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    • 专利摘要:
    1. A method for preparing 3-substituted thiomethyl cephalosporins of the formula RI S pJ - Nx -CHzS Ri, COOH where R is an amino group or a group of the formula R3-CH N in which R-5 is 2-hydroxy-1 or 3,5-di- tert-butyl-4-hydroxyphenyl; R2 is 1,2,3,4-tetrazolsh1-5, free or substituted in position 1 by methyl, ethyl, carboxymethyl, carbamoylmethyl, sulfomethyl, 2oxyethyl, 2-aminoethyl or phenyl, 1,3,4-thiadiazolyl-2, free or substituted in position 5 by methyl, 1,2,3-triazolyl-5, benzoxazolyl-2, benzimidazolyl-2, 2-metsh1-2,5-DIGIDRO-5-OXO-6-OXI-as-triazin-3-un, propyl, phenyl, carboxymethyl or ethoxycarbonylmethyl or their ethyl or diphenylmethyl ethers or their salts by reacting a compound of the formula X 1 with COOH where RI has the indicated values; (L Y is a radical - S - or - S - or its corresponding ester, or its salt with a thiol of formula R 2 - SH, where Rrt has the indicated values, or with its salt in an organic solvent medium at a temperature of from -20 to 80 C differs in that, in order to increase the yield of the target product, anhydrous organic solvent is used and the process is carried out in the presence of a proton acid, a Lewis acid or a complex compound of a Lewis acid. 2. Method POP1, characterized in that acids use pyrophosphoric, sulfuric, chlorineuric, fluorosulfuric acid, monosulfonic acid or superacid. 3. Method POP.2, distinguished by the fact that
    公开号:SU1105116A3
    申请号:SU792786305
    申请日:1979-07-04
    公开日:1984-07-23
    发明作者:Саикава Изаму；Такано Сунтаро；Момонои Кайсу；Такакура Изаму；Курода Сейецу；Танака Киеси；Хаяси Кенсин；Наганаси Бунеи；Кутани Чиаки
    申请人:Тояма Кемикал Ко, Лтд (Фирма)；
    IPC主号:
    专利说明:

    sulphonic acids or superacids use methanesulphonic trifrthrmethanesulphonic, AND -toluenesulphonic, perchloric acids or a complex of fluorocarbonate and tetrafluoride with urine.
    4. The method according to claim 1, about tl and h and roll; and with the fact that zinc or tin halide or boron trifluoride is used as Lewis acid,
    5. The method according to claim 4. characterized by the fact that zinc chloride, zinc bromide, tin chloride or tin bromide are used as zinc or tin halides.
    6
    one
    6. The POP.1 method, characterized in that a complex compound of boron trifluoride with CO-CA dialkyl ether, acetic acid or phenol is used as the complex compound of Lewis acid.
    7. The method according to paragraphs. 1-6, characterized in that nitrile, nitroalkane, organic carboxylic acid, ketone, ether or sulfolane are used as the organic solvent.
    This invention relates to an improved method for producing cephalosporin antibiotics, namely, derivatives of 3-substituted thiomethyl cephalosporins of the formula RI S - -lfs, .CHpS-R2, OT COOH where R, is an amino group or a group of the formula in which R 3 is 2-hydroxyphenyl or 3.5 -di-tert-butyl-4-hydroxy-1; Rg is 1,2,3,4-tetrazolyl-5, unsubstituted or substituted in the position with 1 methyl, ethyl, carboxymethyl, carbamoylmethyl, sulfomethyl, 2-hydroxyethyl, 2-aminoethyl or phenyl, 1,3,4-thiadiazolyl free or substituted in position 5 by methyl, 1,2, 3-triazolyl-5-benzoxazolyl-2, benzimidazolyl-2 2-methyl-2,5-DIGIDRO-5-OK. CO-6-OXI-as-triazin-3-yl , propyl, phenyl, carboxymethyl or ethoxycarbonylmethyl, or their ethyl or diphenyl ethyl ethers, or their salts, which have bactericidal properties. The closest to the proposed technical essence and achievable result is the method of obtaining derivatives of 3-substituted thiomethyl cephalosporins or their esters, or their salts, which is correspondingly substituted in the position of 73-acetoxymethyl-3-cephem-4- carboxylic acid or its ester, or its salt, is subjected to interaction with the corresponding thiol or its salt in an aqueous medium or in an aqueous organic solvent when establishing a pH from 6 to 7 and at a temperature of from -20 to l. The disadvantage of this method is the low yield of the target product, amounting to 30-50%. The aim of the invention is to increase the yield of the target product. This goal is achieved by a process for the preparation of derivatives of the 3-substituted thiomethyl cephalosporins of the formula I or their ethyl or diphenylmethylated ethers or their salts, which is a compound of the formula v-D. where R (has the indicated values of j Y is the radical - g or - g or its corresponding (the ester, or its salt, is subjected to interaction with thiolsm: Rormula R2 -., (IG)
    where RO has the indicated values, with its salt in an anhydrous organic solvent at a temperature of from -20 to in the presence of a proton acid, a Lewis acid or a complex compound of a Lewis acid.
    Pyrophosphoric, sulfuric, chlorosulfuric, fluorosulfuric monosulfonic acid or superacid is preferably used as proton acid.
    Methane sulfonic, trifluoromethanesulfonic G-toluol with ulfonic acid, perchloric acid or complex of fluorosulfuric acid and pentachloride antimony are used as monosulfonic acid or superacid.
    Zinc halide or boron trifluoride is used as Lewis acid.
    Zinc chloride, zinc chloride, zinc bromide, tin chloride or tin bromide are used as zinc or tin halide.
    A complex compound of boron trifluoride with C2-C dialkyl ether, acetic acid or phenol is used as a complex compound of a Lewis acid.
    Solvents which do not adversely affect the reaction, but preferably nitriles, nitroalkanes, organic carboxylic acids, ketones, ethers or sulfolanes are used as organic solvents.
    These solvents may be used in a mixture of two or more. These nitriles include, for example, aliphatic nitriles, aliphatic dinitriles, apo. .aticheskie geterodaklicheskie nitriles and nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile, valeronitrile, isovaleronitrile, capronitrile, enantonitril, kaprilonitril pelargononitril, kaprinitril, moles nonitril, lauronitrile, palmitonitril, stearonitril, acrylonitrile, malononitrile, succinonitrile, glutaronitrile, adiponitrile, benzonitrile, tolunitrile , cinnamonitrile, naphtonitrile, cyanothiophene. Nitroalkanes include nitromethane, nitroethane, nitropropane, nitrobutane, nitropentane, nitrohexane, nitroheptane, nitroooctane.
    Organic carboxylic acids include aliphatic saturated monocarboxylic acids and aliphatic saturated dicarboxylic acid.
    lots, for example, formic acid, acetic acid, propionic acid, lactic acid, isomolic acid, varianoic acid, isovaleric acid, pivalic acid, trifluoroacetic acid.
    The ketones include aliphatic saturated ketones, aliphatic nenasschennye ketones, alicyclic ketones, aromatic ketones and heterocyclic ketones such as acetone, ethyl methyl ketone, methyl propyl, izopropilmetilketon, butyl methyl ketone, isobutyl, diethyl ketone, diizopropilketon, mezitioloksid, metilgeptenon, piklobutanon, cyclopentanone, cyclohexanone, acetophenone, propiophenone , butyrophenone, valerophenone, dibenzylketone, acetothienone, 2-acetofuranone. Ethers include aliphatic naphtsennye ethers, aromatic ethers and cyclic ethers, for example, diethyl ether, diisopropyl ether, dibutyl ether,
    0 diisobutyl ether, methyl ethyl ether, methyl propyl ether, methyl isopropyl ether, methyl butyl ether, methyl isobutyl ether, ethyl propyl ether, ethyl isopropyl ether,
    5 ethyl butyl ether, ethyl isobutyl ether, ethylene glycol dimethyl ether, diallyl ether, methyl lily ether, ethyl lillyl ether, anisole, phenetol, dibenzyl ether,
    0 phenylbenzyl ether, tetrahydrofuran, tetrahydropyran, dioxane.
    Organic solvent, used according to the proposed method, can form a complex
    5 with the specified Lewis acid. This one. the complex can also be used as an organic solvent.
    The amount of proton acid, Lewis acid or Lewis acid complex compound used can be at least one mole per mole of a compound of general formula II, or its derivative with a carboxyl group, or its salt, and preferably at least two moles, in particular 2-10 mole, one mole last.  If a complex compound is used, it can also be used as a solvent, but a mixture of two or more complex compounds can be used.  It is desirable to vary the amount of proton acid, Lewis acid or complex compound of Lewis acids in order to regulate the rate of peaKijjiH depending on the type of solvent used and the thiol or its salt.  The amount of thiol used of the general formula III or its salt should be at least one mole per mole of the compound of the general formula II or its carboxyl group derivative, or its salt, and preferably 1-1.5 mole per mole of the latter.  If a compound containing XY, denoting SO, is used as the starting material, it is preferable to use a thiol or its salt in an amount of 2-3 mol per mole of the starting material.  When using a chemically stable compound of formula II containing 1 Y, equal to G S - O, S is reduced by the presence of a proton acid, Lewis acid or Lewis acid complex compound, resulting in a compound in which Y stands for. output of the target product to 94%, and, in addition, to increase the purity of the target product in connection with the elimination of water and thus eliminate the contamination of the target product with unreacted initial products ktami and decomposition products.  Example 1  2.72 g of 7-aminocephalosporanic acid and 1.16 g of 5-mercapto-1-metsh1-1H-tetrazole are suspended in 14 ml of anhydrous acetonitrile, then 4.26 g of boron trifluoride-diethyl ether complex is added to the resulting suspension. turning the suspension into solution.  This solution is allowed to react at 50 ° C for 2 hours. After the reaction is completed, 14 m of water is added to cool the reaction solution.  Then, 28% ammonia water was added to the solution while cooling with ice to adjust the pH of the solution to A, 0.  The precipitated crystals are separated by filtration, then washed with 5 ml of water and 5 ml of acetone in the specified order, after which they are dried and 3.00 g (yield 91.5%) of 7-amino-3-5-5 (1-methyl -1,2,3,4-tetrazolsh1) thiomesht - D-cefem-4-carboxylic acid, t. square  224-226 ° C (decomp. ).  IR (KBG), cm: 92, 1610, 1520.  NMR (SchO +, M. D. : 3.58 j (2H, S,); 3.84 (3N, S, N-CH), 4.09 (2H, S,); 4.91 (1H, dD 5cps, Cg-H), 5.05 (1H, dJ 5 cp, C7-H).  Found,%: C 36.54; H 3.65; N 25.21.   C, 36.59; H 3.69; Calculated,% N 25.61 If to replace the boron trifluoride complex - DIESEL ester with other boron trifluoride complexes, the results presented in Tael are obtained. one.  If acetonitrile is replaced by propionitrile, the yield is 87.8%.  If you replace acetonitrile with sulfolane, the yield reaches 90.5% when carrying out the reaction at 20 ° C for 10 hours  If to the reaction solution obtained in Example 1, while cooling with ice, add 1.25 ml 12 n.  hydrochloric acid and stirring is continued for 2 hours, then the crystals are separated by filtration, washed twice with 5 ml portions of acetone and dried, this will yield 3.20 g (yield 88.0%) of hydrochloric 7-amino-3-5- (1- methyl-1,2,3,4-tetrazolyl) -thiomethyl-L-cephem-4-carboxylic acid, t. P.  184-186 ° C (decomp. ).  IR (KBr), cm-: 1770.1710, NMR (+ CF ,, C02D) corresponds to the standard sample.  Found,%: C 32.41; H 3.57, N 22.71.   C10 H, Calculated,%: C, 32.91; H 3.59; N 23.03.  Example 2, B 11 ml of acetonitrile are suspended with 1.1 g of 7-aminocephalosporanic acid and 0.72 g of 5-mercapto-1-phenyl-1H-tetrasol, then 1.7 g of boron trifluoride-d-ethyl ester is added turning the resulting suspension into solution.  The solution is heated at for 1 h, then treated as described in example 1, and obtain 1.3 g (yield 82.4%) of 7-amino-3 - 5- (1-phenyl-1,2,3, 4-tetrazolyl) thiomethyl-L-cephem-4-carboxylic acid.  IR (KBr), cm-: 1800 (-lactam), 1610, 1530 (carboxylate), 1500 (phenyl).  NMR (+), M. D. : 3.75 (2H, S,); 4.61, 4.35 (2H, 14 cps,); 5.20 (2H, m, Cj-H,), 7.58 (5H, S, phenyl).  Found,%: C 46.74; H 3.62; N 21.40.  C | 5H, Calculated,%: C 46.16; H 3.62; N 21.53.  Example H. 544 g of 7-aminocephalosporanic acid and 3.00 g of 2-mercaptobenzoxazole are suspended in B 54 mA of acetonitrile, then 8.52 g of boron trifluoride-diethyl ether complex is added to convert the suspension into solution.  The resulting solution was heated at 60 ° C for one hour to proceed. The resulting reaction solution was treated in the same manner as in Example 1 and 6.80 g (yield: 81.1%) 7-amino-3- 2- (benzoxazole 1) thiomegyl - L-cephem-4-carboxylic acid t. square  210-212 ° C (decomp. ).  IR (KBG), CM: -i) c, o 1790, 1600 1495.  NMR (DqO +), M. D. : 3.83 (2H, S,): 4.64 (2H, S, 5.25 (2H, t, Cr-H, Sat-H); 7.53 (4H ha, ::).  Example 4  2.72 g of 7-aminocephalosporanic acid and 1.16 5-mercapto-1-methyl-1H-tetrazole are suspended in 2 ml of acetic acid, then 4.26 g of boron trifluoride-diethyl ether complex is added to the suspension thief.  This solution is heated at 50 for two hours.  At the end of the reaction, the solvent was removed by distillation under reduced pressure. 16 ml of acetone and 16 ml of water were added to the residue to dissolve the residue.  The resulting solution is cooled with ice and the pH is adjusted to 4.0 by the addition of 28% ammonia water.  The precipitated crystals are separated by filtration, washed with 5 ml of water, then 5 ml of acetone, dried, and I get 2.80 g (yield 85.5%) of 7-amino-3-5- (1-methyl-1,2,3,4 tetrazolyl) thiomethyl - & cepheme-4-carboxylic acid.  If acetic acid is replaced by nitromethane (in Example 1), the yield is 82.5%.  If you replace the complex boron TRIFLUORIDE - diethyl ether other complexes of boron TRIFLUORIDE (example 1) get the results presented in table. 2  Example 5  2.72 g of 7-aminocephalosporanic acid and 1.33 g of 2-methyl-5-mercapto-1,3,4-thiadiazole are suspended in 27 ml of acetic acid, and to the resulting suspension 9.64 g of boron ethyl ester trifluoride complex is added. turning the suspension into solution.  This solution is heated at 55 ° C for 30 minutes to proceed, then treated as in Example 4, and 2.96 g (yield: 86.1%) of 7-amino-3- 2- (5-methyl-1 , 3,4-thiazapyl) thiomethyl 11th cephem-4-carboxylic acid, m. square  199-200 ° C (decomp. ).  IR (KBG), cm-: 1790, 1610, 1520.  NMR (+), M. D. : 3.88 (zn, S, -sn), 3.75 (2n, S,); 4.33, 4.61 (2H, ABq3 I4cp9), 5.20 (2H, m, Cb-H, Cf-H).  Found,%: C 37.80; H 3.41; N, 15.7 C ,,, S, Calculated,%: C, 38.38; H 3.51; N 16.28.  Example 6  2.72 g of 7-aminocephalch are suspended in 27 ml of acetic acid. of spororanic acid and 1.00 g of 5-mercapto-1,2,3-triazole, then 9.64 g of boron diethyl ether trifluoride complex is added to the resulting suspension to convert the suspension into solution.  This solution is heated at 55 ° C for 30 minutes to proceed, then it is treated in the same manner as in Example 4, and 2.56 g (yield: 82.1%) of 7-amino-3- 5- (1, 2,3-triazolyl) thiomesh1-st cephhem-4carboxylic acid, m. square  209 C (decomp. ).  IR (KBG), cm-1: s 1800, 1610, 1520.  NMR (+), M. D. : 5, 79-4.45 (4H, m,, 5.15 (1H, dJ 5cp9.  ), 5.28 (IH, dJ 5cp5,) H, 28 (1H, S C-H B.  triazolyl group).  Example 7  1.0 g of 7-aminocephalosporanic acid and 0.55 g of 2-mercaptobenzimidazole are suspended in acetic acid B5mp, then 2.0 boron trifluoride-diethyl ether complex is added to the suspension to dissolve the solution.  This solution is heated at 50 ° C for two hours to proceed, then treated in the same manner as in Example 4, and 1.0 g (yield 75.2%) is obtained with 7-amo-3-2- (benzimidazolyl) thiomesh1 - D-cephem-D-carboxylic acid, m. square  230 C or more.  IR (KVG), cmH 1800 1600 1530.  . NMR (+ СРзСО В), M. D. : 3.93 (2H, g, Cr-H2); 4.76, 4.44 (2H, -ABq 3 12cps); 5.20-5.3 (2H, t, Cg, -H), 7.65 (4H, ha, phenyl).  Example 8  VOm of acetic acid is suspended with 1.10 g of 7-amino cephalosporanic acid and 0.305 g of propanethiol, then 2.0 ml of boron trifluoride-acetic acid complex is added to the suspension (the BF content is approximately 40 wt.  specific gravity 1.351) to convert 616 to solution.  This solution is heated at 50 ° C for one hour to proceed, then treated as in Example 4, to give 0.98 g (yield 84.3%) of 7-amino-3-propylthiomethyl-cefem-4 -carboxylic acid, t. pl, 215 C or more IR (KVg), cm-: 95 1520.  NMR (D20 +), m d. : 0.95 (3N, tJ 7cr5 -CH2CH CH); 1.59 (2H, t, -SNgSNgSN. ,) -, 2.52 (2H, ta 7cps, -СНгСНгСНр; 3.66 (2H, S Cr-Hg), 3.77 (2H, S, C3-СНg); 5.10 (1H, dJ, Sat -H), 5.27 (1H, dJ, CT-H).  Found,%: C 44.79; H 5.27; N 9.55.  C ,,, S2 Calculated,%: C 45.83; H 5.60; N 9.72.  PRI me 9.  The experiment was repeated according to the procedure described in Example 8, with the exception that 0.44 g of thiophenol was used instead of propanethiol, and 1.08 g (83.1% yield) of 7-amino-3-fem | lithiomethyl-d-cephem-4-carboxylic acid, t. square  235 ° C and more.  IR (KBG),, 1610, 1520.  NMR (D20 +), m d. : 3.52 (2H, S,); 4.35, 3.79 (2H, ABa, C-CH); 5.01 (2H, t,); 7.30 (5H, phenyl).  Found,%: C 52.20 g, H 4.36; N 8.60.  C, H, Calculated,%: C 52.17, H 4.38, N 8.69.  Example 10  4.81 g of p-toluenesulfonic acid salt and 7-aminocephalosporanic acid dihydrate and 1.16 g of 5-mercapto-1-methyl-1H-tetrazole are suspended in 50 ml of acetic acid, then 7.10 g of boron trifluoride complex is added to the suspension obtained diethyl ether to convert the suspension into solution.  This solution is heated at 55 ° C for one hour, the reaction proceeds, then treated in the same manner as in Example 4, and 2.49 g (yield) of 77.3% is obtained, 7-amine-3 - 5- (1-methyl -1,2,3,4-tetra3 olyl) thiomethylJ- and -cephem-4-carboxylic acid, IR, NMR spectra, and the like. square  the resulting product is identical to the characteristics of the standard sample.  Example 11  5.80 g of (1K) -7-amino-3-ace oxide is suspended in 50 ml of anhydrous acetonitrile. toxymethyl-D-cephem-4-carboxylic acid and 4.66 g of 5-mercapto-1-methyl-1H-tetrazole, then 15.4 g of boron trifluoride-acetic acid complex (content of BF-40% by weight . %) to convert the suspension into solution.  This solution was allowed to react at 20 ° C for 12 hours, the resulting reaction solution was cooled with ice, and 50 ml of water was added thereto.  The pH of the solution was adjusted to 4.0 by adding 28% ammonia water.  The entered crystals are separated by filtration, washed with 5 ml of water, then with 5 ml of acetone, dried, and 5.28 g of crude crystals are obtained. The crude crystals are dissolved in a mixture of 25 ml of 2N.  hydrochloric acid and 25 ml of methanol and treated with charcoal, after which the pH of the solution was adjusted to 4.0 by addition of 28% ammonia water. The quenched crystals were filtered, washed, dried, and 5.05 g were obtained (yield 76.4 / d) 7-amino-3-W- (1-methyl-1,2,3,4-tetrazol1) thiomethyl} - d. cepheme-4-carboxylic acid.  IR, NMR spectra and t. square  This product is identical to the standard sample.  Example 12  B5,5 ml complex of boron trifluoride-acetic acid (BFj content approximately 40 weight. %; The specific gravity of 1.351) is dissolved in 1.1 g of 7-aminocephalosporanic acid and 0.46 g of 5-mercapto-1-methyl -1H-tetrazole, this solution is heated at 50 ° C for one hour to proceed.  Upon completion of the reaction, 5 ml of water and 5 ml of acetone are added to the resulting reaction solution and the pH of the solution is adjusted to 4.0 by adding 28% ammonia water while cooling with ice.  The supernatant crystals are separated by filtration, washed with 2 ml of water, then with 2 ml of acetone, dried and yielding 1.02 g (yield 76.7%) of 7-amino-3- 5- (1-methyl-1, 2.3, 4-tetrazolyl) -thiomethyl-cephem-4-carboxylic acid.  JK, NMR spectra and t. square  identical to standard specimens.  Example 13  0.47 g of salt of P-toluene sulfonic acid and ethyl 7-aminocephalosporanate and 0.12 g of 5-mercapto -1-methyl-1H-tetrazole are dissolved in B4.7mp of acetonyl, then 0.4 ml of the complex is added to the resulting solution boron trifluoride-acetic acid (content in F approximately 40 weight. %) and the resulting solution is allowed to react at room temperature for 7 hours.  The solvent was distilled off under reduced pressure, and 5 ml of methylene chloride and 5 ml of water were added to the resulting residue to dissolve the residue.  The pH of the resulting solution was then adjusted to 7.0 by adding sodium bicarbonate under ice cooling, the organic layer was separated, washed with water, then dried over anhydrous magnesium sulfate. A solution of 0.19 g of p-toluenesulfonic acid monohydrate was added to the organic layer thus obtained. in 1 ml of methanol, then the solvent is removed by distillation under reduced pressure.  Diethyl ether was added to the obtained residue, the insoluble part was separated by filtration, and 0.44 g (yield, 83.3%) of P-toluene sulphonic acid salt of ethyl 7-amino-3- 5- (1-methyl-1, 2,3, 4-tetrazolyl) thiomethyl -th cephem-4-cara bauxyl, t. square  115122 ° C (decomp. ).  IR (KBG), cm-: about 1790.1715.  NMR (SBSGz), M. D. : 1.23 (ЗН, t J Scps) -, 2.30 (ЗН, S, -СбН -СН)) -, 3.45 (2Н, S, С, -Н); 3.81 (3N, S,:; N-CH-J); 4.30, 4.04 (2H, ABqJ lOcps Cz-CH) -; 4.95 (2H, t, Sb-H); 7.01, 7.59 (4H, ABq J 8cps,:; CgH); 8.37 (2H, br, -mng).  Remark p 14.  B3.0 ml of acetonitrile is suspended with 0.30 g of P-toluenesulfonic acid salt of diphenylmethyl 7-aminocephalosporanate and 0.06 g of 5-mercapto-1-methyl-1H-tetrapazap, then 0.2 ml of boron trifluoride-diethyl ether is added to the resulting suspension (ud. weight 1.125) to convert the suspension to solution.  This solution was allowed to react at room temperature overnight.  The solvent was removed from the polluted reaction solution by distillation under reduced pressure, 2 ml of water and 2 ml of acetone were added to the resulting residue, and the resulting solution was stirred for 30 minutes while cooling with ice.  Then the pH of the solution was adjusted to 4.0 by adding 28% ammonia water, and the precipitated crystals were separated by filtration, washed with 3 ml of water, then 3 ml of acetone, dried, and obtained 0.13 g (yield 80.67 °) of 7-amino 3- 5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl - A cefem-4-carboxylic acid.  IR, NMR spectrum and t. square  This product is identical to the standard sample.  Example 15.  1.1 g of 7-aminocephalosporanic acid and 0.61 g of sodium salt of 1-ethyl-5-mercapto-1, 2, 3, 4-tetrazole are suspended in acetic acid B11 ml, then 1.7 g of boron trifluoride complex is added to the resulting suspension diethyl ether to convert the suspension into solution.  This solution was allowed to pea 1311 for two hours.  At the end of the reaction, the reaction solution was treated in the same manner as in Example 4, and 1.20 g (yield: 86.8%) of 7-amine-3-5 (1-ethyl-1, 2,3,4-tetra-oolyl) thiomethyl 3 was obtained. -A cephem-4-carboxylic acid, t. square  201 (different ).  IR (KBG), cm-: s: about 1785, 1610 1530.  NMR (D20 +), m d. : 1.55 (3H, t3 7crb, -CH2-CH); 3.81 (2H, S, Cg-Hj); 4.35 (2H, S,) 4.42 (2H, q; 3 7srv -CHj-CH), 5.15 (1H, dU 5cp5,); 5.28 (1H,, dl 5cps,), Example 16. 2.72 g of 6-aminocephalosporanic acid and 1.16 g of 5-mercapto 1-metsh1-1H-tetrazole are suspended in 14 ml of anhydrous acetonitrile, then 2.0 g of boron trifluoride is added to the suspension at -5 to 5 ° C. turning the suspension into solution.  the solution is heated at 30 ° C for one hour to react, after which it is treated in the same manner as in Example 1, and 3.08 g (yield 93.9%) of 7 amino-3 5- (1-mets1-152) are obtained , 3,4-tetrazolyl) thiomethyl-d-cephem-4-carboxylic acid, IR, H1P-1 spectra, etc. square  This product is identical to the standard sample.  Example 17 . 2.72 g of 7-aminocephalosperanic acid and 1.33 g of 2-methyl-5-mercapt o-1,3,4-thiadisol are suspended in 14 ml of nitromethane, then added to the suspension at a temperature from 0 to 3, 5 g boron trifluoride to convert the suspension into solution.  This solution was allowed to react at room temperature for two hours, then the resulting reaction solution was cooled and diluted with 15 ml of water, after which the pH of the solution was adjusted to 4.0 by adding 28% ammonia water while cooling with ice. The precipitated crystals separated by filtration, washed with 5 ml of water, then with 5 ml of acetone, dried after cheto and 2.97 g (yield: 86.3%) of 7-amino: -3-2- (5-methyl-1,3,4-thiadiazolyl) are obtained -t methylZ-A-cephem-4carboxylic acid IR ,.  NMR spectra The plate of this product is identical to the standard sample.  Example 18  Suspended in 30 ml of anhydrous acetonitrile, 10.0 with 7-aminocephalosporanic acid and 4.34 g of 2-mercapto-1,3,4-thiadiazole, 8.0 g of boron trifluoride and 50 MP of anhydrous acetonitrile are added to the cured suspension at a temperature of from O to to convert the suspension into solution.  This solution was allowed to react at 25 ° C for 2.5 hours, then treated in the same manner as in Example 1, and 10.7 g (yield 88.4%) of 7-amino-3-2- (1, 3,4-thiadiazolyl) thiomethyl 11th cephem-4-carboxylic acid, m. square  202-204 C (decomp. ).  IR (KBG), cm: -9c-about 1790, 1610, 1530.  NMR (DjO +), M. D. : 3.75 (2H, S, C2-H2); 4.37, 4.55 (2H, ABq,); 5.05-5.24 (2H, m,,); 9.40 (1H, S, N-N).  .   Example 19  According to the procedure described in Example 16, 2.72 g of 7-aminocephalosporanic acid is reacted with 1.60 g of 5-mercapto-1-carboxymethyl-1, 2,3,4-tetrazole.  The resulting reaction solution was treated in the same manner as in Example 18, and 3.1 g (yield: 83.3%) of 7-amino-3- 5- (1-carboxy methyl-1,2,3,4-tetrazolyl) thiomethyl was obtained. - d-cephem-4carboxylic acid, t. square  183C (decomp. ).  IR (KBG), CMS 1800.1735, 1615, 1520.  .  NMR (+ SR: ZSOOO), M. D. : 3.76 (2H, S, Cr-H), 4.41 (2H, S, Cj-CH), 5.22, (1H, d, - 6cp5,); 5.24 (W, d,} 6cp5,); 5.35 (2H, Example 20.  Vlm of anhydrous acetonitrile is suspended 1.0 g of 7-aminocephalosporano g 5-mercapto-1-carb. amoylmethyl-1H-tetrazole, then to the suspension obtained, at 0-5 C, 5 ml of acetonitrile containing O, 80 T of boron trifluoride, to convert the suspension into solution.  This solution was allowed to react at 25 ° C for 2.5 hours, then it was treated in the same manner as in Example 1, and 1.25 g (yield 91.9%) of 7-amio-3-5- (1- carbamoylmethyl-1, 2,3,4 -tetrazolyl) thiomethyl th cefem-A-carboxylic acid, t. square  189190, (decomp. ).  IR (KBG) ,. cm-1790, 1680 1610, 1530, NMR (DjO +), M. D. : 3.73 (2H, S, Gj-H-j), 4.28, 4.37 (2H, AB L 14cp5, C-CH-g); 5.03-5.23 (4H, t, N-CH2-COH2,, St-H).  In the procedure described, 0.48 g of 7-aminocephalosporanic acid is reacted with 0.26 5-mercapto-1-hydroxyethyl-1H-tetrazole to obtain 0.56 g (yield 88.9%) of 7-amino-3-5. - 1- (2-hydroxyethyl) -1,2,3, -tetrazolyl-3-thiomethyl-y-cephem-4carboxylic acid, t. square  190-192 (decomp. ). .  IR (KBG), cm-: 1795.1610, 1540.  NMR (D20 + CF, COOD), m d. : 3.89 (2H, S, C-2-H); 4.12 (2H, t 3 5cp5, -CHjOH) -, 4.48 (2H, S, Cz-CH2), - 4.67 (2H, tl 5cp5, -CH. - 5.30 (1H, d3 5cp5); 5.37 (1H, dD 5cp5, Su-H).  In the interaction of 0.5 g of 7-amine cephalosporanic acid with 0.15 g of 5-mercapto-1,2,3,4-1H-tetrazole, 0.35 g (yield 77.4%) of 7-amine-3- |. 5- (1, 2,3,4-tetrazolyl) thiomethyl J -th cephem-4-carboxylic acid.  1800, 161 IR (KBG), cm1525.  NMR (+), M. D. : 3.80 (2H, S,); 4.35 (2H, ABq: lOcps C5-CH2); 5.19-5.24 (2H, m, s, -n).  PR, and measure 21.  According to the method described in Example 16, 5.4 g of 7-aminocephalosporanic acid is reacted with 2.4 g of ethyl thioglycolate.  The resulting reaction solution was worked up as in Example 16, and it was prepared.  5.4 g (yield 82.2%) 7-amino-3- (ethoxycarbonylmethyl-1Tiomethyl) -D-cephem-4carboxylic acid, t. square  208-210 (decomp. ).  IR (KBG): 1800, 1715 1610, 1520.  NMR (+) m d:  1.29 (3n, tT 7cp9 -CHjCH,), 3.41 (2H, S, -OT2COOEt); 3.74 (2H, S, Cri-Hj); 3.85, 3.95 (2H, ABq 3 7cf Cj-CHj), 4.20 (2H, q} 7cp,,), 5.16 (lH, d5 5cp9,), 5.33 (1H, d3 5cp9 ,) According to the above procedure, 2.72 g of 7-aminocephalosporanic acid is reacted with 1.0 g of thioglycolic acid and 2.5 g (yield: 80.1%) of 7-amino-3- (carboxymethylthiomethyl) -L cephem-4-carboxylic acid, t. pl, 193196 0 (decomp. ), IR (KBG), cm-: 1775, 1695, 1610, 1510.  NMR (D-jO +), M. D. : 3.41 (2H, S,); 3.71 (2H, S, Cr-H); 3.59, 4.04 (2H, ABql 14); 5.10 (1H, dl 5cp9,), 5.25 (1H, d; 3 5, Su-H).  Example 22 Anhydrous acetonitrile is suspended in 0.5ML g of 7-aminocephalosporanic acid and 0.36 g of hydrochloric 5-mercapto-1- (aminoethyl) -1H-tetrazole, then 3.6 ml of acetonitrile are added to the suspension at 0–5 ° C containing 0.57 g of boron trifluoride to convert the suspension into solution.  This solution was allowed to react at 25 ° C for 2.5 hours, then processed, as in Example 1, and 0.56 g (78.8% yield) of 7-amino-3 {5-1- (2-Aminoethyl) -1,2,3,4-tetrazolyl thiomethylI-y-cefem-4-carboxylic acid, t. square  204-207 ° C (decomp. ), IR (KBG), cm 1610 1525.  NMR (+ CF3COOD), M. D. : 3.67 (2H, t3 6cp5,) -, 3.80 (2H, S, C2-Hi) -, 4.29, 4.31 (2H, ABql 14cp9,) -, 4.80 (2H, tl N NX BS N. ,: - - 2); 5, 1 3 (lH, d3 5cps, C. -H), 5.26 (1H, d: 5cp5, C. J-H).  Example 23  Acetic acid is suspended with 0.40 g of 7- (2-hydroxybenzylideneamino) cephalosporonate sodium 0.12 g. 5-mercapto-1-methyl-1H-tetrazole, then 0.70 g of boron trifluoride-acetic acid complex is added to the resulting suspension to convert the suspension into solution.  The solution is then allowed to react at room temperature for five hours. The solvent is removed by distillation under reduced pressure, and 5 ml of acetone and 5 ml of water are added to the residue to dissolve the residue.  The pH of the resulting solution was adjusted to 7.0 by gradually adding powdered sodium bicarbonate to the solution.  The precipitated crystals are separated by filtration, washed with 1 ml of water, then with 2 ml of acetone, drying, and 0.42 g (yield 92%) of 7- (2-hydroxybenzylideneamino) is obtained (1-methyl -1,2,3,4-tetrazol1) Thiomethyl -U-cephem-4-sodium carboxylate.  IR (KBG), CM-: 1760, 1625, 1595.  NMR (dg-DMSO +), M. D. : 3.75 (2H, S,) -, 3.95 (zn, S, ;;: N-CH 4.1-4.40 (2H, t,); 5.27 (1H, d, Cg- H); 5.50 (1H, d, Sat-H); 6.857, 57 (4H, t, aromatic proton), 8.18 (1H, S,).  When replacing the boron trifluoride-acetic acid complex with other boron trifluoride complexes, the following results were obtained: boron trifluoride-diethyl ether complex — yield 93.0% boron-butyl trifluoride complex, ether — output 89.0%.   In a liquid mixture of 3 ml 4 n.  hydrochloric acid and 3 ml of diethyl ether are stirred for 1 h. 0.39 g of 7- (2-hydroxybenzylideneamino) (1-methyl-1,2,3,4-tetrazolyl) thiomethyl-U-cefem-4-carboxanate on three .  Then the aqueous layer is separated and washed twice with 3 ml portions of diethyl ether, after which concentrated ammonia water is added while cooling with ice to bring the pH of the aqueous layer to 3.7.  The precipitated crystals were separated by filtration, washed with water, and dried, and 0.23 g (yield, 83.1%) of 7-amino-3- 5- (1-mets-1, 1.2, 3, -tetrazolyl) thiomethyl-ff- cephem-4carboxylic acid.  T. PC. The IR and NMR spectra of this product are identical to those of a standard sample.  I Example 24.  To a mixture of 0.40 g of 7-2-hydroxybenzylidene sodium) cephalosporanate, 0.12 g of 5-mercapto-1-methyl-1, 2,3,4-tetrazole and 5 ml of acetonitrile are added 0.2 g when cooled with ice.  The resulting mixture was allowed to react at coat temperature for one hour, after which the solvent was distilled off under reduced pressure.  5 ml of water and 5 ml of acetone are added to the resulting 618 tantum to dissolve the residue, then sodium bicarbonate is added to the resulting solution to adjust the pH to 7.0.  The precipitated crystals were separated by filtration, washed with 1 ml of water and then with 2 ml of acetone, dried, and 0.43 g (yield, 94.3%) of 7- (2-hydroxybenzylideneamino) was obtained (1-methyl-1, 2, 3, 4- tetrazolyl) thiomethyl -U-cephem-4-sodium carboxylate.  Example 25  B2 ml of acetonitrile dissolved 0.44 g of ethyl 7- (3,5-di-tert-butyl-4-hydroxybenzylideneamino) cephalosporanate and 0.10 g of 5-mercapto-1-methyl-1H-tetrazole.  To the resulting solution was added 1.0 g of a solution of boron trifluoride in acetoxy nitrile (0.1718 g / g) under ice-cooling, and the mixture was stirred at room temperature for four hours.  At the end of the reaction, the solvent was distilled off under reduced pressure, and 10 ml of ethyl acetate and a solution of 0.13 g of g-toluene sulfonic acid monohydrate in 5 MP water were added to the residue to dissolve the residue, and the resulting solution was stirred for 30 minutes under ice cooling .  The aqueous layer was separated and 5 ml of ethyl acetate was added thereto, after which the pH of the solution was adjusted to 7.0 by the addition of sodium bicarbonate.  Thereafter, the organic layer is separated, washed with water and saturated aqueous chlorine sodium in the listed order, dried over magnesium sulfate, then a solution of O, 1 g of monohydrate P-toluenesulfonic acid in 2 ml of ethyl acetate is added to the dried organic layer.  The solvent was distilled off under reduced pressure, and diethyl ether was added to the resulting residue, after which the mixture was filtered and 0.35 g (77.8% yield) of a finely ground salt of p-toluenesulfonic acid and ethyl 7-amino-3- 5- was obtained. (1-methyl-1, 2,3,4-tetrazolyl) thiometide -U-cephem-4-carboxylate, t. square  115122 ° C (decomp. ).  Example 26  Acetonitrile VZml is dissolved 0.65 g of diphenylmethyl-7- (3,5-DI-7 ret-butyl-4-hydroxybenzylideneamine) de-sposporanate and 0.12 g of 5-mercapto-1-methyl-; H-tetrazole, and to the resulting 1.2 g of a solution of boron trifluoride in acetonitrile (0.1718 g / g) is added to the solution.  The resulting mixture was stirred at 30 ° C for 30 minutes, after which the solvent was distilled off under reduced pressure. To the resulting residue are added 5 ml of water and 10 ml of ethyl acetate to dissolve the residue.  The aqueous layer was then separated and washed with 5 ml of ethyl acetate.  5 ml of acetone is added to this aqueous solution, after which the pH of the solution is adjusted to 4.0 by adding concentrated ammonia water while cooling with ice. The precipitated crystals are filtered, washed with 2 ml of water, then 5 ml of acetone, dried and receiving , 25 g (yield: 76.7%) 7-amino-3- | 5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl 3-th cephem-4-carboxylic acid.  Example 27  2.72 g of 7-amino phalosporanic acid and 1.16 g of 5-mercapto-1-methyl-1H-tetrazole are suspended in 27 ml of acetic acid, and 5.76 g of methanesulfonic acid is added to the resulting suspension to dissolve the suspension.  The resulting solution was allowed to react at 50 ° C for 2.5 hours.  After completion of the reaction, the reaction mixture is cooled and gradually added to 27 ml of water while cooling with ice.  The pH of the mixture was then adjusted to 4.0 by the addition of a 28% (by weight) aqueous solution of ammonia.  The precipitated crystals are separated by filtration, washed with 5 ml of water and 5 ml of acetone in the indicated order, dried, and 2.70 g (yield: 82.3%) of 7-amino-3-5- (1-methyl-1, 2, 3,4-tetrazopyl) thiomethyl-L-cephem-4-carboxylic acid, t. square  224-226 ° C (decomp. ).  IR (KBG), cm-: 1792, 1610.  1520.  NMR (+) m d. : 3.58 (2H, S, C2-H2); 3.84 (3N, S, N-CH3), 4.09 (2H, S,, 4.91 (1H, d, 3 5cps, Cg-H); 5.05 (1H, d, 3 5cps,) .  Found,%: C 36.47j H 3.72; N 25.21.  C, oHj N603Si Calculated,%: C 36.59; H 3.69, N 25.61.  The procedure described above is repeated except that the methanesulfonic acid is replaced by other acids to obtain the results presented in Table. 3  1 to the reaction mixture obtained after the end of the reaction is added an aqueous solution of ammonium acetate (0.77 g of ammonium acetate / 4 ml of water) and 3.3 ml of 12N.  hydrochloric acid.  The resulting mixture was stirred at 15 ° C for 2 hours, after which the precipitated crystals were separated by filtration, washed with two 5-ml portions of acetone, dried, and 2.44 g (yield 67.0%) of hydrochloric 7% was obtained. (1-methyl-1, 2,3,4-tetrazolyl) thiomethyl - y-cephem-4-carboxylic acid, t. square  184-186 ° C (decomp. ).  IR (KBG), 1770, 1710.  NMR (DjO +) are identical to standard samples.  Found,%: C 32.55; - H 3.48; N 22.73.  С | о «in% Oz5zSG Calculated,%: C 32.91; H 3.59; N 23.03.  At m e p 28.  In 80 ml 0.1 n.  0.54 g of 7-aminocephalosporanic acid and 0.25 g of 5-mercapto-1-methyl-1H-tetrazole are dissolved in a solution of perchloric acid and acetic acid, and the solution is allowed to react at 50-55 ° C for 2.5 h.  Upon completion of the reaction, the solvent is distilled off under reduced pressure.  The residue is dissolved in 10 ml of water.  A concentrated aqueous solution of ammonia was added dropwise to the aqueous solution while cooling with ice, then the pH of the solution was adjusted to 3.5, after which the solution was stirred for 15 minutes.  The precipitated crystals are separated by filtration, washed with 2 ml of water and 3 ml of methanol in this order, dried and obtain 0.53 g (yield 80.8%) of 7-amino-3-5- (1-megyl-1,2, 3,4-tetrazolyl) thiomethyl - {-cephem-4-carboxylic acid, t. square  224-226 C (decomp. ).  The IR and NMR spectra of the product are identical to those of a standard sample.  Example 29  B-13.5 ml of acetic acid dissolved 1.36 g of 7-aminocephalosporanic acid and 0.58 g of 5-mercapto-1-methyl-1H-tetrazole, and 3.9 g of anhydrous tin (IV) chloride was added to the resulting suspension to dissolve. The resulting solution was allowed to react for 1.5 hours, after which the solvent was distilled off under reduced pressure.  To the residue was added 10 ml of water, then a 28% (by weight) aqueous solution of ammonia was added to adjust the pH to 7.5 with ice-cooling.  The decayed crystals are filtered, washed with 5 ml of water and 5 ml of acetone in this order, dried, and 1.28 g (yield: 78.0%) of 7-amino-3-5- (1-methyl-1,2, 3, A-tetraeolyl) methyl} - y-cephem-4-carboxylic acid. Example 30.  Vosm acetic acid is suspended with 0.27 g of 7-aminocephalosporanic acid and 0.12 g of 5-mercapto-1-methyl-1H-tetrazole, and 1.36 g of anhydrous zinc chloride is added to the resulting suspension to form a solution.  The resulting solution was allowed to react at 50 ° C for 4 hours, then diluted with 3 ml of water.  The pH of the solution is adjusted to 3.8 by adding a 28% (by weight) aqueous solution of ammonia with ice cooling.  The resulting crystals are separated by filtration, washed with 2 ml of water and 1 ml of 0.1N.  hydrochloric acid, 2 ml of water and 1 ml of acetone in this order, then dried, and 0.26 g (yield: 79.2%) of 7-amino-3-W- (1-methyl-1,2,3, razolil) thiomethylZ-U-cephem-4-carboxylic acid.  IR, NMR spectra and t. square  The product is identical to the standard sample.  When replacing zinc chloride with 3.2 g of zinc bromide, the yield is 77.3%.  Example 31 1.56 g of 7-aminocephalosporanic acid and 0.58 g of 5-mercapto-1-methyl-1H-tetrazole are suspended in 15 ml of acetic acid, and 0.48 g of methanesulfonic acid is added to the resulting suspension to form a solution.  To the resulting solution was added 6j80 g of anhydrous zinc chloride, and the mixture was allowed to react for 4 hours.  At the end of the reaction, the reaction mixture was diluted with 15 ml of water, after which the pH of the reaction mixture was adjusted to 3.8 by adding a 28% (by weight) aqueous solution of ammonia while cooling with ice.  The precipitated crystals are separated by filtration, washed with 10 ml of 0.1 and.  hydrochloric acid, 10 ml of water and 5 ml of acetone in this order, then dried, and 1.35 g (yield: 82.3%) of Y-amino-3m (1-methyl-1,2,3,4-tetrazolyl ) thiomethyl -U-cephem-4-carboxylic acid.  IR, NMR spectra and t. square  The resulting product is identical to the standard sample.  Example 32  Acetic acid VSPR was suspended with 0.305 g of L-toluenesulfonic acid salt of diphenylmethyl 7-aminocephalosporanate and 0.058 g of 5-mercapto-1-methyl-1H-tetrazole, and 0.43 g of trifluoromethane acid 14 was added to the suspension to form a solution.  The resulting solution was allowed to react at 50 ° C for 1.5 hours, after which the solvent was distilled off under reduced pressure.  2.5 ml of water and 2.5 ml of acetone are added to the obtained residue and the mixture is stirred while cooling with ice for 30 minutes. Then a 28% (by weight) aqueous solution of ammonia is added to the mixture to bring the pH of the mixture to 4 , 0.  The crystals entered are separated by filtration, washed with 3 ml of water and 3 ml of acetone in this order, then dried to obtain 0.127 g (77.2% yield) of 7-amino-3-3 (1-methyl-1,2,3 , 4-tetrazolyl) thiomethyl3- & cephem-4-carboxylic acid.  IR, NMR spectra and t. square  The product is identical to the standard sample.  Example 33  0.796 g of 7- (2-hydroxybenzylideneamino) sodium cephalosporanate and 0.232 g of 5-mercapto-1-methyl-1H-tetrazole are suspended in 8 ml of acetic acid, and 1.80 g of trifluoromethanesulfonic acid is added to the resulting suspension to form a solution.  The resulting solution was allowed to react at room temperature for 3 hours.  Under ice cooling, 1 ml of water and 1.5 ml of 12 N are added to the reaction mixture.  hydrochloric acid and the resulting mixture is stirred at room temperature for 2 hours  The crystals are separated by filtration, washed twice with 1-ml portions of acetic acid and twice with 3-ml portions in the order of volume, then the residue is obtained and 0.503 g (yield 6xi, 0%) of hydrochloride 2311 of the native 7-amio-3- 5- is obtained. (1-methyl-1,2,3,4-tetrazolyl) thiomethyl - & cepheme-4-carboxylic acid.  IR, NMR spectra and t. square  The product is identical to the standard sample.  Example 34  In addition, 0.58 g of trifluoromethanesulfonic acid was gradually added dropwise to Wb, 8MP of acetonitrile, and 0.58 g of 5-mercapto-1-methyl-1H-tetrazol and 1.36 g of 7-aminocephalosporanic acid were added to the resulting solution in the indicated order to form a solution.  The resulting solution is heated to 30 ° C, at this temperature the reaction is carried out for 60 minutes, after which the reaction mixture is cooled with ice and gradually 5.7 ml of water is added to it.  The pH of the solution was adjusted to 3.9 by adding a 28% (by weight) aqueous solution of ammonia and the solution was stirred at the same temperature for 2 hours.  The precipitated crystals are separated by filtration, washed twice with 1-ml portions of water and twice with 1-ml portions of acetone in the indicated order, then dried and 1.50 g is obtained (yield 91.5%) with 7-amylo-3-5. - (1-methyl-1,2,3,4-tetrazolyl thiomethyl-D-cephem-4-carboxylic acid.  IR, NMR spectra and t. square  The product is identical to the standard sample.  The reaction described is carried out and 0 is added dropwise to the reaction mixture. 84 ml 12 n.  hydrochloric acid and 0.68 ml of water in this order while cooling with ice, after which the resulting mixture is stirred for 3 hours.  The precipitated crystals are separated by filtration, washed twice. 2 ml portions of acetonitrile and twice 3 ml portions of acetone in this order, then dried to obtain 1.64 g (yield 90.0%) of the hydrochloride salt of 7-amins-E-5- (1-methyl-1, 2,3,4-tetrazolyl) thiomethyl-y-cephem-4-carboxylic acid.  IR, NMR spectra and t. square  The product is identical to the standard sample.  If acetonitrile is replaced by proprionitrile, the yield is 88.4%.  If acetonitrile sulfonane is replaced, the yield is 89.6%.  If acetonitrile is replaced by nitromethane, the yield is 84.3%.  Example 35  2.72 g of 7-aminocephalosporanic acid and 1.16 g of 5-mercapto-1-methyl-1H-tetrazole are suspended in 27 ml of acetonitrile, and 9.75 g of concentrated sulfuric acid is gradually added to the resulting suspension while cooling with ice to form a solution.  The resulting solution was allowed to react for one hour, then the reaction mixture was cooled to 5c and gradually added to 60 ml of water while cooling with ice.  The pH of the solution was adjusted to 3.7 by adding a 28% (by weight) aqueous solution of ammonia, then another 30 MP of water was added.  The resulting solution is stirred at the same temperature for one hour.  The precipitated crystals were separated by filtration, washed twice with 15-ml portions of water and three times with 10-ml portions of acetone in that order, then dried and obtained 2.93 g (yield 89.3%) of 7-amino-3- 5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl - cephaem-4-carboxylic acid.  IR, NMR spectra and t. square  The product is identical to the standard sample.  I.  Example 36  Wb, 8ml acetonitrile. 1.36 g of 7-aminocephalosporanic acid is suspended and 0.60 g of 5-mercapto-1-methyl-1H-tetrazole is suspended, and 3.50 g of concentrated sulfuric acid is gradually added to the resulting mixture while cooling with ice to form a solution.  The resulting solution was allowed to react for 75 minutes, after which 1.7 ml of 12N was added dropwise to it.  hydrochloric acid and 2.0 ml of water in this order, maintaining the same temperature.  The mixture was cooled before and left at 10-15 ° for 2.5 hours to precipitate crystals.  The decayed crystals are filtered, washed twice with 5 ml portions of acetonitrile and twice with 5 ml portions of acetone in this order, then dried to obtain 1.51 g (yield 83.0%) of 7-amino-hydrochloride. 5- (1 methyl-1,2,3,4-tetrazol1) thio251 methyl 3-L-cefem-4-carboxylic acid.  IR, NMR spectra and t. square  The product is identical to the standard sample.  Example 37 1.36 g of 7-aminocephalosporanic acid and 0.58 g of 5-mercapto-1-methyl-1H-tetrazole are suspended in 10 ml of acetic acid, then 6.6 g of tin (IV) bromide is added to the resulting suspension to form a solution.  The resulting solution was allowed to react at 50 ° C for two hours.  The reaction mixture is diluted with 10 ml of water, then a 28% (by weight) aqueous solution of ammonia is added under ice-cooling to adjust the pH of the solution to 3.8.  The crystals entered are separated by filtration and dissolved in 10 ml of a 50% (by weight) aqueous solution of methanol with the addition of a 28% (by weight) aqueous solution of ammonia.  A small amount of the undissolved substances was separated by filtration, after which the pH of the solution was adjusted to 3.8 with the addition of 6N.  hydrochloric acid. The precipitated crystals are filtered off, washed twice with 5 ml portions of water and twice with 5 milliliters. in portions of acetone in this order, then dried to obtain 1.28 g (yield: 78.2%) of 7-amino-3- 5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl -cephem-4-carboxylic acid.  Example 38  1.36 g of 7-aminocephalosporanic acid and 0.60 g of 5-mercapto-1-methyl-1H-tetrazole are suspended in 10 ml of acetic acid, then 8.9 g of pyrophosphoric acid is added to the suspension, after which the mixture is left to react at 45-50 C for 10 hours  At the end of the reaction, the reaction mixture was poured into 10 ml of an ice-water mixture and the pH of the mixture was adjusted to 3.8 by adding 28% (by weight) aqueous solution of ammonia.  The precipitated crystals are separated by filtration, washed twice with 5-ml portions of water and twice with 5-ml portions of acetone in this order, then added, and 1.17 g (70.9% yield) of 7-amino-3- is obtained. G5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl-L-cefem-4-carboxylic acid.  Example 39  B7.0 ml of acetic acid is suspended with 1.35 g of 7-aminocephalosporanic acid and 0.60 g of 5-mercapto-1-methyl-1H-tetrazole, then 0.93 ml of 100% magic acid ( fluororic acid: antimony pentafluoride mol / mol), after which the mixture is left to react at 3 hours.  Upon completion of the reaction, the reaction mixture was drunk in 35 ml of ice-water and the pH of the resulting solution was adjusted to 3.7 with a concentrated aqueous solution of ammonia, after which the solution was stirred for one hour while cooling with ice.  The precipitated crystals are separated by filtration, washed with 10 ml of water and 10 ml of acetone in this order, then dried to obtain 1.34 g (yield 82.0%) of 7-amino-3-5- (1-methyl-1,2 , 3,4-tetrazolyl) thiomethyl -1-cephem-4-carboxylic acid.  Example 40  BG ml of anhydrous acetonitrile suspended 0.29 g of (1R) 7-amino-3-acetoxymethyl-L-cefem-4-carboxylic acid-1-oxide and 0.38 g of 5-mercapto-1-methyl-1H-tetrazole, and while cooling with ice, 0.98 g (0.53 ml) of concentrated sulfuric acid is added to the suspension to turn the suspension into solution.  The reaction is carried out for one hour, and then the reaction mixture is cooled with ice, and then added to 6 ml of water at 5-10 ° C, after which the pH of the resulting mixture is adjusted to 3.5 with 28% aqueous ammonia.  The precipitated crystals are collected by filtration, and then washed with two portions of 1.5 ml of water and two portions of 1 ml of acetone in the specified order, and then dried to obtain 0.25 g (yield 76.2%) of 7-amino -3 -5- (1-methyl-1,2,3, 4-tetrazalyl) thio-methyl-6-cephem-4-carboxylic acid.  T. square  224226 ° С (with decomp).  IR spectrum (KBG): 1792, 1610, 1520.  NMR (D; 0 -f CF,), per million: 3.58 (2H, S,), 3. 84 (3N, S, N-CH,), 4.09 (2H, s, Cz-CH2), 4.91 (1H, d, 1 5 Hz,), 5.05 (1H, a 5 Hz, ).  Example 41  100 mg of 7-aminocephalosporanic acid and 100 mg of 1-sulfonatomethyl-1, 2,3,4-tetrazol-5-thiolate dipotassium salt are suspended in 5 ml of acetonitrile and added to a suspension of 0.2 ml of boron trifluoride ethereal, after which the resulting mixture is kept for 3 hours at 30 ° C.  After completion of the reaction, the solvent was distilled off in vacuo, and the residue thus obtained was dissolved in 10 ml of ethanol.  0.12 ml of pyridine was added to the resulting solution and the precipitated crystals were filtered off.  The crystals thus obtained are washed with 2 ml of ethanol and 5 ml of acetone in this order, after which they are dried to obtain 150 mg of the potassium salt of 7-amino-3- 5- (sulfonatomethyl-1,2,3,4-tetrazolyl) thiomethyl -U .  -cepheme-4-carboxylic acid having t. pp  230240 ° C (with decomp. ).  The potassium salt of 7-amino-3- 5- (1-sulfonatomethyl-1,2,3,4-tetra-zolyl) -thiomethyl -th cephem-4-carboxylic acid thus obtained is dissolved in 3 ml of saturated sodium bicarbonate , and the resulting solution is passed through a column filled with 50 cm of an ion exchange resin (Amberlite IL-120). The resulting solution is concentrated to dryness under reduced pressure,
    Acetic acid complex
    Phenol complex.
    Complex di-N-butyl ether
    Acetic acid complex
    Table 1
    50 ° C, 2 h
    82.5
    50 C, 2 h
    77.5
    50 C, 2 h
    88.7
    , 8 hours, 90.5 parts of 7-amino-3- 5- (1-sulfomethyl-1, 2,3,4-tetrazolyl) -thiomethyl-L-cefem-4-carboxylic acid. Mp 205-215 ° C (with decomp.). IR spectrum (KBG), 1780, 1720. Example 42. 0.54 g of 7-aminocephalosporanic acid and 0.35 g of 2.5-dinitro-6-hydroxy-3-mercapto-5-oxo are suspended in 4 ml of anhydrous acetonitrile asym-triazine and to the resulting suspension was added 1.3 ml of boron trifluoride etherate. This solution is held for 3.5 hours at 30-3-5 ° C. After completion of the reaction, the reaction solution is cooled and 3 ml of water are added under ice-cooling to adjust the pH to 3.5. The crystals precipitated are filtered and then washed with 2 ml of water and acetone in this order, after which they are dried to obtain 0.64 g (yield 86.5%) of 7-amino-3- (2,5-dihydro-6-6xy-2 -methyl-5-oxo-asym-triazin-3-yl) -thiomethyl - & -cephem-4-carboxylic acid, having so pl. 190 C or higher. IR spectrum (KVg),: 1800, 1720, 1640, 1615, 1340. NMR (DgO +), ppm: 3.72 (3N, S, CH); 3.84 (2H, S,); 4.27, 4.62 (2H, ABq, J 15 Hz,), 5.20-5.35 (2H, t,,).
    Type of complex
    Acetic acid complex
    KmimieKC phenol
    Complex di-N-buti .34 lovogo ether
    Concentrated
    6.57 chamois
    Trifluoromethanesulfonic Table 2
    6.0
    84.7
    1.5
    84.5
    50
    权利要求:
    Claims (7)
    [1]
    1. The method of obtaining derivatives of 3-substituted thiomethylcephalosporins of the formula buty or substituted in position
    5 methyl, 1,2,3-triazolyl-5, benzoxazolyl-2, benzimidazolyl-2, 2-methyl-2,5-dihydro-5-oxo-6-hydroxy-as-triazin-3-ip, propyl, phenyl , carboxymethyl or ethoxycarbonylmethyl, or ethyl, or diphenylmethyl ester, or salts thereof by reacting a compound of formula CH 3 OCOCH r COOH wherein R | has the specified values;
    Y is the ^ - radical - S - or - S -.
    or its corresponding ester, or its thiol salt of the formula Q l
    Rg - SH, where Rg has the indicated meanings, or with its salt in an organic solvent at a temperature of from -20 to 80 ° C, characterized in that, with the aim of increasing where R | an amino group or a group of the formula
    R 3 —CH = N “wherein R 3 is 2-hydroxyphenyl or
    3,5-di-tert-butyl-4-hydroxyphenyl;
    Rg - 1,2,3,4-tetrazolyl-5, free or substituted at position 1 with methyl, ethyl, carboxymethyl, carbamoylmethyl, sulfomethyl, 2oxyethyl, 2-aminoethyl or phenyl, 1,3,4-hyadiazolyl-2, swonium yield the target product * use an anhydrous organic solvent and the process is carried out in the presence of protic acid, Lewis acid or a complex of Lewis acid.
    [2]
    2. The method according to claim 1, characterized. in that pyrophosphoric, sulfuric, chloro-sulfuric, fluoro-sulfuric, monosulfonic acid or superacid are used as protonic acid.
    SU,> 1105116
    [3]
    3. The method of pop. 2, distinguishing tout and s with the fact that methanesulfonic trifluoromethanesulfonic, 0-toluenesulfonic, perchloric acid or a complex of fluorosulfuric acid and antimony pentane are used as mono1105116 sulfonic acids or superacids.
    [4]
    4. The method according to claim 1, characterized in that zinc or tin halide or boron trifluoride is used as the Lewis acid.
    [5]
    5. The method according to claim 4, characterized in that zinc chloride, tin zinc chloride, zinc bromide tin chloride or tin bromide are used as zinc halide.
    [6]
    6. The method according to claim 1, characterized in that a complex compound of boron trifluoride with a simple dialkyl ether, acetic acid or phenol is used as the complex compound of the Lewis acid.
    [7]
    7. The method according to PP. 1-6, characterized in that the organic solvent used is nitrile, nitroalkane, organic carboxylic acid, ketone, ether or sulfolane.
    类似技术:
    公开号 | 公开日 | 专利标题
    SU1105116A3|1984-07-23|Method of obtaining derivatives of 3-substituted thiomethylcephalosporins or their salts
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    同族专利:
    公开号 | 公开日
    NL182146B|1987-08-17|
    BG49615A3|1991-12-16|
    CH641809A5|1984-03-15|
    HU179804B|1982-12-28|
    PL123459B1|1982-10-30|
    AR225289A1|1982-03-15|
    DE2926664A1|1980-01-24|
    FI74967B|1987-12-31|
    IN151439B|1983-04-23|
    FI74967C|1988-04-11|
    SE7905899L|1980-01-07|
    NO152653B|1985-07-22|
    FR2430423A1|1980-02-01|
    YU161879A|1982-10-31|
    CA1139744A|1983-01-18|
    IT1118889B|1986-03-03|
    JPS559048A|1980-01-22|
    DK160942B|1991-05-06|
    GR72517B|1983-11-16|
    PL216906A1|1980-04-21|
    GB2027429B|1982-12-08|
    BE877504A|1980-01-07|
    GB2027429A|1980-02-20|
    KE3424A|1984-08-10|
    NL7905246A|1980-01-08|
    MX5545E|1983-10-03|
    FR2430423B1|1983-05-13|
    DE2926664C2|1983-10-20|
    US4312986A|1982-01-26|
    HK8385A|1985-02-08|
    CS208116B2|1981-08-31|
    SE444935B|1986-05-20|
    JPS6027677B2|1985-06-29|
    NL182146C|1988-01-18|
    NZ190938A|1981-10-19|
    ES482252A1|1980-04-01|
    IT7949678D0|1979-07-06|
    ATA472779A|1981-10-15|
    AU515683B2|1981-04-16|
    YU42948B|1989-02-28|
    DD144778A5|1980-11-05|
    NO152653C|1985-10-30|
    DK160942C|1991-10-21|
    FI792117A|1980-01-07|
    EG14330A|1983-09-30|
    AU4839479A|1980-01-10|
    AT370107B|1983-03-10|
    RO78358A|1982-02-26|
    NO792237L|1980-01-08|
    DK284779A|1980-02-11|
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    KR100432425B1|2000-11-16|2004-05-22|씨제이 주식회사|Novel method for preparation of cephem derivatives or salts thereof|
    US7335767B2|2002-10-29|2008-02-26|Lupin Limited|Method for preparation of ceftiofur and salts thereof|
    US9212416B2|2009-08-07|2015-12-15|Swagelok Company|Low temperature carburization under soft vacuum|
    JP6257527B2|2012-01-20|2018-01-10|スウエイジロク・カンパニー|Simultaneous flow of activated gas in low-temperature carburizing.|
    CN106967091A|2017-05-13|2017-07-21|山西千岫制药有限公司|A kind of preparation method of Cefotiam parent nucleus|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP53082377A|JPS6027677B2|1978-07-06|1978-07-06|
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