CN1042535A - A New Synthetic Process of Luflumetol, a New Antimalarial Drug - Google Patents
A New Synthetic Process of Luflumetol, a New Antimalarial Drug Download PDFInfo
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- CN1042535A CN1042535A CN 88107666 CN88107666A CN1042535A CN 1042535 A CN1042535 A CN 1042535A CN 88107666 CN88107666 CN 88107666 CN 88107666 A CN88107666 A CN 88107666A CN 1042535 A CN1042535 A CN 1042535A
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Abstract
一种治疗抗氯喹恶性疟疾新药苯芴醇α-(二正丁氨甲基)-2，7-二氯-9-英寸氯苯亚甲基-4-芴甲醇)化合物的合成新工艺。A new synthesis process of lumefantrine α-(di-n-butylaminomethyl)-2,7-dichloro-9-inch-chlorobenzylidene-4-fluorenylmethanol) compound, a new drug for treating anti-chloroquine falciparum malaria.
本发明的合成路线是：(1)采用工业芴(1)通过①氯化反应，②付氏反应，③硼氢化钾反应，④二正丁胺反应以及⑤与对氯苯甲醛缩合等5个反应步骤，获得苯芴醇。比已有合成路线(需10～12步反应)短。总产率为15％±，高于已有技术方案(9％±)66％。原材料消耗低，并废除了已有合成路线中必须制备的二氯胺丁和重氯甲烷两个反应步骤(制备重气甲烷的原料N-亚硝基-N-甲基脲和重氯甲烷本身都是强致癌的毒性物质，而且易燃易爆)。能减少环境污染，保证安全生产。The synthetic route of the present invention is: (1) adopt industrial fluorene (1) to pass through 1. chlorination reaction, 2. Fourier's reaction, 3. potassium borohydride reaction, 4. di-n-butylamine reaction and 5. condensation with p-chlorobenzaldehyde etc. Reaction steps to obtain lumefantrine. It is shorter than the existing synthetic route (needing 10-12 steps of reaction). The total yield is 15%±, which is 66% higher than that of the prior art (9%±). The consumption of raw materials is low, and the two reaction steps of dichloromethane and dichloromethane that must be prepared in the existing synthetic route are abolished (the raw material N-nitroso-N-methylurea and dichloromethane itself for the preparation of heavy gas methane Both are highly carcinogenic and toxic substances, and are flammable and explosive). It can reduce environmental pollution and ensure safe production.
用本发明的合成工艺制备的苯芴醇，对抗氯喹恶性疟疾的临床有效率为100％，治愈率96％以上。疗效高于氯喹(治愈率30％)3.2倍。The lumefantrine prepared by the synthesis process of the present invention has a clinical effective rate of 100% against chloroquine falciparum malaria, and a cure rate of over 96%. The curative effect is 3.2 times higher than that of chloroquine (30% cure rate).
Description
The present invention relates to a kind of new synthesis process of treatment anti-chloroquine pernicious malaria new drug phenyl fluorenol (α-(two n-butyl amine methyl)-27-two chloro-9-are to chlorobenzene methylene radical-4-Lumefantrine) compound.Belong to the medical and health manufacturing process.
Up to extremely at present, in the existing similar technology, still there is not the report that reacts new synthetic process with the present invention same or analogous five steps both at home and abroad, have only phenyl fluorenol intermediate IV, V synthetic document record (1.2.3).As preparation phenyl fluorenol intermediate IV such as Atkinson in 1974 was from anthranilic acid (I), through compound 2,3,4,5,6,7,8, needed the reaction of 8 steps just can finish altogether.Its reaction equation is as follows:
According to above-mentioned reaction equation, in the synthesis flow of existing phenyl fluorenol intermediate (IV), still needing increases preparation diazomethane (CH
2N
2) and dichloramine-T
Two synthesis steps.Therefore, finish the production of phenyl fluorenol, need the reaction scheme of 10～12 steps altogether.
The technical characterictic of phenyl fluorenol new synthetic process provided by the present invention is:
1. technical scheme is new, technical process short.5 steps reaction of the present invention is that with the fundamental difference of prior art innovation and technical process on the technical solution of the present invention are short, from selecting industrial fluorenes (I) for use, produce 27-dichloro fluorenes (II) through chlorination reaction, II and chloroacetyl chloride carry out the Fu Shi reaction and produce 27-dichloro fluorenes-4-chloroethene ketone (III), 27-dichloro fluorenes-4-oxyethane (IV) is produced in III and POTASSIUM BOROHYDRIDE reaction, α-(two n-butyl amine methyl)-27-two chloro-4-Lumefantrines (V) are produced in IV and Di-n-Butyl Amine reaction, V and 4-chloro-benzaldehyde condensation obtain the end product phenyl fluorenol.Its reaction scheme is as follows:
According to reaction equation, 5 step of phenyl fluorenol new synthetic process provided by the invention, the synthetic of intermediate (IV) only needs 3 to go on foot reaction (prior art needs the reaction of 8 steps).Obtain the end product phenyl fluorenol, be no more than 5 reactions steps (prior art needs 10～12 reactions steps) altogether, thereby shortened technical process, save starting material and time.
According to reaction equation, because the diazomethane and the dichloramine-T two-step reaction that cause public hazards have easily been discarded in the innovation on the 5 step reaction technology schemes of the present invention fully.The prior art scheme, synthetic phenyl fluorenol intermediate (IV) needs the preparation diazomethane, in order to prepare diazomethane, must preparation N-nitroso-group-N-methyl urea.This compound and diazomethane all have bigger toxicity, belong to strong carcinogen, and inflammable and explosive, are absolutely unsafe.Adopt synthesis technique of the present invention to produce phenyl fluorenol, can make the corresponding improvement of deleterious production environment condition, reduced the environmental pollution that causes because of the three wastes.
2. overall yield is higher than the prior art scheme.Adopting the synthetic phenyl fluorenol of prior art, its overall yield is 9% ±, synthesis technique provided by the invention, its overall yield is 15% ±, be higher than prior art 66%.
3. the phenyl fluorenol of producing with synthesis technique of the present invention, the clinical efficacy height.Economize 576 routine anti-chloroquine pernicious malaria patient being used for Yunnan, Hainan etc., it is more than 96% that its clinical effective rate 100% ， Zhi More leads, for chloroquine (Zhi More leads 30%) 3.2 times.
The technology implementation example.
According to 5 step synthetic routes, the embodiment that provides new antimalarial agent phenyl fluorenol new synthetic process is as follows.
Implement synthetic (chlorination reaction) of 1:27-dichloro fluorenes (II).
With industrial Glacial acetic acid 1200ml, water 40ml, fluorenes 120g and iron trichloride 7.2g, the adding capacity is in the there-necked flask of 2 liters successively, weighs mechanical stirring.Reflux condensing tube is installed when heating in putting water-bath.When treating that temperature reaches 35 ℃, feed chlorine from grass tube, temperature remains on 37～41 ℃, stops ventilation when weightening finish 100～110g.Continue down to stir 2 hours at 40 ℃.More than the temperature adjustment to 90 ℃, stir a moment then, pour in the beaker, to be cooled during to room temperature, a large amount of plate crystals of separating out are filtered, wash, with 1500ml industrial ethyl alcohol four streams 1 hour, naturally cooling, filter collection product 61～73g.Fusing point is 120～127 ℃ (molten apart from 3～4 ℃).The productive rate of 27-dichloro fluorenes is 36.1～43.0%.
Synthetic (the Fu Shi reaction of chloroacetyl chloride) of embodiment 2:27-dichloro fluorenes-4-chloroethene ketone (III).
Exsiccant 12-ethylene dichloride 700ml is placed capacity 1 liter there-necked flask, adds chloroacetyl chloride 24g(0.184M), aluminum trichloride (anhydrous) 42g(0.312M).Under agitation when 0～5 ℃ of Nei Wenda, gradation adds 27-dichloro fluorenes 40g(0.17M), added in about 30 minutes, keep 0～5 ℃, reacted 2～3 hours.Allow it heat up naturally, reacted again 2～3 hours.Reactant is slowly poured in the 1 liter frozen water that contains the 250ml concentrated hydrochloric acid then, be stirred well to and tell organic layer, water layer is with 1, and 2-ethylene dichloride washing secondary merges washing lotion and organic layer, washes with water to not showing acid substantially.Steam solvent, add about 2 liter industrial alcohols, boil to complete molten after-filtration, cooling filtrate is separated out solid.Get product 38～44g, 118～126 ℃ of melting ranges (molten) apart from 3～4 ℃.Concentrated mother liquor can be separated out the about 5g of portioned product again, and fusing point is more than 116 ℃, altogether product 43～49g.Productive rate 81.5～92.7%.
Synthetic (the potassium borohydride reduction reaction) of embodiment 3:27-dichloro fluorenes-4-oxyethane (IV)
In the 500ml there-necked flask, place 27-dichloro fluorenes-4-chloroethene ketone 20g, industrial POTASSIUM BOROHYDRIDE 6g and dehydrated alcohol 300ml.Temperature is 40～45 ℃ in the control, stirring reaction 9 hours.Placement is spent the night, and collects white solid, uses bubble, filters, and is washed with water to filtrate and is neutral substantially.Below 60 ℃, dry to constant weight, get white solid, 126～36 ℃ of fusing points (molten) apart from 4 ℃.The ethanol mother liquor is concentrated, and room temperature is placed cooling, separates out a small amount of faint yellow solid again, fusing point 120～30 ℃ (molten) apart from 4 ℃ altogether product 12.5～14.2g productive rate 70～80%.
Embodiment 4: synthetic (the Di-n-Butyl Amine reaction) of α-(two n-butyl amine methyl)-27-two chloro-4-Lumefantrines (V).
In flask at the bottom of the 200ml garden, place 27-dichloro fluorenes-4-oxyethane 20g, Di-n-Butyl Amine 14g and dehydrated alcohol 120ml, reflux 14 hours, filtered while hot is after filtrate is cold, separate out the yellowish white solid, filter, oven dry below 40 ℃ gets 23.4～24.9g, 74～9 ℃ of fusing points (molten apart from 2 ℃), the productive rate of α-(two n-butyl amine methyl) 27-two chloro-4-Lumefantrines is 80～85%.
Embodiment 5: α-(two n-butyl amine methyl) 27-two chloro-9-are to chlorobenzene methylene radical-4-Lumefantrine (with the 4-chloro-benzaldehyde condensation, generating the end product phenyl fluorenol).
On the 500ml there-necked flask, install agitator, Calcium Chloride Powder Anhydrous drying tube and thermometer, add dehydrated alcohol 300ml then, granular sodium hydroxide 3.5g, stirring and dissolving under the room temperature adds α-(two n-butyl amine methyl)-27-two chloro-4-Lumefantrine 10g, at 25 ℃ of left and right sides stirring reactions, through 30 minutes, faint yellow solid was separated out in most solid dissolvings later on gradually approximately.React after 24 hours and placed 1-2 days, filter, wash with water and leach thing to nothing alkalescence, oven dry below 60 ℃, the gained coarse products is faint yellow solid 9～10.5g, 122～127 ℃ of fusing points (molten apart from 2～3 ℃).Raw product dehydrated alcohol recrystallization gets the faint yellow crystallization of phenyl fluorenol 7.6～8.9g, 125～131 ℃ of fusing points (molten) apart from 2～3 ℃, and productive rate is 60～70%.
Reference
1.AD 752624
2.Atkinson ER，efal：J.Med，Chem.17：1009，1974
3. Deng Rong celestial being etc.: Acta Pharmaceutica Sinica 16 920,1981
Claims (6)
1, a kind of new synthetic process for the treatment of anti-chloroquine pernicious malaria new drug phenyl fluorenol.Produce 2.7-dichloro fluorenes (II) by industrial fluorenes (I), produce 2.7-dichloro fluorenes-4-chloroethene ketone (III) with II, with the synthetic phenyl fluorenol intermediate 2.7-dichloro fluorenes of III-4-oxyethane (IV), produce α-(two n-butyl amine methyl)-2.7-two chloro-4-Lumefantrines (V) with IV, make the end product phenyl fluorenol with V, the reaction of totally 5 steps is formed.
2, according to claim 1, anti-chloroquine pernicious malaria new drug phenyl fluorenol new synthetic process is characterized in that industrial fluorenes (I) is passed through chlorination reaction, produces 2.7-dichloro fluorenes (II);
3, according to claim 1, anti-chloroquine pernicious malaria new drug phenyl fluorenol new synthetic process is characterized in that the Fu Shi reaction of 27-dichloro fluorenes (II) by chloroacetyl chloride produce 27-dichloro fluorenes-4-chloroethene ketone (III);
4, according to claim 1, anti-chloroquine pernicious malaria new drug phenyl fluorenol new synthetic process is characterized in that 27-dichloro fluorenes-4-chloroethene ketone (III) is by reacting Synthetic 2 7-dichloro fluorenes-4-oxyethane intermediate (IV) with POTASSIUM BOROHYDRIDE;
5, according to claim 1, anti-chloroquine pernicious malaria new drug phenyl fluorenol new synthetic process is characterized in that 27-dichloro fluorenes-4-oxyethane (IV) is by reacting synthetic α-(two n-butyl amine methyl-27-, two chloro-4-Lumefantrines (V) with Di-n-Butyl Amine;
6, according to claim 1, anti-chloroquine pernicious malaria new drug phenyl fluorenol new synthetic process, it is characterized in that α (two n-butyl amine methyl)-27-two chloro-4-Lumefantrines (V) by with the 4-chloro-benzaldehyde condensation, make phenyl fluorenol.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 88107666 CN1029680C (en) | 1988-11-10 | 1988-11-10 | A New Synthetic Process of Luflumetol, a New Antimalarial Drug |
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| CN 88107666 CN1029680C (en) | 1988-11-10 | 1988-11-10 | A New Synthetic Process of Luflumetol, a New Antimalarial Drug |
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| CN1042535A true CN1042535A (en) | 1990-05-30 |
| CN1029680C CN1029680C (en) | 1995-09-06 |
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Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992002217A1 (en) * | 1990-08-08 | 1992-02-20 | Ciba-Geigy Ag | Antimalarial compositions |
| WO1999067197A1 (en) * | 1998-06-25 | 1999-12-29 | Novartis Ag | Benflumetol derivatives, intermediates thereof and their use against parasitical protozoa and trematodes |
| CN102344423A (en) * | 2011-07-27 | 2012-02-08 | 安徽省郎溪县联科实业有限公司 | Method for refining 2,7-dichlorofluorenyl-4-ethylene oxide |
| CN103193588A (en) * | 2013-04-12 | 2013-07-10 | 彭学东 | New technology for synthesizing 2,7-halogenated fluorene derivative with industrial fluorene as raw material |
| CN103319356A (en) * | 2013-06-17 | 2013-09-25 | 张家港威胜生物医药有限公司 | One-step green synthesis process of antimalarial raw material benflumetol |
| WO2013114118A3 (en) * | 2012-01-31 | 2013-10-10 | Cambridge Display Technology Limited | Polymer |
| CN103353487A (en) * | 2013-06-17 | 2013-10-16 | 张家港威胜生物医药有限公司 | High performance liquid chromatography method for determination of lumefantrine content |
| CN103408509A (en) * | 2013-07-17 | 2013-11-27 | 张家港威胜生物医药有限公司 | Anti-malaria medical raw material benflumetol intermediate 2,7-dichlorofluorene-4-ethylene oxide synthesis process |
| CN105001044A (en) * | 2015-06-30 | 2015-10-28 | 杭州巴洛特生物科技有限公司 | Synthesis method of 2,7-dichlorofluorene |
| CN107501316A (en) * | 2016-06-14 | 2017-12-22 | 安徽贝克联合制药有限公司 | LUMEFANTRINE isomers and preparation method thereof |
| 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 |
| CN114436866A (en) * | 2022-01-19 | 2022-05-06 | 舞阳威森生物医药有限公司 | Refining process of benflumetol crude product |
| TWI800875B (en) * | 2020-07-24 | 2023-05-01 | 中國人民解放軍軍事科學院軍事醫學研究院 | Application of lumefantrine and its derivatives in the treatment of coronavirus infection |
| US11738028B2 (en) | 2017-04-24 | 2023-08-29 | Novartis Ag | Therapeutic regimen |
-
1988
- 1988-11-10 CN CN 88107666 patent/CN1029680C/en not_active Expired - Fee Related
Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992002217A1 (en) * | 1990-08-08 | 1992-02-20 | Ciba-Geigy Ag | Antimalarial compositions |
| WO1999067197A1 (en) * | 1998-06-25 | 1999-12-29 | Novartis Ag | Benflumetol derivatives, intermediates thereof and their use against parasitical protozoa and trematodes |
| CN102344423A (en) * | 2011-07-27 | 2012-02-08 | 安徽省郎溪县联科实业有限公司 | Method for refining 2,7-dichlorofluorenyl-4-ethylene oxide |
| GB2515909A (en) * | 2012-01-31 | 2015-01-07 | Cambridge Display Tech Ltd | Polymer |
| WO2013114118A3 (en) * | 2012-01-31 | 2013-10-10 | Cambridge Display Technology Limited | Polymer |
| GB2515909B (en) * | 2012-01-31 | 2020-07-15 | Cambridge Display Tech Ltd | Composition comprising a fluorescent light-emitting material and triplet-accepting polymer and use thereof |
| US9761820B2 (en) | 2012-01-31 | 2017-09-12 | Cambridge Display Technology Limited | Polymer |
| CN103193588A (en) * | 2013-04-12 | 2013-07-10 | 彭学东 | New technology for synthesizing 2,7-halogenated fluorene derivative with industrial fluorene as raw material |
| CN103319356A (en) * | 2013-06-17 | 2013-09-25 | 张家港威胜生物医药有限公司 | One-step green synthesis process of antimalarial raw material benflumetol |
| CN103353487A (en) * | 2013-06-17 | 2013-10-16 | 张家港威胜生物医药有限公司 | High performance liquid chromatography method for determination of lumefantrine content |
| CN103408509A (en) * | 2013-07-17 | 2013-11-27 | 张家港威胜生物医药有限公司 | Anti-malaria medical raw material benflumetol intermediate 2,7-dichlorofluorene-4-ethylene oxide synthesis process |
| CN105001044A (en) * | 2015-06-30 | 2015-10-28 | 杭州巴洛特生物科技有限公司 | Synthesis method of 2,7-dichlorofluorene |
| CN107501316A (en) * | 2016-06-14 | 2017-12-22 | 安徽贝克联合制药有限公司 | LUMEFANTRINE isomers and preparation method thereof |
| CN107501316B (en) * | 2016-06-14 | 2021-05-18 | 安徽贝克联合制药有限公司 | Phelumefluorenol isomer and preparation method thereof |
| US11738028B2 (en) | 2017-04-24 | 2023-08-29 | Novartis Ag | Therapeutic regimen |
| 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 |
| TWI800875B (en) * | 2020-07-24 | 2023-05-01 | 中國人民解放軍軍事科學院軍事醫學研究院 | Application of lumefantrine and its derivatives in the treatment of coronavirus infection |
| CN114436866A (en) * | 2022-01-19 | 2022-05-06 | 舞阳威森生物医药有限公司 | Refining process of benflumetol crude product |
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| CN1029680C (en) | 1995-09-06 |
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