SU589919A3 - Method of preparing db-7-azidocephalosporin combinations - Google Patents

Claims (2)

No.) COOR, where K has the above values, is reacted with a complex compound of the formula Hc – CH – COX, in (g) where 3 has the above values, X is a halogen atom, a group in an anhydrous organic solvent, in the presence of a tertiary amphen temperatures of O - 20 ° C. New Tob-azido and 7l-aminocephalosporin compounds (where B is hydrogen) are obtained as mixtures of d and C enantiomers, which can be separated according to the methods known in the field to obtain optically active forms. New bc-amino compounds or their enantiomers can be converted to the corresponding new (Jf-7 ./i mivocephalosporin compounds, and these 7 P -substituted can be acylated to produce Egg-G-cephalosporins that have valuable antibiotic properties. Alternatively, as shown below, - azido compounds can be converted to produce antibiotically active 7-substituted, for example, 7-meth (Jsi or 7-methylcephalospores.,. New de-7-aminocephalosporin compounds can be acylated to obtain corresponding new 4 G-acyl hydrophore losporinic compounds that are active against pathogenic gram-negative and gram-positive bacteria.Acylation of new BE-7cA.-amine and spalofalosporins results in the production of new dC cL-acylamido compounds, which can be transformed, using known methods, into new biotic substances 5-acylamido cephalosporins New (Jf-7-acylamido cephalosporins can be cleaved into the corresponding q and E isomers using cleavage techniques well known in the art. As indicated above, the new (-7C-azido or (ZETUg-amino-iifalosporin compounds can be cleaved to obtain the corresponding J or 8-isomers, which can be converted into known useful cephalosporins using techniques well known in the art. Example p-Methoxybenzyl- dPg. 7oC, α-azido-3-methyldazethoxycetafaposporan A solution of p-methoxybenzyl-5-methyl-6H-1,3-thiazine-4-carboxylate (34 mg) 0.123,. modi, (and dry methylene chloride (1 ml) is stirred on ice nsyu bath in an azog atmosphere. To the solution, triethylamine {19 ml, is added to the solution with a syringe. 0.136 mmop.) A solution of azidoacetyl chloride (12 ml, 0.136 mmol) in dry methylene chloride (1 ml) is then added dropwise over 30 minutes. The resulting solution is stirred for an additional 1.5 hours at 0 ° C, then diluted with methylene chloride (l ml), washed with water (2x2 ml) and saturated brine (4 ml), dried over magnesium sulfate and evaporated in vacuo to give a yellowish brown oil (42 mg). The crude product is purified by preparative thin layer chromatography on a 5 mm silica gel plate 6F. About the phenomenon. 10% ethyl acetate in bepzole showing a UV-visible band, which gives p-methoxybenzyl-E-7o1-azido-3-methylcephalosporenag (10 mg) after extraction with ethyl ether,. g. g, 6.61, 7.22. 7.34, 7.69, 8, O1, 8.12, 8.29.8.50, 8.91 and 9.59. nMP (CD "j) T: 7.92 (€, .3.085), 6.82, 6.55 (AVD2, J -ISHx 2-C, H2), 6.18 (SZ OCH), 5.52 (d, 1, J 1.6 I, 7H or 6N), 5.40 (d, lj 1.6 Hi, 6H or 7H), 4.76 (0, 2, CH2A). 3.20 (d, 2, i 9Hz.Ar, H), 2.61 (a, 2 i 9Нг.Аг-Н). The corresponding methyl ester is prepared in a similar manner from 5-methyl-6n -1,3-thiazin-4-carboxy- methyl ester. I w. j-IV1C 1 new acid. Following the procedures described above, IT-methoxybenzyl-5-methoxymethyl-6n-1, 3-thiazin-4-carboxylate, 2,2,2-trichloroethyl 5-methyl-6H-1,3-thiazin-4-carboxylate or methoxymethyl- 5-isobutyloxymethyl-bN, -1, 3-thiazine-4-carboxylate is reacted with azidoacetyl chloride, respectively, to form p-methyxybenzyl-dE-3-methyl-methyl-7 x-azido-3-cephem-4-carbsxylate, 2.2,2, -trichporethyl-E-3-methyl-7 1b -az up to-J-defem-4-carboxylag and Methoxy-teme-d E-3-isobutyryl-synthesite-7 3i -azi. Ao-3-cephem -4-carboxylate. Similarly, methyl ester-tioformamidodiethylphosphonoacetic acid gives methyl-5-aietoxymethyl-6H-1 3-thiazin-4-carbobo "silat. Pr1gmer2.n -Methoxybenzyl Fir (36-7 c1 -azidocephalosporanic acid. A solution of the crude p-methoxybenzyl-acetoxymethyl-6 H -1,3-tiaein-4-carboxylate (1OO mg, 0.3 mmol) in dry methian chloride ( 3 ml) is stirred in ice bath and under nitrogen atmosphere, triethylamine (56 ml, 0.4 mmol) is added with the help of a saddle, followed by a dropwise addition of a solution of azidoacetyl chloride (35 ml, 0.4 mmol) L of dry methylene chloride (2 ml ) for 90 minutes. The resulting solution was stirred an additional 60 minutes at 0 ° C, then diluted with methylene chloride (5 ml), washed with water (2 x 5 ml), dried over magnesium sulphate and evaporated in vacuo to a dark oil (115 mg). The oil is shaken with carbon tetrachloride (2x5 ml), the carbon tetrachloride solution is dried over magnesium sulphate and evaporated in vacuo to yellow oil (ilD mg. ) .. Chromatography of the crude sheodoucry on a snapshot gel (3 g filled with 59b ethylamine in benzene) using 5% ethyl acetate in benzene as an eluting Solvent, gives dtr-7d d-methoxybenzene ester. - Azidocephalosporanes (acid (13 mg) in the form of pure oil., IR) (SSE): 4.73, 5.58, 5.73, 6.20, 6.61, 7.20, 7.37, 8 , 15, 8.47, 8.92 and 9.57. PMR (CDCe): 7.97 (C, 3, OOSNz), 6.65, 6.42 (AB.d, 18Hz2-CHjj), 6 , 13 (С, 3, ОНЭэ), 5.45 (d, 1J 1.8 Нт, 7Н or 6Н), 5.38 (d, 1, 8 Hz, 6Н or 7 Н), 5.20, 5 , 00 1 (AB. D, 2, j 13Hz, CH20Ac), 3.08 (3, 2, i 3 9Hz. AgH), and 2.60 (. 2, j 9H2.AhH Similarly, fetil 5-acetoxymethyl) 6 rt-1,3-tnazin-4-carboxylate gives methyl-Jf-7-0 -azidocephalosporanate IR (SSe): 4.74, 5.56, 5.72, 6.10, 6.96, 7.23 , 8.14, 8.93 and 9.67. PMR (CDCE,); 7.90 (C, 3, OCOCHj), 6.58, 6.32 (AB f, 2, 18, H2), 6, 04 (C, 3, OOCH,); -6.30 (AL, 2, 6H, and 7H) and 5.13, 4.90 (AB, d. 2, .CHaOAc), Example 3. p-Metoxibenznl-dt 7od-azidodeocetoxycephalospore nat. 5-methyl-4- (p-methD-Sibenzyl-ox-n-barbenyl-6-1, 3-thiazine (0, O28 g) is dissolved in 1 ml of GH, C, and cooled to 0 ° C. Griethylamine (0.016 ml ) and the mixture is treated dropwise over 30 minutes by 1 ml of a solution of azidoacetyl trifluoromethylsulfonate. The reaction mixture is stirred for 5 minutes and then diluted with one time washed with cfH7 buffer, dried, and evaporated to a residue, which is purified by preparative TON-LAYER chromatography to obtain α-p-methoxybenzyl-3. . When in the above process, azidoace is used in place of the azidoacrylate of trifluoromethyl sulfonate. tilmethanesulfonate, n-methoxybenzyl-3-7cC-azidoacetoxy-aphalospogranate is also obtained. EXAMPLE 4 p-Methsibenzyl-3t-f azdo-7-m-toxic -1.3 tiazi-4-carboxlla-a (241 mg, O, 72 mmol} in dry methylene chloride (5 ml) is added immediately in one step of solution triethylamine (110 ml, 0.79 mmol} in methylene chloride (1 ml). The resulting mixture was stirred under a nitrogen atmosphere while cooling with an ice bath, while a solution of 2-azido-2-methox-acetyl chloride (119 mg, 0.8 mmolJ in dry methylene chloride (3 ml) was added dropwise over a period of 50 minutes. By After stirring for 1 hour at 0 ° C and 2 hours at room temperature, the reaction mixture is diluted with methylene chloride (10 ml), dried over magnesium sulfate and evaporated in vacuo to give a yellow oil. The crude product is chromatographed on silica gel (9 g) using 10% ethyl acetate in benzene as an eluting solvent gives p-methoxybenzyl-OE - 7ft -Azido-7-methoxyphalosporanate and p-methoxybenzyl-dE-7-01 azide O-7-m tocephalus osporanate. Using a similar procedure, methyl 5-methyl-6H -1,3-thiazin-4-carboxylate gives methyl ester} -7D-azido-7-me-. toxi-3-methyl-dezacetoxycephalosporanic acid and d2 7 oC-azido-7-methoxy-3-methyl-deacetoxycephalosporanic acid methyl ester in an ratio of 3: 1. IR, 7 | Isido isomer 4.73 5, B6, 5.78. 6.97, 7, 30, 6.05, 8.79, and 9.42 L — PMR (CDCe) 7 C. Azidoisomer, G 7.80 (C, 3, CH3), 6.76 (C, 2, SNg ), 6.33 (C, 3, AHSS), 6.13 (C, Z.SCH3) and 5.12 (C, 1.4, 6 N) In addition to the signals at 7.8 O, 6.76 and 6 , 13 The 1H NMR spectrum of the a-ap-isomer shows absorption bands at 6, 30 (3CH) and 5.20 (6N). PRI me R 5. In accordance with the techniques described in paragraph 1, p-megoxyenzyl-5-methoxy-methyl-6B -2,1-thiazine-4-carboxylate, 2,2,2-trichloroethyl-5-methyl6n -1 , 3-thiazin-4-carboxylate or metszhsietil-5-isobutyryloxymethyl-6 H -1,3-tia-ina-4-carboxylate is reacted with 2-azio-2-methoxyacetyl chloride to obtain-methoxybenzyl-dC-3- methoxymethyl-7 & Azido 7C C-methoxy-3-cethem-4-carboxy. 2,2,2-trichloroethyl-d-methyl-7 / 3azido-7oC-methoxy-3-cephem-4-carboxylate and methoxy-methyl-dP-3-isobutyryloxie-1-7 .y-azid-7 oL-methoxy-3-cep - carboxylate, respectively. Example 7.dB-7 (5 -Azido-7-methoxyek}) al (X: paranal caslotte. L Metoxv6enzvl- dE -7 ft -Azido-7-megshsicefapozoanat (250 mg) is treated with anisole (1.0 ml) and trifguaceous acid (5.0 ml with cooling with an ice bath. The mixture was maintained for 1 minute and then evaporated in vacuo to remove trifluoroacetic acid. The residue was taken up in dilute aqueous sodium bicarbonate and extracted twice with ethyl ether. The aqueous portion was separated by ethyl acetate and acidified to pH 2.56 N hydrochloric acid. The ethyl acetate layer is separated, the sulfate is dried. Maga is filtered and evaporated in vacuo to give d8 -7j -Azido-7-methoxycephalosporanic acid. EXAMPLE 8 dC -7 | -amino-7-methoxycephalosporanic acid. Mixture dE -7 / i - -azido -7-methoxycephalosporanic acid (190 mg) disisane (2O ml) and plugins oxides (200 mg) are hydrogenated at 2.8 kg / cm, I fi -in I. ... V for 2 hours. The catalyst then is removed by filtration through diatomaceous earth, which is washed with water, the filtrate and the washings are evaporated in a dry vacuum to obtain (1% amino-7-methoxycephaphospravic acid. . Formula izobreu.ni 1. The method of obtaining sGR-7-) azidocephalo sporine compounds of the formula t n and n "sfy, where AND is n-methoxybenzyl, trichloroethyl, methoxymethyl, hydrogen, methyl, methoxy group, provided that , the aaido group is in the Bdl position, and when Vn is 1 methyl. or a methoxy group, the azido group is in the | L-position, that is, and with the fact that the compound is total f, where R has the above values. 1Aaaa1aaa11 is reacted with an active reagent of the formula N3-ОН-СОХ n гч UmiXk f mf) n «« rWv. Tm ".IT f LLU I1G1 B where B - has the above values in X - a halogen atom, OSCLCFj group, in an aqueous organic solvent in the presence of a tertiary amine at a temperature of O-20 ° C. Sources of information taken on the subject matter 1. Patent USA No. 344336, iL-JLSQ-2-4a J: 0.oe.lRe9. 2. The GDR patent number 941184,. 12 p ,, 4/01, 15.12. 1972.