Process for producing derivatives of cephalosorin or their esters, ethers, or salts, or their hydrat

专利摘要:
Acyl derivatives of the formula <IMAGE> wherein R signifies hydrogen or a protective group which can be split off, R1 signifies lower alkyl and X signifies the group <IMAGE> +TR <IMAGE> wherein one of the residues R2 and R3 represents hydrogen and the other represents alkyl and R4 represents lower alkyl the easily hydrolyzable esters and ethers thereof, the salts and hydrates of the above compounds, esters, ethers and salts.
公开号:SU927119A3
申请号:SU792768351
申请日:1979-05-28
公开日:1982-05-07
发明作者:Монтафон Марк；Рейнер Роланд
申请人:Ф.Хоффманн Ля Рош Унд Ко,Аг(Фирма)；
IPC主号:

专利说明:

C ON "C - CONH CH -SRCHiCOHN, where X has the indicated meanings; R is a chlorine, bromine or iodine atom and the carboxy group can be protected, the halogen acetyl amino protecting group is isolated, and if appropriate, the carboxy group is protected, the carboxy protecting group is cleaved off by treatment with thiourea in an aqueous or anhydrous solvent 6 acidic, neutral or alkaline if necessary, the target product in the form of free acid and / or enol is converted into its ester, ether or salt, or its hydrate or hydrate of its layer) 1 (ether, ether or salt. Target The product may be in blue anti-form or as a mixture of these two forms. The preferred synomeric form or mixture in which synform predominates. The preferred product obtained by the proposed method is {6R, 7R) -7-G2- (2-amino- 4-thiazolyl) -2- (Z-methoxyimino) acetamido-3- f (2,5-dihydro-6-oxit, 2-methyl-5-oxo as-triazin-3-yl) thio-methyl} -8- oxo5-thia-1-azabicyclo (2.0) oct-2-ene-2carboxylic acid, as well as its salts or hydrates of this compound or its salts. By ethers and esters, easily hydrolysable esters are understood. Ethers of compounds of formula (|) are prepared when X represents a 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group. Hydration of the free acids and / or enols of the formula (I), as well as their esters or salts, can occur during the process or during the storage of the anhydrous hygroscopic product. The starting compound of formula (II) can be obtained by N-acylation of the corresponding 3-triazinylthiomethyl 7 aminocephalosporin 2- (2-halo, cet amido-β-thiazolyl) -2-methoxyimino-9 4 with hydrochloric acid or its reactive derivative. A second method for preparing compounds of formula (II) is that 7- 2- (2-haloacetyl-4-thiazolyl) -2 methoxyiminocetamido-3- (substituted methyl group) cephalosporin is reacted with the corresponding triazinyl thiol. The resulting mixture of syn and anti-isomers of compounds of formula (I) can be divided into appropriate syn and anti-forms, for example, by recrystallization or chromatographic methods using a suitable solvent or mixture of solvents. The compounds of formula (I) and (I I), as well as the corresponding easily hydrolysable esters and ethers, and the salts or hydrates of these products have a biological, especially bactericidal, action. They possess a wide action spectrum against gram-positive and gram-negative microorganisms including forming a p-paktamazy various staphylococci and gram-lactamase-forming bacteria, for example Pseudomonas aeruginosa, Haemophifus influenzae, Escherichia coEi, Serratia marcescens, Proteus-and KZebsiettaSpezies, and may find use for the treatment and prevention of infectious diseases. For an adult, a daily dose of approximately 0.1 g to 2 g is used. Parenteral administration of the compounds is especially preferred. In order to prove the antimicrobial effect of the products mentioned, the following compounds are tested. Product A: (6R, 7R) (2-amino4-thiazolyl) -2- (2-methoxyimino) acetamido-3- (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3- yl) thio-methyl) -8 oxy-5-tia-1-azabicyclo (2.0) oct-2-2-carboxylic acid. Product B: (6R, 7R) -7-b-G2- (2chloro-acetamido) -thiazolyl -2- (Z-methoxyimino) acetamido-3- (2,5-Dihydro-6-hydroxy-2-methyl-5- .oxo -ac-triazin-3-yl) thio Methyl-8-oxo-5-thia-1 azabicyclo {A, 2.0) oct-2-en-2 is a carboxylic acid. In vitro activity: minimal inhibitory concentration mg / ml. The test results are shown in Table. one.
Table 1 In vivo activity. The groups, in each of which there are five mice, are infected with an aqueous suspension of Escherichia coti, which is administered intraperitoneally. Three times, i.e. After 1 h, 2.5 h and 4 h after infection, the test substance was administered subcutaneously in physiological saline. On the fourth day, the number of animals surviving is determined. Different dosages are applied and the dose is determined by interpolation, with 50 experimental animals (EDo. Mg / kg) remaining alive. The results are shown in Table. 2. Table 2
Intravenously
Subcutaneously
Orally Products can be used as medicines, for example, in the form of pharmaceutical preparations that contain these products or their salts in a mixture with a suitable organic or inorganic inert excipient such as, for example, water, gelatin, arabia, for entoral or parenteral administration. gum, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylglycols, vaseline, etc. Pharmaceutical preparations can be in solid form, for example, in the form of tablets, dragees, suppositories, or sludge capsules. in liquid form, for example, in the form of solutions, suspensions or emulsions. If appropriate, they are sterilized and / or contain adjuvants, such as conservatives, stabilizers, wetting agents or emulsifiers, salts for altering the osmotic pressure, anesthetics or buffers. However, they may also contain other therapeutic valuable substances. The compounds of formula (1) or their salts or hydrates are used primarily for: parenteral administration. To do this, they are preferably prepared in the form of lyophilisates or a dry powder to dilute
0.16
0,005
250-500 2000- 000 T5000 conventional agents, / for example, water or isotonic saline solution. Easily hydrolyzable esters and ethers of the compounds of formula (1) and their salts or hydrates can also be used for enteral administration. Example 1. Preparation of (6R, 7L) -7-2- {2-aminothiazolyl) -2- (L-methoxyimino) acetamido-3- (2,5-dihydro-6-oxy-2-methyl5-oxy-2-disodium salt of disodium salt) ac -triazin-3-yl) thio-methyl) -8oxo-5-thia-1-azabicyclo (, 2,0) oct-2en-2-carboxylic acid. 15.3 g (6R, 7R) -7- | 2-G2- (2-chloropattamido) - thiazolyl -1-2- (g-methoxyimino acetamido} -3- (2,5-dihydro-6-hydroxy2-methyl. -5-oxo-ac-triazin-3-yl) thio1-methyl-8-oxo-5-thia-1-azabicyclo (i, 2.0) oct-2.-en-2-carboxylic acid (fraction I, see below) are suspended together with 5 g of thiourea in 150 ml of water.When passing nitrogen and stirring, adjust the pH with saturated sodium bicarbonate solution to 6.8-7.0, and an orange solution is formed.With an autotitrator and withstand sodium bicarbonate solution | The reaction solution was kept constant for 6 h at 6.8. Then he added m another 2.5 g of thiourea, and the solution was stirred another 3 hours, the pH being maintained by the addition
992711
saturated sodium bicarbonate solution at 6.8. The red solution is then placed in a refrigerator overnight, where it becomes darker. The pH of this solution is adjusted by adding 5 formic acid to 2.02, 5, and the substance is released. This substance is filtered off with suction and washed with 100 ml of formic acid. The mother liquor is ejected. The brown residue is suspended in suction in 200 ml of water and the pH is adjusted to 7 with triethylamine, and a brown solution is formed. This solution is stirred for 30 minutes with 2 g of 15 active carbon, filtered from the coal and the pH of the still brown filtrate is adjusted with 100% formic acid with good stirring to 3, 5. The precipitated substance is sucked off under suction, washed with 50 ml of 10% formic acid and discarded, the pH of the dark yellow filtrate is adjusted to 2-2.5 with formic acid, and the substance is released 25 washed with ice water and dried. The resulting cephalosporic acid is suspended in order to be converted to the disodium salt in a mixture of 0 ml of 30 acetone and tO ml of water, and 20 ml of 2N is added. solution of sodium salt of 2-ethylcaproic acid in acetic ester. To the resulting orange solution, 50 ml of 35 acetone are added, and a brown resin is released, which is separated by filtration. The yellow filtrate was stirred for 30 minutes, and the disodium salt crystallized. 40 50 ml of acetone are added in portions to the mixture and placed in a refrigerator overnight. Crystallisate is aspirated on suction, washed in turn with a mixture of acetone and water (85:15), pure acetone and low boiling petroleum ether and dried overnight in vacuo at ijOC. 3.5 g () of the proposed substance are obtained in the form of beige crystals, containing 111 mol of substance, 3.5 mol. (with 0.5 in water).
The NMR spectrum and microanalysis correspond to a given structure .55 (): approx. 3.58 {2-SNg.) (AB-Apt., 2); 3.62 (NCH ,,) (c.3); 3.98 (OCH.) (P., 3); . 4.22 (3-CHt), (AB-ap., 2);
910
5.20 (n-6) (d., 1); 5.77 (H-7) (d. 1); 6, 99 (thiazole-H) {s., 1).
Microanalysis (St. Nce M40, SjNa2.-3, 5 NG)) (Mol. V.661,59)
Calculated: C 32,68; H 3.50; M 16, S 1, n, about 9.53;
Found,%: C 32.89; H 3.6; N 16.96; S 1if, Hj.0 9.50.
Used as starting material (6R, 7R) (2-chloroacetamido) -i-thia.zolyl -2- (Z-methoxyamino) acetamido} -3- (2,5-Dihydro-6oxy-2-methyl-5-oxo -ar-triazin-3-yl) thio-methyl-8-oxo-5-thia-1-azabicyclo C, 2.0) oct-2-en-2-carboxylic acid G1 is obtained as follows.
22.24 g of 2- (2-chloroacetamidothiazol-yl) -2- (Z-methoxyamine) acetic acid are suspended in ml of methylene chloride. To this suspension was added 13.39 ml of triethylamine, and a light brown solution was formed. This solution is cooled to 0-5 ° C. 16.72 g of phosphorus pentachloride are added and stirred for 5 minutes at 0-5 ° C and 20 minutes without cooling. The yellow solution is evaporated in vacuo at 35 ° C. The residue after evaporation is shaken twice with n-heptane and the latter is decanted. The gummy residue is treated with 2kO ml of tetrahydrofuran and the undissolved triethylamine hydrochloride is filtered off. Yellow, the filtrate contains an acid chloride.
22, g (7R) -7-amino-3-deacetoxy3- (2,5-dihydro-6-O1 si-2-methyl-5 oxo-as-triazin-3-yl) -thiomethyl cephalosporanic acid is suspended in a mixture of 300 ml of water and 150 ml of tetrahydrofuran. 2N sodium hydroxide solution is added dropwise to the suspension with good nitrogen transmission using an autotitrator until a brown-red solution with a pH of 8 is formed. This solution is cooled to 15% and the above obtained is added dropwise during 15 minutes. a solution of an acid chloride in tetrahydrofuran. Then stirred for 2.5 hours at. The pH of the acylation mixture is maintained by adding 2N sodium hydroxide solution constantly at 8. Practically the black solution is freed from tetrahydrofuran in a vacuum. Then 100 ml of 2N sulfuric acid are added. The precipitated substance is sucked off under suction, washed with water 11 9 and well sucked off. The wet brown residue is dissolved in 1.5 liters of acetone. The dark solution is filtered through hyphlo from a less dark undissolved material, carbon is added, stirred for 30 minutes and filtered again through hyphlo. The orange-red filtrate is dried with sodium sulfate, concentrated in vacuo and evaporated with ethyl acetate. This releases a black resin, which is filtered and discarded. The two-phase filtrate containing more water is subjected to azeotropy three times with benzene in vacuo at. The precipitated substance is sucked off under suction and dried in vacuum at 0 ° C. It is mixed twice, using T l of acetone, and a Brown Resin remains, which is discarded. The collected orange acetone extracts are concentrated in vacuo to kQ ° C to approximately 1bO ml, filtered, and the brown resin is discarded. To the filtrate was added 1 l of ethyl acetate and the mixture was concentrated in vacuo at 0 ° C. The resulting precipitate was filtered off with suction, washed first with ethyl acetate and then with ether. (6R, 7) 12- (2-chloroacetamido) H-thiazolyl -2- (2-methoxyimino) acetam to -3 is obtained; {(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazine-3-id) thio-1-methyl 8-oxy-5-thia-i-azabicyclo (, 2, Q) oct2-enecarbony acid (fraction I: beige amorphous acid). This fraction can be applied directly to obtain the desired Target Product. The mother liquor of ethyl acetate is concentrated in vacuo at kO ° C, diluted with ether, and the precipitated substance is filtered off with suction. (6R, 7PO-7 2- 2- (2-chloroacetamido U4 thiazolyl -2- (Z7metoxymino) acetamido} -3 E (2.5-dihydro-6-hydroxy-2-methyl5 oxo-as-triazine-3- yl) thio-methyl} -8 oxo-5-thia-1-azabicyclo (4,2,0) oct-2-2-carboxylic acid (fraction I: light beige amorphous acid, in thin layer chromatography is slightly cleaner than the fraction I) The total yield of fraction I and I is 18.8 g (49.6% of theory). To obtain the disodium salt, dissolve 3.5 g of the acid (fraction 1) 9 in a mixture of 20 ml of acetone and 11 ml of water. 6 ml of 2N solution of sodium salt of 2-ethylcaproic acid in ethyl acetate are added, and crystallization The disodium salt is added. Then another 25 ml of acetone is added in portions and the mixture is placed for 2 hours in a low-temperature cooler. Then the crystallized mixture is sucked off with suction, washed in turn with 25 ml of an extremely cold mixture of acetone and water (80:20), pure acetone and low-boiling petroleum ether and dried overnight in vacuo, with (6R, 7R) (2-chloroacetamido) -; -thiazolyl disodium salt of 2- (g-methoxyimino) -acetamido} -3 {(2,5-DIHYDRO) 6-hydroxy-2-methyl-5-oxo-triazin-3-yl) thio-methyl} -8-oxo-5-thia-1-azabicyclo (, 2.0) - oct-2-en2-carboxylic acid as light yellowcrystals. W, 7 input). . The NMR spectrum and microanalysis correspond to a given structure. (0.0): Approx. 3.6 (2-СНг.) (АВ-кв., 2); 3.63 (NCHj) (c., 3); , 05 (OCHi) (c., 3); H27 (3-SNg.) (AV-kv.2); , 4.3 (-CO-CHg-C1) (s, 2); b .23 (H-6) (d., 1); 5.83 (.N-7) (d., G); 7, “7 (thiazole-H) (s., 1). Microanalysis, C H NgOj SgСiMa 2. Compound f, 39 water and 0.2 mol of acetone. Calculated,%: C 35.59; H 2, N 16.60; S, 25; .C1 5.25. Found: C36.03; H 2.67; 16.32; S 14.01; Ct 5.16. . PRI m e R: 2. Preparation of sodium .. (6R, 7R) -7-G2- (2-amino-4thiazolyl) -g2- {methoxyimino) acetamido3-oxo-3- (U, 5.6- tetrahydro-4methyl-; 5., 6-dioxo-triazin-3-yl) thio methyl J-5-thia-1-azabicyclo (4,2,0) -oct-2-ene-2-carboxylic acid. 19 g (6R, 7R) (2-chloroacetamido) -t-thiazolyl -2- (methoxyimino) -acetamido -8-oxo-3- (1, 4.5,., 6-tetrahydro-4-methyl-5, 6-dioxo —ac ..... triazin-3-yl) -thio -methyl-5-thia-1aza цикcyclo (4.2.0) oct-2-en g-carbono, howl the acid is suspended together with 9.5 g thiourea in 1.5 ml of water. By passing the nitrogen and stirring, the pH is adjusted with a 5% sodium bicarbonate solution to 6.8, and a yellow-orange sprout is formed (sor. With the help of an autotitrator and with the addition of
The scientific research institutes of sodium bicarbonate solution maintain the pH of the reaction solution for 6 hours constantly at 6.8-7.0. To the orange solution was added formic acid until the pH was 3.5. The precipitated substance was sucked off, suction and washed with 100 ml of formic acid. This residue on suction means T). The pH of the filtrate is adjusted by adding formic acid to 2.5, and the substance is released again. The mixture was kept for 1 h in an ice bath, then the precipitated substance was sucked off with suction and washed with a small amount of ice water. This substance is the so-called fraction I. The orange-brown residue on suction (T) is suspended in 250 ml of water. The pH of the suspension was adjusted to 2N. NaOH to 7, we take an orange-brown solution. Again formic acid is added to this solution until the pH is 3.5. The precipitated substance is sucked off by suction and discarded. The pH of the filtrate is adjusted to 2.5 with formic acid, and the substance is released again. The mixture was kept for 1 h in an ice bath, then the precipitated substance was sucked off with suction and washed with a small amount of ice water (fraction II). Fractions I and II are suspended together in 500 ml of ethanol and evaporated in a rotary evaporator to remove water. After the addition of ether, the mixture is suction filtered with suction and washed in turn with ether and low boiling point petroleum ether. Thus, 7.0 g of the proposed yellowish solid is obtained, which is designated A.
The stock solutions and washings of fractions I and II are concentrated from about 1.7 liters to 250 ml, the pH is adjusted to 2.5 with formic acid and the solution is placed in a refrigerator overnight, and the substance crystallizes again. It is sucked off on the suction and washed with a small amount of water. The residue is subjected to azeotropy with ethanol. A solid, practically colorless suggested substance is obtained, which is designated as B. In thin-layer chromatography 5 is cleaner than A.
91D
To obtain the pure proposed substance, acid B is suspended in 150 ml of methanol and 10 ml of 2N solution of sodium salt of 2-ethylcaproic acid in ethyl acetate are added with stirring. After approximately 10 minutes, a solution forms, to which 100 ml of ethanol is added. The mixture is concentrated strongly under vacuum at. After addition of ethanol, the sodium salt is released in amorphous form. It is filtered off with suction, washed in turn with ethanol and neekokipyu petroleum ether and dried for 2 hours under high vacuum. Obtain k, g of the proposed substance in the form of a practically colorless amorphous powder containing, by mole of the substance, 0.37 mol - 9 ° ( in water).
According to the NMR spectrum, the proposed substance is in the form of a Z / E mixture (90:10). Microanalysis also corresponds to a given structure ..
NMR spectrum.
3, (MCH) (p., 3); approx. 3.60 () (AB-Apt., 2); g, 00 (OCH5) (s., 3); approx. 4.15 (3-CH) (AB-KB.2) i 5.1b (n-6) (d., 1); 5.76 (H-7) (d., 1); 6.9b (thiazole-H) (s., 1).
Microanalysis of NgO / containing 1, 37 mol of water and 0.6 mol of ethanol (Mol. In, 576,55)
Calculated,%: C 38.17; N З ,; N 18, Na 3.81.
Found: C, 38.23; H 3.2; N 18.61; Na A, About.
Used as starting compound (6R, 7R) (2-chloroacetamido) -α-thiazolyl -2- (labeled siimino) -acetamido | -8-oxo-3 {(1 ,, 5,6-tetrahydro-methyl-5,6 dioxo- ac-triazin-3 yl) thio-methyl} 5-thia-1-azabicyclo C, 2,0) oct-2-en2-carboxylic acid can be obtained as follows.

权利要求:
Claims (2)
[1]
  kk g (7L) -7 amino-3-deacet.oxy3 (1, 6-tetrahydro-methyl-5,6-dioxo-as-triazin-3-yl-cephalosporanic acid is suspended in a mixture of 600 ml of water and 300 ml of tetrahydrofuran. K suspensions are added dropwise with good nitrogen transmission and using a 2N sodium hydroxide autotitrator until a brown solution with a pH of 7.8 is formed. This solution is cooled to 0-5 ° C and added dropwise to it m for 15 t5 min solution of 2- (2 chloroacetamidothiazol-4-yl) -2- (g-methoxyimino) acetic acid chloride in tetra-hydrofuran (obtained from, S g correspondingly acid) according to example 1). Then, it is stirred for 2.5 hours at pH 8 and the pH of the acylation mixture is maintained by adding 2N sodium hydroxide using an autotitrator at a constant 7.8-8. The dark solution is released in vacuo at from tetrahydrofuran. The solution is then diluted with water to a volume of 2 liters, the pH is adjusted with 2N sulfuric acid to
[2]
2. The precipitated substance is sucked off under suction, washed with 1 liter of water and dried for 2 days under vacuum at 0 ° C. The crude yield is 60 g. For purification, the substance is dissolved first in a mixture of 100 ml of water and 300 ml of acetone. The dark solution is diluted with acetone to a volume of 2 liters. The dark substance (3.5 g) precipitated in this way is filtered off and discharged. To the filtrate is added 1 l of ethyl acetate. In vacuum at kO С 1 l of solvent is evaporated. The solution is then diluted with 2 L of ethyl acetate. A beige, brown substance that has fallen off is thrown away. The filtrate is concentrated strongly under vacuum, the crystallized acid is sucked off with suction (CJlr). To recrystallize, the acid is first diluted in 800 ml of methanol at reflux temperature. The solution is cooled to 25 ° C and filtered from a slightly orange substance. The yellow solution was stirred for 1, 5 hours in an ice bath, and the acid crystallized. It is filtered off with suction, washed in turn with methanol and low-boiling petroleum ether and dried under vacuum at. This gives 19.5 g of the starting material from the dinene in the form of beige crystals (EUT 25.8% of theory). According to the NMR spectrum, the starting compound is in the form of a Z / E mixture (75:25). , k.-127.9 (with 1 in dimethylformamide) o NMR spectrum. (DMSO-dj) (main component Z-isomer): 3.30 (MCHN), (s ,, 3); 3.68 (2-CHt) (AB-KB., 2); 3.90. (OSIL) (s., 3); , 13 (3-CHg.) (AB-KB., 2); , 37 (-CO-CHt-Ct) (c ,, 2); 5.17 (H-6) (d ,, 1); 5.83 (H-7), (square 1); 7, (thiazole-H) (s ,, 1); 96 9, B9 (-CO-MN-C) (d ,, 1); 12.55 (-CO-NH-C) (s, 1); 13.0 (-COOMl (b, .O, &amp; Example 3, Preparation of methylene (6R, 7R) -7-2- (2-amino-thiazolyl) -2 (Z-methoxyimino) acetamido -3I (2 , 5-dihydro-2-methyl-5-okko-6 (pivoloyloxide) netoxides (-ac-tryazin-3yl) -thio-methyl-8-oxo-5-thia-1-azabicyclo (, 2,0) oct- 2-ene-2-carboxylate pevivalate, 1.85 g of cephalosporin disodium salt prepared in Example 1 are suspended in 50 ml of dimethylformamide and 1.35 g of pivaloyloxymethyl iodide are added with nitrogen flow and the reaction mixture is stirred for 30 minutes at 0-5 ° C and it is then poured onto 500 ml of ethyl acetate. The mixture is washed three times with water, twice with a solution sodium bicarbonate and again with water. The solution is dried with sodium sulfate and concentrated strongly in vacuo. After adding ether, the proposed substance is released in amorphous form. It is sucked off under suction, washed with ether and petroleum ether and dried overnight. high vacuum at 25 ° C, get t), 8 g (3b, 5%) of the proposed substance in the form of a beige amorphous powder. The product does not contain water. The NMR spectrum and microanalysis correspond to a given structure. NMR spectrum. (DMSO-de): 1.17 (2x (CHj) iCO -) (c., L8); approx, 3.6 (2-SNg) (AB-apt., 2); 3.64 (NCHb) (c ,, 3); 3.83 (OCHi) (c., 3); , 28 (3-CHt) (AB-KB ,, 2); 5.18 (H-6) (d., 1); approx, 5.8 (H-7) (square, 1); approx. 5.9 (2x-0-CHg.-0 -) (m., A); 6.75 (thiazolyl-H) (s, 1); 7.17 (PL) (b., 2); 9.70 (NH) (d., 1). Microanalysis (Mol.v,: 782.86) Calculated,%: C, 03; H 4.8S; N 14.31: Found: C, 5.82; H A, 90; N 14.13, Example 4. Preparation of an ampoule with a dry sterile substance for intramuscular administration. A lyophilisate of 1 g of sodium (6R, 7R) -7-C2- (2-amino-4thiazolyl) -2- (2-methoxyimino) acetamido3 sodium salt is obtained. -3- (G (2,5-DIHYDRO-6-hydroxy-2-me.til5-oxo-as-triazin-3-yl) thio1methyl8oxo-5-thia-1-azabicyclo {4.2, 0) oct-2 ene-2-carboxylic acid and poured into ampoules. Before use, 2.5 ml of 2-lidocaine hydrochloride solution was added to the lyophilisate. Claim 1. Method for producing cephalosporin derivatives of general formula:; Y and snk-somDlx I TPG I m. AACH.-SX "rH y Ton in which X is 2.5-DIGIDRO-6-oxo-2methyl-5- the oxo-ac-triazin-3-yl group which is in tautomeric equilibrium with the 1, 2,5,6-titrahydro-2 methyl-5, 6-dioxo-ac-triazin-3-yl group, or 1 (A.C. .b-tetrahydro-methyl-5, 6-dioxo-ac-triazin-3-ylgroup, or their esters, simple esters or salts, or their hydrates or hydrates - their esters of ethers or salts, different - in the compound of the general formula II .C-CONH. In.-sx.18 where X has the indicated values; R is a chlorine, bromine or iodine atom and the carboxy group can be protected, the halogen acetyl amino-protecting group is isolated and, if appropriate, the carboxy group is protected, the carboxy protecting group is cleaved by treatment with thiourea in an aqueous or anhydrous solvent in an acidic or neutral or an alkaline medium and, if necessary, the desired product in the form of the free acid and / or in the form of an enol is converted into its ester, ether or salt or its hydrate with its ester, ether and and salt. .. The method of pop. 1, which is different with the fact that (6R, 7R) (2-amino-β-thiazolyl) -2- (mgmethoxyimino) acetamido-3- (1 (2,5 dihydro-6-hydroxy) -2-methyl-5-oxo-astriazin-3-yl) thio-methyl-8-oxo-5thia-1-azabicyclo (4,2,0) oct 2-ene-2carboxylic acid or its salt or its hydrate or hydrate its salts. Sources of information taken into account during the examination 1. USSR patent in application W 243981.8 / 23-04, class C 07 D 5 (11/3, 1976.

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US3953439A|1976-04-27|Substituted phenylglycylcephalosporins

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US4179502A|1979-12-18|7[2-Hydroxyiminoacetamido]cephalosporins

---

CA1115267A|1981-12-29|7-|-3-|-3-cephem-4- carboxylic acid)

---

US4088761A|1978-05-09|3-[|-acetamido]-cephalosporins and antibacterial compositions containing them

---

US4503221A|1985-03-05|Process for cephalosporanic acid derivatives and intermediate therefor

---

CA1104560A|1981-07-07|Pyrrole cephalosporin derivatives

---

US4034088A|1977-07-05|Cephalosporin derivatives, and compositions containing them

---

US4092480A|1978-05-30|Intermediates for preparing substituted phenylglycylcephalosporins

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IE45758B1|1982-11-17|7- -oxyiminoacylaminocephalosporins

同族专利:

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公开号 | 公开日

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IN151115B|1983-02-26|

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US4327210A|1982-04-27|

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ZA792517B|1980-06-25|

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AR231642A1|1985-01-31|

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MD426C2|1996-07-31|

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CH641468A5|1984-02-29|

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KR830000853B1|1983-04-21|

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RU2504548C1|2012-09-28|2014-01-20|Федеральное Государственное Автономное Образовательное Учреждение Высшего Профессионального Образования "Сибирский Федеральный Университет" |DERIVATIVE OF β-LACTAM CEFTRIAXONE ANTIBIOTIC|SU243A1|1920-06-07|1924-09-15|В.Т. Бовин|Trolley for cable cable road, portable radially around the central support|

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DK379581A|1980-10-06|1982-04-07|Hoffmann La Roche|PROCEDURE FOR THE PREPARATION OF ACYL DERIVATIVES|

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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CH588278A|CH641468A5|1978-05-30|1978-05-30|CEPHEM DERIVATIVES.|LV930506A| LV5519A3|1978-05-30|1993-06-08|Saturation of Cephalosporin Derivatives of their Hydrates and Esters of Derivatives of Esters and Islands and their Hydrates|

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LTRP1324A| LT2471B|1978-05-30|1993-09-30|CEFALOSPORIN DENTAL, OR ESTER, ETERNAL OR SALT OR HYDRAULIC OR ESTER, ETERY OR SALT Hydrate|