CN1044370C - Improved method for preparation of dihydroartemisin ether derivants - Google Patents
Improved method for preparation of dihydroartemisin ether derivants Download PDFInfo
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- CN1044370C CN1044370C CN94101067A CN94101067A CN1044370C CN 1044370 C CN1044370 C CN 1044370C CN 94101067 A CN94101067 A CN 94101067A CN 94101067 A CN94101067 A CN 94101067A CN 1044370 C CN1044370 C CN 1044370C
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Abstract
The present invention relates to an improved method for preparing a dihydroartemisinin ether derivative, which comprises: dihydroartemisinin is dissolved in the mixture of alcohol and non-protonic solvent; under the action of a catalyst selected from trifluoromethanesulfonic acid or perchloric acid, etherification reaction is carried out for 1 to 24 hours within the temperature range of indoor temperature to the boiling temperature of the solvent; then a reaction product is neutralized, and is treated with pressure reduction evaporation for removing solvent; the obtained semi-solid crude product is dissolved in the mixed solution of polar solvent and water; after recrystallization filtration and drying, a dihydroartemisinin ether derivative is obtained. The method has the characteristics of low cost, high yield, convenient operation, stable reaction, mild condition, good product quality, etc., and is suitable for industrialized production.
Description
The present invention relates to a kind of method for preparing dihydroartemisin ether derivant, relate in particular to and a kind ofly prepare improving one's methods of its ether derivative by dihydroarteannuin.
Artemisinin has advantages such as quick-acting, low toxicity to treating various types of malaria, but because its solubleness in oil or water is very little, is difficult to make suitable formulation, has limited its application at clinicing aspect thus to a great extent.In order to address this problem, people such as Li Ying are at " Acta Pharmaceutica Sinica " the 16th volume the 6th phase (429-439 page or leaf, in June, 1981) delivered the article that is entitled as " research of analog of artemisinin " on, reported and relevantly be three kinds of derivatives of intermediate preparation and the antimalarial effect of these derivatives done evaluation with dihydroarteannuin (claiming Reducing arteannuim again), its objective is that the lipotropy of promoting dihydroarteannuin whereby is in the hope of improving antimalarial effect, wherein the ether derivative of dihydroarteannuin prepares by the following method: dihydroarteannuin is mixed with dehydrated alcohol, with BF
3Et
2O is a catalyzer, places in room temperature, and afterreaction was complete substantially in two days, neutralization, pressure reducing and steaming ethanol, resistates benzene extraction, washing, dry, the oily matter that obtains after concentrating uses column chromatography [silica gel, sherwood oil (b.p.60-90 ℃): ethyl acetate=10: 1 is made eluent], and first cut that obtains is β-arteether, white crystals, productive rate are 64.1%.With the normal heptane recrystallization, separate out phenyl ring shape crystal, m.p.81-83 ℃.Second cut is α-arteether, does not have bag oily matter, and productive rate is 11.8%.
People such as Peter Buchs have disclosed a kind of preparation method of arteether in EP-A-330520, at first with NaBH
4For reductive agent is reduced to dihydroarteannuin with Artemisinin, then dihydroarteannuin is dissolved in the mixed solvent of ethanol and benzene, toluene, pentane or hexane, under the acid catalysis effect in 50-80 ℃ temperature range, reacted 2-4 hour, β-the arteether that in normal hexane separation is obtained carries out recrystallization (<0 ℃) then, and yield is about 70%.α-arteether in the mother liquor also can partly be converted into β-arteether under the effect of described catalyzer.Described acid comprises boron tribromide, boron trichloride, Hydrogen bromide, trifluoroacetic acid, tosic acid and hydrochloric acid.
There is following shortcoming in the method for the synthetic dihydroartemisin ether derivant of above-mentioned bibliographical information:
1, in first method people such as () Li Ying, because the little α-arteether content height of antimalarial active, thereby cause the yield of β-arteether on the low side.And use BF
3Et
2O makes catalyzer, uses nitrogen protection usually in reaction process, so technology is complicated, is difficult to adapt to need of industrial production.
2, crystallization is expensive with solvent normal hexane price, make solvent with it hardly in the suitability for industrialized production, and sherwood oil polarity is little, is unfavorable for the removal of α-arteether.And for a long time freezing under-20 ℃-0 ℃ low temperature during the product crystallization, this also is difficult to realize in suitability for industrialized production.
The preparation method of hence one can see that dihydroartemisin ether derivant of the prior art has many shortcomings such as yield is low, cost is high, complex process.
For overcoming the deficiencies in the prior art part, the invention provides a kind of improving one's methods of dihydroartemisin ether derivant that prepare.
The present invention relates to a kind of improving one's methods of dihydroartemisin ether derivant that prepare, this method comprises:
A, dihydroarteannuin is dissolved in the mixture of pure and mild non-protonic solvent,
Add a kind of catalyzer that is selected from trifluoromethanesulfonic acid or perchloric acid in b, the mixing solutions that in step a, obtains,
C, in room temperature to the temperature range of solvent boiling point, the etherification reaction of dihydroarteannuin carried out 1-24 hour,
Acid in the reaction mixture among d, the usefulness alkali neutralization procedure c,
E, pressure reducing and steaming solvent obtain the crude product of semi-solid,
F, the semi-solid crude product that obtains among the step e is dissolved in the mixing solutions of a kind of polar solvent and water, in the white particulate crystallization that after recrystallization, filtration, drying, obtains dihydroartemisin ether derivant below 5 ℃.
The present inventor improves from the various operation conditions of the following aspects to etherification reaction emphatically after the etherification reaction to dihydroarteannuin has carried out further investigation:
(1) the reaction solvent kind reaches and the selection of etherificate with the usage ratio of alcohol
Found through experiments, if simple be unfavorable for the generation of β-isomer in the dihydroartemisin ether derivant with pure as solvent, the yield that is mainly reflected in β-isomer is lower.Use non-protonic solvent instead as the etherificate solvent, then can improve the ratio of β-isomer in the ether derivative.Can be used for non-protonic solvent of the present invention and comprise benzene, toluene, chloroform, ether, methylene dichloride equal solvent.Because the toxicity of benzene, toluene, chloroform is bigger, so ether, methylene dichloride are preferred etherificate solvents in the inventive method.Etherificate comprises methyl alcohol and ethanol with alcohol.Through repeatedly experiment discovery, the usage ratio of described alcohol and non-protonic solvent has certain influence to the ratio of α and β-irregular part in the product ether derivative.The amount ratio of described in the method for the invention alcohol and non-protonic solvent is 1: 1 to 1: 10, is preferably 1: 2-1: 6.
2, selection of catalysts and consumption
Found through experiments, have many problems at aforesaid catalyzer used in the prior art, as use BFaEt
2O makes catalyzer, though technology stability is good, needs nitrogen protection in the reaction process, and large usage quantity; The shortcoming of making catalyzer with hydrochloric acid is that consumption control requires relatively strictness, easily produces hydrolysis, influences quality product; The effect of tosic acid is not as the above two, and reaction is slow and be difficult for complete; The vitriolic catalytic effect is bad; Trifluoroacetic acid source difficulty, price is expensive.And the catalytic effect of perchloric acid that is preferred for the inventive method is best, and catalysis speed is fast, and the impurity that reaction produces is few, and shared ratio is than the reaction height with other catalyzer in product for β-isomer, so yield can correspondingly improve.By following embodiment and comparative example, can clearly be seen that and use of the influence of different catalyzer the etherification reaction yield.Catalyzer of the present invention is 1 to the mol ratio of dihydroarteannuin: 10-1: 1000, be preferably 1: 20-1: 100.
3, the selection in temperature of reaction and reaction times
Decide according to the height of temperature of reaction by repeatedly testing the length of finding the reaction times.If etherification reaction temperature is too high, though can shorten the reaction times, the impurity that produces can increase; If temperature is too low, then reaction is very slow, is unfavorable for suitability for industrialized production.Range of reaction temperature is preferably room temperature to 50 ℃ in the method for the invention.Reaction times is to be no more than 2 hours for good.
4, the selection of recrystallisation solvent
Because the polarity of the alpha-isomer in the dihydroartemisin ether derivant is a bit larger tham β-isomer, so be unfavorable for removing of alpha-isomer with the little solvent of polarity (as sherwood oil).The polar solvent that is adopted in the inventive method and the mixing solutions of water are preferably methanol-water, alcohol-water and acetone-water.The usage ratio of described polar solvent and water is 10: 1 to 1: 10, is preferably 5: 1 to 1: 5.
Of the present invention improving one's methods is preferred for the preparation of Artemether or arteether.
Of the present inventionly improve one's methods that compared with prior art to have a cost low, the yield height, technological operation is easy, stable reaction, mild condition, and the good product quality that obtains are suitable for suitability for industrialized production.
The invention will be further described by the following examples, but be not that the present invention is imposed any restrictions.
Embodiment 1
The preparation of Artemether: 100g dihydroarteannuin (0.35mol) is dissolved in 200ml methyl alcohol and the 400m1 methylene dichloride, adds 5g perchloric acid (0.05mol), 39 ℃ of stirring reactions 1 hour, add the 5g sodium bicarbonate, stirred 15 minutes, 50 ℃ remove solvent under reduced pressure, add 200ml acetone and 1000ml water, in 0 ℃ of crystallization 5 hours, filter, with acetone-water (1: 5) 50ml washed twice, drying, get white particulate crystallization 85g (yield 81%), mp88-89 ℃; [α]
D 20=+169 ° (C=1, EtOH).
Embodiment 2
100g dihydroarteannuin (0.35mol) is dissolved in 100ml methyl alcohol and the 300ml benzene, adds 1g perchloric acid (0.01mol), 80 ℃ were reacted 1 hour, add the 1g sodium bicarbonate, stirred 20 minutes, and removed solvent under reduced pressure, add 200ml methyl alcohol and 1000ml water, in 0 ℃ of crystallization 5 hours, filter, with methanol-water (1: 5) 50m1 washed twice, drying, get white particulate crystallization 77.5g (yield 73.9%), mp86.5-89.0 ℃; [α]
D 20=+168 ° (C=1, EtOH).
Embodiment 3
The preparation of arteether: 100g dihydroarteannuin (0.35mol) is dissolved in 300ml ethanol and the 900ml methylene dichloride, add 0.75g perchloric acid (7.5mmol), 39 ℃ were reacted 45 minutes, added the 0.75g sodium bicarbonate, and 50 ℃ remove solvent under reduced pressure, add 200ml acetone and 1000ml water, in 0 ℃ of crystallization 5 hours, filter, with alcohol-water (1: 5) 50ml washed twice, get white particulate crystallization 89.2g (yield 81.2%), mp80-82 ℃ after the drying; [α]
D 20=+155 ° of (C=1, CHCl
3)
Embodiment 4
100g dihydroarteannuin (0.35mol) is dissolved in 100ml ethanol and the 300ml benzene, add 1g perchloric acid (0.01mol), 80 ℃ were reacted 1 hour, added the 1g sodium bicarbonate, stirred 20 minutes, remove solvent under reduced pressure, add 200ml acetone and 1000ml water,, filter in 0 ℃ of crystallization 5 hours, with acetone-water (1: 5) 50ml washed twice, drying gets white particulate crystallization 79.0g (yield 71.9%), mp79-82 ℃; [α]
D 20=+154.0 ° of (C=1, CHCl
3).
Embodiment 5
100g dihydroarteannuin (0.35mol) is dissolved in 200ml ethanol and the 400ml ether, adds 1g trifluoromethanesulfonic acid (6.7mmol), in 39 ℃ of reactions 45 minutes, add the 1g sodium bicarbonate, stirred 20 minutes, steaming desolventizes, and adds 200ml acetone and 1000ml water, in 0 ℃ of crystallization 5 hours, filter, with acetone-water (1: 5) 50ml washed twice, drying, get white particulate crystallization 87.7g (yield 79.8%), mp79-82 ℃; [α]
D 20=+154 ° of (C=1, CHCl
3).
The comparative example 1
100g dihydroarteannuin (0.35mol) is dissolved in 200ml methyl alcohol and the 400ml methylene dichloride, adds 5g tosic acid (26mmol), 39 ℃ were reacted 1 hour, add the 2g sodium bicarbonate, stirred 20 minutes, and removed solvent under reduced pressure, add 200ml acetone and 1000ml water, in 0 ℃ of crystallization 5 hours, filter, with acetone-water (1: 5) 50ml washed twice, drying, get white particulate crystallization 62g (yield 59%), mp78-81 ℃; [α]
D 20=+167.5 ° (C=1, EtOH).
The comparative example 2
100g dihydroarteannuin (0.35mol) is dissolved in 200ml methyl alcohol and the 400ml methylene dichloride, adds the 5ml boron trifluoride ether solution, 39 ℃ were reacted 1 hour, add the 2g sodium bicarbonate, stirred 20 minutes, steaming desolventizes, and adds 200ml acetone and 1000ml water, in 0 ℃ of crystallization 5 hours, filter, with acetone-water (1: 5) 50ml washed twice, drying, get white particulate crystallization 65.2g (yield 62.1%), mp78-81.5 ℃; [α]
D 20=+167.5 ° (C=1, EtOH).
Claims (10)
1, a kind ofly prepare improving one's methods of dihydroartemisin ether derivant, it is characterized in that this method comprises:
A, dihydroarteannuin is dissolved in the mixture of pure and mild non-protonic solvent,
Add a kind of catalyzer that is selected from trifluoromethanesulfonic acid or perchloric acid in b, the mixing solutions that in step a, obtains,
C, in room temperature to the temperature range of solvent boiling point, the etherification reaction of dihydroarteannuin carried out 1-24 hour,
Acid in the reaction mixture among d, the usefulness alkali neutralization procedure c,
E, pressure reducing and steaming solvent obtain the crude product of semi-solid,
F, the semi-solid crude product that obtains among the step e is dissolved in the mixing solutions of a kind of polar solvent and water, in the white particulate crystallization that after recrystallization, filtration, drying, obtains dihydroartemisin ether derivant below 5 ℃.
2, as claimed in claim 1 improving one's methods is characterized in that described alcohol is methyl alcohol or ethanol.
3, as claimed in claim 1 improving one's methods is characterized in that described non-protonic solvent is selected from a kind of in the following solvent: ether and methylene dichloride.
4, as each described improving one's methods among the claim 1-3, the amount ratio that it is characterized in that described alcohol and non-protonic solvent is 1: 1 to 1: 10.
5, as claimed in claim 1 improving one's methods, the mol ratio that it is characterized in that described dihydroarteannuin and described catalyzer is 100: 1-20: 1.
6,, it is characterized in that described catalyzer is a perchloric acid as claim 1 or 5 described improving one's methods.
7, as claimed in claim 1 improving one's methods is characterized in that temperature of reaction among the step c is a room temperature to 50 ℃, and the reaction times is no more than 2 hours.
8, as claimed in claim 1 improving one's methods, the mixing solutions that it is characterized in that polar solvent described in the step f and water is the mixing solutions of methyl alcohol, ethanol or acetone and water.
9, as claim 1 or 8 described improving one's methods, the ratio that it is characterized in that described polar solvent and water is 10: 1-1: 10.
10, as claimed in claim 1 improving one's methods is characterized in that prepared dihydroartemisin ether derivant is Artemether or arteether.
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Families Citing this family (5)
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WO2009109989A1 (en) * | 2008-01-21 | 2009-09-11 | Calyx Chemicals And Pharmaceuticals Ltd. | A novel process for the preparation of ethers of dihydroartemisinin |
CN102304136A (en) * | 2010-07-10 | 2012-01-04 | 恩施济源药业科技开发有限公司 | Method for producing artemether |
CN102731523B (en) * | 2012-07-10 | 2013-07-03 | 刘志强 | Preparation method of beta-artemether |
CN103113385A (en) * | 2013-01-24 | 2013-05-22 | 张家港威胜生物医药有限公司 | Simple mass production process of preparing artemisinin 10-position ether derivative by using dihydroartemisinin as raw material |
CN103333177B (en) * | 2013-07-03 | 2016-01-27 | 重庆恒星生物技术有限责任公司 | A kind of Artemether mother liquor prepares the method for β-Artemether |
Citations (1)
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EP0330520A1 (en) * | 1988-02-25 | 1989-08-30 | World Health Organisation | Synthesis of artemisininelactol derivatives |
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1994
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EP0330520A1 (en) * | 1988-02-25 | 1989-08-30 | World Health Organisation | Synthesis of artemisininelactol derivatives |
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