CN100334089C - Production method of 9-nitro camptothecin - Google Patents
Production method of 9-nitro camptothecin Download PDFInfo
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- CN100334089C CN100334089C CNB2004100437325A CN200410043732A CN100334089C CN 100334089 C CN100334089 C CN 100334089C CN B2004100437325 A CNB2004100437325 A CN B2004100437325A CN 200410043732 A CN200410043732 A CN 200410043732A CN 100334089 C CN100334089 C CN 100334089C
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- nitrocamptothecin
- camptothecine
- oxidation
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Abstract
The present invention relates to a method for preparing 9-nitro camptothecin. In the method, camptothecin used as a raw material is oxidized to obtain N-oxidized camptothecin; the N-oxidized camptothecin is nitrified to obtain 9-nitro-N-oxidized camptothecin; the 9-nitro-N-oxidized camptothecin is treated with dioxane backflow concentration to obtain a crude product of 9-nitro camptothecin; the crude product is recrystallized to obtain a pure product of 9-nitro camptothecin. In the present invention, after camptothecin used as a raw material is oxidized to obtain N-oxidized camptothecin, the N-oxidized camptothecin is nitrified; thus, the 9-nitro camptothecin in the end product is used as a main product. Therefore, the condition that 12-nitro camptothecin is always used as a main product in a previous method is changed. By the present invention, the yield of a 9-nitro camptothecin product can be increased, the final yield of the product can reach more than 50%, and the purity of the product can reach more than 97%.
Description
Technical field
The semi-synthetic production method of the present invention and natural compounds relates in particular to a kind of production method of 9-nitrocamptothecin.
Background technology
Camplotheca acuminata (Camptotheca acuminate Decaisne) is that Nyssaceae (also claims Nyssaceae, Nyssaceae) camplotheca acuminata belongs to (Camptotheca) plant, be the peculiar tropical trees of China, happiness warm and moist weather, be distributed widely in China Yangtze valley and on the south the each province.
(Camptothecin is to separate obtain a kind of kinds of tumor cells is all had obvious inhibiting alkaloid from camplotheca acuminata CPT) to camptothecine, and anticancer mechanism uniqueness (camptothecine is the topmost topoisomerase I inhibitor of finding up to now).The 9-nitrocamptothecin is a kind of semi-synthetic derivative of camptothecine, has demonstrated good prospects for application in the cancer of some type of treatment.
Provide the excessive a little concentrated nitric acid of a kind of usefulness in the vitriol oil, to handle the method that camptothecine prepares the 9-nitrocamptothecin day patent application 59-51288 of the present disclosure number.But the yield of 9-nitrocamptothecin product only is about 3～7% when using this method, this method produce unwanted by product---the ratio of 12-nitrocamptothecin and 9-nitrocamptothecin is about 3: 1.
Patent Office of State Intellectual Property Office discloses the method for a kind of preparation and purification 9-nitro-20-camptothecine on September 13rd, 2000, this disclosure of the Invention comprise the reaction of 20-camptothecine and at least a inorganic nitrate and that catalysis is generated the nitre ion is effectively sour with at least a, wherein be reflected in the temperature and time that is enough to generate the 9-nitrocamptothecin and carry out.The invention also discloses method with column chromatography or redeposition purification 9-nitrocamptothecin.When using this method, the yield of 9-nitrocamptothecin is still very low, only can reach 29% when the highest, still remains at low levels, and the ratio of 12-nitrocamptothecin and 9-nitrocamptothecin is about 1.4～1.6: 1, and 12-nitrocamptothecin angle is a primary product.
Summary of the invention
The object of the present invention is to provide the production method of a kind of effective raising 9-nitrocamptothecin product yield, 9-nitrocamptothecin that purity is high.
In order to achieve the above object, the technical solution used in the present invention is to be that raw material gets N-oxidation camptothecine through oxidation with the camptothecine, and---nitrated N-oxidation camptothecine gets 9-nitro-N-oxidation camptothecine---dioxane reflux concentrate 9-nitrocamptothecin crude product---, and recrystallization gets the operational path of the pure product of 9-nitrocamptothecin.
Advantage of the present invention is:
1. with the camptothecine to be that raw material carries out after oxidation gets N-oxidation camptothecine more nitrated in the present invention, make that 9 nitrated in position products---9-nitro-N-oxidation camptothecine is a primary product, and make in the end product 9-nitrocamptothecin also be primary product, change the situation that 12-nitrocamptothecin in original method is always primary product.
2. the present invention improves 9-nitrocamptothecin product yield, and the ultimate yield of product can reach more than 50%, and this product purity can reach more than 97%.
Embodiment
Describe in further detail below in conjunction with embodiments of the invention:
With the camptothecine is that raw material gets N-oxidation camptothecine through oxidation, and---nitrated N-oxidation camptothecine gets 9-nitro-N-oxidation camptothecine---dioxane reflux concentrate 9-nitrocamptothecin crude product---, and recrystallization gets the operational path of the pure product of 9-nitrocamptothecin.
The production method of described 9-nitrocamptothecin, the process that camptothecine is oxidized to N-oxidation camptothecine add superoxol for camptothecine is dissolved in acetate, 30～90 ℃ of reactions 0.5～10 hour down.
The production method of described 9-nitrocamptothecin, nitrated N-oxidation camptothecine method comprise N-oxidation camptothecine be dissolved in a kind of acid and add at least a nitrating agent, 0～90 ℃ of reaction 3～72 hours down.
The production method of described 9-nitrocamptothecin, employed acid is acetate, trichoroacetic acid(TCA), trifluoroacetic acid or the vitriol oil in the method for nitrated N-oxidation camptothecine.
The production method of described 9-nitrocamptothecin, nitrating agent are meant nitrosonitric acid or inorganic nitrate.
The production method of described 9-nitrocamptothecin, described inorganic nitrate comprises SODIUMNITRATE, saltpetre, ammonium nitrate, Silver Nitrate, cupric nitrate, zinc nitrate, Mercury pernitrate, magnesium nitrate, aluminum nitrate, iron nitrate, lead nitrate or Iron nitrate.
The production method of described 9-nitrocamptothecin, dioxane return time are 3～72 hours.
The production method of described 9-nitrocamptothecin, recrystallization solvent are ethanol, acetone or acetate.
Embodiment 1
The 40g camptothecine is dissolved in the 1000mL acetate, add 30% hydrogen peroxide 200mL, after reacting 5 hours under 50 ℃, in the impouring 5000mL frozen water, with dichloromethane extraction, concentrate, and residue is dissolved in the 1000mL vitriol oil, drip behind the nitrosonitric acid 80mL 50 ℃ of reactions 24 hours down in the ice-water bath, pour into then in the 5000mL frozen water, dichloromethane extraction, concentrate and to separate out 9-nitro-N-oxidation camptothecine crystallization.Gained 9-nitro-N-oxidation camptothecine is dissolved in dioxane, back flow reaction 48 hours, concentrate 9-nitrocamptothecin crude product, crude product gets the pure product of 9-nitrocamptothecin through ethyl alcohol recrystallization.
Embodiment 2
The 40g camptothecine is dissolved in the 1000mL acetate, add 30% hydrogen peroxide 400mL, after reacting 3 hours under 80 ℃, in the impouring 5000mL frozen water, with dichloromethane extraction, concentrate, and residue is dissolved in the 2000mL acetate, after dripping sulfuric acid 200mL in the ice-water bath, be heated to 30 ℃ and add down 60 gram iron nitrates reactions 72 hours, pour into then in the 5000mL frozen water, dichloromethane extraction, concentrate and separate out 9-nitro-N-oxidation camptothecine crystallization.Gained 9-nitro-N-oxidation camptothecine is dissolved in dioxane, back flow reaction 72 hours, concentrate 9-nitrocamptothecin crude product, crude product gets the pure product of 9-nitrocamptothecin through acetone recrystallization.
Embodiment 3
The 40g camptothecine is dissolved in the 1000mL acetate, add 30% hydrogen peroxide 400mL, after reacting 8 hours under 30 ℃, in the impouring 5000mL frozen water, with dichloromethane extraction, concentrate, and residue is dissolved in the 1000mL trifluoroacetic acid, drip behind the vitriol oil 200mL 70 ℃ in the ice-water bath and add 70g magnesium nitrate reaction 48 hours down, pour into then in the 5000mL frozen water, dichloromethane extraction, concentrate and to separate out 9-nitro-N-oxidation camptothecine crystallization.Gained 9-nitro-N-oxidation camptothecine is dissolved in dioxane, back flow reaction 24 hours, concentrate 9-nitrocamptothecin crude product, crude product gets the pure product of 9-nitrocamptothecin through the acetate recrystallization.
Embodiment 4
The 40g camptothecine is dissolved in the 1000mL acetate, add 30% hydrogen peroxide 400mL, after reacting 1 hour under 90 ℃, in the impouring 5000mL frozen water, with dichloromethane extraction, concentrate, and residue is dissolved in the 1000mL trichoroacetic acid(TCA), drip behind the vitriol oil 200mL 80 ℃ in the ice-water bath and add 70g cupric nitrate reaction 48 hours down, pour into then in the 5000mL frozen water, dichloromethane extraction, concentrate and to separate out 9-nitro-N-oxidation camptothecine crystallization.Gained 9-nitro-N-oxidation camptothecine is dissolved in dioxane, back flow reaction 10 hours, concentrate 9-nitrocamptothecin crude product, crude product gets the pure product of 9-nitrocamptothecin through ethyl alcohol recrystallization.
Embodiment 5
The 40g camptothecine is dissolved in the 1000mL acetate, add 30% hydrogen peroxide 400mL, after reacting 4 hours under 60 ℃, in the impouring 5000mL frozen water, with dichloromethane extraction, concentrate, and residue is dissolved in the 1000mL sulfuric acid, add 60g SODIUMNITRATE reaction 72 hours under the room temperature, pour into then in the 5000mL frozen water, dichloromethane extraction, concentrate and to separate out 9-nitro-N-oxidation camptothecine crystallization.Gained 9-nitro-N-oxidation camptothecine is dissolved in dioxane, back flow reaction 48 hours, concentrate 9-nitrocamptothecin crude product, crude product gets the pure product of 9-nitrocamptothecin through the acetate recrystallization.
Claims (8)
1. the production method of a 9-nitrocamptothecin,---nitrated N-oxidation camptothecine gets 9-nitro-N-oxidation camptothecine---dioxane reflux concentrate 9-nitrocamptothecin crude product---, and recrystallization gets the pure product of 9-nitrocamptothecin to it is characterized in that according to the preparation of following operational path: with the camptothecine is that raw material gets N-oxidation camptothecine through oxidation.
2. according to the production method of the described 9-nitrocamptothecin of claim 1, it is characterized in that: the process that camptothecine is oxidized to N-oxidation camptothecine adds superoxol for camptothecine is dissolved in acetate, 30～90 ℃ of reactions 0.5～10 hour down.
3. according to the production method of the described 9-nitrocamptothecin of claim 1, it is characterized in that: nitrated N-oxidation camptothecine method comprises N-oxidation camptothecine is dissolved in acid and adds at least a nitrating agent, 0～90 ℃ of reaction 3～72 hours down.
4. according to the production method of the described 9-nitrocamptothecin of claim 3, it is characterized in that: employed acid is acetate, trichoroacetic acid(TCA), trifluoroacetic acid or the vitriol oil in the method for nitrated N-oxidation camptothecine.
5. according to the production method of the described 9-nitrocamptothecin of claim 3, it is characterized in that: nitrating agent is meant the mixture of the vitriol oil and nitrosonitric acid or inorganic nitrate.
6. according to the production method of the described 9-nitrocamptothecin of claim 5, it is characterized in that: described inorganic nitrate comprises SODIUMNITRATE, saltpetre, ammonium nitrate, Silver Nitrate, cupric nitrate, zinc nitrate, Mercury pernitrate, magnesium nitrate, aluminum nitrate, iron nitrate, lead nitrate or Iron nitrate.
7. according to the production method of the described 9-nitrocamptothecin of claim 1, it is characterized in that: the dioxane return time is 3～72 hours.
8. according to the production method of the described 9-nitrocamptothecin of claim 1, it is characterized in that: recrystallization solvent is ethanol, acetone or acetate.
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2004100437325A CN100334089C (en) | 2004-07-21 | 2004-07-21 | Production method of 9-nitro camptothecin |
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| CNB2004100437325A CN100334089C (en) | 2004-07-21 | 2004-07-21 | Production method of 9-nitro camptothecin |
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| CN100334089C true CN100334089C (en) | 2007-08-29 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103130814B (en) * | 2011-11-25 | 2016-03-09 | 上海医药工业研究院 | Two kinds of 9-nitrocamptothecin new crystal and preparation method thereof |
| CN104628737B (en) * | 2015-01-28 | 2017-06-06 | 华南理工大学 | Two kinds of 9 nitrocamptothecins of novel crystal forms and preparation method thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5946284A (en) * | 1982-09-10 | 1984-03-15 | Yakult Honsha Co Ltd | 11-nitrocamptothecin derivative and its preparation |
| JPS5951288A (en) * | 1982-09-17 | 1984-03-24 | Yakult Honsha Co Ltd | Novel 9-camptothecin and its preparation |
| WO1995009169A1 (en) * | 1993-09-28 | 1995-04-06 | Pharmacia S.P.A. | Process for the preparation of 9-amino camptothecin |
| CN1222523A (en) * | 1993-08-06 | 1999-07-14 | 法玛西雅厄普约翰公司 | Process for preparation of 9-amino camptothecin |
| CN1266435A (en) * | 1997-08-05 | 2000-09-13 | 斯特林癌症研究基金会 | Process for preparing and purifying 9-nitro-20-camptothecin |
| WO2000053607A1 (en) * | 1999-03-09 | 2000-09-14 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Camptothecin derivatives having antitumor activity |
-
2004
- 2004-07-21 CN CNB2004100437325A patent/CN100334089C/en not_active Expired - Fee Related
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5946284A (en) * | 1982-09-10 | 1984-03-15 | Yakult Honsha Co Ltd | 11-nitrocamptothecin derivative and its preparation |
| JPS5951288A (en) * | 1982-09-17 | 1984-03-24 | Yakult Honsha Co Ltd | Novel 9-camptothecin and its preparation |
| CN1222523A (en) * | 1993-08-06 | 1999-07-14 | 法玛西雅厄普约翰公司 | Process for preparation of 9-amino camptothecin |
| WO1995009169A1 (en) * | 1993-09-28 | 1995-04-06 | Pharmacia S.P.A. | Process for the preparation of 9-amino camptothecin |
| CN1273974A (en) * | 1993-09-28 | 2000-11-22 | 法玛西雅厄普约翰公司 | Camptothecin derviative, its prepn. method and medicinal compsns. containing same |
| CN1266435A (en) * | 1997-08-05 | 2000-09-13 | 斯特林癌症研究基金会 | Process for preparing and purifying 9-nitro-20-camptothecin |
| WO2000053607A1 (en) * | 1999-03-09 | 2000-09-14 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Camptothecin derivatives having antitumor activity |
Non-Patent Citations (3)
| Title |
|---|
| 20(S)-9-硝基-10-羟基喜树碱的制备研究 雷英杰等，应用化工，第29卷第3期 2000 * |
| 20(S)-9-硝基-10-羟基喜树碱的制备研究 雷英杰等，应用化工，第29卷第3期 2000;20(S)-9-硝基喜树碱的制备研究 雷英杰等，西北药学杂志，第15卷第2期 2000 * |
| 20(S)-9-硝基喜树碱的制备研究 雷英杰等，西北药学杂志，第15卷第2期 2000 * |
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