CN1040983C - Method for recovering alpha-isomer of dihydroartemisinin ether derivative - Google Patents
Method for recovering alpha-isomer of dihydroartemisinin ether derivative Download PDFInfo
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- CN1040983C CN1040983C CN94101066A CN94101066A CN1040983C CN 1040983 C CN1040983 C CN 1040983C CN 94101066 A CN94101066 A CN 94101066A CN 94101066 A CN94101066 A CN 94101066A CN 1040983 C CN1040983 C CN 1040983C
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- Prior art keywords
- isomer
- alpha
- aqueous solution
- acetic acid
- dihydroartemisinin
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- 238000000034 method Methods 0.000 title claims abstract description 31
- -1 dihydroartemisinin ether derivative Chemical class 0.000 title abstract description 7
- 229960002521 artenimol Drugs 0.000 title abstract 6
- 229930016266 dihydroartemisinin Natural products 0.000 title abstract 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 48
- 239000007864 aqueous solution Substances 0.000 claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- 238000001035 drying Methods 0.000 claims abstract description 6
- 238000005406 washing Methods 0.000 claims abstract description 3
- 239000000243 solution Substances 0.000 claims abstract 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 22
- 229930187998 Dihydroarteannuin Natural products 0.000 claims description 15
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 14
- 241001597008 Nomeidae Species 0.000 claims description 11
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000008025 crystallization Effects 0.000 claims description 8
- NLYNIRQVMRLPIQ-LTLPSTFDSA-N 10-ethoxydecahydro-3,6,9-trimethyl-(3r,5as,6r,8as,9r,10r,12r,12ar)-3,12-epoxy-12h-pyrano(4,3-j)-1,2-benzodioxepin Chemical compound C1C[C@H]2[C@H](C)CC[C@H]3[C@@H](C)[C@H](OCC)O[C@H]4[C@]32OO[C@@]1(C)O4 NLYNIRQVMRLPIQ-LTLPSTFDSA-N 0.000 claims description 5
- SXYIRMFQILZOAM-CNNNLJIRSA-N α-artemether Chemical group C1C[C@H]2[C@H](C)CC[C@H]3[C@@H](C)[C@H](OC)O[C@H]4[C@]32OO[C@@]1(C)O4 SXYIRMFQILZOAM-CNNNLJIRSA-N 0.000 claims description 5
- 150000002170 ethers Chemical class 0.000 claims 1
- 238000006266 etherification reaction Methods 0.000 abstract description 9
- 239000013078 crystal Substances 0.000 abstract description 6
- 238000003756 stirring Methods 0.000 abstract description 5
- 239000002253 acid Substances 0.000 abstract description 3
- 238000005336 cracking Methods 0.000 abstract description 2
- BJDCWCLMFKKGEE-ISOSDAIHSA-N artenimol Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C BJDCWCLMFKKGEE-ISOSDAIHSA-N 0.000 abstract 3
- 239000002841 Lewis acid Substances 0.000 abstract 1
- 239000003054 catalyst Substances 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 150000007517 lewis acids Chemical class 0.000 abstract 1
- 230000001376 precipitating effect Effects 0.000 abstract 1
- 238000011084 recovery Methods 0.000 description 5
- 229960004191 artemisinin Drugs 0.000 description 3
- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 description 3
- 229930101531 artemisinin Natural products 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000000078 anti-malarial effect Effects 0.000 description 2
- 229960000981 artemether Drugs 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- SXYIRMFQILZOAM-HVNFFKDJSA-N dihydroartemisinin methyl ether Chemical compound C1C[C@H]2[C@H](C)CC[C@H]3[C@@H](C)[C@@H](OC)O[C@H]4[C@]32OO[C@@]1(C)O4 SXYIRMFQILZOAM-HVNFFKDJSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000010413 mother solution Substances 0.000 description 2
- 229910015900 BF3 Inorganic materials 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- NLYNIRQVMRLPIQ-XQLAAWPRSA-N artemotil Chemical compound C1C[C@H]2[C@H](C)CC[C@H]3[C@@H](C)[C@@H](OCC)O[C@H]4[C@]32OO[C@@]1(C)O4 NLYNIRQVMRLPIQ-XQLAAWPRSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a method for cracking alpha-isomer of dihydroartemisinin ether derivative into dihydroartemisinin, which comprises the steps of dissolving the alpha-isomer of the dihydroartemisinin ether derivative in acetic acid aqueous solution with the concentration of 30-70% (v/v), adding a catalyst selected from protonic acid or Lewis acid into the solution, stirring the solution for 2-24 hours at the temperature ranging from room temperature to 80 ℃, precipitating white crude crystals of the dihydroartemisinin, washing the crude crystals obtained by the acetic acid aqueous solution, and drying the crude crystals to obtain a dihydroartemisinin product. The method has the characteristics of simple and convenient process, easy operation, suitability for industrial production, reduction of the cost of etherification reaction and improvement of the reaction yield.
Description
The present invention relates to the recovery method of alpha-isomer in a kind of dihydroartemisin ether derivant, relate in particular to a kind of method that alpha-isomer of dihydroartemisin ether derivant is cracked into dihydroarteannuin.
People such as Li Ying go up (429-439 page or leaf in " Acta Pharmaceutica Sinica " the 16th the 6th phase of volume, in June, 1981) delivered the article that is entitled as " research of analog of artemisinin ", wherein reported the synthetic and antimalarial effect of youngster's analog derivative of Artemisinin, therefrom as can be known Artemisinin through the reduction (obtaining dihydroarteannuin), mainly comprise β-and α-two kind of isomer in prepared pair of hydrogen of etherification reaction (also claim reduction) Artemisinin ether derivative, wherein based on β-isomer, it has fat-soluble good, characteristics such as drug effect height, principal product for the reaction generation, alpha-isomer then antimalarial active is little, only is a kind of by product of etherification reaction.If can recycle described alpha-isomer well, then can reduce reaction cost, improve the etherification reaction yield.
People such as Peter Buchs are at EP-A-330, disclose in 520 a kind of alpha-isomer to be converted into the method for β-isomer, and this method is included under the katalysis of acid and makes alpha-isomer generation isomerization reaction, obtains required β-isomer.Because this method need use column chromatography, operate loaded down with trivial detailsly, thereby be unfavorable for suitability for industrialized production, and this method only is applicable to the conversion of α-arteether, the experiment proved that for α-Artemether and adopt this method to have only small part to be converted into β-Artemether, poor effect, so this method limitation is very big.
For overcoming the deficiencies in the prior art part, the object of the present invention is to provide a kind of method that alpha-isomer of dihydroartemisin ether derivant is cracked into dihydroarteannuin.
The present invention relates to a kind of method that alpha-isomer of dihydroartemisin ether derivant is cracked into dihydroarteannuin, this method comprises alpha-isomer of dihydroartemisin ether derivant is dissolved in the acetic acid aqueous solution that concentration is 30-70% (v/v), then to wherein adding a kind of protonic acid or lewis acidic catalyzer of being selected from, in the temperature range of room temperature to 80 ℃, stirred 2-24 hour, separate out dihydroarteannuin white coarse crystallization, with the coarse crystallization that above-mentioned acetic acid aqueous solution washing obtains, drying obtains the dihydroarteannuin product then.
In the method for the invention, the consumption of described acetic acid aqueous solution be described dihydroartemisin ether derivant alpha-isomer weight 2-10 doubly.
The catalyzer that is used for the inventive method comprises hydrochloric acid, Hydrogen bromide, tosic acid, boron trifluoride, boron tribromide, perchloric acid, trifluoromethanesulfonic acid and trifluoroacetic acid.Preferred catalyzer is a perchloric acid.The mol ratio of described alpha-isomer and described catalyzer is 1000: 1-10: 1, be preferably 100: 1-20: 1.
Temperature of reaction is preferably room temperature to 50 ℃ in the methods of the invention.
Method of the present invention is preferred for the cracking of α-Artemether and α-arteether, and the rate of recovery is generally between 50-70.Because described alpha-isomer is generally stayed in the mother liquor of dihydroarteannuin etherification reaction as by product, and generally can contain reaction principal product β-isomer below 10% (wt.) in the mother liquor, therefore as the starting raw material of the inventive method can two hydrogen SM-224 analog derivatives α-replace with β-mixture of isomers, can reclaim and utilization again the etherification reaction mother liquor like this, thereby reach the reduction reaction cost, improve the purpose of the total recovery of etherification reaction simultaneously.
Method of the present invention compared with prior art has following advantage:
1. technology is easy; Easy handling is suitable for suitability for industrialized production.
2 have reduced the cost of dihydroarteannuin etherification reaction, have avoided simultaneously byproduct of reaction is entered the caused problem of environmental pollution of environment.
3. improved the total recovery of etherification reaction.
Below in conjunction with embodiment method of the present invention is further described, but is not to be restriction the inventive method.
Embodiment 1
20g α-arteether (64.1mmol) is dissolved in the acetic acid aqueous solution of 100ml70%, add 0.3g perchloric acid (3mmol), in 25 ℃ of stirring reactions 5 hours, separate out white crystals, after the filtration, the acetic acid aqueous solution 20ml wash crystallization twice with 50%, dry then, obtain dihydroarteannuin 11.3g (yield 62.1%), m.p.153-158 ℃.
Embodiment 2
20g α-Artemether (67.1mmol) is dissolved in the acetic acid aqueous solution of 100ml70%, add 0.3g perchloric acid (3mmol), in 25 ℃ of stirring reactions 5 hours, filter, twice of acetic acid aqueous solution 20ml wash crystallization with 50%, drying obtains dihydroarteannuin 10.8g (yield 56.7%), m.p.153-158 ℃.
Embodiment 3
The crystalline mother solution that 20g is contained 85% α-Artemether (57.0mmol) and 8% β-Artemether (5.4mmol) is dissolved in the acetic acid aqueous solution of 100ml70%, add 0.3g perchloric acid (3mmol), in 20 ℃ of stirring reactions 5 hours, separate out white crystals, after the filtration, acetic acid aqueous solution 20ml wash crystallization twice with 50% obtains dihydroarteannuin 9.5g (yield 53.6%), m.p.153-158 ℃ after the drying.
Embodiment 4
The crystalline mother solution that 285g is contained 83% α-arteether (758.1mmol) and 9% β-arteether (82.2mmol) is dissolved in the acetic acid aqueous solution of 350ml70%, add 4g perchloric acid (40mmol), in 20 ℃ of stirring reactions 5 hours, separate out white crystals, filter, acetic acid aqueous solution 200ml wash crystallization twice with 50% obtains dihydroarteannuin 122.2g (yield 51.2%), m.p.153-158 ℃ after the drying.
Claims (6)
1. the alpha-isomer with dihydroartemisin ether derivant is cracked into the method for dihydroarteannuin, it is characterized in that this method comprises:
A, the alpha-isomer of described dihydroarremisine ether derivative is dissolved in the acetic acid aqueous solution that concentration is 30-70% (V/V);
Add perchloric acid in b, the solution that in step a, obtains as catalyzer, in the temperature range of room temperature to 80 ℃, stirred 2-24 hour, separate out the white coarse crystallization of dihydroarteannuin,
C, with the acetic acid aqueous solution described in step a washing by the coarse crystallization that obtains among the step b, obtain the dihydroarteannuin product after the drying.
2. the method for claim 1, the consumption that it is characterized in that the acetic acid aqueous solution described in the step a be described dihydroartemisin ether derivant alpha-isomer weight 2-10 doubly.
3. the method for claim 1, the mol ratio that it is characterized in that described alpha-isomer and described catalyzer is 100: 1-20: 1.
4. the method for claim 1 is characterized in that temperature of reaction among the step b is a room temperature to 50 ℃.
5. the method for claim 1, the alpha-isomer that it is characterized in that described dihydroartemisin ether derivant is α-Artemether or α-arteether.
6. the method for claim 1 is characterized in that also containing the following β-isomer of 10% (wt.) in the alpha-isomer of described dihydroartemisin ether derivant.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN94101066A CN1040983C (en) | 1994-01-28 | 1994-01-28 | Method for recovering alpha-isomer of dihydroartemisinin ether derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN94101066A CN1040983C (en) | 1994-01-28 | 1994-01-28 | Method for recovering alpha-isomer of dihydroartemisinin ether derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1106011A CN1106011A (en) | 1995-08-02 |
| CN1040983C true CN1040983C (en) | 1998-12-02 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN94101066A Expired - Fee Related CN1040983C (en) | 1994-01-28 | 1994-01-28 | Method for recovering alpha-isomer of dihydroartemisinin ether derivative |
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| Country | Link |
|---|---|
| CN (1) | CN1040983C (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2360517B (en) * | 2000-03-24 | 2004-09-01 | Council Scient Ind Res | An improved process for the preparation of arteethers from dihydroartemisinin |
| CN102702219B (en) * | 2012-06-06 | 2015-01-21 | 昆明制药集团股份有限公司 | Method for transforming ether derivative of dihydroartemisinin into dihydroartemisinin |
| CN111499651A (en) * | 2019-01-30 | 2020-08-07 | 昆药集团股份有限公司 | Dihydroartemisinin Form A crystal Form and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0330520A1 (en) * | 1988-02-25 | 1989-08-30 | World Health Organisation | Synthesis of artemisininelactol derivatives |
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1994
- 1994-01-28 CN CN94101066A patent/CN1040983C/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0330520A1 (en) * | 1988-02-25 | 1989-08-30 | World Health Organisation | Synthesis of artemisininelactol derivatives |
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| Publication number | Publication date |
|---|---|
| CN1106011A (en) | 1995-08-02 |
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