CN103319356A - One-step green synthesis process of antimalarial raw material benflumetol - Google Patents
One-step green synthesis process of antimalarial raw material benflumetol Download PDFInfo
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- CN103319356A CN103319356A CN2013102381770A CN201310238177A CN103319356A CN 103319356 A CN103319356 A CN 103319356A CN 2013102381770 A CN2013102381770 A CN 2013102381770A CN 201310238177 A CN201310238177 A CN 201310238177A CN 103319356 A CN103319356 A CN 103319356A
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- benzfluorenol
- butyl amine
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Abstract
The invention discloses a semisynthesis process for producing benflumetol by taking alpha (di-n-butylamide)-2,7-dichloro-4-fluorenemethanol as a raw material. The process comprises the following steps: dispersing alpha (di-n-butylamide)-2,7-dichloro-4-fluorenemethanol in a mixed solvent, carrying out alkali catalysis and heating reflux on the obtained mixture, and carrying out condensation reaction on the obtained object and p-chlorobenzaldehyde, reducing the temperature to room temperature, and continuing to stir the obtained product so as to separate out coarse benflumetol grains; carrying out recrystallization on the coarse benflumetol grains by using acetone crystallization so as to obtain a fine benflumetol product with a content and a purity of more than 99.0%.
Description
Technical field
The green that the present invention relates to a kind of anti-malarial bulk drug benzfluorenol is synthetic, being specifically related to synthesis material is key intermediate-α-(Di-n-Butyl Amine base)-2,7-two chloro-4-Lumefantrines, obtain high yield, high purity benzfluorenol with the Semi-polarity solvent crystallization at condensation under alkaline condition.
Background technology
Benzfluorenol is a kind of alkaloid compound that contains multi-aromatic ring, is cis-2-dibutylamino-1-[2,7-two chloro-9-(4-chloro-benzylidene)-9H-fluorenes-4-yl]-ethanol racemize fluorene derivatives.It is to have the Chinese medical officer Academy of Medical Sciences to study successfully, is the pioneering antimalarial agent of China.Benzfluorenol has very high killing rate good activity is arranged aspect antimalarial protozoon and the parasite to anti-chloroquine and plasmodium falciparum, simultaneously animal plasmodium and human malignant's Blood-stage Plasmodium is had significant killing action.Its antimalarial advantage is for having no drug resistance and cross-resistance, and toxicity is low and antimalarial effect is lasting, but the slower shortcoming of onset is arranged.The researchist of Chinese military medicine academy of sciences is rapid-action with itself and antimalarial, killing rate is high, the Artemether of easy recurrence is combined as the antimalarial compound, has reached very perfectly antimalarial effect.This compound ratio is Artemether: benzfluorenol=1: 6, and the present base directory of having included World Health Organization's antimalarial agent in, its consumption also rises year by year, and according to statistics, the benzfluorenol consumption surpassed 1000 tons in 2012, was worth 300,000,000 Renminbi.
So the industrialized process for preparing of benzfluorenol is necessary further investigation, and realize high yield, low-cost large production technique.What benzfluorenol was synthetic is by the celestial team of the Deng Rong of the Military Medical Science Institute report (new synthetic process of new antimalarial agent benzfluorenol the earliest; CN 1029680C); its route is the reaction of five steps; be about to fluorenes chlorination in Glacial acetic acid and obtain 2; 7-dichloro fluorenes; obtain 2 with the Using Aluminium Trichloride as Catalyst acidylate again; 7-two chloro-4-chloracetyl-fluorenes; then obtain 2 with potassium borohydride reduction and strong potassium oxide cyclisation; 7-two chloro-4-Oxyranyle-fluorenes, this compound and Di-n-Butyl Amine at high temperature react and obtain α-(Di-n-Butyl Amine base)-2,7-two chloro-4-Lumefantrines; this compound obtains benzfluorenol with the 4-chloro-benzaldehyde condensation in ethanol at last, and productive rate is about 15%.Route and step have all been continued to use this patent (Ulrich Beutler in numerous benzfluorenol thereafter and the synthetic report of its intermediate, Peter C.Fuenfschilling, and Andreas SteinkemperAn Improved Manufacturing Process for the Antimalaria Drug Coartem.Part II, Organic Process Research ﹠amp; Development2007,11,341-345; Liao Wenbin, Zheng Qing four .CN 101747210 A).India Cipla Ltd. was application Chinese invention patent (improving one's methods of synthetic antimalarial agent in 2006, CN 1865227 A) reported the route of an innovation, the main synthetic route of improving is to use the intermediate 2 that the celestial route of Deng Rong obtains, 7-two chloro-4-Oxyranyle-fluorenes further obtain 2 with the 4-chloro-benzaldehyde condensation, 7-two chloro-4-oxyethane-9-react with Grignard reagent Di-n-Butyl Amine magnesium bromide chlorobenzene methylene radical-fluorenes again, obtain benzfluorenol.
In above method, fluorene derivatives intermediate and 4-chloro-benzaldehyde reaction yield are all below 70%, and Atom economy is low, and production cost is too high.In addition, unreacted supplementary material is too much, causes relatively difficulty of end product benzfluorenol separation and purification, finally obtains high purity elaboration benzfluorenol yield low.Simultaneously, bibliographical information condensation reaction condition is comparatively violent, also has more other impurity to generate in the reaction.The present invention namely solves crucial α-(Di-n-Butyl Amine base)-2, and the problems referred to above of 7-two chloro-4-Lumefantrines and 4-chloro-benzaldehyde condensation realize improving productive rate, reduce cost environmental protection novel process.
The difference of the present invention and aforesaid method is:
(1) α-(Di-n-Butyl Amine base)-2,7-two chloro-4-Lumefantrines and 4-chloro-benzaldehyde condensation reaction system are the mixed solvents such as methyl alcohol, ethanol, toluene and ethylene glycol.
(2) catalysts is highly basic sodium methylate, sodium ethylate or weak base sodium acetate, potassium acetate etc.
(3) reaction unit has refluxing unit, and reflux solvent drying link is removed generation moisture.
(4) temperature of reaction need be controlled in 100 ℃, avoids by product to generate, and can adopt negative pressure mode to high boiling solvent.
(5) benzfluorenol is refining take acetone as solvent, obtains high purity, high-content product.Technique of the present invention is the route of good suitability for industrialized production from economy, environment and Occupational health angle.
Summary of the invention
The key problem that the present invention need to solve is the shortcoming that overcomes existing benzfluorenol synthetic technology, set up environmental friendliness, low cost, high purity, high-content from α-(Di-n-Butyl Amine base)-2,7-two chloro-4-Lumefantrines are to the semi-synthetic industrialization process of benzfluorenol.
Purpose of the present invention is achieved through the following technical solutions, and concrete route is seen Figure of description.
The semi-synthesizing technology route of benzfluorenol is with α-(Di-n-Butyl Amine base)-2, and 7-two chloro-4-Lumefantrines are raw material, and process base catalysis and 4-chloro-benzaldehyde condensation and crystallization recrystallization obtain high-content and highly purified product.Concrete steps are as follows:
(1) with the dissolving of the mixed solvent of 5-10 times of volume, raw material dispersion α-(Di-n-Butyl Amine base)-2,7-two chloro-4-Lumefantrines add 0.01-0.1 single or mixed base doubly again, the pH value about 11, stirring at room 1-2h.
(2) 4-chloro-benzaldehyde of 1-1.1 times of molar weight of adding in above-mentioned reaction system is warming up to backflow, and approximately 70-90 ℃ is reacted 10-16h, and thin-layer chromatography is observed intermediate α-(Di-n-Butyl Amine base)-2, and 7-two chloro-4-Lumefantrine spots disappear.
(3) temperature is down to room temperature, continues stirring reaction 1-3h, have the benzfluorenol crystal to separate out in the process, filtration under diminished pressure, and with a small amount of methyl alcohol or washing with alcohol, obtain the benzfluorenol crude product.
(4) with the benzfluorenol coarse-grain with a certain amount of acetone heating for dissolving, cross secondary filter to crystallizer, concentrating under reduced pressure goes out certain volume acetone, cooling crystallization filters again.Obtain product and obtain elaboration with the dry oven dry of bipyramid, content and purity are greater than 99.0%.
The invention provides the industrialized preparing process of semi-synthetic benzfluorenol, with intermediate α-(Di-n-Butyl Amine base)-2,7-two chloro-4-Lumefantrines are the synthetic antimalarial agent benzfluorenol of raw material.Reaction system is simple, flow process is controlled, production environmental protection, high-level efficiency.
Description of drawings
The semi-synthetic route of benzfluorenol is seen accompanying drawing.
Embodiment
Further illustrate in the following embodiments the present invention, this does not limit the scope of the invention.
Synthesizing of embodiment 1 benzfluorenol
α-(Di-n-Butyl Amine base)-2,7-two chloro-4-Lumefantrine 500.0kg are in the 500L stainless steel cauldron, and (V: V=9: 1) 3000L, stirring at room leaches to add methyl alcohol-ethylene glycol.Then add sodium methylate 10.0kg, again stirring at room reaction 1h.Then disposable adding 4-chloro-benzaldehyde 180.0kg is warming up to backflow again, and is controlled at approximately 15h of 75 ℃ of reactions, thin-layer chromatography monitoring raw material α-(Di-n-Butyl Amine base)-2, and 7-two chloro-4-Lumefantrine spots disappear.While stirring temperature is down to room temperature, continues stirring reaction 2h, the benzfluorenol crystal is separated out, filtration under diminished pressure, and with a small amount of methyl alcohol or washing with alcohol, obtain the benzfluorenol crude product.
Synthesizing of embodiment 2 benzfluorenol
α-(Di-n-Butyl Amine base)-2,7-two chloro-4-Lumefantrine 500.0kg are in the 500L stainless steel cauldron, and (V: V=95: 5) 2500L, stirring at room leaches to add ethanol-ethylene glycol.Then add sodium ethylate 11.0kg, again stirring at room reaction 1h.Then disposable adding 4-chloro-benzaldehyde 180.0kg is warming up to backflow again, and is controlled at approximately 12h of 85 ℃ of reactions, thin-layer chromatography monitoring raw material α-(Di-n-Butyl Amine base)-2, and 7-two chloro-4-Lumefantrine spots disappear.While stirring temperature is down to room temperature, continues stirring reaction 3h, the benzfluorenol crystal is separated out, filtration under diminished pressure, and with a small amount of methyl alcohol or washing with alcohol, obtain the benzfluorenol crude product.
Synthesizing of embodiment 3 benzfluorenol
α-(Di-n-Butyl Amine base)-2,7-two chloro-4-Lumefantrine 500.0kg are in the 500L stainless steel cauldron, and (V: V=85: 15) 2500L, stirring at room leaches to add toluene-ethylene glycol.Then add sodium methylate 5.0kg and Potassium ethanoate 8.0kg, again stirring at room reaction 2h.Then disposable adding 4-chloro-benzaldehyde 185.0kg is warming up to backflow again, and is controlled at approximately 16h of 85 ℃ of reactions, thin-layer chromatography monitoring raw material α-(Di-n-Butyl Amine base)-2, and 7-two chloro-4-Lumefantrine spots disappear.While stirring temperature is down to room temperature, continues stirring reaction 3h, the benzfluorenol crystal is separated out, filtration under diminished pressure, and with a small amount of methyl alcohol or washing with alcohol, obtain the benzfluorenol crude product.
Embodiment 4 benzfluorenol are refining
Benzfluorenol coarse-grain 500kg with 2500L acetone heating for dissolving, is crossed secondary filter to crystallizer, and concentrating under reduced pressure goes out 1000L acetone, and cooling crystallization while stirring filters behind the 2h again.Obtain benzfluorenol elaboration 470kg with the dry oven dry of bipyramid 2h again, content and purity are greater than 99.0%.
Claims (6)
1. a method for preparing anti-malarial bulk drug benzfluorenol is characterized by with α-(Di-n-Butyl Amine base)-2, and 7-two chloro-4-Lumefantrines are raw material.
2. described method according to claim 1, the mixed solvent that it is characterized by with 5-10 times of volume leaches α-(Di-n-Butyl Amine base)-2,7-two chloro-4-Lumefantrines are raw material, mixed solvent be methyl alcohol, ethanol or toluene respectively with the mixture of ethylene glycol different ratios.
3. described method according to claim 1 is characterized in that catalyzer is 0.01-0.1 single or mixed base doubly, comprise highly basic sodium methylate, sodium ethylate and weak base sodium-acetate, Potassium ethanoate, and hierarchy of control pH value is about 11.
4. described method according to claim 1, after it is characterized in that basic catalyst adds, stirring at room reaction 1-2h, drop into again the 4-chloro-benzaldehyde of 1-1.1 times of molar weight, be warming up to backflow, approximately 70-90 ℃ is reacted 10-16h, and thin-layer chromatography is observed intermediate α-(Di-n-Butyl Amine base)-2, and 7-two chloro-4-Lumefantrine spots disappear.
5. described method according to claim 4, it is characterized in that intermediate α-(Di-n-Butyl Amine base)-2, after 7-two chloro-4-Lumefantrine spots disappear, temperature is down to room temperature, continue stirring reaction 1-3h, have the benzfluorenol crystal to separate out filtration under diminished pressure in the process, and with a small amount of methyl alcohol or washing with alcohol, obtain the benzfluorenol crude product.
6. described method according to claim 5 is characterized in that the benzfluorenol coarse-grain with 5 times of amount acetone heating for dissolving, crosses secondary filter to crystallizer, concentrating under reduced pressure goes out approximately 2 times of volume acetone, and cooling crystallization filters again, obtain product and obtain elaboration with the dry oven dry of bipyramid, content and purity are greater than 99.0%.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104910026A (en) * | 2014-03-13 | 2015-09-16 | 昆明制药集团股份有限公司 | Alpha-(di-n-butylamine methyl)-2,7-dichloro-9-p-chlorobenzylidene-4-fluorenemethanol crystal form and preparation method thereof |
| CN106977410A (en) * | 2017-05-15 | 2017-07-25 | 张家港威胜生物医药有限公司 | One kind prepares lumefantrine intermediate α by fluorenes（Di-n-butylamine base）The preparation method of 2,7 dichloro-4,4 fluorenemethanols |
| CN111039804A (en) * | 2019-12-31 | 2020-04-21 | 日照巴洛特药业有限公司 | Benflumetol preparation method and matching system thereof |
| CN111320547A (en) * | 2020-04-03 | 2020-06-23 | 南京昊绿生物科技有限公司 | Synthesis method of lumefantrine-D9 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1042535A (en) * | 1988-11-10 | 1990-05-30 | 军事医学科学院微生物流行病研究所 | The new synthetic process of new antimalarial agent phenyl fluorenol |
| CN1865227A (en) * | 2005-04-25 | 2006-11-22 | 希普拉有限公司 | Improved method for synthesizing antimalarial |
-
2013
- 2013-06-17 CN CN2013102381770A patent/CN103319356A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1042535A (en) * | 1988-11-10 | 1990-05-30 | 军事医学科学院微生物流行病研究所 | The new synthetic process of new antimalarial agent phenyl fluorenol |
| CN1865227A (en) * | 2005-04-25 | 2006-11-22 | 希普拉有限公司 | Improved method for synthesizing antimalarial |
Non-Patent Citations (2)
| Title |
|---|
| BEUTLER ULRICH 等: "An Improved Manufacturing Process for the Antimalaria Drug Coartem. Part II", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》, vol. 11, no. 3, 28 April 2007 (2007-04-28), XP002539923, DOI: doi:10.1021/OP0602425 * |
| 邓蓉仙 等: "芴甲醇类化合物的合成及抗疟作用", 《药学学报》, vol. 32, no. 11, 31 December 1997 (1997-12-31) * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104910026A (en) * | 2014-03-13 | 2015-09-16 | 昆明制药集团股份有限公司 | Alpha-(di-n-butylamine methyl)-2,7-dichloro-9-p-chlorobenzylidene-4-fluorenemethanol crystal form and preparation method thereof |
| CN106977410A (en) * | 2017-05-15 | 2017-07-25 | 张家港威胜生物医药有限公司 | One kind prepares lumefantrine intermediate α by fluorenes（Di-n-butylamine base）The preparation method of 2,7 dichloro-4,4 fluorenemethanols |
| CN111039804A (en) * | 2019-12-31 | 2020-04-21 | 日照巴洛特药业有限公司 | Benflumetol preparation method and matching system thereof |
| CN111320547A (en) * | 2020-04-03 | 2020-06-23 | 南京昊绿生物科技有限公司 | Synthesis method of lumefantrine-D9 |
| CN111320547B (en) * | 2020-04-03 | 2022-05-20 | 南京昊绿生物科技有限公司 | Synthesis method of lumefantrine-D9 |
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Application publication date: 20130925 |