CN100376577C - Method for preparing vindoline and Catharanthine - Google Patents
Method for preparing vindoline and Catharanthine Download PDFInfo
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- CN100376577C CN100376577C CNB2004100165091A CN200410016509A CN100376577C CN 100376577 C CN100376577 C CN 100376577C CN B2004100165091 A CNB2004100165091 A CN B2004100165091A CN 200410016509 A CN200410016509 A CN 200410016509A CN 100376577 C CN100376577 C CN 100376577C
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- vindoline
- catharanthine
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Abstract
The present invention relates to a preparation method of vindoline and catharanthine, which is characterized in that the preparation method comprises the following steps: (1) the overground part of vinca is soaked by sulphuric acid with the concentration of 0.7 %; the pH value of the soaking liquid is regulated to 7 to 8 by ammonia water, and then the soaking liquid is extracted by chloroform; the chloroform layer is concentrated under the condition that the pressure is reduced, and then the total weak alkaloid is prepared; the total weak alkaloid is added to anhydrous alcohol for 0.5 time to be melted into thick liquid; sulphuric acid ethanol liquid with the concentration of 5 % is added to the thick liquid until the pH value is from 3.8 to 4.1 and settled for one night, then crystals are separated and filtered to prepare the mixed vinblastine sulfate; (2) the pH value of the filtrate is regulated to 7 to 8 by the ammonia water and then extracted by the chloroform; the extracted liquid is decompressed and concentrated to prepare free alkaloid; the free alkaloid is mixed with macroporous resin by a dry method and eluted by polar solvents and water with different proportions, and then the eluted liquid is collected, decompressed and concentrated according to the certain volume to respectively prepare catharanthine and vindoline. The vinblastine and the vindoline are important raw materials for synthesizing antitumor medicaments, such as vinorelbine, vinblastine and vincristine. The preparation method has the advantage of low cost of the technology and is suitable for industrial production.
Description
One, technical field:
The present invention relates to the preparation method of a kind of vindoline and Catharanthine, belong to natural medicine technical field.Be specifically related to extract from Vinca the novel process of Catharanthine and vindoline, Catharanthine and vindoline are the important source material of synthesizing antineoplastic medicament Vinorelbine, vinealeucoblastine(VLB) and vincristine(VCR).
Two, background technology:
Vinca antitumour drug system separates the indole alkaloid with antitumour activity that obtains and the derivative of structural modification thereof by apocynaceae plant Vinca (Catharanthus roseus or Vinca rosea L.).Natural is vinealeucoblastine(VLB) (Vinblastine, VLB) and vincristine(VCR) (Vincristine, VCR).Vinealeucoblastine(VLB) is used for the treatment of various solid tumors, and vincristine(VCR) is mainly used in treatment children acute leukemia.The bimolecular indole alkaloid that vinealeucoblastine(VLB) is made up of vindoline (Vindoline) and Wei Erpeng amine (velbenamine).The seventies in last century, Eli Lilly company was by modifying the vindoline part of vinealeucoblastine(VLB), researched and developed the nonsmall-cell lung cancer that is used for the treatment of melanoma, lymphoblast leukemia and late period the vindesine medicine (vindesine, Vindestine, VDS).French Pierre Fa Bai drugmaker in 1989 is by transforming the Wei Erpeng amine moiety of vinealeucoblastine(VLB), France gone on the market the vinorelbine that is used for the treatment of nonsmall-cell lung cancer and advanced breast cancer (Vinrelbine, VNB).Vinorelbine is compared with vincristine(VCR) with vinealeucoblastine(VLB), shows as lower neurotoxicity clinically.(F 81097 anhydrovinblastine and 20,20 '-difluoro Vinorelbine vinflunine) are being carried out clinical study [Duflos, A.et al.Curr.Med.Chem.-Anti-Cancer Agents, 2,55] now to also have two vinealeucoblastine(VLB) analogues.
The content of indole alkaloid vinealeucoblastine(VLB) in Vinca be approximately ten very much the son one, vincristine(VCR) be approximately hundred power molecules-, and the content of the precursor list indole alkaloid vindoline of synthetic vinealeucoblastine(VLB), vincristine(VCR) and Catharanthine is more than their several times in the plant materials, greatly about a sub very much [Uniyal, G.C.et al.Phytochemical Analysis, 12,206].Indole alkaloid vinealeucoblastine(VLB), vincristine(VCR), F 81097, Vinorelbine can prepare [Langlois, N.et al.J.Am.Chem.Soc., 98,7017 by coupling by single indole alkaloid vindoline and Catharanthine; Tan, H.et al.EP0,569,043Al; John, V et al.US4,778,885.], but the vincristine(VCR) of domestic clinical use, Vinorelbine mainly are come from vinealeucoblastine(VLB) is semi-synthetic [Chen Yongjiang etc., Chinese Journal of Pharmaceuticals, 30,6].The lower vinealeucoblastine(VLB) of content is only extracted in domestic Vinca total alkali production from periwinkle, and a large amount of single indole alkaloid vindolines and Catharanthine are abandoned as waste material, causes resource not obtain the good comprehensive utilization.
Three, summary of the invention:
The objective of the invention is to fully utilize the plant resources of Vinca, from total alkali liquor of producing vinealeucoblastine(VLB), separate important as precursors raw material---the vindoline and the Catharanthine of synthetic vinca antitumour drug.
The present invention is achieved in that the preparation method of a kind of vindoline and Catharanthine, it is characterized in that may further comprise the steps:
1, the spring flower over-ground part soaks with the sulfuric acid of quality percentage composition 0.7%, soak solution is regulated PH to 7～8 with ammoniacal liquor, use chloroform extraction then, the chloroform layer decompression concentrates down, always weak alkaloid, total weak alkaloid is added the volume ratio melt into dope of 0.5 times of dehydrated alcohol, add quality percentage composition 5% sulfuric acid ethanol liquid then and place to PH 3.8～4.1 and spend the night, separate out crystallization, filter to such an extent that mix vinblastine sulfate;
2, filtrate is regulated PH to 7～8 with ammoniacal liquor, uses chloroform extraction then, the concentrating under reduced pressure alkaloid that must dissociate, dry method is mixed sample in macroporous adsorbent resin, with polar solvent---water different ratios wash-out, volume collection, concentrating under reduced pressure by certain obtain Catharanthine and vindoline respectively.
The invention has the advantages that: develop first in the Vinca and to separate the total alkali liquor that obtains behind the vinealeucoblastine(VLB), through the macroporous resin chromatographic separation, important synthetic precursor raw material---the vindoline and the Catharanthine of synthetic vinca antitumour drug.Technology cost of the present invention is low, is suitable for suitability for industrialized production.
Four, embodiment:
The present invention is further elaborated below in conjunction with concrete embodiment.
1H-NMR measures with Varian MercuryAMX300 type instrument; MS measures with VG ZAB-HS or VG-7070 type instrument, be EI source (70ev) except that indicating, all solvents are before use all through distillation again, employed macroporous adsorbent resin (DA201,1300, HZ-802 and HZ-841) be that the production of utmost point resin processing plant is examined in the Yadong, Shanghai.
Embodiment 1:
Get Vinca herb 10kg, pulverize the back and extract 3 times with 201 quality percentage compositions, 0.7% sulfuric acid cold soaking, extracting solution merges, regulate PH to 7～8 with ammoniacal liquor, use 101 chloroform counter current continuous extractions then, concentrating under reduced pressure, take out pine with small amount of acetone then, get always weak alkaloid 20.5g.Total weak alkaloid is added 10ml dehydrated alcohol melt into dope, adds quality percentage composition 5% sulfuric acid ethanol liquid then and place to PH 3.8～4.1 and spend the night, separate out crystallization, filter 1.5g mixing vinblastine sulfate.
Filtrate is regulated PH to 7～8 with ammoniacal liquor, uses chloroform extraction then, and concentrating under reduced pressure gets the free alkaloid of 15g.Dry method is mixed sample in 50g macroporous adsorbent resin (DA201), with volume ratio ethanol: water (15: 85,30: 70,50: 50,70: 30,95: 5) wash-out, the 360ml volume is collected, concentrating under reduced pressure.40% ethanol elution cut is separated out Catharanthine, and 60% ethanol elution cut is separated out vindoline.
Embodiment 2:
Get Vinca herb 10kg, pulverize the back and extract 3 times with 201 quality percentage compositions, 0.7% sulfuric acid cold soaking, extracting solution merges, regulate PH to 7～8 with ammoniacal liquor, use 101 chloroform counter current continuous extractions then, concentrating under reduced pressure, take out pine with small amount of acetone then, get always weak alkaloid 20.5g.Total weak alkaloid is added 10ml dehydrated alcohol melt into dope, adds quality percentage composition 5% sulfuric acid ethanol liquid then and place to PH 3.8～4.1 and spend the night, separate out crystallization, filter 1.5g mixing vinblastine sulfate.
Filtrate is regulated PH to 7～8 with ammoniacal liquor, uses chloroform extraction then, and concentrating under reduced pressure gets the free alkaloid of 15g.Dry method is mixed sample in 50g macroporous adsorbent resin (HZ-841), with volume ratio ethanol: water (15: 85,30: 70,50: 50,70: 30,95: 5) wash-out, the 50ml volume is collected, concentrating under reduced pressure.25% ethanol elution cut is separated out Catharanthine, and 40% ethanol elution cut is separated out vindoline.
Claims (3)
1. the preparation method of vindoline and Catharanthine is characterized in that may further comprise the steps:
(1) the Vinca over-ground part soaks with the sulfuric acid of quality percentage composition 0.7%, soak solution is regulated PH to 7～8 with ammoniacal liquor, use chloroform extraction then, the chloroform layer decompression concentrates down, always weak alkaloid, total weak alkaloid is added the volume ratio melt into dope of 0.5 times of dehydrated alcohol, add quality percentage composition 5% sulfuric acid ethanol liquid then and place to PH 3.8～4.1 and spend the night, separate out crystallization, filter to such an extent that mix vinblastine sulfate;
(2) filtrate is regulated PH to 7～8 with ammoniacal liquor, uses chloroform extraction then, the concentrating under reduced pressure alkaloid that must dissociate, mix sample in macroporous adsorbent resin in method, with polar solvent---water different ratios wash-out, volume collection, concentrating under reduced pressure by certain obtain Catharanthine and vindoline respectively.
2. the preparation method of vindoline according to claim 1 and Catharanthine is characterized in that: described polar solvent be choose in methyl alcohol, ethanol, propyl alcohol, Virahol or the acetone a kind of.
3. the preparation method of vindoline according to claim 1 and Catharanthine is characterized in that: described macroporous adsorbent resin be choose among DA201,1300, HZ-802 or the HZ-841 a kind of.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100165091A CN100376577C (en) | 2004-02-24 | 2004-02-24 | Method for preparing vindoline and Catharanthine |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100165091A CN100376577C (en) | 2004-02-24 | 2004-02-24 | Method for preparing vindoline and Catharanthine |
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| CN1660845A CN1660845A (en) | 2005-08-31 |
| CN100376577C true CN100376577C (en) | 2008-03-26 |
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| CNB2004100165091A Expired - Fee Related CN100376577C (en) | 2004-02-24 | 2004-02-24 | Method for preparing vindoline and Catharanthine |
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Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102558200A (en) * | 2010-12-21 | 2012-07-11 | 复旦大学 | Vinblastine derivative, preparation method of vinblastine derivative, and application of vinblastine derivative in medicines |
| CN105949211A (en) * | 2016-05-18 | 2016-09-21 | 上海安体康生植物化学有限公司 | Method for extracting ajmalicine from Catharanthus roseus |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5220016A (en) * | 1991-07-29 | 1993-06-15 | Board Of Regents, The University Of Texas System | Synthesis of navelbine analogs |
| JPH0665133A (en) * | 1992-08-20 | 1994-03-08 | Sumitomo Chem Co Ltd | Production of optically active 4-hydroxy-2-cyclopentenone |
| AU5240999A (en) * | 1998-07-31 | 2000-02-21 | Goldsmith Seeds Inc. | Trimeric and polymeric alkaloids |
| EP1118616A1 (en) * | 2000-01-12 | 2001-07-25 | Eriochem, S.A. | Process for the production of 5'-nor-anhydrovinblastine ditartrate from plants of genus catharanthus |
| JP2002145881A (en) * | 2000-11-02 | 2002-05-22 | Japan Science & Technology Corp | Improvement of method for asymmetric synthesis of (-)- vindolines |
-
2004
- 2004-02-24 CN CNB2004100165091A patent/CN100376577C/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5220016A (en) * | 1991-07-29 | 1993-06-15 | Board Of Regents, The University Of Texas System | Synthesis of navelbine analogs |
| JPH0665133A (en) * | 1992-08-20 | 1994-03-08 | Sumitomo Chem Co Ltd | Production of optically active 4-hydroxy-2-cyclopentenone |
| AU5240999A (en) * | 1998-07-31 | 2000-02-21 | Goldsmith Seeds Inc. | Trimeric and polymeric alkaloids |
| EP1118616A1 (en) * | 2000-01-12 | 2001-07-25 | Eriochem, S.A. | Process for the production of 5'-nor-anhydrovinblastine ditartrate from plants of genus catharanthus |
| JP2002145881A (en) * | 2000-11-02 | 2002-05-22 | Japan Science & Technology Corp | Improvement of method for asymmetric synthesis of (-)- vindolines |
Non-Patent Citations (1)
| Title |
|---|
| 长春花中长春碱含量测定方法的研究/. 丁贤儒，倪坤仪，曹海，陈文佳.中国药科大学学报，第26卷第3期. 1995 * |
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