CN106632160A - Methods for preparing semi-synthetic paclitaxel and intermediate thereof - Google Patents
Methods for preparing semi-synthetic paclitaxel and intermediate thereof Download PDFInfo
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- CN106632160A CN106632160A CN201611191202.4A CN201611191202A CN106632160A CN 106632160 A CN106632160 A CN 106632160A CN 201611191202 A CN201611191202 A CN 201611191202A CN 106632160 A CN106632160 A CN 106632160A
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- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention relates to methods for preparing semi-synthetic paclitaxel and an intermediate thereof. The method for preparing the semi-synthetic paclitaxel comprises the following steps: dissolving 10-DABIII (10-deacetylbaccatinIII) into pyridine, protecting hydroxyl on position-7 carbon on the 10-DABIII with triethyl silicyl to obtain an intermediate I, acetylating hydroxyl on position-10 carbon of the intermediate I to obtain an intermediate II, reacting the intermediate II, a side-chain radical compound and 4-dimethylaminopyridine in an organic solvent to prepare an intermediate III, and reacting the intermediate III with trifluoroacetic acid under an acidic condition to obtain a crude paclitaxel product. The preparation methods are simple and easy for industrialization; the active hydroxyl of the raw material 10-DABIII is effectively protected, so that fewer byproducts are finally generated, and a prepared paclitaxel product has high molar yield of 70 to 81 percent and high paclitaxel purity of 99.5 to 99.9 percent; the residual rate of the raw material in the steps of synthesizing the intermediate II and synthesizing the paclitaxel is low, side reactions are reduced, and the raw material is high in reaction selectivity and utilization rate; the product can be directly used as a raw material for the medical field of treatment of ovarian cancer, breast cancer and the like.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis field, and in particular to the preparation side of a kind of semi-synthetic taxol and its intermediate
Method.
Background technology
Taxol (Paclitaxel, trade name Taxol) is that the one kind isolated from Taxus (Taxus) plant is purple
China fir alkane diterpene-kind compound.Its structure is novel, anticancer mechanism is unique, anticancer effect is notable, anticancer spectrum is wide, it is considered to be institute so far
It was found that one of best cancer therapy drug.Taxol chemistry is fully synthetic to succeed, but complex synthetic route, high cost, only has
There is Research Significance, there is no commercial value fully synthetic with respect to taxol, it is prepared by the one kind with practical value that taxol is semi-synthetic
Method.It is typically all with the 10- deacetylate Bakating III (10- similar with taxol macrocyclic structure that taxol is semi-synthetic
Deacetylbaccatin III, 10-DAB III) for raw material, docked by the side-chain radical compound with taxol and Japanese yew is obtained
Alcohol.10-DAB III can be extracted from the Chinese yew genus plants of abundance and obtained, and yield is high, so as to for taxol it is semi-synthetic
There is provided sufficient raw material.Can also be urged using various in addition to using solvent in the method for semi-synthetic taxol in prior art
To improve reaction yield, such as patent CN200580011712.2 uses imidazoles catalyst to agent, and for example in patent US193263
To using Jones reagent during C7 hydroxyl protections, and to needing to be reacted at -23 DEG C during C10 hydroxyl protections, reaction reagent will
Ask higher, system component is complicated has impurity to produce so that the content of taxol is not high in final refined product.
In a word, common problem is in existing patented technology：With 10-DAB III as raw material, the final taxol for obtaining
Yield is low, and its main cause is：(1) III 10 hydroxyls of 10-DAB are carried out it is acetylizad during, reacting close terminal
When easily produce side reaction and generate other impurity；(2) easily caused carrying out final step open loop deprotection reaction process
Reaction generates other impurity.
Because by the substantial amounts of conversion of raw material, for impurity, therefore yield is low；During taxol purifies and separates are carried out, adopt
Purified with the carrying out of column chromatography and recrystallization, thus resulted in part paclitaxel prodrugs loss and taxol purity improves little.
The content of the invention
In order to solve the above problems, the invention provides a kind of high income, product purity are high, be easy to one kind half of industrialization
The preparation method of taxol biosynthesis and its intermediate.
For achieving the above object, the technical solution used in the present invention is：A kind of preparation method of semi-synthetic taxol includes
Step：
A. intermediate compound I is prepared：10-DAB III is dissolved in pyridine, by hydroxyl silicohetane on 7 carbon on 10-DAB III
Alkyl carries out protecting to obtain intermediate compound I；
B. intermediate II is prepared：Acetylating hydroxyl groups on 10 carbon of intermediate compound I are obtained into intermediate II；
C. intermediate III is prepared：By intermediate II, side-chain radical compound, DMAP in organic solvent
Reaction is obtained intermediate III；
D. taxol crude product is prepared：Intermediate III is reacted into acid condition to obtain taxol crude product with trifluoroacetic acid；
The intermediate I molecular formula：C35H50O10Si, its structural formula is as follows：
The intermediate II molecular formula：C37H52O11Si, its structural formula is as follows：
The molecular formula of the intermediate III：C62H71NO15Si, its structural formula is as follows：
By protecting to the activity hydroxy in 10-DABIII molecular structures, and select suitable side chain radical dough
Chelate compound group causes the yield and purity of taxol to greatly improve, and is suitable to synthesize the taxol of higher quality, and antagonism is swollen
The exploitation of tumor medicine provides support.
Further, step A to D is specific as follows described in the method for above-mentioned semi-synthetic taxol：
A. intermediate compound I is prepared：10-DAB III is added into stirring and dissolving in pyridine, triethylchloro-silicane is added dropwise under nitrogen protection
Alkane, the stopping reaction when the residuals of 10-DAB III are less than 0.2% in reactant liquor, water is added dropwise carries out that reaction is quenched, and is neutralized with concentrated hydrochloric acid
Pyridine, extracts dichloromethane, and concentrate drying obtains intermediate compound I；
B. intermediate II is prepared：Intermediate compound I is added into stirring and dissolving in pyridine, chloroacetic chloride is added dropwise under nitrogen protection, so
Stop reaction when it is 5～10% to react at a temperature of -15～5 DEG C to intermediate compound I residual afterwards, water is added dropwise carries out that reaction is quenched, and uses
In concentrated hydrochloric acid and pyridine, dichloromethane is extracted, concentrate drying obtains intermediate II；
C. intermediate III is prepared：Intermediate II, side-chain radical compound, DMAP are added in toluene and stirred
Dissolving, at 10～30 DEG C of temperature and nitrogen protection condensing agent is added dropwise, and is then reacted to intermediate II at a temperature of 10～30 DEG C
Raw material residual stops reaction less than 0.2%, adds n-hexane stirred crystallization, filtration drying to obtain intermediate III；
D. taxol crude product is prepared：Intermediate III is added in acetic acid, water stirring and dissolving is added, then trifluoroacetic acid is added
Enter system, when it is 5～10% to react at a temperature of 10～30 DEG C to the raw material of intermediate III residual reaction stopped, adding alkali neutralization,
Washed, concentrated, being dried to obtain taxol crude product with Jing after dichloromethane extraction.
System component is relatively easy in the method for taxol biosynthesis, does not require the use of other catalyst, and preparation technology compared with
Routine is easy to industrialization, separates simple.
Further, when the dropwise addition of chlorotriethyl silane is added dropwise described in the method for above-mentioned semi-synthetic taxol in step A
Between be 30～60min, dropping temperature is 10～20 DEG C, is added dropwise to complete rear reaction temperature for 10～30 DEG C；Add in step C
The time of n-hexane stirred crystallization is 1～2 hour.
Further, the time for adding that chloroacetic chloride is added dropwise described in the method for above-mentioned semi-synthetic taxol in step B is 30
～60min, dropping temperature is -15～5 DEG C, is added dropwise to complete rear reaction temperature for -15～5 DEG C.
It is further preferred that adding alkali neutralization specially to add described in the method for above-mentioned semi-synthetic taxol in step D
Weak base adjusts pH to 6～8.
Further, step E is also included described in the method for above-mentioned semi-synthetic taxol after step D, step E is：
E. taxol is prepared：By the organic solvent dissolving of taxol crude product, filter, then Jing liquid chromatograies are separated and received respectively
Eluent of the collection containing taxol, intermediate III, containing Japanese yew alcohol eluen concentrate drying paclitaxel prodrugs are obtained.
Further, the wash-out containing intermediate III collected in step E described in the method for above-mentioned semi-synthetic taxol
Add in step D after the concentrated drying of liquid and reuse.
Further, the intermediate II crude product described in the method for above-mentioned semi-synthetic taxol in step B after concentrate drying
Separate through liquid chromatogram and collect the eluent containing intermediate compound I and the eluent containing intermediate II respectively, containing intermediate compound I
Eluent add after concentrate drying in step B reuse, the eluent containing intermediate II is after concentrate drying
Raw material as step C.
For the recycling of eluent, the utilization rate of raw material can be not only improved, while the addition of eluent can also
There is facilitation to reaction so that final products yield is higher, conversion ratio is higher.
It is further preferred that the raw materials of 10-DAB III and pyridine in step A described in the method for above-mentioned semi-synthetic taxol
Consumption weight ratio is 1：(3～6), the 10-DAB III is=1 with the consumption weight ratio of chlorotriethyl silane：(0.8～2)；Institute
The consumption weight ratio for stating intermediate compound I described in step B and pyridine is 1：The consumption weight ratio of (3～6), intermediate I and chloroacetic chloride
For 1：(0.5～2)；The consumption weight ratio of intermediate II and organic solvent is 1 in step C：(2～5).
Further, organic solvent is methyl alcohol, ethanol, acetonitrile in step C described in the method for above-mentioned semi-synthetic taxol
In one kind.
Further, the liquid chromatogram that intermediate II crude product is purified described in the method for above-mentioned semi-synthetic taxol is detached
Preparing the octadecylsilane chemically bonded silica that filler used by post is 5～60um, the mobile phase of the liquid chromatogram is 50～
One kind in the methyl alcohol of 70vol%, the ethanol of 50～70vol%, the acetonitrile of 50～70vol%；Taxol is thick in step E
The consumption weight ratio of product and organic solvent is 1：(2～5), liquid chromatogram used is detached to prepare filler used by post for 5～60um
Octadecylsilane chemically bonded silica, the mobile phase be the methyl alcohol of 40～60vol% or the ethanol of 40～60vol% or 40～
The acetonitrile of 60vol%.
Product is carried out using simple method for separating liquid phase chromatography separate the practicality that can greatly improve method, passed through
Suitable filler and solvent is selected farthest to ensure the yield of product.
Further, described in the method for above-mentioned semi-synthetic taxol in step C side-chain radical compound be (4S, 5R)-
3- benzoyl -2- (4- methoxyphenyls) -4- phenyl -5- oxazole dicarboxylic acid moieties.The molecular formula of the side-chain radical compound is：
C24H21NO5, its structural formula is as follows：
The selection of side-chain radical compound group is most important for the synthesis of taxol, selects the side-chain radical chemical combination
Thing can reduce the generation of impurity and side reaction product.
Further, intermediate III and side-chain radical compound in step C described in the method for above-mentioned semi-synthetic taxol
Consumption weight ratio be 1：(0.63～1).
Further, intermediate III and DMAP in step C described in the method for above-mentioned semi-synthetic taxol
Consumption weight ratio be 1：(0.05～0.2)；The consumption weight ratio of intermediate III and toluene is 1 in step C：(4～10)；
Condensing agent is in dicyclohexylcarbodiimide or DIC in step C；The He of intermediate III in step C
The consumption weight ratio of condensing agent is 1：(0.2～0.6)；The consumption weight ratio of intermediate III and n-hexane is 1 in step C：
(8～20)；The consumption weight ratio of intermediate III and acetic acid is 1 in step D：(2～4)；The He of intermediate III in step D
The consumption weight ratio of water is 1：(0.1～0.5)；The consumption weight ratio of intermediate III and trifluoroacetic acid is 1 in step D：
(0.5～2).
It is further preferred that weak base is sodium acid carbonate, bicarbonate in step D described in the method for above-mentioned semi-synthetic taxol
One kind in potassium, ammoniacal liquor, can also be that other are dissolved in the weak base of incomplete ionization after water certainly.
The present invention also provides a kind of preparation method of semi-synthetic Japanese yew alcohol intermediate, including step：In the raw materials of 10-DAB III
Middle addition pyridine stirring and dissolving, is added dropwise under nitrogen protection chlorotriethyl silane, when the residuals of 10-DAB III are less than in reactant liquor
Stop reaction when 0.2%, water is added dropwise carries out that reaction is quenched, with concentrated hydrochloric acid and pyridine, extraction dichloromethane, concentrate drying is obtained
Intermediate compound I.
The semi-synthetic taxol and its preparation method of intermediate that the present invention is provided has the advantages that：
1. the inventive method first carries out 7 hydroxyl protections with chlorotriethyl silane and obtains centre with 10-DAB III as raw material
Body I, then with intermediate I and excess acetyl chloride synthetic intermediate II, intermediate II is purified by preparative liquid chromatography and refined
Intermediate II afterwards, the intermediate II after refining is obtained intermediate III, the open loop of intermediate III with the reaction of side-chain radical compound again
Crude product taxol is obtained after deprotection, crude product taxol obtains after purification paclitaxel prodrugs through preparative liquid chromatography.Preparation side
Method is simply easy to industrialization, and effective to the protection of 10-DABIII raw materials activity hydroxy so that final accessory substance is few, obtained
Paclitaxel prodrugs molar yield is up to 70%～81%, taxol high purity 99.5%～99.9%.
2. the inventive method controls to stop when raw material residual is 5～10% in synthetic intermediate II and taxol biosynthesis step
Reaction, i.e., preparation method of the present invention improves the selectivity of raw material, reduces the generation of side reaction, needed for being converted into raw material
Product, the selectivity of the reactions steps of synthetic intermediate II is up to 92%～97%, and the selectivity of taxol biosynthesis reactions steps is high
Up to 93%～97%.
3. the inventive method isolates and purifies intermediate II and taxol using preparative liquid chromatography, by isolated unreacted
The raw material that complete intermediate I and intermediate III is reacted as next step, takes full advantage of raw material.
4. the process that isolates and purifies of taxol crude product obtains paclitaxel prodrugs, operation using the step of preparative liquid chromatography one purifying
It is simple and easy to control, and the paclitaxel prodrugs purity that the liquid chromatogram raw material using present invention offer and solution separation are obtained is high, receives
Rate is high.
5. the inventive method can be widely applied in laboratory and the preparation of industrialization of the semi-synthetic taxols of 10-DAB III, adopt
With the taxol of the inventive method production as the raw material for treating the field of medicaments such as oophoroma and breast cancer.
Specific embodiment
With reference to specific embodiment, the present invention will be further described.It should be noted that the reality described in the present invention
It is only the preferred embodiments of the present invention to apply example, is not limited to the present invention, for a person skilled in the art, this
Invention can have various modifications and variations.All any modifications within the spirit and principles in the present invention, made, equivalent,
Improve etc., should be included within the scope of the present invention.Based on the embodiment in the present invention, those of ordinary skill in the art
The every other embodiment obtained under the premise of creative work is not made, belongs to the scope of protection of the invention.It is following
Amount ratio described in embodiment is unless otherwise specified mass ratio.
Embodiment one
(1) raw materials of 10-DAB III are weighed, the dry pyridine stirring and dissolving of constant weight is added, is then dripped under nitrogen protection
Plus the chlorotriethyl silane of constant weight, time for adding is maintained at 30min, and dropping temperature is controlled at 10 DEG C, after being added dropwise to complete, control
Reaction temperature processed is 10 DEG C, and when 10-DAB III is remained less than 0.2% in reactant liquor reaction is stopped, and water is added dropwise to carry out being quenched instead
Should, then in concentrated hydrochloric acid and pyridine, dichloromethane extraction, concentrate drying obtains intermediate compound I.
(2) intermediate compound I is weighed, the dry pyridine stirring and dissolving of constant weight is added, one is then added dropwise under nitrogen protection
Determine the chloroacetic chloride of weight, time for adding is maintained at 30min, and dropping temperature is controlled at -15 DEG C, after being added dropwise to complete, control reaction temperature
Spend for -15 DEG C, when intermediate compound I residual is 5% in reactant liquor reaction is stopped, water is added dropwise carries out that reaction is quenched, then through dense
In hydrochloric acid and pyridine, dichloromethane extraction, concentrate drying obtains intermediate II.
(3) intermediate II is weighed, with the organic solvent dissolving of constant weight, is filtered, then Jing preparative liquid chromatographies are separated
The eluent containing intermediate compound I, intermediate II is collected respectively, and the difference of the eluent containing intermediate compound I, intermediate II is concentrated dry
Dry to obtain intermediate compound I, intermediate II, used as the raw material of synthetic intermediate II, intermediate II is used as synthetic intermediate III for intermediate compound I
Reaction raw materials.
(4) intermediate II is weighed, side-chain radical compound, the DMAP of constant weight is added, one is added
Determine the dry toluene dissolving of weight, be the condensing agent that constant weight is added dropwise at 10 DEG C under nitrogen protection in temperature, after being added dropwise to complete
It is to react to intermediate II raw material residual at 10 DEG C to obtain reactant liquor less than less than 0.2% stopping reaction in reaction temperature, to anti-
Answer the n-hexane stirred crystallization of addition constant weight in liquid 1 hour, filtration drying obtains intermediate III.
(5) intermediate III is weighed, acetic acid, the water stirring and dissolving of constant weight is added, the trifluoro second of constant weight is added
Acid, when it is 5% to react at temperature is for 10 DEG C to the raw material of intermediate III residual reaction is stopped, and addition weak base adjusts pH to 6, uses two
After chloromethanes extraction, Jing is washed, concentrated, being dried to obtain taxol crude product.
(6) taxol crude product is weighed, with the organic solvent dissolving of constant weight, is filtered, then Jing preparative liquid chromatographies point
From the eluent containing taxol, intermediate III is collected respectively, the difference of the eluent containing taxol, intermediate III is concentrated dry
It is dry to obtain paclitaxel prodrugs, intermediate III, reaction raw materials of the intermediate III as taxol biosynthesis.
(7) dry pyridine of constant weight is the raw materials of 10-DAB III in (1st) step：Dry pyridine=1：3, it is a certain amount of
Chlorotriethyl silane be the raw materials of 10-DAB III：Chlorotriethyl silane=1：0.8.
(8) dry pyridine of constant weight is intermediate compound I in (2nd) step：Dry pyridine=1：3, constant weight
Chloroacetic chloride is intermediate compound I：Chloroacetic chloride=1：0.5.
(9) organic solvent in (3rd) step is methyl alcohol, and the organic solvent of constant weight is intermediate II：It is organic molten
Agent=1：2, preparative liquid chromatography is detached to prepare the octadecylsilane chemically bonded silica that filler used by post is 5um, and mobile phase is
The methyl alcohol of 50vol%.
(10) the side-chain radical compound in (4th) step is (4S, 5R) -3- benzoyl -2- (4- methoxybenzenes
Base) -4- phenyl -5- oxazole dicarboxylic acid moieties, the side-chain radical compound of constant weight is intermediate III：Side-chain radical compound=1：
0.63, the DMAP of constant weight is intermediate III：DMAP=1：0.05, the drying of constant weight
Toluene is intermediate III：Toluene=1：4, condensing agent is dicyclohexylcarbodiimide, and constant weight condensing agent is intermediate III：Contracting
Mixture=1：0.2, constant weight n-hexane is intermediate III：N-hexane=1：8.
(11) acetic acid of constant weight is intermediate III in (5th) step：Acetic acid=1：2, during the water of constant weight is
Mesosome III：Water=1：0.1, the trifluoroacetic acid of constant weight is intermediate III：Trifluoroacetic acid=1：0.5, weak base is sodium acid carbonate.
(12) organic solvent in (6th) step is methyl alcohol, and the organic solvent of constant weight is taxol crude product：It is organic
Solvent=1：2, preparative liquid chromatography is detached to prepare the octadecylsilane chemically bonded silica that filler used by post is 5um, mobile phase
For the methyl alcohol of 40vol%.
Products obtained therefrom taxol molar yield is up to 70%, taxol high purity 99.5%.
Embodiment two
(1) raw materials of 10-DAB III are weighed, the dry pyridine stirring and dissolving of constant weight is added, is then dripped under nitrogen protection
Plus the chlorotriethyl silane of constant weight, time for adding is maintained at 60min, and dropping temperature is controlled at 20 DEG C, after being added dropwise to complete, control
Reaction temperature processed is 30 DEG C, and when 10-DAB III is remained less than 0.2% in reactant liquor reaction is stopped, and water is added dropwise to carry out being quenched instead
Should, then in concentrated hydrochloric acid and pyridine, dichloromethane extraction, concentrate drying obtains intermediate compound I.
(2) intermediate compound I is weighed, the dry pyridine stirring and dissolving of constant weight is added, one is then added dropwise under nitrogen protection
Determine the chloroacetic chloride of weight, time for adding is maintained at 60min, and dropping temperature is controlled in 5 DEG C, after being added dropwise to complete, controlling reaction temperature
For 5 DEG C, when intermediate compound I residual is 10% in reactant liquor reaction is stopped, water is added dropwise carries out that reaction is quenched, then through concentrated hydrochloric acid
Neutralization pyridine, dichloromethane extraction, concentrate drying obtains intermediate II.
(3) intermediate II is weighed, with the organic solvent dissolving of constant weight, is filtered, then Jing preparative liquid chromatographies are separated
The eluent containing intermediate compound I, intermediate II is collected respectively, and the difference of the eluent containing intermediate compound I, intermediate II is concentrated dry
Dry to obtain intermediate compound I, intermediate II, used as the raw material of synthetic intermediate II, intermediate II is used as synthetic intermediate III for intermediate compound I
Reaction raw materials.
(4) intermediate II is weighed, side-chain radical compound, the DMAP of constant weight is added, one is added
Determine the dry toluene dissolving of weight, be the condensing agent that constant weight is added dropwise at 30 DEG C under nitrogen protection in temperature, after being added dropwise to complete
It is to react to intermediate II raw material residual at 30 DEG C to obtain reactant liquor less than less than 0.2% stopping reaction in reaction temperature, to anti-
Answer the n-hexane stirred crystallization of addition constant weight in liquid 2 hours, filtration drying obtains intermediate III.
(5) intermediate III is weighed, acetic acid, the water stirring and dissolving of constant weight is added, the trifluoro second of constant weight is added
Acid, when it is 10% to react at temperature is for 30 DEG C to the raw material of intermediate III residual reaction is stopped, and addition weak base adjusts pH to 8, use
After dichloromethane extraction, Jing is washed, concentrated, being dried to obtain taxol crude product.
(6) taxol crude product is weighed, with the organic solvent dissolving of constant weight, is filtered, then Jing preparative liquid chromatographies point
From the eluent containing taxol, intermediate III is collected respectively, the difference of the eluent containing taxol, intermediate III is concentrated dry
It is dry to obtain paclitaxel prodrugs, intermediate III, reaction raw materials of the intermediate III as taxol biosynthesis.
(7) dry pyridine of constant weight is the raw materials of 10-DAB III in (1st) step：Dry pyridine=1：6, it is a certain amount of
Chlorotriethyl silane be the raw materials of 10-DAB III：Chlorotriethyl silane=1：2.
(8) dry pyridine of constant weight is intermediate compound I in (2nd) step：Dry pyridine=1：6, constant weight
Chloroacetic chloride is intermediate compound I：Chloroacetic chloride=1：2.
(9) organic solvent in (3rd) step is acetonitrile, and the organic solvent of constant weight is intermediate II：It is organic molten
Agent=1：5, preparative liquid chromatography is detached to prepare the octadecylsilane chemically bonded silica that filler used by post is 60um, and mobile phase is
The acetonitrile of 50vol%.
(10) the side-chain radical compound in (4th) step is (4S, 5R) -3- benzoyl -2- (4- methoxybenzenes
Base) -4- phenyl -5- oxazole dicarboxylic acid moieties, the side-chain radical compound of constant weight is intermediate III：Side-chain radical compound=1：
1, the DMAP of constant weight is intermediate III：DMAP=1：0.2, the dry toluene of constant weight
For intermediate III：Toluene=1：10, condensing agent is DIC, and constant weight condensing agent is intermediate III：Condensation
Agent=1：0.6, constant weight n-hexane is intermediate III：N-hexane=1：20.
(11) acetic acid of constant weight is intermediate III in (5th) step：Acetic acid=1：4, during the water of constant weight is
Mesosome III：Water=1：0.5, the trifluoroacetic acid of constant weight is intermediate III：Trifluoroacetic acid=1：2, weak base is ammoniacal liquor.
(12) organic solvent in (6th) step is acetonitrile, and the organic solvent of constant weight is taxol crude product：It is organic
Solvent=1：5, preparative liquid chromatography is detached to prepare the octadecylsilane chemically bonded silica that filler used by post is 60um, mobile phase
For the acetonitrile of 40vol%.
Products obtained therefrom taxol molar yield is up to 81%, taxol high purity 99.9%.
Embodiment three
(1) raw materials of 10-DAB III are weighed, the dry pyridine stirring and dissolving of constant weight is added, is then dripped under nitrogen protection
Plus the chlorotriethyl silane of constant weight, time for adding is maintained at 45min, and dropping temperature is controlled at 15 DEG C, after being added dropwise to complete, control
Reaction temperature processed is 20 DEG C, and when 10-DAB III is remained less than 0.2% in reactant liquor reaction is stopped, and water is added dropwise to carry out being quenched instead
Should, then in concentrated hydrochloric acid and pyridine, dichloromethane extraction, concentrate drying obtains intermediate compound I.
(2) intermediate compound I is weighed, the dry pyridine stirring and dissolving of constant weight is added, one is then added dropwise under nitrogen protection
Determine the chloroacetic chloride of weight, time for adding is maintained at 45min, and dropping temperature is controlled at -5 DEG C, after being added dropwise to complete, controlling reaction temperature
For -5 DEG C, when intermediate compound I residual is 7% in reactant liquor reaction is stopped, water is added dropwise carries out that reaction is quenched, then through concentrated hydrochloric acid
Neutralization pyridine, dichloromethane extraction, concentrate drying obtains intermediate II.
(3) intermediate II is weighed, with the organic solvent dissolving of constant weight, is filtered, then Jing preparative liquid chromatographies are separated
The eluent containing intermediate compound I, intermediate II is collected respectively, and the difference of the eluent containing intermediate compound I, intermediate II is concentrated dry
Dry to obtain intermediate compound I, intermediate II, used as the raw material of synthetic intermediate II, intermediate II is used as synthetic intermediate III for intermediate compound I
Reaction raw materials.
(4) intermediate II is weighed, side-chain radical compound, the DMAP of constant weight is added, one is added
Determine the dry toluene dissolving of weight, be the condensing agent that constant weight is added dropwise at 20 DEG C under nitrogen protection in temperature, after being added dropwise to complete
It is to react to intermediate II raw material residual at 20 DEG C to obtain reactant liquor less than less than 0.2% stopping reaction in reaction temperature, to anti-
Answer the n-hexane stirred crystallization of addition constant weight in liquid 1.5 hours, filtration drying obtains intermediate III.
(5) intermediate III is weighed, acetic acid, the water stirring and dissolving of constant weight is added, the trifluoro second of constant weight is added
Acid, when it is 7% to react at temperature is for 20 DEG C to the raw material of intermediate III residual reaction is stopped, and addition weak base adjusts pH to 7, uses two
After chloromethanes extraction, Jing is washed, concentrated, being dried to obtain taxol crude product.
(6) taxol crude product is weighed, with the organic solvent dissolving of constant weight, is filtered, then Jing preparative liquid chromatographies point
From the eluent containing taxol, intermediate III is collected respectively, the difference of the eluent containing taxol, intermediate III is concentrated dry
It is dry to obtain paclitaxel prodrugs, intermediate III, reaction raw materials of the intermediate III as taxol biosynthesis.
(7) dry pyridine of constant weight is the raw materials of 10-DAB III in (1st) step：Dry pyridine=1：5, it is a certain amount of
Chlorotriethyl silane be the raw materials of 10-DAB III：Chlorotriethyl silane=1：1.5.
(8) dry pyridine of constant weight is intermediate compound I in (2nd) step：Dry pyridine=1：5, constant weight
Chloroacetic chloride is intermediate compound I：Chloroacetic chloride=1：1.5.
(9) organic solvent in (3rd) step is ethanol, and the organic solvent of constant weight is intermediate II：It is organic molten
Agent=1：4, preparative liquid chromatography is detached to prepare the octadecylsilane chemically bonded silica that filler used by post is 10um, and mobile phase is
The ethanol of 50vol%.
(10) the side-chain radical compound in (4th) step is (4S, 5R) -3- benzoyl -2- (4- methoxybenzenes
Base) -4- phenyl -5- oxazole dicarboxylic acid moieties, the side-chain radical compound of constant weight is intermediate III：Side-chain radical compound=1：
0.8, the DMAP of constant weight is intermediate III：DMAP=1：0.1, constant weight is dried first
Benzene is intermediate III：Toluene=1：7, condensing agent is DIC, and constant weight condensing agent is intermediate III：Condensation
Agent=1：0.4, constant weight n-hexane is intermediate III：N-hexane=1：12.
(11) acetic acid of constant weight is intermediate III in (5th) step：Acetic acid=1：3, during the water of constant weight is
Mesosome III：Water=1：0.3, the trifluoroacetic acid of constant weight is intermediate III：Trifluoroacetic acid=1：1, weak base is saleratus.
(12) organic solvent in (6th) step is ethanol, and the organic solvent of constant weight is taxol crude product：It is organic
Solvent=1：4, preparative liquid chromatography is detached to prepare the octadecylsilane chemically bonded silica that filler used by post is 10um, mobile phase
For the ethanol of 40vol%.
Products obtained therefrom taxol molar yield is up to 75%, taxol high purity 99.8%.
Claims (10)
1. a kind of preparation method of semi-synthetic taxol, it is characterised in that：Including step：
A. intermediate compound I is prepared：10-DAB III is dissolved in pyridine, by hydroxyl triethylsilyl on 7 carbon on 10-DAB III
Carry out protecting to obtain intermediate compound I；
B. intermediate II is prepared：Acetylating hydroxyl groups on 10 carbon of intermediate compound I are obtained into intermediate II；
C. intermediate III is prepared：Intermediate II, side-chain radical compound, DMAP are reacted in organic solvent
Prepared intermediate III；The organic solvent is the one kind in methyl alcohol, ethanol, acetonitrile.
D. taxol crude product is prepared：Intermediate III is reacted into acid condition to obtain taxol crude product with trifluoroacetic acid；
The intermediate I molecular formula：C35H50O10Si, its structural formula is as follows：
The intermediate II molecular formula：C37H52O11Si, its structural formula is as follows：
The molecular formula of the intermediate III：C62H71NO15Si, its structural formula is as follows：
2. the method for semi-synthetic taxol according to claim 1, it is characterised in that：The step A to D is specific as follows：
A. intermediate compound I is prepared：10-DAB III is added into stirring and dissolving in pyridine, chlorotriethyl silane is added dropwise under nitrogen protection,
When in reactant liquor the residuals of 10-DAB III less than 0.2% when stop reaction, water is added dropwise carries out that reaction is quenched, with concentrated hydrochloric acid and pyrrole
Pyridine, extracts dichloromethane, and concentrate drying obtains intermediate compound I；
B. intermediate II is prepared：By intermediate compound I add pyridine in stirring and dissolving, chloroacetic chloride is added dropwise under nitrogen protection, then-
React at a temperature of 15～5 DEG C to intermediate compound I residual for 5～10% when stop reaction, be added dropwise water carry out that reaction is quenched, use concentrated hydrochloric acid
Neutralization pyridine, extracts dichloromethane, and concentrate drying obtains intermediate II；
C. intermediate III is prepared：Intermediate II, side-chain radical compound, DMAP are added in toluene and stirs molten
Solution, at 10～30 DEG C of temperature and nitrogen protection condensing agent is added dropwise, and then reacts former to intermediate II at a temperature of 10～30 DEG C
Material residual stops reaction less than 0.2%, adds n-hexane stirred crystallization, filtration drying to obtain intermediate III；
D. taxol crude product is prepared：Intermediate III is added in acetic acid, water stirring and dissolving is added, then trifluoroacetic acid is added into body
System, when it is 5～10% to react at a temperature of 10～30 DEG C to the raw material of intermediate III residual reaction is stopped, and adds alkali neutralization, uses two
Jing is washed, concentrated, being dried to obtain taxol crude product after chloromethanes extraction.
3. the method for semi-synthetic taxol according to claim 2, it is characterised in that：Triethyl group is added dropwise in step A
The time for adding of chlorosilane is 30～60min, and dropping temperature is 10～20 DEG C, is added dropwise to complete rear reaction temperature for 10～30 DEG C；
The time that n-hexane stirred crystallization is added in step C is 1～2 hour.
4. the method for semi-synthetic taxol according to claim 2, it is characterised in that：Chloroacetic chloride is added dropwise in step B
Time for adding be 30～60min, dropping temperature is -15～5 DEG C, is added dropwise to complete rear reaction temperature for -15～5 DEG C.
5. the method for semi-synthetic taxol according to claim 1, it is characterised in that：Side chain radical dough in step C
Compound is (4S, 5R) -3- benzoyl -2- (4- methoxyphenyls) -4- phenyl -5- oxazole dicarboxylic acid moieties；The He of the intermediate III
The consumption weight ratio of side-chain radical compound is 1：(0.63～1)；The molecular formula of the side-chain radical compound is：C24H21NO5,
Its structural formula is as follows：
6. the method for semi-synthetic taxol according to claim 2, it is characterised in that：The He of intermediate III in step C
The consumption weight ratio of DMAP is 1：(0.05～0.2)；The consumption weight of intermediate III and toluene in step C
Than for 1：(4～10)；Condensing agent is in dicyclohexylcarbodiimide or DIC in step C；The step
The consumption weight ratio of intermediate III and condensing agent is 1 in rapid C：(0.2～0.6)；Intermediate III and n-hexane in step C
Consumption weight ratio is 1：(8～20)；The consumption weight ratio of intermediate III and acetic acid is 1 in step D：(2～4)；The step
The consumption weight ratio of intermediate III and water is 1 in rapid D：(0.1～0.5)；The use of intermediate III and trifluoroacetic acid in step D
Amount weight ratio is 1：(0.5～2).
7. the method for semi-synthetic taxol as claimed in any of claims 1 to 6, it is characterised in that：Step D
Also include step E afterwards, step E is：
E. taxol is prepared：By the organic solvent dissolving of taxol crude product, filter, then Jing liquid chromatograies are separated to collect respectively and contained
There are taxol, the eluent of intermediate III, containing Japanese yew alcohol eluen concentrate drying paclitaxel prodrugs are obtained.
8. the method for semi-synthetic taxol according to claim 1, it is characterised in that：10-DAB III is former in step A
Material is 1 with the consumption weight ratio of pyridine：(3～6), the 10-DAB III is=1 with the consumption weight ratio of chlorotriethyl silane：
(0.8～2)；The consumption weight ratio of intermediate compound I described in step B and pyridine is 1：(3～6), intermediate I and chloroacetic chloride
Consumption weight ratio is 1：(0.5～2)；The consumption weight ratio of intermediate II and organic solvent is 1 in step C：(2～5).
9. the method for semi-synthetic taxol according to claim 7, it is characterised in that：The intermediate II crude product Jing liquid phases
Use after chromatography purity, the liquid chromatogram for being adopted is detached prepare filler used by post for 5～60um octadecylsilane key
Silica gel is closed, the mobile phase of the liquid chromatogram is the methyl alcohol of 50～70vol%, the ethanol of 50～70vol%, 50～70vol%
Acetonitrile in one kind；The consumption weight ratio of taxol crude product and organic solvent is 1 in step E：(2～5), liquid phase used
Chromatographic isolation prepares the octadecylsilane chemically bonded silica that filler used by post is 5～60um, and the mobile phase is 40～
The acetonitrile of the methyl alcohol of 60vol% or the ethanol of 40～60vol% or 40～60vol%.
10. a kind of preparation method of semi-synthetic Japanese yew alcohol intermediate, it is characterised in that：Including step：In the raw materials of 10-DAB III
Pyridine stirring and dissolving is added, chlorotriethyl silane is added dropwise under nitrogen protection, when the residuals of 10-DAB III are less than 0.2% in reactant liquor
When stop reaction, water is added dropwise carries out that reaction is quenched, and with concentrated hydrochloric acid and pyridine, extraction dichloromethane, concentrate drying obtains centre
Body I.
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| CN111718309A (en) * | 2019-03-19 | 2020-09-29 | 上海茂晟康慧科技有限公司 | Synthesis method of paclitaxel side chain and analogues thereof |
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| CN108047169A (en) * | 2018-01-12 | 2018-05-18 | 重庆市碚圣医药科技股份有限公司 | A kind of method that low pure Japanese yew raw polyol is prepared into high-purity taxol |
| CN111718309A (en) * | 2019-03-19 | 2020-09-29 | 上海茂晟康慧科技有限公司 | Synthesis method of paclitaxel side chain and analogues thereof |
| CN111718309B (en) * | 2019-03-19 | 2022-08-02 | 上海茂晟康慧科技有限公司 | Synthesis method of paclitaxel side chain and analogues thereof |
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