• 专利附录
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  • 权利要求
  • 类似技术
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  • 引用文献
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    • 专利摘要:
    A process is described for preparing a 3-iodomethyl cephalosporin of the formula which comprisesreacting in an aprotic solvent under substantially anhydrous conditions at a temperature between about 0°C and about 35°C a 3-alkanoylmethyl or 3-carbamoyloxymethyl cephalosporin oftheformula with a trialkylsilyl iodide of the formula where in the above formulas R is the residue of a carboxylic acid as defined in the specification; Ro is hydrogen or methoxy; R1 is C1-C4 alkyl, 2,2,2-trichloroethyl, iodomethyl, diphenylmethyl, benzyl, substituted benzyl substituted by methyl, methoxy or nitro; or R is a trialkylsilyl group of the formula wherein R3, R3, and R- 3; are independentlyC1-C3alkyl; orR1 is sodium or potassium; R'1 has the same meanings as R1, provided that, when R is sodium, potasstum. diphenylmethyl, or p-methoxybenzyl, R'1 is R2 is C1-C4 alkanoyloxy or a carbamoyloxy group of the formula wherein R'2 and R"2 are independently hydrogen or C1-C3 alkyl; and nis 0 or 1; with the limitation that when n is 1, the double bond represented by the dotted bonding lines is in the 3-position. The 3-iodomethyl cephalosporins are useful intermediates for antibiotics.
    公开号:SU1069627A3
    申请号:SU813247948
    申请日:1981-02-19
    公开日:1984-01-23
    发明作者:Бонджоуклайан Розанне
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to methods for the preparation of 3-iodomethyl cephalosporins of the formula I Oak II egs-in COOR, where the dotted line indicates that the double bond can be in the position of 2,3- or 3,4-cephalosporin core; Ry - benzyl, phenoxymethyl, 2-tie. nilitoyl or syn- (2.-tritylaminothiazol-4-yl) methoxyiminomethyl, Ri is a hydrogen atom or methoxy group; RJ is C-C4 / alkyl, benzyl, 4-nitrobenzyl or trimethylsilyl, which are intermediate products in the synthesis of 3-substituted methylcephalosporins with pharmacological activity. There are no general methods for the preparation of 3-iodomethyl-L- and 3-iodomethyl-ig-cephalosporins, respectively, from L-cephalosporins. Usually, 3-iodomethyl-U-cephalospori is obtained through the intermediate preparation of 3-chloromethyl (or 3-bromomethyl) -O-cephalosporin SP. A method of producing 3-iodomethyl-D-cephalosporins is known, which concludes that 3-bromomethyl (or 3-chloromethyl) -1-cephalosporin is reacted with an alkali metal iodide in an inert solvent. The starting 3-bromomethyl (or 3-chloromethyl) -d-cephalosporin was obtained by reacting 3-hydroxymethyl-D-cephalosporin-5-oxide with the corresponding phosphorus halide while cooling in an inert organic solvent in the presence of a base, followed by reduction of the resulting product in the form of S-oxide L21. Thus, the method of producing 3-iodomethyl-l-cephalosporins is a three-stage process, and the product yield is only in the first stage, i.e. The steps for the preparation of 3-bromomethyl (or 3-chloromethyl) -D-cephalosporin-3-oxyd de is about 30%. A one-step method for the preparation of 3-iodomethyl-l-cephalosporins is also known, consisting in that 3-exometilycephalosporium is reacted with an alkali salt of cyclite or a cyclic amidine in the presence of iodine or monobromide or iodine monochloride in a inert organic solvent and dissolved in an inert organic solvent and dissolved in an inert organic solvent and dissolved in an inert organic solvent and dissolved in an inert organic solvent. 80 to GZZ. The yield of the crude product does not exceed 50%. There is also known a method for producing cephalosporins covered by formula I, i.e. both in form l and in form D - "isomers, which consists in the fact that the corresponding 3-acetyloxy (or carbamoyloxy) methylcephalosporin is reacted with hydrogen iodide or iodine ester in the presence of a non-nucleophilic acid as a catalyst, such as. chlorine or benzenesulfonic or Lewis acids at a temperature of from -70 to +100 ° C, preferably at 0, and the resulting 3-iodomethyl-D-cephalosporin is isolated or converted into 3-iodomethyl-g-cephalosporin by three-step synthesis: by oxidation in S -oxide, by isomerization of the A-compound to the -connection and reduction of 3-iodomethyl-cephalosporin-S-oxide to 3-iodomethyl-d-cephalosporin C42. . The disadvantage of the known method is the low yield of the target product in the form of an α-isomer, 50-60%, as for the D-isomers, the method of their preparation consists in total of 4 stages, and correspondingly, taking into account the losses at each stage , and -isomers are obtained in low yield. The aim of the invention is to increase the yield of the target product, as well as simplify the process. This goal is achieved in that, according to the method for producing a 3-iodomethyl cephusporin, a cephalosporin derivative of the formula O Cg R ci i-4-V% "li Q - s JH2Bi where the dotted line means that the double bond can be in position 2,3- or 3,4-cephalosporin core, R jRj, and Rg have the indicated meanings, R / y is C; (is a C / alkanoyloxy group or a carbamoyloxy group of the formula where Rg and Rg are independently of each other a hydrogen atom C / i-C is alkyl, is reacted with trimethylsilyliodide in an aprotic solvent in anhydrous conditions at ambient temperature The process can be carried out in the presence of a hydrogen iodide acceptor, for example, propylene oxide or propylene. The proposed method allows to obtain in one stage both the D - and l - cephalosporin isomers with a high rotation rate. yield of the target product Due to the high reactivity of trimethylsilyl iodide (trimethyl iodomonosilane) with respect to water, the proposed method is carried out under free-flowing anhydrous conditions. The solvents are preferably dried prior to use. Ana is tartal, before use, trimethyl iodmonosilane is stored in the absence of moisture. Aprotic solvents used in the process include chlorinated hydrocarbon solvents, such as chloroform, methylene chloride, 1,2-dichloroethane, 1,1,2-trichloroethane, tetrachloroethane, and similar chlorinated hydrocarbon solvents; organic nitriles, for example acetonitrile and propionitrile, nitroalkanes, such as nitromethane and nitroethane, and sulfones, for example sulfolane. Solution solvents may be any suitable solvent for the cephalosporin starting material that does not react with iodomonosilane. Consider some examples illustrating the method. The data of nuclear magnetic resonance (NMR) spectra given in these examples were obtained on a T-60 spectrometer of Varian Ac sesheets using tetramethylsilane as a comparative standard. The chemical shifts are expressed in delta values (f) in million-to lx, and the combination constant (C) is expressed in cycles per second (cycle / s). the signals are identified as follows: singlet, doublet / quartet, multiplet. The infrared spectrum (IR) is determined on an Acculab 3 spectrometer from Beckmann. The mass spectrum is determined on a Varian NAT 731. Spectrometer. All reactions with the use of trimethyl yodomoiosilane (TM1C) were carried out in a nitrogen atmosphere in flasks dried on a burner. Example 1. 7-phenoxy-acetamido-3-iodomethyl-3-cephem-4-carboxylic acid ndpa-nitrobetchyl ether. To a solution of 241 mg of para-nitrobenzyl ester 7 (L-phenoxyacetamido-3-acetoxymethyl-3-cephem-4-carboxylic acid in 3 ml of methylene chloride, 0.14 ml of trimethyl iodomonosilane was quickly added, and the mixture was stirred for approximately one hour at room temperature The reaction was monitored by means of a thin layer of Xpo photograft. The dark orange reaction mass was transferred to a separatory funnel, further diluted with methylene chloride and washed successively with ice-cold aqueous 10% sodium thiosulfate solution sodium carbonate and a saturated solution of sodium chloride. The reaction mixture was dried over anhydrous magnesium sulphate, filtered and evaporated to dryness in a cold water bath. A solid product was obtained - p-nitrobenzyl ester of T-phenoxyacetamide-3-iodo-methyl-3-cephem-4- carboxylic acid with golden coloration. Yield of the product g (92%). The IR spectrum of the product, taken in deuterated chloroform on the film, showed the presence of adsorption maxima: 1771, 1715, 1678 cm-. The NMR spectrum taken in deuterated chloroform showed the presence of the following signals: 5.88 (quartet, L 6 Hz,), 5.40 (singlet, esophageal 0%, 2H), 5.05 (doublet, 3 6 Hz, Cg -H), 4.55 (singlet, phenoxy-SNg., 2H), 4.40 (singlet, 2H), 3.65 (wide quartet, 3 19 Hz,). The desorption mass spectrum showed the following mass ions: (, (M-12 7) 482. Example 2. 7J-phenyl acetate-3-3-yodomethyl-3-cepheme-4-carboxylic acid benzyl ester. Following the procedure and conditions, describe , in order of Example 1, 812 mg of β-phenyl-acetamido-3-acetoxymethyl-3-cephem-4-carboxylic acid benzyl ester was reacted in 10 ml of methylene chloride with 0.53 ml of trimethyl iodomonosylane at 3-iodomethyl benzyl ester to give in the form of a pale orange solid with a 96% yield (0.9 g). The IR spectrum of the obtained product in deuterated chloroform on the film showed the presence of the following adsorption maxima: 1775, 1715 and 1670. The NMR spectrum of the product in deuterated chloroform detects the following signals: 7.2-7.4 (aromatic, YN), 4.60 (doublet, O 9 Hz, WH), 5.68 (quartet, a 5 Hz and 9 Hz,), 5.21 (singlet, ester CH2, 2H), 4.85 (doublet, P 5 Hz, Cg-H), 4.82 (singlet, 2H ), 3.55 (singlet, amide CH4.2N) and 3.5 (wide quartet, O 19 Hz,, 210. The desorption mass spectrum of the product showed the presence of the following ions: (M + lf 549, (M-127) 421. Example 3. 7-methoxy-7-phenylacetamido-3-iodomethyl-3-cephem ben-eyl ester of 4-carboxylic acid. The procedure and conditions described in Example 1 were repeated; 330 mg of 7oi-methoxy-7 | 4-phenliacetamido-3-acetome simethyl-3-cephem-4-carboxylic acid dissolved in 4 ml of methylene chloride was reacted with 0.2 ml of trimethyl iodomonosi lan. The reaction was carried out for one hour at a temperature of about 20 s. The benzyl 3-iodine methylcepheme ester was isolated as a golden solid with a 95% yield (0.26 g). The IR spectrum of the product in deutrated chloroform on the film showed the presence of the following adsorption maxima: 1770, 1717, and 1680. The NMR spectrum of the product in de-chelated chloroform detected the following signals: 7.1-7.4 aromatic, UN 6.58 (singlet, NH, 1H), 5.27 (singlet, ester CH group, 2H), 5.0 (singlet , Ce (-H), 4.32 singlet, 2H), 3.66 (signallet, amide CHg group, 2H), 3.39 singlet, OSPz), 3.4 broad multiplet, Desorption mass spectrum, the product showed the presence of the following ions M 578, M-127f 541. Example .4. Tpi-2-thienylacetamido) -3-iodomethyl-2-cephem-4-carboxylic acid t-butyl ester. Repeating the procedure and conditions of Example 1, a solution of 313 mg of tert-butyl ether (2-thienylacetamido) -3-acetoxymethyl-2-cephem-4-carboxylic acid in 2 ml of methylene chloride with 0.183 ml of trimethyl iodo-monosilane was performed at 20 ° C . The desired product was obtained in 61% yield (0.22 g). The IR spectrum of the product in deuterated chloroform in the form of a film showed the presence of the following adsorption maxima: 1770, 1728, and 1665 cm. The NMR spectrum of the product in deuterated chloroform showed the presence of the following signals: 6.9-7.2 thienyl H, 3N), 6.47 broad singlet, Cr-H), 5.59 quartet, O 4 Hz and 9 Hz C, -N), 5.21 doublet, 3 4 Hz, Cg-H), 5.17 singlet), 4.19 AB quartet, J 10 Hz, CHlI / 3.81 aminet singlet CH2) and 1.5 singlet, CHj , 9H). The desorption mass spectrum of the product is the presence of the following ions: M + 1) 521, M-127f 393. Example 5. Methyl ether 7 5c: -methoxy-7p-2-thienylacetate-amido) -3-iodomethyl-3-cephem-4 -carboxylic acid. To a solution of 30 mg of 0.068 mmol) of 7o methyl ester (-methoxy-7p-2-thienyl-acetamide) -3-carbamate-3-cepheme-4-carboxamide acid in 1 ml of deuterated chloroform in an NMR tube, quickly add the solvent in a NMR tube and add quickly in an NMR tube. 0.075 mmol) trimethyl iodomonosilane. The reaction was completely completed within 5 minutes, which was detected by the NMR spectrum. The tube was diluted with chloroform and the solution was transferred to a separatory funnel. The solution was sequentially spilled with cooled ice; aqueous solutions of 10% sodium thiosulfate, 10% sodium bicarbonate and a saturated solution of sodium chloride. The solution was dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. Methyl 3-iodomethyl ester was obtained in a yield of 90% 0.033 g) as a pale golden solid. The IR spectrum of the product in chloroform on the film showed the presence of the following absorption maxima: 1762, 1718 and 1685 cm; the NMR spectrum of the product in deuterated chloroform showed the following signals: 6.9-7.3 thiophene CH), 5.02 singlet, CC -H), 4.33 broad singlet, CHgl), 3.82 singlet, side chain CH2), 3.80 singlet, ester CHa, group) and 3.41 broad singlet, Cg-H and OCH3). Example 6. Synthesis of 7 - 2-thienylacetamido) -3-1-methyl-1H-tetrazole-5-ylthiomethyl) -3-cephem-4-carboxylic acid from trimethylsilyl ether, 2-nile acetylido)) 3 - iodomethyl-3-cephem-4-carboxylic acid. To a suspension of 0.836 g 2 lviol) 7jb-2-thienylacetamido) -3-acetoxymethyl-3-cephem-4-sodium carboxylate (Gnatriecephalotin) in 40 ml of dry methylene chloride maintained at reflux temperature under nitrogen, add 0, 7 ml (5.5 mmol) of chlorotrimethylsilane. The silylation reaction of the C-carboxy group was carried out for 18 hours, and the resulting yellow suspension was cooled to room temperature. Then the volume of the suspension was reduced to half under reduced pressure and 0.56 ml (4 mmol) of trimethyl iodisilane was quickly added. The color of the suspension was gradually changed over an hour at room temperature to dark orange. After one and a half hours, 3 ml of dry dimethylformamide and 1 ml of "oxide" were added to the orange suspension.
    权利要求:
    Claims (3)
    [1]
    1. METHOD FOR PRODUCING 3-IODOMETHYLCEPHALOSPORINS <£ in the general formula where the dotted line means that the double bond can be in the position of the 2,3- or 3,4-cephalosporin core,
    R, is benzyl, phenoxymethyl, 2-thienylmethyl or syn- (2-tritylaminothiazol-4-yl) methoxyiminomethyl;
    R ^ is a hydrogen or methoxy atom. ” Group;
    R3 is C 1 -C-alkyl, benzyl, 4-nitrobenzyl or trimethylsilyl, by iodination of the 3-substituted hydroxymethyl where R 5 'and R $ are independently of one another. Hydrogen atom or C 1 -C 3 -alkyl,'
    And iodization is carried out by vz'a. interactions with trimethylsilyl iodide in the body when yes.
    aprotic solution - in anhydrous conditions, ambient temperature 1069627A
    [2]
    2. The method according to π.1, characterized in that the reaction is carried out in the presence of an acceptor of hydrogen iodide.
    [3]
    3. The method of pop.2, characterized in that as the acceptor of hydrogen iodide, propylene oxide or propylene is used.
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    同族专利:
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    CA1147322A|1983-05-31|
    GR72415B|1983-11-03|
    CS225827B2|1984-02-13|
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    KR840000503B1|1984-04-16|
    EP0034924A2|1981-09-02|
    GB2070598B|1984-02-22|
    AU6733581A|1981-08-27|
    GB2070598A|1981-09-09|
    DK73381A|1981-10-02|
    HU183340B|1984-04-28|
    RO81620A|1983-04-29|
    JPH0226634B2|1990-06-12|
    FI810505L|1981-08-21|
    PT72532B|1982-02-10|
    YU37581A|1983-09-30|
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    EP0034924A3|1981-12-02|
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    引用文献:
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    KR940000112B1|1990-07-05|1994-01-05|주식회사 대웅제약|3-substituted cephem compounds|
    KR100194994B1|1993-06-05|1999-06-15|손경식|New cefem compound|
    KR100390548B1|1996-02-10|2003-11-13|주식회사 코오롱|Method for manufacturing cephalosporin intermediate|
    FR2770218B1|1997-10-27|2000-02-18|Rhodia Chimie Sa|PROCESS FOR THE SILYLATION OF CARBON HYDRATES|
    US7847093B2|2003-04-16|2010-12-07|Sandoz Ag|Processes for the preparations of cefepime|
    ES2348299T3|2003-04-16|2010-12-02|Sandoz Ag|PROCEDURES FOR THE PREPARATION OF CEFEPIME.|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US06/122,950|US4266049A|1980-02-20|1980-02-20|Process for 3-iodomethyl cephalosporins|
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