CN104250235B - A kind of preparation method of paclitaxel - Google Patents
A kind of preparation method of paclitaxel Download PDFInfo
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- CN104250235B CN104250235B CN201410496126.2A CN201410496126A CN104250235B CN 104250235 B CN104250235 B CN 104250235B CN 201410496126 A CN201410496126 A CN 201410496126A CN 104250235 B CN104250235 B CN 104250235B
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- DLACRDONFBNRSP-KWIOUIIFSA-N CC(C)([C@@](C1)([C@H]([C@H]([C@]2([C@@H](C[C@@H]3O)OC2)OC(C)=O)[C@]3(C)C([C@@H]2OC(C)=O)=O)OC(c3ccccc3)=O)O)C2=C(C)[C@H]1OC([C@@H]([C@H](c1ccccc1)N)O)=O Chemical compound CC(C)([C@@](C1)([C@H]([C@H]([C@]2([C@@H](C[C@@H]3O)OC2)OC(C)=O)[C@]3(C)C([C@@H]2OC(C)=O)=O)OC(c3ccccc3)=O)O)C2=C(C)[C@H]1OC([C@@H]([C@H](c1ccccc1)N)O)=O DLACRDONFBNRSP-KWIOUIIFSA-N 0.000 description 1
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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
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses the preparation method of a kind of paclitaxel.It carries out double (3R, 4S) 1 benzoyl 3 hydroxyl 4 phenyl azepine 2 butanone that side chain is the protection of diisopropyl alkyl silane of condensation reaction with 13 hydroxyls of 7 TES bar card III.The preparation method of the present invention uses new side chain to carry out condensation reaction, has opened up new preparation method, and byproduct of reaction is few, and yield is high.
Description
Technical field
The present invention relates to technical field of medicine synthesis, be specifically related to the preparation method of a kind of paclitaxel.
Background technology
Paclitaxel (Paclitaxel, trade name Taxol) is to isolate from Taxus (Taxus) plant
A kind of Taxane diterpenes compounds come.Its novel structure, anticancer mechanism are unique, anticancer effect is notable,
Anticancer spectrum is wide it is considered to be one of found best cancer therapy drug.After the U.S., current Ramulus et folium taxi cuspidatae
Alcohol goes through to list in more than 40 countries as a line cancer therapy drug.But, paclitaxel supply is deficient big
Limit greatly its application clinically.At present, the main source of pharmaceutical paclitaxel is from natural Taxus
The bark of plant extracts and separates.But owing to this kind number of plant is few, growth is slow, and content is low, and extracts
Difficulty is quite big, takes a long view and cannot meet growing clinical demand at all.
In recent years, paclitaxel chemistry is complete synthesis to succeed, but complex synthetic route, high cost, so
Only there is Research Significance, there is no commercial value.Comparatively speaking, taxanes molecular design is to have reality
By a kind of preparation method being worth, thus it is particularly important.
Semi-synthetic study general is all with the 10-deacetylate Bakating III similar with paclitaxel macrocyclic structure
(10-DAB) it is initiation material, prepares paclitaxel precursor by docking with the side chain of paclitaxel, finally take off
Protection obtains paclitaxel.10-DAB can extract from the needle of the Chinese yew genus plants of abundance and obtain
Arrive, and yield is high, thus provide sufficient raw material guarantee for the semi-synthetic of paclitaxel.
Prior art discloses the semisynthesis of a kind of paclitaxel, wherein by the C-7 of 10-DAB and
Hydroxyl tribromo-acetyl base in C-10 position is protected, or acetylation C-10 position hydroxyl in the presence of a catalyst.Will
The intermediate obtained and 3-phenyl-2-glycidic acid generation esterification, then make epoxide open with Hydrazoic acid,sodium salt
Ring, makes 7 deprotections simultaneously, and azido is reduced to amino the most again, then carries out benzoylation and obtain purple
China fir alcohol.
Disclosing again with 10-DAB as substrate in prior art, three step " a pot " reactions obtain Ba Kating
III derivant, then by 13 bit esterified condensations, then by the oxazolidine open loop of cyclic pendant and discharge 7 simultaneously
Position hydroxyl obtains paclitaxel.The defect of this reaction is to use silylating group 7 hydroxyls upper to 10-DAB
When the protection resterification of base reacts, conversion yields is only 85%, easily produces side reaction.And the response time
Longer, reaction requires to carry out under the protection of noble gas, and reaction condition is strict, is unfavorable for industry metaplasia
Produce.
But open loop deprotection is all to use ethyl acetate, methanol or ethanol in the method for above-mentioned semi-synthetic paclitaxel
Equal solvent, the response time is long, and by-product is many.
Summary of the invention
In view of this, it is an object of the invention to propose the preparation method of a kind of paclitaxel, this preparation method is adopted
Carrying out condensation reaction with new side chain, opened up new preparation method, byproduct of reaction is few, and yield is high.
For reaching this purpose, the present invention by the following technical solutions:
The preparation method of a kind of paclitaxel, carries out condensation reaction with 13 hydroxyls of 7-TES-baccatin III
Side chain is double (3R, 4S)-1-benzoyl-3-hydroxy-4-phenyl azepine-2-fourths of diisopropyl alkyl silane protection
Ketone, i.e. compound shown in Formula IV, in its structural formula, straight chained alkyl n scope Han carbon number is 6～12；
Preferably, this preparation method, comprise the following steps:
(1) in the presence of CeCl3 7H2O, by the 10 of compound shown in Formulas I (also known as 10-DAB)
Position acetylating hydroxyl groups, obtains compound shown in Formula II (also known as baccatin III)；
(2) 7 hydroxyls of compound shown in Formula II chlorotriethyl silane is protected, obtain formula III shownization
Compound (also known as 7-TES-baccatin III)；
(3) 13 hydroxyls of compound shown in formula III carry out condensation reaction with compound shown in Formula IV and obtain formula
Compound shown in IV, i.e. paclitaxel precursor；
(4) compound shown in formula IV is removed the protected silane base of 2 ', 7, obtains paclitaxel, structure
Formula is as follows:
The preparation method of the present invention uses first 10 hydroxyls of acetylation, then the method protecting 7 hydroxyls, it is to avoid
Side reaction during 7 hydroxyls of protection 10 hydroxyls also protected；Avoid simultaneously and first protect 7 hydroxyls again
The out-of-date methods of 10 hydroxyls of acetylation, the response time is very fast, and by-product is few, and reacts the most at normal temperatures and pressures,
Need not inert gas shielding, be especially suitable for industrialized production.
Preferably, in step (1), in the presence of CeCl3 7H2O, compound shown in Formulas I and acetic acid
Acid anhydride reacts in oxolane and makes its 10 acetylating hydroxyl groups；
Preferably, compound shown in described Formulas I is 1:(0.05～0.2 with the mass ratio of CeCl3 7H2O),
More preferably 1:0.1；
It is further preferred that in terms of g/ml, compound shown in described Formulas I with the mass/volume ratio of acetic anhydride is
1:(2.0～5.0), more preferably 1:3.0；
It is further preferred that in terms of g/ml, the mass/volume ratio of compound shown in described Formulas I and oxolane
For 1:(10～25), more preferably 1:15；
It is further preferred that described reaction temperature is room temperature；
It is further preferred that the described response time is 1～3 hour, more preferably 2 hours.
In the present invention, mass/volume ratio is described as follows, for convenience of calculate, front compound with quality for standard such as g,
Rear compound is liquid, and with volume for standard such as ml, thus mass volume ratio is g/ml meter.
There is the hydroxyl that two activity are stronger on the C-7 position of 10-DAB and C-10 position, and the hydroxyl of C-7 position is lived
Property more than the hydroxyl of C-10 position, when adding acetic anhydride under normal conditions, two hydroxyls all can occur acetylation anti-
Should, by hydroxy esterification.A feature of the present invention is that the efficient specificity catalyst CeCl3 7H2O of selection,
In the presence of the catalyst, hydroxyl generation acetylization reaction C-7 position, C-10 position hydroxyl then will not react,
Reaction is carried out in a mild condition, and yield is high, and by-product is few.
Preferably, concretely comprising the following steps of step (1): compound shown in Formulas I is dissolved in oxolane, stirs
Mix and add CeCl3 7H2O after dissolving, add acetic anhydride, be stirred at room temperature 1～3 hour, after completion of the reaction,
Reactant liquor is poured in frozen water and stand, when extremely separating out without white particle, sucking filtration, it is dried, obtains shown in Formula II
Compound.
As preferably, in step (2), in the presence of imidazoles, compound shown in Formula II and triethylchloro-silicane
Alkane reacts in N,N-dimethylformamide and makes its 7 hydroxyls be protected by chlorotriethyl silane；
It is further preferred that the mass ratio of compound shown in described Formula II and imidazoles is 1:(0.3～1.0), enter
One step is preferably 1:0.6；
It is further preferred that in terms of g/ml, the quality of compound shown in described Formula II and chlorotriethyl silane/
Volume ratio is 1:(0.6～1.5), the most preferably 1:1；
It is further preferred that in terms of g/ml, compound shown in described Formula II and DMF
Mass/volume is than for 1:(3～10), the most preferably 1:5；
It is further preferred that described reaction temperature is ambient temperature, preferably carry out at 0～20 DEG C；
It is further preferred that the described response time is 2～4 hours, more preferably 3 hours.
Preferably, concretely comprising the following steps of step (2): compound shown in Formula II is dissolved in N, N-dimethyl methyl
In amide, after stirring and dissolving, add imidazoles and chlorotriethyl silane, at room temperature reaction 2～4 hours, reaction
Complete, add frozen water stopped reaction, extract with dichloromethane, organic facies is respectively with water and saturated common salt washing
Wash, be dried with anhydrous magnesium sulfate, sucking filtration, it is concentrated under reduced pressure to give compound shown in formula III.
As preferably, in step (3), in the presence of n-BuLi, compound shown in formula III and Formula IV
Shown compound occurs condensation reaction to obtain compound shown in formula IV in oxolane；Described condensation reaction will
13 hydroxy esterifications of formula III compound.
It is further preferred that the mol ratio of compound shown in compound shown in described III and Formula IV be 1:(0.5～
0.7), more preferably 1:0.6；
It is further preferred that the mol ratio of compound shown in described formula III and n-BuLi is 1:(1.0～1.4),
More preferably 1:1.2；
It is further preferred that in terms of g/ml, compound shown in described formula III and the mass/volume of oxolane
Ratio is 1:(10～25), more preferably 1:15；
It is further preferred that the temperature of described reaction is-40～-60 DEG C, more preferably-50 DEG C；
It is further preferred that the described response time is 2～3 hours, more preferably 2.5 hours.
Preferably, the concretely comprising the following steps of step (3): by compound shown in compound shown in formula III and Formula IV
It is dissolved in oxolane, at-50 DEG C, drips n-BuLi, react end in 2～3 hours, add water retention the most anti-
Should, with dichloromethane extract, organic facies respectively with 5% hydrochloric acid, saturated sodium bicarbonate solution and saturated common salt
Water washs, and organic facies adds anhydrous magnesium sulfate and is dried, and sucking filtration is concentrated under reduced pressure to give compound shown in formula IV.
As preferably, in step (4), in oxolane, compound shown in formula IV and tetrabutyl fluorine
Change ammonium reaction so that compound 2 ' shown in formula IV and the protected silane base removing of 7, obtain paclitaxel；
It is further preferred that the mol ratio of compound shown in described formula IV and tetrabutyl ammonium fluoride be 1:(4.0～
4.8), more preferably 1:4.4；
It is further preferred that in terms of g/ml, compound shown in described formula IV and the mass/volume of oxolane
Ratio is 1:(5～15), more preferably 1:10；
It is further preferred that the temperature of described reaction is 20～30 DEG C, more preferably 25 DEG C；
It is further preferred that the described response time is 4～6 hours, more preferably 5 hours；
Preferably, concretely comprising the following steps of step (4): compound shown in formula IV is dissolved in oxolane,
Add tetrabutyl ammonium fluoride stirring reaction 4～6 hours, reactant liquor is poured into the frozen water of 15 times of volumes of reactant liquor
In, stand crystallize, filter, be dried to obtain paclitaxel.
Compared with prior art, beneficial effects of the present invention is as follows: the preparation method of a kind of paclitaxel, its with
13 hydroxyl condensation reaction side chains of 7-TES-baccatin III are the double of diisopropyl alkyl silane protection
(3R, 4S)-1-benzoyl-3-hydroxy-4-phenyl azepine-2-butanone.The present invention uses new side chain to be condensed
Reaction, has opened up new preparation method, and byproduct of reaction is few, and yield is high.
Detailed description of the invention
Technical scheme is further illustrated below by detailed description of the invention.
Raw material in the present embodiment is commercially available.
Embodiment 1
A, the preparation of baccatin III (i.e. Formula II compound)
Under room temperature, 300g 10-DAB and 30g CeCl3 7H2O is added in 6L oxolane, under stirring
Dropping 700mL acetic anhydride, TLC monitors, reacts complete, poured into by reactant liquor in frozen water quiet after 1.5 hours
Put, when extremely separating out without white particle, sucking filtration, it is dried, i.e. obtains Formula II compound 305.1g, yield is to rub
That yield meter, is 94.4%；Molar yield=(the baccatin III amount of actually generating/baccatin III theory growing amount)
× 100%.
The Structural Identification of gained compound:
LC-MS(ESI):587.3[M+H]+, elementary analysis: C 63.46%, H 6.52%, O 30.02%
The preparation of b, 7-TES-baccatin III (i.e. formula III compound)
Under room temperature, 305.1g baccatin III is dissolved in 1200mL DMF, stirring and dissolving
The imidazoles of rear addition 152.6g, 275mL chlorotriethyl silane, TLC monitors, reacts complete after 2.5 hours,
Adding frozen water stopped reaction, extract with dichloromethane, organic facies with water and saturated aqueous common salt washing, is used respectively
Anhydrous magnesium sulfate is dried, sucking filtration, is concentrated under reduced pressure to give 7-TES-baccatin III 321.9g, and yield is with mole receipts
Rate meter, is 88.3%；Molar yield=(the 7-TES-baccatin III amount of actually generating/7-TES-baccatin III
Theoretical growing amount) × 100%.
The Structural Identification of gained compound:
LC-MS(ESI):701.3[M+H]+, elementary analysis: C 63.41%, H 7.47%, O 25.12%,
Si 4.00%
C, the preparation of paclitaxel precursor (i.e. formula IV compound)
Double (3R, 4S)-1-benzene that 300g 7-TES-Bakating III and 217.1g diisopropyl hexyl silane are protected
Formoxyl-3-hydroxy-4-phenyl azepine-2-butanone is dissolved in 4.5L oxolane, is just dripping 0.21L at-50 DEG C
Butyl lithium (2.5M in hexane), reacts end in 2.5 hours, adds water stopped reaction, extracts with dichloromethane
Taking, organic facies is washed with hydrochloric acid, saturated sodium bicarbonate solution and the saturated aqueous common salt of 5% respectively, organic addition
Entering anhydrous magnesium sulfate to be dried, sucking filtration, be concentrated under reduced pressure to give paclitaxel precursor 446.3g, yield is with molar yield
Meter, is 92.8%；Molar yield=(the paclitaxel precursor amount of actually generating/paclitaxel precursor theory growing amount)
× 100%.
The Structural Identification of gained compound:
LC-MS(ESI):2246.1[M+H]+, elementary analysis: C 66.27%, H 7.53%, N 1.25%,
O 19.95%, Si 5.00%
D, the preparation of paclitaxel
440g paclitaxel precursor is dissolved in the mixed solvent of 4.5L oxolane, adds the 225.3g tetrabutyl
Ammonium fluoride stirring reaction 5 hours, pours into reactant liquor in 6.6L frozen water, stands crystallize, filter, be dried
To paclitaxel 306.0g, yield, in terms of molar yield, is 91.5%；Molar yield=(paclitaxel actually generates
Amount/paclitaxel theory growing amount) × 100%.
The Structural Identification of gained compound:
LC-MS(ESI):854.3[M+H]+, elementary analysis: C 66.11%, H 6.01%, N 1.65%, O
26.23%.
Embodiment 2
A, the preparation of baccatin III (i.e. Formula II compound)
Under room temperature, 500g 10-DAB and 25g CeCl3 7H2O is added in 6L oxolane, under stirring
Dropping 1000mL acetic anhydride, TLC monitors, reacts complete, poured into by reactant liquor in frozen water quiet after 2 hours
Put, to when separating out without white particle, sucking filtration, dry, i.e. obtain Bakating III 495.5g, yield with mole
Yield meter, is 92.0%；Molar yield=(the baccatin III amount of actually generating/baccatin III theory growing amount)
× 100%.
The preparation of b, 7-TES-baccatin III (i.e. formula III compound)
Under room temperature, 495.5g baccatin III is dissolved in 1486mL DMF, stirring and dissolving
The imidazoles of rear addition 148.7g, 297.3mL chlorotriethyl silane, TLC monitors, reacts complete after 3 hours,
Adding frozen water stopped reaction, extract with dichloromethane, organic facies with water and saturated aqueous common salt washing, is used respectively
Anhydrous magnesium sulfate is dried, sucking filtration, is concentrated under reduced pressure to give 7-TES-baccatin III 531g, and yield is with molar yield
Meter, is 89.7%；Molar yield=(the 7-TES-baccatin III amount of actually generating/7-TES-baccatin III is theoretical
Growing amount) × 100%.
C, the preparation of paclitaxel precursor (i.e. formula IV compound)
Double by 520g 7-TES-Bakating III and 413.7g diisopropyl dodecyl protected silane
(3R, 4S)-1-benzoyl-3-hydroxy-4-phenyl azepine-2-butanone is dissolved in 7.8L oxolane, at-50 DEG C
Lower dropping 0.36L n-BuLi (2.5M in hexane), reacts end in 2.5 hours, adds water stopped reaction,
Extracting with dichloromethane, organic facies is washed with hydrochloric acid, saturated sodium bicarbonate solution and the saturated common salt of 5% respectively
Washing, organic facies adds anhydrous magnesium sulfate and is dried, and sucking filtration is concentrated under reduced pressure to give paclitaxel precursor 806.1g, receives
Rate, in terms of molar yield, is 93.2%；Molar yield=(the paclitaxel precursor amount of actually generating/paclitaxel precursor reason
Opinion growing amount) × 100%.
The Structural Identification of gained compound:
LC-MS(ESI):2330.2[M+H]+, elementary analysis: C 66.99%, H 7.77%, N 1.20%,
O 19.21%, Si 4.83%
D, the preparation of paclitaxel
800g paclitaxel precursor is dissolved in the mixed solvent of 8L oxolane, adds 394.8g tetrabutyl fluorine
Change ammonium stirring reaction 5 hours, reactant liquor is poured in 12L frozen water, stand crystallize, filter, be dried to obtain
Paclitaxel 538.1g, yield, in terms of molar yield, is 91.8%；Molar yield=(paclitaxel amount of actually generating
/ paclitaxel theory growing amount) × 100%.
Compared with prior art, the invention have the advantages that
1. use double (3R, 4S)-1-benzoyl-3-hydroxy-4-phenyl azepines of diisopropyl alkyl silane protection
-2-butanone carries out condensation reaction as new side chain, has opened up new preparation method, and byproduct of reaction is few, receives
Rate is high.
2. the synthetic method of the present invention avoids the out-of-date methods first protecting 7 hydroxyl 10 hydroxyls of acetylation again,
Response time is very fast, and by-product is few, and reacts the most at normal temperatures and pressures, it is not necessary to inert gas shielding, non-
Often it is suitable for industrialized production；
3. use first 10 hydroxyls of acetylation, then the method protecting 7 hydroxyls, it is to avoid 7 hydroxyls of protection
Time side reaction that 10 hydroxyls are also protected；
The by-product produced in the most whole synthesis process need not column purification, it is only necessary to simply crystallizes
Put in next step reaction, decrease operation link, save production cost；
Applicant states, the present invention illustrates the detailed preparation method of the present invention by above-described embodiment, but this
Invention is not limited to above-mentioned detailed preparation method, does not i.e. mean that the present invention has to rely on above-mentioned detailed preparation
Method could be implemented.Person of ordinary skill in the field is it will be clearly understood that any improvement in the present invention, all
Fall within the scope of protection scope of the present invention and disclosure.
Claims (44)
1. the preparation method of a paclitaxel, it is characterised in that with 13 hydroxyls of 7-TES-baccatin III
The side chain carrying out condensation reaction is double (3R, 4S)-1-benzoyl-3-hydroxyls of diisopropyl alkyl silane protection
-4-phenyl azepine-2-butanone, i.e. compound shown in Formula IV are wherein, straight in structural formula of compound shown in Formula IV
Alkyl group n scope Han carbon number is 6～12；
Preparation method the most according to claim 1, it is characterised in that comprise the following steps:
(1) at CeCl3·7H2In the presence of O, by 10 hydroxyls of 10-DAB, i.e. compound shown in Formulas I
Base acetylation, obtains compound shown in Formula II；
(2) 7 hydroxyls of compound shown in Formula II chlorotriethyl silane is protected, obtain 7-TES-bar card
Booth III, i.e. compound shown in formula III；
(3) compound 13 shown in formula III hydroxyl carries out condensation reaction with compound shown in Formula IV, obtains
Compound shown in formula IV；
(4) the protected silane base of 2 ', 7 of compound shown in formula IV is removed, obtain Formula V shownization
Compound i.e. paclitaxel, structure is as follows:
Preparation method the most according to claim 2, it is characterised in that in step (1), at CeCl3·7H2O
In the presence of, compound shown in Formulas I and acetic anhydride react in oxolane and make its 10 acetylating hydroxyl groups
Obtain compound shown in Formula II.
Preparation method the most according to claim 2, it is characterised in that compound shown in described Formulas I with
CeCl3·7H2O mass ratio is 1:(0.05～0.2).
Preparation method the most according to claim 2, it is characterised in that compound shown in described Formulas I with
CeCl3·7H2O mass ratio is 1:0.1.
Preparation method the most according to claim 3, it is characterised in that in terms of g/ml, described Formulas I
Shown in the mass/volume ratio of compound and acetic anhydride for 1:(2～5).
Preparation method the most according to claim 3, it is characterised in that in terms of g/ml, described Formulas I
Shown in the mass/volume ratio of compound and acetic anhydride for 1:3.
Preparation method the most according to claim 3, it is characterised in that in terms of g/ml, described Formulas I
Shown in the mass/volume ratio of compound and oxolane for 1:(10～25).
Preparation method the most according to claim 3, it is characterised in that in terms of g/ml, described Formulas I
Shown in the mass/volume ratio of compound and oxolane for 1:15.
Preparation method the most according to claim 3, it is characterised in that reaction in described step (1)
Time is 1～3 hour.
11. preparation methoies according to claim 3, it is characterised in that reaction in described step (1)
Time is 2 hours.
12. preparation methoies according to claim 2, it is characterised in that the concrete steps of step (1)
For: compound shown in Formulas I is dissolved in oxolane, after stirring and dissolving, adds CeCl3·7H2O, adds
Acetic anhydride, is stirred at room temperature 1～3 hour, after completion of the reaction, is poured into by reactant liquor in frozen water and stand, to without white
When coloured particles separates out, sucking filtration, it is dried, obtains compound shown in Formula II.
13. preparation methoies according to claim 2, it is characterised in that in step (2), at imidazoles
In the presence of, compound shown in Formula II and chlorotriethyl silane react in DMF and make it
7 hydroxyls are protected by chlorotriethyl silane, obtain compound shown in formula III.
14. preparation methoies according to claim 13, it is characterised in that compound shown in described Formula II
It is 1:(0.3～1.0 with the mass ratio of imidazoles).
15. preparation methoies according to claim 13, it is characterised in that compound shown in described Formula II
It is 1:0.6 with the mass ratio of imidazoles.
16. preparation methoies according to claim 2, it is characterised in that in terms of g/ml, described Formula II
Shown in the mass/volume ratio of compound and chlorotriethyl silane for 1:(0.6～1.5).
17. preparation methoies according to claim 2, it is characterised in that in terms of g/ml, described Formula II
Shown in the mass/volume ratio of compound and chlorotriethyl silane for 1:1.
18. preparation methoies according to claim 13, it is characterised in that in terms of g/ml, described formula
The mass/volume of compound shown in II and N,N-dimethylformamide is than for 1:(3～10).
19. preparation methoies according to claim 13, it is characterised in that in terms of g/ml, described formula
The mass/volume of compound shown in II and N,N-dimethylformamide is than for 1:5.
20. preparation methoies according to claim 13, it is characterised in that anti-in described step (2)
It is 2～4 hours between Ying Shi.
21. preparation methoies according to claim 13, it is characterised in that anti-in described step (2)
It is 3 hours between Ying Shi.
22. preparation methoies according to claim 2, it is characterised in that the concrete steps of step (2)
For: compound shown in Formula II is dissolved in DMF, after stirring and dissolving, adds imidazoles and three second
Base chlorosilane, reaction 2～4 hours, react complete at room temperature, add frozen water stopped reaction, use dichloromethane
Alkane extracts, and organic facies with water and saturated aqueous common salt washing, is dried with anhydrous magnesium sulfate, sucking filtration, decompression respectively
It is concentrated to give compound shown in formula III.
23. preparation methoies according to claim 2, it is characterised in that in step (3), in positive fourth
In the presence of base lithium, compound shown in formula III and compound shown in Formula IV occur condensation anti-in oxolane
Compound shown in formula IV should be obtained.
24. preparation methoies according to claim 2, it is characterised in that compound shown in described III with
The mol ratio of compound shown in Formula IV is 1:(0.5～0.7).
25. preparation methoies according to claim 2, it is characterised in that compound shown in described III with
The mol ratio of compound shown in Formula IV is 1:0.6.
26. preparation methoies according to claim 23, it is characterised in that chemical combination shown in described formula III
Thing is 1:(1.0～1.4 with the mol ratio of n-BuLi).
27. preparation methoies according to claim 23, it is characterised in that chemical combination shown in described formula III
Thing is 1:1.2 with the mol ratio of n-BuLi.
28. preparation methoies according to claim 23, it is characterised in that in terms of g/ml, described formula
The mass/volume of compound shown in III and oxolane is than for 1:(10～25).
29. preparation methoies according to claim 23, it is characterised in that in terms of g/ml, described formula
The mass/volume of compound shown in III and oxolane is than for 1:15.
30. preparation methoies according to claim 23, it is characterised in that anti-in described step (3)
The temperature answered is-40～-60 DEG C.
31. preparation methoies according to claim 23, it is characterised in that anti-in described step (3)
The temperature answered is-50 DEG C.
32. preparation methoies according to claim 23, it is characterised in that anti-in described step (3)
It is 2～3 hours between Ying Shi.
33. preparation methoies according to claim 23, it is characterised in that anti-in described step (3)
It is 2.5 hours between Ying Shi.
34. preparation methoies according to claim 2, it is characterised in that the concrete steps of step (3)
For: compound shown in compound shown in formula III and Formula IV is dissolved in oxolane, at-50 DEG C, drips positive fourth
Base lithium, reacts end in 2～3 hours, adds water stopped reaction, extracts with dichloromethane, and organic facies is used respectively
Hydrochloric acid, saturated sodium bicarbonate solution and the saturated aqueous common salt washing of 5%, organic facies adds anhydrous magnesium sulfate and is dried,
Sucking filtration, is concentrated under reduced pressure to give compound shown in formula IV.
35. preparation methoies according to claim 2, it is characterised in that in step (4), by formula IV
Shown compound is dissolved in oxolane, adds the tetrabutyl ammonium fluoride protected silane base with removing 2 ', 7,
Obtain paclitaxel.
36. preparation methoies according to claim 35, it is characterised in that chemical combination shown in described formula IV
Thing is 1:(4.0～4.8 with the mol ratio of tetrabutyl ammonium fluoride).
37. preparation methoies according to claim 35, it is characterised in that chemical combination shown in described formula IV
Thing is 1:4.4 with the mol ratio of tetrabutyl ammonium fluoride.
38. preparation methoies according to claim 35, it is characterised in that in terms of g/ml, described formula
The mass/volume of compound shown in IV and oxolane is than for 1:(5～15).
39. preparation methoies according to claim 35, it is characterised in that in terms of g/ml, described formula
The mass/volume of compound shown in IV and oxolane is than for 1:10.
40. preparation methoies according to claim 35, it is characterised in that anti-in described step (4)
The temperature answered is 20～30 DEG C.
41. preparation methoies according to claim 35, it is characterised in that anti-in described step (4)
The temperature answered is 25 DEG C.
42. preparation methoies according to claim 35, it is characterised in that anti-in described step (4)
It is 4～6 hours between Ying Shi.
43. preparation methoies according to claim 35, it is characterised in that anti-in described step (4)
It is 5 hours between Ying Shi.
44. preparation methoies according to claim 2, it is characterised in that the concrete steps of step (4)
For: compound shown in formula IV is dissolved in oxolane, adds tetrabutyl ammonium fluoride stirring reaction 4～6 little
Time, reactant liquor is poured in the frozen water of 15 times of volumes of reactant liquor, stand crystallize, filter, be dried to obtain Ramulus et folium taxi cuspidatae
Alcohol.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1101346A (en) * | 1993-01-29 | 1995-04-12 | 佛罗里达州立大学 | C2 taxane derivatives and pharmaceutical compositions containing them |
| WO1996034862A1 (en) * | 1995-05-05 | 1996-11-07 | Sloan-Kettering Institute For Cancer Research | Total synthesis of taxol and analogues thereof |
| EP0856512A2 (en) * | 1997-01-24 | 1998-08-05 | Virginia Tech Intellectual Properties, Inc. | 1-deoxy paclitaxels, method of preparation and pharmaceutical use |
| WO2004007473A1 (en) * | 2002-07-15 | 2004-01-22 | Cipla Limited | Process for preparing of paclitaxel |
| EP1942109A1 (en) * | 2005-10-25 | 2008-07-09 | Daiichi Sankyo Company, Limited | Taxane compound with azetidine ring structure |
-
2014
- 2014-09-24 CN CN201410496126.2A patent/CN104250235B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1101346A (en) * | 1993-01-29 | 1995-04-12 | 佛罗里达州立大学 | C2 taxane derivatives and pharmaceutical compositions containing them |
| WO1996034862A1 (en) * | 1995-05-05 | 1996-11-07 | Sloan-Kettering Institute For Cancer Research | Total synthesis of taxol and analogues thereof |
| EP0856512A2 (en) * | 1997-01-24 | 1998-08-05 | Virginia Tech Intellectual Properties, Inc. | 1-deoxy paclitaxels, method of preparation and pharmaceutical use |
| WO2004007473A1 (en) * | 2002-07-15 | 2004-01-22 | Cipla Limited | Process for preparing of paclitaxel |
| EP1942109A1 (en) * | 2005-10-25 | 2008-07-09 | Daiichi Sankyo Company, Limited | Taxane compound with azetidine ring structure |
Non-Patent Citations (4)
| Title |
|---|
| .《Biochemistry》.1999,第39卷第285-286页. * |
| Donald G. Walker et al.,.SYNTHESIS OF CARBON-14 LABELED TAXOL.《Journal of Labelled Compounds and Radiopharmaceuticals》.1994,第XXXIV卷(第10期), * |
| Yankun Li et al..Conformation of Microtubule-Bound Paclitaxel Determined by Fluorescence Spectroscopy and REDOR NMR† * |
| 位阻型硅烷化试剂在药物合成中的研究与应用;邓锋杰 等;《精细化工中间体》;20051030;第35卷(第5期);第6-9页 * |
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