CN103739477B - Dihydroarteannuic acid synthesis process - Google Patents
Dihydroarteannuic acid synthesis process Download PDFInfo
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- CN103739477B CN103739477B CN201310614726.XA CN201310614726A CN103739477B CN 103739477 B CN103739477 B CN 103739477B CN 201310614726 A CN201310614726 A CN 201310614726A CN 103739477 B CN103739477 B CN 103739477B
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- dihydroartemisinic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/36—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by hydrogenation of carbon-to-carbon unsaturated bonds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/26—All rings being cycloaliphatic the ring system containing ten carbon atoms
- C07C2602/28—Hydrogenated naphthalenes
Abstract
The invention relates to a dihydroarteannuic acid synthesis process, which comprises: dissolving arteannuic acid in an organic solvent, adding hydrazine hydrate and a catalytic amount of a transition metal compound, adjusting the reaction temperature to 25-100 DEG C, adding hydrogen peroxide to the reaction solution in a dropwise manner so as to make the arteannuic acid be reduced into the dihydroarteannuic acid by the diimine produced in the in situ manner, extracting and drying to obtain the dihydroarteannuic acid. The preparation method has characteristics of short synthesis reaction time and high dihydroarteannuic acid yield.
Description
Technical field
The present invention relates to the synthetic method of Artemisinin intermediate, especially relate to a kind of Artemisinin intermediate dihydroartemisinic acid synthesis technique.
Background technology
Artemisinin is one and contains peroxide bridge sesquiterpene lactones compound, has Antimalarial, is by disturbing plasmodial pellicle-mitochondrial function, thus causes the whole of polypide structure to disintegrate.Some derivatives of Artemisinin, as dihydroarteannuin, Artemether etc., have higher antimalarial drug effect.
At present, Artemisinin mainly extracts from Chinese medicinal materials sweet wormwood (Herba Artemisiae annuae).Raw material sweet wormwood is mainly from Chongqing in China sun at the tenth of the twelve Earthly Branches, and the output of sweet wormwood is larger by the impact of environment and weather.Meanwhile, plantation Herba Artemisiae annuae needs tract, and a large amount of organic solvent of leaching process consumption, produces a large amount of waste, thus causes serious soil and the waste of raw material resources.
Wu Yulin also once reported and was obtained by reacting Artemisinin by arteannuinic acid through five steps, and total recovery reaches 37%(see J. Chem. Soc, Chem. Commun., 727,1990).
Peter H. Seeberger in 2012 etc. report under the condition of oxygen and illumination through two-step reaction dihydroartemisinic acid is oxidized to Artemisinin (see Angew. Chem.Int. Ed., 51, pp1706-1709,2012; Following called after scheme 1).
Scheme 1
At present, from the process of arteannuinic acid synthetic artemisinin, in the method having industrial production to be worth, the first step is all that arteannuinic acid is converted into dihydroartemisinic acid, and the method that relevant arteannuinic acid is converted into dihydroartemisinic acid has many reports.
IN 184682 discloses a kind of under nickelous chloride and sodium borohydride existent condition, take methyl alcohol as solvent, arteannuinic acid is reduced to the method for dihydroartemisinic acid by low temperature, but the method reaction process needs low temperature, catalyzer sodium borohydride is expensive, and cis-selectivity not high (being only 7: 1), do not have advantage in the industrial production.
WO 2006128126 A1 discloses a kind of method of arteannuinic acid being reduced dihydroartemisinic acid, as the method by catalytic hydrogenation, handy special catalyzer, as the chiral transition metal such as nickeliferous, palladium, ruthenium, rhodium, radium, rhenium, these catalyzer are expensive, and cis-selectivity is low.
CN 102718773 A discloses a kind of method being prepared Artemisinin by arteannuinic acid, wherein, the process that arteannuinic acid produces dihydroartemisinic acid through reduction reaction is: blue or green punt-pole acid is under reaction solvent exists, with be carried on the palladium of charcoal or hydroxide, be carried on the germanium of aluminium sesquioxide, Raney nickel, platinum oxide one of them for catalyzer, be reductive agent with hydrogen, or be reductive agent with sodium borohydride under the existence of nickelous chloride, blue or green punt-pole acid is 1: 0.01 ~ 1 with the mol ratio of described catalyzer; Its reaction solvent is methyl alcohol, ethanol, propyl alcohol, Virahol, and propyl carbinol, isopropylcarbinol, tetrahydrochysene are barked and muttered or toluene, and temperature of reaction is-50 ~ 60 DEG C.The catalyzer of this invention is expensive, and carries out under reaction needed low temperature, and energy consumption is large.
WO 2011030223 A3 discloses a kind of production method of Artemisinin intermediate, several method is adopted to utilize arteannuinic acid synthesizing dihydro arteannuinic acid, mainly comprise: arteannuinic acid is reduced to dihydroartemisinic acid by the diimine utilizing original position to produce, or adopt hydrogen, under the condition of catalyzer, arteannuinic acid is reduced to dihydroartemisinic acid.Industrially, a kind of rear method, because catalyzer is expensive, reaction yield is lower or cis-selectivity is not high, is used for synthesizing that can to prepare the value of the dihydroartemisinic acid of Artemisinin little.And arteannuinic acid is reduced to dihydroartemisinic acid by the method for the diimine utilizing original position to produce, yield is high, and better (can reach 97: 3), raw material is cheap, and does not need special equipment, is applicable to industrial production for cis-selectivity.
Original position produces the method for diimine, comprises thionamic acid and azanol, azo-2-carboxylic acid's dipotassium and acetic acid, hydrazine hydrate and hydrogen peroxide, sodium methylate and thionamic acid and azanol and dimethyl formamide (DMF).
CN 103087074 A discloses a kind of semisynthesis of Artemisinin, wherein arteannuinic acid is produced the process of dihydroartemisinic acid through reduction reaction and is: blue or green punt-pole acid is in reaction solvent, and the diimine produced with hydrazine hydrate and hydrogen peroxide original position carries out reduction reaction for reductive agent; Its reaction solvent is the polarity and the non-polar solvent that can be used for this reaction, and temperature of reaction is-40 ~ 70 DEG C, and the consumption of solvent is 100 ~ 10000mL/ mole.But the reduction reaction temperature of this invention is on the low side, needs temperature-fall period, production energy consumption is large, and long reaction time, raw material dosage is large.
Summary of the invention
The technical problem to be solved in the present invention is: overcome the deficiencies in the prior art, provides a kind of synthesising reacting time short, the dihydroartemisinic acid synthesis technique that yield is high.
The technical scheme that the present invention solves the employing of its technical problem is:
A kind of dihydroartemisinic acid synthesis technique, step is as follows: be dissolved in by arteannuinic acid in organic solvent, then, add the transistion metal compound of hydrazine hydrate (mass concentration of described hydrazine hydrate is not limit, preferably 40 ~ 80%) and catalytic amount, regulate temperature of reaction to 25 DEG C ~ 100 DEG C, in reaction solution, dripping hydrogen peroxide again, (mass concentration of described hydrogen peroxide is not limit, preferably 25 ~ 50%), make arteannuinic acid be reduced to dihydroartemisinic acid by the diimine that original position produces, obtain dihydroartemisinic acid through extraction, drying.
Chemical equation is:
Further, described organic solvent is the mixture of one or more in alcoholic solvent.
Further, the consumption of described organic solvent is 2 ~ 100 times of arteannuinic acid quality.
Further, the consumption of described hydrazine hydrate is 1.5 ~ 6.0 molar equivalents of arteannuinic acid.
Further, described transistion metal compound is the compound of iron, nickel, cobalt, copper, zinc.
Preferably, the compound of described iron is the one in ferrous sulfate, iron trichloride, and the compound of described nickel is nickelous chloride, and the compound of described cobalt is cobalt chloride, and described copper compound is copper sulfate, and the compound of described zinc is zinc nitrate.
Further, described catalytic amount (transistion metal compound) 0.01 ~ 1.0 molar equivalent that is arteannuinic acid.
Further, the consumption of hydrogen peroxide is 1.0 ~ 7.0 molar equivalents.
Further, described temperature of reaction preferably 45 ~ 55 DEG C.
Beneficial effect of the present invention: the present invention can form the transistion metal compound of coordination compound with hydrazine hydrate by adding in reaction solution, improve the activity of hydrazine hydrate to hydrogen peroxide, decrease the chance that diimine and hydrogen peroxide react, decrease the consumption of raw material hydrazine hydrate; Improve temperature of reaction, omit the cooling operation in synthesis technique, reduce energy consumption, the reaction times is short, simple to operate, and the yield of dihydroartemisinic acid is high, can meet the requirement of large-scale industrial production.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail.
example 1:
2.34g arteannuinic acid is dissolved in 10ml dehydrated alcohol, then, add the hydrazine hydrate of 1.5ml 80%, with containing 30mg FERRIC CHLORIDE ANHYDROUS aqueous solution 1ml, regulate temperature of reaction to 45 DEG C, more slowly drip the hydrogen peroxide 3ml of 30% in reaction solution, dropping process was more than 2 hours, after dripping hydrogen peroxide, then insulation reaction HPLC display reaction in 2 hours is complete; In reaction solution, add water 50ml, with 30ml methyl tertiary butyl ether extracting twice, organic phase anhydrous sodium sulfate drying, filter, concentrated, gained residue is crude product dihydroartemisinic acid 2.5g, and showing purity through HPLC is 90.3%.
example 2:
2.34g arteannuinic acid is dissolved in 10ml dehydrated alcohol, then, add the hydrazine hydrate of 2.5ml 60%, with containing 40mg anhydrous slufuric acid copper liquor 1ml, regulate temperature of reaction to 55 DEG C, more slowly drip the hydrogen peroxide 3ml of 35% in reaction solution, dropping process was more than 2 hours, after dripping hydrogen peroxide, then insulation reaction HPLC display reaction in 2 hours is complete; In reaction solution, add water 50ml, with 30ml methyl tertiary butyl ether extracting twice, organic phase anhydrous sodium sulfate drying, filter, concentrated, gained residue is crude product dihydroartemisinic acid 2.4g, and showing purity through HPLC is 92.6%.
example 3:
2.34g arteannuinic acid is dissolved in 10ml dehydrated alcohol, then, add the hydrazine hydrate of 3.0ml 70%, with containing 50mg six water nickel chloride aqueous solution 1ml, regulate temperature of reaction to 100 DEG C, more slowly drip the hydrogen peroxide 3ml of 50% in reaction solution, dropping process was more than 2 hours, after dripping hydrogen peroxide, then insulation reaction HPLC display reaction in 2 hours is complete; In reaction solution, add water 50ml, with 30ml methyl tertiary butyl ether extracting twice, organic phase anhydrous sodium sulfate drying, filter, concentrated, gained residue is crude product dihydroartemisinic acid 2.3g, and showing purity through HPLC is 94.5%.
example 4:
2.34g arteannuinic acid is dissolved in 10ml dehydrated alcohol, then, add the hydrazine hydrate of 5.0ml 40%, with containing 30mg anhydrous nitric acid zinc aqueous solution 1ml, regulate temperature of reaction to 50 DEG C, more slowly drip the hydrogen peroxide 5ml of 30% in reaction solution, dropping process was more than 2 hours, after dripping hydrogen peroxide, then insulation reaction HPLC display reaction in 2 hours is complete; In reaction solution, add water 50ml, with 30ml methyl tertiary butyl ether extracting twice, organic phase anhydrous sodium sulfate drying, filter, concentrated, gained residue is crude product dihydroartemisinic acid 2.3g, and showing purity through HPLC is 92.7%.
example 5:
Be dissolved in by 2.34g arteannuinic acid in 10ml dehydrated alcohol, then, add the hydrazine hydrate of 1.5ml 80%, and containing 80mg CoCL2 6H2O aqueous solution 1ml, regulate temperature of reaction to 25 DEG C, more slowly drip the hydrogen peroxide 2ml of 50% in reaction solution, dropping process is more than 2
Hour, after dripping hydrogen peroxide, then insulation reaction HPLC display reaction in 2 hours is complete; In reaction solution, add water 50ml, with 30ml methyl tertiary butyl ether extracting twice, organic phase anhydrous sodium sulfate drying, filter, concentrated, gained residue is crude product dihydroartemisinic acid 2.35g, and showing purity through HPLC is 94.3%.
example 6:
10g arteannuinic acid is dissolved in the mixing solutions of 25ml dehydrated alcohol and 25ml anhydrous isopropyl alcohol, then, add the hydrazine hydrate of 7.0ml 50% and the aqueous solution 5ml containing 200mg iron vitriol, regulate temperature of reaction to 45 DEG C, the hydrogen peroxide 5ml of 27.5% is slowly dripped again in reaction solution, dropping process was more than 2 hours, and after dripping hydrogen peroxide, then insulation reaction HPLC display reaction in 2 hours is complete; In reaction solution, add water 200ml, with 100ml methyl tertiary butyl ether extracting twice, organic phase anhydrous sodium sulfate drying, filter, concentrated, gained residue is crude product dihydroartemisinic acid 10.5g, and showing purity through HPLC is 92.9%.
Claims (8)
1. a dihydroartemisinic acid synthesis technique, it is characterized in that, step is as follows: be dissolved in by arteannuinic acid in organic solvent, then, add the transistion metal compound of hydrazine hydrate and catalytic amount, regulate temperature of reaction to 25 DEG C ~ 100 DEG C, hydrogen peroxide is dripped again in reaction solution, make arteannuinic acid be reduced to dihydroartemisinic acid by the diimine that original position produces, through extraction, drying, obtain dihydroartemisinic acid;
Described transistion metal compound is ferrous sulfate, iron trichloride, nickelous chloride, cobalt chloride or zinc nitrate.
2. dihydroartemisinic acid synthesis technique as claimed in claim 1, it is characterized in that, described organic solvent is the mixture of one or more in alcoholic solvent.
3. dihydroartemisinic acid synthesis technique as claimed in claim 1 or 2, it is characterized in that, the consumption of described organic solvent is 2 ~ 100 times of arteannuinic acid quality.
4. dihydroartemisinic acid synthesis technique as claimed in claim 1, it is characterized in that, the mass concentration of described hydrazine hydrate is 40 ~ 80%.
5. the dihydroartemisinic acid synthesis technique as described in claim 1 or 4, is characterized in that, the consumption of described hydrazine hydrate is 1.5 ~ 6.0 molar equivalents of arteannuinic acid.
6. dihydroartemisinic acid synthesis technique as claimed in claim 1, it is characterized in that, the concentration of described hydrogen peroxide is 30%.
7. the dihydroartemisinic acid synthesis technique as described in claim 1 or 6, is characterized in that, the consumption of described hydrogen peroxide is 1.0 ~ 7.0 molar equivalents.
8. the dihydroartemisinic acid synthesis technique as described in claim 1 or 2 or 4, is characterized in that, described temperature of reaction is 45 ~ 55 DEG C.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103087074A (en) * | 2012-12-14 | 2013-05-08 | 湖南科源生物制品有限公司 | Method of semi-synthesizing artemisinin |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103087074A (en) * | 2012-12-14 | 2013-05-08 | 湖南科源生物制品有限公司 | Method of semi-synthesizing artemisinin |
Non-Patent Citations (1)
| Title |
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| Chemistry of Diimide.Some New Systems for the Hydrogenation of Multiple Bonds;E.J.Corey,et al.,;《Tetrahedron Letters》;19611231(第11期);第347-352页 * |
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