A kind of preparation method of apoxicillin trihydrate
A technology of apoxicillin trihydrate and mixed solvents, which is applied in the field of pharmaceutical production, can solve the problems of long synthetic route, high difficulty, and increased impurity spectrum, and achieve the effect of short synthetic route, large industrial value and improved quality
Active Publication Date: 2015-09-30
ZHEJIANG APELOA TOSPO PHARMA +1
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Problems solved by technology
DCU is difficult to remove in actual production, and this impurity will always be brought into the product
[0009] Third, the activity of the activation reagent is not high. In the activation reaction, DCC is required to catalyze, and the yield is low
[0010] Fourth, thiobenzamide is used as an additive for deprotection, which increases the impurity spectrum, that is, it is necessary to study NPS-Cl and dechlorinated products, as well as thiobenzamide residues, DCC residues, and product DCU residues. Amine residues, etc.; and triethylamine is used as a solvent residue detection, the reproducibility is not good, and it is difficult in quality research
However, there are still too long synthetic routes (requires six-step reaction), and still need amino protection, deprotection and other procedures, making the operation inconvenient
Method used
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[0042] The preferred embodiments of the present invention will be described in detail below.
[0043] The present invention aims to protect the whole synthetic route, and the following synthetic examples are only to prove that the synthetic route is feasible. But the content of invention protection is not limited to examples.
[0044] 1) Preparation of aspartic acid-β-methyl ester hydrochloride
[0045] Weigh 133.0g (1.0mol) of D-aspartic acid into a 2L three-neck flask, add 300mL of methanol and stir at 25-35°C (the solid does not dissolve and becomes white and turbid), and another 109.0g (1.1mol, 1.1 eq), use methanol 300mL, stir to dissolve, add BTC methanol solution dropwise to aspartic acid reaction liquid. Control the rate of addition so that the temperature of the reaction solution is not higher than 40°C. After the dropwise addition was completed, the reaction was stirred at 25-35° C. for 30-60 min, and the reaction was detected by TLC. (take a sample of 0.5mL, add...
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The present invention discloses an aspoxicillin trihydrate preparation method, which comprises: 1, carrying out a reaction of D-aspartic acid and BTC in methanol, and adding a solvent after completing the reaction to precipitate aspartic acid-beta-methyl ester hydrochloride; 2, carrying out a reaction of the aspartic acid-beta-methyl ester hydrochloride and a methylamine solution to produce D-aspartic acid-beta-formamide, adding a solvent in a dropwise manner after completing the reaction to precipitate the D-aspartic acid-beta-formamide crude product, and carrying out recrystallization and drying on the D-aspartic acid-beta-formamide crude product to obtain the D-aspartic acid-beta-formamide; 3, carrying out a reaction of the D-aspartic acid-beta-formamide and BTC in a solvent to produce D-aspartic acid-N-cyclic anhydride, and adding a solvent after completing the reaction to precipitate the D-aspartic acid-N-cyclic anhydride; and 4, carrying out a reaction of the D-aspartic acid-N-cyclic anhydride and amoxicillin in a solvent of acetonitrile and a sodium hydroxide aqueous solution to remove one molecule of carbon dioxide to prepare an aspoxicillin crude product, and carrying out decoloration, recrystallization, filtration and drying on the aspoxicillin crude product to obtain the aspoxicillin trihydrate.
Description
technical field [0001] The invention belongs to the technical field of pharmaceutical production, and in particular relates to a preparation method of apoxicillin trihydrate. Background of the invention [0002] Apoxicillin (aspartame, ASPC, DOYE) is a semi-synthetic broad-spectrum penicillin antibiotic with strong antibacterial effect, and its antibacterial spectrum includes Gram-positive bacteria such as Staphylococcus, Streptococcus, and Pneumococcus and Gram-negative bacteria such as Escherichia coli, influenza bacillus and anaerobic bacteria Bacteroides. It is clinically used for sepsis, endocarditis, respiratory tract infection, biliary tract infection, peritonitis, etc. caused by sensitive bacteria. [0003] This product is the "ace" antibiotic with the strongest effect on Pseudomonas aeruginosa among similar drugs, and its antibacterial activity is 2-4 times stronger than that of similar drugs; it is effective against most enzyme-producing and non-enzyme-producing G...
Claims
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IPC IPC(8): C07D499/68C07D499/06
Inventor 孙家强陈亮黄艳芳付凌燕李如宏吴剑波厉莹
Owner ZHEJIANG APELOA TOSPO PHARMA
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