CN1621406A - Production process of camptothecin - Google Patents
Production process of camptothecin Download PDFInfo
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- CN1621406A CN1621406A CN 200310111050 CN200310111050A CN1621406A CN 1621406 A CN1621406 A CN 1621406A CN 200310111050 CN200310111050 CN 200310111050 CN 200310111050 A CN200310111050 A CN 200310111050A CN 1621406 A CN1621406 A CN 1621406A
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Abstract
The production process of camptothecine with camptotheca fruit containing camptothecine in 800-1000 ppm as material includes the steps of: crushing, ethanol diacolation, concentration of percolate, filtering to obtain filtrate, solvent extraction, re-crystallization in the first mixed solvent for purification, re-crystallization in the second mixed solvent for purification to obtain coarse product, and refining with the third mixed solvent to obtain refined product. The process has less investment in apparatus, simple technological process, low production cost, product purity higher than 94 % and product yield higher than 400 ppm, and is suitable for industrial production.
Description
The present invention relates to extract from plant natural constituent, particularly a kind of is raw material with the fruit of camptotheca acuminata, the technology of production camptothecine.
Camptothecine (camptothecin, CPT), faint yellow plate crystal, molecular formula: C20H16N2O4, molecular weight 348.3, camptothecine are a kind of alkaloids that extensively is distributed in root, skin, stem and the seed of China southern Nyssaceae drought Nelumbo deciduous tree camplotheca acuminata (Camptotheca acuminata Decsne); People such as Wall in 1966 from the leaf of camplotheca acuminata and bark, isolate camptothecine (Camptothecin, CPT) and proved conclusively structure, it has very strong anti-tumor activity, and is especially effective to digestive tract tumor, leukemia, chorioepithelioma, bladder cancer; Through structural modification deutero-camptothecin antineoplastic agents irinotecan (irinotecan is arranged, CPT-11), topotecan (topotecan) and 10-hydroxycamptothecine, a plurality of active compounds are arranged, be in the clinical study stage as 9-aminocamptothecin (9-amino-Camptothecin), 9-nitrocamptothecin (9-nitro-camptothecin) etc.;
At present, camptothecine generally is to extract to obtain from fruit of camptotheca acuminata; Patent Office of State Intellectual Property Office discloses the patents of several relevant camptothecine extraction processes respectively at the following time: technology 1:1996 May disclosed a kind of camptothecine on the 8th extracting method, number of patent application is 94111946.7, this patent of invention is a raw material with fruit of camptotheca acuminata or root skin, adopt abrasive dust → poach → boil liquid to concentrate → paste → ethanol to separate the operational path that gummy impurity → separate out crude product → chloroform mixed solution repeatedly obtains product behind the recrystallization, product purity 92%, output capacity is about 2/10000; Technology 2:1999 December disclosed a kind of camptothecine on the 22nd production method, number of patent application is 99112767.6, this invention is main raw material with the leaf of Common Camptotheca, fruit is an auxiliary material, leftover materials after pulverizing → ethanol percolation → supercritical carbon dioxide extraction → diacolation extracts → concentrated percolate and extraction liquid → macroporous adsorptive resins layer → recrystallization get the operational path of product, product purity 97.5%, productive rate 2/10000～3/10000; Technology 3:2000 April disclosed a kind of camptothecine on the 26th production method, number of patent application: 99113256.4, this invention is a raw material with leaf of Common Camptotheca and seed, get the operational path of product through pulverizing → ethanol and water diacolation → concentrated percolate → macroporous adsorptive resins layer → recrystallization, product purity 97.5%, productive rate 2/10000～3/10000; Technology 4:2003 April disclosed camptothecine on the 16th production technique, number of patent application is 01128211.8,
This invention is raw material with the leaf of Common Camptotheca, through pulverizing → ethanol or buck extraction → extraction liquid is concentrated into medicinal extract → solvent extraction and crystallization gets the operational path that coarse-grain → recrystallization gets product, product purity 97.5%, productive rate 2/10000.
According to our discovering: the product yield of technology 1 is lower, is about 2/10000; The product yield of technology 2 and technology 3 all is no more than 3/10000, and treatment processs such as supercritical carbon dioxide extraction or macroporous adsorbent resin column chromatography have been used in the operational path, production operation treating processes more complicated, it is bigger to produce input and equipment front-end investment, and production cost is higher; Technology 4 is to be raw material with the leaf of Common Camptotheca, product yield also lower (2/10000).
The object of the present invention is to provide a kind of is the technology of raw material, production camptothecine with fruit of camptotheca acuminata.This technological operation is easier, extract that yield is higher, good product purity, be fit to suitability for industrialized production.
The present invention constitutes like this: the content of camptothecine is bigger in the fruit of camptotheca acuminata, is 2/10000～14/10000, and the camptothecine content of general commercially available fruit of camptotheca acuminata can reach more than 8/10000.The present invention is a raw material with 8/10000～10/10000 fruit of camptotheca acuminata, through pulverizing to such an extent that medicinal material coarse powder → adding concentration is 8～10 times of amount 60%～90% alcohol immersion diacolation → collection percolates after 24～48 hours, concentrate, leaving standstill 5～48 hours → filtration → chloroform extraction filtrate → concentrated chloroform extraction liquid → paste → recrystallizing methanol purifying gets crude product → chloroform-methanol mixed solvent recrystallization purifying and gets camptothecine coarse-grain → N, the refining purifying of dinethylformamide-alcohol mixed solvent gets camptothecine elaboration (gained camptothecine product purity is greater than 94%, and the product yield is greater than 4.0/10000).
Specifically: with the fruit of camptotheca acuminata is raw material, it is pulverized the back measures 60%～90% ethanol with 8～10 times it is soaked diacolation after 24～72 hours, the diacolation time is 10～15 hours, reduce pressure 70～80 ℃ of concentrated percolates to 1/6～1/9 of original volume, the gained concentrated solution was left standstill 5～48 hours, filter, with chloroform extraction filtrate, consumption is 0.5～3 times of amount of concentrated solution volume, extraction times is 2～4 times, the combined chloroform extraction liquid through concentrate paste, make solvent with methyl alcohol successively again and it is carried out recrystallization purifying get the camptothecine crude product, with chloroform-methanol (1: 3～3: 1) mixed solvent gained crude product recrystallization purifying is got the camptothecine coarse-grain, with N, dinethylformamide-ethanol (1: 5～5: 1) mixed organic solvents is made with extra care purifying to coarse-grain and is got the camptothecine elaboration, i.e. the camptothecine product; Among the present invention, use solvent extraction filtrate, solvent for use can replace chloroform with methylene dichloride during extraction, replace methyl alcohol to carry out recrystallization purifying with ethanol and get crude product as solvent, replacing chloroform-methanol (1: 3～3: 1) with chloroform-ethanol (1: 3～3: 1) is that the solvent recrystallization purifying gets coarse-grain, with N, dinethylformamide-methyl alcohol (1: 5～5: 1) replaces N, and dinethylformamide-ethanol (1: 5～5: 1) gets the camptothecine elaboration for the solvent treatment purifying.
Compare with the production technique of existing camptothecine, product yield of the present invention is higher, is 4.0/10000, and purity is greater than 94%.The present invention is the raw material production camptothecine with the fruit of camptotheca acuminata, and raw material is gathered conveniently, and the camplotheca acuminata resource is not had destruction, has realized Sustainable utilization of resources.Several mixed organic solvents that production technique provided by the invention has been selected for use with technology was different in the past carry out recrystallization repeatedly to the camptothecine crude product, extraction → extraction → recrystallization promptly gets product repeatedly through diacolation, the production unit of production technique drops into little, equipment is simple, easy and simple to handle, be easy to suitability for industrialized production.
Embodiments of the invention 1: get fruit of camptotheca acuminata dry product 100Kg, pulverize the crude drug meal, with 8 times of amount 60% ethanol it is soaked diacolation after 24 hours, collect percolate, the dregs of a decoction wash with suitable quantity of water, washings is used for next batch and oozes the foot of a hill or mountain and apply mechanically; With ethanol percolation liquid concentrating under reduced pressure (70～80 ℃), reclaim ethanol to 1/9 volume, filter, filtrate is measured chloroform extractions 3 times with 1.0,0.8,0.5 times respectively, the combined chloroform extraction liquid, reclaim chloroform and get paste, get the camptothecine crude product with the dissolve with methanol recrystallization, with chloroform-methanol (1: 3) mixed solvent this camptothecine crude product recrystallization is got the camptothecine coarse-grain again, at last with N, dinethylformamide-ethanol (1: 5) promptly gets camptothecine crystalline product 40g, purity 95.4%, yield 4.0/10000 to its recrystallizing and refining.
Embodiments of the invention 2: get fruit of camptotheca acuminata dry product 500Kg, pulverize the crude drug meal, with diacolation behind 10 times of amount 90% alcohol immersion 24h, collect percolate, with ethanol percolation liquid concentrating under reduced pressure (70～80 ℃), reclaim about ethanol to 1/6 volume, filter, filtrate is respectively with 1.5,1.0,0.5 doubly measure chloroform extraction 3 times, the combined chloroform extraction liquid, reclaim chloroform and get paste, get the camptothecine crude product, with chloroform-methanol (3: 1) mixed solvent this camptothecine crude product recrystallization is got the camptothecine coarse-grain again with the dissolve with methanol recrystallization, at last with N, dinethylformamide-ethanol (5: 1) promptly gets camptothecine crystalline product 205g, purity 94.4%, yield 4.1/10000 to its recrystallizing and refining.
Embodiments of the invention 3: it is that 80% weight is that the ethanol water of 9 times of amounts of raw material soaks diacolation after 48 hours to it with concentration that the 1000Kg fruit of camptotheca acuminata is pulverized the back, the diacolation time is 15 hours, concentrate percolate then, percolate is concentrated into 1/8 of original volume through reducing pressure 70～80 ℃, the gained concentrated solution was left standstill 5 hours, filter, with dichloromethane extraction filtrate, consumption is 0.3 of a concentrated solution weight, 0.2 doubly measure, extract 2 times, concentrate dichloromethane extraction liquid and obtain paste, it gets crude product as the solvent recrystallization purifying with ethanol again, with chloroform: ethanol=1: 1 is that the solvent recrystallization purifying gets coarse-grain, with N, dinethylformamide: methyl alcohol=1: 1 gets the camptothecine elaboration for the solvent treatment purifying.
Claims (2)
1, a kind of production technique of camptothecine, it is characterized in that: be raw material with the fruit of camptotheca acuminata, it is pulverized the back measures 60%～90% ethanol with 8～10 times it is soaked diacolation after 24～48 hours, the diacolation time is 10～15 hours, reduce pressure 70～80 ℃ of concentrated percolates to 1/6～1/9 of original volume, the gained concentrated solution was left standstill 5～48 hours, filter, with chloroform extraction filtrate, consumption is 0.5～3.0 times of amount of concentrated solution volume, extraction times is 2～4 times, the combined chloroform extraction liquid through concentrate paste, making solvent with methyl alcohol successively again carries out recrystallization purifying to it and gets the camptothecine crude product, with chloroform-methanol (1: 3～3: 1) mixed solvent gained crude product recrystallization purifying is got the camptothecine coarse-grain, with N, dinethylformamide-ethanol (1: 5～5: 1) mixed solvent is made with extra care purifying to coarse-grain and is got the camptothecine elaboration, i.e. the camptothecine product.
2, according to the production technique of the described camptothecine of claim 1, it is characterized in that: use solvent extraction filtrate, solvent for use can replace chloroform with methylene dichloride during extraction, replace methyl alcohol to carry out recrystallization purifying with ethanol and get crude product as solvent, replacing chloroform-methanol (1: 3～3: 1) with chloroform-ethanol (1: 3～3: 1) is that the solvent recrystallization purifying gets coarse-grain, with N, dinethylformamide-methyl alcohol (1: 5～5: 1) replaces N, and dinethylformamide-ethanol (1: 5～5: 1) gets the camptothecine elaboration for the solvent treatment purifying.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200310111050 CN1260230C (en) | 2003-11-28 | 2003-11-28 | Production process of camptothecin |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200310111050 CN1260230C (en) | 2003-11-28 | 2003-11-28 | Production process of camptothecin |
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|---|---|
| CN1621406A true CN1621406A (en) | 2005-06-01 |
| CN1260230C CN1260230C (en) | 2006-06-21 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN 200310111050 Expired - Fee Related CN1260230C (en) | 2003-11-28 | 2003-11-28 | Production process of camptothecin |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102093375A (en) * | 2011-02-28 | 2011-06-15 | 中国科学院过程工程研究所 | Method for extracting steam explosion common camptotheca fruits and preparing camptothecin |
| CN102603757A (en) * | 2012-01-17 | 2012-07-25 | 花垣恒远植物生化有限责任公司 | Method for extracting and separating camptothecin from Nothapodytes pittosporoides (Oliv.) Sleum. |
-
2003
- 2003-11-28 CN CN 200310111050 patent/CN1260230C/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102093375A (en) * | 2011-02-28 | 2011-06-15 | 中国科学院过程工程研究所 | Method for extracting steam explosion common camptotheca fruits and preparing camptothecin |
| CN102603757A (en) * | 2012-01-17 | 2012-07-25 | 花垣恒远植物生化有限责任公司 | Method for extracting and separating camptothecin from Nothapodytes pittosporoides (Oliv.) Sleum. |
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| Publication number | Publication date |
|---|---|
| CN1260230C (en) | 2006-06-21 |
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