CN102659721A - 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 the pharmaceutical chemistry field, relate in particular to the compound method of his match (Cabazitaxel) of a kind of kappa.
Background technology
Prostate cancer is male sex's common cancer, and regular incidence is second largest common male cancer except that skin carcinoma in elderly men in the U.S..According to disease prevention and control center's statistics, there were 203415 male sex to suffer from prostate cancer approximately in 2006, wherein 28372 people are dead.
His match (Cabazitaxel) of kappa is the two wires medicine of the prostate cancer of Sanofi company research and development, and its commodity are called Jevtana.Cabazitaxel is a kind of chemical partially synthetic taxinane micromolecular compound, and its critical materials mainly extracts from the Ramulus et folium taxi cuspidatae needle.The antitumous effect mechanism of Cabazitaxel is similar with docetaxel with characteristics, belongs to anti-microtubule class medicine.He matches kappa through combining with tubulin; Promote it to be assembled into microtubule; Stop the microtubule 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).
?
Kappa he match in 2010 by drugs approved by FDA, with prednisone (prednisone) drug combination, be applied to treat the intractable metastatic prostate cancer patient of the hormone of once accepting the docetaxel therapy.His match of kappa is behind docetaxel, the 2nd the prostate treatment medicine in U.S.'s approval listing.
Kappa he to match molecular formula be C
45H
57NO
14,White crystals, water insoluble, solvable and ethanol, chemistry (2R by name; 3S)-3-t-butoxycarbonyl amino-2-hydroxyl-3-phenylpropionic acid-4 α-ethanoyl-2 α-benzoyl--5 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 to be raw material, under the condition of pyridine 7 with 10-deacetylate baccatin III (10-deacetylbaccatin III, 10-DAB III); Introduce triethyl silica-based (TES) protection base for 13; Be under the condition of alkali at sodium hydride then, introduce methyl at 10, remove TES protection base again with methyl iodide; Be alkali in order to sodium hydride at low temperatures; Introduce methyl with methyl iodide at 7, Yu oxazolidine carboxylic acid side chain condensation then, Chun Xie oxazole ring obtains his match of target compound kappa under acidic conditions again.This method is when introducing TES protection base and methyl, and yield is all very low, and harsh to the requirement of reaction conditions, is not suitable for suitability for industrialized production; The second route is to be raw material with 10-DAB III; Introduce trichloro-ethoxycarbonyl (Troc) protection base, Yu oxazolidine carboxylic acid side chain condensation then at 7,10 earlier; Remove Troc protection base again; Introduce methyl through 7,10 hydroxyls of Pummerer rearrangement reaction and Raney nickel reduction, Chun Xie oxazole ring obtains his match of target compound kappa under acidic conditions at last.This method has been introduced chirality De oxazolidine carboxylic acid side chain from the beginning, causes the waste of more expensive material, and Pummerer rearrangement reaction and Raney nickel reduction yield are general.
In reported method, route is complicated, and by product is many, and shortcomings such as the low and cost height of yield cause the cost of his match of kappa high.Therefore, urgent need will be sought a suitable suitability for industrialized production, and he matches production cost to reduce kappa, and he matches the compound method of quality product to improve kappa.
Summary of the invention
The object of the invention be to provide a kind of new kappa he the match (Cabazitaxel) compound method, to overcome the shortcoming that exists in the former synthetic route.Compound method of the present invention can significantly reduce medical treatment cost, and relieve patient ' s burden has broad prospects on industrial application.
He the method for match may further comprise the steps said synthetic kappa:
(1) compound shown in the formula I is carried out hydroxyl selective protection and prepare compound shown in the formula II
(2) compound carries out the selectivity hydroxyl protection shown in the formula II that step (1) is prepared, and prepares compound shown in the formula III
，
(3) slough the R in the compound shown in the formula III that step (2) prepares
1The protection base prepares formula IV compound
(4) compound shown in the formula IV that step (3) is prepared carries out the HM reaction, prepares compound shown in the formula V
(5) slough the R of compound shown in the formula V that step (4) prepares
2The protection base prepares compound shown in the formula VI
(6) compound shown in compound and the formula VII shown in the formula VI that step (5) is prepared carries out condensation reaction and prepares the compound shown in the formula VIII
(7) the compound deprotection shown in the formula VIII that step (6) is prepared obtains his match of kappa;
R wherein
1And R
2Inequality, be respectively any substituted C
1-C
4Alkyl, C
1-C
4Alkyl replace silica-based, any substituted C
1-C
4Carbonyl.
More specifically, in the above-mentioned steps (1), be that 7 and 10 hydroxyls to formula I compound (10-DAB III) carry out 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 described hydroxyl protection of step (1) is this area ordinary method; Under alkaline condition; Compound shown in hydroxyl protection reagent and the formula I is reacted in organic solvent, 7,10 hydroxyl of the compound shown in the formula I is carried out selective protection obtain the compound shown in the formula II.
For example, when selecting benzyloxymethyl (BOM), methoxyl methyl (MOM), methoxy (ethoxy) methyl substituent methyls such as (MEM) as R
1During the protection base, used protection reagent includes but not limited to 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, 1,4-dioxy six alkane, methylene dichloride, DMF, DMF equal solvent.
Alkaline reagents is added the organic solvent that contains compound shown in the formula I; Under-10 ℃～50 ℃ conditions, stirred 1～12 hour; And then become the ether reaction with said hydroxy-protecting agent, 7,10 hydroxyls are carried out selective protection obtain the compound shown in the formula II.
Silica-based when selecting triethyl silica-based (TES), tertiary butyl dimethyl silyl (TBS), trimethyl silicon based (TMS) etc. to replace as R
1During the protection base, used protection reagent includes but not limited to TESX, TBSX, TMSX etc., and wherein X is F, Cl, Br, I.
Described alkaline condition comprises: salt of wormwood, yellow soda ash, sodium hydroxide, triethylamine etc.; Described organic solvent comprises pyridine, THF, methylene dichloride etc.
Compound shown in the formula I and protection reagent are added in the organic solvent, add appropriate bases, room temperature to 80 a ℃ stirring obtained the compound shown in the formula II in 1～10 hour.
When selecting trichloro-ethoxycarbonyl (Troc) is R
1During the protection base; Select TrocCl reagent; In such as organic solvents such as pyridine, THF, methylene dichloride, optional 4-dimethylaminopyridine (DMAP) catalyzer stirred 1～14 hour in 0 ℃～80 ℃; Behind extraction, washing, drying, post separation or recrystallization, obtain the compound shown in the formula II.
When selecting tertbutyloxycarbonyl (BOC) is R
1During the protection base, select BOC acid anhydrides (BOC
2O) reagent, preferred organic solvent dichloromethane, THF, optional DMAP catalyzer stirred 1～10 hour at 0 ℃～80 ℃, through extraction, washing, dry, post separates or recrystallization after, obtain the compound shown in the formula II.
In the above-mentioned steps (2), be that 13 hydroxyls to the compound shown in the formula II carry out selective protection, prepare the compound shown in the 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).
Said hydroxyl protection reaction method is identical with the said method of step (1).
In the above-mentioned steps (3), described hydroxyl deprotection method is this area domestic method, for example, works as R
1Protection base be benzyloxymethyl (BOM), methoxyl methyl (MOM), methoxy (ethoxy) methyl substituent methyls such as (MEM) as protecting when basic; The formula III compound is at acidic conditions; Under the lewis acidic participation, in the organic solvent, in 0 ℃ of reflux temperature to solvent for use; Reacted 1～12 hour, and obtained the compound shown in the formula IV.Described acidic conditions comprises hydrochloric acid, trifluoroacetic acid, Glacial acetic acid min. 99.5 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
1Protection base is that replacements such as triethyl silica-based (TES), tertiary butyl dimethyl silyl (TBS), trimethyl silicon based (TMS) are when silica-based; The formula III compound is at acidic conditions, in the organic solvent, in 0 ℃ of reflux temperature to solvent for use; Reacted 1～24 hour, and obtained the compound shown in the formula IV.Described acidic conditions comprises hydrochloric acid, Hydrocerol A, hydrofluoric acid etc.; Described organic solvent is selected from methylene dichloride, ether, THF.
Work as R
1The protection base can be selected zinc powder and/or copper powder, acetic acid when being trichloro-ethoxycarbonyl (Troc), in ethanol or methanol solvate, between the room temperature to 90 ℃, reacts and obtains the compound shown in the formula IV in 15～20 hours.
Work as R
1Protection base can be in organic solvents such as dioxane, methylene dichloride when being tertbutyloxycarbonyl (BOC), and use concentrated hydrochloric acid or trifluoroacetic acid under the reflux temperature condition of room temperature to solvent for use, react and obtained the compound shown in the formula IV in 1～20 hour.
Methylation reaction described in the step (4), nitrogen or argon shield in the organic solvent, under the alkaline condition, methylate to 7,10 hydroxyls with methyl iodide.Said solvent is THF or 1,4-dioxy six alkane; Described alkali is NaH.Described reaction is that formula IV compound is dissolved in the organic solvent, is cooled between-20 ℃～0 ℃, adds NaH, stirs, and slowly adds methyl iodide then to reaction solution, is warming up to 50 ℃ then, reacts 2～20 hours, obtains the compound shown in the formula V.
Deprotection described in the step (5) is identical with the method for sloughing corresponding protection base in the step (3).
Condensation reaction described in the step (6) is with formula VI compound and formula VII compound ianthone oxazolidine carboxylic acid side chain) be dissolved in such as in methylene dichloride, toluene, the THF equal solvent; Use NSC 57182 (DCC); Under the reflux temperature of room temperature to agents useful for same, react 2～15 hours compounds shown in the acquisition formula VIII.Can add 4-dimethylaminopyridine (DMAP) or 4-pyrrolidyl pyridine (PPY) in the reaction is catalyzer.
Deprotection reaction method described in the step (7) is those skilled in the art's domestic method, and formula VIII compound in ethanol solution hydrochloride, under 0 ℃ of condition, was reacted 16 hours, and he matches (Cabazitaxel) to obtain the end product kappa.
The method of the invention agents useful for same is cheap; Effectively reduce production costs, select suitable protection base and deprotection method, in the end Lian Jie oxazolidine carboxylic acid side chain; Have yield height, gentle, the simple operation and other advantages of reaction conditions, help suitability for industrialized production.
Because 7 of the compound shown in the selected starting material formula I and 10 hydroxyl activities are stronger than 13 hydroxyl activities among the present invention; In reaction easily and hydroxyl protection reagent react, reaction yield is higher, by product is less; 7 and 10 hydroxyls are at first protected; Again 13 hydroxyls are protected, can be avoided protecting 13 hydroxyl protections of part that produced incomplete to three position hydroxyls simultaneously, also can effectively solve the problem of the cost rising that produces because of wastage of material.
The yield in each step of whole piece reaction scheme all effectively improves, and has also reduced the usage quantity of raw material simultaneously, thereby realizes reducing product price.
Description of drawings
Fig. 1 is the hydroxyl ranking of compound shown in the formula I.
Embodiment
Only if definition is arranged in addition, all technology that the present invention uses and the implication of scientific terminology are identical with the implication of the affiliated technical field those of ordinary skill common sense of the present invention.Usually, the name and the following experimental technique of the present invention's use all are well known in the art or commonly used.
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 be enumerated embodiment below, and the present invention is further explained.
Embodiment
Embodiment 1
route 1
(1) formula
II-1Synthesizing of compound:
In the 250ml three-necked bottle, nitrogen protection is dissolved in the 100ml anhydrous pyridine with the 10-deacetylate baccatin III of 10.81g, is cooled to 0 ℃ and stirs 10 minutes; The 8ml trichloroethyl chloroformate is dissolved in the 50ml anhydrous methylene chloride, slowly drips reaction solution, keep 0 ℃ to stir 30 minutes, rose to the room temperature restir 30 minutes; Slowly drip the less water termination reaction, concentration of reaction solution adds the dissolving of 100ml methylene dichloride to oily, uses 2M hydrochloric acid to be washed till water layer and is acidity; Wash (50ml * 2) with saturated sodium bicarbonate solution respectively again, washing (50ml * 2), saturated nacl aqueous solution is washed (50ml * 2), stirs down; With anhydrous magnesium sulfate drying 2 hours, filter, revolve dried.The mixing solutions that adds 20ml ether/sherwood oil (volume ratio 1/1), stirring at room 2 hours is filtered, and 40 ℃ of vacuum-dryings get 7, two (the trichloro-ethoxycarbonyl)-10-deacetylate baccatin III 16.12g of 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, with 9.73g 7, two (the trichloro-ethoxycarbonyl)-10-deacetylate baccatin IIIs of 10-are dissolved in the 150ml diisopropyl ethyl amine (DIPEA), add the benzyl chloride methyl ether of 1.87g; Stirred overnight after reaction solution adds 200ml water, with ETHYLE ACETATE (100ml * 3) extraction, merges organic layer; Washing (50ml * 2), saturated common salt water washing (50ml * 2), anhydrous magnesium sulfate drying 3 hours; Behind the filtering siccative, revolve driedly, separate with sherwood oil/methylene dichloride (volume ratio 2/1) silica gel column chromatography; Obtain 7 of 9.67g, two (the trichloro-ethoxycarbonyl)-13-benzyloxies of 10--10-deacetylate baccatin III, 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 the room temperature, earlier with 7 of 2.81g, the zinc powder of two (the trichloro-ethoxycarbonyl)-13-benzyloxies of 10--10-deacetylate baccatin III and 1.43g adds in the 150ml there-necked flask, adds the Glacial acetic acid min. 99.5 of 10ml and the absolute ethyl alcohol of 100ml then; After being warming up to 60 ℃, reacted 30 minutes cooling; Filter, revolve, in reaction solution, add 150ml water except that ethanol; With ETHYLE ACETATE (100ml * 3) extraction, merge organic layer, saturated sodium bicarbonate solution wash water layer is to weakly alkaline; Washing (50ml * 2), saturated sodium-chloride is washed (50ml * 2), behind anhydrous magnesium sulfate drying, the 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 the nitrogen protection condition ,-10 ℃, the NaH of 0.01g is suspended among the anhydrous THF of 30ml, add 1.49g 13-benzyloxy-10-deacetylate baccatin III again; Slowly the methyl iodide of injection 0.4ml slowly rises to room temperature, stirs after 20 hours; In reaction solution, add 50ml water,, merge organic layer with ETHYLE ACETATE (30ml * 3) extraction; Washing (30ml * 2), saturated sodium-chloride washing (30ml * 2) is behind anhydrous magnesium sulfate drying, the 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, adds the 2M HCl of 5ml then, stirring at room 2.5 hours; In reaction solution, add 60ml water,, merge organic layer with ETHYLE ACETATE (30ml * 3) extraction; Washing (50ml * 2), saturated sodium-chloride washing (50ml * 2) is behind anhydrous magnesium sulfate drying, the 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:
Formula VI compound, 6.24g De oxazolidine carboxylic acid side chain, the 4-Dimethylamino pyridine (DMAP) of catalytic amount and the NSC 57182 (DCC) of 3.87g of 3.58g are added in the there-necked flask, add the anhydrous methylene chloride of 100ml again, stirring at room 4 hours; Filter, filtrating is frozen 4h in refrigerator and cooled, refilters; Filtrating is washed till weakly alkaline with the protection sodium hydrogen carbonate solution, water washing again (50ml * 2), saturated common salt water washing (50ml * 2), anhydrous magnesium sulfate drying; Behind the filtering siccative; With petrol ether/ethyl acetate (volume ratio 5/1) silica gel column chromatography, obtain his pre-games body of formula VIII compound kappa 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) his match of kappa is synthetic:
His the pre-games body of kappa of 5.37g is dissolved in the saturated solution of acidic alcohol of 80ml, under 0 ℃ of condition, stirred 16 hours; In reaction solution, add 100ml water then, use methylene dichloride (100ml * 3) extraction again, 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; Behind the filtering siccative, remove solvent under reduced pressure, with petrol ether/ethyl acetate (volume ratio 3/1) recrystallization; He matches yield 92.0% kappa of acquisition 5.18g.
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
(1) formula II-2 compound 7, two (the trichloro-ethoxycarbonyl)-10-deacetylate baccatin IIIs of 10-synthetic:
With reference to embodiment 1 described method, obtain formula II-2 compound, yield 91.2%.
(2) formula III-2 compound is synthetic:
With 7 of 3.44g, two (the trichloro-ethoxycarbonyl)-10-deacetylate baccatin IIIs of 10-are dissolved in the 50ml pyridine, slowly splash into TESCl (chlorotriethyl silane) 0.62g then; Be heated to 120 ℃, stirred 4 hours, in reaction solution, add 100ml water; Use ETHYLE ACETATE (100ml * 3) aqueous layer extracted again, merge organic layer, washing (50ml * 2); Saturated common salt washing (50ml * 2) adds anhydrous magnesium sulfate drying, with sherwood oil/methylene dichloride (volume ratio 2/1) silica gel column chromatography; Promptly obtain 7 of 2.92g, two (the trichloro-ethoxycarbonyl)-13-chlorotriethyl silanes of 10--10-deacetylate baccatin III, 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 embodiment 1 described method, obtain formula IV-2 compound, yield 81.2%.
(4) formula V-2 compound is synthetic:
Like embodiment 1 described method, obtain formula V-2 compound, yield 90.8%.
(5) formula VI compound is synthetic:
Nitrogen protection is dissolved in the formula V-2 compound of 2.06g in the 30ml methylene dichloride, slowly adds 50mg hydrofluoric acid-triethylamine title complex down at 0 ℃; Keep 0 ℃ to stir 30 hours, in reaction solution, add 100ml water, use methylene dichloride (50ml * 3) aqueous layer extracted again; Merge organic layer, washing (50ml * 2), saturated common salt washing (50ml * 2); Add anhydrous magnesium sulfate drying; With petrol ether/ethyl acetate (volume ratio 3/1) silica gel column chromatography, promptly 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:
Like embodiment 1 described method, obtain formula VIII compound, yield 92.7%.
(7) his match of kappa is synthetic:
Like embodiment 1 described method, he matches to obtain kappa, yield 93.0%.
Embodiment 3
(1) formula II-3 compound is synthetic:
In the 250ml three-necked bottle, nitrogen protection is dissolved in the 100ml anhydrous pyridine with the 10-deacetylate baccatin III of 10.81g, is cooled to 0 ℃ and stirs 10 minutes; 8ml methoxy (ethoxy) methane is dissolved in the 50ml anhydrous methylene chloride, slowly drips reaction solution, keep 0 ℃ to stir 30 minutes, rose to the room temperature restir 40 minutes; Slowly drip the less water termination reaction, concentration of reaction solution adds the dissolving of 100ml methylene dichloride to oily, uses 2M hydrochloric acid to be washed till water layer and is acidity; Wash (50ml * 2) with saturated sodium bicarbonate solution respectively again, washing (50ml * 2), saturated nacl aqueous solution is washed (50ml * 2), stirs down; With anhydrous magnesium sulfate drying 2 hours, filter, revolve dried.The mixing solutions that adds 20ml ether/sherwood oil (volume ratio 1/1), stirring at room 2.5 hours is filtered, and 40 ℃ of vacuum-dryings get 7, two (methoxy (ethoxy) the methyl)-10-deacetylate baccatin III 14.57g of 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:
With 7 of 3.44g, two (methoxy (ethoxy) the methyl)-10-deacetylate baccatin IIIs of 10-are dissolved in the 50ml pyridine, slowly splash into TMSCl (trimethylchlorosilane) 0.62g then; Be heated to 120 ℃, stirred 4 hours, in reaction solution, add 100ml water; Use ETHYLE ACETATE (100ml * 3) aqueous layer extracted again, merge organic layer, washing (50ml * 2); Saturated common salt washing (50ml * 2) adds anhydrous magnesium sulfate drying, with sherwood oil/methylene dichloride (volume ratio 2/1) silica gel column chromatography; Promptly obtain 7 of 2.76g, two (methoxy (ethoxy) the methyl)-13-trimethylchlorosilanes of 10--10-deacetylate baccatin III, 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 the room temperature, earlier with 7 of 2.95g, the zinc powder of two (methoxy (ethoxy) the methyl)-13-trimethylchlorosilanes of 10--10-deacetylate baccatin III and 1.43g adds in the 150ml there-necked flask, adds the trifluoroacetic acid of 10ml and the absolute ethyl alcohol of 100ml then; After being warming up to 60 ℃, reacted 30 minutes cooling; Filter, revolve, in reaction solution, add 150ml water except that ethanol; With ETHYLE ACETATE (100ml * 3) extraction, merge organic layer, saturated sodium bicarbonate solution wash water layer is to weakly alkaline; Washing (50ml * 2), saturated sodium-chloride is washed (50ml * 2), behind anhydrous magnesium sulfate drying, the 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 the nitrogen protection condition ,-10 ℃, the NaH of 0.01g is suspended among the anhydrous THF of 30ml, add 1.52g 13-trimethylchlorosilane-10-deacetylate baccatin III again; Slowly the methyl iodide of injection 0.4ml slowly rises to room temperature, stirs after 20 hours; In reaction solution, add 50ml water,, merge organic layer with ETHYLE ACETATE (30ml * 3) extraction; Washing (30ml * 2), saturated sodium-chloride washing (30ml * 2) is behind anhydrous magnesium sulfate drying, the 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, adds the 2M HCl of 5ml then, stirring at room 2.5 hours; In reaction solution, add 60ml water,, merge organic layer with ETHYLE ACETATE (30ml * 3) extraction; Washing (50ml * 2), saturated sodium-chloride washing (50ml * 2) is behind anhydrous magnesium sulfate drying, the 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:
Formula VI compound, 6.41g De oxazolidine carboxylic acid side chain, the 4-Dimethylamino pyridine (DMAP) of catalytic amount and the NSC 57182 (DCC) of 3.87g of 3.32g are added in the there-necked flask, add the anhydrous methylene chloride of 100ml again, stirring at room 4 hours; Filter, filtrating is frozen 4h in refrigerator and cooled, refilters; Filtrating is washed till weakly alkaline with the protection sodium hydrogen carbonate solution, water washing again (50ml * 2), saturated common salt water washing (50ml * 2), anhydrous magnesium sulfate drying; Behind the filtering siccative; With petrol ether/ethyl acetate (volume ratio 5/1) silica gel column chromatography, obtain his pre-games body of formula VIII compound kappa 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) his match of kappa is synthetic:
His the pre-games body of kappa of 6.23g is dissolved in the saturated solution of acidic alcohol of 80ml, under 0 ℃ of condition, stirred 16 hours; In reaction solution, add 100ml water then, use methylene dichloride (100ml * 3) extraction again, 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; Behind the filtering siccative, remove solvent under reduced pressure, with petrol ether/ethyl acetate (volume ratio 3/1) recrystallization; He matches yield 91.2% kappa of acquisition 5.05g.
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）。
Though the present invention discloses as above with preferred embodiment; Right its is not in order to limiting the present invention, anyly has the knack of this art, do not breaking away from the spirit and scope of the present invention; When can doing to change and retouching, so protection scope of the present invention is as the criterion when looking the scope that the accompanying Claim book defined.
Claims (4)
1. the compound method of his match of a kappa said method comprising the steps of:
(1) compound shown in the formula (I) is carried out hydroxyl selective protection and prepare the compound shown in the formula (II)
(2) compound shown in the formula (II) that step (1) is prepared carries out the selectivity hydroxyl protection, prepares the compound shown in the formula (III)
；
(3) slough R in the compound shown in the formula (III) that step (2) prepares
1The protection base prepares the compound shown in the formula (IV)
(4) compound shown in the formula IV that step (3) is prepared carries out the HM reaction, prepares the compound shown in the formula V
(5) slough the R of the compound shown in the formula V that step (4) prepares
2The protection base prepares the compound shown in the formula (VI)
；
(6) compound shown in the formula (VI) that step (5) is prepared and the compound shown in the formula (VII) carry out condensation reaction and prepare the compound shown in the formula (VIII)
(7) the compound deprotection shown in the formula (VIII) that step (6) is prepared obtains his match of kappa;
R wherein
1And R
2Inequality, be respectively any substituted C
1-C
4Alkyl, C
1-C
4Alkyl replace silica-based, any substituted C
1-C
4Carbonyl.
2. like the described method of claim 1, it is characterized in that R
1And R
2Be respectively benzyloxymethyl, methoxyl methyl, methoxy (ethoxy) methyl, tertiary butyl dimethyl silyl, trimethyl silicon based, triethyl is silica-based, trichloro-ethoxycarbonyl, tertbutyloxycarbonyl.
3. the method for claim 1 is characterized in that step (4) is is methylating reagent with the methyl iodide, carries out HM to the compound shown in the formula (IV) under nitrogen or argon shield.
4. the method for claim 1 is characterized in that R
1The protection base is a trichloro-ethoxycarbonyl; R
2The protection base is that benzyloxymethyl, triethyl are silica-based.
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| CN102898406A (en) * | 2012-11-02 | 2013-01-30 | 上海金和生物技术有限公司 | Cabazitaxel crystal and preparation method thereof |
| CN103044364A (en) * | 2013-01-07 | 2013-04-17 | 重庆泰濠制药有限公司 | Cabazitaxel amorphous crystal and preparation method thereof |
| CN104418826A (en) * | 2013-08-28 | 2015-03-18 | 江苏恒瑞医药股份有限公司 | Preparation method of 7beta,10beta-dimethoxy-10-deacetyl baccatin III |
| CN104557798A (en) * | 2013-10-29 | 2015-04-29 | 神威药业集团有限公司 | Preparation method for dimethoxy docetaxel |
| CN107353263A (en) * | 2017-05-25 | 2017-11-17 | 浙江叠智医药科技有限公司 | The method that 7,10 pairs of deacetylate Bakating IIIs of tri-chloroethoxy base formyl chloride 10 are prepared using micro passage reaction |
| CN114751876A (en) * | 2022-01-24 | 2022-07-15 | 上海健佑生物科技有限公司 | Method for synthesizing rivastigmine and docetaxel from 9-dihydro-13-acetylbaccatin III |
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| CN102898406A (en) * | 2012-11-02 | 2013-01-30 | 上海金和生物技术有限公司 | Cabazitaxel crystal and preparation method thereof |
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| CN103044364B (en) * | 2013-01-07 | 2016-01-20 | 重庆泰濠制药有限公司 | Amorphous crystalline substance of a kind of Cabazitaxel and preparation method thereof |
| CN104418826A (en) * | 2013-08-28 | 2015-03-18 | 江苏恒瑞医药股份有限公司 | Preparation method of 7beta,10beta-dimethoxy-10-deacetyl baccatin III |
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| CN104418826B (en) * | 2013-08-28 | 2017-06-30 | 江苏恒瑞医药股份有限公司 | 7 β, the preparation method of the deacetylate Baccatine III of 10 β dimethoxys 10 |
| CN106632158B (en) * | 2013-08-28 | 2018-11-06 | 江苏恒瑞医药股份有限公司 | The preparation method of 7 β, 10 β-dimethoxy -10- deacetylate Baccatine IIIs |
| CN104557798A (en) * | 2013-10-29 | 2015-04-29 | 神威药业集团有限公司 | Preparation method for dimethoxy docetaxel |
| CN107353263A (en) * | 2017-05-25 | 2017-11-17 | 浙江叠智医药科技有限公司 | The method that 7,10 pairs of deacetylate Bakating IIIs of tri-chloroethoxy base formyl chloride 10 are prepared using micro passage reaction |
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