CN106800542A - A kind of hydrophily paclitaxel analog compound and preparation method thereof - Google Patents
A kind of hydrophily paclitaxel analog compound and preparation method thereof Download PDFInfo
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- CN106800542A CN106800542A CN201611264228.7A CN201611264228A CN106800542A CN 106800542 A CN106800542 A CN 106800542A CN 201611264228 A CN201611264228 A CN 201611264228A CN 106800542 A CN106800542 A CN 106800542A
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- hydrophily
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- taxol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
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- 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
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention belongs to field of medicine preparing technology, it particularly relates to arrive a kind of hydrophily paclitaxel analog compound and preparation method thereof.The preparation method step of the hydrophily paclitaxel analog compound is specific as follows:By taxol and hydrophilic small molecules compound, reaction obtains hydrophily taxol compound precursor under base catalyst catalysis, then sloughs protectiveness group and obtains final product hydrophily taxol compound.Compared with prior art, hydrophily paclitaxel analog compound preparation method of the present invention has the advantages that easy, quick, high income;After taxol is through the method structural modification, stable chemical nature, water solubility improves a lot.
Description
Technical field
The invention belongs to field of medicine preparing technology, it particularly relates to arrive a kind of hydrophily paclitaxel analog compound and
Its preparation method.
Background technology
Taxol is a kind of diterpene-kind compound with efficient active anticancer extracted from Chinese yew genus plants.1977
The drug candidate that year is confirmed as anticancer starts clinical trial, and be subsequently found taxol has very strong work to various human tumors
Property.U.S. FDA official approval taxol is used for the treatment of oophoroma within 1992, and hereafter taxol is applied to various common evils quickly
Property tumour is such as:Breast cancer, lung cancer, colorectal cancer, melanoma, incidence cancer etc., and achieve significant curative effect.Taxol is fat
Soluble drug, the solubility in water only has 0.25ug/mL, causes to the limitation in terms of the medicine formulation application, can only be by
Injection is made in cosolvent to use.Clinically the injection of tradition application uses non-ionic surfactant polyoxyethylene castor oil
(Cremophor EL) is used as solvent, but its toxicity is big, and allergic reaction incidence is high, easily causes low blood pressure, fash and breathing tired
The adverse reactions such as difficulty.Therefore, the water solubility problems of taxol, the focus as taxol new drug research in recent years are solved.
The existing method for solving taxol soluble problem includes changing formulation and the broad aspect of modifying for chemical structure two.Its
In, changing the method for formulation includes preparing Paclitaxel liposome, yew alcohol micro-emulsion, taxol microballoon and taxol albumin nano
Grain etc..Although above-mentioned drug-loading system improves the water solubility of medicine to a certain extent, many defects are there is also, such as:
Only Paclitaxel liposome of the content less than 2% is stable on physical and chemical state, and taxol microballoon is also proved exist
Toxicity problem, and the method for change formulation can only mitigate adverse reaction, but cannot fundamentally improve drug effect.
Chemical modification technology is drug modified technology the most frequently used during modern medicines are modified.The water solubility carried out to taxol
The most commonly used water soluble group of transformation includes various organic acids and water-soluble amino acids, and it is exactly it that this kind of carrier has a big advantage
With the hydroxyl of active compound into can further be made salt, such as carboxylate after ester, sulfonate, phosphate or ammonium salt etc. are significantly carried
Water solubility high.But the improper chemical instability for being possible to that prodrug can be caused of selection of carrier, or ester bond is excessively stablized,
Generation active compound cannot be cracked in vivo.Some carriers can also cause adverse reaction in itself, or even produce toxic and side effect.So carrier
Selection is extremely important, and carrier is in addition to water miscible feature is improved, it is necessary to possess nontoxic, and accretion rate is suitable, biological
The characteristic such as compatibility is good.
The content of the invention
In order to solve the above technical problems, the invention provides a kind of constitutionally stable hydrophily paclitaxel analog compound and its
Preparation method.
We are selected containing two and three micromolecular compounds of carboxylic acid as carrier, and difference is carried out to Docetaxel
The derivatization of hydroxyl.Containing two and three micromolecular compounds of carboxylic acid, one carboxyl and taxol into after ester, another
Free carboxyl group can again be made sodium salt, further improve water-soluble.According to above mentality of designing, selected hydrophilic small molecules chemical combination
Thing, directly carrying out reaction with taxol can produce multiple accessory substances.In order that the hydroxyl selectivity of taxol is small with hydrophily
One carboxyl of molecule first carries out the protection of side chain into ester to micromolecular compound.The structure of taxol is analyzed it can be found that dividing
Containing the unstable groups such as benzoyloxy, ester group, amide groups and multiple chiral carbons in son, these cause the change of taxol
Learn unstability;Additionally, in molecule house have four alcoholic extract hydroxyl groups, except 1-OH due to steric hindrance influence reactivity very it is low it
Outward, other three reactivities of hydroxyl are approached.Lot of unstable factor proposes higher to the malic acid derivatization of taxol
It is required that.Therefore, it is necessary to select relatively mild reaction condition in order to avoid destroying taxol parent nucleus, and reaction is set to be in regioselectivity.Through
The investigation that system is carried out into ester method to bearing taxanes is crossed, violent esterification condition such as chloride method, acid is found
Acid anhydride method is not suitable for Docetaxel;Most popular method is such as dicyclohexylcarbodiimide (DCC) in carbodiimide class dehydrating agent,
In the presence of DIC (DIC) etc. and catalyst DMAP (DMAP), the ester of acid and alcohol is directly carried out
Change.
A kind of hydrophily paclitaxel analog compound of the present invention, the concrete structure of the compound is as follows:
Wherein, R1It is small molecule hydrophilic compounds carboxylate, R2It is hydrogen.
The step of preparation method of hydrophily paclitaxel analog compound of the present invention, preparation method, is specific as follows:
By taxol and hydrophilic small molecules compound, reaction obtains hydrophily taxol compound precursor under base catalyst catalysis,
Then slough protectiveness group and obtain final product hydrophily taxol compound.
The step of preparation method of hydrophily paclitaxel analog compound of the present invention, preparation method, is specific as follows:
During 20-100mg taxols and hydrophilic small molecules carboxylic acid compound 5-50mg added into 2-10mL anhydrous methylene chlorides in proportion,
Dehydrating condensation agent and base catalyst, low temperature is added to stir under cryogenic conditions 5-10 hours, suction filtration, washing, saturated common salt washing
Wash, anhydrous sodium sulfate drying;Filtering is concentrated under reduced pressure, and residue is purified with silica gel column chromatography, with petroleum ether:Ethyl acetate is wash-out
Agent, obtains water-soluble paclitaxel compound precursor 1;The 50-100mg of water-soluble paclitaxel compound precursor 1 is dissolved in HOAc, THF
And H2The mixed solution of O, is recovered under reduced pressure removing organic solvent, plus 5-20mL water dilution residue, lyophilized to obtain crude product, through preparing
Efficient liquid phase is isolated and purified, with acetonitrile:Water (1:1) it is mobile phase, obtains water-soluble paclitaxel compound precursor 2;Will be water-soluble purple
The 50-100mg of China fir alcoholic compound precursor 2 is dissolved in acetone 2-10ml, is stirred l-3 hours in the NaHCO3 aqueous solution;It is recovered under reduced pressure and removes
Acetone, residue is gone to freeze, obtain final product.
The preparation method of hydrophily paclitaxel analog compound of the present invention, the base catalyst is triethylamine, 4- bis-
One or more in methylamino pyridine, N- oxidation lycopodines M, sodium carbonate, potassium carbonate and sodium acid carbonate.
The preparation method of hydrophily paclitaxel analog compound of the present invention, the hydrophilic small molecules compound is apple
Acid, citric acid, tartaric acid, succinic acid, lactic acid, metatartaric acid, adipic acid, fumaric acid, 2- hydroxyl glutaric acids.
The preparation method of hydrophily paclitaxel analog compound of the present invention, the dehydrating condensation agent is DCC or/and DIC.
The preparation method of hydrophily paclitaxel analog compound of the present invention, described HOAc, THF and H2The mixed solution of O
Middle HOAc, THF and H2The ratio of O is (1-2):(1-2):1.
Compared with prior art, hydrophily paclitaxel analog compound preparation method of the present invention have it is easy, quick,
The advantages of high income;After taxol is through the method structural modification, stable chemical nature, water solubility improves a lot.
Brief description of the drawings
Fig. 1 is the synthetic route chart of the hydrophily paclitaxel analog compound in embodiment 1.
Specific embodiment
With reference to specific embodiment hydrophily paclitaxel analog compound of the present invention and preparation method thereof is made into
One step is illustrated, but protection scope of the present invention is not limited to this.
Embodiment 1
Malic acid 1.86g (13.8mmol) is added in acetone 72ml, and p-methyl benzenesulfonic acid 86mg is added in reaction solution
(0.5mmol), mixedliquor is stirred at room temperature 24 hours.Triethylamine neutralization reaction liquid is concentrated under reduced pressure to pH 6.7, and residue is with silica gel
Column chromatography is purified, with petroleum ether:Acetone (3:1) it is eluant, eluent, obtains slurry, drying under reduced pressure overnight obtains white solid 1,2- afterwards
O- isopropylidenes-malic acid 1.20g.
Under argon gas protection, by taxol 80.8mg (0.1mmol) and 1,2-O- isopropylidene-malic acid 19.1mg
(0.11mmol) is added in 2.5mL anhydrous methylene chlorides, is cooled to -10 DEG C.Then add DCC 30.9mg (0.15mmol) and
DMAP l8.3mg (0.15mmol), keep -10 DEG C of low temperature to stir 7 hours, suction filtration, washing, saturated common salt water washing, anhydrous sulphur
Sour sodium is dried.Filtering is concentrated under reduced pressure, and residue is purified with silica gel column chromatography, with petroleum ether:Ethyl acetate (2:1) it is eluant, eluent,
Obtain white solid 2'- (1,2-O- isopropylidene-malic acid -4- bases)-taxol 67.4mg, yield 70%.
Compound 2'- (1,2-O- isopropylidenes-malic acid -4- bases)-taxol 96.4mg (0.10mmol) is dissolved in mixed
Close Solution H OAc-THF-H2O(5:5:5mL), stir 20 hours at 25 DEG C, be recovered under reduced pressure removing organic solvent, plus 10mL water is dilute
Residue is released, it is lyophilized to obtain crude product, isolated and purified through preparing efficient liquid phase, with acetonitrile:Water (1:1) it is mobile phase, obtains white
Solid 2'- (malic acid -4- bases)-taxol 79.5mg.
Compound 2'- (malic acid -4- bases)-taxol 92.4mg (0.10mmol) is dissolved in acetone 4ml, by NaHC03
The aqueous solution 8ml of 8.4mg (0.10mmol) adds reaction solution.Reaction solution is stirred l hours at 25 DEG C.Removing third is recovered under reduced pressure
Ketone, residue is lyophilized to obtain white solid Docetaxel 2 '-natrium malicum 94.6mg, yield 93.2%.
Embodiment 2
2- hydroxyls-glutaric acid 2.07g (13.8mmol) is added in acetone 75ml, and p-methyl benzenesulfonic acid 86mg is added in reaction solution
(0.5mmol), mixedliquor is stirred at room temperature 24 hours.Triethylamine neutralization reaction liquid is concentrated under reduced pressure to pH 6.7, and residue is with silica gel
Column chromatography is purified, with petroleum ether:Acetone (3:1) it is eluant, eluent, obtains slurry, drying under reduced pressure overnight obtains white solid 1,2- afterwards
O- isopropylidenes-valeric acid 1.27g.
Under argon gas protection, by taxol 80.8mg (0.1mmol) and 1,2-O- isopropylidene-valeric acid 20.4mg
(0.11mmol) is added in 2.5mL anhydrous methylene chlorides, is cooled to -10 DEG C.Then add DCC 30.9mg (0.15mmol) and
DMAP l8.3mg (0.15mmol), keep -10 DEG C of low temperature to stir 7 hours, suction filtration, washing, saturated common salt water washing, anhydrous sulphur
Sour sodium is dried.Filtering is concentrated under reduced pressure, and residue is purified with silica gel column chromatography, with petroleum ether:Ethyl acetate (2:1) it is eluant, eluent,
Obtain white solid 2'- (1,2-O- isopropylidene-valeric acid -4- bases)-taxol 65.8mg, yield 68.3%.
Compound 2'- (1,2-O- isopropylidenes-valeric acid -4- bases)-taxol 94.2mg (0.10mmol) is dissolved in mixing
Solution H OAc-THF-H2O(5:5:5mL), stir 20 hours at 25 DEG C, removing organic solvent, plus the dilution of 10mL water is recovered under reduced pressure
Residue, it is lyophilized to obtain crude product, isolated and purified through preparing efficient liquid phase, with acetonitrile:Water (1:1) it is mobile phase, obtains white solid
Body 2'- (valeric acid -4- bases)-taxol 78.2mg.
Compound 2'- (valeric acid -4- bases)-taxol 92.4mg (0.10mmol) is dissolved in acetone 4ml, by NaHC03
The aqueous solution 8ml of 8.4mg (0.10mmol) adds reaction solution.Reaction solution is stirred l hours at 25 DEG C.Removing third is recovered under reduced pressure
Ketone, residue is lyophilized to obtain white solid Docetaxel 2 '-natrium malicum 91.8mg, yield 90.5%.
Embodiment 3
2- hydroxyls-glutaric acid 2.07g (13.8mmol) is added in acetone 75ml, and p-methyl benzenesulfonic acid 86mg is added in reaction solution
(0.5mmol), mixedliquor is stirred at room temperature 24 hours.N- aoxidizes lycopodine M neutralization reaction liquid to pH6.7, is concentrated under reduced pressure, residue
Purified with silica gel column chromatography, with petroleum ether:Acetone (3:1) be eluant, eluent, obtain slurry, drying under reduced pressure overnight afterwards it is white solid
Body 1,2-O- isopropylidenes-valeric acid 1.51g.
Under argon gas protection, by taxol 80.8mg (0.1mmol) and 1,2-O- isopropylidene-valeric acid 20.4mg
(0.11mmol) is added in 2.5mL anhydrous methylene chlorides, is cooled to -10 DEG C.Then add DCC 30.9mg (0.15mmol) and
DMAP l8.3mg (0.15mmol), keep -10 DEG C of low temperature to stir 7 hours, suction filtration, washing, saturated common salt water washing, anhydrous sulphur
Sour sodium is dried.Filtering is concentrated under reduced pressure, and residue is purified with silica gel column chromatography, with petroleum ether:Ethyl acetate (2:1) it is eluant, eluent,
Obtain white solid 2'- (1,2-O- isopropylidene-valeric acid -4- bases)-taxol 65.8mg, yield 68.3%.
Compound 2'- (1,2-O- isopropylidenes-valeric acid -4- bases)-taxol 94.2mg (0.10mmol) is dissolved in mixing
Solution H OAc-THF-H2O(5:5:5mL), stir 20 hours at 25 DEG C, removing organic solvent, plus the dilution of 10mL water is recovered under reduced pressure
Residue, it is lyophilized to obtain crude product, isolated and purified through preparing efficient liquid phase, with acetonitrile:Water (1:1) it is mobile phase, obtains white solid
Body 2'- (valeric acid -4- bases)-taxol 78.2mg.
Compound 2'- (valeric acid -4- bases)-taxol 92.4mg (0.10mmol) is dissolved in acetone 4ml, by NaHC03
The aqueous solution 8ml of 8.4mg (0.10mmol) adds reaction solution.Reaction solution is stirred l hours at 25 DEG C.Removing third is recovered under reduced pressure
Ketone, residue is lyophilized to obtain white solid Docetaxel 2 '-natrium malicum 91.8mg, yield 90.5%.
Claims (7)
1. a kind of hydrophily paclitaxel analog compound, it is characterised in that the concrete structure of the compound is as follows:
Wherein, R1It is small molecule hydrophilic compounds carboxylate, R2It is hydrogen.
2. the preparation method of hydrophily paclitaxel analog compound according to claim 1, it is characterised in that the preparation method
The step of it is specific as follows:By taxol and hydrophilic small molecules compound, reaction obtains hydrophily purple under base catalyst catalysis
China fir alcoholic compound precursor, then sloughs protectiveness group and obtains final product hydrophily taxol compound.
3. the preparation method of hydrophily paclitaxel analog compound according to claim 2, it is characterised in that the preparation method
The step of it is specific as follows:20-100mg taxols and hydrophilic small molecules carboxylic acid compound 5-50mg are added into 2-10mL in proportion
In anhydrous methylene chloride, dehydrating condensation agent and base catalyst, low temperature is added to stir under cryogenic conditions 5-10 hours, suction filtration, water
Wash, saturated common salt water washing, anhydrous sodium sulfate drying;Filtering is concentrated under reduced pressure, and residue is purified with silica gel column chromatography, with oil
Ether:Ethyl acetate is eluant, eluent, obtains water-soluble paclitaxel compound precursor 1;By the 50- of water-soluble paclitaxel compound precursor 1
100mg is dissolved in mixed solution HOAc-THF-H2O, is recovered under reduced pressure removing organic solvent, plus 5-20mL water dilution residue, freezes
Crude product is obtained, is isolated and purified through preparing efficient liquid phase, with acetonitrile:Water (1:1) it is mobile phase, before obtaining water-soluble paclitaxel compound
Body 2;The 50-100mg of water-soluble paclitaxel compound precursor 2 is dissolved in acetone 2-10ml, l-3 is stirred in the NaHCO3 aqueous solution
Hour;Removing acetone is recovered under reduced pressure, residue is freezed, obtained final product.
4. the preparation method of hydrophily paclitaxel analog compound according to claim 3, it is characterised in that the base catalysis
Agent is one or more in triethylamine, DMAP, sodium carbonate, potassium carbonate and sodium acid carbonate.
5. the preparation method of hydrophily paclitaxel analog compound according to claim 3, it is characterised in that the hydrophily is small
Molecular compound is malic acid, citric acid, tartaric acid, succinic acid, lactic acid, metatartaric acid, adipic acid, fumaric acid, 2- hydroxyls penta
Diacid.
6. the preparation method of hydrophily paclitaxel analog compound according to claim 3, it is characterised in that the dehydrating condensation
Agent is DCC or/and DIC.
7. the preparation method of hydrophily paclitaxel analog compound according to claim 3, it is characterised in that the HOAc-
THF-H2The ratio of O is (1-2):(1-2):1.
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115385875A (en) * | 2022-07-18 | 2022-11-25 | 中国药科大学 | Taxol derivative and preparation method and application thereof |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1059337A (en) * | 1990-08-28 | 1992-03-11 | 弗吉尼亚科技知识产权有限公司 | The soluble derivative of taxol |
WO2000001682A1 (en) * | 1998-07-01 | 2000-01-13 | Bcm Developpement Inc. | Water-soluble derivatives of paclitaxel, method for producing same and uses thereof |
WO2000010988A1 (en) * | 1998-08-21 | 2000-03-02 | Pharmachemie B.V. | Water soluble analogs and prodrugs of paclitaxel |
-
2016
- 2016-12-31 CN CN201611264228.7A patent/CN106800542A/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1059337A (en) * | 1990-08-28 | 1992-03-11 | 弗吉尼亚科技知识产权有限公司 | The soluble derivative of taxol |
WO2000001682A1 (en) * | 1998-07-01 | 2000-01-13 | Bcm Developpement Inc. | Water-soluble derivatives of paclitaxel, method for producing same and uses thereof |
WO2000010988A1 (en) * | 1998-08-21 | 2000-03-02 | Pharmachemie B.V. | Water soluble analogs and prodrugs of paclitaxel |
Non-Patent Citations (1)
Title |
---|
杨恩慈 等: "改善紫杉醇水溶性方法的研究进展", 《中南药学》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115385875A (en) * | 2022-07-18 | 2022-11-25 | 中国药科大学 | Taxol derivative and preparation method and application thereof |
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Application publication date: 20170606 |