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Convenient method for preparing aspoxicillin sodium

A technology for apocillin sodium and a compound, which is applied in the field of convenient preparation of apocillin sodium, can solve the problems of high toxicity of 2-nitrothiophenol, inability to guarantee production safety, strong odor, etc. The effect of low environmental pressure, low labor protection intensity and high productivity

Active Publication Date: 2014-08-20
NANJING YOUKE BIOLOGICAL MEDICAL RES +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] At present, in the process of synthesizing apoxicillin in domestic and foreign literature, there are mainly three methods (active ester method, acid chloride method and acid anhydride method), such as: in the active ester synthesis method reported in patent document US4053609, the intermediate The carboxyl and amino groups of formamide are protected separately, then condensed with amoxicillin whose carboxyl group is protected, and finally hydrogenated and deprotected to obtain the product; but the 2-nitrothiophenol used in it is very toxic and has a strong odor , and the yield is low, the hydrogenation deprotection reaction adopted, the safety of industrial scale-up production cannot be guaranteed

Method used

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  • Convenient method for preparing aspoxicillin sodium
  • Convenient method for preparing aspoxicillin sodium
  • Convenient method for preparing aspoxicillin sodium

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Embodiment 1

[0032] Synthesis of embodiment 1 formula II compound

[0033]Suspend D-aspartic acid (160g, 1.2mol) in 850mL of methanol, cool down to -5~0°C, slowly add thionyl chloride (178.4g, 1.5mol) dropwise, after the drop is complete, heat up to 25~35 ℃, stirred and reacted for 4-5 hours, after the reaction was completed, methanol was distilled off under reduced pressure, and the obtained white solid was added to 500 mL of ethyl acetate, stirred and washed for 0.5 hours, filtered, and dried to obtain 192 g of the compound of formula II, with a yield of 87%, mp: 185 ~186°C.

[0034]

Embodiment 2

[0035] The synthesis of embodiment 2 formula III compound

[0036] (2) Dissolve the compound of formula II (192g, 1.05mol) in 400mL of water, cool down to 0-5°C, add 350mL of 40% methylamine aqueous solution dropwise, after the drop is completed, heat up to 25-35°C, and stir for 12-14h , the reaction was completed, concentrated under reduced pressure, adjusted the pH to 5 with 1 mol / L hydrochloric acid, concentrated under reduced pressure to dryness, added 550 mL of acetone, stirred for 1 h, filtered a large amount of precipitated solids, and dried to obtain 127 g of the compound of formula III, with a yield of 83%. mp: 188-189°C.

[0037]

Embodiment 3

[0038] Synthesis of embodiment 3 formula IV compound

[0039] The compound of formula III (127g, 0.87mol) was dissolved in 500mL of methanol, triethylamine (96g, 0.95mol) was added, and ethyl trifluoroacetate (184.6g, 1.3mol) was added dropwise at a controlled temperature of 40-45°C. After completion, keep the temperature at 30-35°C for 14-16h. After the reaction is completed, concentrate under reduced pressure, add 500mL of dichloromethane, stir and crystallize at a temperature of 0-5°C for 1h, and collect the precipitated solid to obtain 164g of the compound of formula IV. 78%.

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Abstract

The invention discloses a convenient method for preparing aspoxicillin sodium. The method comprises the steps of adding D-aspartic acid into a mixed solution of thionyl chloride and methanol, reacting to prepare D-aspartic acid methyl ester hydrochloride, reacting the D-aspartic acid methyl ester hydrochloride with an aqueous solution of methylamine to obtain aspartic formamide, protecting the first amino on the aspartic formamide by using trifluoroacetyl, then reacting the aspartic formamide with carbonyldimidazole to form an active mixed acid anhydride, condensing the active mixed acid anhydride with an amoxicillin triethylamine salt, finally removing the protective ground and forming a sodium salt under the alkali condition to obtain a crude aspoxicillin product of the target product, and refining the crude product to obtain the high-purity aspoxicillin sodium finished product. The method has the advantages that the reagents are cheap, readily available and low in toxicity and environmental pressure, the process operation is compact and stable, the purity of the product is high and the like.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical production, and in particular relates to a convenient method for preparing apoxicillin sodium. Background technique [0002] Apoxicillin chemical name: (2S, 5R, 6R)-6-[(2R)-2-amino-3-(N-methylcarbamoyl)propionamido]-2-(p-hydroxyphenyl)acetamide Base]-3,3-Dimethyl-7-oxo-4-thia-1-amobicyclo[3,2,0]-heptane-2-carboxylic acid trihydrate, also known as methyl -Aspartoyl-Amoxicillin, the structural formula is as follows: [0003] . [0004] Apoxicillin was developed by Japanese company Tanabe Seiyaku in July 1987. It belongs to a new generation of broad-spectrum semi-synthetic penicillin antibiotics and is in the leading position in the world. It is widely clinically used in dozens of countries in Southeast Asia, including Hong Kong, China. Apoxicillin has a strong antibacterial effect, and its antibacterial spectrum includes Gram-positive bacteria such as Staphylococcus, Streptococcus, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D499/68C07D499/16
CPCY02P20/55C07D499/68C07D499/16
Inventor 闵涛张鹏郭彦飞徐晓霞李上车晓明朱素华张峰
Owner NANJING YOUKE BIOLOGICAL MEDICAL RES
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