 2 eq at 50-60 s for I -4 h, c. V.), 1-hydroxybenzotriazole (1.2 equivalents), N, N-dicyclohexyl carc

body imide (1.2 equivalents) and dioxane (5 h). After stirring at 0 ° C for 3.5 hours, the mixture is acidified with 1N hydrochloric acid (5 hours) and filtered. The filtrate and the acetone washing (50 hours) of the solid product are combined, purified by chromatography on silica gel and lyophilized. The result is (2-benzsh10xycarbonylamino-4-thiazolyl) -4-benzyloxycarboxy1-2-, butenoylamino-3-pyridinemethyl-3- cephem-4-carboxylate. Yield 50.8%

Example 3 (deprotection from carboxy group).

The result is a corresponding carboxylic acid with a yield of 40-50%, 4, Acetic acid (10 hours) and zinc powder (2 hours) are added to a solution of para-nitrobenzyl ester in dichloromethane (60 hours). After stirring for 2 hours

50 while the mixture is filtered to remove the solid, diluted with water and extracted with dichloromethane. The extract solution is washed with water and extracted with an aqueous solution.

55 sodium hydrogen carbonate. The aqueous layer is washed with hydrochloric acid until it reaches pH 2, extracted with d g chloromethan. The organic layer is washed with water, dried and concentrated in baI. The solution of the tert-butyl, paramethoxybenzyl or diphenylmethyl ester given in Table. 10–13, in a mixture of dichloromethane (0.3–3 h), trifluoroacetic acid (0.3–3 h) and anisole (0.5–5 h) are stirred for 2–3 h at a temperature from -10 to AO C. This solution is concentrated to remove the solvent and reagent. Residual. the product is washed with benzene or ether and the corresponding acid is obtained with the yield

sewn and concentrated, resulting in an appropriate free

30 acid with a yield of 90-95%. Remove the protection of the tert-butoxycarbonylamino group, the N-tert-byproxycarbonyl of the N-meth- oxymethylamino group or the benzyloxycarbonylamino group, in the case of their presence, with the formation of an amino group,

3, Into a solution of tert-butyl, benzyl, para-methylbenzyl, para-methoxybenzyl or diphenylmethyl ester are introduced

DO 90% formic acid (5-6 hours) and anisole (2-3 hours). The mixture is stirred at 50-60 seconds for 1-4 hours, c.

DO 90% formic acid (5-6 hours) and anisole (2-3 hours). The mixture is stirred at 50-60 seconds for 1-4 hours, c.

45

The result is a corresponding carboxylic acid with a yield of 40-50%, 4, Acetic acid (10 hours) and zinc powder (2 hours) are added to a solution of para-nitrobenzyl ester in dichloromethane (60 hours). After stirring for 2 hours

50 while the mixture is filtered to remove the solid, diluted with water and extracted with dichloromethane. The extract solution is washed with water and extracted with an aqueous solution.

55 sodium hydrogen carbonate. The aqueous layer is washed with hydrochloric acid until it reaches pH 2, extracted with d g chloromethan. The organic layer is washed with water, dried and concentrated in wa11.

in order to obtain the corresponding free acid in a yield of 60-80%.

5. The same ester can be de-esterified by agitating with hydrogen in the presence of the same amount of 5% palladium on charcoal in dioxane at room temperature for 2 hours,

6, B solution of diphenylmethyl ester of 7-G2- (2-benzyloxycarbonylamino-4-thiazolyl) -4-benzyloxycarbonyl-2-butenoylamino-3- (1-methyl-5-tetrazolyl) thiomethyl-3- cephem-4-carboxylic acid in anisole (12 h,) is added chloride aluminum (9 equivalents). After stirring for 4 hours at 0 ° C, the mixture is neutralized with a 5% aqueous solution of sodium hydrogencarbonate, filter filtration to remove the solid product, washed with ethyl acetate. The aqueous layer is acidified with hydrochloric acid, washed with ethyl acetate and passed through a column filled with HP2O or SP207 (synthetic adsorbent prepared by 1st Mitsubishi Chemical K.K.), the adsorbed product is eluted with 80% methanol to give 7- f2- (2-Amino-4-thiazolyl) -4-carboxy-2-butyloyl-amino-J-3- (1-methyl-5-t-tetrazolyl) thiomethyl-3-cephem-4-carboxylic acid. Yield 65%

7. Suspension of (2-benzyloxy-carbonylamino-4-thiazolyl) -4-benzyloxycarbonyl-2-butenoylamino-3-pyridine-methyl-3-cephem-4-carboxylic acid in anisole (2 hours) is introduced aluminum chloride (9 equivalents) in anisole (2 h,) at 0 ° C. After stirring for 3.5 hours, the mixture is acidified with 10% hydrochloric acid and washed with ethyl acetate. Water layer

150016312

1, Solution of tert-butoxycarbonyl-. nosocompounds listed in Table 10-

13, in a mixture of dichloromethane (0.3–3 h,), trifluoroacetic acid (0.3–3 h,) and anisole (0.5–5 h) are stirred for 10 min (3 h) at a temperature of up to. The solution is concentrated to remove the solvent and the reagent. The residue was washed with benzene to obtain a suitable amino compound in 70-80% yield.

2, To a solution of 1 h, tert-butoxy-5 carbonylamino, benzyloxycarbonylamino, methylbenzyloxycarbonylamino, methoxyethoxymethylamino or tritylamino compounds. In a mixture of -c dichloride with methane (5-9 hours) and anisole (2-8 hours)

20, aluminum chloride, tetrachloride tin or titanium tetrachloride (3-12 equivalents) are introduced at a temperature of from-10 to 10, the mixture is stirred for 1-24 hours. The mixture

25 is extracted with dilute hydrochloric acid and water, the aqueous layer is passed through a column filled with the adsorbent HP-20, and the result is a free amino compound with a stroke of 60-80%. In the case when tert-butyl, benzyl, para-methylbenzyl, is present a para-methybenzyl or diphenylmethyl ether group, it is removed from the top with carboxylic carboxylic acid

3, To the solution of chloroacetamido compounds listed in Table. 10-13, in the mixture of tetrahydrofuran (15 h) with thiourea and methanol (15 h)

40 or N-methyldithiocarbamate (4 equivalents) and sodium acetate (2. equivalents). After overnight at room temperature, the mixture is concentrated, diluted with ethyl acetate.

passed through a column filled with washed with brine, vyDiaion HP-20. The adsorbed product is eluted with an aqueous 5% acetone solution and the eluate is lyophilized. The result is (2-amino-4-thiazolyl) -3-carbs-methylmethylamine J-3-pyridinomethyl-3-cephem-4-carboxylic acid. Yield 55% ,.

8 In a similar way, the free carboxyl compound shown in Table 14-17 is obtained from the corresponding compound with a carboxy-protected group shown in the scoreboard 10-13,

Example 4 (deprotection from an amino group),

sew and concentrate. The residual product is subjected to chromatographic separation, resulting in the corresponding amino

50 dining,

4. To a solution of formamido, Schiff bases, silylamino or trimethylaminos compounds in formic acid, acetic acid or ethanol (10 hours,

55 enter 1-3 n, hydrochloric acid (0.1-3 h,), mix for 1-3 h at room temperature. The reaction mixture was concentrated, diluted with dichloromethane, washed with aqueous solution.

sew and concentrate. The residual product is subjected to chromatographic separation, as a result of which a corresponding amino compound is obtained.

4. To a solution of formamido, Schiff bases, silylamino or trimethylaminos compounds in formic acid, acetic acid or ethanol (10 hours)

55 enter 1-3 n, hydrochloric acid (0.1-3 h,), mix for 1-3 h at room temperature. The reaction mixture was concentrated, diluted with dichloromethane, and washed with an aqueous plant. 1 thief of sodium carbonate and water, extract and concentrate. The pure product is purified in the usual way, and the result is a corresponding free amino compound.

5. In a solution of benzyloxycarbonyl-amino compounds, in a mixture of ethanol and ethyl acetate (30 parts 1: 1), 5% α-palladium-charcoal (0.5 hours) is added, the mixture is shaken in hydrogen medium until no starting product is consumed. The reaction mixture is filtered to remove the solid product and concentrated to give the corresponding amine compound.

PRI me R 5 (esterification to ester).

1.RJ and / or K-diphenylmethyl,

In a solution of compound (I), in which R and / or Kg is hydrogen, diphenyl diazomethane (2 equivalents) is introduced in a mixture of dichloromethane and ethanol (10 weight parts, each). After stirring for 1 hour, the mixture is washed with hydrochloric acid and water, dried and concentrated. The residue is crystallized from ethyl acetate and the corresponding diphenylmethyl ester is obtained.

2.Kz and / or Rg-nOM.

In a solution of compound (I) in which R, and / or Rg is potassium, iodomethylpivalate (1 to 2 equivalents) is added in N, N-dimethylformamide (2–5 hours) (1 to 2 equivalents) while cooling with ice – salt. After stirring for 15 minutes - 2 hours, the mixture is diluted with ethyl acetate, washed with ice water and an aqueous solution of sodium hydrogencarbonate, dried and concentrated in vacuo. The residual product is recrystallized from ethyl acetate and as a result, the pivaloyloxymethyl carboxylic ester is given in Table. 18.

3. The potassium salt is replaced with the sodium salt and as a result, the same products are obtained under the same condition.

4. Pivaloyloxymethyl ester (250 mg), corn starch

(150 mg) and magnesium stearate (5 mg) are mixed, granulated and encapsulated. This capsule (2-3 capsules)

3IA

administered orally to the body to treat patients suffering from an infectious disease caused by susceptible E. coli,

5, Rj and / or Rg-AOM. Instead of iodomethyl 1 givalivate, iodomethyl acetate is used under the same reaction conditions, and the corresponding acetoxymethyl ester is obtained as shown in Table 18.

The compounds of formula (I) obtained according to the invention have very low acute toxicity. If RS

means hydrogen, the oral LD value exceeds 10 g / kg (rats) and is more than 5 g / kg for dogs (when administered orally). The values presented are better than those for intravenous administration of cefazolin (the corresponding values are 3 for rat and 1.25 t / kg for dogs). In addition to the MIC data listed for the compounds in Table. 5-8 additional information on the antimicrobial activity of the compounds of formula (I) obtained according to the proposed method.

The multiplicity of improvements in the MIC values of the compounds of the formula

in comparison with the known cephalosporins, which have no carboxyl substituent in the side chain, is given in Table. nineteen,

From Table 19, it can be seen that the introduction of the COOH group into the R j substituent, i.e. in alkylene, the compounds of formula (I) significantly improve antimicrobial activity, expressed in terms of the minimum inhibitory concentration. Activity values are relative values. For example, the number 8 means that the proposed compound in its activity 8-fold exceeds the activity of a cephalosporin compound that does not have a COOH group in the RJ substituent. Such an effect is of great importance for the clinical treatment of infectious infections caused by gram-negative bacteria.

Claims (1)

Invention Formula Method for preparing carboxyalkene-docephalosporins of general formula C11 C-R 15s СОМН-т-Г in, -shit de u - hydrogen or chlorine; 15 Rj is a simple bond, C -Ca | -kapkylene is normal or iso-structure or thiomethylene; siCi — independently, hydrogen, alkali metal, 20 lower alkyl of normal or iso-construction, which may be substituted by phenyl, lower alkenyl of normal or iso-structure, which may be replaced by phenyl, lower alkanoyloxymethyl, diphenylmethyl or benzyl, which may be substituted by methyl, methoxy or nitro; CL - hydrogen or methoxy group; Rj is hydrogen or chlorine, methyl, which may be substituted by methoxy, acetoxy, or es carbamoyloxy, vinyl, which may be substituted by cyano, carboxy, tert-butoxycarbonyl or trifluoromethyl, hydroxy, hydroxy, methanesulfonic,. a sigroup, mono- or trifluoromethylthio group, vinylthio group, or a radical of the formula -CHj-S-Rg, where Rg is methyl, difluoromethyl, cyanomethyl, triazolyl, methyltetrazolyl, or thiadiazolyl, which may be substituted with 50 methyl, amino, tert-butoxycarbonylamino, aminomethyl or tert-butoxycarbonylaminomethyl; R is phenyl, thienyl, substituted / - 55 amino, tert-butoxycarbonylamino or benzyloxycarbonylamino, isoxazazolyl or thiadiazolyl, free thiazolyl or substituted by a free amino group or protected by tert-butoxycarbonyl, benzyloxy by arbonyl, methylbenzyloxycarbonyl, formyl, chloroacetyl, tert-butyldimethylsilyl or p-nitrobenzyl, or as a salt with a salt or trifluoroacetic amino acid thiazolyl; X is oxygen, sulfur, or sulfinyl; under the condition that RU is thiomethylene, then R / is chlorine and the carboxy and amide groups are carboxyalkenamidosis; the amideller is in the cis position, or their esters, or their salts with alkali metals, o and l and h - I n and in order that the compound of the general formula R / t  V t x  one O N-f-Rs SOOYab where R "is Rg and X have the indicated values,. or its reactive derivative is reacted with 1.1-2 mol of carboxylic acid of the general formula R, -C-COOH one (Iii) R .j-COOR, where R is Rj and Ry have the indicated values, or its reactive derivative in 3-36 volumes of solvent selected from chloroform, dichloroethane, dimethoxyethane, dimethyl acetamide, dioxane, ethyl acetate, ethylene chloride, methyl isobutylketone, tetrahydrofuran, toluene and water, in the presence of an appropriate condensing agent in the amount of 0 - 2.5 mol selected from carbonyldiimidazole, cyanuric chloride, cyanuric chloride – pyridine complex, cyclohexane-d-cycloheximide di-cycloheximide, diethoxyphosphonic acid bromide, ethyl ethoxydihydroquinoline, hydroxybenztriazole, chlorine Dridi oxalic ki 71 slots, phosphorus oxychloride, thionyl chloride, trfluoroacetic anhydride, trimethylsilyl chloride and Vilsmeier reagent, and 0-6 mol of base selected from dimethylaniline, lutidine, methylmorpholine, picoline, pyridine and triethylamine, from 15 min to 15 h besides The procedure is from -50 ° C to room temperature and the protective groups possibly protecting the amino group and / or carboxyl in the target compound, in which at least one of the substituents Rj is in protected form, in 3.9-41 volumes of the corresponding solvent, selected from acetic acid, anisole, dichloromethane, ethanol, nitromethane, tetrahydrofuran, toluene, and water, by treating 3-18 moles of an agent to remove protecting groups selected from aluminum chloride, hydrochloric acid, methyl N-methyldithiocarbamate, palladium complex - triphenyl spine, sodium hydrocarbonate, tin chloride, thiourea, titanium tetrachloride, trifluoroacetic acid and zinc, for 30 minutes to 24 hours with and / or the desired product, at least one of the substituents RJ and Rfe in the rotor - hydrogen, neutralized with 1 mol or more of the corresponding base at room temperature to give the desired product as an alkali metal salt. Priority signs: 04.10.83 when RI is hydrogen; R. - simple bond or C ;, - C3-alkylene nor maximal or isostructural; R and R are independently hydrogen, alkali metal, normal or iso lower alkyl, which may be substituted by phenyl, normal lower alkenyl or iso isostructure, which may be replaced by phenyl, lower alkanoyloxymethyl, diphenylmethyl or benzyl, which may be substituted by methyl, methoxy or nitro; R is hydrogen; Rj is hydrogen or chlorine, methyl, which can be substituted by methoxy, acetoxy or carbamoyloxy, vinyl, which can be substituted by cyano, carboxy, tert-butoxycarbonyl or trifluoromethyl, hydroxy, methane sulfonicloxy, mono- or tri - fluoromethylthio, vinylthio group 15 01 Q 20 25 thirty 35 40 45 0 five 63. 18 or a radical of the formula in which Rg is methyl, difluoromethyl, cyanomethyl, triazolyl, methyltetrazolyl or thiadiazolyl, which may be substituted with methyl, amino, tert-butoxycarbonylamino, aminomethyl or tert-butoxycarbonylaminomethyl; RV is substituted by a free amino group or protected by tert-butoxycarbonyl, benz-Loxycarbonyl, methylbenzyloxycarbonyl, formyl, chloroacetyl, tert-butyldimethylsilyl or p-nitrobenzyl aminothiazolyl; X is sulfur. 03.02.84 with hydrogen or chlorine; R 2 is a simple bond, normal or iso-halogen or thiomethylene; Rj and R are independently hydrogen, alkali metal, lower alkyl of normal or iso-construction, which may be substituted with α-phenyl, lower alkenyl of normal or iso-construction, which may be substituted with phenyl, lower alkanoyl-yloxymethyl, diphenylmethyl or benzyl, which may be substituted by methyl, methoxy or nitro; . 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" CM E - “CNl - about . 1L | u-1 - -1S / Z -E- 00 N o - r  o - - l-  O OOi, m o ON - 00 Q .. o x Q - and CM I S & CNJ - I II ABOUT n - n  H CM I X I cj  X CM C-, CM i " a. „ -o q about oh oh x  cm 1L s cs 1L g . ate go " - - s and  Q e ;: - X  about X cm VO CTN - x cm with s  with and a - - CHO 1L -: t 1Л CM X t- U vt - -E cm v- o - about g- “o t-g - Ich1L "I X D see Oh with Cho - about. about 1L - n Ift with and N 00 o X - and see CHO cm x cm - U, with SP ) and about, about CJ4 -about " - - t g-  / - X go cm Yu - cm about joint venture with about about 00 HO about - about with - about 1L G - vO in o- 00 cm fO with - "- about "lh00smso m-- | & e tS -dJ tl Z T W f and ate and T & r1 "L cm ABOUT Z eleven Yu I and "with; 0X t; X Xo bye sa 01a saX from 00 cm - see cm l S cm g X cm  about ax about cm / -N g SP ".. yo I- - o s -C7-. I "ta . vO VD about with cho o (j st. "I OO N 10  X -4 vO o o N a O ten .00 s -N - X about .. vO / -Ч a 1 ICM i  00 - oh oh and g: -3- " "F11 X X cm cm u-1 CM - cho with - lA oo oh oh about g- -a vo with - 1L 00 Xq 01s en ABOUT) (Es t o t in r co-z g 0 g w CM E o Z-; th V cm  l: o 135 2 SP s u with I s and :with; os Rzh about SPY Yeo. From wx and X se but -. CM ) . oh oh " SP about X p - oh CN - about from Article 2 about VO - about .kO - / W: t I m - about CO . . fc "o about u vO .. x-1O with as - "  m  .. " SS about  s 1-, p / tt X ffi : with tN CS  sch 00 m 00L about I cho z . iO .-. .. V0  g -. -about -  G- from “h and oo " g 5 X X with cm about  and ..fi I cm d about v in "  g p -G. 00 oi o - - and - c; g cm 1P X PR with g- " X t 1 -1L U  1L / -S 1L i cm in "I ft "o   -) with. "with" -.- N & "Well - about about . "" Pts uh - " X t and g fO- in "" and II U  cm 1- o CJ "G" "" Is -h-- About "o" q Pts h “X y - in 00 ". 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C-4 I / F cm p -  5 5 and s Z, -4 o in 00 t "o  Z - h in Cl "o .about f o X " - VO w o “Cho rw - P XX - cm 4t About vO X L sm  about “With and g Very long "With -J-e-". Yu L | X -. cm x x cm -  about - t-t g “Go with to - one "  sh . .. -, with -. . . A.and X l w  II  "In og" -- " P CS " Ui "and  h e about G cho 1L about with about g C oh oo o m sm Ov g o cm - -- oh oh oh - see sm about art. Mr. - about sh 00 about 1 VO W OOOOSOOOOOOOO OJOvOCMOOSMG COSMOO SOG CGGGGOGHOSHSM with - - со.- ™ - "- - o o och sm with gh. with - pa au about "I sh I-h X 0) X 01 0-t-so-z l / -V CJ ate x u. h one but to I to about five §. ft ("Scent and yo five ft E-1 and § Tr. NsNOfP N-1 R CH, H 1780, 1720,  .1670, 1620, 1515, 1340 “Is NOrPN-, JH-NCH .. IM Jf b "|" $ 1mb | gss WCM CH, H 1780, 1730, 1540, 1280 Cis N NH eeHiVJmimu KapSoHUjt 1720, 1620, 1340 f720, I62S, 1340 1730, 1280 1770 1690, .1290 5.13 (s, 2H); 5.95 and 6.04 (dd, J, - 5 Hz, Jt 9 Hz, IH); 6,, 66 (M, IH); 6.83 (T, J - 8 Hz, 0.5H); 6.95 (s, 1H) J 7,, 50 (M, 16.5H)} 8.52 (d, J - 9 Hz IH)) 8.75 and 8.84 (d, J 2 Hz, IH) 3,, 73 (M, 2H), 3.50 (d, J - 7.5 Hz, 2H); 5.02 (d, J - 5 Hz, IH); 5.17 (s, 2H); 5.99 (dz, 5 Hz, ... Jt, - 8 Hz, IH); 6,, 68 (m, 1H)} 6.99 (s, 1H)} 7,, 6 (m, 1711) 8.07 and 8.21 (AB m 2, J - 9 Hz, 4H) (8 , 71 (d, J - 8 Hz IH); 9.20 (s, 1H) 3.13l 3.75 (m, 2H); 3.77 (d, J 7 Hz, 2H); 5.03 (d, J - 5 Hz, W); 5.18 (s, 2H); 5.98 (YES, Ji 5 Hz, Ji - 8 Hz, 1H); 6,, 70 (m, 1H); 6.92 (t, J - 7 Hz, 1H); 7.01 (s,; 1H); 7, 6 (m, 16H) {8.09 and 8.23 (AB squ., J - 8 Hz, 4H); 8.83 (d, J - 8 Hz, 1H); 9.21 (s) H) 3, 31 (m, 1H) 3.64n 3.50 (AB squ., J - GO Hz, 1H); 3.67 and 3.81 (2xd, J - 7 Hz, 2H); 4.71 and 4.84 (2xd, J - 5 Hz, 1H); 5.04 and 5.11 (2xC, JH); 5.22 and 5.29 (AV.kv., J - 12 Hz, 1H) (5.22 (m, 1H); 5,, 1 (m, 0.5H); 6,, 7 (m, 1H ); 6.22 and ", 87 (2xC, lH) i 7,, 7 (m, 23H); 8.33 and (2xd, J 8 Hz, W) 2, 24 (m, 2H)} 4.88 (d, J - 5 Hz, 1H); 5.11 (s, 2H) t 5,, 17 and 5.32 (L8 sq., J - 13 Hz, 2H) 6.09 and 6.16 (dd, J, - 8 Hz, Ji - 5 Hz, 1H); 6.52 (and, | H); 6.86 (s, 1H); 7.01 (s, 1H); 7.27 (m, 20H); 8.46 (d, J - 8 Hz, W) Continuation of table 14 1H) fCDjSOCDj-CD, OD-CpCl 1,2,3 - thiadiazole - 5 Il.