cas 95603-44-4, 7,10-Bis-O-(2,2,2-trichloroethoxycarbonyl)-10-deacetylbaccatin III

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Preparation method of cabazitaxel
The invention discloses a preparation method of cabazitaxel, which comprises the following specific steps: dissolving 10-deacetylbaccatin III with dichloromethane and pyridine, dropwise adding 2,2,2-trichloroethyl chloroformate, and treating to obtain an intermediate I; mixing toluene, 4-dimethylaminopyridine, the intermediate I and (4S,5R)-3-tert-butoxycarbony-2-(4-anisy)- 4-phenyl-5-oxazolidinecarboxylic acid, stirring, dropwise adding N,N'-dicyclohexylcarbodiimide, and stirring for reaction to obtain an intermediate II; dissolving the intermediate II with ethyl acetate and acetic acid, adding zinc powder, carrying out a stirring reaction to obtain an intermediate III, dissolving the intermediate III with dichloromethane, adding 1,8-bis(dimethylamino)naphthalene, a molecular sieve and trimethyloxonium tetrafluoroborate, and carrying out a stirring reaction to obtain an intermediate IV; dissolving and clarifying the intermediate IV with methanol, dropwise adding a hydrochloric acid methanol solution having a concentration of 1mol/L, and stirring for reaction to obtain cabazitaxel. According to the method, methylation can be realized at room temperature, the product purity is good, the yield is high, starting materials are easy to obtain, and large-scale preparation can be carried out.
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Paragraph 0016; 0035-0038; 0050-0052; 0061-0063

(2021/11/27)

Semisynthesis method for docetaxel
The invention relates to a semisynthesis method for docetaxel. The semisynthesis method comprises the following steps: protecting hydroxyl groups on 7-carbon and 10-carbon on 10-DAB III by using chloroformic acid-2,2,2-trichloroethyl ester so as to obtain an intermediate I, performing a condensation reaction on the intermediate I and a five-membered ring side chain so as to obtain an intermediateII, performing ring opening on the intermediate II under the action of hydrochloric acid to remove a protecting group on the five-membered ring side chain so as to obtain an intermediate III, and removing a Troc protecting group from the intermediate III under an acidic condition so as to obtain the docetaxel. The semisynthesis method provided by the invention has the advantages of simple processroute, mild reaction conditions, fewer impurities generated in the reaction process, higher yield and stable properties of obtained intermediates, and applicability to industrial large-scale production.
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Paragraph 0028-0030; 0035-0037; 0042-0044

(2020/06/02)

Method for synthesizing cabazitaxel from 10-deacetylbaccatin III
The invention discloses a method for synthesizing cabazitaxel from 10-deacetylbaccatin III. According to the method, 10-deacetylbaccatin III is used as a raw material, and 7,10-(di)Troc-10-DAB is prepared in the presence of a solvent, a catalyst and chloroformic acid 2, 2, 2-trichloroethyl ester; then 7,10-(di)Troc-10-DAB is condensed with a side chain of docetaxel to prepare an intermediate II, the intermediate II is subjected to protective group removal to obtain a kappa precursor I, the kappa precursor I is further prepared into a kappa precursor II, the kappa precursor II is subjected to sulfur methyl removal, and then is hydrolyzed under acidic conditions to obtain crude cabazitaxel; the crude cabazitaxel is subjected to recrystallization, column chromatography, recrystallization andpurification to obtain the cabazitaxel with the content being greater than 99%. The method provided by the invention has the advantages that the reaction conditions are mild and controllable, some ofthe reactions can be carried out in one pot, a methylation reagent used is a non-toxic reagent, and is safe, reliable, low in cost and high in yield, and the obtained product is high in purity, less in impurity content, and suitable for industrial production and marketing applications.
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Paragraph 0013; 0038-0039; 0046-0047; 0054-0055

(2019/09/17)

Method for purifying docetaxel
The invention discloses a method for purifying docetaxel. A docetaxel solid precipitates from a dichloromethane and toluene mixed solution. The purifying method has the advantages of great reduction of the single content of every impurity in docetaxel, introduction of few impurities, improvement of the purity of the product, and high yield, and is very suitable for industrial large-scale production, and the obtained product meets preparation demands, and can be directly used to prepare a docetaxel injection.
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Paragraph 0038-0041

(2019/07/04)

Method for preparing 7,10-dichloro-ethoxymethyl chloride-10-deacetylbaccatin III by using microchannel reactor
The invention provides a method for preparing 7,10-dichloro-ethoxymethyl chloride-10-deacetylbaccatin III by using a microchannel reactor. According to the invention, a selective esterification reaction is carried out in the microchannel reactor with inlets and an outlet, the method comprises the following steps: S1) preparing 10-deacetylbaccatin III source liquid and chloro-carbonic acid-2,2,2-trichloro ethyl ester source liquid, S2) conveying the 10-deacetylbaccatin III source liquid and chloro-carbonic acid-2,2,2-trichloro ethyl ester source liquid into two inlets of the microchannel reactor through a transfer pump; and S3) passing two source liquid through a mixing module and a reaction module in order, performing the selective esterification reaction, controlling the temperature of the mixing module and the reaction module being 25-50 DEG C, wherein the stay time is 30-120.6 s, and flowing a reaction solution out from the outlet. The method employs the microchannel reactor for synthesis of the 7,10-dichloro-ethoxymethyl chloride-10-deacetylbaccatin III, which solves the problems of long synthesis time, low yield and complex operation of the 7,10-dichloro-ethoxymethyl chloride-10-deacetylbaccatin III.
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Paragraph 0069; 0070; 0071; 0072; 0073; 0075; 0076-0089

(2017/12/09)

Docetaxel side chain 2'-derived novel taxanes antitumor compound as well as synthesis method and application thereof
The invention discloses a docetaxel side chain 2'-derived novel taxanes antitumor compound shown as the general structure formula (I) as well as a synthesis method and application thereof. In the formula, X is N or O, R is H or acetyl, and R' is H, nitryl, cyano, methoxyl or a halogen group. The synthesis method takes 10-deacetylbaccatin is used as a raw material; after 7-OH and 10-OH are protected, condensation with phenylisoserine (side chain) protecting 3'-NHBoc and 2'-OH in the presence of condensation agents DCC (Dicyclohexylcarbodiimide) and DMAP (Dimethylaminopyridine) is performed; esterification with substituted phenyl isoxazole carboxylic acid or substituted phenyl oxadiazole methyl carboxylic acid in the presence of the DCC and the DMAP is performed; finally, a protecting group is removed to obtain the compound. The compound disclosed by the invention has relatively high activity on tumor cells.
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Paragraph 0019

(2017/08/29)

Novel taxane anti-tumor compound as well as synthesis method and application thereof
The invention discloses a novel taxane anti-tumor compound shown in a structural formula (I). 10-DAB (10-deacetylbaccatin) is adopted as a raw material, and is condensed with phenylisoserine (side chain) with protected 3'-NH2 and 2'-OH in the presence of condensing agents DCC and DMAP after 7-OH and 10-OH are protected, the side chain and a protecting group on a baccatin ring are simultaneously removed in the presence of zinc powder, and coupling is performed with substituted phenylisoxazole in an alkaline medium to obtain a target product. The compound has relatively high anti-tumor activity. (The structural formula (I) is shown in the description.).
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Paragraph 0017

(2017/08/29)

Method for semisynthesis of Docetaxel and intermediate of Docetaxel
The invention relates to a method for semisynthesis of Docetaxel and an intermediate of the Docetaxel. The method provided by the invention comprises the steps of firstly, carrying out hydroxyl protection on C7 and C10 of 10-DAB III (10-deacetylbaccatin III) by using 2,2,2-trichloroethylchloroformate so as to obtain an intermediate I, subjecting the intermediate I to a reaction with a side chain radical compound so as to prepare an intermediate II, subjecting the intermediate II to a hydrogenation reaction under the catalysis of palladium-charcoal so as to prepare an intermediate III, subjecting the intermediate III to a reaction under acidic conditions so as to obtain a Docetaxel crude product, and subjecting the Docetaxel crude product to purification, thereby obtaining a purified product. According to the method provided by the invention, the 10-DAB III raw material can be sufficiently utilized, finally-produced byproducts are few, the final product Docetaxel has the purity of 99.6% to 99.9%, the mole yield reaches up to 73% to 82%, and the utilization ratio of the 10-DAB III can be greatly increased.
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Paragraph 0043; 0044; 0057; 0058; 0071; 0072

(2017/10/27)

Biological evaluation of new antitumor taxoids: Alteration of substitution at the C-7 and C-10 of docetaxel
A series of new docetaxol analogues have been designed and synthesized. And their cytotoxicities against cancer cells have been evaluated by MTT method. Most of these compounds showed selective inhibitions on human cancer cell lines. Among them, compound 8 exhibited higher inhibitory activity than Paclitaxel (Taxol) against several cancer cell lines. This work indicated that appropriate modification at C-7 and C-10 of docetaxel might be a promising approach for this unique class of anticancer compounds.
Li, Caihong,Qiu, Yatao,Li, Xing,Liu, Nianjin,Yao, Zhiyi
supporting information
p. 855 - 859
(2014/02/14)

Design, synthesis and cytotoxicity of novel 3′-N-alkoxycarbonyl docetaxel analogs
By-product 9a exhibited potent cytotoxicity against both SK-OV-3 and A549 cell lines. The structure of 9a was characterized using 1D and 2D NMR experiments and confirmed by synthesis to afford a diastereomeric mixture (16a) that was identical to 9a, as well as a pair of diastereomers (R)-16b and (S)-16c. The preliminary SAR study demonstrated that analogs with an (R)-configuration were slightly more potent than analogs with an (S)-configuration. In addition, α,α-gem-dimethyl analogs 16g-i were the most potent analogs in this series, exhibiting similar potency to docetaxel and greater potency than Taxol against the SK-OV-3 cell line. For the A549 cell line, analogs 16g-i were more potent (>65-fold) than both docetaxel and Taxol.
Chang, Jun,Hao, Xiao-Dong,Hao, Yun-Peng,Lu, Hong-Fu,Yu, Jian-Ming,Sun, Xun
p. 6834 - 6837
(2014/01/06)

Regio- and stereoselective methods for the conversion of (2S,3R)-β-phenylglycidic acid esters to taxoids and other enantiopure (2R,3S)-phenylisoserine esters
A novel efficient method was proposed for the synthesis of enantiopure precursors of taxane-containing cytostatics, i.e., methyl esters of (2R,3S)- and (2S,3R)-N-benzoylphenylisoserine and similar taxoid esters. The method is based on the regio- and stereoselective hydrobromolysis of the corresponding trans-β-phenyl glycidate enatiomers, consecutive reactions of O-acylcarbamoylation of the obtained 3-bromohydrins, intramolecular cyclization to 4-phenyloxazolidin-2-one-5-carboxylic acid derivatives, and oxazolidinone ring opening.
Afon'Kin,Kostrikin,Shumeiko,Popov,Matveev,Matvienko,Zabudkin
p. 2149 - 2162
(2013/10/01)

Alternative synthesis and the determination of absolute configuration of docetaxel, an anticancer drug
A simple, efficient, and alternative synthetic route for docetaxel with better control on the protection-deprotection sequence has been developed. The process is easily scalable and commercially viable, and critical impurities can be controlled efficiently. For the first time, absolute configuration of docetaxel was determined unambiguously by single-crystal X-ray diffraction.
Sekhar,Vishweshwar, Peddy,Acharyulu, Palle V. R.,Anjaneyulu, Yerramilli
experimental part
p. 3482 - 3492
(2012/10/18)

Synthesis, cytotoxicity, metabolic stability and pharmacokinetic evaluation of fluorinated docetaxel analogs
Three novel fluorinated docetaxel analogs, along with six previous reported, were evaluated for their cytotoxicity against five tumor cell lines. The results indicated that these analogs maintained similar/more potent activity than docetaxel against these tumor cell lines. They were also evaluated for their metabolic stability and pharmacokinetics, which demonstrated that these analogs showed better profiles of metabolic stability and pharmacokinetics than that of docetaxel.
Lu, Hong-Fu,Xie, Cheng,Chang, Jun,Lin, Guo-Qiang,Sun, Xun
scheme or table
p. 1743 - 1748
(2011/05/06)

Design, synthesis and biological evaluation of novel fluorinated docetaxel analogues
A series of novel fluorinated docetaxel analogues have been synthesized and evaluated in vitro and in vivo. Incorporated one, two or three fluorine atom(s) either at both meta position on C-2 benzolate and 3′-N-tert-butyloxyl group or only at 3′-N-tert-butyloxyl group has resulted in potent analogues which have comparable or superior in vitro and in vivo cytotoxicity to docetaxel. Among them, compounds 14d and 14e have displayed more potent cytotoxicity than docetaxel both in human cancer cell line SK-OV-3 in vitro and in human non-small cell lung cancer A549 xenografts in vivo. Preliminary data show that compound 14a has reduced acute animal toxicity in mice compared with docetaxel.
Lu, Hong-Fu,Sun, Xun,Xu, Liang,Lou, Li-Guang,Lin, Guo-Qiang
experimental part
p. 482 - 491
(2009/09/06)

Crystalline forms of docetaxel and process for preparation thereof
New anhydrous crystalline form of docetaxel and process of making anhydrous docetaxel and docetaxel trihydrate are provided.
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Page/Page column 2

(2008/12/04)

DOCETAXEL POLYMORPHS AND PROCESSES
The present invention provides crystalline polymorphs of docetaxel and processes for preparing them, a method for preparing amorphous docetaxel, and a process for preparing docetaxel.
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Page/Page column 29

(2008/06/13)

CHEMICAL STUDIES OF 10-DEACETYL BACCATIN III. HEMISYNTHESIS OF TAXOL DERIVATIVES.
The chemical reactivities of 10-deacetyl baccatin III and of baccatin III, two natural products extracted from Taxus baccata L., were studied with aim of synthesizing taxol analogues having a modified side-chain at C-13, thereby restoring good binding to tubulin.
Gueritte-Voegelein, F.,Senilh, V.,David, B.,Guenard, B.,Potier, P.
p. 4451 - 4460
(2007/10/02)