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Synthesis method of aspoxicillin sodium

A technology of apocillin sodium and a synthetic method, applied in the field of apocillin sodium synthesis, can solve the problems of high production and synthesis cost, high price and the like, and achieve the effects of avoiding amino acid racemization reaction, simple method and avoiding environmental pollution

Pending Publication Date: 2022-02-01
HAINAN HAILING CHEMIPHARMA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There is also the use of o-nitrobenzenesulfinic acid chloride as an amino protective agent, but the commercially available are all imported, the price is expensive, and the synthesis cost is too high

Method used

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  • Synthesis method of aspoxicillin sodium
  • Synthesis method of aspoxicillin sodium

Examples

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Embodiment 1

[0029] A kind of synthetic method of apoxicillin sodium, comprises the following steps:

[0030] (1) reacting D-aspartic acid-β-methyl ester with TrCl under alkaline conditions to obtain compound II;

[0031] (2) Compound II is methylated in an aqueous solution of methylamine to obtain Compound III;

[0032] (3) Compound Ⅲ and N-hydroxysuccinimide are reacted with tetrahydrofuran and N,N-diisopropylcarbodiimide to form compound Ⅳ;

[0033] (4) Prepared by reacting compound IV with amoxicillin triethylamine salt, compound V;

[0034] (5) Compound V removes the trityl group under mild acidic conditions to obtain apoxicillin;

[0035] (6) Apoxicillin is reacted in a solution of N,N-dimethylformamide and sodium carbonate to obtain apoxicillin sodium.

[0036] Step (1) is specifically: D-aspartic acid-β-methyl ester is dissolved in the solution of methanol and sodium hydroxide, the pH is adjusted to 8 with hydrochloric acid, and TrCl is added dropwise while stirring at 0°C to mi...

Embodiment 2

[0043] A kind of synthetic method of apoxicillin sodium, comprises the following steps:

[0044] (1) reacting D-aspartic acid-β-methyl ester with TrCl under alkaline conditions to obtain compound II;

[0045] (2) Compound II is subjected to a methylation reaction in an aqueous solution of methylamine to obtain Compound III;

[0046] (3) Compound III and N-hydroxysuccinimide are reacted with tetrahydrofuran and N,N-diisopropylcarbodiimide to form compound IV;

[0047] (4) Prepared by reacting compound IV with amoxicillin triethylamine salt, compound V;

[0048] (5) Compound V removes the trityl group under mild acidic conditions to obtain apoxicillin;

[0049] (6) Apoxicillin is reacted in a solution of N,N-dimethylformamide and sodium carbonate to obtain apoxicillin sodium.

[0050] Step (1) is specifically: D-aspartic acid-β-methyl ester is dissolved in a solution of methanol and sodium hydroxide, the pH is adjusted to 9 with hydrochloric acid, and triphenylchloromethane i...

Embodiment 3

[0057] A kind of synthetic method of apoxicillin sodium, comprises the following steps:

[0058] (1) reacting D-aspartic acid-β-methyl ester with TrCl under alkaline conditions to obtain compound II;

[0059] (2) Compound II is subjected to a methylation reaction in an aqueous solution of methylamine to obtain Compound III;

[0060] (3) Compound III and N-hydroxysuccinimide are reacted with tetrahydrofuran and N,N-diisopropylcarbodiimide to form compound IV;

[0061] (4) Prepared by reacting compound IV with amoxicillin triethylamine salt, compound V;

[0062] (5) Compound V removes the trityl group under mild acidic conditions to obtain apoxicillin;

[0063] (6) Apoxicillin is reacted in a solution of N,N-dimethylformamide and sodium carbonate to obtain apoxicillin sodium.

[0064] Step (1) is specifically: D-aspartic acid-β-methyl ester is dissolved in a solution of methanol and sodium hydroxide, the pH is adjusted to 8 with hydrochloric acid, and triphenylchloromethane i...

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Abstract

The invention discloses a synthesis method of aspoxicillin sodium, the synthesis method comprises the following steps: reacting D-aspartic acid-beta-methyl ester with triphenylchloromethane or triphenylbromomethane under an alkaline condition to prepare a compound II; performing methylamine reaction on the compound II in a methylamine aqueous solution, and preparing a compound III; reacting the compound III with N-hydroxysuccinimide under the action of tetrahydrofuran and N, N-diisopropyl carbodiimide to generate a compound IV; reacting the compound IV with amoxicillin triethylamine salt to obtain a compound V; removing triphenylmethyl from the compound V under an acidic condition to obtain the aspoxicillin. Apoxicillin reacts in a solution of N, N-dimethylformamide and sodium carbonate to prepare the apoxicillin sodium. The amino protection of the D-aspartic acid-beta-methyl ester is carried out by utilizing the triphenylchloromethane or the triphenylbromomethane, and the amino is removed in a mild acid environment so that the method is suitable for large-scale production, and particularly, the triphenylchloromethane is easy to store and operate at normal temperature and normal pressure, and thus the environmental pollution is avoided.

Description

technical field [0001] The invention relates to the technical field of apoxicillin sodium synthesis, in particular to a synthesis method of apoxicillin sodium. Background technique [0002] Apoxicillin, also known as aspartame, ASPC, DOYE, is a semi-synthetic broad-spectrum penicillin antibiotic with strong antibacterial effect. The antibacterial spectrum includes Gram-positive bacteria such as Staphylococcus, Streptococcus, and Pneumococcus bacteria 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. The structural formula is as follows: [0003] [0004] Apoxicillin is a white crystal or crystalline powder, hardly soluble in water and methanol, almost insoluble in ethanol and ether, easily soluble in N,N-dimethylformamide (DMF), and the pH value of the aqueous solut...

Claims

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Application Information

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IPC IPC(8): C07D499/16C07D499/68
CPCC07D499/16C07D499/68
Inventor 李一青韩勇
Owner HAINAN HAILING CHEMIPHARMA CORP
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