前苏联专利SU1722229A3 Method for synthesis of cephalosporin derivatives and theirs salts, hydrates or salts of theirs hydr

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专利摘要:
The present invention relates to novel cephalosporin derivatives, processes for preparing thereof, compositions for preventing and/or treating infectious diseases which comprise the novel cephalosporin derivatives as active components, and the intermediate compounds in the synthesis of cephalosporin derivatives and processes for producing thereof. The present invention is based on the selection of groups containing a condensed heterocyclic ring, particularly a triazolopyrimidine ring or a thiadiazolopyrimidine ring, as substituents at the 3-position of the cephem skeleton, and of groups containing a catechol moiety, particularly a catechol carboxymethyloxyimino moiety or a catechol carboxyimino moiety, as substituents at the 7-position of the cephem skeleton. The compounds of the present invention containing the aforementioned substituents have a strong antibacterial activity against Gram-negative bacteria and also against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus. These compounds are extremely useful for the treatment of infectious diseases.
公开号:SU1722229A3
申请号:SU864028552
申请日:1986-11-28
公开日:1992-03-23
发明作者:Охниси Харуо；Косузуме Хироси；Мизота Масахиро；Сузуки Ясуо；Мотида Еи
申请人:Мотида Фармасьютикал Ко., Лтд (Фирма)；
IPC主号:

专利说明:

the agent is N.N-diethylaniline at a temperature of (-30 ° C) to room temperature. If necessary, the protective groups are removed and the desired product is isolated in free or hydrated form, or as the desired salt.
(treatment with base or acid). New substances have low toxicity (LDso 1000 mg / mg) and are active against both gram-positive and gram-negative microorganisms. 4 tab.
The invention relates to a method for producing cephalosporino-new antibiotics of the series, which, due to their antibacterial effect, can be used in medicine for the treatment and / or prevention of infectious diseases.
The aim of the invention is to obtain new antibiotics of the cephalosporin series, possessing high activity simultaneously against both gram-positive and gram-negative microorganisms.
Example 1. Preparation of (6R, 7R) (2- amino-4-thiazolyl) -2- {2- (4-acetoxy-2-carbox-5-hydroxyphenyl) methyl-oximino} acetamido-3- (2 -carboxy-5-methyl-5-three azolo 1,5-a pyrimidin-7-yl) -thiomethyl -8-oxo-5-thia-1-azabicyclo 4.2.0 oct-2-en-2-c-arbon acids (compound 5).
Step 1. Preparation of 2-bromomethyl-4,5-diacetoxybenzoic acid diphenylmethyl ester.
Thionyl chloride (14.3 ml) and 2 drops of dimethylformamide are added to a suspension of 11.9 g of 4,5-diacetoxy-2-methylbenzoic acid in 140 ml of benzene, then the mixture is stirred at 50-70 ° C for 1 hour. - the solvent is removed under reduced pressure and the residue is redissolved in benzene and concentrated under reduced pressure to remove the remaining thionyl chloride. The residue is refluxed together with 240 ml of benzene, 8.45 g of N-bromosuccinimide and 230 mg of benzoyl peroxide for 2 hours. Refluxing is continued for an additional 2 hours after the addition of 8.45 g of N-bromosuccinimide and 230 mg benzoyl peroxide. The resulting solution was allowed to stand until it reached room temperature, and then concentrated under reduced pressure. The residue is dissolved in carbon tetrachloride, insoluble substances are filtered off, and the filtrate is concentrated under reduced pressure. To a solution of the residue in 250 ml of methylene chloride was added 8.7 g of diphenylmethanol and 3.82 ml of pyridine while cooling with ice and the solution was stirred overnight at room temperature. The resulting solution was washed with 1N hydrochloric acid and brine, and then dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, to give 8.8 g of the target compound.
NMR (5): 7.9-7.2 (12H, m), 7.1 (1 H, s), 5.0 (2H, s), 2.3 (6H, s).
Step 2. Preparation of 5-acetoxy-4-hydroxy-2-M-phthaloyloxymethyl-benzoic acid diphenylmethyl ester.
To a suspension of 2.9 g of N-hydroxyphthalimide in 100 ml of acetonitrile, 2.46 ml of triethylamine are added under ice-cooling. The product obtained in step 1 (8.8 g) is then dissolved in 65 ml of acetonitrile and added dropwise to the suspension. The resulting mixture was stirred for 15 minutes while cooling with ice. 2.9 g of N-hydroxyphthalimide is added and stirring is continued for an additional 10 minutes.
The resulting solution was poured into a 1N solution of citric acid under ice-cooling and extracted twice with ethyl acetate. The organic layer is washed with a saturated sodium hydrogen carbonate solution, water and brine in this order and dried over anhydrous sodium sulfate. The dried solution is concentrated under reduced pressure and the residue is purified by column chromatography.
silica gel to obtain 3.03 g of the intended compound.
NMR (COCl3, 5): 7.9-7.2 (16H, m), 7.0 (1H, s), 5.6 (2N.s.), 2.3 (ZN, s).
Step 3. Preparation of 2- (2-triphenylmethylamino-4-thiazolyl) -2- {2- (4-acetoxy-5hydroxy-2-diphenylmethyloxycarbonylphenyl) methyl-hydroxyimino} -acetic acid.
To a solution of 1.5 g of the product obtained
in stage 2, in 30 ml of methylene chloride
0.15 ml of methylhydrazine is added slowly while cooling at -60 ° C. The solution was stirred at -60 ° C for 10 minutes and at 0 ° C for an additional 4 hours. After filtering off insolubles, the filtrate is concentrated at
reduced pressure and the residue is dissolved in methanol. This solution is added to a solution of 0.7 g of (2-triphenylmethylamino-4-thiazolyl) glyoxylic acid in 40 ml of methanol. The mixture was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel, thus obtaining 0.65 g of the target compound as pale yellow crystals.
NMR (DMCO-de, 5): 8.8 (1H, broadband), 7.8-7.0 (28H, m), 6.8 (1H, s), 5.4 (2H, s), , 3 (ZN, s).
Step 4. Preparation of (6R, 7P) -7- (2- (2-triphenylmethylamino-4-thiazolyl) -2- {2- (4-acetoxy-2-diphenylmethyloxycarbonyl-5-hydroxyphenyl) diphenylmethyl ester) ) - -methyl-oxyimino} -acetamidoZ-3- (2-diphenylmethyloxycarbonyl-5-methyl-5-triazo, 5-a pyrimidin-7-yl) -thiomethyl-8-oxo-5-thia-3- azabicyclo 4.2.0 oct-2-en-2-carboxylic acid.
To an ice-cooled solution of 0.63 g of the product obtained in Stage 3 and 0.5 g of diphenylmethyl ether (6R, 7H) -7-amino-3- (2-diphenylmethyloxycarbonyl-5-methyl 5-triazolo 1,5-a pyrimidin-7-yl) -thiomethyl-8-oxo-5-thia-1-azabicyclo 4.2.0 oct-2-en-2-carboxylic acid in 20 ml of dry methylene chloride is added 0.178 g of dicyclohexylcarbodiimide. The mixture is stirred overnight at room temperature. After filtering off the insoluble materials, the filtrate is concentrated under reduced pressure and the residue is purified by silica gel column chromatography, to give 0.15 g of the target compound.
NMR (DMCO-de), 10.5, (1 H, s), 9.6 (1 N. d), 8.8 (1 H, br. S), 7.8 (1 H, s), 7.7-6.9 (50H, m), b, 8 (1H, s), 5.9 (1H, dd), 5.4 (2H, s), 5.3 (1H, d) , 4.3 (2H, br. S), 3.7 (2H, AB sq.), 2.6 (ZN, s), 2.3 (ZN, s).
Step 5: Preparation of (6R, 7R) (2- amino-4-thiazolyl) -2- {2- (4-acetoxy-2-carboxy-5-hydroxyphenyl) methyl-oximino} -acetamido-3- ( 2-carboxy-5-methyl-5-tri-aol o-1, and rimidi n-7-yl) -thiomethyl-8-oxo-5-thia-1-aeabicyclo 4.2.0 oct-2-en- 2- carboxylic acid.
To an ice-cooled solution of 0.3 g of the product obtained in stage 4 in 5.5 ml of dichloroethane was added 0.2 ml of anisole and 0.7 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 2 hours. After removing the solvent by decantation, the residue was washed with dichloroethane and crystallized with ether, to give 0.105 g of the title compound as
pale yellow crystals (in the form of a trifluoroacetic acid salt).
IR (KBG), 1772, 1676, 1637, 1598, 1511.1202.
NMR (DMCO-de, (5): 9.7 (1H, d, J - 8 Hz),
7.6 (1H, s), 7.4 (1H, s), 7.0 (1H, s), 6.8 (1H, s), 5.9 (1H, d d, J 5 and 8 Hz), 5.5 (2H, s), 5.2 (1 H, d, J 5 Hz), 4.4 (2H, br. S), 3.6 (2H, AB sq.), 2.6 (ZN, s), 2.2 (ZN, s).
EXAMPLE 2. Preparation of (6R, 7R) (2-a m and n o-4-thiazol and l) -2- {2-1 - (3,4-d and hydroxybenzoyl) - 1-methylethyl-hydroxyimino} -acetam- (2-carboxy-5-methyl-5-triazolo 1,5-a pyrimidin-7-yl) -thiomethyl-8-oxo-5-tya
-1-azabicyclo 4.2.0 oct-2-ene-2-carboxylic acid (compound 6).
Step 1. Preparation of (6R, 7P) diphenylmethyl ether (2-triphenylmethylamino-4-thiazolyl} -2- {2- {1- {3,4-diacetoxybenzoyl) -1-methylethyl-hydroxyimino} -acetamido -3- (2-Diphenylmethyloxycarbonyl-5-methyl-5-triazolo 1,5-a pyrimidin-7-yl) -thiomethyl-8-oxo-5-thia-1-azabicyclo 4.2.0 oct-2-en-2-carboxylic acid .
To a solution of 5.1 g 2- (2-triphenylmethylamino-4-thiazolyl) -2- {1- 1- (3,4-diacetoxybenzo-ole) -1-methylethyl-hydroxyimino-acetic acid in 50 ml of dry methylene chloride 5.0 g of (6R, 7P) -7-amino-3- (2-diphenylmethyloxycarbonyl-5-methyl-5-triazolo 1, 5-a pyrimidin-7-yl) -thiomethyl-8- was added to 5.0 g of diphenylmethyl ester oxo-5 a-1-azabicyclo 4.2.0 oct-2-en-2-carboxylic acid and 50 ml of dioxane. 1.5 g of dicyclohexylcarbodiimide was added to the mixture while cooling with ice and stirring was continued at room temperature for 3 hours. After filtering off the insoluble substances, the filtrate was concentrated under reduced pressure and ethyl acetate was added to the residue. The insolubles are filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on
silica gel to give 3.85 g of the desired compound.
IR (KBG), 1781, 1735, 1686, 1596, 1508.1372.1242.701;
NMR (DMCO-d6, 5): 9.7 (1H, d, J 9 Hz), 8.9 (1H, s), 8.3-7.2 (40H, m), 6, 9 (1H, c) 6.7
(1H, s), 5.9 (1H, dd), Hz), 5.3 (1H, d, J 5 Hz), 4.4 (2H, broadband s), 3.7 (2H, AB squared ), 2.6 (3N, s), 2.3 (6H, s). 1.5 (6H, s).
Step 2. Preparation of (6R, 7R) (2-aMMno-4-thiazolyl) -2- {2- 1- (3,4-diacetoxybenzoyl) -1-methylethyl-oximino} acetamido 3- (2-carboxy-5 -methyl-5-triazolo 1,5-a pyrimidin-7-yl) -thiomethyl-8-oxo-5-thia-1 -az abicyclo 4 .2 oct-2-ene-2-carboxylic acid.
1.95 ml of anisole and 3.8 ml of trifluoroacetic acid are added to an ice-cooled solution of 3.8 g of the product obtained in stage 1 in 28 ml of dichloroethane. The mixture was stirred at room temperature for 3.5 hours. After removing the solvent by decantation, the residue was washed twice with dichloroethane and crystallized with ether to obtain 1.8 g of the intended compound (as a trifluoroacetic acid salt).
IR (KBr), cm 1: 1774, 1685, 1636, 1598, 1509.1373.1203.1112.
NMR (DMCO-de, 5): 9.7 (1H, d, J 9 Hz), 8.1-7.3 (4H, m), 6.7 (1H, s), 5.9 (1H, dd, J- 5 and 9 Hz), 5.2 (1H. d, J 5 Hz), 4.4 (2H, broadband s), 3.7 (2H, AB sq.), 2.6 (ЗН, c), 2.3 (6H, s), 1.5 (6H, s).
Step 3. Preparation of (6R, 7B) (2-amino-4-thiazolyl) -2- {2-1- (3,4-dihydroxybenzoyl) -1-methylethyl-oximino} -acetamido-3 - ( 2-carboxy-5-methyl-5-triazolo 1,5-a pyrimidin-7-yl) -thiomethyl-8-oxo-5-thia-1-azabicyclo 4.2.0 oct-2-ene-2-carboxylic acid .
The product obtained in step 2 (0.6 g) is suspended in 20 ml of water and the pH of the suspension is adjusted to 8.0 with sodium hydrogen carbonate. After stirring at 30 ° C for 5 hours, the resulting solution was applied to a column with a carrier such as Diaion HP 10.
The fractions of the desired product, eluted with a mixture of methanol and water, are collected and lyophilized to obtain 0.34 g of the intended compound (as the sodium salt).
IR (KBG), 1772, 1598, 1513. 1406, 1363.1189.1163.
NMR (DMCO-de, 3): 9.6 (1H, d, J 9 Hz), 7.7-6.6 (4H, m), 6.6 (1 H, s), 5.8 (1 H, d d, J - 5 and 9 Hz), 5.1 (1H, d, J - 5 Hz), 4.6 (2H, AB, q), 3.7 (2H, AB q), 2, 6 (ZN, s), 1.5 (6H, s).
Example Preparation of (6R, 7R) (2-amino-4-thiazolyl) -2- {2- (5) -carboxy (3,4-d-and acetoxyphenyl) methyl-hydroxyimino-acetamido} -3- (2- carboxy-5-methyl-5-triazolo 1, 5-a pyrimidin-7-yl) -thiomethyl-8-oxo-5-thia-1-azabicyclo 4,2.0 oct-2-ene-2-carboxylic acid ( connection 7).
Step 1. Preparation of 2-bromo (3,4-diacetoxyphenyl) acetic acid.
60 ml of thionyl chloride is added to a suspension of 51.1 g of 3,4-diacetoxyphenylacetic acid in 105 ml of carbon tetrachloride and the mixture is heated at 70 ° C for 1 hour. After cooling to room temperature, 42.3 g is added. N-bromosuccinimide, 105 ml of carbon tetrachloride and a small amount of hydrobromic acid are then heated for another 1 hour. The mixture is concentrated under reduced pressure and the residue is again dissolved in carbon tetrachloride. After filtering off the insoluble materials, the filtrate is dissolved in 400 ml of acetone and the pH of the solution is adjusted to 4.0 with a saturated aqueous solution of sodium hydrogencarbonate while cooling with ice. The mixture was extracted with chloroform. The chloroform layer is washed with brine and dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure to give 61.4 g of the title compound.
NMR (CDCI3, b): 9.0 (1H, br. S), 7.5-7.1 (ZN, m), 5.3 (1H, s), 2.3 (6H, s).
Step 2. Preparation of 2-bromo- (3,4-diacetoxyphenyl) -acetic acid diphenylmethyl ester.
Diphenyl diazomethane is added to a solution of 61.4 g of the product obtained in stage 1 in .500 ml of acetone, and the resulting solution is stirred at room temperature for 1 hour. The resulting solution is concentrated under reduced pressure and the residue is purified by column chromatography on silica gel, to obtain 48 , 4 target compounds.
IR (KBr), cm 1: 1772, 1756, 1752, 1505, 1371, 1259, 1212, 1113.701.
NMR (CDCIs, 5): 7.4-7.1 (13H, m), 6.9 (1 H, s), 5.4 (1 H, s), 2.3 (6H, s).
Step 3, Preparation of 2-M-phthaloyloxy- (3,4-diacetoxyphenyl) acetic acid diphenylmethyl ester,
To an ice-cooled suspension of 15.9 g of N-hydroxyphthalimide in 300 ml of acetonitrile was added 13.6 ml of triethylamine and a solution of 48.4 g of the product obtained in step 2. in 200 ml of acetonitrile. The mixture was stirred while cooling with ice. 1.5 hours. The resulting solution is concentrated under reduced pressure and again dissolved in ethyl acetate. The solution is washed with water, 1N citric acid and brine in this order. The washed solution was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 15.3 g of the target compound.
IR (KBG), cm 1: -1772, 1735, 1506, 1371, 1260, 1209, 1186, 1114,700.
NMR (CDCI3, 5): 7.7 (4H, s), 8.0-7.1 (13H, m), 6.9 (1H, s), 2.3 (6H, s).
Step 4. Preparation of diphenylmethyl ester of 2-amino-oxy- (3,4-diacetoxyphenyl) acetic acid.
To a solution of 15.3 g of the product obtained in step 3 in 200 ml of methylene chloride is added. 1.34 ml of methyl hydrazine slowly at -60 ° C, and the mixture was allowed to stand until it reached room temperature. After stirring for 2 hours, 0.07 ml of methyl hydrazine was added to the mixture, followed by stirring for another 30 minutes. The insolubles were filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, to give 8.7 g of the target compound.
IR (KBG), cm t: 1772, 1752, 1506, 1371, 1256.1210.1180.1113.702.
NMR (CDCIa, 5): 7.7-7.0 (13H, m), 6.9 (1H, s), 5.2 (1H, s), 2.27 (ZN, s), 2, 26 (ЗН, s).
Step 5. Preparation of 2- (2-triphenylmethylamino-4-thiazolyl) -2- {2-diphenylmethyl-hydroxycarbonyl- (3,4-diacetoxyphenyl) -methyl-hydroxyimo} acetic acid.
To a solution of 7.62 g of (2-triphenylmethylamino-4-thiazolyl) glyoxylic acid in 400 ml of methanol was added dropwise a solution of 8.7 g of the product obtained in stage 4 in 150 ml of methanol. The mixture was stirred at room temperature for 1.5 hours and concentrated under reduced pressure to give 16.0 g of the title compound as a crude product.
IR (KBr) 1: 1772, 1256, 1209, 1180, 754, 701.
NMR (DMCO-de, 5): 8.9 (1H, s), 7.8-7.2 (28H, m), 6.9 (1H, s), 6.8 (1H, s) , 5.9 (1 H, s), 2.3 (6H, s).
Step 6. Preparation of (6R, 7P) diphenylmethyl ester (2-triphenylmethylamino-4-thiazolyl) -2- {2-diphenylmethyloxycarbonyl- (3,4-diacetoxyphenyl) methyl-oxoxy mino-acetamido - ester 3- (2-diphenylmethyloxycarbonyl-5-methyl-5-triazolo 1, imdin-7-yl) -thiomethyl-8-oxo-5-thia-1-aza-bicyclo 4.2.0 oct-2-en-2 -carboxylic acid.
To an ice-cooled solution of 5.6 g of the crude product obtained in step 5 and 5.0 g of (6R, 7K) -7-amino-3- (2-diphenylmethyloxycarbonyl-5-methyl-5-triazolo 1) diphenylmethyl ester , 5-a1-pyrimidin-7-yl) -thio methyl-8-oxo-5-thia-1-azabicyclo-4.2.0 oct-2-en-2-carboxylic acid 1.4 g of dicyclohexylcarbodiimide are added to 170 ml of methylene chloride . The resulting mixture was then stirred at room temperature for 5 hours. After filtering off the insoluble materials, the filtrate was concentrated under reduced pressure. The residue is dissolved in ethyl acetate and the insoluble materials are filtered off. The filtrate is washed with brine and dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, to give 0.73 g (less polar form) and 1.39 g (more polar form) of the desired compounds.
Less than full form.
IR (KBG), 1780, 1742, 1737, 1507, 1249,1205,1182,700.
NMR (DMCO-de, 5): 9.7 (1H, d, J 8 Hz), 8.9 (1H, br. S). 7.5-7.1 (50H, m), 6.9 (1H, s), 6.82 (1H, s), 6.78 (1H, s), 5.9 (1H, s ), 5.8 (1 N, d d, J 4 and 8 Hz), 5.2 (1H, d, J 4 Hz), 4.3 (2H, br. S), 3.6 (2H, AB , square), 2.6 (3N, s), 2.2 (6H, s).
More polna form.
IR (KBG), 1780, 1742, 1596, 1507, 1450, 1372, 1205, 1182,700.
NMR (DMCO-de, 5): 9.7 (1H, d, J 9 Hz), 8.9 (1H, s), 7.4-7.2 (50H. M), 7.0 (1H, c), 6.82 (1H, s), 6.76 (1H, s), 5.9 (1H, s), 5.9 (1H, d d, J 4 and 9 Hz), 5.2 ( 1H, d, J - 4 Hz), 4.3 (2H, br. S), 3.7 (2H, AB squ), 2.6 (ZN, s), 2.20 (6H, s).
Step 7. Preparation of (6R, 7H) (2-amino-4-thiazolyl) -2- {E- (5) -carboxy- (3,4-diacetoxyphenyl) -methyl-oximino} -acetam- ( 2-carboxy-5-methyl-5-triazolo 1,5-a pyrimidin-7-yl) -thiomethyl-8-oxo-5-thia -1-azabicyclo 4.2.0 oct-2-ene-2-carboxylic acid.
0.4 ml of anisole and 0.8 ml of trifluoroacetic acid are added to a solution of 0.73 g of the less polar form of the product obtained in stage 6 in 3 ml of dichloroethane while cooling with ice, and the resulting solution is stirred at room temperature for 3 hours Additional trifluoroacetic acid (0.6 ml) was added and the mixture was stirred for 30 minutes. After removing the solvent by decantation, the residue is washed with dichloroethane and crystallized with ether to obtain 0.3 g of the target compound (in the form of a trifluoroacetic acid salt).
IR (KBG), 1773, 1735, 1684, 1637, 1598, 1509, 1373, 1206, 1186.
NMR (DMCO-de, 5): 9.6 (1H, d, J - 8 Hz), 7.6-7.2 (4H, m), 6.8 (1H, s), 5.8 ( 1H, dd, J 4 and 8 Hz), 5.6 (1 H, s), 5.2 (1 H, d, J - 4 Hz), 4.4 (2H, lush s), 3.72 (1 H, d, J 22 Hz), 3.48 (1 H, d, J 22 Hz), 2.6 (3N, s), 2.2 (6H, s).
-2.9 ° (c 1.0, methanol: acetone 1: 1).
Example 4. Preparation of (6R, 7R) (2-amino-4-thiazolyl) -2- {g- (5) -carboxy (3,4-dihydroxyphenyl) methyl-hydroxyimino} acetamido-3- (2- carboxy-5-methyl-5-triazolo 1,5-a pyrimidin-7-yl) -thiomethyl-8-oko-5-thia-1-azabicyclo 4.2.0 oct-2-en-2-carboxylic acid ( connection 9).
0.27 g of the product obtained in Stage 7 of Example 3 is suspended in 11 ml of water and the pH of the mixture is adjusted to 8.0 with sodium hydrogen carbonate. After stirring at room temperature for 6 hours, the resulting solution was applied to a column packed with Diyon HP 10. The desired product fractions were eluted with water, collected and lyophilized to obtain 0.14 g of the title compound (as the sodium salt).
And K (KB g), cm 1: 1763, 1599, 1514, 1474, 1404.1360.1314.
. NMR (D20, 5): 7.2 (1H, s), 7.0-6.8 (4H, m), 5.7 (1H, d, 5.4 (1H, s), 5.0 (1H, d, J 5 Hz), 4.3 (2H, AB, q), 3.4 (2H, AB, q), 2.6 (ZN, s).
a o25 + 27.4 ° (c 1.0, water).
Example 5. Preparation of (6R, (2-amino-4-thiazolyl) -2- {2-) -carboxy (3,4-dihydroxyphenyl) methyl-oxoimino} acetamido-3- (2-carboxy-5 -methyl-5-triazolo 1, rimidi n-7-yl) -thiomethyl-8-o-co-5-thia-1-azabicyclo 4.2.0 oct-2-en-2-carboxylic acid (compound 10).
Step 1, Preparation of (6R, 7R) (2-aMH-but-4-thiazolyl) -2- {g -) - carboxy- (3,4-diacetoxyphenyl) methyl-oximyl} -acetamido-3 - (2-carboxy-5-methyl-5-tria--, 5-a pyrimidin-7-yl) -thiomethyl -8-QKCO-5 -thia-1-azabicyclo 4.2. 2-ene-2-carboxylic acid.
0.8 ml of anisole and 1.6 ml of trifluoroacetic acid are added to a solution of the more polar form of the product obtained in Step 6 of Example 3 (1.3 g) in 6 ml of dichloroethane while cooling with ice. The resulting solution was stirred at room temperature for 4 hours. After adding 6 ml of dichloroethane, the solvent was removed by decantation. The residue was washed with dichloroethane and crystallized with ether, to give 0.78 g of the desired compound (as a trifluoroacetic acid salt).
IR (KBG), 1773, 1735, 1683, 1598, 1636, 1509, 1373, 1205, 1185.
NMR (DMCO-de, 5): 9.7 (1H, d, J - 9 Hz), 7.4-7.2 (4H, m), 6.8 (1H, s), 5.8 (1H , d d, J 4 and 9 Hz), 5.6 (1H, s), 5.2 (1 H, d, J 4 Hz), 4.5 (2H, br. s), 3.79 (1H , d, J - 17 Hz), 3.60 (1H, d, J - 17 Hz), 2.6 (3N, s), 2.3 (6H, s).
-17.4 ° (c 1.0; methanol: -1: 1).
: acetone
Step 2. Preparation of (6R, 7R) (2-amino-4-thiazolyl) -2- {g -) - carboxy- (3,4-dihydroxyphenyl) methyl 3-oxyimino} -acetamido-3- (2- carboxy-5-methyl-5-triazolo
1,5-a pyrimidine-7-yl) -thiomethyl-8-oxo-5-thia-1-azabicyclo 4.2.0 oct-2-ene-carboxylic acid.
0.5 g of the product obtained in stage 1 is suspended in 20 ml of water and the pH of the mixture is
adjusted to 7.6-8.0 with sodium hydrogen carbonate. After stirring at room temperature for 6 hours, the resulting solution was applied on a column of HP 10 dia. 10. The fractions of the expected product,
eluted with water, collected and lyophilized to obtain 0.2 g of the intended compound (as the sodium salt).
And K (KBG), 1763, 1601, 1516, 1474, 1404, 1358, 1314.
NMR (020, 5): 7.2 (1H, s), 7.0-6.9 (4H, m), 5.6 (1H, d, J - 5 Hz), 5.4 (1 H, s), 5.0 (1 H, d, J 5 Hz), 4.4 (2H, AB, q), 3.4 (2H, AB q), 2.6 (ЗН, s).
a o25 + 21.8 ° (c 1.0; water).
Example Preparation of (6R, 7R) (2-amino-4-thiazolyl) -2- {2-carboxy- (3,4-dihydroxyphenyl) methyl-oxoimino} -acetam- (2-carboxy-5-methyl-5-triazolo 1,5-a pyrimidine-7-yl) -thiomethyl-8-oxo-5-thia-1-azabicyclo 4 .2.0 oct-2-en-2-carboxylic acid.
Step 1. Preparation of 2- (2-amino-4-thiazolyl) -2- {2-diphenylmethyloxycarbonyl (3,4-diacetoxyphenyl) methyl} -oximimino} -uc
succinic acid.
To an ice-cooled solution of 5.3 g of the product obtained in step 4 of Example 3 in 18 ml of dimethylformamide was added 2.03 g of (2-aminothiazolyl-4-yl) glyoxylic acid.
acid. The mixture is stirred overnight at room temperature. The resulting solution was poured into ice-water (100 ml) and the mixture acidified (pH 2) with 1N hydrochloric
acids and extracted with ethyl acetate. The organic layer is washed with brine and dried over anhydrous magnesium sulphate. The dried solution is concentrated under reduced pressure and the residue
crystallized with ether to obtain 6.30 g of the desired compound.
NMR (DMCO-de, 5): 7.5-7.2 (15H, m), 6.85 (1H, s), 6.83 (1H, s), 5.9 (1H, s). 2.3 (6H, s). Stage 2. Preparation of (6R, 7P) diphenylmethyl ester (2-amino-4-thiazolyl) -2- {g-diphenylmethyloxycarbonyl- (3,4-diacetoxyphenyl) methyl-hydroxyimino} -acetamido-3- ( 2-diphenylmethyloxycarbonyl-5-methyl-8-triazolo 1,5-a pyrimidin-7-yl) thiomethyl-8-oxo-5-thia-1-azabicyclo 4, 2.0 oct-2-en-2-carboxylic acid.
To an ice-cooled solution containing 3.0 g of the product obtained in step 1 and 3.75 gdiphenylmethyl ester (6K, 7P) -7-amino-3- (2-diphenylmethyloxycarbonyl-5-methyl-3-triazole 1.5 -and pyrimidin-7-yl) -thiomethyl-8-oxo-5-thia-1-azabicyclo 4.2.0 oct-2-yen-2-carboxylic acid in 100 ml of methylene chloride, 1.54 g of dicyclohexylcarbodiimide is added. The mixture is stirred at room temperature. After filtering off the insoluble materials, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, to give 4.8 g of the target compound.
NMR (DMCO-de, 5): 9.9 and 9.8 (1H, d, J 8 Hz), 7.4-6.8 (38H, m), 5.9 (1H, m), 5, 9 (1H, s), 5.3 and 5.2 (1H, d, J 5 Hz), 4.3 (2H, broadband s), 3.6 (2H, AB sq.), 2.6 (3N , s), 2.3 (AH, s), 2.2 (AH, s).
Step 3: Preparation of (6R, 7R) (2-amino-4-thiazolyl) -2- {2-carboxy- (3,4-diacetoxyphenyl) methyl-hydroxyimino} acetam- (2-carboxy-5- methyl 3-triazolo 1.5 and ri and d and n-7-yl) xyo-5-thia-1-azabicyclo 4.2.0 oct-2-en-2-carboxylic acid.
0.8 ml of anisole and 2.4 ml of trifluoroacetic acid are added to a solution of 0.87 g of the product obtained in stage 2 in 1.6 ml of dichloroethane while cooling with ice. The resulting solution was stirred at room temperature for 2 hours. After removing the solvent by decantation, the residue was washed with dichloroethane and crystallized with ether to obtain 0.6 g of the intended compound (as a trifluoroacetic acid salt).
NMR (DMCO-de, (5): 9.8 and 9.6 (1H, d, J 8 Hz), 7.4-6.9 (4H, m), 6.83 and 6.79 (1 H , c), 5.8 (1H, m), 5.6 (1H, s), 5.2 (1H, m), 4.4 (2H, broadband s), 3.7 (2H, AB q ), 2.6 (ЗН, с), 2.26 (ЗН, с), 2.24 (ЗН, с).
Step 4. Preparation of (6R, 7R) (2-amino-4-thiazolyl) -2- {2-carboxy- (3,4-digidroxyphenyl) methyl-hydroxyimino-acetamide} -3- (2- carboxy-5-methyl-3-triazolo 1,5-a pyrimidin-7-yl) -thiomethyl-8-oxo-5-thia -1-azabicyclo 4.2.0 oct-2-ene-2-carboxylic acid.
0.25 g of the product obtained in stage 3 is suspended in 10 ml of water and the pH of the mixture is adjusted to 8.0 with sodium hydrogen carbonate. After stirring at room temperature for 6 hours, the resulting solution was applied to a column with a nozzle such as Diaion HP 10. The fractions of the target product eluted with
water is collected and lyophilized to obtain 0.14 g of the intended compound (as the sodium salt).
NMR (D20, d): 7.2-6.9 (5H, m), 5.7 (1H, m),
5.4 (1H, s), 5.0 (1H, m), 4.3 (2H, AVq), 3.4 (2H, ABq), 2.6 (ЗН, s).
Example 7. Preparation of (6R, 7R) (2- amino-4-thiazolyl) -2- {2- {1-carboxy-1- (3,4-dihydroxyphenyl) -ethyl-oximino} acetamido-3- (2 -carboxy-5-methyl-3-triazolo 1, 5-a pyrimidin-7-yl) -thiomethyl-8-oxo-5-thia-1-azabicyclo 4.2.0 oct-2-ene-carboxylic acid (compound eleven).
Step 1. Preparation of alpha-bromo-alpha-methyl-3,4-diacetoxyphenylacetic acid diphenylmethyl ester.
12 ml of a suspension of 10.0 g of alpha-methyl-3,4-diacetoxyphenylacetic acid in 10 ml of carbon tetrachloride are added.
thionyl chloride and a small amount of dimethylformamide. The mixture was stirred at 70 ° C for 30 minutes. The solvent is removed under reduced pressure and the residue is redissolved in tetrachloride.
carbon (20 ml). To the solution were added 5 ml of thionyl chloride, 7.22 g of N-bromosuccinimide and 0.1 ml of hydrobromic acid. The mixture was stirred at 85 ° C for 1.5 hours.
After filtering off the insoluble materials, the filtrate is concentrated under reduced pressure. The residue is dissolved in 60 ml of acetone and the pH of the solution is adjusted to 5 with a saturated acidic solution.
sodium carbonate while cooling with ice, then adjust the pH to 1 with 1N hydrochloric acid. The acidified mixture is extracted with 400 ml of ethyl acetate and the extract is washed
brine and dry over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure and the residue was dissolved in acetone (60 ml) and 7.0 g of diphenyldiazomethane was added to the mixture. The solution is stirred overnight and the resulting solution is concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 4.1 g of the intended compound.
NMR (CDCI3, (5): 7.4-7.0 (13H, m), 6.9 (1H, s), 2.28 (6H, s), 2.27 (ZN, s).
Stage 2. Preparation of alpha-methyl-alpha-phthaloyloxy-3,4-diacetoxyphenylacetic acid diphenylmethyl ester.
To an ice-cooled solution of 4.1 g of the product obtained in step 1, 1.31 g of N-hydroxyphthalimide, and then anhydrous potassium carbonate are added over 10 minutes. After stirring at room temperature for 1.5 hours, the resulting solution was poured into 1N aqueous citric acid solution (100 ml) and extracted with 100 ml of ethyl acetate. The extract is washed three times with brine and dried over anhydrous sodium sulfate. After the solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, to obtain 1.3 g of the target compound.
IR (KBG), 1773, 1741, 1736, 1372, 1263, 1208, 1191, 1170, 1119.702.
NMR (CDCIa, 3): 7.8 (4H, m), 7.4-7.2 (13H, m), 6.9 (1H, s), 2.28 (ZN, s), 2, 27 (ZN, s), 1.9 (ZN, s).
Stage 3. Preparation of alpha-aminooxy-alpha-methyl-3,4-diacetoxyphenylacetic acid diphenylmethyl ester.
0.2 g of methyl hydrazine is added to a solution of 1.3 g of the product obtained in stage 2 in 20 ml of dry methylene chloride at -70 ° C under a stream of nitrogen and the solution is stirred at -70 ° C for 10 minutes and then at 0 ° C for 40 min. After filtering off the insoluble materials, the filtrate is concentrated under reduced pressure, and the residue is purified by column chromatography on silica gel, thus obtaining 0.61 g of the target compound.
NMR (CDCI3, 5): 7.3-7.0 (13H, m), 6.9 (1 H, s), 2.28 (ZN, s), 2.26 (ZN, s), 1.19 ( ZN, with).
Stage 4. Preparation of 2- (2-triphenylmethylamino-4-thiazolyl) -2- {g-1-diphenylmethyloxycarbonyl-1- (3,4-diacetoxyphenyl) -ethyl-hydroxyimino} -acetic acid.
To a solution of 0.49 g of (2-triphenylmethylamino-4-thiazolyl) glyoxylic acid in 25 ml of methanol is added dropwise a solution of 0.61 g of the product obtained in step 3 in 10 ml of methanol. The mixture is stirred at room temperature for 1.5 hours and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.8 g of the intended compound.
IR (KBG), 1773, 1751, 1743, 1262, 1209, 1168, 1115.701.
NMR (DMCO-de, 5): 8.8 (1H, s), 7.3-7.1 (28H, m) .6.8 (1H, s), 6.7 (1H, s), , 3 (6H, s). 1.9 (ZN.s).
Step 5. Preparation of (6R, 7B) diphenylmethyl ester (2-triphenylmethylamino-4-thiazolyl) -2- {g-1-diphenylmethyloxycarbonyl-1- (3,4-diacetoxyphenyl) -ethyl-hydroxyimino} -acetamido -3- (2-diphenylmethyloxycarbonyl-5-methyl-5-triazolo 1,5-a pyrimidin-7-yl) -thiomethyl -8-oxo-5-thia-1 -azabicyclo 4,2.0 oct-2 -en-2-carboxylic acid.
To an ice-cooled solution of 0.8 g of the product obtained in stage 4 and 0.7 g of (6R, 7H) -7-amino-3- (2-diphenylmethyloxycarbonyl-5-methyl-5-triazolo) diphenylmethyl ester 1, 5-a-pyrimidin-7-yl) thio-methyl} -8-oxo-5-thia-1-azabicyclo 4.2. -2-en-2-carboxylic acid in 30 ml of methylene chloride are added 0.19 g of dicyclo- hexylcarbodiimide. The mixture is stirred
overnight at room temperature. After filtering off the insoluble materials, the filtrate is concentrated under reduced pressure, and the residue is purified by column chromatography on silica gel,
obtaining 0.6 g of the title compound.
IR (KBr), cm 1: 1791, 1774, 1741, 1736, 1507, 1207, 1171,700.
NMR (DMCO-de, (5): 9.9 and 9.7 (1H, d, J 8 Hz), 8.9 (1H, s), 7.5-6.8 (53H, m), , 9-5,7
(1 H, m), 5.2 (1H, d, J 5 Hz), 4.3 (2H, broadband s), 3.7 (2H, AB square), 2.6 (MN, s), 2.23 (ZN, s), 2.19 (ZN, s), 1.9 (ZN, s).
Step 6: Preparation of (6R, 7R) (2- amino-4-thiazolyl) -2- {1- {1-carboxy-1- (3,4-diacetoxyphenyl) -ethyl-hydroxyimino-aceta- (2-carboxy-5- methyl 5-triazolo 1,5-a pyrimidin-7-yl) -thiomethyl-8-oxo-5 thia-1-azabicyclo 4.2.0 oct-2-en-2-carboxylic acid.
To a solution of 0.6 g of the product obtained in stage 5 in 1 ml of dichloroethane, 0.5 ml of anisole and 1 ml of trifluoroacetic acid are added under ice-cooling. The mixture is stirred at room temperature in
over 2 hours. Then 1 ml of trifluoroacetic acid is added and the mixture is stirred overnight at room temperature. After the addition of 20 ml of dyleloroethane to the solution obtained, the solution is removed by decantation.
the solvent and the residue are crystallized with ether to obtain 0.31 g of the intended compound (as a trifluoroacetic acid salt).
IR (KBG), 1772, 1735, 1683, 1636,
1597.1509.1263, 1232, 1203, 1172.
NMR (DMCO-d6, fy: 9.8-9.7 (1H, m), 7.4-7.0 (4H, m), 6.78 and 6.74 (1H, s), 5, 8-5.7 (1H, m), 5.3-5.2 (1H, m), 4.4 (2H, br. S), 3.7-3.6 (2H, m), 2, 6 (3N, s), 2.2 (6H, s), 1.8 (3N, lush s).
Step 7. Preparation of (6R, 7P) (2-amino-4-thiazolyl) -2- {7- 1-carboxy-1- (3,4-digidroxyphenyl) -ethyl-oxoimino} -acetam- ( 2-car5oxy-5-methyl-5-triazolo 1,5-a pyrimidin-7-yl) -thiomethyl-8-oxo-5-thia-azabicyclo 4 .2.0 oct-2-ene-2-carboxylic acid.
0.28 g of the product obtained in step 6 is suspended in 11 ml and the pH of the mixture is adjusted to 8.5 with acid carbonate.
on three . The mixture was stirred at room temperature for 5.5 hours and the resulting solution was applied to a column with a nozzle such as Dione HP 10. The fractions of the desired product were collected and lyophilized to obtain 0.094 g of the title compound (as sodium salt).
IR (KBG), 1772, 1596, 1509, 1404, 1395, 1389, 1355, 1311.
NMR (D20, 5): 7.2-6.8 (5H, m), 50.8-5.7 (1 H, m), 5.2-5.1 (1H, m), 4.5 (2H, AV kV), 3.5 (2H, AV kV), 2.6 (ZN, s), 1.8 (ZN, s).
Example Preparation of (6R, 7R) (2-amino-4-thiazolyl) -3- {2-carboxy- (3,4,5-trihydroxyphenyl) methyl-hydroxyimino} acetamido-3- (2-carboxy-5 -methyl-3-triazolo, 5-a-pyrimidin-7-yl) -thiomethyl-8-oxo-5-thia-1-azabicyclo 4.2.0 oct-2-en-2-carboxylic acid (compound 12) .
Step 1. Preparation of alpha-bromo-3,4,5-triacetoxyphenylacetic acid diphenylmethyl ester.
To a suspension of 34.5 g of 3,4,5-triacetoxyphenylacetic acid in 90 ml of carbon tetrachloride, 32.5 ml of thionyl chloride and 0.2 ml of dimethylformamide are added. The mixture is stirred at 60 ° C for 1 hour and cooled to room temperature. Then 23.7 g of N-bromosuccinimide, 60 ml of tetraporous carbon and a small amount of hydrobromic acid are added, the mixture is stirred for 3 hours. Insoluble matters are filtered off and the filtrate is concentrated under reduced pressure. The residue was dissolved in 200 ml of acetone and the pH of the solution was adjusted to 5.0 with saturated sodium carbonate solution, then to 1.0 with 1N hydrochloric acid solution with ice cooling. The acidified mixture is diluted with water and extracted with ethyl acetate. The extract is washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is dissolved in 200 ml of acetone and 20.5 g of diphenyldiazomethane are added. The solution was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 30 g of the desirable compound.
NMR (DMCO-de, 5): 7.5-7.3 (12H, m), 6.9 (1H, s), 6.2 (1H, s), 2.3 (9H, s).
Stage 2. Preparation of alpha-M-phthaloyloxy-3,4,5-triacetoxyphenylacetic acid diphenylmethyl ester.
To an ice-cooled solution of 8.8 g of M-hydroxyphthalimide in 180 ml of acetonitrile was added 7.5 ml of triethylamine, then a solution of 30 g of the product obtained in stage 1 in 120 ml of acetonitrile. The mixture is stirred while cooling.
ice for 15 minutes, add 1.5 liters of ethyl acetate, and the resulting solution is washed with 600 ml of an ice-cooled 1N citric acid solution and brine, and then dried over anhydrous
sodium sulfate. The dried solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, to give 10 g of the target compound.
IR (KBG), cm 1: 1782, 1735, 1372, 1208,
1187,1054,700.
NMR (DMCO-de, 3): 7.7 (4H, s), 6.9 (1H, s), 6.2 (1H, s), 2.32 (ZN, s), 2.29 ( 6H, s).
Step 3. Preparation of alpha-emino-oxy-3,4,5-triacetoxyphenylacetic acid diphenylmethyl ester.
To a solution of 10 g of the product obtained in stage 2 in 120 ml of methylene chloride was added 0.83 ml of methyl hydrazine slowly at -60 ° C. The mixture was stirred at 0 ° C for 40 minutes. The insolubles are filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on
silica gel, to give 2.2 g of the title compound.
NMR (CDCIs, 5): 7.3-7.1 (12H, m), 6.9 (1 H, s), 5.2 (1 H, s), 2.27 (ZN, s), 2.23 (6H, s).
Step 4. Preparation of 2- (2-triphenylmethylamino-4-thiazolyl) -2-7-diphenylmethyl-hydroxycarbonyl- (3,4,5-triacetoxyphenyl) methyl-hydroxyimino-acetic acid.
To a solution of 1.7 g (2-triphenylmethylaminothiazol-4-yl) glyoxylic acid in
100 ml of methanol was added dropwise a solution of 2.2 g of the product obtained in stage 3 in 40 ml of methanol. The solution is stirred at room temperature for 1 hour, and the resulting solution is concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2.2 g of the intended product.
IR (KBr), cm 1: 1780, 1752, 1496, 1370, 1206, 1186, 1053.701.
NMR (DMCO-de, 5): 8.9 (1H, s), 7.3-7.2 (27H, m), 6.86 (1H, s), 6.83 (1H, s), , 9 (1H, s), 2.30 (ZN, s), 2.28 (6H, s).
Step 5. Preparation of (6R, 7B) diphenylmethyl ester (2-triphenylmethylamino-4-thiazolyl) -2- {2-diphenylmethyloxycarbonyl (3,4,5-triacetoxyphenyl) methyl-oxyimino} -acetamido -3- (2-Diphenylmethoxycarbonyl-5-methyl-5-triazolo 1,5-a pyrimidin-7-yl) -thiomethyl-8-oxo-5-thia-1
- azabicyclo 4.2.0 oct-2-en-2-carboxylic acid.
To an ice-cooled solution containing 2.2 g of the product obtained in step 4 and 1.84 g of diphenylmethyl ether (6R, 7P) -7-amino-3- (2-diphenylmethyloxycarbonyl-5-methyl-3-triazolo 1,5-a pyrim go n-7-yl) -thiomethyl-8-oxo-5-thia-1-azabi cyclo 4.2.0 oct-2-en-2-carboxylic acid in 65 ml of methylene chloride, add 0 , 59 g of dicyclohexylcarbodiimide. The mixture is stirred overnight at room temperature. The insolubles are filtered off and the filtrate is concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the insolubles removed by filtration. The filtrate is washed with brine and dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 0.86 g (less polar form) and 0.94 g (more polar form) of the target compound.
Less polar is the (3) isomer.
And K (KB g), cm 1: 1782, 1742, 1521, 1508, 1498.1371,1185,1054,700.
NMR (DMCO-de, 5): 9.6 (1H, d, J 9 Hz), 8.7 (1H, s), 7.5-7.2 (49H, m), 6.9 (1H, c), 6.83 (1H, s), 6.80 (1H, s), 5.9 (1H, s), 5.8 (1H, d, J5 and 9 Hz), 5.2 ( 1H, d, J 5 Hz), 4.3 (2H, br. S), 3.6 (2H, AB q), 2.6 (ZN, s), 2.20 (ZN, s), 2, 18 (6H, s).
The more polar form (3) is the isomer,
PC (KBG), cm 1: 1782, 1742, 1596, 1498, 1450.1371,744,700.
NMR (DMCO-de, d): 9.8 (1H, d, J 7 Hz), 8.9 (1H, s), 7.5-7.2 (49H, m), 6.9 (1H, c), 6.82 (1H, s), 6.76 (1H, s), 5.9 (1H, s), 5.8 (1H, d d, J 5 and 7 Hz), 5.2 (1 N, d, J - 5 Hz), 4,3 (2H, br. S), 3.6 (2H, AB sq.), 2.6 (ZN, s), 2.3 (ZN, s) 2.2 (6H, s).
Step 6. Preparation of (6R, 7R) (2-amino-4-thiazolyl) -2- {2- (3) -carboxy (3,4,5-triacetoxyphenyl) methyl-oximino} -acetamido-3- (2 -carboxy-5-methyl-3-triazolo 1,5-a pyrimidin-7-yl) -thiomethyl-8-oxo-5-thia-1-azabicyclo 4.2.0 oct-2-en-2-carboxylic acid .
To a solution of 0.8 g of the product obtained in stage 5 as a less polar form, in 7 ml of dichloroethane, 0.36 ml of anisole and 0.73 ml of trifluoroacetic acid are added with cooling with ice. The resulting solution was then stirred at room temperature for 3 hours. The solvent was removed by decantation, the residue was washed with 5 ml of dichloroethane and crystallized with
ether, yielding 0.45 g of the title compound (as trifluoroacetic acid salt).
IR (KVG), 1774, 1676, 1630, 1597, 1509 1193
NMR (DMCO-de, 3): 9.5 (1H, d, J 9 Hz),
7.4 (1 H, s), 7.3 (2H, s), 6.8 (1 H, s), 5.8 (1 H, d d, J 5 and 9 Hz), 5.6 ( 1 H, s), 5.2 (1 H, d, J 5 Hz), 4.4 (2H, broad s), 3.7 (2H, ABsq), 2.6 (ZN, s), 2.3 (9H, s).
Step 7. Preparation (Rj-isomer of the compound obtained in Example 8, step 6. The compound obtained in Step 5 as a more polar form is processed according to the method described in Step
6, obtaining 0.25 g of the title compound.
IR (KBG), cm t: 1774, 1676, 1636, 1625, 1597, 1374, 1194.
NMR (DMCO-de, 5): 9.8 (1H, d, J 7 Hz), 7.4 (1 H, s), 7.3 (2H, s), 6.8 (1 H, s) , 5.8 (1 N, d d,
J 5 and 7 Hz), 5.6 (1 H, s), 5.2 (1 H, d. J 5 Hz), 4.4 (2H, br. S), 3.7 (2H, AB q ), 2.6 (3N, s), 2.3 (9H, s).
Step 8. Preparation of (6R, 7P) (2-amino-4-thiazolyl) -2- {2- (3) -carboxy (3,4,5-trihydroxyphenyl) -methyl-oximino} acetam- (2- carboxy-5-methyl-3-triazolo 1,5-a pyrimidin-7-yl) -thiomethyl-8-oxo-5-thia- -1-azabicyclo 4,2.0 oct-2-ene-2-carboxylic acid,
0.43 g of the compound obtained in step 6 is suspended in 12 ml of water and the pH of the mixture is adjusted to 8.0 with sodium hydrogen carbonate under a stream of nitrogen. After stirring at room temperature for 5 hours, the resulting solution was applied to a column with a nozzle such as Diaion HP 10. The fractions of the title compound, eluted with water, were collected and lyophilized, yielding 0.15 g of the desired compound.
compounds (as sodium salt).
IR (KBG), 1772, 1597, 1513, 1402, 1318.
NMR (D20, 5): 7.2 (1H, s), 7.0 (1H, s), 6.6 (2H, s), 5.6 (1 H, d, J 5 Hz), 5, 3 Q1 H, s), 5.0 (1 H,
d, J - 5 Hz), 4.3 (2H, AB sq), 3.4 (2H, Ab sq), 2.6 (ZN, s).
Step 9. Preparation of the (P) -isomer of the compound obtained in Step 8.
The compound obtained in stage 7 in
as a more polar form, it is processed according to the method described in step 8 to obtain 0.1 g of the intended compound (as the sodium salt).
IR (KBG), cm 1: 1773, 1596, 1517.1311.
NMR (D20, 5): 7.2 (1H, s), 7.0 (1H, s), 6.6 (2H, s), 5.6 (1H, d,), 5.3 (1H, c), 5.0 (1H, d, J 4 Hz), 4.4 (2H, AB sq.), 3.3 (2H, sq.), 2.6 (ЗН, s).
Example 9. Preparation of (6R, 7R) -7- {2- (2-amino-4-thiazolyl) -2- {2-carboxy (3,4-dihydroxyphenyl) methyl-oxoimino} -aceta (8- carboxytetrazolo 1,5-in pyridazin-6-yl) -thiomethyl-8-oxo-5-thia-1-azab-itcyclo 4.2.0 oct-2-ene-2-carboxylic acid.
Step 1. Preparation of (6R, 7B) diphenylmethyl ester (2-triphenylmethylamino-4-thiazolyl) -2- {2-diphenylmethyloxycarbonyl- (3,4-diacetoxyphenyl) methyl-oxioimo} -acetamido -3- (8-diphenylmethyl-hydroxycarbonyltetrazolo 1,5-to pyridazin-6-yl) -thiomethyl-8-oxo-5-thia-1-azabicyclo 4.2.0 oct-2-en-2-carboxylic acid.
To an ice-cooled solution containing 1.0 g of the compound obtained in Step 5 of Example 8 and 0.90 g of (6R, 7P) -7-amino-3- (8-diphenylmethyloxycarbonyltetrazol 1) diphenylmethyl ester, - readazine -6-yl) -thiomethyl-8-oxo-5-thia-1-az abicyclo 4.2.0 oct-2-en-2-carboxylic acid in 50 ml of methylene chloride, 0.24 g of dicyclohexylcarbodiimide is added, the mixture is stirred in overnight at room temperature. Insoluble substances are filtered off, the filtrate is concentrated under reduced pressure. The residue is redissolved in acetone and the insoluble materials are filtered off. The filtrate is concentrated under reduced pressure, the residue is purified by silica gel column chromatography, to give 0.75 g of the target compound.
IR (KBG), 1774, 1734, 1363, 1297, 1225,1083,700.
NMR (CDCIs, 5): 8.1-6.7 (551-1, m), 6.1 and 6.0 (1H, s), 5.9 (1H, m), 4.9 (1H, m), 4.7 (2H, AB squ), 3.2 (2H, AVq), 2.3 (6H, s).
Step 2. Preparation of (6R, 7P) (2-amino-4-thiazolyl) -2- {2-carboxy- (3,4-diaceto-xyphenyl) methyl-hydroxyimo} -acetamido} -3- (8- carboxy-tetrazolo 1,5-in pyridazin-6-yl) -thiomethyl-8-oxo-5-thia-1-azabicyclo 4.2.0 oct-2-ene-2-carboxylic acid.
To a solution of 0.75 g of the compound obtained in stage 1 in 3 ml of dichloroethane was added 0.05 ml of anisole and 3 ml of trifluoroacetic acid under ice-cooling. The resulting solution was stirred at room temperature for 3.5 hours. The resulting solution was concentrated under reduced pressure and the residue was again dissolved in 15 ml of dichloroethane. The solvent was removed by decantation, and the residue was washed with 20 ml of dichloroethane and crystallized with ether to obtain 0.27 g of the intended compound (as a trifluoroacetic acid salt).
IR (KBG), cm 1: 1773, 1676, 1638, 1374, 1208;
NMR (DMCO-de, 5): 9.7 (1H, m), 8.1 (1 H, s), 7.4-7.0 (3N, m), 6.81 and 6.76 (1 H, s), 5.8 (1H, m), 5.6 (1H, s), 5.1 (1H, m), 4.3 (2H, ABsq), 3.6 (2H , AB square), 2.3 (6H, s).
Step 3: Preparation of (6R, 7R) (2-aMH-but-4-thiazolyl) -2- {2-carboxy- {3,4-dihydroxy-phenyl) methyl-hydroxyimo} -acetamido - 3 - {(8 -carboxy-tetrazolo 1,5-a pyridazin-6-yl) -thiomethyl-8-oxo-5-thia-1-azabicyclo 4.2.0 oct-2-en-2-carboxylic acid.
0.25 g of the compound obtained in Step 2 is suspended in 6 ml of water and the pH of the mixture is adjusted to pH 8.5 with sodium hydrogen carbonate. The mixture was stirred under an atmosphere of nitrogen at room temperature for 5 hours and the resulting solution was applied to a column with a nozzle of the Dione HP 10 type. The fractions of the title compound, eluted with water, were collected and lyophilized to obtain 0.15 g of the title compound. salt). IR (KBG), 1766, 1589, 1388,
NMR (DaO, (5): 7.8 (1 H, s), 7.2-6.8 (4H, m), 5.7 (1 H, m), 5.4 (1 H, s) , 5.0 (1 N, m), 4.1 (2H, AV kV), 3.4 (2H, AV kV).
The physico-chemical characteristics of cephalosporin derivatives are given in table 1.
To demonstrate the usefulness of the compounds obtained by the proposed method, data on the antibacterial activity of individual compounds are shown below.
Compound 1: (6R, 7P) (2-amino-4-thiazolyl) -2- {2- (3,4,5-trihydroxybenzoyl) - oxyimino-acetamido} -3- (2-carboxy-5-methyl-5 -triazolo 1,5-a pyrimidin-7-yl) thiomethyl-8-oxo-5-thia-1-azabicyclo 4.2.0 oct-2-en-2-carboxylic acid.
Compound 2: (6R, 7P) (2-amino-4-thiazolyl) -2- {7- (4,5-diacetoxy-2-methylbenzoyl) -oxyimino-acetamido} -3- (2-carbox - s- 5-methyl-3-triazolo 1,5-a pyrimidin-7-yl) -thiomethyl-8-oxo-5-thia-1-aza bicycle of 4.2.0 oct-2-en-2-carboxylic acid,
Compound 3: (6R, 7P) (2-amino-4-thiazolyl) -2- {7- (4,5-dihydroxy-2-methylbenzoyl) -oxyimino-acetamido} -3- (carboxy-5-methyl -5-triazolo 1,5-a pyrimidin-7-yl) -thiomethyl -8-o-cco-5-thia-1-azabicyc. 2.0 oct-2-en-2-carboxylic acid.
Compound 4: (6R, 7P) (2-amino-4-thiazolyl) -2- {2- (4,5-dihydroxy-2-methylbenzoyl) -oxyimino-acetamido} -3- (7-methyl-5H -5-OXO-1,3,4-thiadiazolo 1,5-a pyrimide
in-2-yl) -thiomethyl-8-oxo-5-thia-1-azabic 2 .2.0 oct-2-ene-2-carboxylic acid.
Compound 5: (6R, 7K) (2-amino-4-thiazolyl) -2- {2- (4-acetoxy-2-carboxy-5g hydroxyphenyl) methyl-hydroxyimino-acetamide-3- (2-carboxy- 5-methyl-3-triazo-, 5-a-pyrimidin-7-yl) -thiomethyl-8-oxo-5-thia-1-azabicyclo 4.2.0 oct-2-ene-2-carboxylic acid.
Compound 6: (6R, 7H) (2-amino-4-thiazolyl) -2- {2-1- {3,4-dihydroxybenzoyl) - 1-methylethyl-hydroxyimo-acetamide} -3- (2-carboxy-5 -methyl-3-triazolo 1,5-a pyrimidin-7-yl) -thiomethyl-8-oxo-5-thia-1-azabitz-iclo-4.2.0 oct-2-en-2-carboxylic acid.
Compound 7: (6R, 7B) (2-amino-4-thiazolyl) -2- {2- (3) -carboxy- (3,4-diacetoxy-siphenyl) -methyl-oximino} -acetamido-3- (2 -carb9xy-5-methyl-3-triazolo 1, imidin-7-yl) -thiomethyl-8-oxo-5-thia-1-aza-bicyclo 4.2.0 oct-2-ene-carboxylic acid.
Compound 8: (6R, 7R) (2-aMHHo-4-thiazolyl) -2- {2-) -carboxy- (3,4-diacetoxy-diphenyl) methyl-oxoimino} acetamido-3- (2-carboxy -5-methyl-3-triazolo 1, imidin-7-yl) -thiomethyl-8-oxo-5-thia-1-aza-bicyclo 4,2.0 oct-2-en-2-carboxylic acid.
Compound 9: (6R, (2-amino-4-thiazolyl) -2- {7- (3) -carboxy- {3,4-dihydroxyphenyl) methyl-oxoimino} acetamido-3- (2-carboxy -5-methyl-3-triazolo 1, imidin-7-yl) -thiomethyl -8-o-cco-5-thia-1-aza bicyclo 4.2.0 oct-2-en-2-carboxylic acid.
Compound 10: (6R, 7R) (2-aMHHO-4-thiazolyl) -2- {2- (P) -carboxy- (3,4-dihydroxyphenyl) -methyl 3-oxyimino} -acetamido-3- (2 -carboxy-5-methyl-3-triazolo 1, they di n-7-yl) -thiomethyl 3-8-oxo-5-thia-1-a-bicyclo 4.2.0 oct-2-en-2-carboxylic acid.
Compound 11: (6R, 7R) (2-aMHHO-4-thiazolyl) -2- {2- (1-carboxy-1- (3,4-dihydroxyphenyl) -ethyl-hydroxyimido} -acetamido-3- ( 2-carboxy-5-methyl-3-triazolo 1,-midin-7-yl) -thiomethyl-8-oxo-5-thia-1-azab-itcyclo 4.2.0 oct-2-ene-2-carboxylic acid.
Compound 12: (6R, 7P) (2-amino-4-thiazolyl) -2- {2-carboxy- (3,4,5-trihydrox-yphenyl) -methyl 3-oxyimino} -acetamido-3- (2-ka rbo xi-5-methyl-3-triazolo 1, ir - imidinyl-7) -thiomethyl-8-oxo-5-thia-1-aza-bicyclo 4.2.0 oct-2-ene-2-carboxylic acid.
Compound 13: (6R, (2-amino-4-thiazolyl) -2- {2-carboxy- (3,4-dihydroxy-phenyl) -methyl-oxoimino} acetamido-3- (80
five
0
five
0
five
0
five
0
five
carboxytetrazolo 1,5-in pyridazin-6-yl) thiomethyl-8-oxo-5-thia-1-azabicyclo 4.2.0 oct-2-en-2-carboxylic acid.
Compound 14: (6R, 7P) (2-amino-4-thiazolyl) -2- (3,4-Dihydroxybenzoylamino) acetamido-3- (2-carboxy-5-methyl-3-tria, 5-a pyrimidine -7-yl) -thiomethyl -8-oxo-5-thia-1-azabicyclo 4.2.0 oct-2-en-2-carboxacid.
In vitro antibacterial activity is determined according to the agar plate dilution method.
Each platinum loop of the test bacteria (106 cells / ml) cultured in Müller Hinton's liquid medium was infected on Müller Hinton agar plates that contained the test compounds at various concentrations. After cultivation at 37 ° C for 20 hours, the minimum inhibitory concentration (MIC, µg / ml) is determined.
The results of the experiments are presented in table. 2
Protective capacity against systemic infection is determined as follows. Aqueous suspension of the tested bacteria is injected intraperitoneally to 10 1CR mice of four weeks of age. One hour after infection, test compounds were intravenously administered. The number of surviving mice was counted 1 week after injection to determine the dose at which 50% of the test animals were animals (EDBO, mg / kg).
The values of effective doses of the tested compounds (EDso, mg / kg) are given in table. 3
Values LDso proposed compounds are presented in table. 4 (LDso values are determined by probit analysis).
The proposed compounds are active against both gram-positive aerobic bacteria, such as Scaphylococcus aureus, Streptococci, and against gram-negative aerobic bacteria, such as aphrophysia, Proteus mirabilis, aphrophysia, Proteus mirabilis, aphrophysia, aphrophysia, Proteus mirabilis, aphus, and as well as anaerobic bacteria such as Peptococci, Peptostreptococci, Bacteroides and Hemophilus influenzae and Streptococcus pneumoniae, infective endocarditis with
via Streptococcus epidermidis, Staphylococcus aureus and Klebslella pneumoniae, pneumonia using Pseudomonas aeruginosa, Hemophllus influenzae, Klebsiella pneumoniae, and Stapholococcus aureus, and pyelonephritis using Escherichia cot, Klebsiella, Proreus and Pseudomonas.
Cephalosporin derivatives obtained by the proposed method can be applied in the form of pharmaceutical compositions, for example, in the form of pharmaceutical compositions containing cephalosporin derivatives together with appropriate pharmaceutical acceptable carriers. The pharmaceutical composition may be in solid form (e.g., tablets, capsules) or in liquid form (e.g., injections). The compositions may be sterilized and contain adjuvants commonly used in pharmaceutical practice.
In addition, it is preferred to use the compounds after they are formed as a freeze-dried product, or in the form of powders, followed by dissolving them in a conventional solvent, for example water or saline, for their subsequent use. The compounds may be used orally or parenterally. The dose varies depending on the age and condition of the patient, circumstances and type of disease, a dose of about 0.1-10 g, preferably 0.2-5 g. They can be used as an everyday dose for an adult. Parenteral administration of the compounds is particularly preferred.
Formulas and acquisitions A method for preparing cephalosporin derivatives of general formula I
R, S,
(j-tfMJk-x
S
Kt-Ssn-T-rh / sj
kn
CQOR6
in the form of syn-isomers,
where RI is hydrogen or an amino protecting group;
R2 is hydrogen or methyl;
R3 is hydrogen, methyl, or a free or protected carboxy group, or R2 and R3 together are oxygen;
R4 and RS are each hydrogen, or RA and RS together are oxygen;
Re is hydrogen or an ester protecting group;
a and b each is 0 or 1;
X is hydrogen, a hydroxyl group or a group of the general formula ft. N
h
(NH) DHp-R9
Hi re
where R is hydrogen or chlorine, methyl, hydroxy, isopropyl, methoxy, acetoxy or carboxyl;
RS and Rg are the same or different, each is hydrogen, hydroxy, acetoxy, methyl, methoxy, ethoxy, chloroacetoxy, butanoyloxy, methanesulfonyloxy, amino, nitro, acetamino, benzyloxycarbonyl- a mino, methanesulfonyl or paratoluenesulfonyloxy group, or taken together form an ethylenedioxy or carbonyldioxy group.
Rio is hydrogen, hydroxy-, methyl, methoxy-, nitro, chloroacetoxy- or acetoxy group;
Z is nitrogen or methine group;
with 0 or 1;
Y - halogen, acetoxy group or group of general formulas $ Н1 Ч-г ИАО-ОД тт0 - Ч-f1 rV-У -3-зАгТогОДТпннв-Н
1a un-yes "
N- # Y nnLOOE N-Mf-NA N
-SWcH, -SW. H. where Rn is hydrogen or a free or protected carboxy group;
R12 is hydrogen or carboxyl-protecting group;
Ri3 is a methyl, hydroxy, or free or protected carboxy or carboxymethyl group;
Ri4 is hydrogen, either free or protected by a carboxy or hydroxysulfonyl group,
or their salts, hydrates or salts of their hydrates, characterized in that the compound of the general formula ED. EDO
0
five
0
five
0
five
0
five
hell
COQR6
where Re and Y have the indicated meanings, provided that the carboxy or hydroxysulfonyl groups are present in the substituent, they are protected as a benzhydryl ester, are reacted with a compound of the general formula
Rt Q4CV4CVX n ij R5 Kt-s-soon
l
R, KK
st
in the form of syn-isomer,
where RI-RS, a, b and X have the indicated meanings, provided that, in the case of the presence of carboxy groups in substituent X, they are protected as a benzhydryl ester, in an inert organic solvent such as methylene chloride, tetrahydrofuran or a mixture thereof, in the presence of NN-dicyclohexylcarbodiimide as a condensing agent, or in the presence of phosphorus oxychloride as a condensing agent and simultaneously with a phosphorus oxychloride deacylation agent, such as NN-diethylaniline, at a temperature from -30 ° C to room temperature - baths followed, if necessary, by deprotection of the protective groups, and the desired product is isolated in free form or in the form of a hydrate, or converted into salt by treatment with a base or acid.
Priority signs: 01.04.85 with Ri, Re, a and b have the values indicated in the claims; Ra is hydrogen or methyl, RS is hydrogen, methyl or carboxy; R4 and RS are oxygen together, X is a group of the general formula in
. X y

RT He
where R is hydrogen or chlorine, methyl, hydroxy, isopropyl, methoxy or acetoxy, RS and Rg are the same or different, each is hydrogen, hydroxy, acetoxy, methoxy, ethoxy, chloroacetoxy, butanoloxy, meta nsulfonyloxy, amino, nitro, acetamino or methanesulfonyl or taken together form an ethylenedioxy or carbonyldioxy group, y is a group of the general formula
S
where Rn is a free or protected carboxy group;
05/17/85 for Ri, R4, RS, Re. a and b are as defined in the claims; R2 is hydrogen or methyl; RS is hydrogen, methyl or free or protected carboxy; X is a group of the general formula
L
Rg
RP
where Re and Rg are the same or different, each is a hydroxy or acetoxy group, Z is a nitrogen or methine group, Y is a group of the general formula -S
50
five
0
50
five
0
five
VD
-kk
where Rn is a free or protected carboxy group;
04.07.85 with Ri, Re, a and b are as defined in the claims, R2 is hydrogen or methyl, RG is hydrogen, methyl or free or protected carboxy, R4 and RS are oxygen together, X is a group of the general formula
Rio
pi .- /
/ L p
"KOU-ONILI G9
R7 R &
where R is hydrogen or chlorine, methyl, hydroxy, isopropyl or carboxy, Re is hydrogen, hydroxy or acetoxy, Rg is hydrogen, hydroxy, acetoxy or amino, Rio is hydrogen, hydroxy or acetoxy, Y is a group of the general formula
1ono
AN-Nm-K USCO N-NA,
N / -CH-Chy, -S -W IM | -VSrCHj
where Ri3 is methyl or a free or protected carboxy group, Ri4 is as defined in the claims;
27.07.85 with RI and Re are as defined in the claims, R2 is hydrogen, RS is free or protected carboxy, and 1 is; b O, X is a group of the general formula -O-Rg
R8
where Re and Rg are the same or different, each is hydrogen or a hydroxy group, Y is a group of formulas nk
-S
LN-К Н-Н H - N
V g –UCH, Hf to3 (Bjad-, s s-w:
-s
Hjc
AM 11
toW gpn
S not
N-MV ° U11
1 ii-. to r
Mw, HMHV.
or
H3C
COOH
-L
03/10/86-established for all features of the claims.
N- NgmL
R2 RI,
W-jVicM Rj R5
SONN-r- -S
COOH
Table 1
-4 GO
go go you
0
-j yu to yu
(
-j you go th
-j you kz go
tO
Bzl is a benzyl group.
Ts is a p-toluenesulfonyl group.
Strain resistant to methicillin.
table 2
Table 3
Table 4

权利要求:
Claims (2)
[1]
Claim
The method of obtaining derivatives of cephalosporin of General formula I
R, H, in the form of syn isomers, where Ri is hydrogen or an amino protecting group;
R2 is hydrogen or methyl;
R3 is hydrogen, methyl, or a free or protected carboxy group, or R2 and R3 together are oxygen;
R4 and Rs are each hydrogen, or R4 and Rs together are oxygen;
R6 is hydrogen or an ester protecting group;
a and b are each 0 or 1;
X is hydrogen, a hydroxyl group or a group of the general formula - (ΝΗ) φ ^ R7 Where R7 is hydrogen or chloro, methyl, hydroxy, isopropyl, methoxy, acetoxy or carboxy 10;
Re and Rg are the same or different, each is hydrogen, hydroxy, acetoxy, methyl, methoxy, ethoxy, chloroacetoxy, butanoyloxy, methanesulfonyloxy, amino, 15 nitro, acetamino, benzyloxycarbonylamino, methanesulfonyl or a paratoluenesulfonyloxy group, or, taken together, form an ethylenedioxy or carbonyldioxy group.
20 R10 is hydrogen, hydroxy, methyl, si, nitro, chloroacetoxy or acetoxy group;
Z is nitrogen or a methine group; c = 0 or 1;
25 V - halogen, acetoxy group or group
-s of the general formulas NN Г- No. <O) -G-C ° ^Y. H-r '
-S '*' *
SVD.
about OH 5- COCR _tl
K-nah. knlLLOOIP
-sVn ^ -AV. Β ₁ ο ^Λ ΛΛ „“ ^, -Α · ^κ Η ' ^ίί where Ri 1 is hydrogen or a free or protected carboxy ^group , ·
R12 is hydrogen or a carboxyl protecting group 35;
R13 ^_ methyl, hydroxy, or a free or protected carboxyl or carboxymethyl group;
R14 is hydrogen, or a free or protected carboxy or hydroxysulfonyl group, or their salts, hydrates or salts of their hydrates, characterized in that the compound of the general formula wherein R6 and Y have the indicated meanings, provided that Y is present in the substituent carboxy or hydroxysulfonyl groups, they are protected as a benzhydryl ester, are reacted with a compound of the general formula
Ri%
H Rj R _S
K — COOH aJ
W ^s where Rs and Rg are the same or different, each is a hydroxy or acetoxy group, Z is nitrogen or a methine group, Y is a group of the general formula —3 in the form of the syn-isomer, where R1-R5, a, b and X have the indicated meanings, provided that if carboxy groups are present in substituent X, they are protected as a benzhydryl ester, ⁵ in an inert organic solvent such as methylene chloride, tetrahydrofuran or a mixture thereof, in the presence of присутствии, Ν'-dicyclohexylcarbodiimide as a condensing agent or in ¹⁰ Wii the presence a condensing agent aux chloride with phosphorus oxychloride and phosphorus simultaneously deacylated agent such as Ν, Ν-diethylaniline, at a temperature from -30 ° C to room tem- ¹⁵ perature, followed, if necessary, deprotecting and isolating the desired product in the free form or in the form of a hydrate, or they are converted into salt by treatment with a base or acid. ² θ
Priority on the grounds: 04/01/85 at Ri, R6, a and b have the meanings indicated in the claims; R _{2 is} hydrogen or methyl; R ₃ is hydrogen, methyl or carboxy; R4 and Rs are together oxygen, ² $ X is a group of the general formula where R11 is a free or protected carboxy group;
07/04/85 at Ri, R6, a and b have the meanings indicated in the claims, R _{2 is} hydrogen or methyl, R3 is hydrogen, methyl or a free or protected carboxy group, R4 and Rs are together oxygen, X is a group of the general formula or
R
Kt K & where R7 is hydrogen or chlorine, methyl, hydroxy, isopropyl, methoxy or acetoxy, Rs and Rg are the same or different, each hydrogen, hydroxy, acetoxy, methoxy, 35 ethoxy, chloroacetoxy, butanoloxy, methanesulfonyloxy, amino, nitro, acetamino or methanesulfonyl or taken together form an ethylenedioxy or carbonyldioxy group, y is a group of general formula 40 where R7 is hydrogen or chloro, methyl, hydroxy, isopropyl or carboxy, Rs is hydrogen, hydroxy or acetoxy, Rg is hydrogen, hydroxy, acetoxy or amino, R10 is hydrogen, hydroxy and acetoxy, Y is a group of the general formula ’ it is about £ N m_cAyC0gH Ν — N-k
S
K ^ R — N
45 where R11 is a free or protected carboxy group;
05.17.85 when Ri, R4, Rs, Rs> a and b have the meanings indicated in the claims, R ₂ is hydrogen or methyl, R3 is hydrogen, 50 is methyl or a free or protected carboxy group, X is a group of the general formula where R13 is methyl or a free or protected carboxy group, R14 is as defined in the claims;
07/27/85 at Ri and Re have the meanings indicated in the claims, R ₂ is hydrogen, R3 is a free or protected carboxy group, a = 1; b = .0, X is a group of general formula ^ 8 where Rs and R9 are the same or different, each is hydrogen or a hydroxy group, Y is a group of formulas N — K N — NN — N
03/10/86-is established by all signs of the claims.
Cd = f
S s: y
Cd Η o
oh ac
SO about:
LD oz io oo
I
£s> ST s; oh oh 'Σ' =; oh oh about. > s α1- o s χ n > > s> g Θ Θ * ABOUT 1x G ^-t CM T ^-
Continuation of table 1
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Continuation of table 1
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Continuation of the table.
about* “· • r -co from 'ί b- ^ ί, τ σ>' ^ -ίΐ'χ'ΐ ^υ 2 -'From Ο- ^ Ι, -77 “e *” Χ'-ό'-77 “τ'- - ^ ⁰³ οι ο ι οω со, - '-, ^Σ . X- -, _ '' Τ. count m d 3 / Ζ Г ¹¹ f '- from χ - co' SS ° - i 88 SStfii ^ SdS- ^ S · ⁴ ® c ”= $ 2® ⁴ · (θ'- F- .. c £ - - '—'Sz.to Pw-co £ g γ £ -J * | cH§ - D co tn i T- + - ta. And'G < _{5 7 S} □ - ll - £ ¹⁰ ' Z - с. o ° - And τ II 5 <- ^ _ ιι ш ο --- 71-- S ⁴ 5 -. * II 5Γ ο ^s Yu -. - + _, £ S - r- * 5 - - cr j - co about Ltd with T— g- ** - g * X X X with X X X Yu Ltd CO e rs r ^{δ Ί} ^ νντ ¥ ^ χτ СО с / О ι Icn £ h CD g ^> -X ⁵ g — T ^ G-m> X / A ΓΌ A A Z sz £ - f ⁵ ' ^and c-0 “O C-” TJ CD CD CD CD O CD I CD & 6 ^s 7 O 'Co ⁴ 77 о о о о о О: z ΪΖ 4Z>> θ θ θ. B έ- t- from o »-» - ΟΙ 04 1
Continuation of the table.
l r from =: from: from about about 0 about υiZ > > > Θ Θ Θ n t cm with cm cm cm
Continuation of the table.
Continuation of table 1
GTfrom;e; ABOUT about about ABOUT ω and> > > e .е e £ b n with σ> about cm cm with
Continuation of the table.
Continuation of the table.
with -
g X X X with X X X
.Ω ςς about about about about and andS '> > > e Θ Θ fc fc tLD with with With With
Continuation of the table.
49 1722229
Continuation of the table.
about _ · Cn tf> 3 -. ** t'oo = ί. I ® ^h - © I ί ScSo “> · χ '. ^ 3“> ϊ = · ϊ ”ο; ο 3S8§n - < D ^u .i: g “S ^ lTS- 'SExS & r sZ- t- * -> r— q - H ^- in * - T- * q 4Li <O cm" - <-cZZ-. 3 X -, оС “'T' S- / co '' ^ —-, - ς.-Ξ '- in'iS'-r'σ>: - *“ Yu 'E. in · - ^ cm -g X _(r r 1 - X О, = r - T- Ό x _- l_ I CM ·, - ТЗ I r- t- 1 <C _T | tn „1 X, ⁴⁰ m -SCH- -1- ”- 1 Χ, ° rh-cm. I 7 = -CO CM Ο ά ¹¹ ,, £ - ° 4; о in 4 ·„ „r- o> ° 'Г and iri 4 · “® S (c ° in 'T. <+ to _ = -> + ~ о ^ x * <σ- ^ ing, Joo" διηχ cm - £ ¹¹ —X ¹¹ I s ¹¹ ~ Χ ¹¹ S k II -X ¹¹ £ tS χ □ C S3 · OS SK ¹ 'g-'<-> σ> Ltd with g- XXX with X X X 4 5 Ltd. ίχ3 ρζί g a Io, -, χ} g zzj § Л-й-> »-% 7 ά ώ ¹ CM 3d 32. ё co S χ! <=> ίτί 1 g ·> 4- ^s ^ _s ⁸ 4 g— 3 ^s ς. Oh Oh. SM o 'T ΪΖ> e tl
Continuation of the table.
l with; oh oh J3Oh Oh l <5 O O> > > Θ Θ Θ tb with * = G Yu h
Continuation of the table.
about 4 'O 4 with Z. II. "'Ωχ II ζ - ^ ττο ^ Χ- £ -o'" $ e °. ”-CNI d - II ο ^ ΞιοΙ ^ S _OT §ίΖ .7“ ° 0χ £ 7ί1ι Ί £ “17о О ^ оо α ^ Ρ αί о Д «7 i Jp с '<J>"S' Si ω E Q3C ^O 3 ^ · _Σ Q = £ °. Cn5 ς £ о o 3 * “ ⁰⁰ ° ——co i - x ° ii x ° CL clO— “* i7 * 2 ^s 1 ^ 5 ⁵ iS ^ T ^s O1 Ltd 00 T- o o g- I II with I I I Yu^{1 1} about II with S tx α K X ⁰ z! z; S-V „L U“ F “° za 1 i CM X! co ”1 ^. _e = = h— 'ΰΓ' Ξ 'c coh oh<j o>> »θ θ ’b tCO t-
Continuation of the table.
about H - II. . -g'Ξ “”. LO -S3 ΙΟ -r JL 2 - t- ^ ci in'ςΐ'ο'lo with O ^ '' Ξτ in '“r / Zu'®'<oσ>""b'^^хЦ' -S ** 3 2 S3 & Ln ⁰⁵ tu ° ν ° 'τ Ϊ' ^, · ^< : ι: '£ ο Ρ - ¹ · -I rj ^Ν > Ρ _ <ί. • or ^J - -TM4 ·. · '· 1 “-in it £ i. - in. 1 x ⁴ 'n't 2 1 Г.1Л i 2- · ^. O'— '. “To in O _s 4-r ° f ⁴ · S 0 5 w w to Z ^b J £ _ <o 7 Cm Γή Σ“ -ιη% 72Σ ^% ~ 7 IO s “-t- 'u - ° 7 £ "· °. ϊ Д 5 ^v x § gT» to, col- x X m -_a О to, ¹ - r_ £ I S3 ο σ> α. <ο'σ> £ 3 £ 3 ^ 2α. S ^{ί ϋ} . # α. «>σ> £ 3 s Σ'χΐι s. 5χΦ4 s σ: ^ϋ ιι h ss ο Ο £ 1 ο; ° ό- about Τ “f · * - 00 h — g — g— g- <o ’T СО 1 ^{1 1 5} χ - ¹ 5 with JXi _Α Γ ^> cz t-g t— ^ gN ί ά V ¹ mid qj W -r- t—><—>> - ^L - · 1 α G 'Σ' GT 72 *<4 <= ϊ «4Ltdο ο οiZ s>>>θ θ θto t toσ> o * ~h in in.
1722229
Continuation of the table.
so * g- x
^u *. G- II H CM VI S ⁰⁰ ETE8 L_ gi_ e ώ ¹ And hh - "X" 5 Σ -> t -, - 5 os ”
co x co
X .O with * 4 3 =
4> S O o J3 with about 4>oh oh> > > Θ Θ θ b b to. cm with 4J- 1L Yu w
Continuation of the table.
ID from I J- T '• -''fcZ!, - * co £ 2 i ° o r- £ 2 i id' Ξΐ Γζ-ί. ¹ ". About h
CO aI II 'CD CD -,' T <- 'CD
ID about SM about
and about d Σ «X coX £ i ί X * Γ— (0 (*. ID CD ΓΙ'- co '2 о
v ίί co S <0 i- ’CT> ID
X * X τ- II cm “σ'x'i f X -r-'X-rtX dO> ctb'ID 'CO x ~ X = 0S2d <3 cm о <0 X' 'U'X .co' TO
K a <cr "
I — with d
- -> 'TO CM
3 -ϊΐ ⁰⁴ I — Z ¹ 30 '/ in ⁰
ο. Σ
Cj
X σ>. b- co ui dco ^ cq'o'X
- S d— '’L · 7 = X
CxtST from; from; about ABOUT about about about about bg > > > θ Θ Θ £ £ £ in CD b- ID ID Id
00 С0 id with bτ £
B61
Continuation of the table.
about NMR (D ₂ 0, <5): 7.4-7.2! (1H, s), 7.0 (1H, s), 6.8-6.6 (H.s.), 5.7 (1H, m), 5.2 (1H, m), 5.0 ( 1H, m), 4.5 (2H, AB q), 3.7 (2H, AB q), 3.0 (2H, m). 2.6, (ZN, s). IR, cm ': 1765, 1597, 1516, 1474.1408.1356, 1314 NMR (d, DMSO-de): 9.4 (1H, d, ΰ = 8Γκ), 7.4 (1H, s), 7.3 (1H, s). 7.0 (1H, s), 6.8 (1H, s), 5.8 (1H, dd, J = 4.8 Hz), 5.7 (1H, s), 5.1 (1H, d, J = 4 Hz), 4.4 (2H, br s), 3.6 (2H, AB q), 2.6 (ZN, s), 2.4 (ZN, s), 2 , 2 (6H, s). IR, cm ' ¹ : 1772, 1741, 1654 NMR (d, U ₂ 0): 7,3-6,6 (4H, m), 5,63-5,59 (2H, m), 5,014,95 (1H, m), 4,8-4, 4 (2H, m). 3.6-3.0 (2H, m). 2.6 (ZN, s), 2.23 and 2.17 (ZN, s). IR, cm ' ¹ : 1770, 1597, 1513, 1407.1384.1311 o> about aboutabout 00 - Gg- x ' XX with X XX Yu X o o and XX o o (J X XX with YesCX)yes yes ΎΎ ΎWith1 go yes - _X SE O - - I mid YesSH "yes ιV go go yes yes se se sx »se se se se YesSEl " from;8> f s h o and S '> Θ n o> yс о о S '> θ fc о co
Continuation of the table.
T 'Z ·' “X, cm ABOUTg- 'x'®-4 "ιο - S '' S ^s .X £ ° .yuI X I ““t- "- -"- c £ co CO <- CO _ _ς γιο _s + cj о co co Л „С i 0 rg ^ s ^ dCM i + - From S3 СО S -о * to g ^^ - Z-x ^W> - ξ; - x ^u σί °°. ^ ^χ ^ χ co to о о. ; co'2 σ> co «o SS CM £ v- .. ο ω ³SM about aboutG * “ <OSS CM S Ό - 4 CO I * S · CO Yu ³ - о 0 °. O> -f ⁰⁴ ω * “. y T ς ^x cm '' I £ y О -, '-r ^s В “'Ης ^ ι: .0 - -'“ 'co.co co SggS5 ~ oF in S ϋί -'-- ⁴ * _ςΓ4 ”“ cmG “05 about w ° - ^Σ χ'5 “^ x χ'ο ^ ^< 2 d Г- со 'τ (X r-'co'to ψ * - ¹⁰ , b ΙΟ Σ ^4l , δ '<χχВ ^s -iiS ^sQ - 00 <5. w cm _ · gs, -ω 'g - «ξ g- - о -Г^ .X _ X s О 'Τζ · «- X cm, T “ 05 about about about with ν— - - g * X X X C0 X X XX X X w about about about about about ABOUT about ABOUTX X X with co8 ^; z:.Ύ Ύ γ th "_JO§ th M °. RP S. . yes “ ^§ 'No. ^{g o§} / th”T with1 BUT Yes SE CXJ • s_e | cm,Yu) cx>1S γ 3G sgc; Ζ from;about about aboutabout about aboutΪΖΪΖ t— > > >θ Θ eB t tΤ- cm withwith with with
65 1722229 66
Continuation of the table.
word about
D-x
X X X
(0 X X X X XX XX LO aboutabout aboutABOUTaboutabout aboutaboutaboutabout about<_>XX XX - X With YuS ~ wGd £ μ Oq / -S ’ϊ Y4 ws x hg-ec * a d_) cx> 1 1 το1 With1x CX)Ihe X(-1 X CXI X se cm x ΐX 1cx> x> x.Ιό) 1 That)
* 3 * 3 from;from: e: about ABOUT about ABOUT and ABOUT and Q <0 Az With Az Z ZZ sr 1D With b- CD With with with
Continuation of the table.
/and
Continuation of the table.
's' X 'Ξ' 5 ~. ϋ χ'φ- CO Χιη <CT> ^ -γ ^ϋ - £ o X '-, r-'X-co' co - · 4 ^ sL ο ιη ° τQ Χτ ^r £ 2 s ίέχ'ο S 0- Х. ЧГ iZ Σ co ^ aS К LO Σ о " 3
1L ГСО с со ю ю с со Ю τϊ <Χ * οΧ S.m '£ i co
TjE h
X
О X r-'X _с ”cj s х'О x '£ in“ aaChso ”ο ΙΟ < ⁰⁴ £ ns - □ Τι έΐ a.
* LO'T Ι '“* cm <
Ιοί
SzioSi σ>, -ς co ' ^υ οό ¹ '
[2]
2 - Thu Ο m <οΤχ ίέχ 'o. X Σ όκ σ o σ> '_ _-' o ’'’, <o -L - co o> £ ST co co - co r- * ”
about about aboutaboutabout co -. --- r ~ X XXX co X 'xXX IX) Cool CoolCoolCool 4- X XX'X co as = <= £1> -s 525 = 4.. co Ie / eJ & x: SE = {OQ ΛXXI a 1L3 <== ^ 5S Ή, ^m = - <to 1
c c; ςfrom; ABOUT about ABOUT ABOUT ϋ <j about about co . m Az sv Z Z Ζ, Ζ, CM co CH Yu Γ— G- g * G-
71 1722229
Continuation of the table.
S with Σ mid P ' about σ> 1L X .x LOh * mid * o * o * . about Cd with <Ρχ from (about 1 ** = -
X x <2. ABOUT Si 2 o g— Z. O. Oh ixi with S S mid S IOOS with *
about about about about about about 00 T ““ - - g- X X X X X with X X X X X X X X X X 1L about about about about about about about about about about c_> about about ω about X X X X X
l J3 L 4) L ς ς from; from; about about about about ABOUT 0 0 0 0 0 GO go GO go go Ζ Ζ, Ζ Ζ, Ζ * with g- 00 ABOUT) about g * g-> - with
73 1722229
Continuation of the table.
σ> o about
with "g- X" O x l s; oh oh
X& ABOUT η Cd cd 8 . zd , CD CD
t— " CD r ^> 33 CD =: Tzj CD CD CD CD CD CDCD cd ^CD
from; О о> Θ cm * Bzl is a benzyl group.
** Ts is a p-toluenesulfonyl group.
table 2
[Connection- MIC, M to g / ml nie Staphylococ Esherichia I serratia I klebsiella Pseudomo- Bacteroides CUS aureus Smith coli 67 marcescensF03759 pneumoniae hiae IF0331 ' nas' aeruginosa IF03445 fragilii |5524 1 0.78 <0.05 <0.05 <0.05 3.13 He is defined 2 0.78 <0.05 <0.05 <0.05 0.20 It 3 Not determined <0.05 <0.05 <0.05 0.20 4 0.39 0.78 <0.05 <0.05 3.13 5 1,56 <0.05 <0.05 <0.05 0.20 - - 6 6.25 <0.05 <0.05 <0.05 0.78 7 Not determined 0.20 0.10 <0.05 1,56 80.20 0.10 <0.05 3.13 9 0.78 0.10 0.05 <0.05 1,56 6.25 10 0.78 0.20 0.10 <0.05 6.25 He is defined eleven 0.78 <0.05 0.20 <0.05 0.78 _ __ 12 0.78 0.10 He is defined <0.05 6.25 thirteen 1,56 0.20 0.20 <0.05 0.78 It
Table 3
Compound EDso mg / kg I Escherichia coli111 Serratia marcescenes 274 Pseudomonas aeruginosa IFO 3445 Staphylococcus aureus 242 * 2 2.28 3.08 212 7.90 3 He is defined 1.73 407 1.79 Ceftazidime 6.55 4.23 229 > 100 Cefamandol He is defined He is defined He is defined 31,0 5 - ”- 2,56 - ”- 12,4 8 " 10.5 II He is defined 9 1.73 0.47 95.0 3.34 10 He is defined 28.6 He is defined He is defined ^thirteen1.05 - ”- H Ceftazidime 3.91 6.41 230 > 2100 I cefamandol He is defined He is defined He is defined 8.94
* Methicillin resistant strain.
Table 4
Compound LDso mg / kg (intravenously) 1 > 1000 2 > 1000 4 > 1000 6 > 1000 9 > 1000 thirteen > 1000

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引用文献:

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DE150507T1|1983-12-29|1987-02-26|Mochida Pharmaceutical Co., Ltd., Tokio/Tokyo, Jp|CEPHALOSPORINE COMPOUNDS, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS.|DE150507T1|1983-12-29|1987-02-26|Mochida Pharmaceutical Co., Ltd., Tokio/Tokyo, Jp|CEPHALOSPORINE COMPOUNDS, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS.|

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GB8626245D0|1985-11-27|1986-12-03|Ici Pharma|Cephalosporin compounds|

CA1283404C|1986-07-01|1991-04-23|Shigeru Sanai|Cephalosporin compounds, processes for their preparation and antibacterial agents|

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IL83993D0|1986-09-26|1988-02-29|Glaxo Group Ltd|Cephalosporins,their preparation and pharmaceutical compositions containing them|

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MC1921A1|1987-04-10|1989-04-06|Sankei Yakuhin Kk|ACYL DERIVATIVES|

DK170088A|1987-04-10|1988-10-11|Hoffmann La Roche|Spreadable water-in-oil emulsion|

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法律状态:

优先权:

申请号 | 申请日 | 专利标题

JP60068866A|JPS6277391A|1984-12-21|1985-04-01|Cephalosporin derivative, production thereof and antibacterial agent containing said derivative as active component|

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JP60166259A|JPS62167784A|1985-07-27|1985-07-27|Novel cephalosporin derivative, production thereof and antimicrobial agent containing said derivative as active ingredient|

US06/838,309|US4840945A|1985-04-01|1986-03-10|Cephalosporin derivatives|

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