CN101450949B - Chemical semi-synthetic process of 10-hydroxycamptothecin - Google Patents
Chemical semi-synthetic process of 10-hydroxycamptothecin Download PDFInfo
- Publication number
- CN101450949B CN101450949B CN2007101719712A CN200710171971A CN101450949B CN 101450949 B CN101450949 B CN 101450949B CN 2007101719712 A CN2007101719712 A CN 2007101719712A CN 200710171971 A CN200710171971 A CN 200710171971A CN 101450949 B CN101450949 B CN 101450949B
- Authority
- CN
- China
- Prior art keywords
- reaction
- hydroxycamptothecine
- palladium
- semisynthesis
- camptothecine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Landscapes
- Catalysts (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a semisynthesis method for 10-hydroxycamptothecin, which takes camptothecin as a raw material to prepare the 10-hydroxycamptothecin through the combination of catalytic hydrogenation and oxidation. The method is characterized by realizing a process of the combination of hydrogenation and oxidation, saving operation steps, in particular improving a catalyst by using a Pd/C catalyst containing 5 to 10 percent of palladium and recycling the catalyst, improving the manageability of the reaction by changing high-temperature reaction to normal-temperature reaction, and improving the selectivity of oxidation by applying oxidizers such as 2-iodoxybenzoic acid during the oxidation reaction. Compared with the prior art, the method has the advantages of hydrogenation reaction which is simple and convenient in operation and is low in cost, oxidation reaction which is high in selectivity, total yield of the two reactions of the whole production process which is increased to more than 85 percent, and suitability for industrial production.
Description
Technical field
The present invention relates to 10-hydroxycamptothecine, more specifically to a kind of chemical semisynthesis of 10-hydroxycamptothecine.
Background technology
Camptothecine is because toxic side effect is less, and the anti-tumor activity height increases its domestic clinical demand amount and export volume year by year.In order to satisfy the needs in market, the study on the synthesis of this class medicine also comes into one's own more and more, especially the preparation of hydroxycamptothecine, because it not only itself is exactly a clinical effectiveness good antitumor medicine, but also be the important intermediate of other camptothecin derivatives such as preparation irinotecan and topotecan.Therefore, the preparation technology of hydroxycamptothecine is studied have very important realistic meaning.
10-hydroxycamptothecine (10-Hydroxycamptothecin, chemical structure HCPT) is similar to camptothecine, only is that the hydrogen on 10 is replaced by hydroxyl, the structural formula See Figure:
At present, the preparation method of 10-hydroxycamptothecine mainly contains four kinds: by extracting in the plant, being that raw material is through biotransformation method, the complete synthesis and chemical semisynthetic method of chemistry with the camptothecine.The content of 10-hydroxycamptothecine in natural camplotheca acuminata is about 2/100000ths, adopts the method for directly extracting because content is low excessively, need expend a large amount of organic solvents, the extraction process complexity, and cost is high, and environmental pollution simultaneously is bigger.Since the eighties, both at home and abroad successively relevant for patent and the paper publishing of camptothecine through bio-transformation or chemical semi-synthetic system 10-hydroxycamptothecine method.Because the content of camptothecine in camplotheca acuminata is 10 times more than of 10-hydroxycamptothecine approximately, in addition the extraction process of camptothecine oneself obtain significant improvement, the cost of natural camptothecine is significantly reduced, and is the comparatively economical rationality of method of feedstock production 10-hydroxycamptothecine with the camptothecine therefore.The patent of invention CN85100520A of Zhu Guanping utilizes biotransformation method, is raw material with the camptothecine, and by flavus bacterial spawn T-419 bio-transformation, fermented liquid refluxes enriched material through filling macroporous resin extraction again in ethyl acetate and methyl alcohol.This scheme adopts flavus T-419 bacterial strain, improved biological transformation ratio, have certain economic effect and development potentiality, but this technology is ripe not enough, exists following shortcoming: the cultivation of (1) bacterial strain need expend time in, and equipment long, that need is many, culture condition is harsh; (2) product concentration is low in the fermented liquid, and leaching process is loaded down with trivial details, and it is big to extract quantity of solvent, and environmental pollution is serious.Therefore, camptothecine is also very high through the cost that bio-transformation prepares 10-hydroxycamptothecine.
Obtain camptothecine by the complete synthesis method of chemistry also is one of chemist's direction of making great efforts always.Although the chirality that E.J.Coery in 1975 has realized camptothecine is complete synthesis, this synthetic route reached more than 21 steps, and synthetic total recovery has only 0.3%.After the eighties in 20th century, researcher is updated the total synthesis method of camptothecine, has improved total recovery, but too many because of step eventually, yield is lower, and cost is too high, thereby its industrialization can't be realized.
Therefore, the extensive at present method that obtains 10-hydroxycamptothecine mainly is raw material with the camptothecine, semi-synthetic preparation 10-hydroxycamptothecine.This method technology is simple, easy handling, and yield is relatively stable, uses more widely industrial having obtained.
People such as Miyasaka disclose two kinds of methods of semi-synthetic 10-hydroxycamptothecine in U.S. Pat 4473692, US4545880 and European patent EP 0074256.One is: in the acetate system, with hydrogen peroxide camptothecine is oxidized to the oxynitrides of 1-position, the oxynitride with camptothecine prepares 10-hydroxycamptothecine through ultraviolet lighting then, and total recovery is 79.9%.But (spectroscopy and spectroscopic analysis such as Xu Chunyan, 25:1772～1774) and (Beijing University of Chemical Technology's journal such as Li Bin, 31:71～75) article all adopts the method for oxidation, illumination to prepare 10-hydroxycamptothecine, total recovery has only 49.9% and 47.06%, this illustrates this method less stable, and operability is not strong.It two is: in the acetate system; with the platinum oxide is catalyzer; under normal pressure, the camptothecine shortening is prepared 1; 2; 6; the 7-tetrahydro camptothecin; the gained tetrahydro camptothecin obtains 1-ethanoyl-10-nitro tetrahydro camptothecin under pyridine and acid anhydrides effect; obtain 10-nitro tetrahydro camptothecin through deacetylation then; resulting 10-nitro tetrahydro camptothecin is through peroxidation, and reduction obtains the 10-amino camptothecin, passes through diazotization reaction again; the hydroxyl replacement obtains 10-hydroxycamptothecine, and total recovery is 22.4%.They disclosed the another kind of method for preparing 10-hydroxycamptothecine at patent JP59005188 (1984) again afterwards.This method is under the normal temperature and pressure, to obtain 1,2,6 with acidifying platinum catalyst hydrogenation of camptothecin in acetate, the 7-tetrahydro camptothecin; Obtain 10-hydroxycamptothecine with oxygenant oxidation tetrahydro camptothecins such as lead tetra-acetate, CAN (cerous nitrate (IV) ammonium) or Fremy salt, total recovery is 56.4%.But because the catalytic activity of acidifying platinum is very good, over-hydrogenation very easily occurs, hydrogenation is difficult to rest on just the level of tetrahydrochysene.Although the contriver attempts to utilize temperature to control reactive activity, such as room temperature hydrogenation, but still be difficult to accomplish not over-hydrogenation, this may be the unsettled reason of this method yield.People such as J.M.Tumnake also disclose the method for another semi-synthetic 10-hydroxycamptothecine in patent CN91110656.1 (approval in 1992), in Glacial acetic acid, Pt/C after poisoning with DMSO is a catalyzer, the high-pressure hydrogenation camptothecine obtains tetrahydro camptothecin, obtain 10-hydroxycamptothecine with acetate iodobenzene or two trifluoroacetic acid iodobenzene oxidation tetrahydro camptothecin again, total recovery is 78%.In addition, Xu Nin adopts the identical high pressure shortening and the step of oxidation that camptothecine is converted into 10-hydroxycamptothecine in patent CN1834097, and catalyzer carried out recycle, and the method purified product that adopts the high-pressure liquid phase preparative column to combine simultaneously with recrystallization, total recovery is 66.3%.
Oxidation-luminescence method of Miyasaka once had been widely adopted as the method for producing 10-hydroxycamptothecine the 80s and 90s in last century in the above method.Need high-power ultraviolet source, yield instability, poor operability but this method exists, be difficult to realize fairly large shortcomings such as production.It is too much that another first nitration oxidation restores method steps, and cost is too high, lacks the actual production meaning.And the redox method transformation efficiency of Miyasaka has obtained certain raising, but as easy as rolling off a log over-hydrogenation in the experiment, operate wayward, thereby yield instability.People such as J.M.Tumnake have further improved this method, and over-hydrogenation problem when they have adopted the method that adds the catalysis poisonous agent to solve hydrogenation of camptothecin has found again to have more optionally that oxygenant comes the oxidation tetrahydro camptothecin.But these are improved one's methods and still exist noble metal platinum to cost an arm and a leg, and cost is higher, and high-pressure hydrogenation must carry out in autoclave, and there are a series of problems of potential safety hazard or the like in complicated operation.
Summary of the invention
The objective of the invention is to disclose a kind of chemical semisynthesis of 10-hydroxycamptothecine, particularly improve, to overcome the above-mentioned defective that prior art exists at the catalyzer in the hydrogenation.
Technical scheme of the present invention is as follows: camptothecine is under the effect of Pd/C, and heating hydrogenation is tetrahydro camptothecin in solvent; Again with oxygenant with the tetrahydro camptothecin oxidation, obtain 10-hydroxycamptothecine, reaction formula is as follows:
The preparation method of 10-hydroxycamptothecine of the present invention may further comprise the steps:
(1) Preparation of catalysts:
At first with the activated carbon mineral acid treatment, used mineral acid has sulfuric acid, nitric acid, hydrochloric acid, and wherein nitric acid is the most suitable; After being washed with water to neutrality then, at high temperature drying obtains activity carbon carrier.With the solution impregnation activity carbon carrier that contains the Pd compound, make to contain that Pd is compound loaded to obtain catalyst precursor to activated carbon.We adopt hydrazine hydrate, formaldehyde or hydrogen etc. that catalyzer is carried out activation treatment, find directly to activate the most suitable with hydrogen.Wherein the adsorption activity of activated carbon, inorganic impurity are all wanted strict control, the high purity of Pd compound is crucial simultaneously, otherwise the Pd/C activity for preparing is on the low side, and can't realize good catalytic hydrogenation, also can prolong the reaction times greatly, thereby the catalysis by product increases.Catalyzer after the activation treatment is filtered, washing, the high-temperature vacuum drying, cooling preservation is standby under the hydrogen shield.In controlling catalyst, palladium content is about 5%～10% among the present invention, and palladium content is lower than 5%, and is active on the low side; Palladium content is greater than 10%, and also can there be a small amount of over-hydrogenation problem in active can increasing during reaction, and it is 6～8% the most suitable to find in the research that palladium is controlled at.The present invention also can select to use 5%～10% commercially available palladium carbon.
The hydrogenant key is to control catalytic activity, and temperature and pressure is adjusted to a proper level, makes the level of catalyzed reaction basic controlling at tetrahydro camptothecin, and is unlikely to over-hydrogenation.The Pt/C that the present invention poisons need changes active moderate Pd/C into, and the preparation process of the control Pd/C by strictness, the content of control palladium come the activity of control catalyst, and no longer needs to add poisonous agent such as DMSO.Successful realization the control of hydrogenation, almost do not have the over-hydrogenation phenomenon to occur, also saved many costs simultaneously.
(2) hydrogenation process:
Camptothecine is dissolved in solvent, and under the effect of palladium carbon Pd/C, reacting by heating hydrogenation is tetrahydro camptothecin under the normal pressure.
In the above-mentioned catalytic hydrogenation, solvent is glacial acetic acid, tetrahydrofuran (THF) or 1,4-dioxane, preferred glacial acetic acid; Pressure is 0.1～0.5MPa, and temperature is controlled at 60～100 ℃, is preferably 90 ℃; Palladium catalyst carbon charging capacity is 20%～60% of a raw material, is preferably 30%～40%.
(3) oxidising process:
Above-mentioned tetrahydro camptothecin obtains 10-hydroxycamptothecine with the oxygenant oxidation at normal temperatures.
Described oxidising process can be directly used in oxidizing reaction with catalytic hydrogenation liquid filtration catalizer, tetrahydro camptothecin need not be separated to obtain, and realizes that substantially the hydrogenation oxidation " cooks all things in one pot ", has avoided tetrahydro camptothecin to separate the problem of oxidation by air like this.Described oxygenant is IBX (2-iodoxy phenylformic acid), acetic acid iodobenzene or plumbic acetate, is preferably IBX.IBX oxidation capacity gentleness has significantly reduced the ratio that the product 10-hydroxycamptothecine again be oxidized.Described oxidizing temperature is controlled between 20～40 ℃ and is advisable, and temperature is low excessively, and oxidation rate is slow excessively, has increased the further oxidized probability of the 10-hydroxycamptothecine that obtains, and yield is on the low side; Temperature is too high, can increase the solvability of 10-hydroxycamptothecine in reaction system, equally also can increase its oxidized probability.The equivalence ratio of described oxygenant charging capacity and raw material camptothecine charging capacity is 3～4, charging capacity very little, oxidation is incomplete, charging capacity can cause over oxidation again too much.
Beneficial effect of the present invention:
The chemical semi-synthetic technology that has realized that hydrogenation, oxidation " are cooked all things in one pot " of 10-hydroxycamptothecine of the present invention, promptly hydrogenation liquid filters, and not treated next step oxidizing reaction that is directly used in of filtrate has been saved operation steps, has improved the total recovery of product.Simultaneously, hydrogenation adopts homemade Pd/C catalyzer, for Pt/C, has the low advantage of price, and in reaction, avoided the use of poisonous agent DMSO, successfully realized the control of catalytic hydrogenation, almost do not have the phenomenon of over-hydrogenation, yield also is improved relatively, has reduced production cost.Simultaneously the Pd/C catalyzer of filtered and recycled still has good catalytic activity, and catalytic effect does not obviously descend, and can reuse 3～5 times, and the shared cost of metal catalytic has been reduced to approximately 2% by original 12% like this, has saved production cost.Hydrogenation process is improved to normal pressure by high pressure, has strengthened operability, has reduced the danger coefficient in producing, simplified control, thus avoid using autoclave, also reduced disposable equipment input, reduced cost.
Two-step reaction total recovery of the present invention is improved, and production cost has obtained reduction, and simple and safe operation is more suitable in industrial production.
Embodiment
Embodiment 1: the preparation of palladium carbon
With the nitric acid acidwashing 5h of 100g 4～8 order activated carbon with 1mol/L, be washed with water to neutrality, dry 10h under 100 ℃, the carrier that obtains activated carbon is standby.Get the palladium solution 3.2g that contains palladium 16%, add deionized water to 40mL, the aqueous sodium hydroxide solution of adding 10% adjusts to 5～7 with the palladium pH value of solution, behind the solution-stabilized 1h of palladium, above-mentioned treated activated carbon with palladium solution impregnation 3h, is obtained catalyst precursor.The catalyst precursor 24h that wears out with high-purity hydrogen gas disposal catalyst precursor 5h, filters under hydrogen shield, is washed with water to neutrality.Catalyzer is 180 ℃ and vacuum tightness 1.013 * 10
-3Dry 72h under the Pa, nitrogen protection drops to room temperature and comes out of the stove.Finished product is with the airtight preservation of hydrogen shield.The catalyzer that makes contains palladium about 8%.
Embodiment 2:
Add the Pd/C of 200g camptothecine and 120g 5% in three mouthfuls of round-bottomed flasks of 5L, add 1 of 3L, the 4-dioxane.Feed hydrogen under normal pressure stirs and be heated to 80 ℃, reaction 24h.After reaction finishes, with the reaction solution cooling, remove by filter catalyst for reaction, reaction solution is directly used in next step oxidizing reaction.
With above-mentioned 1,4-dioxane reaction solution (about 3.1L) is transferred in the reaction flask of 20L, adds the water dilute reaction solution of equivalent, and (about 40 ℃) vigorous stirring at room temperature, divides 5 batches in the 2h in reaction solution and adds 320g IBX (2.0eq), and 2h adds.Then 158g (1.0eq) IBX is divided into three batches of intervals added in one hour.After oxygenant added, stirring reaction 12h after-filtration obtained product, uses washed with methanol, and drying obtains about 119g product (wherein product HCPT content is 47%).
Embodiment 3:
The Pd/C that adds 200g camptothecine and 100g 10% in three mouthfuls of round-bottomed flasks of 5L, the tetrahydrofuran (THF) of adding 3L.Feed hydrogen under normal pressure stirs and be heated to 60 ℃, reaction 24h.After reaction finishes, with the reaction solution cooling, remove by filter catalyst for reaction, reaction solution is directly used in next step oxidizing reaction.
(about 3.1L) transfers in the reaction flask of 20L with above-mentioned tetrahydrofuran (THF) reaction solution, adds the water dilute reaction solution of equivalent, and (about 20 ℃) vigorous stirring at room temperature, divides 5 batches in the 2h in reaction solution and adds 320g IBX (2.0eq), and 2h adds.Then 176g (1.1eq) IBX is divided into three batches of intervals added in one hour.After oxygenant added, stirring reaction 12h after-filtration obtained product, uses washed with methanol, and drying obtains about 72g product (wherein product HCPT content is 41%).
Embodiment 4:
The Pd/C (self-control) that adds 200g camptothecine and 100g 8% in the 5L high-pressure hydrogenation still, the 3L Glacial acetic acid.At 0.5Mpa, 90 ℃ feed hydrogen stirring reaction 24h down.Reaction is removed catalyst for reaction with the reaction solution cooled and filtered after finishing, and reaction solution is directly used in next step oxidizing reaction.
(about 3.1L) transfers in the reaction flask of 20L with above-mentioned acetic acid reaction liquid, adds the water dilute reaction solution of equivalent, and (about 20 ℃) vigorous stirring at room temperature, divides 5 batches in the 2h in reaction solution and adds 320g IBX (2.0eq).Then 176g (1.1eq) IBX is divided into three batches of intervals added in one hour.After oxygenant added, stirring reaction 12h after-filtration obtained product, uses washed with methanol, and drying obtains about 185g product (productive rate 88%).
Embodiment 5:
The Pd/C (self-control) that adds 200g camptothecine and 100g 8% in three mouthfuls of round-bottomed flasks of 5L, the Glacial acetic acid of adding 3L.Feed hydrogen under normal pressure stirs and be heated to 90 ℃, reaction 24h.After reaction finishes, with the reaction solution cooling, remove by filter catalyst for reaction, reaction solution is directly used in next step oxidizing reaction.
(about 3.1L) transfers in the reaction flask of 20L with above-mentioned acetic acid reaction liquid, adds the water dilute reaction solution of equivalent, and (about 20 ℃) vigorous stirring at room temperature, divides 5 batches in the 2h in reaction solution and adds 320g IBX (2.0eq), and 2h adds.Then 176g (1.1eq) IBX is divided into three batches of intervals added in one hour.After oxygenant added, stirring reaction 12h after-filtration obtained product, uses washed with methanol, and drying obtains about 180g product (productive rate 86%).
Embodiment 6:
The Pd/C (self-control) that adds 200g camptothecine and 100g 8% in three mouthfuls of round-bottomed flasks of 5L, the Glacial acetic acid of adding 3L.Feed hydrogen under normal pressure stirs and be heated to 100 ℃, reaction 24h.After reaction finishes, with the reaction solution cooling, remove by filter catalyst for reaction, reaction solution is directly used in next step oxidizing reaction.
(about 3.1L) transfers in the reaction flask of 20L with above-mentioned acetic acid reaction liquid, adds the water dilute reaction solution of equivalent, and (about 35 ℃) vigorous stirring at room temperature, divides 5 batches in the 2h in reaction solution and adds 320g IBX (2.0eq), and 2h adds.Then 176g (1.1eq) IBX is divided into three batches of intervals added in one hour.After oxygenant added, stirring reaction 12h after-filtration obtained product, uses washed with methanol, and drying obtains about 160g product (productive rate 76%).
Embodiment 7:
The Pd/C (self-control) that adds 200g camptothecine and 40g 8% in three mouthfuls of round-bottomed flasks of 5L, the Glacial acetic acid of adding 3L.Feed hydrogen under normal pressure stirs and be heated to 90 ℃, reaction 24h.After reaction finishes, with the reaction solution cooling, remove by filter catalyst for reaction, reaction solution is directly used in next step oxidizing reaction.
(about 3.1L) transfers in the reaction flask of 20L with above-mentioned acetic acid reaction liquid, adds the water dilute reaction solution of equivalent, and (about 25 ℃) vigorous stirring at room temperature, divides 5 batches in the 2h in reaction solution and adds 320g IBX (2.0eq), and 2h adds.Then 176g (1.1eq) IBX is divided into three batches of intervals added in one hour.After oxygenant added, stirring reaction 12h after-filtration obtained product, uses washed with methanol, and drying obtains about 109g product (productive rate 52%).
Embodiment 8:
The Pd/C (self-control) that adds 200g camptothecine and 100g 8% in three mouthfuls of round-bottomed flasks of 5L, the Glacial acetic acid of adding 3L.Feed hydrogen under normal pressure stirs and be heated to 90 ℃, reaction 24h.Reaction is removed catalyzer with the reaction solution cooled and filtered after finishing, and reaction solution is directly used in next step oxidizing reaction.
(about 3.1L) transfers in the reaction flask of 20L with above-mentioned acetic acid reaction liquid, adds the water dilute reaction solution of equivalent, and (about 20 ℃) vigorous stirring at room temperature, divides 5 batches in the 2h in reaction solution and adds 310g plumbic acetates (2.0eq).Then 170g (1.1eq) plumbic acetate is divided into three batches of intervals added in one hour.After oxygenant added, stirring reaction 12h after-filtration obtained product, uses washed with methanol, and drying obtains about 148g product (productive rate 71%).
Embodiment 9:
The Pd/C (self-control) that adds 200g camptothecine and 100g 8% in three mouthfuls of round-bottomed flasks of 5L, the Glacial acetic acid of adding 3L.Feed hydrogen under normal pressure stirs and be heated to 90 ℃, reaction 24h.Reaction is removed catalyzer with the reaction solution cooled and filtered after finishing, and reaction solution is directly used in next step oxidizing reaction.
(about 3.1L) transfers in the reaction flask of 20L with above-mentioned acetic acid reaction liquid, adds the water dilute reaction solution of equivalent, and (about 20 ℃) vigorous stirring at room temperature, divides 5 batches in the 2h in reaction solution and adds 370g acetic acid iodobenzenes (2.0eq).Then 370g (2.0eq) acetic acid iodobenzene is divided into three batches of intervals added in one hour.After oxygenant added, stirring reaction 12h after-filtration obtained product, uses washed with methanol, and drying obtains about 162g product (productive rate 80%).
Comparative Examples 1
The Pt/C (Merck buys) that adds 200g camptothecine and 100g 5% in the 5L high-pressure hydrogenation still, 75mL DMSO, 3L Glacial acetic acid.At 0.7Mpa, 90 ℃ feed hydrogen stirring reaction 24h down.Reaction is removed catalyst for reaction with the reaction solution cooled and filtered after finishing, and reaction solution is directly used in next step oxidizing reaction.
(about 3.1L) transfers in the reaction flask of 20L with above-mentioned acetic acid reaction liquid, adds the water dilute reaction solution of equivalent, and (about 20 ℃) vigorous stirring at room temperature, divides 5 batches in the 2h in reaction solution and adds 320g IBX (2.0eq).Then 176g (1.1eq) IBX is divided into three batches of intervals added in one hour.After oxygenant added, stirring reaction 12h after-filtration obtained product, uses washed with methanol, and drying obtains about 153g product (productive rate 73%).
Comparative Examples 2:
The Pt/C (Merck buys) that adds 200g camptothecine and 100g 10% in the 5L high-pressure hydrogenation still, 75mL DMSO, 3L Glacial acetic acid.At 0.7Mpa, 90 ℃ feed hydrogen stirring reaction 24h down.Reaction is removed catalyst for reaction with the reaction solution cooled and filtered after finishing, and reaction solution is directly used in next step oxidizing reaction.
(about 3.1L) transfers in the reaction flask of 20L with above-mentioned acetic acid reaction liquid, adds the water dilute reaction solution of equivalent, and (about 20 ℃) vigorous stirring at room temperature, divides 5 batches in the 2h in reaction solution and adds 320g IBX (2.0eq).Then 176g (1.1eq) IBX is divided into three batches of intervals added in one hour.After oxygenant added, stirring reaction 12h after-filtration obtained product, uses washed with methanol, and drying obtains about 87g product (productive rate 42%).
Claims (8)
1. the semisynthesis of a 10-hydroxycamptothecine comprises the steps:
1) catalytic hydrogenation: camptothecine is dissolved in solvent, adds palladium-carbon catalyst, and heating is reacted, and obtains tetrahydro camptothecin, and wherein, the preparation method of described palladium-carbon catalyst is as follows:
1. with the nitric acid acidwashing 5h of 100g 4～8 order activated carbon, be washed with water to neutrality with 1mol/L, dry 10h under 100 ℃, the carrier that obtains activated carbon is standby;
2. get the palladium solution 3.2g that contains palladium 16%, add deionized water to 40mL, the aqueous sodium hydroxide solution of adding 10% adjusts to 5～7 with the palladium pH value of solution, behind the solution-stabilized 1h of palladium, above-mentioned treated activated carbon with palladium solution impregnation 3h, is obtained catalyst precursor;
3. the aging 24h of catalyst precursor with high-purity hydrogen gas disposal catalyst precursor 5h, filters under hydrogen shield, is washed with water to neutrality;
4. catalyzer is 180 ℃ and vacuum tightness 1.013 * 10
-3Dry 72h under the Pa, nitrogen protection drops to room temperature comes out of the stove, and finished product is with the airtight preservation of hydrogen shield, and the catalyzer that makes contains palladium about 8%;
2) oxidizing reaction: the tetrahydro camptothecin and the oxygenant of gained react, and obtain 10-hydroxycamptothecine;
2. the semisynthesis of 10-hydroxycamptothecine as claimed in claim 1, it is characterized in that: the solvent described in the step 1) is glacial acetic acid, tetrahydrofuran (THF) or 1, the 4-dioxane.
3. the semisynthesis of 10-hydroxycamptothecine as claimed in claim 1, it is characterized in that: palladium carbon charging capacity is 20%～60% of a camptothecine charging capacity in the step 1), by percentage to the quality; Step 2) charging capacity of oxygenant and the equivalence ratio of raw material camptothecine charging capacity are 3～4 in.
4. the semisynthesis of 10-hydroxycamptothecine as claimed in claim 1, it is characterized in that: the catalytic hydrogenation temperature is controlled at 60～100 ℃.
5. the semisynthesis of 10-hydroxycamptothecine as claimed in claim 4, it is characterized in that: the catalytic hydrogenation temperature is controlled at 90 ℃.
6. the semisynthesis of 10-hydroxycamptothecine as claimed in claim 1, it is characterized in that: employed oxygenant is 2-iodoxy phenylformic acid, plumbic acetate or acetic acid iodobenzene in the oxidizing reaction.
7. the semisynthesis of 10-hydroxycamptothecine as claimed in claim 1, it is characterized in that: oxidizing reaction temperature is controlled at 20～40 ℃.
8. the semisynthesis of 10-hydroxycamptothecine as claimed in claim 1, it is characterized in that: catalytic hydrogenation liquid filtration catalizer, tetrahydro camptothecin is directly used in oxidizing reaction without separation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007101719712A CN101450949B (en) | 2007-12-07 | 2007-12-07 | Chemical semi-synthetic process of 10-hydroxycamptothecin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007101719712A CN101450949B (en) | 2007-12-07 | 2007-12-07 | Chemical semi-synthetic process of 10-hydroxycamptothecin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101450949A CN101450949A (en) | 2009-06-10 |
| CN101450949B true CN101450949B (en) | 2011-10-05 |
Family
ID=40733451
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2007101719712A Active CN101450949B (en) | 2007-12-07 | 2007-12-07 | Chemical semi-synthetic process of 10-hydroxycamptothecin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101450949B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4473692A (en) * | 1981-09-04 | 1984-09-25 | Kabushiki Kaisha Yakult Honsha | Camptothecin derivatives and process for preparing same |
| CN1062731A (en) * | 1990-09-28 | 1992-07-15 | 史密丝克莱恩比彻姆公司 | Water soluble camptothecin analogs and intermediates preparation thereof are by the compound and the using method thereof of described method preparation |
| CN1834097A (en) * | 2005-03-18 | 2006-09-20 | 上海骏杰生物技术有限公司 | Method of producing 10-hydroxy camptothein |
-
2007
- 2007-12-07 CN CN2007101719712A patent/CN101450949B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4473692A (en) * | 1981-09-04 | 1984-09-25 | Kabushiki Kaisha Yakult Honsha | Camptothecin derivatives and process for preparing same |
| CN1062731A (en) * | 1990-09-28 | 1992-07-15 | 史密丝克莱恩比彻姆公司 | Water soluble camptothecin analogs and intermediates preparation thereof are by the compound and the using method thereof of described method preparation |
| CN1834097A (en) * | 2005-03-18 | 2006-09-20 | 上海骏杰生物技术有限公司 | Method of producing 10-hydroxy camptothein |
Non-Patent Citations (3)
| Title |
|---|
| JP昭59-5188A 1984.01.12 |
| 徐春艳等.10-羟基喜树碱的合成及光谱表征.《光谱学与光谱分析》.2005,第25卷(第11期),第1772-1774页. * |
| 李斌等.10-羟基喜树碱的合成.《北京化工大学学报》.2004,第31卷(第1期),第71-75页. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101450949A (en) | 2009-06-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109675602B (en) | Supported cobalt-nitrogen doped carbon catalyst and preparation method and application thereof | |
| CN105251482A (en) | Ruthenium palladium/carbon catalyst of cyclohexanecarboxylic acid synthesized through benzoic acid hydrogenation and preparation method and application thereof | |
| CN107056688B (en) | Preparation method of 2, 3-dichloropyridine | |
| CN102040584B (en) | Synthesis method of dicyclohexyl-18-crown-6 | |
| CN101450949B (en) | Chemical semi-synthetic process of 10-hydroxycamptothecin | |
| CN106749098B (en) | A kind of preparation method preparing dioxopromethazine hydrochloride using oxygen as oxidant | |
| CN107935971B (en) | Preparation method of (S) -3-hydroxytetrahydrofuran | |
| CN108948117B (en) | Synthetic method of obeticholic acid | |
| CN114728979B (en) | Method for preparing 5-isosorbide mononitrate by utilizing microchannel continuous flow reactor | |
| CN114621097A (en) | Method for preparing 2, 4-difluoroaniline through catalytic hydrogenation of 2, 4-difluoronitrobenzene | |
| CN104447531B (en) | Preparation method of 3,5-dibromopyridine-N-oxide | |
| CN107119085A (en) | A kind of method that naringenin is prepared based on aspergillus niger cell catalysis aurantiin hydrolysis | |
| CN108752409B (en) | Method for preparing epiandrosterone by using androstenedione as raw material | |
| CN103992238B (en) | The preparation method of 3-aminosallcylic acid | |
| CN103204835B (en) | A kind of preparation method of butyrolactone | |
| CN102206146B (en) | Preparation method of vanillin | |
| CN105949076B (en) | A kind of preparation method of 3,5 diaminobenzoic acid | |
| CN114950452B (en) | Catalyst for synthesizing L-2-aminopropanol and preparation method thereof, and method for synthesizing L-2-aminopropanol | |
| CN113024502B (en) | Preparation method of 3,5,7,3',4',5' -hexahydroxy flavone | |
| CN103992230A (en) | Method for preparing diaminobenzene and aniline from nitrobenzene mixture containing dinitrobenzene | |
| CN103086858B (en) | Synthetic method of 3-methyl-cyclopentanone | |
| CN114835639B (en) | Preparation method of nevirapine intermediate | |
| CN113248380B (en) | Synthetic method of acetic acid alpha-asaryl alcohol ester and alpha-fine octanol | |
| CN102502777A (en) | Method for preparing silver nitrate with various types of silver-ion-containing waste water as raw materials | |
| CN102649729A (en) | Method for producing oxalate through CO gas phase coupled catalytic reaction |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |