CN103450118A - Method for preparing paclitaxel by virtue of semi-synthesis - Google Patents
Method for preparing paclitaxel by virtue of semi-synthesis Download PDFInfo
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Abstract
The invention discloses a method for preparing paclitaxel by virtue of semi-synthesis, and the method comprises the following steps: firstly, acetylizing the tenth hydroxyl of 10-DAB (Diaminobenzidine) in the presence of CeCl3.7H2O; secondly, protecting the seventh hydroxyl of the 10-DAB by use of triethylchlorosilane, performing condensation reaction on the tenth acetylized hydroxyl, a compound of which the seventh hydroxyl is protected and (4S,5R)-2,4-diphenyl-4,5-dihydrogen oxazole-5-carboxylic acid to obtain a paclitaxel precursor; finally, opening a side chain oxazole ring of the paclitaxel precursor, and synchronously removing the seventh trichloroacetic protecting group to obtain the paclitaxel. The method has high reaction yield and few byproducts, and is moderate in reaction condition, fast in reaction, simple and convenient in post treatment, and suitable for industries for industrial production.
Description
Technical field
The present invention relates to technical field of medicine synthesis, be specifically related to a kind of method that semi-synthesis method prepares taxol.
Background technology
Taxol (Paclitaxel, trade(brand)name Taxol) is a kind of Taxan diterpene-kind compound of separating from Taxus (Taxus) plant.Its novel structure, anticancer mechanism are unique, anticancer effect is remarkable, anticancer spectrum is wide, is considered to one of the best cancer therapy drug of finding so far.After the U.S., taxol goes through to go on the market in more than 40 countries as a line cancer therapy drug at present.Yet taxol supply scarcity has limited its application clinically greatly.At present, the main source of pharmaceutical paclitaxel is to extract and separate from the bark of natural Chinese yew genus plants.But because this kind number of plant is few, growth is slow, and content is low, and it is quite large to extract difficulty, takes a long view and can't meet growing clinical demand at all.
In recent years, complete synthesis the succeeding of taxol chemistry, but complex synthetic route, high cost, so only have Research Significance, there is no commercial value.Comparatively speaking, the taxanes molecular design is a kind of preparation method with practical value, thereby seems particularly important.
Semi-synthetic study general is all that take with the similar 10-deacetylate of taxol macrocyclic structure Bakating III (10-DAB) is starting raw material, and by with the side chain of taxol, docking and make the taxol precursor, last deprotection obtains taxol.10-DAB can extract and obtain from the needle of the abundant Chinese yew genus plants of originating, and yield is high, thereby provides sufficient raw material guarantee for taxol semi-synthetic.
Can prepare taxol by semisynthesis according to the numerous methods described in science and technology and patent documentation at present.
Italian patent CN1286828C discloses a kind of semisynthesis of taxol, wherein by tribromo-acetyl base protection for the C-7 of 10-DAB and C-10 position hydroxyl, or under the existence of catalyzer acetylize C-10 position hydroxyl.By intermediate and the 3-phenyl-2-glycidic acid generation esterification obtained, then make the epoxide open loop with sodiumazide, make 7 deprotections simultaneously, finally again azido-is reduced to amino, then carry out benzoylation and obtain taxol.
French Patent CN101128448A discloses take 10-DAB as substrate, and three steps " a pot " reaction obtains the Bakating III derivative, then, by 13 bit esterified condensations, then by the oxazolidine open loop of ring-type side chain, also discharge 7 hydroxyls obtains taxol simultaneously.When the defect of this reaction is to use the methyl group to the protection resterification reaction of upper 7 hydroxyls of 10-DAB, conversion yields is only 85%, easily produces side reaction.And the reaction times is longer, reaction requires to carry out under the protection of rare gas element, and reaction conditions is strict, is unfavorable for suitability for industrialized production.
From document, can obviously find out: a semi-synthetic key issue of taxol is the hydroxyl of optionally protecting on 10-DAB, makes C-10 position acetylization reaction.The active order of upper each hydroxyl of 10-DAB is C-7>C-10>C-13, wants to allow the acetylize of C-10 position and the C-7 position does not react, and just the C-7 position must be protected.The most frequently used protecting group is triethyl silica-based (TES).
In the method for above-mentioned semi-synthetic taxol, the open loop deprotection is all to use ethyl acetate, methyl alcohol or ethanol equal solvent, long reaction time, and by product is many.
Summary of the invention
The object of the invention is to propose a kind of method that semi-synthesis method prepares taxol, the method reaction yield is higher, reaction conditions is gentle, the reaction times is very fast, by product is less, aftertreatment is easy, be suitable for the industry of suitability for industrialized production.
For reaching this purpose, the present invention by the following technical solutions:
A kind of method for preparing taxol, it comprises the following steps:
(1) at CeCl
3.7H
2under the existence of O, by 10 glycoloyl of compound shown in formula I (claiming again 10-DAB), obtain compound shown in formula II (claiming again baccatin III);
(2) 7 hydroxyls of compound shown in formula II are protected with chlorotriethyl silane, obtained compound shown in formula III (claiming again the 7-TES-baccatin III);
(3) compound shown in formula III and (4S, 5R)-2,4-phenylbenzene-4,5-dihydro-oxazole-5-carboxylic acid obtains compound shown in formula IV (taxol precursor) through condensation reaction;
(4) by the side chain oxazole ring open loop of compound shown in formula IV, and the tribromo-acetyl protecting group of 7 of simultaneous removings, taxol obtained.
As preferably, in step (1), at CeCl
3.7H
2under the existence of O, compound shown in formula I reacts in tetrahydrofuran (THF) with diacetyl oxide and makes its 10 glycoloyl.Two hydroxyls that activity is stronger are arranged on the C-7 position of 10-DAB and C-10 position, and the hydroxyl activity of C-7 position is greater than the hydroxyl of C-10 position, while adding diacetyl oxide under normal conditions, acetylization reaction all can occur in two hydroxyls, by hydroxy esterification; Characteristics of the present invention just are to select efficient specificity catalyzer CeCl
3.7H
2o, under this catalyzer exists, hydroxyl generation acetylization reaction C-7 position, C-10 position hydroxyl can not react, and reaction is carried out under mild conditions, and yield is high, and by product is few.
Further preferably, compound and CeCl shown in described formula I
3.7H
2the mass ratio of O is 1:(0.05～0.2), 1:0.1 more preferably;
Further preferably, in g/ml, the mass volume ratio of compound and diacetyl oxide shown in described formula I is 1:(2.0～5.0), 1:3.0 more preferably;
Further preferably, in g/ml, the mass volume ratio of compound and tetrahydrofuran (THF) shown in described formula I is 1:(10～25), 1:15 more preferably;
Further preferably, described temperature of reaction is room temperature;
Further preferably, the described reaction times is 1～3 hour, more preferably 2 hours.
More preferably, the concrete steps of step (1) are: compound shown in formula I is dissolved in tetrahydrofuran (THF), adds CeCl after stirring and dissolving
3.7H
2o, then add diacetyl oxide, stirring at room 1～3 hour, after completion of the reaction, reaction solution is poured in frozen water standing, when separating out without white particle, suction filtration, drying, obtain compound shown in formula II.
As preferably, in step (2), under the existence of imidazoles, compound shown in formula II reacts in DMF with chlorotriethyl silane and its 7 hydroxyls is protected by chlorotriethyl silane;
Further preferably, the mass ratio of compound and imidazoles shown in described formula II is 1:(0.3～1.0), 1:0.6 more preferably;
Further preferably, in g/ml, the mass volume ratio of compound and chlorotriethyl silane shown in described formula II is 1:(0.6～1.5), further be preferably 1:1;
Further preferably, in g/ml, the mass volume ratio of compound and DMF shown in described formula II is 1:(3～10), further be preferably 1:5;
Further preferably, described temperature of reaction is envrionment temperature, preferably under 0～20 ℃, carries out.
Further preferably, the described reaction times is 2～4 hours, more preferably 3 hours.
More preferably, the concrete steps of step (2) are: compound shown in formula II is dissolved in DMF, adds imidazoles and chlorotriethyl silane after stirring and dissolving, under room temperature, react 2～4 hours, react complete, add the frozen water stopped reaction, use dichloromethane extraction, organic phase is water and saturated common salt water washing respectively, use anhydrous magnesium sulfate drying, suction filtration, concentrating under reduced pressure obtains compound shown in formula III.
As preferably, in step (3), under the existence of DMAP (DMAP) and dicyclohexylcarbodiimide (DCC), compound shown in formula III and (4S, 5R)-2,4-phenylbenzene-4, condensation reaction occurs and obtains compound shown in formula IV in 5-dihydro-oxazole-5-carboxylic acid in DMF; Described condensation reaction is by 13 hydroxy esterifications of formula III compound.
Further preferably, the mass ratio of compound and DMAP shown in described formula III is 1:(0.02～0.05), 1:0.03 more preferably;
Further preferably, the mass ratio of compound and dicyclohexylcarbodiimide shown in described formula III is 1:(0.5～1.0), 1:0.7 more preferably;
Further preferably, compound shown in described formula III and (4S, 5R)-2,4-phenylbenzene-4, the mass ratio of 5-dihydro-oxazole-5-carboxylic acid is 1:(0.5～0.9), 1:0.8 more preferably;
Further preferably, in g/ml, the mass volume ratio of compound and DMF shown in described formula III is 1:(10～25), 1:15 more preferably;
Further preferably, described temperature of reaction is room temperature;
Further preferably, the described reaction times is 2～3 hours, more preferably 2.5 hours.
More preferably, the concrete steps of step (3) are: compound shown in formula III is dissolved in to N, dinethylformamide, after stirring at room is dissolved, add (4S, 5R)-2,4-phenylbenzene-4,5-dihydro-oxazole-5-carboxylic acid, DMAP and dicyclohexylcarbodiimide, react end in 2～3 hours, add the water stopped reaction, use dichloromethane extraction, organic phase is used respectively 5% hydrochloric acid, saturated sodium bicarbonate solution and saturated common salt water washing, and organic phase adds anhydrous magnesium sulfate drying, suction filtration, concentrating under reduced pressure obtains compound shown in formula IV.
As preferably, in step (4), in the mixed solvent of methyl alcohol and tetrahydrofuran (THF), compound shown in formula IV and 1:10 hydrochloric acid reaction be so that the side chain oxazole ring open loop of compound shown in formula IV, after add saturated sodium bicarbonate solution to continue reaction to remove the tribromo-acetyl protecting group of 7; Described 1:10 hydrochloric acid is for commercially available concentrated hydrochloric acid and the water hydrochloric acid soln formulated according to volume ratio 1:10, and the mass percent of described commercially available concentrated hydrochloric acid is about 37%.
Further preferably, in g/ml, the mass volume ratio of compound shown in described formula IV and 1:10 hydrochloric acid is 1:(3～4), 1:3.5 more preferably;
Further preferably, in g/ml, the mass volume ratio of compound and methyl alcohol shown in described formula IV is 1:(5～15), 1:10 more preferably;
Further preferably, in g/ml, the mass volume ratio of compound and tetrahydrofuran (THF) shown in described formula IV is 1:(5～15), 1:10 more preferably;
Further preferably, the temperature of described reaction is 5～25 ℃, more preferably 15 ℃;
Further preferably, the reaction times of compound shown in formula IV and 1:10 hydrochloric acid reaction is 3～5 hours, more preferably 4 hours;
Further preferably, the continuation reaction times that adds saturated sodium bicarbonate solution is 1～2 hour, more preferably 1.5 hours.
More preferably, the concrete steps of step (4) are: compound shown in formula IV is dissolved in the mixed solvent of methyl alcohol and tetrahydrofuran (THF), add 1:10 hydrochloric acid stirring reaction 3～5 hours, then add saturated sodium bicarbonate solution, continue reaction 1～2 hour, reaction solution is poured in the frozen water of 5 times of volumes of reaction solution into to standing crystallization, filter, drying obtains taxol; Described 1:10 hydrochloric acid is for commercially available concentrated hydrochloric acid and the water hydrochloric acid soln formulated according to volume ratio 1:10, and the mass percent of described commercially available concentrated hydrochloric acid is about 37%.
Compared with prior art, the present invention has the following advantages:
1. synthetic method of the present invention has avoided first protecting 7 hydroxyls out-of-date methods of 10 hydroxyls of acetylize again, and the reaction times is very fast, and by product is few, and all reactions at normal temperatures and pressures, does not need protection of inert gas, is applicable to very much suitability for industrialized production;
2. adopt 10 hydroxyls of first acetylize, then protect the method for 7 hydroxyls, the side reaction of while having avoided protecting 7 hydroxyls, 10 hydroxyls also having been protected;
3. in the process of side chain open loop and 7 deprotections, select the mixed solvent of methyl alcohol and tetrahydrofuran (THF), react under 5～25 ℃ of conditions and just can complete in 4～6 hours, the reaction times is shorter, and by product is few;
4. the by product produced in whole synthesis process does not need column purification, only needs simple crystallization can drop in next step reaction, has reduced operation link, has saved production cost;
5. byproduct of reaction is few, and yield is high.
Embodiment
Further illustrate technical scheme of the present invention below by embodiment.
Embodiment 1
The preparation of a, baccatin III (being formula II compound)
Under room temperature, by 300g10-DAB and 30g CeCl
3.7H
2o adds in the 6L tetrahydrofuran (THF), stirs the lower 700mL of dropping diacetyl oxide, the TLC monitoring, after 1.5 hours reaction complete, reaction solution is poured in frozen water standing, when separating out without white particle, suction filtration, drying, obtain formula II compound 305.1g, molar yield is 94.4%; Molar yield=(the theoretical molar weight that generates of the actual generation molar weight of baccatin III/baccatin III) * 100%.
The Structural Identification of gained compound:
LC-MS (ESI): 587.3[M+H]
+, ultimate analysis: C63.46%, H6.52%, O30.02%
The preparation of b, 7-TES-baccatin III (being the formula III compound)
Under room temperature, the 305.1g baccatin III is dissolved in the 1200mL DMF, the imidazoles that adds 152.6g after stirring and dissolving, 275mL chlorotriethyl silane, TLC monitoring, 2.5 after hour, reaction is complete, add the frozen water stopped reaction, use dichloromethane extraction, organic phase is water and saturated common salt water washing respectively, use anhydrous magnesium sulfate drying, suction filtration, concentrating under reduced pressure obtains 7-TES-baccatin III 321.9g, and molar yield is 88.3%; Molar yield=(the theoretical molar weight that generates of the actual generation molar weight of 7-TES-baccatin III/7-TES-baccatin III) * 100%.
The Structural Identification of gained compound:
LC-MS (ESI): 701.3[M+H]
+, ultimate analysis: C63.41%, H7.47%, O25.12%, Si4.00%
The preparation of c, taxol precursor (being formula IV compound)
The 321.9g7-TES-Bakating III is dissolved in to 3.2L N, dinethylformamide, after stirring at room is dissolved, add 177g (4S, 5R)-2,4-phenylbenzene-4,5-dihydro-oxazole-5-carboxylic acid, 9.7g4-Dimethylamino pyridine and 225.3g dicyclohexylcarbodiimide, react end in 2 hours, adds the water stopped reaction, use dichloromethane extraction, organic phase is used respectively 5% hydrochloric acid, saturated sodium bicarbonate solution and saturated common salt water washing, and organic phase adds anhydrous magnesium sulfate drying, suction filtration, concentrating under reduced pressure obtains taxol precursor 411g, and molar yield is 94.2%; Molar yield=(the theoretical molar weight that generates of the actual generation molar weight of taxol precursor/taxol precursor) * 100%.
The Structural Identification of gained compound:
LC-MS (ESI): 950.5[M+H]
+, ultimate analysis: C67.01%, H6.67%, N1.48%, O21.88%, Si2.96%
The preparation of d, taxol
411g taxol precursor is dissolved in the mixed solvent of 3.2L methyl alcohol and 3.5L tetrahydrofuran (THF), add 1.3L1:10 hydrochloric acid (1:10 hydrochloric acid is formulated according to volume ratio 1:10 for be about 37% commercially available concentrated hydrochloric acid and water with mass percent), under 20 ℃ of conditions, stirring reaction added saturated sodium bicarbonate solution after 3.5 hours, continued reaction 1 hour, and reaction solution is poured in the 39.5L frozen water, standing crystallization, filter, drying obtains taxol 335g, and molar yield is 90.7%; Molar yield=(the theoretical molar weight that generates of the actual generation molar weight of taxol/taxol) * 100%.
The Structural Identification of gained compound:
LC-MS (ESI): 854.3[M+H]
+, ultimate analysis: C66.12%, H6.01%, N1.65%, O26.22%.
Embodiment 2
The preparation of a, baccatin III (being formula II compound)
Under room temperature, by 500g10-DAB and 25g CeCl
3.7H
2o adds in the 6L tetrahydrofuran (THF), stirs the lower 1000mL of dropping diacetyl oxide, the TLC monitoring, after 2 hours reaction complete, reaction solution is poured in frozen water standing, when separating out without white particle, suction filtration, drying, obtain Bakating III 495.5g, molar yield is 92.0%; Molar yield=(the theoretical molar weight that generates of the actual generation molar weight of baccatin III/baccatin III) * 100%.
The preparation of b, 7-TES-baccatin III (being the formula III compound)
Under room temperature, the 495.5g baccatin III is dissolved in the 1486mL DMF, the imidazoles that adds 148.7g after stirring and dissolving, 297.3mL chlorotriethyl silane, TLC monitoring, after 3 hours, reaction is complete, add the frozen water stopped reaction, use dichloromethane extraction, organic phase is water and saturated common salt water washing respectively, use anhydrous magnesium sulfate drying, suction filtration, concentrating under reduced pressure obtains 7-TES-baccatin III 531g, and molar yield is 89.7%; Molar yield=(the theoretical molar weight that generates of the actual generation molar weight of 7-TES-baccatin III/7-TES-baccatin III) * 100%.
The preparation of c, taxol precursor (being formula IV compound)
The 531g7-TES-baccatin III is dissolved in to 5.3L N, dinethylformamide, after stirring at room is dissolved, add 265.5g (4S, 5R)-2,4-phenylbenzene-4,5-dihydro-oxazole-5-carboxylic acid, 10.6g4-Dimethylamino pyridine and 265.5g dicyclohexylcarbodiimide, react end in 2.5 hours, adds the water stopped reaction, use dichloromethane extraction, organic phase is used respectively 5% hydrochloric acid, saturated sodium bicarbonate solution and saturated common salt water washing, and organic phase adds anhydrous magnesium sulfate drying, suction filtration, concentrating under reduced pressure obtains taxol precursor 673g, and molar yield is 93.5%; Molar yield=(the theoretical molar weight that generates of the actual generation molar weight of taxol precursor/taxol precursor) * 100%.
The preparation of d, taxol
673g taxol precursor is dissolved in the mixed solvent of 3365mL methyl alcohol and 3365mL tetrahydrofuran (THF), add 2.0L1:10 hydrochloric acid (1:10 hydrochloric acid is formulated according to volume ratio 1:10 for be about 37% commercially available concentrated hydrochloric acid and water with mass percent), under 20 ℃ of conditions, stirring reaction added saturated sodium bicarbonate solution after 4 hours, continued reaction 1 hour, and reaction solution is poured in the 43.6L frozen water, standing crystallization, filter, drying obtains taxol 551.6g, and molar yield is 91.2%; Molar yield=(the theoretical molar weight that generates of the actual generation molar weight of taxol/taxol) * 100%.
Applicant's statement, the present invention illustrates detailed preparation method of the present invention by above-described embodiment, but the present invention is not limited to above-mentioned detailed preparation method, does not mean that the present invention must rely on above-mentioned detailed preparation method and could implement.The person of ordinary skill in the field should understand, any improvement in the present invention, within all dropping on protection scope of the present invention and open scope.
Claims (9)
1. a method for preparing taxol, it comprises the following steps:
(1) at CeCl
3.7H
2under the existence of O, 10 glycoloyl by compound shown in formula I, obtain compound shown in formula II;
(2) 7 hydroxyls of compound shown in formula II are protected with chlorotriethyl silane, obtained compound shown in formula III;
(3) compound shown in formula III and (4S, 5R)-2,4-phenylbenzene-4,5-dihydro-oxazole-5-carboxylic acid obtains compound shown in formula IV through condensation reaction;
(4) by the side chain oxazole ring open loop of compound shown in formula IV, and the tribromo-acetyl protecting group of 7 of simultaneous removings, taxol obtained.
2. method according to claim 1, is characterized in that, in step (1), at CeCl
3.7H
2under the existence of O, compound shown in formula I reacts in tetrahydrofuran (THF) with diacetyl oxide and makes its 10 glycoloyl;
Preferably, compound and CeCl shown in described formula I
3.7H
2the mass ratio of O is 1:(0.05～0.2), 1:0.1 more preferably;
Preferably, in g/ml, the mass volume ratio of compound and diacetyl oxide shown in described formula I is 1:(2.0～5.0), 1:3.0 more preferably;
Preferably, in g/ml, the mass volume ratio of compound and tetrahydrofuran (THF) shown in described formula I is 1:(10～25), 1:15 more preferably;
Preferably, the described reaction times is 1～3 hour, more preferably 2 hours.
3. method according to claim 1 and 2, is characterized in that, the concrete steps of step (1) are: compound shown in formula I is dissolved in tetrahydrofuran (THF), adds CeCl after stirring and dissolving
3.7H
2o, then add diacetyl oxide, stirring at room 1～3 hour, after completion of the reaction, reaction solution is poured in frozen water standing, when separating out without white particle, suction filtration, drying, obtain compound shown in formula II.
4. according to the described method of claim 1-3 any one, it is characterized in that, in step (2), under the existence of imidazoles, compound shown in formula II reacts in DMF with chlorotriethyl silane and its 7 hydroxyls is protected by chlorotriethyl silane;
Preferably, the mass ratio of compound and imidazoles shown in described formula II is 1:(0.3～1.0), 1:0.6 more preferably;
Preferably, in g/ml, the mass volume ratio of compound and chlorotriethyl silane shown in described formula II is 1:(0.6～1.5), 1:1 more preferably;
Preferably, in g/ml, the mass volume ratio of compound and DMF shown in described formula II is 1:(3～10), 1:5 more preferably;
Preferably, the described reaction times is 2～4 hours, more preferably 3 hours.
5. according to the described method of claim 1-4 any one, it is characterized in that, the concrete steps of step (2) are: compound shown in formula II is dissolved in to N, in dinethylformamide, add imidazoles and chlorotriethyl silane after stirring and dissolving, react under room temperature 2～4 hours, react complete, add the frozen water stopped reaction, use dichloromethane extraction, organic phase is water and saturated common salt water washing respectively, uses anhydrous magnesium sulfate drying, suction filtration, concentrating under reduced pressure obtains compound shown in formula III.
6. according to the described method of claim 1-5 any one, it is characterized in that, in step (3), under the existence of DMAP and dicyclohexylcarbodiimide, compound shown in formula III and (4S, 5R)-2,4-phenylbenzene-4, condensation reaction occurs and obtains compound shown in formula IV in 5-dihydro-oxazole-5-carboxylic acid in DMF;
Preferably, the mass ratio of compound and DMAP shown in described III is 1:(0.02～0.05), 1:0.03 more preferably;
Preferably, the mass ratio of compound and dicyclohexylcarbodiimide shown in described formula III is 1:(0.5～1.0), 1:0.7 more preferably;
Preferably, compound shown in described formula III and (4S, 5R)-2,4-phenylbenzene-4, the mass ratio of 5-dihydro-oxazole-5-carboxylic acid is 1:(0.5～0.9), 1:0.8 more preferably;
Preferably, in g/ml, the mass volume ratio of compound and DMF shown in described formula III is 1:(10～25), 1:15 more preferably;
Preferably, the described reaction times is 2～3 hours, more preferably 2.5 hours.
7. according to the described method of claim 1-6 any one, it is characterized in that, the concrete steps of step (3) are: compound shown in formula III is dissolved in to N, dinethylformamide, after stirring at room is dissolved, add (4S, 5R)-2, 4-phenylbenzene-4, 5-dihydro-oxazole-5-carboxylic acid, DMAP and dicyclohexylcarbodiimide, react end in 2～3 hours, add the water stopped reaction, use dichloromethane extraction, organic phase is used respectively 5% hydrochloric acid, saturated sodium bicarbonate solution and saturated common salt water washing, organic phase adds anhydrous magnesium sulfate drying, suction filtration, concentrating under reduced pressure obtains compound shown in formula IV.
8. according to the described method of claim 1-7 any one, it is characterized in that, in step (4), in the mixed solvent of methyl alcohol and tetrahydrofuran (THF), compound shown in formula IV and 1:10 hydrochloric acid reaction be so that the side chain oxazole ring open loop of compound shown in formula IV, after add saturated sodium bicarbonate solution to continue reaction to remove the tribromo-acetyl protecting group of 7; Described 1:10 hydrochloric acid is for commercially available concentrated hydrochloric acid and the water hydrochloric acid soln formulated according to volume ratio 1:10;
Preferably, in g/ml, the mass volume ratio of compound shown in described formula IV and 1:10 hydrochloric acid is 1:(3～4), 1:3.5 more preferably;
Preferably, in g/ml, the mass volume ratio of compound and methyl alcohol shown in described formula IV is 1:(5～15), 1:10 more preferably;
Preferably, in g/ml, the mass volume ratio of compound and tetrahydrofuran (THF) shown in described formula IV is 1:(5～15), 1:10 more preferably;
Preferably, the temperature of described reaction is 5～25 ℃, more preferably 15 ℃;
Preferably, the reaction times of compound shown in formula IV and 1:10 hydrochloric acid reaction is 3～5 hours, more preferably 4 hours;
Preferably, the continuation reaction times that adds saturated sodium bicarbonate solution is 1～2 hour, more preferably 1.5 hours.
9. according to the described method of claim 1-8 any one, it is characterized in that, the concrete steps of step (4) are: compound shown in formula IV is dissolved in the mixed solvent of methyl alcohol and tetrahydrofuran (THF), add 1:10 hydrochloric acid stirring reaction 3～5 hours, then add saturated sodium bicarbonate solution, continue reaction 1～2 hour, reaction solution is poured in the frozen water of 5 times of volumes of reaction solution, standing crystallization, filter, and drying obtains taxol; Described 1:10 hydrochloric acid is for commercially available concentrated hydrochloric acid and the water hydrochloric acid soln formulated according to volume ratio 1:10.
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| CN104251896A (en) * | 2014-09-30 | 2014-12-31 | 江苏红豆杉药业有限公司 | Quality control method of semi-synthetic paclitaxel |
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| CN1571779A (en) * | 2001-10-19 | 2005-01-26 | 因德纳有限公司 | Process for the preparation of the 14beta-hydroxy-baccatin III -1,14-carbonate |
| CN101863862A (en) * | 2010-06-18 | 2010-10-20 | 云南汉德生物技术有限公司 | Method for semi-synthesis of paclitaxel on industrialized basis |
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| CN1571779A (en) * | 2001-10-19 | 2005-01-26 | 因德纳有限公司 | Process for the preparation of the 14beta-hydroxy-baccatin III -1,14-carbonate |
| CN101863862A (en) * | 2010-06-18 | 2010-10-20 | 云南汉德生物技术有限公司 | Method for semi-synthesis of paclitaxel on industrialized basis |
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