CN101054381A - Semi-synthesis method for 10-hydroxyl camptothecin - Google Patents
Semi-synthesis method for 10-hydroxyl camptothecin Download PDFInfo
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- CN101054381A CN101054381A CN 200710041372 CN200710041372A CN101054381A CN 101054381 A CN101054381 A CN 101054381A CN 200710041372 CN200710041372 CN 200710041372 CN 200710041372 A CN200710041372 A CN 200710041372A CN 101054381 A CN101054381 A CN 101054381A
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Abstract
The present invention belongs to medicine technology field, more specificly a half-synthesis method for 10-hydroy camptothecin. The steps are that: 20(S)- camptothecin is catalyticly hydrogenated to generate tetrahydro camptothecin catalyzed by noble metal catalyst and added with mitigator. tetrahydro camptothecin is oxidized to 10-hydroy camptothecin by normal method. 10-hydroy camptothecin crude product is recrystallized and purified. Wherein, the catalyst is platinum carbon or rhodium carbon catalyst. The mitigator contains organic compound. The method is simply operated, total yield can amount to 70-75%, prouduct purity is larger than 98.5%, which is suitable for large scale production.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of synthetic method of cancer therapy drug 10-hydroxycamptothecine.
Background technology
Camptothecine (camptothecin, CPT, C1) and 10-hydroxycamptothecine (10-hydroxycamptothecin, HCPT is to extract the class tryptophane-terpenes alkaloid anticarcinogen that obtains in China the distinctive Nyssaceae drought lotus plant camptotheca acuminata (camptotheca acuminata Decne) C2).Chemical structure and the numbering of C1 and C2 are as follows:
People such as M.E.Wall isolated camptothecine and had determined structure in 1966, had the tumour of inhibition and antileukemie physiologically active because camptothecine is found, thereby were subjected to Pharmaceutical Chemist, physiologist and organic synthesis worker's strong interest.But in clinical application, also find C1 and C2 because the solubleness in water is relatively poor, produce many comparatively severe side effect, as vomiting, diarrhoea, bone marrow depression etc., so people once sharply descended to the alkaloidal interest of camptothecin.But by 1985, scientists finds that again the special plant alkaloid of this class can suppress dna replication dna, transcribe and mitotic division by acting on DNA topoisomerase I (DNAtopoisomerase I), thereby cause people's attention again, research interest heats up day by day.After entering the nineties, countries such as Japan, the U.S., Britain and Canada drop into great amount of manpower and material resources and carry out the research and development of camptothecin material, and design synthesizes a series of active high, good water solubility and the low camptothecin derivative of toxic side effect.At present, extract from camplotheca acuminata and synthetic, semisynthetic camptothecine reaches kind more than 200, camptothecine and series derivates thereof become the bright spot on the antitumor drug market, the world rapidly.The camptothecine antitumous effect has many advantages, as high-efficiency low-toxicity, antitumor spectrum is wide, side effect is little, and is safe and reliable, do not have cross resistance or the like with other antitumor drug, is easily accepted by the patient as the cancer therapy drug of pure natural.Early 1990s, clinical experiment through the specified authoritative medical research institute of U.S. FDA tissue shows, camptothecine PTS " topotecan " (Topotecan, C3) and " Erie for health " (Irinotecan, C4) antitumous effect is suitable with taxol generally, and some aspect also is better than taxol.Drugs approved by FDA " topotecan " in 1996 and " Erie is for health " (Irinotecan) listing, clinical application is in treatment colorectal carcinoma in late period, the rectum cancer, ovarian cancer, lung cancer etc., and the development through in a few years becomes the nova on the antitumor drug market rapidly.
10-hydroxycamptothecine (HCPT) is the strongest a kind of of antitumour activity in the natural camptothecin derivative monomer of kind more than 20, anticancer spectrum is wide, all curative effect is obvious to digestive system tumor (comprising primary hepatocarcinoma, cancer of the stomach, colorectal cancer, carcinoma of the pancreas and esophagus cancer), lung cancer, incidence cancer and acute and chronic leukemia etc., be used for bladder cancer (can irrigation of bladder, the injection of knurl body and intravenous administration) in addition, but and intracavitary administration be used for the treatment of pernicious chest, seroperitoneum; As synthesizing topotecan and Erie important intermediate, use increasingly extensive simultaneously for camptothecin derivatives such as health.Therefore HCPT's is synthetic, particularly important in aspect meanings such as cancer therapy drug researchs.
At present, 10-hydroxycamptothecine synthetic mainly contains following three kinds of methods: complete synthesizing process, biotransformation method and semi-synthesis method.Though wherein complete synthesizing process can make 10-hydroxycamptothecine, its step causes total recovery very low too much, and products obtained therefrom need split isomer D type and L type, cause cost further to raise, thereby its actual production has little significance.And there is following shortcoming in biotransformation method: the cultivation of (1) bacterial strain need expend long time and more financial resources; (2) leaching process of fermented liquid is cumbersome, has expended a large amount of solvents, and has caused environmental pollution.The camptothecine that adopts natural extract in recent years is a raw material, adopts semisynthesis to prepare 10-hydroxycamptothecine, becomes the focus of research.The advantage of semi-synthesis method is:
A): raw material is easy to get: camplotheca acuminata is China's endemic plant, and it is wide to distribute, aboundresources, and the content of camptothecine is higher in the camplotheca acuminata, and along with the improvement of extraction process, it is simple that the acquisition of camptothecine becomes;
B): reactions steps is short, and the production cycle is fast, and is with low cost, is beneficial to scale operation and application;
C): raw material and product have natural chirality, need not split, and the purifying of the finished product is simple.
The semi-synthetic research bibliographical information of 10-hydroxycamptothecine mainly contains two kinds of methods at present:
1) photochemical method: patent (US 4473692 and CN 200410024909) has been introduced elder generation camptothecine (CPT) has been become the N-oxide compound through hydrogen peroxide oxidation, resets the method that obtains 10-hydroxycamptothecine through illumination again,
Present method is the comparatively general method of using at present.The first step particularly, productive rate is very high, realizes easily.But second step needed to use special reactor owing to relate to the short molecular transposition of light, and reaction conditions is difficult to be grasped, and the yield fluctuation is big, the technology instability.And even in order to prevent uneven illumination, the reactor volume of design can not be excessive, so the limitation of this method also is very tangible.
2) method that reoxidizes of reduction earlier: such as patent (CN91110656 and CN200510024487) introduction, its elementary tactics is at first CPT optionally to be reduced to obtain tetrahydro camptothecin C5, and then is oxidized to 10-hydroxycamptothecine.
The key issue of the required solution of this method is how to avoid further drastic reduction (over hydrogenation) after CPT is converted into C5 fully, and prevent the deep oxidation of product HCPT in reaction process, and need to optimize product separation purification condition, make it be more suitable for relatively large preparation.
Summary of the invention
The object of the present invention is to provide the semisynthesis of the highly purified 10-hydroxycamptothecine that a kind of technology stability is good, with short production cycle, cost is low, productive rate is high.
The synthetic method of the highly purified 10-hydroxycamptothecine that the present invention proposes is a raw material with 20 (s)-camptothecine, the synthetic route that adopts first hydrogenation to reoxidize, and concrete steps are as follows:
(1) under noble metal catalyst (as the platinum C catalyst) catalysis, 20 (S)-camptothecine selective catalytic hydrogenations is generated tetrahydro camptothecin.This method is existing report in patent (CN91110656 and CN200510024487).But, the contriver finds in concrete experiment, activity of such catalysts plays crucial effects in this step reaction, if directly adopt the platinum C catalyst of prepared fresh, then the further hydrogenation of meeting behind 20 (S)-camptothecine selective catalytic hydrogenations generation tetrahydro camptothecin has a strong impact on the reaction of back.Must add negative catalyst in the reaction for this reason the catalyst activity is decreased, mention adding DMSO in the patent noted earlier and make the active reduction of catalyst, yet the contriver find that the described method of above-mentioned patent is not very good.For this reason, the contriver has carried out a large amount of screenings, has found the kind and the consumption of suitable negative catalyst, and suitably adjusts the condition of catalytic hydrogenation, make camptothecine catalytic hydrogenation generation more fully tetrahydro camptothecin, and prevent the over hydrogenation reaction to greatest extent.Specific as follows:
Among the present invention, the catalyzer that catalytic hydrogenation adopted is 5% platinum C catalyst or 5% rhodium C catalyst, and catalyst levels is the 10-80% of raw material 20-(s) camptothecine weight, preferred 20-50%.
Among the present invention, catalyst system therefor also is added with negative catalyst, the negative catalyst that adopts is one or more the mixture in organic compounds containing sulfur such as mercaptoethanol, 2-Thiovanic acid, 3-thiohydracrylic acid, thiophene phenol, dimethyl sulfoxide (DMSO), tetramethylene sulfone or the thiodiphenylamine etc., the consumption of negative catalyst is the 0.2-20% of catalyst weight, preferred 1-10%.
Catalytic hydrogenation solvent for use of the present invention is the mixture of Glacial acetic acid or Glacial acetic acid and lower aliphatic alcohols, and lower aliphatic alcohols is methyl alcohol, ethanol, apart from propyl alcohol, Virahol or propyl carbinol etc.
The hydrogen pressure that catalytic hydrogenation of the present invention is used is 5-60psi.
Catalytic hydrogenation temperature of the present invention is 5-60 ℃, preferred 20-50 ℃.
The catalytic hydrogenation time of the present invention is 10-100 hour, preferred 24-72 hour.
Catalytic hydrogenation of the present invention finishes the back and according to ordinary method catalyzer is removed by filter, and gained filtrate is the solution of tetrahydro camptothecin, and this solution needn't be done further processing, can directly carry out next step oxidizing reaction.
(2) adopt ordinary method that tetrahydro camptothecin is oxidized to 10-hydroxycamptothecine.
(3) adopt the method for recrystallization that step (2) gained 10-hydroxycamptothecine crude product is carried out purifying, obtain highly purified 10-hydroxycamptothecine.The used solvent of recrystallization is Glacial acetic acid or Glacial acetic acid and N, the mixture of dinethylformamide.The purity of final product 10-hydroxycamptothecine is greater than 98.5% (HPLC), and C1, C2, C3 step total recovery are 70-75%.
The semisynthesis of 10-hydroxycamptothecine provided by the present invention is easy and simple to handle, total recovery is high, good product purity, is fit to fairly large production.
Embodiment
The invention is further illustrated by the following examples, but be not limited to these embodiment.
Embodiment 1:
1,2,6,7-tetrahydro camptothecin synthetic:
Wave in the still at 500mL Parr hydrogenation, add Glacial acetic acid 300mL, 20 (S)-camptothecine, 20 grams, 5% platinum C catalyst, 5 grams, tetramethylene sulfone 0.3 gram, the capping still, with hydrogen thorough washing reaction system, in reactor, charge into the hydrogen of 60psi, and reaction system is heated to 50 ℃, reacted stopped reaction 48 hours.Be cooled to room temperature, filter and with 30mL Glacial acetic acid washing catalyst, filtrate is 1,2,6, the solution of 7-tetrahydro camptothecin is directly used in next step oxidizing reaction.
Embodiment 2:
Synthesizing of 10-hydroxycamptothecine:
1 liter is equipped with in the churned mechanically three-necked bottle and adds gained 1,2,6 among the embodiment 1, the solution of 7-tetrahydro camptothecin and 500mL distilled water, stir 40 grams of adding down, two acetoxy group iodobenzenes, vigorous stirring is 2 hours under the room temperature, and then adds 25 grams, two acetoxy group iodobenzenes, continue to stir 15 hours under the room temperature, obtain the xanchromatic suspension liquid, suction filtration is also used 100mL Glacial acetic acid washing solid, drains as far as possible, obtaining product needn't dry, and directly carries out next step recrystallization.
Embodiment 3:
The purifying of 10-hydroxycamptothecine:
The 10-hydroxycamptothecine crude product that embodiment 2 is obtained adds in 2 liters of reaction flasks, and add 1600mL Glacial acetic acid and 5 and restrain gacs, reflux 30 minutes, filtered while hot, solid is separated out in the filtrate cooling, and suction filtration also with the washing of 50mL Glacial acetic acid, gets faint yellow solid.This solid is used 1000mL Glacial acetic acid recrystallization once again, and 70 ℃ of vacuum-dryings get product 10-hydroxycamptothecine 12.5 grams, productive rate 59.8% (three step overall yields), purity 99.1% (HPLC).The mother liquor of twice recrystallization is concentrated into dried, with Glacial acetic acid-DMF (volume ratio 80: 20) recrystallization 2 times, 70 ℃ of vacuum-dryings, product 10-hydroxycamptothecine 2.3 grams, purity 98.6% (HPLC).Two batches of products totally 14.8 restrain total recovery 70.8%.
Embodiment 4:
1,2,6,7-tetrahydro camptothecin synthetic:
Wave in the still at 500mL Parr hydrogenation, add Glacial acetic acid 260mL, methyl alcohol 40mL, 20 (S)-camptothecine, 20 grams, 5% platinum C catalyst, 10 grams, dimethyl sulfoxide (DMSO) 0.5 gram, 3-thiohydracrylic acid 0.5 gram, the capping still, with hydrogen thorough washing reaction system, in reactor, charge into the hydrogen of 60psi, and reaction system is heated to 50 ℃, reacted stopped reaction 36 hours.Be cooled to room temperature, filter and with 50mL Glacial acetic acid washing catalyst, filtrate is 1,2,6, the solution of 7-tetrahydro camptothecin is directly used in next step oxidizing reaction.
Embodiment 5:
Synthesizing of 10-hydroxycamptothecine:
1 liter is equipped with in the churned mechanically three-necked bottle and adds gained 1,2,6 among the embodiment 4, the solution of 7-tetrahydro camptothecin and 500mL distilled water, stir 50 grams of adding down, two acetoxy group iodobenzenes, vigorous stirring is 2 hours under the room temperature, and then adds 25 grams, two acetoxy group iodobenzenes, continue to stir 15 hours under the room temperature, obtain the xanchromatic suspension liquid, suction filtration is also used 100mL Glacial acetic acid washing solid, drains as far as possible, obtaining product needn't dry, and directly carries out next step recrystallization.
Embodiment 6:
The purifying of 10-hydroxycamptothecine:
The 10-hydroxycamptothecine crude product that embodiment 5 is obtained adds in 2 liters of reaction flasks, and add 1600mL Glacial acetic acid and 5 and restrain gacs, reflux 30 minutes, filtered while hot, solid is separated out in the filtrate cooling, and suction filtration also with the washing of 50mL Glacial acetic acid, gets faint yellow solid.This solid is used 1000mL Glacial acetic acid recrystallization once again, and 70 ℃ of vacuum-dryings get product 10-hydroxycamptothecine 13.1 grams, productive rate 62.6% (three step overall yields), purity 99.0% (HPLC).The mother liquor of twice recrystallization is concentrated into dried, with Glacial acetic acid-DMF (volume ratio 80: 20) recrystallization 2 times, 70 ℃ of vacuum-dryings, product 10-hydroxycamptothecine 2.3 grams, purity 98.7% (HPLC).Two batches of products totally 15.4 restrain total recovery 73.6%.
Claims (3)
1. the semisynthesis of a 10-hydroxycamptothecine is characterized in that concrete steps are as follows:
The first step is under the noble metal catalyst catalysis that adds negative catalyst, and the camptothecine catalytic hydrogenation is generated tetrahydro camptothecin;
Second step was to adopt ordinary method that the tetrahydro camptothecin that first step generates is oxidized to 10-hydroxycamptothecine;
The 3rd step was that the 10-hydroxycamptothecine crude product recrystallization that second step obtained is carried out purifying;
Wherein, described noble metal catalyst is 5% platinum C catalyst or 5% rhodium C catalyst, catalyst levels is the 10-80% of raw material 20 (s)-camptothecine weight, used negative catalyst is one or more the mixture in mercaptoethanol, 2-Thiovanic acid, 3-thiohydracrylic acid, thiophene phenol, dimethyl sulfoxide (DMSO), tetramethylene sulfone or the thiodiphenylamine, and the consumption of negative catalyst is the 0.2-20% of catalyst weight;
2. the semisynthesis of 10-hydroxycamptothecine according to claim 1, it is characterized in that the catalytic hydrogenation solvent for use is the mixture of Glacial acetic acid or Glacial acetic acid and lower aliphatic alcohols, wherein, lower aliphatic alcohols is methyl alcohol, ethanol, n-propyl alcohol, Virahol or propyl carbinol.
3. the semisynthesis of 10-hydroxycamptothecine according to claim 1 is characterized in that the hydrogen pressure that catalytic hydrogenation is used is 5-60psi, and temperature of reaction is 5-60 ℃, and the reaction times is 10-100 hour.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103145720A (en) * | 2013-02-20 | 2013-06-12 | 上海北卡医药技术有限公司 | Preparation method of 10-hydroxycamptothecin monohydrate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103145720A (en) * | 2013-02-20 | 2013-06-12 | 上海北卡医药技术有限公司 | Preparation method of 10-hydroxycamptothecin monohydrate |
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