CN102417491A - Method for preparing cabazitaxel by taking 10-deacetylate-baccatin III as raw material - Google Patents
Method for preparing cabazitaxel by taking 10-deacetylate-baccatin III as raw material Download PDFInfo
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Abstract
The invention relates to a method for preparing cabazitaxel, particularly relates to a method for preparing the cabazitaxel by taking 10-deacetylate-baccatin III as a raw material and belongs to the technical field of drug synthesis. The method comprises the following steps: firstly, reacting 10-DAB with chlorocarbonate-2,2,2-trichloro ethyl ester, thereby obtaining a product; reacting the product with DMAP (dimethylamino pyridine), DCC (dicyclohexylcarbodiimide) and (4S, 5R)-2,2-dimethyl-4-phenyl-3-tert-butoxycarbonyl-3.5-oxazolidine formic acid, thereby obtaining a product; reacting the product with acetic acid and zinc powder, and then methylating the product; and lastly, adding a p-methyl benzenesulfonic acid, thereby reacting and obtaining a cabazitaxel product. The cabazitaxel prepared according to the method can be widely applied to the treatment of prostate cancer. Compared with a traditional technique for preparing the cabazitaxel, the method has the advantages that the preparation quantity is greatly increased, the operation steps are simplified, the manpower is saved and the method has industrial application value and prospect.
Description
Technical field
The present invention relates to a kind of method for preparing his match of kappa, be specifically related to a kind of method that is his match of feedstock production kappa with 10-deacetylate-Ba Kading III, belong to technical field of medicine synthesis.
Background technology
He matches cabazitaxel (JEVTANA) the anti-prostate cancer medicine kappa of in June, 2010 U.S.'s approval listing, and promptly 7, the two Docetaxel (CAS#:183133-96-2 that methylate of 10-; Chemical Formula:C
45H
57NO
14) skeleton symbol following:
Prostate cancer is higher at American-European sickness rate; Sickness rate is relatively low and in the Asia; Research shows that this disease and life style and dietary structure etc. have substantial connection, and for example prostate cancer is very low at Japanese sickness rate, but in case migrate the U.S.; The offspring that they grow up in the U.S., sickness rate and American that this is sick are remained basically stable.Because carnivorous intake of compatriots and dietary structure after the several years, will face this sick huge challenge in recent years great variety, also will bring great demand.
Cabazitaxel is that castration resistivity patients with prostate cancer provides a kind of novel therapeutic.Though the use of Taxan does not bring curative breakthrough, has prolonged survival time, this has brought hope to patients with prostate cancer.Prostate cancer vaccine sipuleucel-T has gone through to use, though only obtained the moderate income, has confirmed the validity of prostate cancer immunotherapy.The therapeutic strategy that the entering III phase tests; Comprise the more strong inhibition of androgen receptor signal; The adjusting (this can have influence on the prostate gland patient in late period more than 90%) of novel signal path during bone shifts; And the reinforcement antineoplastic immune, perhaps the effectiveness of these methods be not only to make the survival time of patients with prostate cancer that prolongation arranged slightly.
The preparation technology of this compound that can inquire at present be with 10-deacetylate-Ba Kading III (hereinafter to be referred as: 10-DAB) as starting raw material, through 7,13 hydroxyl protections-10DAB, 10 HMs-7; 13 protection base-10DAB, 7,13 hydroxyls go protection acquisition 10 to methylate-10DAB; 7 HMs get 7 again; 10-methylates-10-DAB, and again through the side chain coupling, he matches to go to protect two steps to obtain kappa.Synthesis path is following:
This synthesis path is longer, and he matches need to carry out the final synthetic acquisition kappa of six-step process ability.And the synthesis technique of describing in this patent is (50mg rank) in a small amount.
Summary of the invention
The objective of the invention is to overcome above-mentioned weak point, provide a kind of can be through the method for his match of simple five prepared in reaction kappas, its response path is simple than existing technology, and each step all adapts to the above preparation of measuring of 100g.
According to technical scheme provided by the invention, a kind of is the method for his match of feedstock production kappa with 10-deacetylate-Ba Kading III, and reaction formula is following:
Concrete steps are:
(1) by 10-deacetylate-Ba Kading III (being 10-DAB): organic solvent takes by weighing reactant by mass volume ratio 1: 20～30, and 10-DAB is dissolved in the organic solvent, presses pyridine: the 10-DAB volume mass adds pyridine than 1: 0.4～0.6; Stir down for 0～5 ℃ in temperature; Press chloroformic acid-2,2, the 2-trichloro ethyl ester: 10-DAB mol ratio 1: 2.1～2.5 drips chloroformic acid-2; 2, the 2-trichloro ethyl ester; Be warming up to normal temperature, restir 0.2～1h after stirring 1～2h; With 0.5～3 times of reactant volume, the Hydrogen chloride washing reaction thing of 0.5～1mol/L 1～2 time is used the saturated aqueous common salt washing reaction thing of 2～3 times of reactant volumes again; Collect organic phase; Be concentrated into 1/4～1/3 of original volume, add sherwood oil or normal hexane, crystallization obtains white product 1;
(2) get step (1) gained white product 1 and be dissolved in the toluene, successively white product in molar ratio: 4-Dimethylamino pyridine 1: 0.01～0.1, white product: NSC 57182 1: 1.5～3 by mass volume ratio 1: 15～30; White product: (4S; 5R)-2,2-dimethyl--4-phenyl-3-tert-butoxycarbonyl-3,5-oxazolidine formic acid 1: 1～1.2 adds reactant; Stirring at normal temperature 2～4h crosses and filters filtrating; With purified water wash filtrate 1～2 time, use the saturated common salt water washing again, to paste, use ETHYLE ACETATE: the mixing solutions recrystallization of sherwood oil or normal hexane volume ratio 1: 10～20 obtains compound 2 with the solution concentration after the gained washing;
(3) getting step (2) gained compound 2 is dissolved in the ETHYLE ACETATE; Press compound: acetic acid mass volume ratio 1: 0.4～1 adds acetic acid; Add compound again: the zinc powder of zinc powder volume ratio 1: 1～3, stirring at normal temperature 2～4h filters three times; Filtrating is adopted purified water, saturated sodium bicarbonate aqueous solution and saturated aqueous common salt, reaction solution successively: the filtrate volume ratio is 1: 1～3; Collect the reaction solution after filtering, be concentrated into 0.5～0.66 of original volume, add sherwood oil or normal hexane recrystallization and promptly get product 3;
(4) getting step (3) products therefrom 3 is dissolved in the organic solvent; Solution is cooled to-70～-30 ℃; Press product 3: dehydrogenation compound mol ratio 1: 2～2.2 adds the dehydrogenation compound; Press product 3 again: methylating reagent mol ratio 1: 2～25 adds methylating reagents, control reaction temperature-40～0 ℃, stirring reaction 1～2h; The purified water that adds 15～40 times of gained reaction solution volumes is crossed and is filtered thick product; With the thick product of gained with reversed-phase silica gel column chromatography separate product 4;
(5) getting product 4 is dissolved in the methyl alcohol; By product 4: the p-methyl benzenesulfonic acid mol ratio is 1: 0.01～0.1 to add p-methyl benzenesulfonic acid, and stirring at normal temperature 1～4h adds frozen water and gets white precipitate; Filter, he matches after separating through reversed-phase silica gel column chromatography, promptly to get the product kappa.
The said organic solvent of step 1 is methylene dichloride or chloroform.
The said organic solvent of step (4) is methyl-sulphoxide, THF or N, dinethylformamide.
The said dehydrogenation compound of step (4) is sodium Metal 99.5, sodium hydroxide, sodium hydride, potassium metal, potassium hydride KH or Pottasium Hydroxide.
The said methylating reagent of step (4) is methyl iodide, methyl-sulfate, trifluoromethanesulfonic acid methyl esters, trimethyl phosphite 99, methylcarbonate.
The present invention has following advantage: the kappa of the present invention's preparation he match can be widely used in the treatment of prostate cancer; Technology than his match of existing preparation kappa has not only increased the preparation metering; Also simple operation steps has been saved manual work, and the value and the prospect of industrial application arranged.
Description of drawings
He matches nuclear magnetic spectrum to Fig. 1 for the kappa of embodiment 3 preparation.
Embodiment
Embodiment 1
(1) in the reaction flask of 500mL, 10.0g (0.018mol) 10-DAB is suspended in the chloroform of 250mL, under churned mechanically situation, adds the 5mL pyridine, with cryosel water-bath controlled temperature to 0 ℃.20mL chloroformic solution with trichloroethyl chloroformate 5.46mL (0.040mol) drops in the reaction flask then.Dropwise about 1 hour, rate of addition is controlled in the reaction flask reacting liquid temperature below 5 degrees centigrade.Restir recession in 1 hour deicing salt bath; After finishing to 10-DAB reaction according to detecting of TLC, open to leave standstill behind the hydrochloric acid that is added dropwise to 100mL 0.5mol/L under the situation that cryosel bathes and tell lower floor's water, tell lower floor's water after adding the hydrochloric acid solution and stirring of 100mL 0.5mol/L once more.Pass through the washing of 50mL saturated aqueous common salt then, organic phase solution is concentrated into 70mL.A large amount of white precipitates appears in the sherwood oil that the cooling back adds 3L.Its filtration drying is got product 1 white powder 15.48g, yield 98%.Nucleus magnetic hydrogen spectrum is consistent with document, content 99.5% (HPLC).
(2) in the reaction flask of 500mL, 12g (0.013mol) product 1 is dissolved in the 200mL toluene; The 4-Dimethylamino pyridine DMAP that adds 0.1g (0.0008mol) then, the NSC 57182 (DCC) of 5.0g (0.024mol), (4S; 5R)-2; 2-dimethyl--4-phenyl-3-tert-butoxycarbonyl-3,5-oxazolidine formic acid 5.26g (0.014mol) stirs a large amount of depositions of appearance after 2 hours.Detect according to TLC, the initiator complete reaction finishes.Cross and filter filtrating, will filtrate respectively through twice 600mL water washing, the water washing of 40mL saturated common salt is concentrated into the light yellow oil paste with filtrating then.With the light yellow oil paste with sherwood oil and ETHYLE ACETATE 240mL volume ratio 15: 1) recrystallization gets white powder, cross and filter filter cake.Get product 2, white powder 15.91g, content 99.0% (HPLC), yield 96.3% behind the filtration cakes torrefaction.
(3) in the reaction flask of 300mL, add 15.00g (0.012mol) product 2, add 100mL ETHYLE ACETATE, add Glacial acetic acid min. 99.5 7mL, add zinc powder 10 grams and stir after 4 hours, detect product 2 complete reactions according to TLC and finish.Reaction solution passes through 60mL water respectively, and the 60mL saturated sodium bicarbonate solution is concentrated into 60mL with organic phase after the water washing of 50mL saturated common salt.The sherwood oil that adds 200mL again produces a large amount of white precipitates.Cross and filter filter cake.Filter cake gets product 3 white solid 10.22g after super-dry, content 99%, and (HPLC) yield is 92.7%.
(4) in the reaction flask of 1L, add 10.0g (0.011mol) product 3, add the THF of 200mL through the anhydrous and oxygen-free processing.Unlatching outer circulation cooling is reduced to-40 degrees centigrade with reacting liquid temperature in the reaction flask, adds 90% NaH pressed powder 0.66g (0.024mol) in batches.Stir after 20 minutes, add the methyl-sulfate solution of 20mL.React and after 40 minutes temperature is increased to 0 degree centigrade, restir adds the 4L frozen water after half hour.A large amount of white precipitates occurs, filter the filter handle through quick mistake.Obtain product 4 white solid 6.92g after will filtering handle process C18 reversed phase column chromatography, content 99%, (HPLC) yield 66.9%.
(5) in the reaction flask of 5L, 7.00g (0.0074mol) product 4 is dissolved in the methyl alcohol of 150mL, adds the 0.02g p-methyl benzenesulfonic acid and stirred 4 hours.Follow the tracks of product 4 completely dissolve onboard according to TLC, add the 200mL pure water and produce a large amount of white precipitates.Continue to stir 1 hour, leave standstill 2 hours again after, cross and filter 6.2g (25～45um) reversed phase column chromatographies get his match of 5.9g kappa, content 99.6%, yield: 97% through C18 again.
Nuclear-magnetism is following: 1.22 (s, 6H); 1.37 (s, 9H); 1.65 (s, 2H); 1.66 (s, 3H); 1.76 (dd, J=16.2,1H); 1.86 (s, 3H); 2.09 (m, 2H); 2.37 (s, 3H); 2.65 (dd, J=16.2,1H); 3.30 (s, 3H); 3.45 (s, 3H); 3.83 (m, 2H); 4.12 (d, J=8,1H); 4.29 (d, J=8,1H); 4.63 (s, 1H); 4.80 (s, 1H); 4.95 (d, J=12.8,1H); 5.26 (bs, 1H); 5.44 (d, J=12.4,1H); 5.62 (d, J=8,1H); 6.19 (t, J=10,1H); 7.24-7.64 (mt, 8H); 8.08 (d, J=10,2H).
Embodiment 2
(1) in the reaction flask of 500mL, 100.0g (0.18mol) 10-DAB is suspended in the methylene dichloride of 2.5L, under churned mechanically situation, adds 50mL pyridine cryosel water-bath to 0 degree centigrade.200mL dichloromethane solution with trichloroethyl chloroformate 54.6mL (0.40mol) drops in the reaction flask then.Dropwise about 1 hour, rate of addition is controlled in the reaction flask reacting liquid temperature below 5 degrees centigrade.Restir recession in 1 hour deicing salt bath; After finishing to 10-DAB reaction according to detecting of TLC, open to leave standstill behind the hydrochloric acid that is added dropwise to 1000mL 0.5mol/L under the situation of ice bath and tell lower floor's water, tell lower floor's water after adding the hydrochloric acid solution and stirring of 1000mL0.5mol/L again.Pass through the washing of 500mL saturated aqueous common salt then, organic phase solution is concentrated into 600mL.A large amount of white precipitates appears in the sherwood oil that the cooling back adds 3L.Its filtration drying is got product 1 white powder 158.9g yield 100%.Nucleus magnetic hydrogen spectrum is consistent with document, content 99.5% (HPLC).
(2) in the reaction flask of 5L, 120g (0.13mol) product 1 is dissolved in the DMAP that adds 1g in the 2L toluene then; The DCC of 50g, (4S, 5R)-2; 2-dimethyl--4-phenyl-3-tert-butoxycarbonyl-3; 5-oxazolidine formic acid 52.6g (0.14mol) stirs to occur after 2 hours precipitating according to TLC in a large number and detects, and the initiator complete reaction finishes.Cross and filter filtrating, will filtrate respectively through twice 600mL water washing, the water washing of 400mL saturated common salt is concentrated into the light yellow oil paste with filtrating then.The light yellow oil paste is got white powder with sherwood oil and ETHYLE ACETATE (15: 1) recrystallization, cross and filter the filter handle.Get product 2 white powder 160.2g, content 99.0% (HPLC), yield 97.0% after the filter handle drying.
(3) in the reaction flask of 3L, add 150.0g (0.12mol) product 2, add 1L ETHYLE ACETATE, add Glacial acetic acid min. 99.5 70mL, add zinc powder 100 grams and stir after 4 hours, detect product 2 complete reactions according to TLC and finish.Reaction solution passes through 600mL water respectively, and the 600mL saturated sodium bicarbonate solution is concentrated into 600mL with organic phase after the water washing of 500mL saturated common salt.The sherwood oil that adds 2L again produces a large amount of white precipitates.Cross and filter filter cake.Filter cake gets product 3 white solid 106.2g after super-dry, content 99%, and (HPLC) yield is 96.3%.
(4) in the reaction flask of 10L, add 100.0g (0.11mol) product 3, add the THF of 2L through the anhydrous and oxygen-free processing.Unlatching outer circulation cooling is reduced to-40 degrees centigrade with reacting liquid temperature in the reaction flask, adds 90% NaH pressed powder 6.58g (0.24mol) in batches.Stir after 20 minutes, add the methyl-sulfate solution of 208mL.React and after 40 minutes temperature is increased to 0 degree centigrade, restir adds the 4L frozen water after half hour.A large amount of white precipitates occurs, filter the filter handle through quick mistake.Obtain product 4 white solid 70.1g content 99% (HPLC) yields 68% after will filtering handle process C18 reversed phase column chromatography.
(5) in the reaction flask of 5L, 70.0g (0.074mol) product 4 is dissolved in the methyl alcohol of 1.5L, the p-methyl benzenesulfonic acid that adds 0.2 gram stirred 4 hours.Follow the tracks of product 4 completely dissolve onboard according to TLC, add the 2L pure water and produce a large amount of white precipitates.Continue to stir 1 hour, leave standstill 2 hours again after, cross and filter 60.5g (25～45um) reversed phase column chromatographies get his match of 59.0g kappa, content 99.6% yield: 97% through C18 again.
Nuclear-magnetism is following: 1.22 (s, 6H); 1.37 (s, 9H); 1.65 (s, 2H); 1.66 (s, 3H); 1.76 (dd, J=16.2,1H); 1.86 (s, 3H); 2.09 (m, 2H); 2.37 (s, 3H); 2.65 (dd, J=16.2,1H); 3.30 (s, 3H); 3.45 (s, 3H); 3.83 (m, 2H); 4.12 (d, J=8,1H); 4.29 (d, J=8,1H); 4.63 (s, 1H); 4.80 (s, 1H); 4.95 (d, J=12.8,1H); 5.26 (bs, 1H); 5.44 (d, J=12.4,1H); 5.62 (d, J=8,1H); 6.19 (t, J=10,1H); 7.24-7.64 (mt, 8H); 8.08 (d, J=10,2H).
Embodiment 3
(1) in the reaction flask of 10L, 200.0g (0.36mol) 10-DAB is suspended in the chloroform of 6L, under churned mechanically situation, adds 100mL pyridine cryosel water-bath to 0 degree centigrade.400mL dichloromethane solution with trichloroethyl chloroformate 109.2mL (0.80mol) drops in the reaction flask then.Dropwise about 1 hour, rate of addition is controlled in the reaction flask reacting liquid temperature below 5 degrees centigrade.Restir recession in 1 hour deicing salt bath; After finishing to 10-DAB reaction according to detecting of TLC, open to leave standstill behind the hydrochloric acid that is added dropwise to 2000mL 0.5mol/L under the situation of ice bath and tell lower floor's water, tell lower floor's water after adding the hydrochloric acid solution and stirring of 2000mL0.5mol/L again.Pass through the washing of 1000mL saturated aqueous common salt then, organic phase solution is concentrated into 1200mL.A large amount of white precipitates appears in the sherwood oil that the cooling back adds 6.3L.Its filtration drying is got product 1 white powder 314.6g yield 99%.Nucleus magnetic hydrogen spectrum is consistent with document, content 99.5% (HPLC).
(2) in the reaction flask of 10L, 240.0g (0.26mol) product 1 is dissolved in the DMAP that adds 1.8g in the 7L toluene then; The DCC of 90g, (4S, 5R)-2; 2-dimethyl--4-phenyl-3-tert-butoxycarbonyl-3; 5-oxazolidine formic acid 112.4g (0.28mol) stirs to occur after 2 hours precipitating according to TLC in a large number and detects, and the initiator complete reaction finishes.Cross and filter filtrating, will filtrate respectively through twice 1200mL water washing, the water washing of 800mL saturated common salt is concentrated into the light yellow oil paste with filtrating then.The light yellow oil paste is got white powder with sherwood oil and ETHYLE ACETATE 4.8L (15: 1) recrystallization, cross and filter the filter handle.Get product 2 white powder 160.2g, content 99.0% (HPLC), yield 97.0% after the filter handle drying.
(3) in the reaction flask of 3L, add 300.0g (0.24mol) product 2, adding 2L ETHYLE ACETATE adds Glacial acetic acid min. 99.5 140mL, adds zinc powder 200 grams and stirs after 4 hours, after finishing according to TLC detection product 2 complete reactions.Reaction solution passes through 1200mL water respectively, and the 1200mL saturated sodium bicarbonate solution is concentrated into 600mL with organic phase after the water washing of 1000mL saturated common salt.The sherwood oil that adds 4L again produces a large amount of white precipitates.Cross and filter the filter handle.The filter handle gets product 3 white solid 214.9g content 99% (HPLC) yields after super-dry be 97.1%.
(4) in the reaction flask of 20L, add 200.0g (0.22mol) product 3, add the THF of 2L through the anhydrous and oxygen-free processing.Unlatching outer circulation cooling is reduced to-40 degrees centigrade with reacting liquid temperature in the reaction flask, adds 90% NaH pressed powder 13.16g (0.48mol) in batches.Stir after 20 minutes, add the methyl-sulfate solution of 400mL.React and after 40 minutes temperature is increased to 0 degree centigrade, restir adds the 4L frozen water after half hour.A large amount of white precipitates occurs, filter the filter handle through quick mistake.Obtain product 4 white solid 142.1g content 99% (HPLC) yields 69.0% after will filtering handle process C18 reversed phase column chromatography.
(5) in the reaction flask of 5L, 140.0g (0.148mol) product 4 is dissolved in the methyl alcohol of 3L, the p-methyl benzenesulfonic acid that adds 0.4 (0.0023) gram stirred 4 hours.Follow the tracks of product 4 completely dissolve onboard according to TLC, add the 4L pure water and produce a large amount of white precipitates.Continue to stir 1 hour, leave standstill 2 hours again after, cross and filter 122.5g (25～45um) reversed phase column chromatographies get his match of 117.6g kappa, content 99.0% yield: 97% through C18 again.
Nuclear-magnetism figure is as shown in Figure 1: 1.22 (s, 6H); 1.37 (s, 9H); 1.65 (s, 2H); 1.66 (s, 3H); 1.76 (dd, J=16.2,1H); 1.86 (s, 3H); 2.09 (m, 2H); 2.37 (s, 3H); 2.65 (dd, J=16.2,1H); 3.30 (s, 3H); 3.45 (s, 3H); 3.83 (m, 2H); 4.12 (d, J=8,1H); 4.29 (d, J=8,1H); 4.63 (s, 1H); 4.80 (s, 1H); 4.95 (d, J=12.8,1H); 5.26 (bs, 1H); 5.44 (d, J=12.4,1H); 5.62 (d, J=8,1H); 6.19 (t, J=10,1H); 7.24-7.64 (mt, 8H); 8.08 (d, J=10,2H).
Claims (5)
- One kind with 10-deacetylate-Ba Kading III be the feedstock production kappa he the match method, it is characterized in that step is:(1) be 10-DAB by 10-deacetylate-Ba Kading III: organic solvent takes by weighing reactant by mass volume ratio 1: 20～30, and 10-DAB is dissolved in the organic solvent, presses pyridine: the 10-DAB volume mass adds pyridine than 1: 0.4～0.6; Stir down for 0～5 ℃ in temperature; Press chloroformic acid-2,2, the 2-trichloro ethyl ester: 10-DAB mol ratio 1: 2.1～2.5 drips chloroformic acid-2; 2, the 2-trichloro ethyl ester; Be warming up to normal temperature, restir 0.2～1h after stirring 1～2h; With 0.5～3 times of reactant volume, the Hydrogen chloride washing reaction thing of 0.5～1mol/L 1～2 time is used the saturated aqueous common salt washing reaction thing of 2～3 times of reactant volumes again; Collect organic phase; Be concentrated into 1/4～1/3 of original volume, add sherwood oil or normal hexane, crystallization obtains white product 1;(2) get step (1) gained white product 1 and be dissolved in the toluene, successively white product in molar ratio: 4-Dimethylamino pyridine 1: 0.01～0.1, white product: NSC 57182 1: 1.5～3 by mass volume ratio 1: 15～30; White product: (4S; 5R)-2,2-dimethyl--4-phenyl-3-tert-butoxycarbonyl-3,5-oxazolidine formic acid 1: 1～1.2 adds reactant; Stirring at normal temperature 2～4h crosses and filters filtrating; With purified water wash filtrate 1～2 time, use the saturated common salt water washing again, to paste, use ETHYLE ACETATE: the mixing solutions recrystallization of sherwood oil or normal hexane volume ratio 1: 10～20 obtains compound 2 with the solution concentration after the gained washing;(3) getting step (2) gained compound 2 is dissolved in the ETHYLE ACETATE; Press compound: acetic acid mass volume ratio 1: 0.4～1 adds acetic acid; Add compound again: the zinc powder of zinc powder volume ratio 1: 1～3, stirring at normal temperature 2～4h filters three times; Filtrating is adopted purified water, saturated sodium bicarbonate aqueous solution and saturated aqueous common salt, reaction solution successively: the filtrate volume ratio is 1: 1～3; Collect the reaction solution after filtering, be concentrated into 0.5～0.66 of original volume, add sherwood oil or normal hexane recrystallization and promptly get product 3;(4) getting step (3) products therefrom 3 is dissolved in the organic solvent; Solution is cooled to-70～-30 ℃; Press product 3: dehydrogenation compound mol ratio 1: 2～2.2 adds the dehydrogenation compound; Press product 3 again: methylating reagent mol ratio 1: 2～25 adds methylating reagents, control reaction temperature-40～0 ℃, stirring reaction 1～2h; The purified water that adds 15～40 times of gained reaction solution volumes is crossed and is filtered thick product; With the thick product of gained with reversed-phase silica gel column chromatography separate product 4;(5) getting product 4 is dissolved in the methyl alcohol; By product 4: the p-methyl benzenesulfonic acid mol ratio is 1: 0.01～0.1 to add p-methyl benzenesulfonic acid, and stirring at normal temperature 1～4h adds frozen water and gets white precipitate; Filter, he matches after separating through reversed-phase silica gel column chromatography, promptly to get the product kappa.
- 2. according to claim 1 is the method for his match of feedstock production kappa with 10-deacetylate-Ba Kading III, and it is characterized in that: the said organic solvent of step 1 is methylene dichloride or chloroform.
- 3. according to claim 1 is the method for his match of feedstock production kappa with 10-deacetylate-Ba Kading III, and it is characterized in that: the said organic solvent of step (4) is methyl-sulphoxide, THF or N, dinethylformamide.
- 4. according to claim 1 is the method for his match of feedstock production kappa with 10-deacetylate-Ba Kading III, and it is characterized in that: the said dehydrogenation compound of step (4) is sodium Metal 99.5, sodium hydroxide, sodium hydride, potassium metal, potassium hydride KH or Pottasium Hydroxide.
- 5. according to claim 1 is the method for his match of feedstock production kappa with 10-deacetylate-Ba Kading III, and it is characterized in that: the said methylating reagent of step (4) is methyl iodide, methyl-sulfate, trifluoromethanesulfonic acid methyl esters, trimethyl phosphite 99, methylcarbonate.
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| US20150307468A1 (en) * | 2012-11-09 | 2015-10-29 | Intas Pharmaceuticals Limited | Process for the preparation of cabazitaxel and its intermediates |
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| CN102775434A (en) * | 2012-08-21 | 2012-11-14 | 江苏红豆杉生物科技有限公司 | Synthesis method of 7, 10-methoxyl taxane compound intermediate |
| CN102775434B (en) * | 2012-08-21 | 2015-04-08 | 江苏红豆杉生物科技股份有限公司 | Synthesis method of 7, 10-methoxyl taxane compound intermediate |
| WO2014067207A1 (en) * | 2012-11-02 | 2014-05-08 | 上海金和生物技术有限公司 | Cabazitaxel crystalline and preparation method therefor |
| CN102887877A (en) * | 2012-11-05 | 2013-01-23 | 江苏红豆杉生物科技股份有限公司 | Method for purifying cabazitaxel |
| US9487496B2 (en) * | 2012-11-09 | 2016-11-08 | Intas Pharmaceuticals Limited | Process for the preparation of cabazitaxel and its intermediates |
| EP2917192B1 (en) | 2012-11-09 | 2019-03-20 | Intas Pharmaceuticals Limited | Process for the preparation of cabazitaxel and its intermediates |
| US20150307468A1 (en) * | 2012-11-09 | 2015-10-29 | Intas Pharmaceuticals Limited | Process for the preparation of cabazitaxel and its intermediates |
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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 |
| 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 |
| 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 |
| CN111662276A (en) * | 2019-03-08 | 2020-09-15 | 天津大学 | Synthetic route to the paclitaxel derivative cabazitaxel using novel catalysts |
| CN110078686A (en) * | 2019-04-28 | 2019-08-02 | 云南汉德生物技术有限公司 | The method of 10- deacetylate Bakating III synthesis Cabazitaxel |
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