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Refining method of cefprozil

A technology of cefprozil and refining method, which is applied in the field of medicine, can solve problems such as residues, many impurities, and reduced yield, and achieve the effect of reducing impurities and reducing the content of impurities in products

Active Publication Date: 2018-05-11
SHANDONG YUXIN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this route, because there is no selectivity when the 3-position side chain is connected, more E-type isomer by-products are mixed in the Z-type product. Due to its similar structure and properties, it is difficult to separate, and it may even remain in the final cefprozil. Affect the efficacy of drugs; and need to use phenol, trifluoroacetic acid, phosphorus pentachloride, etc. which are harmful to the environment, which are highly corrosive, and the reaction conditions are harsh and the yield is low
[0006] Chinese patents CN101225088B and CN101058584B use cheap and easy-to-get 7-ACA as the starting material to replace GCLE, which is in short supply, but likewise, when combined with acetaldehyde through the wittig reaction, the Wittig reaction yield is not high, the reaction is slow and the selectivity is poor , the Z-type product is mixed with more E-type isomer by-products, which are difficult to separate due to their similar structures and properties, and may even remain in the final cefprozil, affecting drug efficacy and safety
[0007] And present refining method all has certain defect, Chinese patent CN101225088B directly joins cefprozil crude product into water and stirs, filters, washes with acetone, dries, and obtains refined cefprozil, because cefprozil is not completely dissolved in water, causes Partial loss reduces its yield to some extent. In addition, the E-type isomer content obtained after this refining method is still very high; in Chinese patent CN101798312B and CN102030762B, the crude product of cefprozil is dissolved in water, and the pH is adjusted to After 4.5, add in methanol and stir to react, filter, wash with 50% methanol aqueous solution and acetone, and dry under reduced pressure to obtain cefprozil. Although the E-type isomer content is reduced in this method, the overall yield is not high. There will be some cefprozil dissolved in methanol, causing loss; Chinese patent CN102911187B adds the crude product to a mixed solvent of water and isopropanol, adjusts the pH to 1.1 with hydrochloric acid, stirs, decolorizes, filters, and then adjusts the pH to 6.5-6.6, stirring, cooling, suction filtration, washing with acetone, and vacuum drying to obtain the finished product of cefprozil. This refining method has a high yield, but the later detection found that the purity and cis-trans ratio did not increase significantly
[0008] In summary, in the prior art, only obtain cefprozil by the method for direct preparation, product purity is not high, impurity is more, and yield is lower, and present refining method also has certain defect, therefore it is necessary to develop a A new refining method to obtain cefprozil with high purity, high yield and high cis isomer content

Method used

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  • Refining method of cefprozil

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Embodiment 1

[0032]Under nitrogen protection, 10.89g (40mmol) of 3-acetoxymethyl-5-thio-7-amino-8-oxo-1-azabicyclooct-2-ene-2carboxylic acid, 100mL of acetonitrile, 46mmol of N , put O-bistrimethylsilylacetamide (BSA) in the reaction bottle, stir the reaction at room temperature for 4h, add dropwise N,N-diethylaniline 4~6mL, trimethyl iodosilane (TMSI) 44mmol, in 10~ React at 15°C for 1h, add 11.02g (42mmol) of triphenylphosphine, continue the reaction for 1h, add 7.34g (40mmol) of sodium hexamethyldisilazide, stir at room temperature for 45min, separate the organic layer and wash with water, then wash with 20%w / w NaCl aqueous solution washing, anhydrous MgSO 4 After drying, 22.21 g of compound 3 was obtained, with a yield of 89.8%.

Embodiment 2

[0034] [C 4 MIm]PF 6 Preparation of ionic liquid: 6.896g KPF will be dissolved 6 50mL of acetone solution was placed in a 250mL three-necked flask, and then 10mL containing 5.47g [C 4 MIm]Br in acetone solution, a white precipitate appeared immediately, after stirring at room temperature for 2 hours, the precipitated solid KBr was removed by suction filtration, acetone was removed by rotary evaporation, and the crude product was obtained as a yellow liquid at room temperature. with 30mLCH 2 Cl 2 Treat 3-5 times until the KBr solid is removed, the dichloromethane solution of the ionic liquid is dried overnight with anhydrous magnesium sulfate, filtered, and the dichloromethane is removed by rotary evaporation to obtain a light yellow viscous liquid product [C 4 MIm]PF 6 .

[0035] Dissolve 18.55g (30mmol) of compound 3 in 50mL [C 4 MIm]PF 6 1.85g (42mmol) of acetaldehyde and 2.51g of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) were added under stirring, and reacted at room...

Embodiment 3

[0037] Prepare a solution of trimethylaluminum hexane with a concentration of 2M at 5°C for subsequent use; slowly dissolve 5.28g (22mmol) of compound 2 in 50mL of dichloromethane, stir well, and then gradually add a solution of trimethylaluminum with a concentration of 2M Hexane solution 12.5mL (25mmol), stirred at room temperature for 2h, then added 3.62g (20mmol) of L-p-hydroxyphenylglycine methyl ester in batches, and reacted at 35°C for 2h, TLC monitored the completion of the reaction, cooled to room temperature, added 50mL Quench the reaction with water, let stand to separate layers, collect the water phase, add 6% dilute hydrochloric acid aqueous solution, adjust the pH to about 5.0, cool down to 5-10°C, slowly add 50mL of acetone, stir for 1h, filter with suction, and filter the cake with acetone Washing, drying, and vacuum drying gave 7.57 g of crude cefprozil, with a yield of 96.81% and a purity of 99.68%.

[0038] Part Two: The Refining Method of Cefprozil

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Abstract

The invention relates to a refining method of cefprozil. The method comprises steps of synthesis of crude cefprozil and refining of cefprozil, wherein the refining step specifically comprises the following steps: 1) adding crude cefprozil to ethanol, stirring the mixture, regulating pH to 2.0-2.2 by a diluted hydrochloric acid aqueous solution, stirring and dissolving the crude cefprozil, and performing filtering to obtain a crude product solution of a cefprozil salt; 2) adding a 4% sodium bicarbonate solution dropwise to the obtained solution, regulating pH to 4.6-5.0, cooling the solution, performing stirring in a temperature keeping manner, and performing suction filtration, washing and draining to obtain a solid; 3) dissolving the solid obtained in step 2) in water, adding activated carbon, heating the mixture to 30-35 DEG C, sufficiently stirring and filtering the mixture to obtain a filtrate, cooling the filtrate to 0-5 DEG C, adding the filtrate to a mixed solvent, performing crystallization, growing grains for 1.5 h by controlling temperature and stirring speed, and performing filtering, washing, draining and vacuum drying to obtain pure cefprozil. The refining method has the advantages of simple conditions, high cis-isomer content, high product purity and the like.

Description

technical field [0001] The invention relates to the technical field of medicines, in particular to a method for refining cefprozil. Background technique [0002] Cefprozil (Cefprozil), chemical name: (6R,7R)-7-[(2R)-amino(4-hydroxyphenyl)acetamido]-8-oxo-3-(1-propenyl)-5 - Thio-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, a second-generation cephalosporin antibiotic, is a cephalosporin spectrum developed by Bristol-Myers Squibb Antibacterial drug, with strong antibacterial activity against G+, G- bacteria and anaerobic bacteria, especially against G+ bacteria, clinically used for mild and moderate infections caused by sensitive bacteria, including upper and lower respiratory tract infections, as well as skin and skin Soft tissue infection. Its structural formula is as follows: [0003] [0004] Since the C3-position of cefprozil is connected to the propenyl group, there are two geometric isomers of this compound, one is cis-cefazil and the other is trans-cefazil. Th...

Claims

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Application Information

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IPC IPC(8): C07D501/22C07D501/12
CPCC07D501/12C07D501/22
Inventor 刘振腾王军王广明王春艳
Owner SHANDONG YUXIN PHARMA CO LTD