CN101585843B - Process for preparing rifaximin - Google Patents
Process for preparing rifaximin Download PDFInfo
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- CN101585843B CN101585843B CN2008100697068A CN200810069706A CN101585843B CN 101585843 B CN101585843 B CN 101585843B CN 2008100697068 A CN2008100697068 A CN 2008100697068A CN 200810069706 A CN200810069706 A CN 200810069706A CN 101585843 B CN101585843 B CN 101585843B
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- rifaximin
- rifamycin
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- picoline
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Abstract
The invention discloses a process for preparing rifaximin, which comprises the following steps: fortimicin O is reacted with excessive 2-amino-4-picolyl for 20-24 hours at 35-45 DEG C by using ethanolas a reaction solvent; after the reaction, anhydrous potassium carbonate is added, wherein the mole number of the added anhydrous potassium carbonate is 0.9-1.1 times of that of the fortimicin O; the obtained mixture is stirred and filtered, and deionized water is added to obtained filter liquor for crystallizing; obtained filter mass is filtered; and after the filter mass is dried, a finished ri faximin product is obtained. The invention has the advantages of short time of the preparation process, simple and convenient post treatment, environmental protection, low consumption, high yield and low cost.
Description
Technical field
The present invention relates to a kind of technology of chemical synthetic drug, particularly a kind of synthesis technique of rifaximin.
Background technology
Rifaximin (Rifaximin), chemical name: 4-deoxidation-4 '-picoline is the sharp good fortune SV of [1 ', 2 '-1,2] imidazo [5,4-C] also, and structural formula is as follows:
Rifaximin is the potent highly selective enteron aisle of first a non-aminoglycosides microbiotic, this medicine anti-microbial effect is strong, has a broad antifungal spectrum, compare with aminoglycosides, this product has high activity to clostridium difficile, staphylococcus epidermidis and streptococcus faecium, the Bacteroides etc. in gram aerophil, the gram anerobe, and aminoglycosides antibiotics is to the basic non-activity of above Pseudomonas.In addition, this product also has good activity or high activity to Salmonellas, intestinal bacteria, Shigellae, yersinia entero-colitica etc.Be mainly used in infectious diarrhea, comprehensive diarrhoea, hepatogenic encephalopathy (door body divergency), postoperative infection prophylactic treatment, diverticulum disease etc.Rifaximin has been the clinical choice drug of diseases such as developed country's treatment infectivity, comprehensive diarrhoea at present.
According to data and patent documentation
[1～4]Record, at present, the operational path of synthetic rifaximin mainly can reduce following two:
(1) rifamycin-S gets 3-bromine rifamycin-S through bromo, again with 2-amino-4-picoline cyclization, promptly gets rifaximin through reduction then, and synthetic route is as follows:
(2) rifamycin B is changed into the intermediate rifamycin-O, rifamycin-O and 2-amino-4-picoline reaction can obtain rifaximin then, and synthetic route is as follows:
The starting material of above-mentioned two operational paths are easy to get, side chain 2-amino-4-picoline and intermediate 3-bromine rifamycin-S or all easy domestic purchase of rifamycin-O.But consider that industrial pollution, the three wastes are handled and the stability of technology, most of second operational path that adopts is that raw material obtains the target compound rifaximin by one-step synthesis with the rifamycin-O, is about 80% with the rifamycin-O calculated yield.Yet owing to adopt the stronger methylene dichloride of toxicity to make reaction solvent, operating environment is bigger to the human injury, and the methylene dichloride contaminate environment of discharging; And, because last handling process comprises operations (as shown in Figure 2) such as salt acid elution, twice ordinary water washing, anhydrous sodium sulfate drying, vacuum concentration system crude product, complex process, production efficiency is low, and raw material and energy consumption are big, the cost height.
Reference:
[1]USP?4,557,866
[2]USP?4,341,785
[3]J.Med.Chem.28，960-963(1985)
[4]The?Journal?of?Antibiotics.No.12，1611-1622(1984)
Summary of the invention
Technical problem to be solved by this invention is to provide that a kind of technology is simple, cost is low, yield is high and the preparation technology of the rifaximin of environment-protection low-consumption.
To achieve these goals, the technical solution adopted in the present invention is: with rifamycin-O and excessive 2-amino-4-picoline reaction, reaction solvent is an ethanol, and temperature of reaction is 35～45 ℃, 20～24 hours reaction times, after reaction finishes, add Anhydrous potassium carbonate, the mole number that adds Anhydrous potassium carbonate is 0.9～1.1 times of rifamycin-O mole number, agitation and filtration, add the deionized water crystallization in the filtrate, filter, get the rifaximin finished product behind the filtration cakes torrefaction.
The ratio of the mole number of above-mentioned rifamycin-O and 2-amino-4-picoline is 1: 2～1: 3, and the best is 1: 2.5.
Compare with traditional synthesis process, the present invention has following advantage:
(1) increased substantially yield, brought up to average yield 88% by former average yield 80%;
(2) as shown in table 1, the present invention has reduced product master consumption and total consumption significantly.Main consumption is reduced to 1.4806g/g by 1.7138g/g.Total consumption is reduced to 4.7961g/g by 35.9879g/g;
Table 1: novel process raw material consumption and main consumption
(3) simplify technology, the shortened process time, saved the energy.The novel process reaction times reduced to 24 hours by 48 hours, the time that operations such as salt acid elution, twice ordinary water washing, vacuum concentration system crude product have been saved in aftertreatment simultaneously, had saved water, electric energy;
(4) reduce the discharging of waste water, waste residue significantly, reduced the disposal of waste gas, water and industrial residue cost, protected environment;
(5) adopt the alternative stronger methylene dichloride of toxicity of ethanol of low toxicity to make reaction solvent, improved operating environment, reduced environmental pollution.
Description of drawings
Fig. 1 is preparation technology's schema of the present invention;
Fig. 2 is preparation technology's schema of rifaximin before improving.
Embodiment
Embodiment 1
Fig. 1 is preparation technology's schema of the present invention, electric mixer is housed, temperature is taken into account in three mouthfuls of round-bottomed flasks of 1000ml of reflux, add 400ml ethanol, stir and add 75.4g (0.1mol) rifamycin-O and 27g (0.25mol) 2-amino-4-picoline down successively, be warming up to 40 ℃, stirring reaction 24 hours.Reaction is complete, adds 12.5g (0.09mol) Anhydrous potassium carbonate, stirs after 30 minutes, filters, and filtrate adds deionized water 170ml, carries out crystallization, filters, and gets rifaximin finished product 70.1g, fusing point: 200～205 ℃ (decomposition), yield 89% behind the filtration cakes torrefaction.
Embodiment 2
Reaction vessel is identical with embodiment 1, adds 500ml ethanol, stirs down to add 75.4g (0.1mol) rifamycin-O and 21.6g (0.2mol) 2-amino-4-picoline successively, is warming up to 45 ℃, stirring reaction 20 hours.React and finish, add 13.8g (0.1mol) Anhydrous potassium carbonate, stir after 30 minutes, filter, filtrate adds deionized water 180ml, carries out crystallization, gets rifaximin finished product 68.5g, yield 87%.
Embodiment 3
Preparation technology is with embodiment 1, and the addition of different is 2-amino-4-picoline is 32.4g (0.3mol), after reaction finishes, adds Anhydrous potassium carbonate 15.2g (0.11mol), final rifaximin finished product 69.3g, yield 88%.
Claims (3)
1. the preparation technology of a rifaximin, with rifamycin-O and excessive 2-amino-4-picoline reaction, it is characterized in that: the reaction solvent of rifamycin-O and 2-amino-4-picoline is an ethanol, temperature of reaction is 35～45 ℃, 20～24 hours reaction times, after reaction finishes, add Anhydrous potassium carbonate, the mole number that adds Anhydrous potassium carbonate is 0.9～1.1 times of rifamycin-O mole number, agitation and filtration, add the deionized water crystallization in the filtrate, filter, get the rifaximin finished product behind the filtration cakes torrefaction.
2. the preparation technology of a kind of rifaximin according to claim 1 is characterized in that: the ratio of the mole number of described rifamycin-O and 2-amino-4-picoline 1: 2～1: 3.
3. the preparation technology of a kind of rifaximin according to claim 2 is characterized in that: the ratio of the mole number of described rifamycin-O and 2-amino-4-picoline 1: 2.5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008100697068A CN101585843B (en) | 2008-05-21 | 2008-05-21 | Process for preparing rifaximin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008100697068A CN101585843B (en) | 2008-05-21 | 2008-05-21 | Process for preparing rifaximin |
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| CN101585843A CN101585843A (en) | 2009-11-25 |
| CN101585843B true CN101585843B (en) | 2011-07-06 |
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| CN2008100697068A Active CN101585843B (en) | 2008-05-21 | 2008-05-21 | Process for preparing rifaximin |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012155981A1 (en) * | 2011-05-19 | 2012-11-22 | Friulchem Spa | New process for the synthesis of rifaximin and a new pseudo-crystalline form of rifaximin obtained thereby |
| CN111423456A (en) * | 2020-04-03 | 2020-07-17 | 南京昊绿生物科技有限公司 | Synthesis process of rifaximin-D6 |
| CN111560027A (en) * | 2020-07-14 | 2020-08-21 | 北京维德维康生物技术有限公司 | Rifaximin hapten, artificial antigen, preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4557866A (en) * | 1984-05-15 | 1985-12-10 | Alfa Farmaceutici S.P.A. | Process for the synthesis of pyrido-imidazo rifamycins |
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2008
- 2008-05-21 CN CN2008100697068A patent/CN101585843B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4557866A (en) * | 1984-05-15 | 1985-12-10 | Alfa Farmaceutici S.P.A. | Process for the synthesis of pyrido-imidazo rifamycins |
Non-Patent Citations (1)
| Title |
|---|
| 张祖兵.利福昔明的结构确认和质量标准研究.《中国优秀博硕士学位论文数据库（硕士）医药卫生科技辑》.2006,(第02期),E079-13. * |
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| CN101585843A (en) | 2009-11-25 |
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Effective date of registration: 20211223 Address after: Room a639-07, building 2, No. 351, GuoShouJing Road, China (Shanghai) pilot Free Trade Zone, Pudong New Area, Shanghai 200120 Patentee after: KNOWSHINE (SHANGHAI) PHARMACHEMICALS Inc. Address before: Jiulongpo Branch Park four street 400041 Chongqing City No. 57 Patentee before: CHONGQING SAINUO BIOPHARMACEUTICAL Co.,Ltd. |
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Effective date of registration: 20230414 Address after: 400000 No. 28, Gaoxin Avenue, Jiulongpo District, Chongqing Patentee after: CHONGQING SAINUO BIOPHARMACEUTICAL Co.,Ltd. Address before: Room a639-07, building 2, No. 351, GuoShouJing Road, China (Shanghai) pilot Free Trade Zone, Pudong New Area, Shanghai 200120 Patentee before: KNOWSHINE (SHANGHAI) PHARMACHEMICALS Inc. |