CN102887876B - A kind of semisynthesis of Docetaxel of improvement - Google Patents
A kind of semisynthesis of Docetaxel of improvement Download PDFInfo
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- CN102887876B CN102887876B CN201210033115.1A CN201210033115A CN102887876B CN 102887876 B CN102887876 B CN 102887876B CN 201210033115 A CN201210033115 A CN 201210033115A CN 102887876 B CN102887876 B CN 102887876B
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- RPUSRLKKXPQSGP-UHFFFAOYSA-N COC(CCc1ccccc1)=O Chemical compound COC(CCc1ccccc1)=O RPUSRLKKXPQSGP-UHFFFAOYSA-N 0.000 description 1
- NMPPJJIBQQCOOI-SECBINFHSA-N COC([C@@H](Cc1ccccc1)O)=O Chemical compound COC([C@@H](Cc1ccccc1)O)=O NMPPJJIBQQCOOI-SECBINFHSA-N 0.000 description 1
- XNYAYZKPDARAIN-VUHGHZMFSA-N COC([C@@H]1OC(C(Br)(Br)Br)N[C@H]1c1ccccc1)=O Chemical compound COC([C@@H]1OC(C(Br)(Br)Br)N[C@H]1c1ccccc1)=O XNYAYZKPDARAIN-VUHGHZMFSA-N 0.000 description 1
- 0 COC([C@@]1O*N[C@]1c1ccccc1)=O Chemical compound COC([C@@]1O*N[C@]1c1ccccc1)=O 0.000 description 1
- YPUFMQSUFUJSDR-JGVFFNPUSA-N OC([C@@H]([C@H](c1ccccc1)N1)O/C1=S\C(Br)(Br)Br)=O Chemical compound OC([C@@H]([C@H](c1ccccc1)N1)O/C1=S\C(Br)(Br)Br)=O YPUFMQSUFUJSDR-JGVFFNPUSA-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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a kind of semisynthesis of Docetaxel of improvement.The present invention is with 10-deacetylation bar card fourth III for starting raw material, and first by the hydroxyl protection by 7-position and 10-position, then introduce light in its 13-position and revolve side chain synthetic intermediate, finally hydrolysis obtains target product Docetaxel.The synthesis of side chain instead should obtain oxazole woods intermediate by (2R, 3S)-3-phenylisoserine methyl ester and tribromoacetaldehyde, more obtained through being hydrolyzed.Preparation method's synthesis step of the present invention is simple, and side reaction is few, and productive rate is high, isomer-free by product, and foreign matter content is low, and high yield high purity, reduces cost greatly, therefore, it is possible to promote the business preparation of Docetaxel.This, for protection Chinese yew species and resource, reduction oncotherapy expense etc., all has very important meaning and huge economic benefit.
Description
Technical field
The present invention relates to a kind of semisynthesis of Docetaxel of improvement; specifically; relate to a kind of synthesis of Docetaxel side chain and female ring 10-deacetylate bar card fourth III (10-DAB) is modified, then female ring and side chain generation condensation thus obtain Docetaxel.
Background technology
Taxol (Taxol) is a kind of natural organic-compound by Chinese yew genus plants bark or needle separation and Extraction, 1963, Americanized scholar Wall (MonreE.Wall) and Wani (M.C.Wani) were separated to the crude extract of taxol first from peaceful red deal (PacificYew) bark and timber.In screening experiment, Wani and Wall finds that the mouse tumour cell of taxol crude extract to isolated culture has very high reactivity, and starts to be separated this active ingredient, and determining taxol in 1969 is activeconstituents wherein.Because this active ingredient content in plant is extremely low, until (J.Am.Chem.Soc. in 1971,1971,93,2325), chemistry professor Mu Kefaer (AndreT.McPhail) cooperation of their ability same Du Ke (Duke) university, determines the chemical structure-tetracyclic diterpene compound of this active ingredient by x-ray analysis, and its called after taxol (Taxol).1972, Schiff (Nature, 1979,277,665) etc. confirmed unique pharmacology mechanism that taxol acts on tumour cell tubulin; Taxol promotes tubulin polymerization, stops cell mitogen, and Tumor suppression grows.1992, taxol was approved listing by U.S. FDA, and treated the invalid ovarian cancer of conventional chemotherapy and mammary cancer.
The content of taxol in bark of Ramulus et folium taxi cuspidatae is only ten thousand/, the taxol used in amounts of a course for the treatment of an of cancer patient is extracted and is obtained from three to five century-old raw bark of Ramulus et folium taxi cuspidatae, and therefore, taxol drug is always short and hold at high price.Further, Taxus is in rare and endangered tree species, and resource scarcity, distributes sparse, seldom grow into forest, and the poor growth whole world only has 11 kinds, and population density is little, and self-reproduction degree is low.Obtain enough taxols for clinical application and fundamental research, rely on merely and extract and certainly will bring great threat to the existence of Chinese yew genus plants from natural phant.In addition, the poly-ethoxy of taxol medicine preparation employing as solubilizing agent, easily causes anaphylaxis when clinical application for Viscotrol C.In order to expand taxanes bulk drug source; reduce clinical application expense; meet the needs of oncotherapy, fundamentally effectively protect Chinese yew not to be exterminated, the novel taxane series antineoplastic medicament that high reactivity low toxicity was explored and developed to employing chemosynthesis means is imperative simultaneously.
Taxane substances is because of its complex structure, and by the restriction of the factor such as polyfunctional group and multichiral center, complete synthesis route is complicated, yield is low, cost is too high, and artificial semisynthesis is the most effective chemical process obtaining taxane substances at present.10-deacetylate bar card fourth III (10-deacetylbaccatinIII; be called for short 10-DAB) be a by product of industrial extraction taxol; it is found that afterwards, its content in Ramulus et folium taxi cuspidatae, up to thousandth, is 10 times of content of taxol.1985, French Rhone-Poulenc Rorer and French National Natural Science research centre, using 10-DAB as parent nucleus skeleton, manually semi-synthetic Docetaxel (Docetaxol).Docetaxel is the bearing taxanes of a class formation complexity, and its constructional feature is similar to taxol, and its difference is only that the acetoxyl group on taxol parent nucleus C-10 is optionally substituted by a hydroxyl group, and the benzoyl on C-13 side chain N is replaced by tertbutyloxycarbonyl.Structural characteristic is most important for the In Vitro Anti tubulin activity of Docetaxel: it is 2 times of taxol to the avidity of microtubule combining site; As microtubule stabilizer and assembling promotor, large 2 times of specific activity taxol; In anti-tumor activity in vitro tests, confirmed that Docetaxel activity is 1.3 ~ 12 times of taxol, and toxic side effect is little, water-soluble increase makes it easily make preparation.After nineteen ninety-five Docetaxel injection Initial Public Offering, more than 40, country's listing uses the line medication becoming oncotherapy at present.Within 2003, Docetaxel patent medicine has exceeded taxol first in global marketing, and Docetaxel is one of current broad spectrum anticancer medicine the most excellent in the world, and the market requirement increases day by day.To the study on the synthesis of Docetaxel and applied research very valuable.
The route that current synthesis Docetaxel is extensively taked is for side chain with straight chain isoserine side chain and tetra-atomic ring azetidinone, dock with parent nucleus and prepare Docetaxel, but there is various shortcoming, as: step is many, and condition is harsh, experimental implementation difficulty is large, chiral separation difficulty, product cost is high, intermediate is unstable, and product is difficult to depositing of separation and purification etc., is difficult to the demand adapting to suitability for industrialized production.Therefore, the method preparing Docetaxel of new improvement is still needed.The present invention is intended to overcome the problems referred to above; with the cheapness of applicable suitability for industrialized production and brief reaction scheme, mild condition prepare Docetaxel; this is for protection Chinese yew species resource; maintain human kind sustainable development; reduce Docetaxel price and oncotherapy expense, all there is important social effect and economic worth.
Summary of the invention
In order to avoid the existing shortcoming preparing Docetaxel technique; reduce synthesis step; remove isomer impurities; improve reaction conditions; reduce side reaction to produce, reduce the content of impurity, improve the utilization ratio of main raw material 10-deacetylation bar card fourth III; reduce costs, we have invented a kind of Docetaxel synthetic method of improvement.Technical scheme of the present invention is as follows:
1. the synthesis of side chain:
Toluene or dimethylbenzene or DMF are solvent, and (2R, 3S)-3-phenylisoserine methyl ester and tribromoacetaldehyde generate Ti oxazoline 2 between Zhong under tosic acid pyridinium salt or Catalyzed by p-Toluenesulfonic Acid agent catalysis; Intermediate 2 obtains the side chain 3 for the preparation of Docetaxel through hydrolysis of ester group in the methanol aqueous solution of lithium hydroxide or sodium hydroxide or potassium hydroxide.
2. the synthesis of Docetaxel:
The synthesis of Docetaxel comprises parent nucleus protection, condensation, open loop, side-chain amino group protection, hydrolysis five steps:
Protection Step II I: at anhydrous and oxygen-free and under nitrogen or argon shield; in the pyridine of compound 4 or methylene dichloride or DMF solution; trichoroacetic chloride is added under ice bath; under the organic bases such as pyridine or triethylamine condition;-5 DEG C ~ 25 DEG C reactions; TLC detects after raw material disappears and to go out reaction with shrend, and aftertreatment purifying obtains compound 5.
Condensation step IV: under anhydrous and oxygen-free environment, compound 5 and side chain 3 are under the organic bases conditions such as N, N-dimethyl aminopyridine or pyridine, and 1,3-dicyclohexyl carbodiimide or dipropyl carbonate exist lower generation condensation reaction and obtain compound 6;
Open loop step V and side-chain amino group protection step VI: compound 6 under formic acid or acetic acid or phenylformic acid or oxalic acid or dilute hydrochloric acid condition, the open loop of C-13 oxazole side chain occurs and obtains intermediate 7, then reacts to obtain the intermediate 8 protected of side-chain amino group under alkaline conditions with tert-Butyl dicarbonate;
Hydrolysing step VII: intermediate 8 is sloughed 7-OH and 10-OH blocking group at ammonia or ammonium hydroxide or ammonium acetate or inorganic ammonium salt Water Under solution and can obtain target product Docetaxel (Docetaxel).
Beneficial effect
The preparation method of Docetaxel of the present invention, had both overcome light and had revolved the many shortcomings of side chain reactions steps, solved again the problem that racemization side chain has isomer impurities.Concrete advantage is as follows:
(1) the present invention is with (2R, 3S)-3-phenylisoserine methyl ester and tribromoacetaldehyde are the side chain of Material synthesis Docetaxel, compare side chain (4S, 5R)-2-trichloromethyl-4-phenyl-5-carboxyl-1, the synthesis of 3-oxazolidine, side chain synthesis yield exceeds almost ten percentage points: side chain (4S in the present invention, 5R)-2-trisbromomethyl-4-phenyl-5-carboxyl-1, the synthetic yield of 3-oxazolidine is 89%, side chain (4S in publication KR101032761B, 5R)-2-trichloromethyl-4-phenyl-5-carboxyl-1, the synthetic yield of 3-oxazolidine is 81%.Change C-2 substituting group into trisbromomethyl by trichloromethyl, same experimental conditions, productive rate significantly improves, and this effect is not conventional can be expected.
(2) the present invention is with (4S, 5R)-2-trisbromomethyl-4-phenyl-5-carboxyl-1, 3-oxazolidine is side chain, tribromo-acetyl base protection parent nucleus 7-OH and 10-OH, be prepared into Docetaxel, total recovery is 82%, high purity 99.6%, by changing side chain substituents and parent nucleus protecting group, overall yield compares similar technique KR101032761B (with (4S, 5R)-2-trichloromethyl-4-phenyl-5-carboxyl-1, 3-oxazolidine is side chain, three acetyl bromide protection parent nucleus 7-OH and 10-OH, yield 72%, purity 99.4%) total recovery exceeds ten percentage points, purity is also significantly improved, great amount of cost is saved in production for Docetaxel, bring obvious competitive edge.This beneficial effect is also conventional can not be expected.
(3) preparation method of this patent disclosed synthesis Docetaxel, often step reaction is all simple to operate, and mild condition, reagent low toxicity, aftertreatment is easy, is easy to industrialization.
Embodiment
Following examples are only used for further illustrating the present invention, but do not mean any limitation of the invention.
Embodiment 1
In the round-bottomed flask of 25mL, (2R, 3S)-3-phenylisoserine methyl ester (1.0g, 5.1mmol) be dissolved in toluene, add the tosic acid pyridinium salt of tribromoacetaldehyde (1.57g, 5.6mmol) and catalytic amount, oil bath 120 DEG C, stir 2 hours, TLC detects, and raw material disappears, stopped reaction, decompression removing toluene, column chromatography purification (sherwood oil: ethyl acetate=5: 1) obtain product 2:2.29g, productive rate 98%.
(4S, 5R)-2-trichloromethyl-4-phenyl-5-carboxyl-1,3-oxazolidine: ESI-MSm/z:455.8454 [M+H]
+;
1h-NMR (400MHz, CDCl
3): δ 7.52 (d, 2H), 7.51-7.32 (m, 3H), 5.47 (d, 1H), 4.71 (s, 1H), 4.70 (d, 1H), 3.76 (s, 3H).
Embodiment 2
By compound 2 (457.9mg, 1.0mmol) be dissolved in 4.5mL alcohol-water (8: 1), drop into lithium hydroxide (71.8mg, 3.0mmol), stirring at room temperature 3h, decompression takes methanol solvate away, 2N hcl acidifying, extraction into ethyl acetate, anhydrous sodium sulfate drying, filter, underpressure distillation obtains compound 3:403.9mg, productive rate 91%.
(4S, 5R)-2-trichloromethyl-4-phenyl-5-carboxyl-1,3-oxazolidine: ESI-MSm/z:441.8309 [M+H]
+;
1h-NMR (400MHz, DMSO): δ 7.60 (d, 2H), 7.36-7.25 (m, 3H), 5.42 (s, 1H), 5.39 (s, 1H), 4.94-4.90 (m, 1H), 4.63-4.59 (m, 2H), 4.34 (d, 1H).
Embodiment 3
By 10-DAB (544.6mg; 1mmol) be dissolved in 5mL anhydrous pyridine; nitrogen protection, under cryosel bath condition, slowly drips trichoroacetic chloride (600.0mg; 3.3mmol); temperature controls, at subzero 5 degree, after trichoroacetic chloride dropwises, to be naturally raised to room temperature; TLC detects; after 1.5h, raw material disappears, and under condition of ice bath, agitation and dropping is as deionized water; extraction into ethyl acetate; anhydrous sodium sulfate drying, filters, and decompression steams solvent; column chromatography obtains compound 5:1.08g, productive rate 96%.
1H-NMR(400MHz，CDCl
3)：δ7.67(t，2H)，7.60(t，1H)，7.47(t，2H)，6.27(s，1H)，5.66-5.60(m，2H)，4.99(d，1H)，4.92(d，1H)，4.60(d，1H)，4.32(d，1H)，4.15(d，1H)，3.98(d，1H)，2.64-2.62(m，1H)，2.30(s，3H)，2.16(s，3H)，2.15-1.86(m，2H)，1.84(s，3H)，1.14(s，3H)，1.11(s，3H).
Embodiment 4
By compound 5 (1.13g, 1mmol) and compound 3 (577.1mg, 1.3mmol), be dissolved in toluene, under stirring, add 1,3-dicyclohexyl carbodiimide (123.7mg, 1.6mmol) and N, N-Dimethylamino pyridine (61.0mg, 0.5mmol), react at 80 DEG C, TLC detects, and reacts completely after 2 hours, pressure reducing and steaming toluene, column chromatography purification (sherwood oil: ethyl acetate=5: 1) obtain product 6:1.24g, productive rate 98%.
1H-NMR(400MHz，CDCl
3)：δ8.04(d，2H)，7.64(t，1H)，7.50(t，2H)，7.40-7.35(m，5H)，6.28(t，1H)，6.25(s，1H)，5.66(d，1H)，5.57(q，2H)，4.90(d，2H)，4.78(brd，1H)，4.60(d，1H)，4.48(d，1H)，4.15(d，1H)，4.28(d，1H)，4.12(d，1H)，3.89(d，1H)，2.64-2.58(m，1H)，2.21-2.18(m，1H)，2.05(s，3H)，1.95(s，3H)，1.76(s，3H)，1.26(s，3H)，1.18(s，3H).
Embodiment 5
By compound 6 (1.26g, 1mmol), be dissolved in 10mL formic acid solution, stirred at ambient temperature, TLC follows the tracks of, and 2 as a child reacted completely, and pressurization steaming desolventizes, and column chromatography purification obtains compound 7:948.6mg, productive rate 95%.
1H-NMR(400MHz，CDCl
3)：δ8.05(d，2H)，7.66(t，1H)，7.52(t，2H)，7.44-7.35(m，4H)，7.22-7.28(m，1H)，6.22(s，1H)，6.14(t，1H)，5.64(d，1H)，5.55(q，1H)，4.94-4.90(m，2H)，4.58(d，1H)，4.37-4.26(m，2H)，4.15-4.09(d，2H)，3.85(d，1H)，2.61-2.58(m，2H)，2.18(s，3H)，2.01(s，3H)，1.83(s，3H)，1.23(s，3H)，1.10(s，3H).
Embodiment 6
Compound 7 (998.5mg, 1mmol) and tert-Butyl dicarbonate (262.3mg, 1.2mmol) are dissolved in dry tetrahydrofuran solution, then anhydrous sodium carbonate (255mg, 3.0mmol) is added, stirred at ambient temperature, TLC follows the tracks of, and reacts completely after 4h, extraction into ethyl acetate, water, saturated common salt water washing respectively, anhydrous sodium sulfate drying, filters, and filtrate decompression is distilled, column chromatography purification obtains compound 8:1.02g, productive rate 93%.
1H-NMR(400MHz，CDCl
3)：δ8.05(d，2H)，7.66(t，1H)，7.52(t，2H)，7.44-7.35(m，4H)，7.22-7.28(m，1H)，6.22(s，1H)，6.14(t，1H)，5.64(d，1H)，5.55(q，1H)，4.94-4.90(m，2H)，4.58(d，1H)，4.37-4.26(m，2H)，4.15-4.09(d，2H)，3.85(d，1H)，2.61-2.58(m，2H)，2.18(s，3H)，2.01(s，3H)，1.83(s，3H)，1.35(s，9H)，1.23(s，3H)，1.10(s，3H).
Embodiment 7
Compound 8 (1.10g, 1mmol) is dissolved in the methanol solution of the fresh saturated ammonia of 10mL, stirring at room temperature 2 hours, TLC detects raw material complete reaction, remove solvent under reduced pressure, residue is dissolved in methylene dichloride, washes with water, anhydrous sodium sulfate drying, filter, pressurization is concentrated, and crude product is through column chromatographic isolation and purification, obtain Docetaxel 791.7mg, productive rate 98%.It is 99.5% that HPLC detects normalization method content.
1HNMR(400MHz，DMSO)：δ7.97(d，2H)，7.68(t，1H)，7.60(t，2H)，7.41-7.34(m，3H)，7.28(d，2H)，7.19(t，1H)，5.85(t，2H)，5.40(d，1H)，5.08(d，1H)，5.00(d，1H)，4.93(d，1H)，4.90-4.85(m，2H)，4.50(s，1H)，4.32(t，1H)，4.05-3.98(m，3H)，3.65(d，1H)，2.48(m，2H)，2.26-2.22(m，1H)，2.22(s，3H)，1.89-1.86(m，1H)，1.73(s，1H)，1.86(s，3H)，1.51(s，3H)，1.34(s，9H)，1.00(s，3H)，0.97(s，3H).
13CNMR(100M，DMSO)：δ209.3，172.8，169.7，165.3，155.1，139.6，136.8，135.6，133.4，131.5，130.1，129.5，128.7，128.2，127.3，83.7，80.3，78.1，76.9，75.5，74.8，73.9，73.8，70.8，70.0，57.3，57.0，46.0，42.9，36.5，35.0，28.2，26.5，22.4，20.7，13.7，9.8。
Claims (1)
1. a compound
3synthetic method, the method comprises the steps:
Step I:
In the round-bottomed flask of 25mL, (2R, 3S)-3-phenylisoserine methyl ester 1.0g, 5.1mmol, is dissolved in toluene, adds tribromoacetaldehyde 1.57g, 5.6mmol, and the tosic acid pyridinium salt of catalytic amount, oil bath 120
oc, stirs 2 hours, and TLC detects, and raw material disappears, stopped reaction, decompression removing toluene, and column chromatography purification: sherwood oil: ethyl acetate=5:1, obtains product 2:2.29g, productive rate 98%;
Step II:
By compound
2457.9mg, 1.0mmol, be dissolved in 4.5mL alcohol-water=8:1, drops into lithium hydroxide 71.8mg, 3.0mmol, stirring at room temperature 3h, and decompression takes methanol solvate away, 2N hcl acidifying, extraction into ethyl acetate, anhydrous sodium sulfate drying, and filter, underpressure distillation obtains compound
3: 403.9mg, productive rate 91%.
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| CN201210114709.5A CN103254187B (en) | 2012-02-15 | 2012-02-15 | A kind of preparation method of Taxane derivative |
| CN201210033115.1A CN102887876B (en) | 2012-02-15 | 2012-02-15 | A kind of semisynthesis of Docetaxel of improvement |
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| CN114621985B (en) * | 2020-12-10 | 2024-04-16 | 湖南引航生物科技有限公司 | Method for synthesizing taxol side chain by biocatalysis |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1174844A (en) * | 1996-08-28 | 1998-03-04 | 中国科学院成都有机化学研究所 | N -protection aspartic sweet piptide preparation method |
| CN1509277A (en) * | 2000-12-06 | 2004-06-30 | Process for preparing paclitaxel | |
| CN101163688A (en) * | 2005-04-12 | 2008-04-16 | 因德纳有限公司 | A process for the purification of 10-deacetylbaccatine iii from 10-de acet yl-2- debenzoyl-2-pentenoylbaccatine iii |
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| KR101032761B1 (en) * | 2008-08-06 | 2011-05-06 | 주식회사 셀트리온화학연구소 | A method for preparing docetaxel and new intermediates for preparing the same |
-
2012
- 2012-02-15 CN CN201210114709.5A patent/CN103254187B/en not_active Expired - Fee Related
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1174844A (en) * | 1996-08-28 | 1998-03-04 | 中国科学院成都有机化学研究所 | N -protection aspartic sweet piptide preparation method |
| CN1509277A (en) * | 2000-12-06 | 2004-06-30 | Process for preparing paclitaxel | |
| CN101163688A (en) * | 2005-04-12 | 2008-04-16 | 因德纳有限公司 | A process for the purification of 10-deacetylbaccatine iii from 10-de acet yl-2- debenzoyl-2-pentenoylbaccatine iii |
Non-Patent Citations (1)
| Title |
|---|
| Expeditious Semisynthesis of Docetaxel Using 2-Trichloromethyl-1，3-Oxazolidine as Side-Chain Protection;Eric Didier et al.;《Tetrahedron Letters》;19941231;第35卷(第19期);第3063-3064页 * |
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| CN103254187B (en) | 2016-05-25 |
| CN102887876A (en) | 2013-01-23 |
| CN103254187A (en) | 2013-08-21 |
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