阅读说明：本技术 一种利福昔明-d6的合成工艺 (Synthesis process of rifaximin-D6 ) 是由 贲昊玺 于海涛 孙爱学 于 2020-04-03 设计创作，主要内容包括：本发明提供了一种利福昔明-D6的合成工艺,包括如下步骤：步骤1),以化合物Ⅰ2-氨基-4-甲基吡啶和D<Sub>2</Sub>O为原料,在5wt%钯碳存在下和氮气保护下反应,得到氘代物中间体,即化合物Ⅱ4-甲基-2-氨基吡啶-D6；步骤2),将利福霉素S和步骤1)所制备的氘代中间体化合物Ⅱ4-甲基-2-氨基吡啶-D6溶于二氯甲烷,氮气保护下,室温搅拌,滴加溶解有碘单质的二氯甲烷溶液,室温反应过夜18小时后,滴加L-抗坏血酸水溶液,搅拌,反应完全后,洗涤纯化制得产物利福昔明-D6。本发明具有如下技术效果：利福昔明-D6的中间体II的合成方法简便,原料易得；合成利福昔明-D6步骤简短、易操作。(The invention provides a synthesis process of rifaximin-D6, which comprises the following steps: step 1) with the compounds I2-amino-4-methylpyridine and D 2 O is taken as a raw material, and reacts with nitrogen protection in the presence of 5wt% palladium carbon to obtain a deuterated intermediate, namely a compound II 4-methyl-2-aminopyridine-D6, and step 2), rifamycin S and the deuterated intermediate compound II 4-methyl-2-aminopyridine-D6 prepared in step 1) are dissolved in dichloromethane, and are stirred at room temperature under the protection of nitrogen, a dichloromethane solution with iodine simple substances is dropwise added, after the reaction is carried out overnight for 18 hours at room temperature, L-ascorbic acid aqueous solution is dropwise added, and after the reaction is completed, the rifaximin-D6. product is obtained by washing and purifying.)

1. A synthesis process of rifaximin-D6 is characterized by comprising the following steps:

step 1) with the compounds I2-amino-4-methylpyridine and D₂O is taken as a raw material, and reacts with nitrogen under the existence of 5wt% palladium carbon to obtain a deuteron intermediate, namely a compound II 4-methyl-2-aminopyridine-D6;

the reaction route is as follows:

and 2) dissolving rifamycin S and the deuterated intermediate compound II 4-methyl-2-aminopyridine-D6 prepared in the step 1) in dichloromethane, stirring at room temperature under the protection of nitrogen, dropwise adding a dichloromethane solution dissolved with an iodine simple substance, reacting overnight at room temperature for 18 hours, dropwise adding a L-ascorbic acid aqueous solution, stirring, washing and purifying after complete reaction to obtain the product rifaximin-D6.

2. The process for the synthesis of rifaximin-D6 according to claim 1, wherein in step 1), the reactants 2-amino-4-methylpyridine and D₂The molar ratio of O is: 1: 55.36.

3. the process for the synthesis of rifaximin-D6, according to claim 1, wherein in step 2), the molar ratio of reactants rifamycin S and deuterated intermediate is: 1: 3.05.

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis process of rifaximin-D6.

Background

Rifaximin is a rifamycin derivative, the first non-aminoglycoside intestinal antibiotic. The product has strong action and broad antibacterial spectrum. The product can be used for treating Staphylococcus aureus, Staphylococcus epidermidis and Streptococcus faecalis in gram-positive aerobic bacteria; for salmonella, escherichia coli, shigella, yersinia enterocolitica and coccus in gram-negative irregular oxygen bacteria; bacteroides in gram-negative anaerobes are highly active.

rifaximin-D6 is a stable isotope labeled rifaximin which can be used for studying rifaximin toxicology and pharmacology, and a synthesis method of the rifaximin-D6 is not reported at present.

The structural formula of rifaximin-D6 is as follows:

the existing synthesis method of rifaximin is as follows:

if rifaximin-D6 is synthesized according to the existing rifaximin synthesis method, the following technical problems exist:

1) commercially available as 4-methyl-2-aminopyridine-D6;

2) the synthetic route of the 4-methyl-2-aminopyridine-D6 is complex and has no synthetic significance.

3) The General method of organizing and utilizing the General method D₂O with hetereogenous Pd/C reports hydrogen deuterium exchange of 4-methyl-2-aminopyridine-D6, but high temperature reaction is required under hydrogen atmosphere, and the safety is not enough.

Disclosure of Invention

In order to overcome the defects of the prior art, the invention provides a synthesis process of rifaximin-D6.

The inventor of the invention finds that deuterium water is used as a deuterium source, through heavy metal catalysis, 4-methyl-2-aminopyridine-D6 can be obtained through hydrogen and deuterium exchange under a high temperature condition, the mass spectrum shows that the deuteration rate is more than 98%, and then rifaximin-D6 is synthesized, and the deuteration rate of a final product is more than 98%.

The technical scheme of the invention is as follows:

a synthesis process of rifaximin-D6 comprises the following steps:

step 1) with the compounds I2-amino-4-methylpyridine and D₂O is taken as a raw material, and reacts with nitrogen under the existence of 5wt% palladium carbon to obtain a deuteron intermediate, namely a compound II 4-methyl-2-aminopyridine-D6;

the reaction route is as follows:

and 2) dissolving rifamycin S and the deuterated intermediate compound II 4-methyl-2-aminopyridine-D6 prepared in the step 1) in dichloromethane, stirring at room temperature under the protection of nitrogen, dropwise adding a dichloromethane solution dissolved with an iodine simple substance, reacting overnight at room temperature for 18 hours, dropwise adding a L-ascorbic acid aqueous solution, stirring, washing and purifying after complete reaction to obtain the product rifaximin-D6.

Preferably, the first and second electrodes are formed of a metal,

in the step 1), reactants 2-amino-4-methylpyridine and D₂The molar ratio of O is: 1: 55.36.

in the step 2), the molar ratio of the reactants rifamycin S and the deuterated intermediate is as follows: 1: 3.05.

"5 wt% palladium on carbon" in the present invention means a Pd/C catalyst with a Pd loading of 5 wt%.

The inventor finds out through experimental research that deuterium and hydrogen exchange can be carried out without hydrogen atmosphere, and the purpose of deuterium and hydrogen exchange can be achieved by catalysis of a 5wt% palladium-carbon catalyst. The amount of deuterium used is greatly reduced compared with the prior art, and the rate of deuterium substitution can reach more than 98% by one-time exchange. The invention has great technical progress in terms of the combination of heavy metal catalyst, reaction condition safety and deuterium water usage amount.

The invention adopts nitrogen atmosphere to protect the reaction system for experimental safety, and can also adopt other inert gases.

The invention has the following technical effects: the synthesis method of the intermediate II of rifaximin-D6 is simple and convenient, and the raw materials are easy to obtain; the synthesis process of the rifaximin-D6 is short and easy to operate.

Drawings

Figure 1 is a nuclear magnetic spectrum of rifaximin-D6.

Figure 2 is a mass spectrum of rifaximin-D6.

Detailed Description

Rifamycin S is commercially available.

The present invention will be described in detail with reference to specific examples.