CN102887876A

CN102887876A - Improved method for semi-synthesizing docetaxel

Info

Publication number: CN102887876A
Application number: CN2012100331151A
Authority: CN
Inventors: 陈艳君; 高坤
Original assignee: Ningbo Institute of Technology of ZJU
Current assignee: Ningbo Institute of Technology of ZJU
Priority date: 2012-02-15
Filing date: 2012-02-15
Publication date: 2013-01-23
Anticipated expiration: 2032-02-15
Also published as: CN103254187A; CN103254187B; CN102887876B

Abstract

The invention discloses an improved method for semi-synthesizing docetaxel. The method comprises the following steps of: protecting hydroxyl radicals at the 7th position and the 10th position of 10-deacetyl baccatin III which is taken as an initial raw material, introducing an optical rotation side chain at the 13th position of the 10-deacetyl baccatin III to synthesize an intermediate, and finally, hydrolyzing to obtain a target product, namely the docetaxel. The side chain is synthesized by reacting (2R,3S)-3-phenylpropionate with tribromoacetaldehyde to obtain an oxazoline intermediate, and hydrolyzing the oxazoline intermediate. The preparation method is simple, few side reactions are performed, the yield and the purity are high, isomer byproducts are avoided, the content of impurities is low, and the cost is greatly reduced, so the commercial preparation of the docetaxel can be promoted. The method has an important significance and a huge economic benefit for protecting the species and resource of Taxus chinensis plants, reducing the treatment cost of tumor and the like.

Description

A kind of semisynthesis of improved Docetaxel

Technical field

The present invention relates to a kind of semisynthesis of improved Docetaxel; specifically; relate to the synthetic of a kind of Docetaxel side chain and female ring 10-deacetylate bar card fourth III (10-DAB) is modified, thereby then female ring and side chain generation condensation 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 (Monre E.Wall) and Wani (M.C.Wani) were separated to the crude extract of taxol first from peaceful red deal (Pacific Yew) bark and timber.In screening experiment, Wani and Wall find that the taxol crude extract has very high reactivity to the mouse tumour cell of isolated culture, and begin to separate this active ingredient, have determined that in 1969 taxol is activeconstituents wherein.Because this active ingredient content in plant is extremely low, until (J.Am.Chem.Soc. in 1971,1971,93,2325), they are chemistry professor Mu Kefaer (Andre T.McPhail) cooperation of same Du Ke (Duke) university, has determined the chemical structure of this active ingredient-tetracyclic diterpene compound by x-ray analysis, and its called after taxol (Taxol).1972, Schiff (Nature, 1979,277,665) etc. confirmed that taxol acts on unique pharmacology mechanism of tumour cell tubulin; Taxol promotes tubulin polymerization, ends cell mitogen, suppresses tumor growth.1992, taxol obtained the drugs approved by FDA listing, treats ovarian cancer and the mammary cancer invalid to conventional chemotherapy.

The content of taxol in bark of Ramulus et folium taxi cuspidatae only is ten thousand/, from three to five of the taxol used in amounts of a course for the treatment of an of cancer patient are century-old gives birth to extract the bark of Ramulus et folium taxi cuspidatae and obtains, therefore, always shortage of taxol drug and holding at high price.And Taxus is in rare and endangered tree species, and resource scarcity distributes sparse, seldom grows into forest, and the poor growth whole world only has 11 kinds, and population density is little, and the self-reproduction degree is low.Obtain enough taxols and be used for clinical application and fundamental research, rely on merely from natural phant, to extract and to bring great threat to the existence of Chinese yew genus plants.In addition, the poly-ethoxy of taxol medicine preparation employing as solubilizing agent, easily causes anaphylaxis for Viscotrol C when clinical application.In order to enlarge taxanes bulk drug source; reduce the clinical application expense; satisfy the needs of oncotherapy, simultaneously fundamentally effectively protect Chinese yew not to be exterminated, adopt the chemosynthesis means to explore and develop the novel taxane series antineoplastic medicament of high reactivity low toxicity imperative.

Taxane substances is subjected to the restriction of the factors such as polyfunctional group and multichiral center because of its complex structure, and complete synthesis route is complicated, yield is low, cost is too high, and artificial semisynthesis is the most effective chemical process of obtaining at present taxane substances.10-deacetylate bar card fourth III (10-deacetyl baccatin III; 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 is up to thousandth, is 10 times of content of taxol.1985, French Rhone-Poulenc Rorer and French National Nature research establishment, with 10-DAB as the parent nucleus skeleton, artificial 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 only is that the acetoxyl group on the taxol parent nucleus C-10 is replaced by hydroxyl, and the benzoyl on the C-13 side chain N is replaced by tertbutyloxycarbonyl.Structural characteristic is most important for the In Vitro Anti tubulin activity of Docetaxel: its avidity to the microtubule combining site is 2 times of taxol; As microtubule stabilizer and assembling promotor, large 2 times of specific activity taxol; In the anti-tumor activity in vitro tests, confirmed that the Docetaxel activity is 1.3～12 times of taxol, and toxic side effect is little, water-soluble increase makes it easily make preparation.After the nineteen ninety-five Docetaxel injection Initial Public Offering, use a line medication that becomes oncotherapy more than 40 country's listings at present.Docetaxel patent medicine had surpassed taxol first in global marketing in 2003, and Docetaxel is present one of the best broad spectrum anticancer medicine in the world, and the market requirement increases day by day.Study on the synthesis and applied research to Docetaxel are very valuable.

At present the route extensively taked of synthetic Docetaxel is as side chain take straight chain isoserine side chain and tetra-atomic ring azetidinone, dock the preparation Docetaxel with parent nucleus, but there are various shortcomings, as: step is many, and condition is harsh, the experimental implementation difficulty is large, the chiral separation difficulty, product cost is high, intermediate is unstable, and product is difficult to depositing of separation and purification etc., is difficult to adapt to the demand of suitability for industrialized production.Therefore, still need the new improved method for preparing Docetaxel.The present invention is intended to overcome the problems referred to above; with cheap and brief reaction scheme, the mild condition ground preparation Docetaxel that is fit to suitability for industrialized production; this is for protection Chinese yew species resource; keep human kind sustainable development; reduce Docetaxel price and oncotherapy expense, all have important social effect and economic worth.

Summary of the invention

Shortcoming for fear of existing preparation Docetaxel technique; reduce synthesis step; remove isomer impurities; improve reaction conditions; reduce side reaction and produce, the content of impurity reduction improves the utilization ratio that main raw material 10-deacetylation bar blocks fourth III; reduce cost, we have invented a kind of improved Docetaxel synthetic method.Technical scheme of the present invention is as follows:

1. side chain is synthetic:

Toluene or dimethylbenzene or DMF are solvent, Jian Ti oxazoline 2 during (2R, 3S)-3-phenylisoserine methyl esters and tribromoacetaldehyde generate under tosic acid pyridinium salt or Catalyzed by p-Toluenesulfonic Acid agent catalysis; Intermediate 2 obtains 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. Docetaxel is synthetic:

Synthetic parent nucleus protection, condensation, open loop, side chain amido protecting, the hydrolysis five steps of comprising of Docetaxel:

Protection Step II I: under anhydrous and oxygen-free and nitrogen or argon shield; in the pyridine of compound 4 or methylene dichloride or the DMF solution; add trichoroacetic chloride under the ice bath; under the organic bases conditions such as pyridine or triethylamine;-5 ℃～25 ℃ reactions; the water cancellation was reacted after TLC detected the raw material disappearance, and the aftertreatment purifying gets compound 5.

Condensation step IV: under the anhydrous and oxygen-free environment, compound 5 and side chain 3 are at N, and under the organic bases conditions such as N-dimethyl aminopyridine or pyridine, 1,3-dicyclohexyl carbodiimide or dipropyl carbonate exist lower generation condensation reaction to get compound 6;

Open loop step V and side chain amido protecting step VI: the open loop of C-13 oxazole side chain occurs and gets intermediate 7 in compound 6 under formic acid or acetic acid or phenylformic acid or oxalic acid or dilute hydrochloric acid condition, then reacts to get the intermediate 8 of side chain amido protecting with tert-Butyl dicarbonate under the alkali condition;

Hydrolysing step VII: with intermediate 8 at ammonia or ammonium hydroxide or ammonium acetate or inorganic ammonium salt Water Under solution is sloughed 7-OH and the 10-OH blocking group can obtain target product Docetaxel (Docetaxel).

Beneficial effect

The preparation method of Docetaxel of the present invention both overcome light and revolved the many shortcomings of side chain reactions steps, solved again the problem that the racemization side chain has isomer impurities.Concrete advantage is as follows:

(1) the present invention is with (2R, 3S)-3-phenylisoserine methyl esters and tribromoacetaldehyde are the side chain of the synthetic Docetaxel of raw material, compare side chain (4S, 5R)-2-trichloromethyl-4-phenyl-5-carboxyl-1, synthesizing of 3-oxazolidine, the side chain synthesis yield exceeds almost ten percentage points: side chain (4S among the present invention, 5R)-2-trisbromomethyl-4-phenyl-5-carboxyl-1, the synthetic yield of 3-oxazolidine is 89%, side chain (4S among the publication KR101032761B, 5R)-and 2-trichloromethyl-4-phenyl-5-carboxyl-1, the synthetic yield of 3-oxazolidine is 81%.Change the C-2 substituting group into trisbromomethyl by trichloromethyl, same experimental conditions, productive rate obviously improves, and this effect is not conventional can expecting.

(2) the present invention is with (4S; 5R)-2-trisbromomethyl-4-phenyl-5-carboxyl-1; the 3-oxazolidine is side chain; tribromo-acetyl base protection parent nucleus 7-OH and 10-OH; be prepared into Docetaxel; total recovery is 82%; purity is up to 99.6%; by changing side chain substituents and parent nucleus protecting group; whole yield is compared similar technology KR101032761B, and (with (4S, 5R)-2-trichloromethyl-4-phenyl-5-carboxyl-1, the 3-oxazolidine is side chain; three acetyl bromides protection parent nucleus 7-OH and 10-OH; yield 72%, purity 99.4%) total recovery exceeds ten percentage points, and purity also is significantly improved; to save great amount of cost for the production of Docetaxel, bring obvious competitive edge.This beneficial effect also is conventional can not expecting.

(3) preparation method of the disclosed synthetic Docetaxel of this patent, per step reaction is all simple to operate, mild condition, the reagent low toxicity, aftertreatment is easy, is easy to industrialization.

Embodiment

Following examples only are used for further specifying 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 esters (1.0g, 5.1mmol) be dissolved in the toluene, add the tosic acid pyridinium salt of tribromoacetaldehyde (1.57g, 5.6mmol) and catalytic amount, 120 ℃ of oil baths, stirred 2 hours, TLC detects, and raw material disappears, stopped reaction, toluene is removed in decompression, column chromatography purification (sherwood oil: ethyl acetate=5: 1) get product 2:2.29g, productive rate 98%.

(4S, 5R)-2-trichloromethyl-4-phenyl-5-carboxyl-1,3-oxazolidine: ESI-MS m/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

With compound 2 (457.9mg, 1.0mmol) be dissolved in the 4.5mL alcohol-water (8: 1), drop into lithium hydroxide (71.8mg, 3.0mmol), stirring at room 3h, methanol solvate, 2N hcl acidifying, ethyl acetate extraction are taken in decompression away, anhydrous sodium sulfate drying, filter, underpressure distillation gets compound 3:403.9mg, productive rate 91%.

(4S, 5R)-2-trichloromethyl-4-phenyl-5-carboxyl-1,3-oxazolidine: ESI-MS m/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

10-DAB (544.6mg, 1mmol) is dissolved in the 5mL anhydrous pyridine, and nitrogen protection is under the cryosel bath condition; slowly drip trichoroacetic chloride (600.0mg, 3.3mmol), temperature is controlled at subzero 5 degree; after trichoroacetic chloride dropwises, naturally be raised to room temperature, TLC detects; 1.5h after, raw material disappears, agitation and dropping such as deionized water under the condition of ice bath; ethyl acetate extraction, anhydrous sodium sulfate drying filters; decompression steams solvent, and column chromatography gets 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

With compound 5 (1.13g, 1mmol) and compound 3 (577.1mg, 1.3mmol), be dissolved in the toluene, stir lower 1, the 3-of adding dicyclohexyl carbodiimide (123.7mg, 1.6mmol) and N, N-Dimethylamino pyridine (61.0mg, 0.5mmol), 80 ℃ of lower reactions, TLC detects, and afterreaction was complete in 2 hours, pressure reducing and steaming toluene, column chromatography purification (sherwood oil: ethyl acetate=5: 1) get 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

With compound 6 (1.26g, 1mmol), be dissolved in the 10mL formic acid solution, stir under the room temperature, TLC follows the tracks of, and 2 as a child reacted completely, and pressurization is steamed and is desolventized, and column chromatography purification gets 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 the dry tetrahydrofuran solution, then add anhydrous sodium carbonate (255mg, 3.0mmol), stir under the room temperature, TLC follows the tracks of, and the 4h afterreaction is complete, ethyl acetate extraction, respectively water, saturated common salt water washing, anhydrous sodium sulfate drying filters, the filtrate decompression distillation, column chromatography purification gets 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 2 hours, TLC detects the raw material complete reaction, remove solvent under reduced pressure, residue is dissolved in the methylene dichloride, washes with water, anhydrous sodium sulfate drying, filter, pressurization is concentrated, and crude product is through column chromatographic isolation and purification, get Docetaxel 791.7mg, productive rate 98%.It is 99.5% that HPLC detects normalization method content.

¹H?NMR(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).

¹³C?NMR(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. the synthetic method of an improved Docetaxel comprises the steps:

Synthesizing of side chain:

Synthesizing of Docetaxel:

1. side chain compound 3 is synthetic:

Step I:(2R, 3S)-3-phenylisoserine methyl esters and tribromoacetaldehyde catalysis generation Zhong Jian Ti oxazoline 2;

Step II: intermediate 2 obtains side chain 3 for the preparation of Docetaxel through hydrolysis of ester group;

2. Docetaxel is synthetic:

Protection Step II I: reaction obtains compound 5 to compound 4 with trichoroacetic chloride under the organic bases condition;

Condensation step IV: condensation reaction occurs and gets compound 6 in compound 5 and side chain compound 3 in the presence of condensing agent and alkali;

Open loop step V and side chain amido protecting step VI: the open loop of C-13 oxazole side chain occurs and gets intermediate 7 in compound 6 under acidic conditions, then reacts to get the intermediate 8 of side chain amido protecting with tert-Butyl dicarbonate under the alkali condition;

2. synthetic method as claimed in claim 1, wherein in side chain synthetic, it is characterized in that, described step I is reacted under tosic acid pyridinium salt or Catalyzed by p-Toluenesulfonic Acid agent condition by (2R, 3S)-3-phenylisoserine methyl esters and tribromoacetaldehyde.

3. synthetic method as claimed in claim 1 in side chain synthetic, is characterized in that wherein described synthesis step I, reaction solvent are toluene or dimethylbenzene or DMF.

4. synthetic method as claimed in claim 1 in side chain synthetic, is characterized in that wherein Step II is under the alkali condition ester hydrolysis reaction to occur.

5. synthetic method as claimed in claim 1 in side chain synthetic, is characterized in that wherein synthesis step II, used alkali are lithium hydroxide or sodium hydroxide or potassium hydroxide.

6. synthetic method as claimed in claim 1 wherein in Docetaxel synthetic, is characterized in that, among described protection Step II I and the condensation step IV, needs the reaction conditions of anhydrous and oxygen-free, vacuumizes nitrogen or argon replaces, passes into nitrogen or argon shield.

7. such as the synthetic method of the Docetaxel of claim 1 or 6, it is characterized in that, among the described protection Step II I, described alkali is the organic basess such as pyridine or triethylamine.

8. the synthetic method of Docetaxel as claimed in claim 7 is characterized in that, among the described protection Step II I, temperature of reaction is-5 ℃～25 ℃.

9. the synthetic method of Docetaxel as claimed in claim 8 is characterized in that, among the described protection Step II I, reaction medium is pyridine or methylene dichloride or DMF, and reaction finishes water cancellation reaction.

10. the synthetic method of Docetaxel as claimed in claim 1 is characterized in that, the described condensing agent of condensation step IV is 1,3-dicyclohexyl carbodiimide or dipropyl carbonate, described alkali is N, the N-dimethyl aminopyridine, and other can also select the organic basess such as pyridine.

11. the synthetic method of Docetaxel as claimed in claim 1 is characterized in that, step V is that open loop gets compound 7 under formic acid or acetic acid or phenylformic acid or oxalic acid or dilute hydrochloric acid condition.

12. the synthetic method of Docetaxel is characterized in that as described in claim 1, the protecting group of 7-OH and 10-OH is by with ammonia or NH among the step VII ₄OH or (NH ₄) ₂OAc or NH ₄Cl processes in methyl alcohol or tetrahydrofuran solvent and to remove.