• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
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  • 优先权
    • 专利摘要:
    3-Halomethyl-3-cephems are provided by reacting a 3-methylenecepham with an alkali metal salt of a lower alcohol or a bicyclic amidine base in the presence of a positive halogenating agent at a temperature ranging from -80 DEG to about 20 DEG C. The 3-halomethylcephems provided by this invention are useful intermediates for the preparation of known cephalosporin antibiotics.
    公开号:SU965357A3
    申请号:SU772462785
    申请日:1977-03-21
    公开日:1982-10-07
    发明作者:Аллен Коппел Гари
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to methods for producing 3-halomethyl cephemes of the general formula No. 4.  2 (I) Il2CH2CO: NH-p | P4 COORi where X is a halogen atom; q g O or 1; tert-butyl, 4-methoxybenzyl, benzhydryl, 4-nitrobenzyl or 2,2,2-trichloroethyl; phenoxy, phenyl, thienyl-2 or 5-bromothien-2, which are valuable intermediates in the preparation of cephalosporin antibiotics.  A method of producing 3-halomethyl cephemes is known, which consists in the fact that the 3-methylene cephamic compound is reacted with free halogen at a low temperature in an organic solvent medium and the intermediate 3-halo-H-halomethyl cepheme compound is treated with a base with heating solvent 1.  The disadvantage of the known method is that the target product is obtained in two stages.  The purpose of the invention is to simplify the process technology.  This objective is achieved by a process for the preparation of compounds of the general formula I, which consists in the compound of the Formula where q- has the indicated meanings; R "is a phenyloxy group, phenyl or thienyl-2, is reacted with a base made up from the group consisting of an alkali metal salt of a secondary alcohol, used in number of equivalents, an alkali metal salt of a primary or tertiary alcohol, used in coca.  The halogenation (termination reaction; halogenation) agent is added in order to bind an excess of the booking agent and thus stop or significantly reduce the reaction between the excess brominating agent and the reactive side 2-thienylacetamido group of the starting compound and the resulting 3-halomethyl cephamic . Typical halogen-breaking reagents used in the implementation of the proposed method are halogen-reducing compounds, however, other halogen-breaking compounds that react with an excess of halogenating reagent are acceptable faster than the latter reacts with H-halo-compounds.  Halogenating compounds are di (, alkyl) sulfides, tri (, alkyl).  phosphites, olefins, acetylenes, as well as aqueous solutions of the known reducing neocanic salts, such as bisulfide metabisulfite, thiosulfate or dithium salts.  Preferably, dimethyl sulfide or trimethyl phosphite is used as the quenching agent.  The amount of halogenation reaction agent used is not a determining factor.  Usually, a 1-10 fold excess or more of the haliding agent is terminated.  When using such agents, it is possible to achieve higher yields of 3-halomethyl cephema, therefore stopping the halogenation reaction.  compounds are usually used in the implementation of the proposed, even if the original exomethylenes does not contain reactive side groups.  The reaction time is usually from 2 minutes to 1 hour, depending on the nature of the starting reagents, the solvents used and the temperature at which the reaction is carried out.  The reaction is completed within 5-15 minutes after the reactants are mixed at the preferred temperature.  The composition of the reaction mixture can be controlled, for example, by comparative thin-layer chromatography, which will determine the end of the halogenation reaction.  For the analysis of compounds, the NMR method was used on a T-BVO Varia Associates spectrometer, where tetramethylsilane was used as a standard.  The chemical shifts are expressed in e values in parts per million (h / mlk), and the interaction constants (J) are expressed in cycles per second.  Example 1  4-nitrobenzyl 7-phenoxyacetamido-3-bromomethyl-3-cephem-47carboxylate.  BUT.  To a solution of 248 g of DVN in 20 ml of tetrahydrofuran (THF) at -78 ° C, 0.109 ml of bromine is added.  Immediately after this, a solution of 0.483 g of 4-nitrobenzyl 7-phenoxyacetamido-3-methylene cephamide-4-carboxylate in 15 ml is added.  Within 10 minutes, the reaction mixture was changed at -78 ° C, then the temperature was raised to and the mixture was stirred for another 10 minutes.  After that, 0.118 ml of trimethyl phosphite a is added.  The reaction mixture is evaporated to dryness under vacuum, c.  resulting in a reddish brown residue, which is then dissolved in methylene chloride, successively washed with 5% hydrochloric acid and a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate and evaporated to dryness, resulting in a yield of 536 mg (95%) of the indicated product in the form of a pink foam residue NMR (CDGl) with: 3.6 (bs,: 2) 4.46 (bs, 2, Cz-CH Bg), 4.58 (s, 2,; side chain CH), 5.05 (d, 1, J 5 Hz, C, -H), 5.40 (s, 2, ester СНо), 5. 95 (q, 1, J 5 and 9 Hz, IC-T-H) and 6.8-8.3 (AGN).  B.  0.12 ml of bromine is poured into a solution of 0.336 g of tert-butoxide potassium in THF at -80 ° C.  A solution of 0.483 g of 4-nitrobenzyl 7-phenoxyacetamido-3-methylene cephamide-4-carboxylate in 4 ml THF is then added.  The temperature of the reaction mixture is raised to and the solution is stirred for 10 minutes, after which 10 drops of trimethyl phosphite are added.  The reaction mixture is evaporated to dryness under vacuum, and a residue is obtained, which is dissolved in methylene chloride, washed successively with 5% hydrochloric acid and twice with brine, dried with anhydrous magnesium sulfate and again evaporated to dryness under vacuum.  The resulting product was purified by preparative thin layer chromatography to obtain 0.50 g of the indicated product.  The NMR spectrum of the obtained product is identical to the NMR spectrum of the product obtained by the rto method / described in part A.  Into a solution of 36.48 g of DBU in 820 ml of THF at -80 ° C, 14.4 mL of bromine and a solution of 38.64 g of 4-nitrobenzyl 7-phenoxyacetamido-3-methylene cephamide-4-carboxylate in 160 ml of THF are added.  The mixture was stirred for 10 minutes at -800 ° C, and then, over the course of 6 minutes, 14.4 ml of trimethylphosphite was added dropwise.   After adjusting the temperature of the reaction mixture to 0 ° C, an additional 60 ml of trimethylphosphite are added.  The reaction mixture is then evaporated to dryness and the residue is dissolved in methylene chloride. The methylene chloride solution is successively washed with 5% hydrochloric acid and saturated sodium chloride solution, and then filtered through a layer of silica gel and activated carbon.  After this, the filter is evaporated to dryness under vacuum, resulting in a yield of 35.6 g (80%) of the indicated product.  G.  To a solution of 0, 45b g of DBU in 15 ml of THF, 0.18 ml of bromine are then poured. Then. a solution of 0.483 g of 4-nit robenzyl 7-phenoxyacetamido-3-methylene to cefam-4-carboxylate in 4 ml THF is added.  When the temperature reaches 0 ° C, the reaction mixture is stirred for 10 minutes.  Then it is filtered through a layer of silica gel, using ethyl acetate as eluent. The combined eluates are evaporated under vacuum to dryness, resulting in the obtained product, which is identified by NMR.  .  Example 2  4-Nitrobenyl 7-f-noxy-acetamido-3-bromomethyl-3-cephem-4-carboxylate.   .  BUT.  0.82 ml of bromine is poured into a solution of 2.28 g of DBU in 50 ml of THF at -20 ° C and then immediately a solution of 2.415 g of 4-nitrobenzyl 7-phenoxy-acetamido-3-methylenecepham-4-carboxylate. and in 20 ml of THF, the reaction mixture is stirred at -20 to for 30 min.  After that, 50 MP of methylene chloride and 150 ml of iodine solution of sodium metabisulfite are added.  The organic layer is separated and washed twice with sodium bisulfite solution.  After evaporation under vacuum to dryness. 2.90 g of product is obtained, which is dissolved in 75 ml of methylene chloride.  The resulting solution is washed three times with a saturated solution. sodium chloride with 5% hydrochloric acid, dried with anhydrous magnesium sulphate and evaporated under vacuum to dryness.  The resulting product is suspended in 50 ml of diethyl ether and the mixture is stirred for 2 hours.  After filtration, 1.71 g (60.8%) of the indicated product.  B.  All operations were carried out in accordance with the procedure described in Example 2A, but sodium bisulfite was used instead of sodium metabisulfite.  The output of the specified product. composition L5 | RT 59.4%.  Example 3  4-Nitrobenzyl 7-phenoxyacetamido-3-bromomethyl-3-cephem-4-carboxylate.  BUT.  0.082 ml of bromine is poured into a solution of 0.228 g of DBU in 20 ml of methylene chloride with (dry ice / acetone) followed by a solution of 0.241 g of 4-nitrobenzyl 7-phenoxy-acetamido-3-methylene cephamide-4-carboxylate in 15 ml of methylene chloride.  The reaction mixture is stirred for 10 minutes at -78 ° C, then the temperature is raised to 0 ° C and stirred for another 10-15 minutes.  Thereafter, 0.07 ml of dimethyl sulfide is introduced into the reaction mixture.  The reaction, the mixture is evaporated to dryness under vacuum and the resulting residue is dissolved in methylene chloride.  The methylene chloride solution is washed with 5% hydrochloric acid, saturated sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated to dryness under vacuum, giving 300 mg of a brown foamy residue.  In accordance with the results of comparative thin-layer chromatography and NMR spectra, the bulk of the product is the substance indicated.  B.  All operations were carried out in accordance with the procedure described in paragraph A, but toluene was used instead of methylene chloride as a solvent.  Data from thin-layer chromatography and NMR confirm the formation of the indicated product.  The yield of the crude product is 256 mg.  AT.  Repeat c. This sequence of operations (of the operations described in Paragraph A, but 1,1,2-trichloro tan is used as a solvent instead of methylene chloride; to prevent freezing of solvent or dry mixture instead of cooling. ice / acetone use a mixture of nitrogen / acetonitrile (-41 ° C) and instead of dimethyl sulfide, use trimethylphosphite as an agent that terminates the halogenation reaction.  According to the results of thin layer chromatography and NMR, the yield of said product is 100 mg.  G.  According to the procedure described in clause A, but using methanol chloride instead of methylene chloride and trimethylphosphite instead of dimethyl sulfide as methylene chloride as the reaction medium, 229 mg of the crude product are obtained. Thin layer chromatography and NMR methods undergo the required reamtion and formation of the indicated product.  D.  The entire sequence of operations is carried out in accordance with the procedure described in paragraph A, but instead of methylene chloride is used as a solvent, instead of a dry ice / acetone cooling mixture, a liquid nitrogen / acetonitrile cooling mixture (-41 ° C) is used as interrupting the halogenation reaction agent instead of dimethyl sulfide is used trimethyl phosphite.  According to thin layer chromatography, this is indicated by.  Sized product with a yield of 150 mg.  E.  The entire sequence is opera-  The steps are carried out in accordance with the procedure described in point A, but 1,4-di is used as a solvent instead of methylene chloride. In order to prevent the solvent from freezing, instead of a dry ice / acetone cooling mixture, pure ice is used, and trimethyl phosphite is used instead of dimethyl sulfide to terminate the halogenation reaction.  According to thin layer chromatography, the indicated product is obtained, yield 150 mg.  G.  The entire sequence of operations is carried out in accordance with the procedure described in paragraph A, but 1,2-dimethoxyethane is used as a solvent for carrying out NIN reactions instead of methyl chloride; liquid nitrogen / acetonitrile (-41 ° C) is used to prevent freezing the solvent instead of a dry ice / acetone cooling mixture; and trimethylphosphite is used instead of dimethyl sulfide as an interrupter in the halogenation reaction.  According to thin layer chromatography, the indicated product was obtained, yield 279 mg.  3  The entire sequence of operations is carried out in accordance with the procedure described in paragraph A, but as a solvent. dimethylformamide is used instead of methylene chloride, and trimethylphosphite is used instead of dimethyl sulfide as a haliding agent.  According to thin layer chromatography, the final crude product was identified as the indicated compound.  PRI me R 4.  4-nitrobenzyl 7-fe.  noxyacetamido-3-bromomethyl-3-cephem-4-carboxylate.  1.15 ml of a 1.75 M solution of methyl lithium is poured into a solution of 64 mg of methanol in 20 ml of THF at -80 ° C.  After 5 minutes, 0.11 ml of bromine was added to the resulting solution of lithium methylate in THF.  Then a solution of 0.483 g of 4-nitrobenzyl 7-pheno-xiacetamido-3-methylene cephamide-4-carboxylate in 4 ml of THF is added dropwise.  After the introduction of the tetrahydrofuran solution of the methylene phase substrate, the mixture is stirred for 5 minutes at and then it is raised to 0 ° C.  After stirring for 10 minutes at 0 ° C, 4 drops of trimethylphosphite are added.  After this reaction. the mixture is evaporated under vacuum to dryness, the resulting residue is dissolved in methylene chloride, the solution is successor: BUT, washed with 5% hydrochloric acid with water and a saturated solution of sodium chloride.  The organic layer is separated, dried over anhydrous sodium sulphate and evaporated to dryness under vacuum.  The resulting product is pure. using preparative thin layer chromatography using silica gel plates, shown by solution | benzene: ethyl acetate in a ratio of 7: 3, There is 126 mg of the specified product.  The NMR spectrum of the product is identical to the spectrum of the product obtained in example 1. .  Example 5  4-nitrobenzyl 7-phenoxyacetamido-3-bromomethyl-3-cephem-4-carboxylate-1-oxide.  0.36 ml of bromine is poured into a solution of 0.912 g of DBU in 15 ml of THF at -80 ° C.  Then, a solution of 0.499 g of 4-nitrobenzyl 7-phenoxyacetamido-3-methylene cepha-4-carboxylate-1-oxide in 4 ml of HMPA is added, and after 10 minutes 0.186 ml of trimethyl phosphite.  The temperature of the reaction mixture was raised to 0 ° C and after 5 minutes an additional 2 ml of trimethyl phosphite was added.  The reaction mixture is evaporated to dryness under vacuum and the resulting residue is dissolved in methylene chloride.  The methylene chloride solution is washed successively with 5% hydrochloric acid, water, twice with a saturated solution of sodium chloride, dried over anhydrous sodium sulfate and evaporated) T under vacuum to dryness, resulting in a product that is purified using preparative thin layer chromatography, 60 mg of the title compound are isolated.  NMR  (DMSO a-6) cL: 3.96 (bs, 2, C. 2-H), 4.57 (s, 2, SZ-CH BG), 4.73 (s, 2, side chain CH), 5.09 (d, 1, J 5 Hz, Ci-H), 5 , 50 (, CH ester), 6.10 (q, i; J 10 and 5 Hz, C7-H) and 6.9-8.2 (ArN).   Note 6.  4-Nitrobenzyl 7- (2-thienylacetamido) -3-bromomethyl-Zepham-4-carboxylate.  .  To solution 9. 12 g of DBU in 200 ml of dry THF at -78 ° C (a mixture of dry ice and acetone) were added with 3.5 ml of bromine, and the mixture was stirred at -78 s for 10 min.  A solution of 9.46 g of 4-nitrobenzyl 7- (2-thienylacetamido) -3-methylene cephamide-4-carboxylate in 100 ml of THF is then added dropwise over 5 minutes.  After the introduction of the basic reagent solution is complete, the mixture is stirred for 10 min at.  The bath with a mixture of dry ice and acetone is replaced with an ice bath and the mixture is stirred for 6 minutes, after which 5.0 ml of trimethylphosphite are added.  The mixture is stirred for 10 m. Inut, and then evaporated under vacuum to dryness and get a dark residue.  This residue. It is dissolved in methylene chloride and the resulting solution is washed successively with water, 5% hydrochloric acid and saturated sodium chloride solution, and then dried with anhydrous sodium sulfate.  After that, about 10 g of Darko G-60 is added.  The solution is filtered and the resulting yellowish-orange filtrate is evaporated under vacuum to dryness.  The resulting residue was recrystallized from a mixture of methylene chloride and hexane, to give 6.96 g (63% of the title compound).   NMR CDMSO d-b) c: 3.80 (bs, 4, bo Chained SNp +), 4.55 (bs,: 2), 5.20 (d, I, J 4.5 Hz C. -H 5.82 (dd, I, J 4.5 and 9 Hz,) and 6.9-8.4 (AHH).  Example 7  Benzhydryl 7- (2-thienylacetamido) -3-bromomethyl-3-cep-4-carboxylate.  Benzhydryl 7- (2-thienylacetamido) 3-methylene cec) am-4-carboxylate 4, 91 g is converted to the indicated compound in accordance with the procedure described in example b.  NMR (CWAe) 3.50 (S5,2, C, -H) 3.84 (s, 2, CH side chain), 4.30 (S, 2, C3-CH BG), 4.98 (d, I, J 4.5 Hz, Ce-H), 5.86 (q, I, J 4.5 and 9 Hz,), 6.84 (d, 1, J 9 Hz, side chain NH) and 7, 0-7.6 (AGN).  Example 8  4-Nitrobenzyl-7. - (2-thienylacetamido) -3-bromomethyl-3-cephem-4-carboxylate.  - Tidrbbromid perbromide DBU is synthesized as follows.  To a solution of 20.3 g of DBU in 100 ml of 48% hydrobromic acid at -5 ° C dropwise, 32.06 g of bromine are added over 10 minutes.  The orange precipitate formed is filtered off, washed with acetic acid and water, and then dissolved in methylene chloride iie.  The resulting methylene chloride solution is washed with water and dried without water.  sodium sulfate.  Ethyl acetate is then added to the methylene chloride solution while cooling to initiate.  crystallization process.  After settling the solution for 2 hours, the perbromide is filtered off and washed with ethyl acetate and sulfuric ether; The product yield is 22.6 g T (, l 119-122 C.  The remaining filtrate is evaporated and, after cooling, an additional 9.5 g of perbromide is obtained in the form of orange crystals (TPA.  118-121 ° C).  The total yield of the product is 32.1 g (62%).  To a solution of 2.35 g of perbromide hydrobromide DBU and 0.34 g of DBU in 20 ml of THF at room temperature will be added 9.946 g of 4-nitrobenzyl 7- (2-thierylacetamido) -3-methylene cepham-4-carb | rxylat and 20 ml of THF.  The solution immediately becomes dark in color.  After 2 minutes, 0.5 ml of trimethylphosphite are poured in and the reaction mixture is immediately evaporated under vacuum to dryness.  The resulting residue is dissolved in methylene chloride and the solution is washed with 5% hydrochloric acid solution and then saturated with sodium chloride solution, dried over anhydrous sodium sulfate and then evaporated under vacuum to dryness.  The residue is crystallized from methylene chloride / ethanol and 0.92 g of the expected product is obtained in the form of crystals.  The structure of the product is confirmed by NMR spectrum and thin layer chromatography.  Example 9  4-Nitrobenzyl.  (5-bromothienylacetamido) -3-bromomethyl-3-cephem-4, carboxylate.  1.8 ml of bromine is added to a solution of 4.56 g of DBU and 50 ml of THF at -78 ° C.  The mixture is then stirred for 15 minutes at -78 ° C and a solution of 4.73 g of 4-nitrobenzyl 7- (2-thienes1 amido) -3-methylene cepha-4-carboxylate is added.  in 40 ml of THF.  The mixture was adjusted to -5 ° C for 30 minutes, then 250 ml of water and 150 ml of methylene chloride were added.  The organic layer is separated, washed with 5% hydrochloric acid and water, and dried over anhydrous sodium sulfate.  Then the methylene chloride solution is filtered through 150 g of silica gel and eluted with methylene chloride.  The eluent, which contains the largest part of the reaction product, is evaporated in vacuo to dryness.  The residue thus obtained is recrystallized from methylene chloride / hexane, as a result of which the said compound is obtained in the form of light yellow crystals in the amount of 370 mg; Mp 144-14b ° C (decomp. . . B10N 260 mm (19600); NMR (DMSO d-6) 0: 6.79 and 7.05 (ds each, J 3.5 Hz, C 3 thiophene and C4 protons).  Elemental analysis.  .  .  Calculated: C 39.01; H 2.63; N 6.50; Bg 24.764 Nay-ddeno: C 40.22; H 2.57; N 6.59; Br 24.37.  Example 10  4 Nitrobenzyl 7-phenoxyacetamido-3-chloromethyl-3-cephem-4-carboxylate.  0.286 ml of tert-butyl hypochlorite is poured into a solution of 0.312 t DBU in 15 ml of THF at -80 ° C.  To the mixture cooled to -80 ° C, a solution of 0.483 g of 4-nitrobenzyl 7-phenoxyacetate amido) -3-methylene cepha-4-carboxylate in 4 ml of THF is added.  After stirring the reaction mixture at -80 ° C for 10 minutes, 10 drops of trimethyl phosphite are added to it.  The temperature of the mixture is raised to 0 ° C and the mixture is then evaporated to dryness under vacuum.  The residue is dissolved in methylene chloride and the resulting solution is washed with 5% hydrochloric acid and saturated with sodium chloride solution, separated, dried over anhydrous sodium sulphate and evaporated under vacuum to dryness, to give 260 mg of the title compound.  NMR (CDClI) s: 3.60 (bs, 2, C, -H), 4.58 (s, 4, Cz-CH2, C1 + side chain CHg), 5.03 (d, I, J / 5 Hz, Sat-H), 5.38 (s, 2, ester CH), 5.93
    (q, 1, J / 5 and 9 Hz, C -, - H) and 6.8-8.4 (Arn).
    Example 11. 4-Nitrobenzyl 7-phenoxyacetamido-3-fluoromethyl-3-cephem-4-carboxylate.
    A solution of 0.483 g of 4-nitrobenzyl 7-phenoxy-acetamido-3-methylene cephamic-4-carboxylate in 30 ml of dry THF is added under a dry nitrogen atmosphere to 25 t / ui of a dry saturated solution of perchloride fluoride in dimethyl form, amide (4.7 g RSUD / liter at 25 ° C), obtained by passing a gaseous gas: the chlorine fluoride through dimethylformamide at room temperature for 10 minutes. A solution of 0.153 g of DBU was poured into the obtained piacTvore of the main methylilephalus and perchloryl fluoride at -78 ° C, drop by drop, in 5 ml of dry THF for 5 minutes. At the end of the addition of the DBU solution, the mixture is stirred for 3 minutes at -78 ° C, after which 0.118 g of trimethylphosphite is added. Then the reaction mixture is evaporated under vacuum almost to dryness. The resulting residue is dissolved in methylene chloride and the solution is washed successively with 1N. hydrochloric acid solution with water and twice the solution of sodium chloride. The washed methylene chloride solution is dried over anhydrous sodium sulfate, and then evaporated to dryness under vacuum, resulting in a yield of 443 mg of a colorless foam. After primary purification using liquid chromatography under pressure, the product is finally purified using preparative thin layer chromatography using 7: 3 benzene / ethyl acetate solvent to produce silica gel plates.
    Extraction of the corresponding band by methylene chloride affords 21.1 mg of the title compound As a colorless gum.
    NMR (CDCl1): 3.56 (bs, 2,), 4.55 (s, 2, side chain CH), 5.0 (d, I, J 5 Hz, Cfe-H), 5.35 ( d, ABqs, 2 JF 47 Hz, Cj-CHiF), 5.32 (s, 2, ester CH, 2), 5.91 (q, 1, 5 and 9 Hz, C-7-H) and 6 , 7-8,2 (ArN); Fluoride magnetic resonance (CDQj) triplet, L 47 Hz.
    Example 12. Benzhydryl 7- (2-thienylacetamyl) -3-fluoromethyl-3-cephem-4-carboxylate.
    The compound is obtained from benzhydryl 7- (2-thienylacetamido) -3-methylene cephamide-4-carboxylate according to the procedure described in example 11.
    NMR (CDCIj): 3.44 (s, 2,), 3.80 (s, 2, CH7 side chain) 4.89 (d, I, J 5 Hz, Cfc-H), 4.84 and 5, 64 (2 bs, I each, Jp 48 Hz, Cz-CH7R), 5.86 (q, I, J 5 and 9 Hz),
    6.65 (d, I, J 9 Hz, side chain NH) and 6.8-7.5 (ArN).
    Example 13. 4-Nitrobenzyl 7-phenoxyacetamido-3-iodomethyl-3-cephem-4-carboxylate.
    To a solution of 0.456 g of DNU in 15 ml of THF, a solution of 0.84 iodine in 4 ml of THF is added, and then a drop of a solution of 0.483 g of 4-nitrobenzyl 7-phenoxyacetamido-3-methylenecephamine-4-car-oxilate in 4 ml of THF is added. After thermostating the mixture for 5 minutes at -80 ° C, 0.983 ml of trimethyl phosphite was added and the temperature of the reaction mixture was raised to 0 ° C. After about 10 minutes, an additional 1 ml of trimethylphosphite is added. Then the reaction mixture is evaporated to dryness under vacuum, the resulting residue is dissolved in methylene chloride and washed with succession of 5% hydrochloric acid, water and twice with a saturated solution of sodium chloride. The methylene chloride solution is dried over anhydrous sodium sulfate, and then evaporated under vacuum to dryness. A crude product is obtained which is passed through a silica gel chromatography column and 260 mg of the title compound are isolated:
    NMR CCDCI,) 3.44 and 3.82 (ABq, 2, J 18 Hz, Cj-H), 4.40 (s, 2, C, -CH ,, J 4.54 (s, 2, side chain CH) 4.98 (d, 1, J 5 Hz, Cfe-H), 5.34 (s, 2, ester CHj) 5.82 (q, I, J 5 I. 9 Hz, C -, - H) and 6.8-8.4 (ArH) -.
    Example 14. 4-Nitrobenzyl 7-phenoxyacetamido-3 chloromethyl-3-cephem-4-carboxylate.
    To a solution of 0.12 g of isopropanol in 20 ml of THF, 1.1 ml of a 1.84 M solution of methyl lithium in THF are poured into it. cooling the resulting mixture to -80 ° C. 0.286 ml of tert-butyl hypochlorite and a solution of 0.483 g of 4-nitrobenzyl 7-phenoxyacetamido-3-methylene cephamide-4-carboxylate in 4 ml of THF were successively introduced into it. Then the temperature of the reaction mixture is raised to. After thermostating at OS for 10 minutes, 1 ml was added. acetic acid and 1 ml of trimethylphosphite. Thereafter, the mixture is evaporated under vacuum to dryness, as a result of which a residue is obtained, which is dissolved in methylene chloride and washed with an aqueous solution of sodium bicarbonate. The methylene chloride solution is dried - and evaporated under vacuum to dryness. The resulting product was purified by preparative thick layer chromatography (silica gel plates) eluting with benzene / ethyl acetate and 100 mg of the title compound were isolated.
    NMR (CBC1) cL: 3.63 (brs, 2, C.-H), 4.58 (s, 4, Cj-H and side chain .СНа), 5.05 (d, I, L 5 Hz, C (, - N),.
    权利要求:
    Claims (2)
    [1]
    Claim
    1. The method of obtaining 3-halomethylcephemes of the general formula I where X is a halogen atom; q is 0 or 1;
    R is tert-butyl, 4-methoxybenzyl, benzhydryl, 4-nitrobeneyl or 2,2,2-trichloroethyl;
    R 2 is phenoxy, phenyl, thienyl-2 or 5-bromothienyl-2, using a 3-methylene-cephem compound; a halogenating agent and a base, characterized in that, in order to simplify the process technology, a 3-methylene-cephem compound of the formula II>
    B 2 CH 2 CiINI £ —ΐ— υ COO “t where q and R ^ have the indicated 'meanings;
    R ^ is a phenoxy group, phenyl or thienyl-2, is reacted with a base selected from the group consisting of an alkali metal salt, a secondary C 3 -C 7 alcohol, used in an amount of 3-6 equivalents, a primary C 4 -C 7 alkali metal salt or tertiary C 4 -C 7 . alcohol, used in an amount of 1-3 equivalents, and a bicyclic amidine base of the formula III χ—— where z = 3, 4 or 5, in the presence of 1-6 equivalents of a positive halogenating agent selected from the group consisting of tert-butyl hypochlorite, bromine, tert -, -butylhypobromite, 1,5-diazabicyclo (5.4.0) undec-5-ene hydrobromide perbromide, iodine and fluoride perchloride, in an inert, organic solvent at -80 to 20 ° C, provided that the salt alkali metal primary C 4 -C 7 alcohol is used in combination with any halogenating agent used except tert- tilgipohlorita, and in the case where the compound of formula II, wherein .Rl-thienyl, and armoring agent, to obtain the desired product, wherein R ^ - thienyl process is carried out in the presence galoidgasyaschego agent at a temperature below 0 ° C.
    [2]
    2. The method according to π. 1, σ л и тем with the fact that dimethyl sulfide or trimethyl phosphite is used as a halogen-suppressing agent.
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    同族专利:
    公开号 | 公开日
    DE2712046A1|1977-09-29|
    ES457057A1|1978-08-16|
    PT66317B|1978-08-14|
    PH12481A|1979-03-23|
    AR222446A1|1981-05-29|
    NL7703063A|1977-09-26|
    SE433219B|1984-05-14|
    HU177432B|1981-10-28|
    BG27754A3|1979-12-12|
    JPS613352B2|1986-01-31|
    IE44599B1|1982-01-27|
    PT66317A|1977-04-01|
    IE44599L|1977-09-22|
    DK123277A|1977-09-23|
    PL196820A1|1978-01-16|
    FR2345454A1|1977-10-21|
    US4042585A|1977-08-16|
    CS196355B2|1980-03-31|
    ZA77713B|1978-09-27|
    FR2345454B1|1980-02-15|
    CH632512A5|1982-10-15|
    ATA194477A|1980-02-15|
    IL51432D0|1977-04-29|
    GR66422B|1981-03-20|
    AU2220077A|1978-08-17|
    SE7702734L|1977-09-23|
    DE2712046C2|1985-12-12|
    RO70462A|1981-01-30|
    NZ183307A|1978-07-28|
    IL51432A|1980-01-31|
    GB1575693A|1980-09-24|
    AT358729B|1980-09-25|
    DD129913A5|1978-02-15|
    CA1093548A|1981-01-13|
    BE852668A|1977-09-19|
    MX4594E|1982-06-25|
    JPS52113994A|1977-09-24|
    PL109389B1|1980-05-31|
    AU506267B2|1979-12-20|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    GB1241657A|1967-08-21|1971-08-04|Glaxo Lab Ltd|Improvements in or relating to cephalosporin compounds|
    US3637678A|1969-01-13|1972-01-25|Lilly Co Eli|Delta-2 cephalosporin compounds|
    US3705897A|1970-07-07|1972-12-12|Lilly Co Eli|Method for converting delta2 cephalosporin to delta3 cephalosporin|
    US3883518A|1972-05-15|1975-05-13|Merck & Co Inc|3-Methylene cephalosporins|DE2655949A1|1976-12-10|1978-06-15|Gruenenthal Gmbh|NEW CEPHALOSPORIN AND PENICILLIN DERIVATIVES, PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THESE PRODUCTS|
    US4182870A|1977-09-07|1980-01-08|Gist-Brocades N.V.|Preparation of 3-bromomethyl-3-cephem sulfoxides|
    JPS611027B2|1978-02-23|1986-01-13|Shionogi & Co|
    US4211702A|1979-02-01|1980-07-08|Eli Lilly And Company|Process for preparation of penicillin and cephalosporin imino halides|
    US4283397A|1979-08-01|1981-08-11|Merck & Co., Inc.|7-N-Heterocyclyl cephalosporins and antibiotic pharmaceutical compositions containing them|
    US4266049A|1980-02-20|1981-05-05|Eli Lilly And Company|Process for 3-iodomethyl cephalosporins|
    KR19980073026A|1997-03-11|1998-11-05|구광시|Method for preparing 3-halomethyl-3-cepem|
    JP4659959B2|2000-09-29|2011-03-30|大塚化学株式会社|3-CEPHEM COMPOUND AND PROCESS FOR PRODUCING THE SAME|
    JP5417705B2|2007-12-03|2014-02-19|セントラル硝子株式会社|Removal method of ClO3F|
    CN106749335B|2016-11-29|2019-02-12|浙江新和成股份有限公司|A kind of preparation method and application of halogenated oxygen cephalo-type intermediate|
    CN107118224B|2017-06-15|2019-09-17|浙江新和成股份有限公司|A kind of preparation method of oxygen cephalosporin nucleus intermediate, its solvated compounds and preparation method thereof|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US05/669,365|US4042585A|1976-03-22|1976-03-22|Process for preparation of 3-halomethylcephems|
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