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A kind of refining method of d-penicillamine

A purification method, penicillamine technology, applied in chemical instruments and methods, preparation of organic compounds, organic chemistry, etc., can solve problems such as safety hazards, drug safety doubts, and sulfonic acid derivatives impurity limit regulations, to ensure Product yield, easy separation and removal effect

Active Publication Date: 2019-09-06
浙江东邦药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But, no matter be total synthesis method or penicillin degradation method, the purity and the quality of the D-penicillamine that above-mentioned two kinds of methods obtain are not high, and this is because in the D-penicillamine molecular structure contains carboxyl, amino and sulfhydryl, In the process of reaction and post-treatment, bimolecular condensation will easily occur when encountering air, and the impurity dithiopenicillamine will be generated, and will continue to react to generate penicillaminesulfonic acid derivative impurities. The properties of these impurities are very similar to D-penicillamine , the subsequent recrystallization purification is very difficult, and it is not easy to obtain high-purity D-penicillamine products that can meet the pharmaceutical requirements
[0006] The D-penicillamine products that have been listed on the existing market, whether they are preparations or raw materials, have a very high content of dithiopenicillamine impurities and sulfonic acid derivative impurities. This is due to the fact that the commercially available penicillamine raw materials The dithiopenicillamine impurity is already very high, and there is a further increasing trend in the subsequent preparation of penicillamine preparations, so the United States Pharmacopoeia stipulates that the limit of dithiopenicillamine impurities in penicillamine is API (API )<1.0%, capsules (Capsules)<2.0%, tablets (Tablets)<3.0%, such a high impurity limit is very rare, and it also makes people question the safety of the drug
The dithiopenicillamine impurity can be quantitatively studied after the relatively pure product is prepared, but the sulfonic acid derivative impurity is not easy to separate and obtain, so neither the Chinese Pharmacopoeia nor the United States Pharmacopoeia has a limit regulation on the sulfonic acid derivative impurity
We analyzed the sulfonic acid derivative impurity in the reference drug (RLD), and its proportion should reach 0.78%, which far exceeds the requirement of 0.1% of the unknown impurity limit stipulated by ICH, which brings serious hidden dangers to the safety of medication , so it is necessary to develop a simple method for purifying penicillamine in order to obtain safer drugs

Method used

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  • A kind of refining method of d-penicillamine
  • A kind of refining method of d-penicillamine
  • A kind of refining method of d-penicillamine

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Effect test

Embodiment 1

[0031] Preparation of D-penicillamine aqueous reaction solution

[0032] Add penicillin G potassium (100.0g), n-butanol (1600mL), hydrazine hydrate (23.7g), concentrated hydrochloric acid (45.6g) successively to the 2000mL there-necked flask, and be heated to 80 ℃~90 ℃ of temperature conditions to carry out reaction 4 After the reaction was completed, the reaction solution was slowly cooled to room temperature and filtered, and the filter cake was washed with a small amount of acid water, and the filtrate and the acid water washing solution were mixed to obtain a D-penicillamine acid water reaction solution for subsequent use. The acid water here can be an acidic system such as a hydrochloric acid solvent, a dilute trifluoroacetic acid solution or a phosphoric acid solution. Using HPLC test, the results show that the impurities of dithiopenicillamine are about 4%, and the impurities of sulfonic acid derivatives are about 1%, and the content of penicillamine is calculated.

Embodiment 2

[0034] Selecting the D-penicillamine aqueous reaction solution obtained in the above embodiment 1, is equivalent to making D-penicillamine in an acidic system, and then adding about 5wt% of the Pd / C catalyst, which is equivalent to making the amount of metal catalyst added. It is 5% of the mass of D-penicillamine. After replacing it with nitrogen, hydrogen is introduced to carry out catalytic hydrogenation reaction. The temperature of catalytic hydrogenation reaction is 60 ° C to 80 ° C, and the reaction is started after about 2 hours. The sample is measured every 1 hour. Dithiopenicillamine impurity and sulfonic acid derivative impurity content, stop feeding hydrogen when both are less than 0.1%, replace with nitrogen, remove Pd / C catalyst by filtration, and then add ammonia water to the filtrate to adjust the pH of the system to 5.5, to precipitate a large amount of white solids or crystals, filter, wash with water, and dry to obtain purified D-penicillamine. Determination o...

Embodiment 3

[0042] The specific purification and purification method of this embodiment is basically the same as that of embodiment 2, except that the precious metal catalyst palladium carbon is respectively platinum / carbon, platinum oxide, rhodium octoate or ruthenium carbon, and the added catalytic amount is 5%. The corresponding purified D-penicillamine was obtained. The obtained D-penicillamine is tested, and the purity of D-penicillamine can reach more than 99.5%, and the impurity contents of dithiopenicillamine and sulfonic acid derivatives are both less than 0.1%.

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Abstract

The invention relates to a method for refining D-penicillamine, and belongs to the technical field of drug purification. In order to solve the problem of high impurity content in the prior art, the method for refining the D-penicillamine is provided, and comprises the steps of: performing in-situ refining treatment in an acidic system under the condition of coexistence of a reduction system containing a metal catalyst and the to-be-refined D-penicillamine so as to obtain a corresponding reaction liquid, wherein metal in the metal catalyst is selected from metal in transition elements and / or aluminum; and performing filtration to remove insoluble matter, and adjusting the pH value until the D-penicillamine is precipitated so as to obtain the refined D-penicillamine. Through the method, a penicillamine disulfide impurity and a sulfonic acid derivative impurity in the D-penicillamine can be remove so as to reduce the content of the two impurities effectively, and the content of the two impurities can be effectively controlled within 0.1%.

Description

technical field [0001] The invention relates to a method for purifying D-penicillamine, which belongs to the technical field of drug purification. Background technique [0002] D-penicillamine is the amino acid metabolite of penicillin, but it has no antibacterial properties. It is widely used clinically in the treatment of heavy metal poisoning and hepatolenticular degeneration (Wilson disease), as well as in severe active rheumatoid arthritis for which other drug treatments fail, as well as in the treatment of chronic active hepatitis, scleroderma, dry mouth and eyes. , arthritis syndrome and other autoimmune diseases, all have obvious curative effect. It has been included in the World Health Organization's Essential Medicines List (a list of the most important medicines needed by the healthcare system). [0003] D-penicillamine can be used as an API or an intermediate, and further processed into penicillamine derivatives. Among them, the chemical name of D-penicillamin...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C319/28C07C323/58
Inventor 王海平孙明磊池瀛周辉高扬
Owner 浙江东邦药业有限公司