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Procaine penicillin, preparation method thereof, impurity and impurity control method

A technology of procaine penicillin and a control method, which is applied in the field of drug preparation and can solve the problems of difficulty in quality monitoring, unclear impurities of procaine penicillin and the like

Pending Publication Date: 2022-04-01
NORTH CHINA PHARM GRP SEMISYNTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The object of the present invention is to provide a kind of procaine penicillin and preparation method thereof, impurity and impurity control method, to provide a kind of preparation method of higher quality procaine penicillin, solve the problem of procaine in the prior art The impurity of penicillin is unclear and the quality monitoring is difficult

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  • Procaine penicillin, preparation method thereof, impurity and impurity control method
  • Procaine penicillin, preparation method thereof, impurity and impurity control method
  • Procaine penicillin, preparation method thereof, impurity and impurity control method

Examples

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Embodiment 1

[0032] A procaine penicillin impurity is characterized as a compound shown in formula (1), and the compound English name: 2-{[2-(4-aminobenzoyloxy)ethyl](ethly)amino}ethyl-4-aminobenzoate. Chinese name: 2-{[2-(4-aminobenzoyloxy)ethyl](ethyl)amino}ethyl-4-aminobenzoate. Molecular formula: C 20 h 25 N 3 o 4 . Molecular weight: 371.

[0033]

[0034] Structure confirmation: LC-MS analysis of RRT0.24 impurity, [M+H] + =372, the molecular weight is 371, see attached figure 1 . The RRT0.24 impurity was analyzed by nuclear magnetic resonance, the data is shown in Table 1, and the spectrum is attached figure 2 , 3 . Analysis of hydrogen spectrum data: (1) There is one methyl group in the structure: it is adjacent to the methylene group (triple peak), and the chemical shift is δ1.11ppm. (2) There are 5 methylene groups in the structure: adjacent to heteroatoms, they are divided into 3 groups of signals, and the chemical shifts are between δ2.7-4.4ppm. (3) There are 8 a...

Embodiment 2

[0040] The synthesis process of the procaine penicillin RRT0.24 impurity is as follows:

[0041]

[0042]The impurity is introduced by the raw material procaine hydrochloride and is generated during the synthesis of procaine hydrochloride. In the synthesis process of procaine hydrochloride, diethylamine is used to add ethylene oxide to obtain diethylaminoethanol, and then form an intermediate with p-nitrobenzoic acid through esterification, and then reduce to obtain procaine. Due to the presence of ethylamine in the starting material diethylamine, N,N'-di(2-ethanolyl)ethylamine is generated during the addition of ethylene oxide, and further undergoes esterification reaction with two molecules of p-nitrobenzoic acid , post-reduction produces RRT0.24 impurity. The production process of procaine penicillin does not have the conditions for the formation of this impurity.

Embodiment 3

[0044] Preparation of procaine penicillin:

[0045] (1) prepare procaine hydrochloride solution: detect the content of RRT0.24 impurity in raw material procaine hydrochloride, its content is 0.036%, 15.3g procaine hydrochloride is added in 41mL purified water under room temperature, ultrasonically dissolves to After clarification, add water to 53mL.

[0046] (2) Preparation of penicillin potassium salt buffer: 0.47g buffer salt (Na 2 HPO 4 and NaH 2 PO 4 The mass ratio is 6:1 or 0.40g Na 2 HPO 4 +0.067g NaH 2 PO 4 ) into 61mL of purified water, then 0.067g of NaCl, ultrasonically dissolved until clarified, at room temperature, add 20g of penicillin potassium salt, ultrasonically dissolved until clarified, and replenish water to 93mL.

[0047] (3) Crystallization unit: slowly add 0.2mL procaine hydrochloride solution and 0.024g seed crystal into the penicillin potassium salt buffer respectively, and grow the crystal for 7min. Add procaine hydrochloride solution to the ...

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Abstract

The invention provides procaine penicillin as well as a preparation method, an impurity and an impurity control method thereof. The content of an RRT 0.24 impurity in the procaine penicillin is less than 0.13%. According to the preparation method, the content of an RRT0.24 impurity in a used raw material procaine hydrochloride is controlled to be not higher than 0.05%, and the RRT0.24 impurity is 2-{[2-(4-aminobenzoyloxy) ethyl] (ethyl) amino} ethyl-4-aminobenzoate. The content y of the RRT 0.24 impurity in the product procaine penicillin and the content x of the RRT 0.24 impurity in the raw material procaine hydrochloride meet a linear relation model y = 2.4835 x, wherein the model R2 = 0.9546. The invention discloses a novel impurity of procaine penicillin, which plays an important role in quality control of procaine penicillin.

Description

technical field [0001] The present invention relates to the technical field of medicine preparation, in particular to a kind of procaine penicillin and its preparation method, impurity and impurity control method. Background technique [0002] Procaine penicillin, its chemical name is: p-aminobenzoic acid 2-(diethylamino)ethyl ester (6R)-6-(2-phenylacetamido) penicillate monohydrate. The structural formula is: [0003] [0004] Procaine penicillin is the procaine salt of penicillin, and its antibacterial active ingredient is penicillin, which is a long-acting variety of penicillin. Penicillin exerts its bactericidal effect by inhibiting the synthesis of bacterial cell walls. The preparation method is as follows: penicillin potassium solution and procaine hydrochloride solution undergo double decomposition reaction, crystallize, wash and dry to obtain procaine penicillin crystalline powder. [0005] Drug consistency evaluation, that is, drug consistency research, is the...

Claims

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Application Information

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IPC IPC(8): C07D499/46C07D499/18C07C229/60C07C227/42G01N30/02
CPCC07C229/60G01N30/02C07D499/46C07C227/42C07D499/18
Inventor 张民严正人吴海瑶马向向黄娟周玉敏郭强
Owner NORTH CHINA PHARM GRP SEMISYNTECH CO LTD
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