• 专利附录
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    • 专利摘要:
    Heteromonocyclic and heterobicyclic derivatives of unsaturated 7-ayclamide-3-cephem-4-carboxylic acid are disclosed, and process for preparing same. These compounds are suitable for treating infections caused by Gram-positive and Gram-negative microorganisms.
    公开号:SU845788A3
    申请号:SU772516753
    申请日:1977-08-22
    公开日:1981-07-07
    发明作者:Наннини Джулиано；Перроне Этторе；Северино Дино；Мейнарди Джузеппе；Монти Джизелла；Бьянчи Альберта；Форджоне Анджело；Конфалоньери Карло
    申请人:Фармиталия Карло Эрба С.П.А. (Фирма)；
    IPC主号:
    专利说明:

    or a salt thereof, which is that the compound of the general formula H.Tf-pY-S -lf is CH2-B where B has the indicated values, or its reactive derivative is reacted with an acid of the general formula ZAS-CH.J.-OOOH , idil) where Z and A have the indicated values, or with its reactive derivative at a temperature of from -20 to in a solvent selected from the group including acetone, dioxane, tetrahydrofuran, acetonitrile, chloroform, methylene chloride and dime formamide, in the presence of a base, selected from the group including sodium bicarbonate ri and potassium and trial, kylamine, and / or, condensing a gene, such as N, N, dicyclohexylcarbodiimide, and isolate the desired product in free form or in salt form. The reactive derivative of the compound of formula Ii may be, for example, the amine salt of a strong ester or a metal salt. The reactive derivative of the dinene of formula I. It is, for example, an acid halide, anhydride and mixed anhydride, amide, azide, ester or a salt, for example, a salt formed by alkali or alkaline earth metals, ammonia or organic bases. Example 1. To a solution containing (L-cyanoethylene - (trans) -thiox acid (2.88 g) and triethylamine (2.8 g in anhydrous acetone {20 ml), add a few drops of N-methylmorphol. Mixed pivaloyl chloride / (2.44 ml), dissolved in without aqueous acetone (30 ml), and then after stirring for 30 minutes, and a solution containing 7 -ami-3-C (1-methyl-1,2,3,4-tetrazol-5-yl thiomethyl-D-3-cephem-4-carboxylic acid, d) and triethylamine (2.8 mol) in 50% acetone (240 ml) cooled to -20 ° C. Transfer mixture It is evaporated at -20 ° C for 1 hour, and then at room temperature for 2 hours, the acetone is evaporated in vacuo, the residue is taken up in water, partitioned with ethyl acetate and the mixture is adjusted to a pH of 2.5 with 40% phosphoric acid. After filtering, the ethyl acetate is separated and the organic phase is washed with water, dried over sodium sulfate and evaporated to a small volume. Upon addition of diethyl ether, a solid is formed, which is filtered and mixed with diethyl ether. The solid is again filtered to obtain 5.4 g (yield 60%) 7-jb cyanoethylene- (trans) -thioacetamido-3-O-methyl-1,2,3,4-tetrazol-5-yl) -thiomethyl-3 -feat-4-carboxylic acid, so pl. 1 1 8-1 20s 1c decomp.) Analysis results: Found,%: C 39.83; H, 3.42; N 21.31; S 20.87. C So, Calculated,%: C 39.80; H 3.33; N 21.60; S 2.20. UV spectrum (pH 7.4, phosphate buffered saline),. 267 microns; 411. Thin layer chromatography: R (.0.55 CHC & 2,: CH OH: HCOOH 160: 40: 40). IR (potassium bromide tablets) cm: conjugated bonds 2200; V (C-0) p-lactam 1776 () vtor.amid 1670, NMR spectrum - (dimethyl sulfoxide sZe)) 3.73 (41 |, broad singlets, S-CH, -cb and 2 - CH,.; 3 , 94 (ZN, singlet, SI-M}; 4.33 (2H, quadruplet, 3-CHj); 5.11 (1H, doublet, 6-H; 5.64 (W, doublet, H C-CH) ; 5.7 (1H, double doublet, 7-H), Zbn-7N Hz; 7.82 OH, doublet CH-S), JcHrCH-trans 16Hz, 9.28 (1H, doublet, -CO N N N,, 8 Hz. L-Cyanoethylene- (trans;) -acetic acid used as starting material is prepared according to the following methods: Method A. To a solution of 70% thioglycolic acid (2.1 ml) and triethylamine (5 , 6 ml) in water (50 ml), cooled to 5 ° C, is added dropwise. target trans-p) -hlorakrilonitrila (1.73 g) in tetrahydrofuran (7 ml). The mixture was peremeshivayutv for 30 min
    at room temperature and acidified with 20% sulfuric acid. The precipitate obtained is extracted with ethyl acetate, the extracts are washed with a saturated solution of sodium chloride, dried over sodium sulphate, treated with charcoal and evaporated to obtain an oil which solidifies with (formation of cyanoethylene) ( trans) -thioussus acid (2.5 g; yield 88%), mp 81-86 C.
    Found,%: C 41.81; H 3, 71 S22.31.
    CgHgNOaS Calculated,%: C 41.94; H 3.52; N 9.78; & 22.39.
    IR spectrum (potassium bromide tablets): / O (CHN) -conjugated bonds 2220 () acid 1720 cm; lJ () -connected bonds 1575 cm; . (С-Н): С С-trans 930.
    NMR Spectrum: Odimethyl sulfoxide (sZ): 5.56 CP (doublet, NC-CH), 7.78 s (doublet, CH-S); J (trans) 16 Hz.
    Method B, To a solution of 70% thioglycolic acid (0.5 ml) and sodium bicarbonate (0.84 mg) in water (50 m was added with stirring | b tosylacrylonitrile (1.03 g). The mixture was stirred for 3 at room temperature and filtered, the solution is acidified with 20% sulfuric acid and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and evaporated to dryness to obtain — and; io ethylene (trans) -thioacetic acid (0.65 g, yield 91 %).
    As a result of purification by the formation of a salt of dicyclohexylamine, a product identical to that obtained by the method A. JJ) -Tosiacrylonitrile, used as a starting material, is obtained, prepared by carrying out the reaction between sodium
    salt of P-TOLUOLSULFINE KI. SLOTS and
    | L-chloroacrylonitrile in a mixture of dioxane, water and boric acid in accordance with a known method.
    PRI me R 2. Analogously to example 1, the interaction of (b-cyanoethylene- (trans) -thioacetic acid and 7-azl. No-3- | C1, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid semi . 7-pz-cyanostilfonyltrans-thio-acetamido-3-f (1, 3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid. Yield 68%, so pl. (with
    . Found,%: C 39.66; H 2.91; 15.25; S 28.05.
    C, 5H, ZKDO 5 ..
    Calculated,%: C 39.54; H 2.87; L 15.37; S 28.15.
    UV spectrum (pH 7.4, phosphate buffer solution) μm; 569.7
    Thin layer chromatography: RC 0, (CHCfej: CFijOH: HCOOH).
    IR spectrum (potassium bromide tablets), cm: v C N) conjugated bonds 2215; L-lactam 1775 S () sec.-Amide 1675.
    EXAMPLE 3 To a solution of p-cyanoethylene (cis) -thioacetic acid (1.44 g) and triethylamine (1.4 ml) in anhydrous acetone (80 ml) was added a few drops of N-methylformalin. The solution is cooled before and after that pivaloyl chloride (ml), dissolved in anhydrous acetone (20 ml), is added with stirring. The mixture is stirred for 30 minutes and then a solution containing 7-amino-3-0-methyl-1,2,3,4-tetrazol-5-yl j -thiomethyl 3-cephem-4-carboxylic acid is added to it. (3.28g and triethylamine (1.4 ml) in 50% acetone and Ob ml).
    After the addition, the solution is stirred for 1 hour at RT and then for 2 hours at room temperature. Acetone is evaporated in vacuo. The residue is dissolved in water and washed with ethyl acetate. After separation, the aqueous phase is layered with ethyl acetate and the pH is adjusted to 2 with 20% sulfuric acid.
    The residue is filtered and the organic phase is separated, dried over anhydrous sulphate on ri and evaporated to a small volume. The residue is dissolved in diethyl ether to give 7-CP-cyanethylene- (cis) -thio-acetamido) -3- (1-methyl-1,2,3,4-tetrazol-5-yl) -thiomersh13-3-cephem-4 -carboxylic acid (2.7 g, yield 60%), so pl. PZ-1150S (with dec)
    Found%: C 39.78; H 3.43; N 21.40; at 20.78;
    Calculated,%: C 39.80; H 3.33;
    N21,60; S 2G, 20n
    UV Absorption Spectrum (pH 7.4, phosphate buffered saline)
    ttofo 463
    msm toj.
    IR spectrum (potassium bromide tablets), V () conjugate
    Communications 2210; V () (L-Covenants 1775, V () sec, amide 1680 G {C-N) + f (f (N-H) sec. Amid 1540.
    NMR spectrum of parts x 10 dimethyl sulfoxide -d): 3.68 (2H, quadruplet, 2-CH2; 3.73 (2H, singlet.-3-CHN-CO); 3.94UH, singlet, CHj-N) ; 4.31 (2H, quadruplet, 3-CHj): 5.10 (1H, doublet, 6H); 5.63 (1H, doubled 7-H doublet); 5.72 pH, doublet, NC — CH); 7.63 (1H, doublet, CH-S), JcH4H (4 "c, c, 9.2 (H, doublet, - CO-NHJ.
    The starting material used (L-cyanoethylene (cis) -thioacetic acid) is prepared as follows.
    To a solution of (b-carboxamido ethylene- (cis) thioacetic acid (4 g) in a mixture of dimethylformamide and diethyl ether (3: 2,100 ml) cooled to 0 ° C), added with stirring, phosphorus chloride (5.2 g) while maintaining temperature. After that, the solution is stirred for 2 hours and the ether layer is separated. The aqueous layer is extracted with four 50 ml portions of ethyl acetate. The combined extracts are dried over sodium sulfate and then evaporated to dryness at a temperature not exceeding 40 ° C to obtain a yellowish oil, which is a solution of in methanol |. (10 ml. To the resulting solution was added a stoichiometric amount of dicyclohexylamine to obtain a precipitate of dicyclohexylamine salt {b-cyanoethylene (cis) -thioacetic acid, which after filtration is re-washed with diethyl ether (m.p. 180-183 sec) .
    . The salt is dissolved in a mixture of water-ethyl acetate (5: 7, 120 ml) with acid and the solution is acidified, and 40% orthophosphoric acid (10 ml) is added dropwise. The resulting solution is extracted with three portions of ethyl acetate, and the combined organic extracts are washed with water, saturated sodium chloride, dried over sodium sulfate, and evaporated to dryness to obtain | b-cyanoethylene (cis) -thioacetic acid
    N 9у78; S 22.39.
    IR spectrum (potassium bromide tablets): () -conjugated bonds 2220; () acid 1720 ...
    Nuclear Magnetic Resonance Spectrum (dimethyl sulfoxides) 5, 4 (doublet NC-CH), 7.46 (doublet, CH-S), (4MC) Yu Hz.
    Using the above procedure, -Ciao-ethylene (cis) thioacetamido, 2,3,4-tetrazol-5-yl-thiomethyl-3-cephem-4-carboxylic acid is obtained.
    Found,%: C 38.48 H 3.05; 22.15; S 21.65.
    N
    Smn., "7,
    Calculated,%: C 38.26; H 2.98;
    N 22.31; S 21.89.
    UV spectrum (7.4, phosphate bug, /
    Fer) 273 microns; ,
    416.
    Thin layer liquid
    chromatography: R 30,34 (SNSE ,,
    CHrtjOH:: UNSAs 160: 50: 20).
    IR spectrum (KBG), (SSCh conjugated bonds 2220, () (L lactam 1780; acid 1660; CC-N) S) (.- amiZ, 1530.
    Example 4 A reaction between jb-cyano ethylene (cis) -thioacetic acid and 7-amino-3-fO, 2, 3,4-thiadiazol-2-yl) thio-methyl-3- is carried out according to the method described in example 3. cephem-4-carboxylic acid, to obtain -cyanoethylene (cis) thioacetamido-3 - 1, 3,4-thiadiazol-2-yl) -thiomethyl-3-cepheme-4-carboxylic acid. Output 63%, so pl. 93-95 0 (with diff.)
    Found%: C 39.33; H 2.94; 12.20; 527.93.
    N
    C (5
    0 5e
    Calculated,%: C 39.54; H 2.87; 0 N 15.37; S 28.15.
    UV spectrum (pH 7.4, phosphate buffered saline): TV .., -., - 273 μm, gyu / o 504 ICM
    Thin layer chromatography: Bj 0.56 (CHCEj,: CH.jOH: HCOOH 160: 40: 20).
    IR Spectrum (potassium bromide tablets), () mate links 2220; () jb-la, ctam 1775, V () sec. -amide 1715,) (C — N) + (N – H) sec. of amid 1540.
    权利要求:
    Claims (3)
    [1]
    EXAMPLE 5 As described in Example 3, j-cyano ethylene; :( cis) thioacetic acid and 7-aminocephalosporanic acid are reacted to give 7-jb-cyano ethylene, (cis) -thioacetamido-cefaposporanic acid. Yield 70%, so pl. 132134 ° С (с,., Decomp.) Found,%: С 45.15; H 3.93; N 10.33; S.15,99; , 06 Sa Calculated,%: C 45.32; H. 3.80; N10, .57; 16.13. For example, to a solution of fi-carboxy xamidoethylene- (trans) -thioacetic acid (6.81 g) in a mixture of acetonitrile-dimethylformamide (2: 1.60 ml) was added triethylamine (0.7 ml) and 2 drops of N-methylmorpholine The mixture is cooled to -5 and a solution of pivaloyl chloride (0.061 ml) in anhydrous acetonitrile (10 ml) is added while stirring. After stirring for 30 minutes, the solution of 7-amino-3-C 1 - is added while maintaining the temperature. methyl -1, 2,3,4 tetrazol-3-yl) -thiomethyl} -3-cephem-4-carboxylic acid (0.64 g) and tr. ethylamine (0.7 ml) in an acetonitrile-water mixture 1: 1570 ml. The mixture is stirred for 1 hour at then 2 hours at room temperature and evaporated to dryness; The residue is dissolved in water and layered with ethyl acetate, and the pH is adjusted to 2.5 with 40% orthophosphoric acid. After filtering off the residue and evaporation of ethyl acetate, the organic phase is washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The resulting crude was dissolved in methanol-acetone (1: 1.15 ml) and added dropwise to diethyl ether (.200 ml). After stirring for 2 hours and filtering, 7 - (| L -carboxyamidoethylene- (trans) -thioacetamide-3- (l-methyl-1, 2,3,4-tetrazol-5-yl) -thiomethyl-3-cephem -4- carboxylic acid, 1.18 g, yield 50%), so pl. 146 150 ° C (with decomp.) Found.%: C 38.44; H 3.71; N 20.68; N 20.03. 15 17 T 5 b Calculated,%: C 38.2; H 3.63; N 20.79; S 20.4. The UV spectrum (phosphate buffer solution, pH 7.4) is 270 μm, / -71, cm471. Thin layer chromatography: RJ 0.35 (SLEEL: CHP, OH: HCOOH 160: 20: 2 IR spectrum (tablets with potassium bromide), cm: SI (CsO) (B-lactam 1780 () acid 1670; c; j + (M-H) 1560. L-Carboxamido ethylene- (trans-thioacetic acid used in 810 as a starting product, is prepared as follows. To a solution of 70% thioglycolic acid (2.12 ml) in 2. Of the hydrate solution sodium oxide (20 ml) is added in portions at 5 ° C with trans-chloro-acrylamide (2.11 g). The resulting solution is stirred for 3 hours at room temperature, washed with ethyl acetate, the last aqueous phase is separated acidified with 20% sulfuric acid to obtain a precipitate (L - rboxamido ethylene - (trais) -thioacetic acid O-, 16 g), t. op. 190 (Found,%: C 37.19; H 4.35; "8.6TS519, 78; CdH NOj, S Calculated,%: C 37.25; H 4.37; N 8.69 5-19.89. IR spectrum of a potassium bromide tablet: (NH), group 3420, 3290, () acid 1690; -} (C-H), (trans) 940. NMR spectrum (dimethyl sulfoxide-b (|) 5.9Sa (doublet — CO-SNL); 7.63 cG (doublet ; SI- S); JCHSCH-country) 5.5 Hz. Example7. According to the method described in Example 6, by the interaction of β-carboxamido ethylene- (cis) -thioacetic acid and 7-amino-3 -1 (1-methyl-1, 2,3,4-tetrazol-5-yl) -thiomethyl -Z-cephem-4-carboxylic acid get 7- | L-carboxamido-ethylene- (cis) -thioacetamido1-3-p-methyl-1, 2.3 4-tetrazol-5-yl) -thiomethylZ-3 -def -4-carboxylic acid. Yield 65%, so pl. 150 ° C (with decomp.) Found,%: C 38.35; H 3.72; N 20.43 52T5,17; S ,. Calculated% C 38.20; H 3.63; N20.79; S 20.40. UV spectrum (pH 7.4, phosphate buffer solution: lmi 277 µm, W. Thin-layer chromatography; R 6.30 (. CHC 4JCH OH: HCOOH: i66: 4b: 20) IR spectrum (tablets with potassium bromide , cm () p-lactam 1775) amide with conjugated bonds 1650, (p-tt.H) b-c-am3. 1540 p) -Carboxyamido ethylene- (cis) thioussonic acid used in (the quality of the starting product is prepared as follows. To a solution of propylene, onamide (b, 9 g) in water (20 ml) is added with stirring at a temperature of about 70% thioglycolic acid (10 ml) in a 20% sodium hydroxide solution (18.9 ml). The solution is again stirred for 1 h at and then 1 h at room temperature. At the end of stirring, the solution is acidified with stoichiometric stirring the amount of 70% perchloric acid. After cooling to about the solid which is filtered is dissolved in water (45 ml1, stirred for 10 minutes, filtered again and dried, 12.6 g of a mixture (9: 1) of L-carboxamido ethylene (trans) - thioxonic acid are obtained and jb - Capacidamide ethylene (trans) thioacetic acid. Both acids have different solubility in water and therefore, by stirring the mixture with a sufficient amount of water, the whole trans isomer can be dissolved, and approximately 8/9 of the cis isomer remain insoluble (the purification process can be controlled by thin layer chromatography (acetone: water acetic acid, 180: 10: 10) is produced e.g. t three successive washing, two rinsing with 50 ml of water and thereafter 100 ml of water) - to yield pure cis-isomer 72% yield t, pl. 180-181; Found: C 37.22; H 4.37; N 8.66 620.00. Calculated,%: C 37.25; H 4.37; N 8.69; & 19.89. IR spectrum. Tablets with potassium bromide),) (- n)) NHQi.rp inna3450 ,, Vtc o) KMCAOTq -1685, amide 1625 NMR spectrum (dimethylsulfoxide-d,). 3.43, (f (singlet, - S-CH (j-); 5,94СЯ Doublet -CO-CH;); 6.97 cG (dupet. CH-S); 7.16 (f (doublet, - CO-NH.j); 12eOO cP (broad singlet, OH);) 10 Hz. EXAMPLE 8 Use the method described in Example 6, but use carboxamido ethylene ethylene thioacetic acid as the starting product instead of p-carboxamido ethylenyl- (tran-thioacetic acid, 7- (carboxamidoethynylene thioacetamido) -3 1-methyl-1, 2,3,4-tetrazole 5-yl} thiomethyl-3-cephem-4-carboxylic acid yield 47%. Found: C 38, 25; H 3.31; N / 20.70 & li, 81. with sHisNiOsSa. Calculated: C 38.40; H 3.27; N 20.90; S20.05. IR spectrum (KBpJ, cm: Vf.jh-AorRTaM 1780; V (CN) ((NH) L, op.-aMMd 1540. UV spectrum (pH 7.4 phosphate buffer) MOtc 270 µm ... Thin layer chromatography: Rf. 0.30 (sleep: CHj, OH: HCOOH 6b: 20: 20;. 11 p and measure. 9. K a solution of cyanoethenylene mercaptioacetic acid, 2 in anhydrous acetone (.60, ml) and tr ethylamine MJ, scintilated with ome, are added With stirring, isobutyl chloroformate (1, 7 ml) dissolved in anhydrous acetone O 6 ml); Stirring is continued for 30 minutes at -10 ° C, after which the mixture is cooled until a solution containing 7-amino-3-1-methyl-1, 2,3,4-tetrazol-5-yl) thiomethyl-3- is added to the mixture. cephem-4-carboxylic acid (2.8 g) and triethylamine (4 ml) in 50% acetone, and the resulting mixture was stirred at (-20) - (30) ° C and then for 1 hour at (-5} - (O) -C, then 3 hours at room temperature. The acetone solution is filtered and evaporated in vacuo, the residue is dissolved in water (20 D ml) and extracted with diethyl ether (two portions of 100 ml). After separation of the layers, the aqueous solution follows t to p 2.5 with 10% hydrochloric acid and extraction with acetylacetate.The organic phase is washed with water, dried over sodium sulfate, concentrated to a small volume and poured into a hexane loop to obtain 7 - (cyanoethynylene thioacetamido) -3- (1 -methyl-1,2,3,4-tetrazol-5-yl) -thiomethyl -3-cephem-4carboxylic acid. Found: C 39.60; H 3.01; IN 21.50, S 21.01 C sHibN O; ,,,. Calculated,%: C 39.90; H 2.91; N 21.70; S 21.30. UV spectrum (pH 7.4, phosphate buffer): AMSYAX 273 microns. Thin-layer chromatography: S 0.58 (CHCELSN ,, OH:: HCOOH; 60:40:20 IR spectrum (KBt), cm: () conjugated bonds 2210, (C-0) | b-lactam 1775;} ; vtormid. 1680., the following compound is obtained in the same way: i 7- (Cyanoethylenothioacetamido} -cepha jopropanoic acid Found%: C 45h, 41; H 3.42; N 10.40; 5 16.01. qgHftVeSaCalculated,%: С 45.60; H 3.31; N 10.64; S16.2. UV spectrum (pH 7.4; phosphate buffer MCTiiC 270 μm. Thin layer chromatography: R, O, bOCNSS t CH-OH: HCOOH-160: 40:20, IR spectrum (KBG), () E-l there 1780;) C-C conjugated bonds 2220; J sec, amide 1715; 7- (Cyanoethynylene thioacetamido) -W. - (1,3,4 -thiadiazol-2-yl) -thiomethylZ-3 -cephem-4-carb Found:% C 39.50; H 2.51; N 15.30; 5 27.91. Calculated: C 39.70; H 2.44; 15.45; 6 28 , 25. UV spectrum (pH 7.4 phosphate buffer MotX-C 73 μm. Thin layer chromatography: Rr-O, 50 (СNЕ, СН, ОН: НСОО 1АП.лп.9п .160: 40: 20. (С MGSopr IR spectrum (KBr), softened bonds 2220, V () | J-lactam 1775;) sec, amide 1715. Example 10. To a solution containing L-cyanoethylene (cis-j-thioacetic-acid (1, 44 g) and triethyl amine (1.4 ml) in anhydrous acetone. (.80 ml), add a few drops of N-methylmorpholine. After cooling, a solution of pivaloyl (j, 22 ml) in anhydrous acetone (20 ml) is poured with stirring. The mixture is stirred for 30 minutes at and then a solution of 7-amno-3-Q-methyl-1,3,4-triazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid ( 3.25 g) and triethylamine U, 4 ml) in 50% acetone (60 ml). After the addition, the solution is stirred for 1 hour at 0 ° C and then for 2 hours at room temperature. The acetone is evaporated in vacuo, the residue is dissolved in water and washed with ethyl acetate. After separation of the phases, the aqueous phase is layered with ethyl acetate and the pH is adjusted to 2 with 20% sulfuric acid. The residue is filtered, the organic phase is dried over sodium sulfate and evaporated to a small volume. The residue is dissolved in diethyl ether. Filtration of 7-f | L-cyano-ethylene- (cis) -thioacetamido D -3-f (l-methyl-1, 3 4-triazol-2-yl) -thio14 is isolated. methyl 3-cephem-4-carboxylic acid 2.5 g, yield 55%; m.p. 125130 With (with razl); - Found: With 42.77; H 3.96; N 1.8.27; S 20.87. C, b,. Calculated by:,. C 42.50; H, 3.56} N, 18.60; 521.20. UV spectrum (pH 7.4, phosphate buffer solution) 1 maize 267 microns; E 458. Thin layer chromatography:, R {0.32 (.EnEv: CHOH: HCOOH 160: 40: 20) G-spectrum (tablets with potassium bromide), cm: C) conjugated bonds 2215; J ((L-lactam .1775;) sec. -Amide 1675. The following compounds are prepared in an analogous manner: 7-HE-cyano-ethylene (trans) io-acetamido C D v G-methyl-1,3,4 triazol-2-yl) - tiometsh11-3-tsefem4-carboxylic acid, t, pl. 127131 0 (with diff). Found,%: C 42.82; H 3.67; N 18.33; 520.73 CifeH e faO Calculated,%: C 42.50; H 3.56; N 18.60, S 20.20. UV spectrum (pH 7.4, phosphate buffer solution: Monyv 267 µm, E | 444. Thin layer chromatography: 5tgO, 28 CHCg, j: CH, j, OH: HCOOH 160: 40: 20). IR spectrum of Caium bromide stabilizers (cm): CCSN) conjugated bonds 2216; )) B-lactam 1775, (CsO) tor.amid 1675. 7-tib-Cyano ester- (cis) -thioacetamido -3- | 5-metsh1-1, 3,4-triazol-2yl-thiomes-1J-3-cefeme-4-carboxylic acids Found: C 42,63; H 3.73; N 18.40 6 20.91 .. H «-« 6 Ne, 0.54 Calculated,%: C 42.50; H 3.56; N18.60; S21.20. Example 11. To a solution of 7-amiHO-3- | 1 (l-methyl-1, 2,3,4-tetrazol-5-yl) thiomethyl} -3-cephem-4-carboxylic acid (3.28 rj and bicarbonate sodium chloride (j2 g) 50% aqueous acetone (60 ml), cooled to, was added with stirring a solution of the acid chloride 2.18 g of | L-cyanoatethylenes thioacetic acid (obtained from the acid by reacting oxalic acid chloride in medium cimethylformamide at) in acetone (30 ml). The mixture is stirred for 20 min at (0) - (5) 00. The acetone is evaporated, ethyl acetate is added to the resulting aqueous solution and thereafter slab was 8% hydrochloric acid to pH
    [2]
    2. The organic phase is washed with water, dried and evaporated in vacuo. The residue is treated with diethyl ether and filtered to obtain-cyano ethylene (trans) -t-acetamido-3-{{1-methyl-I, 2,3,4-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid ( 2.3 g)., T. Pl, 1 8-120 ° C (with decomp). The results of microanalysis, thin-layer chromatography, IR and NMR spectra show that this compound is identical to that described in Example 1. Example 12. To a jb solution of cyanoethylene (cis) .- thioacetic acid (1.44 g) in anhydrous tetrahydrofuran 50 ml of dicyclohexylcarbodiimide (2.1 g} is added and the mixture is stirred for 30 minutes at room temperature. A solution of 7-amino-3 - {(1-methyl-1, 2,3,4-tetrazole-5 -yl) -thiomethyl -3-cephem of 4-carboxylic acid (3.28 g) and sodium bicarbo (O, 84 g in a mixture of tetrahydrofuran with water (1: 1, 60 ml). After stirring neither for 3 h at room temperature is tetrahydrofuran evaporated in vacuo, the residue is dissolved in water and dicyclohexylurea is filtered off, the filtrate is partitioned with ethyl acetate, acidified with 20% sulfuric acid to pH 2.5, the organic layer is separated, washed with water, evaporated, to a small volume and then diethyl ether is added to obtain a solid. The latter is filtered off and then mixed with cythyln-1 ether to obtain 7-C (L-dianoethylen- (cistiadoad, about -3-1 methyl 1,2,3,4-tetrazol-5 -yl thiome Tyl-3-cephem-4-carboxylic acid, m. square 113-115 0 (with decomp.) The results of microanalysis, UV spectrum, thin layer chromatography, IR and NMR spectra are identical to those shown in the example
    [3]
    3. Example 13. To an aqueous suspension of 7-LP-cyano-ethylene- (cis) -thioadetamido-3-O-methyl-, 2,3,4-tetrazol-5-yl) -thiomethyl 3-3-cephem-4-carboxylic acid (34.53 g) in water (80 ml), a stoichiometric amount of sodium bicarbonate is added and a solution of compound 8 is obtained. This solution is then lyophilized to obtain the 7-Pb-cyanoethylene- / cis-thioadetamido-sodium / 4 3-1 sodium salt ( 1-methyl-1,2,3,4-tetrazol-5-yl thiomethyl-3-cephem-4-carboxylic acid: Found: C 37.71, H 2, 20.55;, 15; Nq 4 , 75., I, N-70 /, 9iNa. Calculated,%: C 37.88; H 2.39; N 20.62; 6 20.23; No 4.83. IR spectrum (KBr}, (conjugated bonds 2210, (C) p) -lact; m 1775, (sec. amid 1670,) fC-N) +, + Cf (Hn) vt 1540. Example 14. To the solution -. -diano-ethylene- (| dis) -thioacetamido-3- (-methyl-1,2 , 3,4-tetrazol-5-yl) -thiomethyl-3-defem-4-carboxylic acid, 1.13 g) in ethyl acetate, 30 ml) are added a stoichiometric amount of a 30% strength solution of 2-ethylhexanoic acid sodium salt in isopropyl alcohol. After stirring for 30 minutes at room temperature, the mixture is diluted with petroleum ether and the resulting precipitate is filtered to obtain the sodium salt of 7-1-diethylethylene (dis) - thioadetamide-3- (1-methyl-1,2,3,4-tetrazole -5-yl} -thiomethyl -3 --- Cef-4-carboxylic acid. Found:%, C 37.71; H 2.43; N 20.55; 5 20.15; wa 4.75. H, /, Na, Calculated,%: C 37.88; H 2.39; N 20.62; S 20.23; Noi4.83. IR spectrum (KBI) cmT (SNS) conjugated links 2210, 9 (C-0) Covenants 1775, IS-O Vtorgamid 1670, (.C-M) + +0 (NH) sec. 1540. The invention The method of obtaining non-produced 7-α-thylamido-3-def-4-carbo ovo acids of general formula ZAS- (I о о.: n-uD- (H2-in where Z-cyano or carbamoyl; -trans-CH-CH, dis-CH; H- or-acetyloxy or -S-Het, where Het- a group of the general formula L, A.if, 1784578 where C is a hydrogen atom or methyl, or A JLj-t, where C and Cdz independently of each other are a hydrogen atom or methyl, or their salts, I distinguish between .and and, that a compound of the general formula where B has the values indicated above, or its reactive derivative is reacted with an acid of the general formula 2-AS-CH, -COOH, 5 to 15 2Q 8 where Z and A have the above values, or its reactive derivative at a temperature of from -20 to in a solvent selected from the group including acetone, dioxane, tetrahydrofuran, acetonitrile, chloroform, milling chloride and dimethylformamide in the presence of a base selected from the group comprising sodium bicarbonate and potassium and trialkylamine and / or condensing agent t, as, Vl-dicyclohexylcarbodiimide ,,. and isolate the desired product in its free form or as a salt. Sources of information taken into account in the examination 1. US Patent No. 3875153, cl. 260-243 C, published. 1975.
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    IT20173/77A|IT1075277B|1977-02-11|1977-02-11|UNSATURATED AND EPOXY DERIVATIVES OF ACIO 7-ACYLAMIDE-3-CEFEM-4-CARBOXYL AND PROCEDURE FOR THEIR PREPARATION|
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