CN100417649C - Preparation method of doxytasai - Google Patents
Preparation method of doxytasai Download PDFInfo
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- CN100417649C CN100417649C CNB2006100107930A CN200610010793A CN100417649C CN 100417649 C CN100417649 C CN 100417649C CN B2006100107930 A CNB2006100107930 A CN B2006100107930A CN 200610010793 A CN200610010793 A CN 200610010793A CN 100417649 C CN100417649 C CN 100417649C
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Abstract
The present invention relates to a preparation method of docetaxel, which belongs to the technical field of pharmaceutical synthesis in pharmaceutical chemistry. 1g of 10-deacetyl baccatin III of which the hydroxyl groups at C-7 and C-10 are protected by hydroxyl protection groups is dissolved in 12 ml of pyridinium; 1.0 to 1.2g of tributylphosphane as a catalyst is added into the pyridinium; the mixture is stirred for 20 minutes at the temperature of 10 to 15DEG C; 10 ml of pyridinium solution containing 2.5g of side-chain precursor of racemic beta-lactam docetaxel is added into the mixture for reaction at the temperature of 15 to 20DEG C for 3 to 6 hours; after the reaction is finished, 20 ml of 1 mol/L of hydrochloric acid is added for stopping the reaction; a crude product solution of a docetaxel intermediate is obtained; the solution is concentrated and is purified by a column chromatography method; the unreacted side-chain precursor of racemic beta-lactam docetaxel is recovered for use in the next reaction; then, after the crude product of docetaxel is hydrolyzed and recrystallized, docetaxel of which the purity is over 99% is obtained. The present invention has the advantages of simple synthesis technology, high yield, mild reaction condition, low toxicity of used reagents, low production cost, easy realization of industrial production, etc.
Description
Technical field:
The invention belongs to the technical field of medicine synthesis in the pharmaceutical chemistry, be specifically related to the method for the preparation of anticancer bulk drug docetaxel.
Background technology:
The docetaxel chemistry is by name: [2aR-(2a α, 4 β, 4a β, 6 β, 9 α, (aR*, β S*), 11 α, 12 α, 12a α, 12b α)]-β-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-Alpha-hydroxy phenylpropionic acid [12b-acetyl oxygen-12-benzoyl oxygen-2a, 3,4,4a, 5,6,9,10,11,12,12a, 12b-ten dihydros-4,6,11-trihydroxy--4a, 8,13,13-tetramethyl--5-oxo-7,11-methylene radical-1H-ring pentaene in the last of the ten Heavenly stems is benzo [1,2-b] oxa-fourth ring-9-yl also-[3,4]] ester.Molecular weight: 807.89, CAS No.:114977-28-5, molecular formula is: C
43H
53NO
14Structural formula is
Docetaxel (Docetaxel) is on the architecture basics of natural antitumor drug taxol, a kind of new antitumor drug that obtains after the artificial structure modifies.Docetaxel is the taxanes antitumour drug, plays antitumor action by interference cell mitotic division and the necessary microtubule network of interkinesis cell function.Because its solubility property is better than taxol, so drug effect is stronger than taxol.Invisible spectro studies show that, at people's mammary gland, colon, bladder and epithelioid cell strain, its IC50 is lower 9 times than taxol., the high resistance tumor promotion is arranged in vivo, mouse tumour and mouse transplanting tumor can disappear fully after the medication.The more important thing is that docetaxel can spontaneously not produce cross resistance to docetaxel to the cell strain of taxol resistance.Clinical studies show, this medicine is to controlling the transitivity breast cancer patient who resists with the anthracene nucleus class initially, again, and the overall average of single use docetaxel is efficient to be respectively 59%, 43% and 37%.At present, state food and drug administration approval docetaxel is used for the treatment of late period of chemotherapy failure in advance or metastatic breast cancer and the late period of failing based on the chemotherapy of cis-platinum or the treatment of transitivity nonsmall-cell lung cancer.
According to relevant bibliographical information, the preparation docetaxel mainly adopts straight chain, side chain, the ring-like side chain of thiazolidine and beta-lactam type side chain three class synthetic methods.Have following deficiency in the aforesaid method: the straight chain of a. racemization carries out esterification with the 10-DAB that is with blocking group and has significant limitation, not only needs very harsh reaction conditions, and the transformation efficiency of reaction is low, can form the epi-position isomerate of C-2 '; B. thiazolidine type side chain exists the quality yield not high, long reaction time, and severe reaction conditions, the reagent of use is more and toxicity is big, problems such as synthesis step complexity.
Chinese patent CN95193482.1, CN95193480.5, CN95195914.X, CN96192946.4, CN96192886.7, CN96192884.0, CN97192042.7, CN96199168.2 disclose the method for manufacturer An Wante with 10-DAB and the synthetic docetaxel of the ring-like side chain reaction of thiazolidine.Repeated experiments through the inventor finds that this synthesis technique quality exists yield not high, long reaction time, and severe reaction conditions, the reagent of use is more and toxicity is big, and production cost is higher, is difficult for realizing problems such as suitability for industrialized production.
Summary of the invention:
The objective of the invention is to overcome the deficiency of prior art, and provide a kind of synthesis technique simple, yield height, the preparation method of the docetaxel that production cost is low.
Preparation method of the present invention is made up of purifying and recovery, hydrolysis reaction and the recrystallization operation of esterification, intermediate, wherein:
1, esterification: the 10-deacetyl baccatin III (as Fig. 1) that 1 gram C-7 position and C-10 position hydroxyl protected by hydroxyl protecting group is dissolved in the 12ml pyridine, tributylphosphine (production of the Arcos company) catalyzer that adds the 1.0-1.2 gram, under the 10-15 degrees celsius, stirred 20 minutes, add again and contain the beta-lactam type docetaxel side chain precursor of racemization (as Fig. 2, buy on the market) the 2.5 10ml pyridine solutions that restrain, reaction is 3-6 hour under the 15-20 degrees celsius, react the hydrochloric acid termination reaction that adds the 1mol/L of 20ml after finishing, get the crude product solution of intermediate (as Fig. 3);
2, the purifying of intermediate and recovery: with solution concentration, carry out purifying and recovery with column chromatography, reclaim the intact beta-lactam type docetaxel side chain precursor (as Fig. 4) of unreacted, when descending secondary response, the intact racemization side chain precursor conduct of unreacted uses, during following secondary response, the charging capacity of racemization side chain precursor increases to 4 grams;
3. hydrolysis reaction: with back docetaxel synthetic intermediate 1 gram (as Fig. 3), add 2 gram zinc powders, 15ml Glacial acetic acid and 7ml water, under 55 degrees celsius stirring reaction 4-6 hour;
4, the recrystallization of docetaxel crude product: with docetaxel crude product column chromatography purifying, the pure product of Fractional Collections, impure part is crossed post again, concentrate the cut of pure product dried, dissolve under 40 degrees celsius with ethyl acetate, freezing crystallization 2-4 hour, suction filtration, with purified water washing leaching cake 3 times, promptly obtain purity and be the docetaxel more than 99%.
The docetaxel that the inventive method obtains, through infared spectrum (IR), uv-spectrogram (UV), high performance liquid phase (HPLC) detects, the docetaxel collection of illustrative plates that this method is prepared is consistent with the docetaxel reagent collection of illustrative plates of buying from Sigma company, proves that the product of this method preparation is a docetaxel.
Part operation of the inventive method and the same prior art of operational condition.In addition, adopt racemization beta-lactam type docetaxel side chain, with carrying out esterification under the catalysis of efficient catalyst tributylphosphine, Stereoselective obtains the product of C-13 esterification, and reaction generates the ratio of isomer less than 2%.Reaction yield is more than 80%.Simultaneously, the beta-lactam type side chain with the excessive racemization type that feeds intake reclaims by the method for column chromatography once more to the intact part of unreacted.
It is simple that method of the present invention has a synthesis technique, the yield height, and the reaction conditions gentleness, the reagent toxicity of use is low, production cost is low, easily realizes advantages such as suitability for industrialized production.
Description of drawings:
The structural formula of the 10-deacetyl baccatin III that Fig. 1 is protected by hydroxyl protecting group for C-7 position and C-10 position hydroxyl.
Fig. 2 is the structural formula of the beta-lactam type docetaxel side chain precursor of racemization.
Fig. 3 is the structural formula of the intact docetaxel intermediate of esterification.
Fig. 4 is for reclaiming the structural formula of the intact beta-lactam type docetaxel side chain precursor of unreacted.
Embodiment:
Part operation of the inventive method and the same prior art of operational condition.
Embodiment 1:
The 10-DAB (10-deacetyl baccatin III such as Fig. 1) that 1 gram C-7 position and C-10 position hydroxyl protected by the triethylchloro-silicane alkyl; be dissolved in the 12ml pyridine; add catalyzer 1.2 gram tributylphosphines again; under 10 degrees celsius, stirred 20 minutes; slowly add the 10ml pyridine solution that contains racemization lactan type docetaxel side chain precursor (as Fig. 2) 2.5 grams with constant pressure funnel, controlled temperature reacted 3 hours under 20 degrees celsius.Reacted the 1mol/L hydrochloric acid soln termination reaction of back adding 20ml.The methylene dichloride that adds 200ml afterwards is fully mixed, and organic phase adds the salt pickling of the 1mol/L of 200ml and arrives acidity, uses the saturated NaHCO of 200ml again
3Wash alkalescence, wash pH=7 with 200ml afterwards.
After the extracting and washing, organic phase adds the anhydrous magnesium sulfate drying of 30 grams, and 40 degrees centigrade are evaporated to dried.Carry out purifying with column chromatography again, use the glass silicagel column of 2 * 20cm, silica gel order number is 300 orders, wet method upper prop, gradient elution.Use volume ratio acetone: hexanaphthene=1: 70 intact beta-lactam type docetaxel side chain precursor (as Fig. 4) of wash-out unreacted, use TLC to detect cut.Treat the intact back use of side chain wash-out acetone: hexanaphthene=1: 6 wash-out intermediate.The intact racemization side chain precursor (as Fig. 4) of unreacted uses during as secondary response down, and during following secondary response, the charging capacity of racemization side chain precursor increases to 4 grams.Obtain the intact beta-lactam type docetaxel side chain precursor of unreacted 1 gram through column chromatography, docetaxel intermediate 0.96 gram.
With back docetaxel synthetic intermediate (as Fig. 3) 1 gram, add 2 gram zinc powders, 15ml Glacial acetic acid and 7ml water, stirring reaction is 4 hours under 55 degrees celsius.Afterwards product is used the column chromatography purifying, the eluent proportioning is the volume ratio methylene dichloride: hexanaphthene=6: 4, the pure product of Fractional Collections, use TLC to detect cut, impure part (purity is lower than 98%) goes up column purification again, and the cut of pure product is concentrated dried, dissolve under 40 degrees celsius with ethyl acetate, freezing crystallization 2 hours, suction filtration is used purified water washing leaching cake 3 times.Can obtain purity like this and be docetaxel 0.44 gram more than 99%.
Embodiment 2:
The 10-DAB (10-deacetyl baccatin III such as Fig. 1) that 1 gram C-7 position and C-10 position hydroxyl protected by the triethylchloro-silicane alkyl; be dissolved in the 12ml pyridine; add catalyzer 1.1 gram tributylphosphines again; under 12 degrees celsius, stirred 20 minutes; slowly add the 10ml pyridine solution that contains racemization lactan type docetaxel side chain precursor (as Fig. 2) 2.5 grams with constant pressure funnel, controlled temperature reacted 5 hours under 18 degrees celsius.Reacted the 1mol/L hydrochloric acid soln termination reaction of back adding 20ml.The methylene dichloride that adds 200ml afterwards is fully mixed, and organic phase adds the salt pickling of the 1mol/L of 200ml and arrives acidity, uses the saturated NaHCO of 200ml again
3Wash alkalescence, wash pH=7 with 200ml afterwards.After the extracting and washing, organic phase adds the anhydrous magnesium sulfate drying of 30 grams, and 40 degrees centigrade are evaporated to dried.Carry out purifying with column chromatography again, use the glass silicagel column of 2 * 20cm, silica gel order number is 400 orders, wet method upper prop, gradient elution.Use volume ratio acetone: hexanaphthene=1: 70 intact beta-lactam type docetaxel side chain precursor (as figure) of wash-out unreacted, use TLC to detect cut.Treat the intact back use of side chain wash-out acetone: hexanaphthene=1: 6 wash-out intermediate.The intact racemization side chain precursor (as Fig. 4) of unreacted uses during as secondary response down, and during following secondary response, the charging capacity of racemization side chain precursor increases to 4 grams.Obtain the intact beta-lactam type docetaxel side chain precursor of unreacted 1 gram through column chromatography, docetaxel intermediate 0.96 gram.
With back docetaxel synthetic intermediate (as Fig. 3) 1 gram, add 2 gram zinc powders, 15ml Glacial acetic acid and 7ml water, stirring reaction is 5 hours under 55 degrees celsius.Afterwards product is used the column chromatography purifying, the eluent proportioning is the volume ratio methylene dichloride: hexanaphthene=6: 4, the pure product of Fractional Collections, use TLC to detect cut, impure part (purity is lower than 98%) goes up column purification again, and the cut of pure product is concentrated dried, dissolve under 40 degrees celsius with ethyl acetate, freezing crystallization 4 hours, suction filtration is used purified water washing leaching cake 3 times.Can obtain purity like this and be docetaxel 0.43 gram more than 99%.
Embodiment 3:
The 10-DAB (10-deacetyl baccatin III such as Fig. 1) that 1 gram C-7 position and C-10 position hydroxyl protected by the triethylchloro-silicane alkyl; be dissolved in the 12ml pyridine; add catalyzer 1.0 gram tributylphosphines again; under 15 degrees celsius, stirred 20 minutes; slowly add the 10ml pyridine solution that contains racemization lactan type docetaxel side chain precursor (as Fig. 2) 2.5 grams with constant pressure funnel, controlled temperature reacted 6 hours under 15 degrees celsius.Reacted the 1mol/L hydrochloric acid soln termination reaction of back adding 20ml.The methylene dichloride that adds 200ml afterwards is fully mixed, and organic phase adds the salt pickling of the 1mol/L of 200ml and arrives acidity, uses the saturated NaHCO of 200ml again
3Wash alkalescence, wash pH=7 with 200ml afterwards.After the extracting and washing, organic phase adds the anhydrous magnesium sulfate drying of 30 grams, and 40 degrees centigrade are evaporated to dried.Carry out purifying with column chromatography again, use the glass silicagel column of 2 * 20cm, silica gel order number is 400 orders, wet method upper prop, gradient elution.Use volume ratio acetone: hexanaphthene=1: 70 intact beta-lactam type docetaxel side chain precursor (as figure) of wash-out unreacted, use TLC to detect cut.Treat the intact back use of side chain wash-out acetone: hexanaphthene=1: 6 wash-out intermediate.The intact racemization side chain precursor of unreacted uses during as secondary response down, and during following secondary response, the charging capacity of racemization side chain precursor increases to 4 grams.Obtain the intact beta-lactam type docetaxel side chain precursor of unreacted 1 gram through column chromatography, docetaxel intermediate 0.96 gram.
With back docetaxel synthetic intermediate 1 gram, add 2 gram zinc powders, 15ml Glacial acetic acid and 7ml water, stirring reaction is 6 hours under 55 degrees celsius.Afterwards product is used the column chromatography purifying, the eluent proportioning is the volume ratio methylene dichloride: hexanaphthene=6: 4, the pure product of Fractional Collections, use TLC to detect cut, impure part (purity is lower than 98%) goes up column purification again, and the cut of pure product is concentrated dried, dissolve under 40 degrees celsius with ethyl acetate, during freezing crystallization 3, suction filtration is with purified water washing leaching cake 3 times.Can obtain purity like this and be docetaxel 0.42 gram more than 99%.
Claims (1)
1. the preparation method of a docetaxel comprises purifying, hydrolysis reaction and the recrystallization operation of esterification, intermediate it is characterized in that this preparation method also comprises the recovery process of intermediate; Wherein:
A. esterification: the 10-deacetyl baccatin III that 1 gram C-7 position and C-10 position hydroxyl are protected by hydroxyl protecting group is dissolved in the 12ml pyridine, the tributylphosphine catalyzer that adds the 1.0-1.2 gram, under the 10-15 degrees celsius, stirred 20 minutes, the 10ml pyridine solution that adds beta-lactam type docetaxel side chain precursor 2.5 grams that contain racemization again, reaction is 3-6 hour under the 15-20 degrees celsius, react the hydrochloric acid termination reaction that adds the 1mol/L of 20ml after finishing, obtain the crude product solution of docetaxel intermediate;
B. the purifying of intermediate and recovery: with solution concentration, carry out purifying and reclaim the intact beta-lactam type docetaxel side chain precursor of unreacted with column chromatography, the intact racemization side chain precursor of unreacted uses during as secondary response down, and during following secondary response, the charging capacity of racemization side chain precursor increases to 4 grams;
The chemical structural formula of the beta-lactam type docetaxel side chain precursor that c. above-mentioned a and b stated is:
D. hydrolysis reaction: with back docetaxel synthetic intermediate 1 gram, add 2 gram zinc powders, 15ml Glacial acetic acid and 7ml water, under 55 degrees celsius stirring reaction 4-6 hour;
E. the recrystallization of docetaxel crude product: crude product column chromatography purifying, the pure product of Fractional Collections, purity is lower than 98% part and crosses post again, concentrate the cut of pure product dried, dissolve under 40 degrees celsius with ethyl acetate ,-20 degrees centigrade freezing crystallization 2-4 hour, suction filtration, with purified water washing leaching cake 3 times, promptly obtain purity and be the docetaxel more than 99%.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103012328A (en) * | 2011-09-23 | 2013-04-03 | 复旦大学 | Method for preparing second-generation taxol anticancer drug Cabazitaxel |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US8791279B2 (en) * | 2010-12-13 | 2014-07-29 | Yung Shin Pharm. Ind. Co., Ltd. | Process for preparing taxoids from baccatin derivatives using lewis acid catalyst |
| CN113563288A (en) * | 2021-08-27 | 2021-10-29 | 常熟纳微生物科技有限公司 | Separation and purification method of docetaxel |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4814470A (en) * | 1986-07-17 | 1989-03-21 | Rhone-Poulenc Sante | Taxol derivatives, their preparation and pharmaceutical compositions containing them |
| US5739359A (en) * | 1997-01-24 | 1998-04-14 | Virginia Tech Intellectual Properties, Inc. | Methods for preparing 1-deoxy paclitaxels |
| WO1999054322A1 (en) * | 1998-04-20 | 1999-10-28 | Lolita Zamir | The semi-synthesis of baccatin iii |
| US20050288520A1 (en) * | 2004-06-25 | 2005-12-29 | Phytogen Life Sciences Inc. | One pot synthesis of taxane derivatives and their conversion to paclitaxel and docetaxel |
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2006
- 2006-04-05 CN CNB2006100107930A patent/CN100417649C/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4814470A (en) * | 1986-07-17 | 1989-03-21 | Rhone-Poulenc Sante | Taxol derivatives, their preparation and pharmaceutical compositions containing them |
| US5739359A (en) * | 1997-01-24 | 1998-04-14 | Virginia Tech Intellectual Properties, Inc. | Methods for preparing 1-deoxy paclitaxels |
| WO1999054322A1 (en) * | 1998-04-20 | 1999-10-28 | Lolita Zamir | The semi-synthesis of baccatin iii |
| US20050288520A1 (en) * | 2004-06-25 | 2005-12-29 | Phytogen Life Sciences Inc. | One pot synthesis of taxane derivatives and their conversion to paclitaxel and docetaxel |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103012328A (en) * | 2011-09-23 | 2013-04-03 | 复旦大学 | Method for preparing second-generation taxol anticancer drug Cabazitaxel |
| CN103012328B (en) * | 2011-09-23 | 2015-03-04 | 复旦大学 | Method for preparing second-generation taxol anticancer drug Cabazitaxel |
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