CN1392145A - Semi synthetic method for taxol - Google Patents

Abstract

Taxol is a kind of antineoplastic medicine, which is usually extracted for the bark and leaf of taxad plant and has complicated chemical structure and unique action mechanism. It has very low content in plant material and thus very high extracting cost. The taxol molecule mother nuclide nuclide tetracyclo diterpenoid 10-deacetyl Bakating III (10-dab) may be extracted from masson's pine or coarse Chinese torreya easily or obtained from the side product of taxol extracting process. The present invention synthesizes taxol with 10-dab as initial material, i.e., through the condensation between the side chain precursor cis-1-phenyl-3-(1-carbit)-4-phenyl azetidine-2-one and 10-deacetyl Bakating III derivative and the produced taxol has the same chemical structure as that from taxad.

Description

A kind of semi synthetic method for taxol

Taxol (paclitaxel, trade(brand)name Taxol) is the diterpene-kind compound by a kind of unique antitumour activity of Chinese yew genus plants bark or needle separation and Extraction, and its chemical structure is novel complicated, and the mechanism of action uniqueness is active strong.As the broad spectrum anticancer new drug, taxol is now got permission clinical application in more than 40 countries, is considered to one of best cancer therapy drug of the human so far curative effect of finding.Yet content of taxol is extremely low in the Chinese yew genus plants, and is about about 0.007%, and actual production 1kg taxol needs about 30 tons of bark of Ramulus et folium taxi cuspidatae.Thereby existing taxol production method certainly will will destroy a large amount of Ramulus et folium taxi cuspidatae.Ramulus et folium taxi cuspidatae is the glacial epoch Relict Plant, the countries in the world resource-constrained.Even the Ramulus et folium taxi cuspidatae of cultivation shrub kind, extraction cost also is very high.Thereby, taxol drug always the shortage and hold at high price.Countries in the world and China have all made laws and have gone into overdrive to protect Chinese yew genus plants, therefore extract taxol by bark and have been subjected to jural restriction.In order to enlarge the paclitaxel api source, reduce the clinical application expense, satisfy the needs of oncotherapy, fundamentally protect Ramulus et folium taxi cuspidatae not to be exterminated effectively simultaneously, it is imperative to adopt chemical synthesis process to produce taxol.

The taxol molecule is made of parent nucleus Fourth Ring diterpene and the active side chain two portions of C-13.The present invention relates to the semi-synthetic novel method of anti-cancer medicine paclitaxel.Its method is for adopting aza cyclo-butanone derivatives as taxol C-13 side chain precursor, and (10-deacetylbaccatin III, taxol is made in derivative condensation 10-dab) to take off the acetyl baccatin III with 10-.

Since the later stage eighties 20th century, numerous chemists is devoted to the complete synthesis and semi-synthetic work of taxol, but makes slow progress, and this largely is because the textural factor of this compound complexity.Especially complete synthesis step reached for 40～60 steps, and the reagent raw material is rare, the cost height, and productive rate is low, is difficult to practical application.The chemosynthesis of taxol reduces medical expense etc. for the application of protecting Chinese yew species and resource, expansion clinical tumor, all has very important meaning and huge economic benefit.

Novelty of the present invention is: 1. 10-dab can derive from China frequently seen plants Pinus massoniana Lamb, caephalotaxus sinensis or by the berry Ramulus et folium taxi cuspidatae, also can extract by product or the chemosynthesis that taxol produced by appliable plant, and wide material sources are with low cost.2. do not adopt external semi-synthetic employed taxol C-13 side chain: N-benzoyl-(2R, 3S)-3-phenylisoserine [N-benzoyl-(2R, 3S)-3-phenylisoserine], this side chain synthesis step is tediously long, and cost is too high and can not be directly in the 10-dab condensation.What the present invention adopted is a kind of taxol C-13 side chain precursor of organic synthesis: suitable-1-phenyl-3-(1-ethoxy oxyethyl group)-4-phenyl azetidine-2-ketone [cis-1-benzoyl-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one], and with the condensation of 10-dab derivative.Synthetic method is simple, and condition control only needed for 4 steps can make taxol easily.Thereby simplified synthesis step, improved productive rate.The inventive method is fit to suitability for industrialized production.

The starting raw material that the present invention adopts is 10-dab; in this compound 7; 10; 13 hydroxyl activity differences; earlier with 7 hydroxyls of chlorination triethyl silicane protection; obtain 7-triethyl silicane-10-and take off acetyl baccatin III (3), 10 hydroxyls of acetylize obtain 7-triethyl silicane baccatin III (4) again.Use side chain precursor (2) and side chain precursor condensation then, make taxol (1).Identify confirmation through wave spectrum, this compound and natural product, promptly in full accord by the taxol structure of Ramulus et folium taxi cuspidatae extraction purifying.

The semi-synthetic route of taxol is as follows: The semi-synthetic route of taxol

Embodiment:

7-triethyl silicane 10-takes off acetyl baccatin III (3)

Getting 10-takes off acetyl baccatin III 10g (1.8mmol) and is dissolved in anhydrous pyridine 1000ml, logical nitrogen, stir, slowly drip chlorotriethyl silane 67ml (67g, 40mmol), yellow reaction liquid is stirred 24h down at 0 ℃, add each 2000ml of ethyl acetate and water, stir the back standing demix, organic layer is through copper/saturated copper sulphate solution washing (300ml * 3), until excessive pyridine is all removed, water and saturated sodium-chloride 1000ml washing again.By anhydrous sodium sulfate drying, filter the back removal of solvent under reduced pressure then, enriched material is through 230～400 order silica gel-60 (Merck) chromatographic column purifying, and (v: v=99: 1) wash-out gets compound 3 11.2g, yield: 79% with methylene chloride-methanol.Mp256～257 ℃ (methylene dichloride-pentane), [α] D23-23.6o (c=0.41, methyl alcohol).1H NMR δ: 0.48～0.70 (m, 6H), 0.94 (t, J=8Hz, 9H), 1.08 (s, 6H), 1.57 (s, 1H), 1.74 (s, 3H), 1.86～1.95 (m, 1H), 2.02 (d, J=5Hz, 1H), 2.09 (d, J=1.1Hz, 3H), 2.25～2.35 (m, 2H), 2.28 (s, 3H), 2.42～2.52 (m, 1H), 3.95 (d, J=7Hz, 1H), 4.24 (Abq, JAB=8.4Hz, δ A δ B=42,2H), 4.31 (d, J=2Hz, 1H), 4.41 (dd, J=6.6 and 10.6Hz, 1H), 4.85～4.90 (m, 1H), 4.95 (dd, J=1.9 and 9.6Hz, 1H), 5.17 (d, J=2Hz, 1H), 5.60 (d, J=7Hz, 1H), 7.44～7.50 (m, 2H), 7.57～7.62 (m, 1H), 8.08～8.11 (m, 2H).

7-triethyl silicane baccatin III (4)

Compound 3 10g (1.5mmol) are dissolved in anhydrous pyridine 430ml, and dripping acetyl chloride 6ml continues down to stir 20h at 0 ℃ again, adds each 500ml of ethyl acetate and water, stirs, and behind the standing demix, extracts water with ethyl acetate (300ml * 2).Merge organic phase, remove fully with copper/saturated copper sulphate solution washing to pyridine.Water and saturated nacl aqueous solution washing successively then by anhydrous sodium sulfate drying, is filtered the back concentrating under reduced pressure, 230～400 order silica gel (Merck) chromatographic columns on the enriched material, (v: v=99: 1) wash-out gets compound 410.3g, yield: 86% with methylene chloride-methanol.Mp253～254 ℃ (methylene dichloride-pentane), [α] D23-49 ° (c=0.4 methyl alcohol).1H NMR δ: 0.52～0.65 (m, 6H), 0.93 (t, J=8Hz, 9H), 1.04 (s, 3H), 1.20 (s, 3H), 1.61 (s, 1H), 1.68 (s, 3H), 1.83～1.92 (m, 1H), 2.01 (d, J=5Hz, 9H), 2.17 (s, 3H), 2.19 (d, J=1.1Hz, 3H), 2.24～2.28 (m, 2H), 2.29 (s, 3H), 2.41～2.58 (m, 1H), 3.88 (d, J=7Hz, 1H), 4.24 (Abq, JAB=8.1Hz, δ A-δ B=45,2H), 4.49 (dd, J=6.6 and 10.5Hz, 1H), 4.84 (m, 1H), 4.96 (d, J=9.6Hz, 1H), 5.63 (d, J=7Hz, 1H), 6.46 (s, 1H), 7.45～7,50 (m, 2H), 7.57～7.63 (m, 1H), 8.09～8.12 (m, 2H).

2 '-(1-ethoxy oxyethyl group)-7-triethyl silicane taxol (5)

In full-automatic retort, add suitable-1-phenyl-3-(1-ethoxy oxyethyl group)-4-phenyl azetidine-2-ketone (2) 109g (0.32mmol), 4 45g (0.064mmol), DMAP 7.8g (0.064mmol) and pyridine 320ml.Mixed solution stirs 12h down at 25 ℃, then with ethyl acetate 100L dilution, ethyl acetate layer washs with 10% copper sulfate solution 20L, by anhydrous sodium sulfate drying, and concentrating under reduced pressure, enriched material filters by silicagel column, with ethyl acetate-hexane (1: 2) wash-out, recrystallization in ethyl acetate-hexane obtains 5 61g then, yield: 92%, be non-enantiomer mixture (2: 1).

Taxol (1)

Get 5 50g, be dissolved in ethanol 20L, add 0.5% aqueous hydrochloric acid 5L, mixed solution stirs 30h down at 0 ℃, with ethyl acetate 500L dilution, solution passes through anhydrous sodium sulfate drying with saturated sodium bicarbonate aqueous solution 200L washing again, concentrating under reduced pressure, silica gel column chromatography on the enriched material with ethyl acetate-hexane (1: 1) wash-out, gets taxol 130g, yield 90% is white solid.[α] D22-44.1 ° (c=0.27 methyl alcohol), mp192～194 ℃, 1H NMR (CDCl3) δ: 1.12 (s, 3H), 1.22 (s, 3H), 1.67 (s, 3H0,1.77 (s, 3H), 1.86 (m, 1H), 2.21 (s, 3H), 2.26 (s, 3H), 2.26 (dd, J=15.4,8.9Hz, 1H), 2.34 (dd, J=15.4,8.9Hz, 1H), 2.36 (s, 3H), 2.43 (bs, 1H), 2.53 (ddd, J=15.5,9.6,6.0Hz, 1H), 3.55 (bs, 1H), 3.78 (d, J=7.0Hz, 1H), 4.18 ((d, J=8.4Hz, 1H), 4.28 (d, J=8.4Hz, 1H), 4.38 (dd, J=10.6,6.8, Hz, 1H), 4.77 (d, J=2.1Hz, 1H), 4.92 (bd, J=8.9Hz, 1H), 5.65 (d, J=7.0Hz, 1H), 5.77 (dd, J=8.8,2.6Hz, 1H), 6.21 (bt, J=9.0Hz, 1H), 6.25 (s, 1H), 6.97 (d, J=8.8Hz, 1H), 7.33 (m, 5H), 7.54 (m, 5H), 7.59 (t, J=7.1Hz, 1H), 7.71 (d, J=7.9Hz, 2H), 8.11 (d, J=7.9Hz, 2H); 13C NMR (CDCl3) δ: 9.59,14.83,20.87,21.81,22.62,26.84,35.65,43.16,45.66,55.11,58.56,72.23,73.24,74.93,75.58,76.54,79.00,81.11,84.40,127.05,128.33,128.68,128.99,130.20,131.95,133.13,133.73,137.98,141.98,167.09,166.97,170.39,171.25,172.70,203.64.

Claims (4)

1, a kind of semisynthesis of antitumor drug taxol is characterized in that adopting 10-to take off the acetyl baccatin III and synthetic taxol C-13 side chain precursor carries out semi-synthetic taxol.

2, in accordance with the method for claim 1, wherein taxol C-13 side chain precursor is an aza cyclo-butanone derivatives.

3, in accordance with the method for claim 1, wherein 10-takes off bark or the needle that the source of acetyl baccatin III (10-dab) is Pinus massoniana Lamb, caephalotaxus sinensis or berry Ramulus et folium taxi cuspidatae, also can derive from the by product and the synthetic synthetic product that produce in the taxol extraction process.

4, in accordance with the method for claim 1,10-take off the acetyl baccatin III with the side chain precursor condensation reaction before must carry out the silane group protection of 7 hydroxyls and the acetylize of 10 hydroxyls.Make its 13 hydroxyls and side chain precursor condensation, make taxol.