CN102659721B - Synthetic method of cabazitaxel - Google Patents
Synthetic method of cabazitaxel Download PDFInfo
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Abstract
The invention relates to a synthetic method of cabazitaxel, which comprises the following steps: taking a compound 10-deacetylbaccatin III as a starting raw material and reacting with a protective agent to carry out selective protection on 7 and 10 hydroxyls; then carrying out selective protection on 13 hydroxyls of the compound, removing 7 and 10 protection radicals and carrying out methylation reaction; removing 13 protection radicals and carrying out condensation reaction with an oxazolidine carboxylic acid side chain; and removing and protecting a condensation product to obtain the cabazitaxel. The synthetic method has the beneficial effects that the proper protection radicals and a removal and protection method are selected, the oxazolidine carboxylic acid side chain is finally connected, and the synthetic method has the characteristics of low production cost, high yield, mild reaction conditions and simplicity in operation and is particularly suitable for industrial production.
Description
Technical field
The present invention relates to pharmaceutical chemistry field, relate in particular to the synthetic method of a kind of Cabazitaxel (Cabazitaxel).
Background technology
Prostate cancer is male sex's common cancer, and regular incidence, in elderly men, is second largest common male cancer except skin carcinoma in the U.S..According to disease prevention and control center's statistics, within 2006, approximately there are 203415 male sex to suffer from prostate cancer, wherein 28372 people's death.
Cabazitaxel (Cabazitaxel) is the Second line Drug of the prostate cancer of Sanofi company research and development, and its commodity are called Jevtana.Cabazitaxel is a kind of molecular design taxanes micromolecular compound, and its critical materials mainly extracts from Ramulus et folium taxi cuspidatae needle.The mechanism of anticancer action of Cabazitaxel is similar to docetaxel with feature, belongs to anti-microtubule class medicine.Cabazitaxel by with tubulin binding, promote it to be assembled into microtubule, stop the microtubule having assembled to disintegrate simultaneously, make microtubule stable, and then suppress the mitotic division of cell and the performance of interval cell function (interphase cellular functions).
Cabazitaxel was ratified by U.S. FDA in 2010, with prednisone (prednisone) drug combination, was applied to treatment and once accepted the hormone refractory metastatic prostate cancer patient of docetaxel therapy.Cabazitaxel is after docetaxel, the 2nd the prostate treatment medicine in U.S.'s approval listing.
Cabazitaxel molecular formula is C
45h
57nO
14,white crystals; water insoluble, solvable and ethanol; chemistry (2R by name; 3S)-α-benzoyl-5, α-ethanoyl-2,3-t-butoxycarbonyl amino-PLA-4 β; 20-epoxy-1 beta-hydroxy-7 β, 10 β-dimethoxy-9-oxygen-11-Japanese yew alkene-13 α-ester, its structural formula is as follows:
At present, patent US5889043 discloses two synthetic routes:
Article one, be with 10-deacetylate baccatin III (10-deacetylbaccatin III; 10-DAB III) be raw material; under the condition of pyridine 7; introduce triethyl silica-based (TES) protecting group for 13; then under the condition that is alkali at sodium hydride; with methyl iodide 10 introduce methyl; remove again TES protecting group; be alkali in order to sodium hydride at low temperatures; with methyl iodide 7 introduce methyl; then Yu oxazolidine carboxylic acid side chain condensation, then Chun Xie oxazole ring obtains target compound Cabazitaxel under acidic conditions.This method is in the time introducing TES protecting group and methyl, and yield is all very low, and harsher to the requirement of reaction conditions, is not suitable for suitability for industrialized production; Article 2 route is taking 10-DAB III as raw material; first 7; introduce trichloro-ethoxycarbonyl (Troc) protecting group for 10; then Yu oxazolidine carboxylic acid side chain condensation; remove again Troc protecting group; introduce methyl by Pummerer rearrangement reaction and 7,10 hydroxyls of Raney nickel reduction, finally under acidic conditions, Chun Xie oxazole ring obtains target compound Cabazitaxel.This method has been introduced chirality oxazolidine carboxylic acid side chain from the beginning, causes the waste of more expensive material, and Pummerer rearrangement reaction and Raney nickel reduction yield general.
In the method for having reported, route complexity, by product is many, and the low and high in cost of production shortcoming of yield causes the cost of Cabazitaxel high.Therefore, urgent need will be found an applicable suitability for industrialized production, reduces Cabazitaxel production cost, improves the synthetic method of Cabazitaxel quality product.
Summary of the invention
The object of the invention is to provide a kind of new Cabazitaxel (Cabazitaxel) synthetic method, to overcome the shortcoming existing in former synthetic route.Synthetic method of the present invention can significantly reduce medical treatment cost, and relieve patient ' s burden has broad prospects in industrial application.
The method of described synthetic Cabazitaxel comprises the following steps:
(1) compound shown in formula I is carried out to hydroxyl selective protection and prepare compound shown in formula II
，
(2) shown in formula II step (1) being prepared, compound carries out selectivity hydroxyl protection, prepares compound shown in formula III
，
(3) slough the R in compound shown in the formula III that step (2) prepares
1protecting group, prepares formula IV compound
；
(4) shown in formula IV step (3) being prepared, compound carries out HM reaction, prepares compound shown in formula V
；
(5) slough the R of compound shown in the formula V that step (4) prepares
2protecting group, prepares compound shown in formula VI
；
(6) compound shown in compound and formula VII shown in formula VI step (5) being prepared carries out condensation reaction and prepares the compound shown in formula VIII
；
(7) the compound deprotection shown in formula VIII step (6) being prepared obtains Cabazitaxel;
Wherein R
1and R
2not identical, be respectively the C replacing arbitrarily
1-C
4alkyl, C
1-C
4alkyl replace the C of silica-based, any replacement
1-C
4carbonyl.
More specifically, in above-mentioned steps (1), be that 7 and 10 hydroxyls of formula I compound (10-DAB III) are carried out to selective protection, described R
1be preferably benzyloxymethyl (BOM), methoxyl methyl (MOM), methoxy (ethoxy) methyl (MEM), tertiary butyl dimethyl silyl (TBS), triethyl silica-based (TES), trimethyl silicon based (TMS), trichloro-ethoxycarbonyl (Troc), tertbutyloxycarbonyl (BOC).
The method of the hydroxyl protection described in step (1) is this area ordinary method; under alkaline condition; hydroxyl protection reagent is reacted in organic solvent with the compound shown in formula I, and the hydroxyl of 7,10 to the compound shown in formula I carries out selective protection and obtains the compound shown in formula II.
For example,, when selecting the substituent methyls such as benzyloxymethyl (BOM), methoxyl methyl (MOM), methoxy (ethoxy) methyl (MEM) as R
1when protecting group, protection reagent used includes but not limited to the reagent such as BOMX, MOMX, MEMX, and wherein said X is F, Cl, Br, I.
Described alkaline condition comprises sodium hydride, salt of wormwood, sodium hydroxide etc., and described organic solvent comprises: THF, Isosorbide-5-Nitrae-dioxy six alkane, methylene dichloride, DMF, DMF equal solvent.
Alkaline reagents is added to the organic solvent that contains compound shown in formula I; under-10 DEG C～50 DEG C conditions, stir 1～12 hour; and then become ether reaction with described hydroxy-protecting agent, the hydroxyls of 7,10 are carried out to selective protection and obtain the compound shown in formula II.
Silica-based as R when selecting triethyl silica-based (TES), tertiary butyl dimethyl silyl (TBS), trimethyl silicon based (TMS) etc. to replace
1when protecting group, protection reagent used includes but not limited to TESX, TBSX, TMSX etc., and wherein X is F, Cl, Br, I.
Described alkaline condition comprises: salt of wormwood, sodium carbonate, sodium hydroxide, triethylamine etc.; Described organic solvent comprises pyridine, THF, methylene dichloride etc.
Compound shown in formula I and protection reagent are added in organic solvent, add appropriate bases, room temperature to 80 DEG C stirs and within 1～10 hour, obtains the compound shown in formula II.
Be R when selecting trichloro-ethoxycarbonyl (Troc)
1when protecting group; select TrocCl reagent; in the organic solvent such as such as pyridine, THF, methylene dichloride; optional 4-dimethylaminopyridine (DMAP) catalyzer; stir 1～14 hour in 0 DEG C～80 DEG C; through extraction, washing, dry, post separate or recrystallization after, obtain the compound shown in formula II.
Be R when selecting tertbutyloxycarbonyl (BOC)
1when protecting group, select BOC acid anhydrides (BOC
2o) reagent, preferably organic solvent dichloromethane, tetrahydrofuran (THF), optional DMAP catalyzer, stirs 1～10 hour at 0 DEG C～80 DEG C, through extraction, washing, dry, post separate or recrystallization after, obtain the compound shown in formula II.
In above-mentioned steps (2), be that 13 hydroxyls of the compound shown in formula II are carried out to selective protection, prepare the compound shown in formula III; R
2be preferably benzyloxymethyl (BOM), methoxyl methyl (MOM), methoxy (ethoxy) methyl (MEM), tertiary butyl dimethyl silyl (TBS), trimethyl silicon based (TMS), triethyl silica-based (TES), trichloro-ethoxycarbonyl (Troc), tertbutyloxycarbonyl (BOC).
Described hydroxyl protection reaction method is identical with the described method of step (1).
In above-mentioned steps (3), described hydroxyl deprotection method is this area common method, for example, works as R
1protecting group is that the substituent methyls such as benzyloxymethyl (BOM), methoxyl methyl (MOM), methoxy (ethoxy) methyl (MEM) are during as protecting group; formula III compound is at acidic conditions; under lewis acidic participation; in organic solvent; in 0 DEG C of reflux temperature to solvent for use; react 1～12 hour, obtain the compound shown in formula IV.Described acidic conditions comprises hydrochloric acid, trifluoroacetic acid, Glacial acetic acid etc., and described Lewis acid is selected from ZnBr
2, TiCl
4, MgBr
2, FeCl
3deng, described organic solvent is selected from methylene dichloride, ether, THF.
Work as R
1protecting group is that triethyl silica-based (TES), tertiary butyl dimethyl silyl (TBS), trimethyl silicon based (TMS) etc. replace when silica-based; formula III compound is at acidic conditions, in organic solvent, in 0 DEG C of reflux temperature to solvent for use; react 1～24 hour, obtain the compound shown in formula IV.Described acidic conditions comprises hydrochloric acid, citric acid, hydrofluoric acid etc.; Described organic solvent is selected from methylene dichloride, ether, THF.
Work as R
1when protecting group is trichloro-ethoxycarbonyl (Troc), can select zinc powder and/or copper powder, acetic acid, in ethanol or methanol solvate, between room temperature to 90 DEG C, react and within 15～20 hours, obtain the compound shown in formula IV.
Work as R
1when protecting group is tertbutyloxycarbonyl (BOC), can, in the organic solvent such as dioxane, methylene dichloride, use concentrated hydrochloric acid or trifluoroacetic acid, under the reflux temperature condition in room temperature to solvent for use, react and within 1～20 hour, obtain the compound shown in formula IV.
Methylation reaction described in step (4), nitrogen or argon shield, in organic solvent, under alkaline condition, methylate to 7,10 hydroxyls with methyl iodide.Described solvent is THF or Isosorbide-5-Nitrae-dioxy six alkane; Described alkali is NaH.Described reaction, is that formula IV compound is dissolved in organic solvent, is cooled between-20 DEG C～0 DEG C, adds NaH, stirs, and then slowly adds methyl iodide to reaction solution, is then warming up to 50 DEG C, reacts 2～20 hours, obtains the compound shown in formula V.
Deprotection described in step (5) is identical with the method for sloughing corresponding protecting group in step (3).
Condensation reaction described in step (6) is by formula VI compound and formula VII compound (oxazolidine carboxylic acid side chain) be dissolved in such as in methylene dichloride, toluene, THF equal solvent, use dicyclohexylcarbodiimide (DCC),, to the reflux temperature of agents useful for same, react and within 2～15 hours, obtain the compound shown in formula VIII in room temperature.In reaction, can add 4-dimethylaminopyridine (DMAP) or 4-pyrrolidyl pyridine (PPY) is catalyzer.
Deprotection reaction method described in step (7) is those skilled in the art's common method, and formula VIII compound, in ethanol solution hydrochloride, under 0 DEG C of condition, is reacted 16 hours, obtains end product Cabazitaxel (Cabazitaxel).
The method of the invention agents useful for same is cheap; effectively reduce production costs, select suitable protecting group and deprotection method, in the end Lian Jie oxazolidine carboxylic acid side chain; have that yield is high, reaction conditions is gentle, simple operation and other advantages, be conducive to suitability for industrialized production.
Due to 7 of the compound shown in selected starting material formula I in the present invention and 10 hydroxyl activities stronger than 13 hydroxyl activities; in reaction easily and hydroxyl protection reagent react; reaction yield is higher; by product is less; first 7 and 10 hydroxyls protected; again 13 hydroxyls are protected, can be avoided being protected 13 hydroxyl protections of produced part incomplete to three position hydroxyls simultaneously, also can effectively solve the problem of the cost rising producing because of wastage of material.
The yield of each step of whole piece reaction scheme all effectively improves, and has also reduced the usage quantity of raw material simultaneously, reduces product price thereby realize.
Brief description of the drawings
Fig. 1 is the hydroxyl ranking of compound shown in formula I.
Embodiment
Unless otherwise defined, the implication that all technology that the present invention uses and the implication of scientific terminology are understood conventionally with the technical field of the invention those of ordinary skill is identical.Conventionally name and following experimental technique that, the present invention uses are all well known in the art or conventional.
In order to make technique means of the present invention, creation characteristic and the beneficial effect of the invention more clear, easy to understand, will enumerate embodiment below, and the present invention is further explained.
Embodiment
Embodiment 1
route 1
(1) formula
iI-1synthesizing of compound:
In 250ml three-necked bottle, nitrogen protection, the 10-deacetylate baccatin III of 10.81g is dissolved in to 100ml anhydrous pyridine, being cooled to 0 DEG C stirs 10 minutes, 8ml trichloroethyl chloroformate is dissolved in 50ml anhydrous methylene chloride, slowly drip into reaction solution, keep 0 DEG C to stir 30 minutes, rising to room temperature stirs 30 minutes again, slowly drip a small amount of water termination reaction, concentration of reaction solution is to oily, add 100ml methylene dichloride to dissolve, it is acid being washed till water layer with 2M hydrochloric acid, wash (50ml × 2) with saturated sodium bicarbonate solution respectively again, washing (50ml × 2), saturated nacl aqueous solution is washed (50ml × 2), under stirring, with anhydrous magnesium sulfate drying 2 hours, filter, be spin-dried for.Add the mixing solutions of 20ml ether/sherwood oil (volume ratio 1/1), stirring at room temperature 2 hours, filters, and 40 DEG C of vacuum-dryings obtain two (the trichloro-ethoxycarbonyl)-10-deacetylate baccatin III 16.12g of 7,10-, yield: 90.6%.
1H-NMR（400 MHz，CDCl
3）
δ=1.12(s，3H)，1.15（s，3H），1.84（s，3H），2.05（m，1H），2.14（m，1H），2.17（s，3H），2.31（m，2H），2.32（s，3H），2.64（m，1H），3.98（d，
J=6.8Hz，1H），4.15（d，
J=8.0Hz，1H），4.34（d，
J=8.0Hz，1H），4.61（d，
J=12.0Hz，1H），4.76（d，
J=12.0Hz，1H），4.81（d，
J=12.0Hz，1H），4.90（m，1H），4.92（d，
J=12.0Hz，1H），5.00（d，
J=8.0Hz，1H），5.64（m，1H），5.65（d，
J=6.8Hz，1H），6.27（s，1H），7.49（t，
J=8.0Hz，2H），7.62（t，
J=8.0Hz，2H），8.10（d，
J=7.2Hz，2H）。
(2) formula
iII-1synthesizing of compound:
At room temperature, by 9.73g 7, two (the trichloro-ethoxycarbonyl)-10-deacetylate baccatin IIIs of 10-are dissolved in 150ml diisopropyl ethyl amine (DIPEA), add the benzyl chloride methyl ether of 1.87g, stirring is spent the night, add after 200ml water to reaction solution, extract by ethyl acetate (100ml × 3), merge organic layer, washing (50ml × 2), saturated common salt water washing (50ml × 2), anhydrous magnesium sulfate drying 3 hours, after filtering siccative, be spin-dried for, separate with sherwood oil/methylene dichloride (volume ratio 2/1) silica gel column chromatography, obtain 7 of 9.67g, two (the trichloro-ethoxycarbonyl)-13-benzyloxy-10-deacetylate baccatin IIIs of 10-, yield 89.0%.
1H-NMR（400 MHz，CDCl
3）
δ=0.55（m，6H），0.93（t，
J=8.0Hz，9H），1.14（s，6H），1.53（m，1H），1.90（s，3H），2.06（m，1H），2.14（s，3H），2.19（m，1H），2.25（m，1H），2.30（s，3H），2.63（m，1H），3.93（d，
J=6.4Hz，1H），4.18（d，
J=7.6Hz，1H），4.36（d，
J=8.0Hz，1H），4.65（d，
J=12.0Hz，1H），4.80（d，
J=12.0Hz，1H），4.83（d，
J=12.0Hz，1H），4.86（m，1H），4.97（d，
J=12.0Hz，1H），5.03（d，
J=8.0Hz，1H），5.64（m，1H），5.65（d，
J=6.8Hz，1H），6.26（s，1H），7.47（t，
J=7.6Hz，2H），7.60（t，
J=8.0Hz，2H），8.10（d，
J=8.4Hz，2H）。
(3) formula
iV-1synthesizing of compound:
Under room temperature, first by 7 of 2.81g, the zinc powder of two (the trichloro-ethoxycarbonyl)-13-benzyloxy-10-deacetylate baccatin IIIs of 10-and 1.43g adds in 150ml there-necked flask, then add the Glacial acetic acid of 10ml and the dehydrated alcohol of 100ml, be warming up to after 60 DEG C, react 30 minutes, cooling, filter, revolve except ethanol, in reaction solution, add 150ml water, extract by ethyl acetate (100ml × 3), merge organic layer, saturated sodium bicarbonate solution wash water layer is to weakly alkaline, washing (50ml × 2), saturated sodium-chloride is washed (50ml × 2), anhydrous magnesium sulfate drying, after filtering siccative, with petrol ether/ethyl acetate (volume ratio 1/1) silica gel column chromatography, obtain 13-benzyloxy-10-deacetylate baccatin III of 2.24g, yield 79.7%.
(4) formula V-1 compound is synthetic:
Under nitrogen protection condition,-10 DEG C, the NaH of 0.01g is suspended in the anhydrous THF of 30ml, add again 1.49g 13-benzyloxy-10-deacetylate baccatin III, the slowly methyl iodide of injection 0.4ml, slowly rise to room temperature, stir after 20 hours, in reaction solution, add 50ml water, extract by ethyl acetate (30ml × 3), merge organic layer, washing (30ml × 2), saturated sodium-chloride washing (30ml × 2), anhydrous magnesium sulfate drying, after filtering siccative, with petrol ether/ethyl acetate (volume ratio 5/1) silica gel column chromatography, obtain the formula V-1 compound of 1.41g, yield 91.1%.
(5) formula VI compound is synthetic:
The formula V-1 compound of 2.79g is dissolved in the methyl alcohol of 30ml, then add the 2M HCl of 5ml, stirring at room temperature 2.5 hours adds 60ml water in reaction solution, extract by ethyl acetate (30ml × 3), merge organic layer, washing (50ml × 2), saturated sodium-chloride washing (50ml × 2), after anhydrous magnesium sulfate drying, filtering siccative, with petrol ether/ethyl acetate (volume ratio 5/1) silica gel column chromatography, obtain the formula VI compound of 1.56g, yield 64.9%.
1H-NMR（400 MHz，DMSO-
d 6）
δ=0.93（s，6H），1.48（m，1H），1.51（s，3H），1.97（s，3H），2.18（m，2H），2.20（s，3H），2.69（m，1H），3.16（s，3H），3.29（s，3H），3.75（d，
J=6.8Hz，1H），3.81（m，1H），4.02（m，2H），4.39（s，1H），4.65（m，1H），4.75（s，1H），4.97（d，
J=8.8Hz，1H），5.30（d，
J=4.8Hz，1H），5.37（d，
J=6.8Hz，1H），7.56（t，
J=7.6Hz，2H），7.66（t，
J=7.2Hz，2H），8.01（d，
J=7.6Hz，2H）。
(6) formula VIII compound is synthetic:
By the formula VI compound of 3.58g, 6.24g oxazolidine carboxylic acid side chain, the DMAP (DMAP) of catalytic amount and the dicyclohexylcarbodiimide (DCC) of 3.87g add in there-necked flask, add again the anhydrous methylene chloride of 100ml, stirring at room temperature 4 hours, filter, filtrate is frozen 4h in refrigerator and cooled, refilter, filtrate is washed till weakly alkaline with protection sodium hydrogen carbonate solution, water washing again (50ml × 2), saturated common salt water washing (50ml × 2), anhydrous magnesium sulfate drying, after filtering siccative, with petrol ether/ethyl acetate (volume ratio 5/1) silica gel column chromatography, obtain the formula VIII compound Cabazitaxel precursor of 5.37g, yield 90.1%.
1H-NMR（400 MHz，CDCl
3）
δ=1.05（s，9H），1.16(s，3H)，1.19（s，3H），1.67（s，3H），1.69（s，3H），1.72（m，4H），2.02（m，1H），2.19（m，1H），2.64（m，1H），3.26（s，3H），3.40（s，3H），3.71（d，
J=7.2Hz，1H），3.81（s，3H），3.81（m，1H），4.13（d，
J=7.2Hz，1H），4.22（d，
J=8.4Hz，1H），4.57（d，
J=3.6Hz，1H），4.70（s，1H），4.89（d，
J=8.8Hz，1H），5.40（s，1H），5.57（d，
J=7.2Hz，1H），6.12（d，
J=3.6Hz，1H），6.42（br s，1H），6.92（d，
J=8.8Hz，2H），7.45（m，7H），7.50（t，
J=8.0Hz，2H），7.62（t，
J=7.6Hz，2H），8.02（d，
J=7.2Hz，2H）。
(7) Cabazitaxel is synthetic:
The Cabazitaxel precursor of 5.37g is dissolved in the saturated solution of acidic alcohol of 80ml, under 0 DEG C of condition, stir 16 hours, then in reaction solution, add 100ml water, use again methylene dichloride (100ml × 3) extraction, merging organic layer, saturated sodium bicarbonate solution are washed till neutrality, water washing (50ml × 2), saturated common salt water washing (50ml × 2), anhydrous magnesium sulfate drying, after filtering siccative, remove solvent under reduced pressure, with petrol ether/ethyl acetate (volume ratio 3/1) recrystallization, obtain the Cabazitaxel of 5.18g, yield 92.0%.
1H-NMR（400 MHz，CDCl
3）
δ=1.20（s，6H），1.35（s，9H），1.69（s，3H），1.79（m，1H），1.87（s，3H），2.29（m，2H），2.36（s，3H），2.69（m，1H），3.30（s，3H），3.45（s，3H），3.80（m，2H），4.16（d，
J=8.8Hz，1H），4.29（d，
J=8.4Hz，1H），4.63（s，1H），4.79（s，1H），4.97（d，
J=8.4Hz，1H），5.28（d，
J=7.2Hz，1H），5.47（d，
J=7.2Hz，1H），5.63（d，
J=6.8Hz，1H），6.20（t，
J=6.4Hz，1H），7.33（m，1H），7.39（m，4H），7.48（t，
J=8.0Hz，2H），7.60（t，
J=7.6Hz，2H），8.09（d，
J=7.2Hz，2H）。
Embodiment 2
route 2
(1) formula II-2 compound 7, two (the trichloro-ethoxycarbonyl)-10-deacetylate baccatin IIIs of 10-synthetic:
With reference to the method described in embodiment 1, obtain formula II-2 compound, yield 91.2%.
(2) formula III-2 compound is synthetic:
By 7 of 3.44g, two (the trichloro-ethoxycarbonyl)-10-deacetylate baccatin IIIs of 10-are dissolved in 50ml pyridine, then slowly splash into TESCl(chlorotriethyl silane) 0.62g, be heated to 120 DEG C, stir 4 hours, in reaction solution, add 100ml water, use again ethyl acetate (100ml × 3) aqueous layer extracted, merge organic layer, washing (50ml × 2), saturated common salt washing (50ml × 2), add anhydrous magnesium sulfate drying, with sherwood oil/methylene dichloride (volume ratio 2/1) silica gel column chromatography, obtain 7 of 2.92g, two (the trichloro-ethoxycarbonyl)-13-chlorotriethyl silane-10-deacetylate baccatin IIIs of 10-, yield 90.0%.
1H-NMR（400 MHz，CDCl
3）
δ=0.55（m，6H），0.93（t，
J=8.0Hz，9H），1.14（s，6H），1.53（m，1H），1.90（s，3H），2.06（m，1H），2.14（s，3H），2.19（m，1H），2.25（m，1H），2.30（s，3H），2.63（m，1H），3.93（d，
J=6.4Hz，1H），4.18（d，
J=7.6Hz，1H），4.36（d，
J=8.0Hz，1H），4.65（d，
J=12.0Hz，1H），4.80（d，
J=12.0Hz，1H），4.83（d，
J=12.0Hz，1H），4.86（m，1H），4.97（d，
J=12.0Hz，1H），5.03（d，
J=8.0Hz，1H），5.64（m，1H），5.65（d，
J=6.8Hz，1H），6.26（s，1H），7.47（t，
J=7.6Hz，2H），7.60（t，
J=8.0Hz，2H），8.10（d，
J=8.4Hz，2H）。
7.60（t，
J=8.0Hz，2H），8.10（d，
J=8.4Hz，2H）。
(3) formula IV-2 compound is synthetic:
With reference to the method described in embodiment 1, obtain formula IV-2 compound, yield 81.2%.
(4) formula V-2 compound is synthetic:
Method as described in Example 1, obtains formula V-2 compound, yield 90.8%.
(5) formula VI compound is synthetic:
Nitrogen protection; the formula V-2 compound of 2.06g is dissolved in 30ml methylene dichloride; at 0 DEG C, slowly add 50mg hydrofluoric acid-triethylamine title complex; keep 0 DEG C to stir 30 hours; in reaction solution, add 100ml water; use again methylene dichloride (50ml × 3) aqueous layer extracted; merge organic layer; washing (50ml × 2); saturated common salt washing (50ml × 2), adds anhydrous magnesium sulfate drying, with petrol ether/ethyl acetate (volume ratio 3/1) silica gel column chromatography; obtain the compound VI of 1.41g, yield 82.0%.
1H-NMR（400 MHz，DMSO-
d 6）
δ=0.93（s，6H），1.48（m，1H），1.51（s，3H），1.97（s，3H），2.18（m，2H），2.20（s，3H），2.69（m，1H），3.16（s，3H），3.29（s，3H），3.75（d，
J=6.8Hz，1H），3.81（m，1H），4.02（m，2H），4.39（s，1H），4.65（m，1H），4.75（s，1H），4.97（d，
J=8.8Hz，1H），5.30（d，
J=4.8Hz，1H），5.37（d，
J=6.8Hz，1H），7.56（t，
J=7.6Hz，2H），7.66（t，
J=7.2Hz，2H），8.01（d，
J=7.6Hz，2H）。
(6) formula VIII compound is synthetic:
Method as described in Example 1, obtains formula VIII compound, yield 92.7%.
(7) Cabazitaxel is synthetic:
Method as described in Example 1, obtains Cabazitaxel, yield 93.0%.
Embodiment 3
route 3
(1) formula II-3 compound is synthetic:
In 250ml three-necked bottle, nitrogen protection, the 10-deacetylate baccatin III of 10.81g is dissolved in to 100ml anhydrous pyridine, being cooled to 0 DEG C stirs 10 minutes, 8ml methoxy (ethoxy) methane is dissolved in 50ml anhydrous methylene chloride, slowly drip into reaction solution, keep 0 DEG C to stir 30 minutes, rising to room temperature stirs 40 minutes again, slowly drip a small amount of water termination reaction, concentration of reaction solution is to oily, add 100ml methylene dichloride to dissolve, it is acid being washed till water layer with 2M hydrochloric acid, wash (50ml × 2) with saturated sodium bicarbonate solution respectively again, washing (50ml × 2), saturated nacl aqueous solution is washed (50ml × 2), under stirring, with anhydrous magnesium sulfate drying 2 hours, filter, be spin-dried for.Add the mixing solutions of 20ml ether/sherwood oil (volume ratio 1/1), stirring at room temperature 2.5 hours, filters, and 40 DEG C of vacuum-dryings obtain two (methoxy (ethoxy) the methyl)-10-deacetylate baccatin III 14.57g of 7,10-, yield: 87.6%.
1H-NMR（400 MHz，CDCl
3）
δ=1.12(s，3H)，1.15（s，3H），1.84（s，3H），2.05（m，1H），2.14（m，1H），2.17（s，3H），2.31（m，2H），2.32（s，3H），2.64（m，1H），3.98（d，
J=6.8Hz，1H），4.15（d，
J=8.0Hz，1H），4.34（d，
J=8.0Hz，1H），4.61（d，
J=12.0Hz，1H），4.76（d，
J=12.0Hz，1H），4.81（d，
J=12.0Hz，1H），4.90（m，1H），4.92（d，
J=12.0Hz，1H），5.00（d，
J=8.0Hz，1H），5.64（m，1H），5.65（d，
J=6.8Hz，1H），6.27（s，1H），7.49（t，
J=8.0Hz，2H），7.62（t，
J=8.0Hz，2H），8.10（d，
J=7.2Hz，2H）。
(2) formula III-3 compound is synthetic:
By 7 of 3.44g, two (methoxy (ethoxy) the methyl)-10-deacetylate baccatin IIIs of 10-are dissolved in 50ml pyridine, then slowly splash into TMSCl(trimethylchlorosilane) 0.62g, be heated to 120 DEG C, stir 4 hours, in reaction solution, add 100ml water, use again ethyl acetate (100ml × 3) aqueous layer extracted, merge organic layer, washing (50ml × 2), saturated common salt washing (50ml × 2), add anhydrous magnesium sulfate drying, with sherwood oil/methylene dichloride (volume ratio 2/1) silica gel column chromatography, obtain 7 of 2.76g, two (methoxy (ethoxy) the methyl)-13-trimethylchlorosilane-10-deacetylate baccatin IIIs of 10-, yield 88.2%.
1H-NMR（400 MHz，CDCl
3）
δ=0.55（m，6H），0.93（t，
J=8.0Hz，9H），1.14（s，6H），1.53（m，1H），1.90（s，3H），2.06（m，1H），2.14（s，3H），2.19（m，1H），2.25（m，1H），2.30（s，3H），2.63（m，1H），3.93（d，
J=6.4Hz，1H），4.18（d，
J=7.6Hz，1H），4.36（d，
J=8.0Hz，1H），4.65（d，
J=12.0Hz，1H），4.80（d，
J=12.0Hz，1H），4.83（d，
J=12.0Hz，1H），4.86（m，1H），4.97（d，
J=12.0Hz，1H），5.03（d，
J=8.0Hz，1H），5.64（m，1H），5.65（d，
J=6.8Hz，1H），6.26（s，1H），7.47（t，
J=7.6Hz，2H），7.60（t，
J=8.0Hz，2H），8.10（d，
J=8.4Hz，2H）。
(3) formula IV-3 compound is synthetic:
Under room temperature, first by 7 of 2.95g, the zinc powder of two (methoxy (ethoxy) the methyl)-13-trimethylchlorosilane-10-deacetylate baccatin IIIs of 10-and 1.43g adds in 150ml there-necked flask, then add the trifluoroacetic acid of 10ml and the dehydrated alcohol of 100ml, be warming up to after 60 DEG C, react 30 minutes, cooling, filter, revolve except ethanol, in reaction solution, add 150ml water, extract by ethyl acetate (100ml × 3), merge organic layer, saturated sodium bicarbonate solution wash water layer is to weakly alkaline, washing (50ml × 2), saturated sodium-chloride is washed (50ml × 2), anhydrous magnesium sulfate drying, after filtering siccative, with petrol ether/ethyl acetate (volume ratio 1/1) silica gel column chromatography, obtain 13-trimethylchlorosilane-10-deacetylate baccatin III of 2.28g, yield 73.5%.
(4) formula V-3 compound is synthetic:
Under nitrogen protection condition,-10 DEG C, the NaH of 0.01g is suspended in the anhydrous THF of 30ml, add again 1.52g 13-trimethylchlorosilane-10-deacetylate baccatin III, the slowly methyl iodide of injection 0.4ml, slowly rise to room temperature, stir after 20 hours, in reaction solution, add 50ml water, extract by ethyl acetate (30ml × 3), merge organic layer, washing (30ml × 2), saturated sodium-chloride washing (30ml × 2), anhydrous magnesium sulfate drying, after filtering siccative, with petrol ether/ethyl acetate (volume ratio 5/1) silica gel column chromatography, obtain the formula V-3 compound of 1.53g, yield 87.4%.
(5) formula VI compound is synthetic:
The formula V-3 compound of 2.82g is dissolved in the methyl alcohol of 30ml, then add the 2M HCl of 5ml, stirring at room temperature 2.5 hours adds 60ml water in reaction solution, extract by ethyl acetate (30ml × 3), merge organic layer, washing (50ml × 2), saturated sodium-chloride washing (50ml × 2), after anhydrous magnesium sulfate drying, filtering siccative, with petrol ether/ethyl acetate (volume ratio 5/1) silica gel column chromatography, obtain the formula VI compound of 1.58g, yield 64.1%.
1H-NMR（400 MHz，DMSO-
d 6）
δ=0.93（s，6H），1.48（m，1H），1.51（s，3H），1.97（s，3H），2.18（m，2H），2.20（s，3H），2.69（m，1H），3.16（s，3H），3.29（s，3H），3.75（d，
J=6.8Hz，1H），3.81（m，1H），4.02（m，2H），4.39（s，1H），4.65（m，1H），4.75（s，1H），4.97（d，
J=8.8Hz，1H），5.30（d，
J=4.8Hz，1H），5.37（d，
J=6.8Hz，1H），7.56（t，
J=7.6Hz，2H），7.66（t，
J=7.2Hz，2H），8.01（d，
J=7.6Hz，2H）。
(6) formula VIII compound is synthetic:
By the formula VI compound of 3.32g, 6.41g oxazolidine carboxylic acid side chain, the DMAP (DMAP) of catalytic amount and the dicyclohexylcarbodiimide (DCC) of 3.87g add in there-necked flask, add again the anhydrous methylene chloride of 100ml, stirring at room temperature 4 hours, filter, filtrate is frozen 4h in refrigerator and cooled, refilter, filtrate is washed till weakly alkaline with protection sodium hydrogen carbonate solution, water washing again (50ml × 2), saturated common salt water washing (50ml × 2), anhydrous magnesium sulfate drying, after filtering siccative, with petrol ether/ethyl acetate (volume ratio 5/1) silica gel column chromatography, obtain the formula VIII compound Cabazitaxel precursor of 5.39g, yield 89.3%.
1H-NMR（400 MHz，CDCl
3）
δ=1.05（s，9H），1.16(s，3H)，1.19（s，3H），1.67（s，3H），1.69（s，3H），1.72（m，4H），2.02（m，1H），2.19（m，1H），2.64（m，1H），3.26（s，3H），3.40（s，3H），3.71（d，
J=7.2Hz，1H），3.81（s，3H），3.81（m，1H），4.13（d，
J=7.2Hz，1H），4.22（d，
J=8.4Hz，1H），4.57（d，
J=3.6Hz，1H），4.70（s，1H），4.89（d，
J=8.8Hz，1H），5.40（s，1H），5.57（d，
J=7.2Hz，1H），6.12（d，
J=3.6Hz，1H），6.42（br s，1H），6.92（d，
J=8.8Hz，2H），7.45（m，7H），7.50（t，
J=8.0Hz，2H），7.62（t，
J=7.6Hz，2H），8.02（d，
J=7.2Hz，2H）。
(7) Cabazitaxel is synthetic:
The Cabazitaxel precursor of 6.23g is dissolved in the saturated solution of acidic alcohol of 80ml, under 0 DEG C of condition, stir 16 hours, then in reaction solution, add 100ml water, use again methylene dichloride (100ml × 3) extraction, merging organic layer, saturated sodium bicarbonate solution are washed till neutrality, water washing (50ml × 2), saturated common salt water washing (50ml × 2), anhydrous magnesium sulfate drying, after filtering siccative, remove solvent under reduced pressure, with petrol ether/ethyl acetate (volume ratio 3/1) recrystallization, obtain the Cabazitaxel of 5.05g, yield 91.2%.
1H-NMR（400 MHz，CDCl
3）
δ=1.20（s，6H），1.35（s，9H），1.69（s，3H），1.79（m，1H），1.87（s，3H），2.29（m，2H），2.36（s，3H），2.69（m，1H），3.30（s，3H），3.45（s，3H），3.80（m，2H），4.16（d，
J=8.8Hz，1H），4.29（d，
J=8.4Hz，1H），4.63（s，1H），4.79（s，1H），4.97（d，
J=8.4Hz，1H），5.28（d，
J=7.2Hz，1H），5.47（d，
J=7.2Hz，1H），5.63（d，
J=6.8Hz，1H），6.20（t，
J=6.4Hz，1H），7.33（m，1H），7.39（m，4H），7.48（t，
J=8.0Hz，2H），7.60（t，
J=7.6Hz，2H），8.09（d，
J=7.2Hz，2H）。
Although the present invention discloses as above with preferred embodiment; so it is not in order to limit the present invention, anyly has the knack of this skill person, without departing from the spirit and scope of the present invention; when doing to change and retouching, the scope that therefore protection scope of the present invention ought define depending on accompanying claims is as the criterion.
Claims (3)
1. a synthetic method for Cabazitaxel, said method comprising the steps of:
(1) compound shown in formula (I) is carried out to hydroxyl selective protection and prepare the compound shown in formula (II)
(2) compound shown in the formula (II) step (1) being prepared carries out selectivity hydroxyl protection, prepares the compound shown in formula (III)
(3) slough the R1 protecting group in the compound shown in the formula (III) that step (2) prepares, prepare the compound shown in formula (IV)
(4) compound shown in formula IV step (3) being prepared carries out HM reaction, prepares the compound shown in formula (V)
(5) slough the R of the compound shown in the formula (V) that step (4) prepares
2protecting group, prepares the compound shown in formula (VI)
(6) compound shown in the compound shown in the formula (VI) step (5) being prepared and formula (VII) carries out condensation reaction and prepares the compound shown in formula (VIII)
(7) the compound deprotection shown in the formula (VIII) step (6) being prepared obtains Cabazitaxel;
Wherein R
1and R
2not identical, be respectively benzyloxymethyl, methoxyl methyl, methoxy (ethoxy) methyl, tertiary butyl dimethyl silyl, trimethyl silicon based, triethyl is silica-based, trichloro-ethoxycarbonyl, tertbutyloxycarbonyl.
2. the method for claim 1, is characterized in that step (4) is taking methyl iodide as methylating reagent, under nitrogen or argon shield, the compound shown in formula (IV) is carried out to HM.
3. the method for claim 1, is characterized in that R
1protecting group is trichloro-ethoxycarbonyl; R
2protecting group is that benzyloxymethyl, triethyl are silica-based.
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| CN104557798A (en) * | 2013-10-29 | 2015-04-29 | 神威药业集团有限公司 | Preparation method for dimethoxy docetaxel |
| CN107353263B (en) * | 2017-05-25 | 2019-09-13 | 浙江叠智医药科技有限公司 | The method for preparing the chloro- 10- deacetylate Bakating III of the bis- tri-chloroethoxy base formyls of 7,10- using micro passage reaction |
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