WO2008116387A1 - Procédé de fabrication de taxol et de dérivés de taxol - Google Patents

Procédé de fabrication de taxol et de dérivés de taxol Download PDF

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Publication number
WO2008116387A1
WO2008116387A1 PCT/CN2008/000593 CN2008000593W WO2008116387A1 WO 2008116387 A1 WO2008116387 A1 WO 2008116387A1 CN 2008000593 W CN2008000593 W CN 2008000593W WO 2008116387 A1 WO2008116387 A1 WO 2008116387A1
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Prior art keywords
paclitaxel
group
reaction
derivative
taxane
Prior art date
Application number
PCT/CN2008/000593
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English (en)
Chinese (zh)
Inventor
Ling Yang
Yanyan Zhang
Guangbo Ge
Original Assignee
Dalian Institute Of Chemical Physics, Chinese Academy Of Sciences
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Publication date
Application filed by Dalian Institute Of Chemical Physics, Chinese Academy Of Sciences filed Critical Dalian Institute Of Chemical Physics, Chinese Academy Of Sciences
Publication of WO2008116387A1 publication Critical patent/WO2008116387A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems

Definitions

  • the present invention relates to a "one-pot process" suitable for industrial applications for the preparation of paclitaxel and its derivatives.
  • it relates to a reaction of selectively acetylating C(2') and C(10) hydroxyl groups by selectively acetylating a C(2') acetyl group by using a 10-deacetyl-taxane compound as a raw material,
  • the two-step reaction is placed in the same reaction system, and a "one-pot" synthesis is carried out to obtain a C(10) hydroxyacetylated docetaxan compound.
  • Paclitaxel (formula W, l) and docetaxel (formula V) are currently widely used as clinical first-line drugs for the treatment of different types of tumors.
  • Paclitaxel and 10-deacetyl-paclitaxel V Docetaxel can be obtained by extracting from Taxus, plant cell culture, biosynthesis, fungal fermentation and chemical semi-synthesis to obtain a large amount of 10-deacetyl-taxane compounds.
  • 10-deacetyl-paclitaxel formula IV, 2), 10-deacetyl-desmanectin and the like.
  • Taxol (Taxol) or other taxane compounds having extremely high antitumor activity can be obtained by acylating a hydroxyl group at the C(10) position.
  • Sisti et al. (US6048990, US6066749) dissolves 10-deacetyl-paclitaxel (alkane) having a protected hydroxyl group at the C(2,) position in a THF reaction system, and a lithium salt is added thereto to activate a hydroxyl group at the C(10) position. Further, TEA is added as an acid binding agent, and acetyl chloride is used as an acylating agent to selectively obtain paclitaxel having a C(2,)-hydroxyl group. Chattopadhyay et al.
  • the starting material can be completely converted into 10-deacetyl-paclitaxel.
  • the 2'-0-acetyl-paclitaxel mentioned in the present invention did not involve the 2'-0-acetyl-paclitaxel mentioned in the present invention as a raw material, and the problem of selectively hydrolyzing the C(2') acetyl group to obtain paclitaxel.
  • the invention relates to 10-deacetyl-paclitaxel ( ⁇ ) as a raw material, in a one-pot reaction, simultaneously completed
  • C(10) and C(2, M stand on the acetylation of two hydroxyl groups, and the subsequent two-step reaction process of C(2,) position deacetylation.
  • the completion of the acetylation of the C(10) hydroxyl group provides a means of adapting to industrial production in order to effectively utilize the taxane resources.
  • Disclosure of invention It is an object of the present invention to provide a method for selectively acetylating a C(10) hydroxyl group on 10-deacetyl-paclitaxel ( ⁇ ), which involves the addition of two at the C(2') and C(10) positions.
  • the two-step reaction process of hydroxyacetylation and subsequent deacetylation of the C(2') position is carried out in the same reaction system, which is a "one-pot method" suitable for industrial applications.
  • the present invention provides a process for preparing paclitaxel and a derivative thereof, which comprises the following steps: using a 10-deacetyl-taxane compound having the structural formula I as a raw material:
  • R1 is H, an OT, - OSi (T) 3 or an OCOT
  • R2 and R are the same or different and are a T or an OT
  • D is 11, C1 to C20 is a straight chain, a branch or a ring a hydrocarbon group, an aryl group, an aryl fluorenyl group, or a substituent of the above three hydrocarbon groups, the substituent includes a hydroxyl group, a C1 to C8 alkoxy group, an acetal, a ketal, a halogen, a nitro group and an amino group;
  • the reaction process is:
  • Rl, R2, and R3 are as defined above.
  • the present invention is specifically carried out by mixing a salt of a Group IIIB metal element as a catalyst with a 10-deacetyl-paclitaxel (alk H) o starting material in an inert organic solvent, and using acetic anhydride as an acylating agent.
  • the C (B2, ) and C (10) hydroxyl groups can be selectively activated to precede C ⁇ , :
  • the catalyst used in the selective acylation reaction is derived from a halide of a steroid metal element of the periodic table, a nitrate and a triflate.
  • Preferred are ruthenium chloride, ruthenium chloride, ruthenium fluoride, ruthenium nitrate, ruthenium nitrate, ruthenium nitrate, ruthenium trifluoromethanesulfonate, ruthenium trifluoromethanesulfonate, ruthenium trifluoromethylsulfonate.
  • the present invention subsequently relates to a method for selectively hydrolyzing a C(2') acetyl group,
  • the excess acetic anhydride in the previous reaction is removed by adding a certain amount of water to the system, while the alkaline substance is used to maintain the reaction system to be weakly alkaline.
  • the acetyl group having the C(2') position of the docetaxel of the formula II can be selectively hydrolyzed, and the reaction of the hydrolyzed acetyl group is carried out on the taxane C ( The acetyl group at position 10 has no effect.
  • C(10) hydroxyacylated docetaxel can be obtained with high selectivity under "one pot cooking” conditions.
  • the process flow and chemical reaction formula of the present invention are as shown in Formula V:
  • the acetal and ketal moieties referred to herein have the structural formula, wherein XI, X2, X3, X4 represents hydrogen or a hydrocarbyl group, and the hydrocarbyl group may be substituted by any substituent as defined herein, which may include an acetal or a ketal made from a saccharide or a substituted saccharide such as glucose or xylose ( Koppaka V. Rao, J. Heterocyclic Chem. 34, 676 (1997)), when this moiety is introduced into the docetaxel of the present invention as a protecting group for the C(7) hydroxyl group, the XI or X2 generation refers to the docetaxel moiety.
  • the alkaline substance used in the selective hydrolysis reaction is derived from I A, II A in the periodic table.
  • ⁇ ⁇ , ⁇ bismuth metal bicarbonate, hydrogen phosphate, carbonate, hydroxide. Its role is mainly to maintain the reaction under weak alkaline conditions.
  • These basic substances are preferably selected from the group consisting of: potassium hydrogencarbonate, sodium hydrogencarbonate, disodium hydrogen phosphate, sodium carbonate, potassium carbonate, calcium carbonate, barium carbonate, barium carbonate, cadmium carbonate, lithium hydroxide, barium hydroxide, calcium hydroxide, Iron hydroxide.
  • the reaction time is also shortened accordingly.
  • the peroxide involved in the selective hydrolysis reaction is commercially available hydrogen peroxide, m-chloroperoxybenzoic acid, peracetic acid, peroxybenzoic acid, t-butyl hydroperoxide, and not less than 1 mole of docetaxel equivalent.
  • the ratio, as a reactant, is added to the reaction system to selectively react with the acyl group at the taxane C (2':) position.
  • the time required for the reaction to reach equilibrium will vary.
  • the above two-step selective acetylation reaction and selective hydrolysis reaction can be carried out smoothly at room temperature, but appropriate temperature rise is advantageous for the reaction to reach equilibrium as soon as possible, and it is generally preferred to carry out at -80 Torr to 100 °C. Since the hydroxyl group of the taxane C (7) at the room temperature is prone to epimerization in an alkaline environment, the reaction temperature can be appropriately lowered to below 0 ⁇ during the progress of the hydrolysis reaction, thereby reducing the side reaction to the target product. Impact.
  • the "one-pot" reaction is preferably carried out in an ether solvent having a good solubility for docetaxel, such as tetrahydrofuran, diethyl ether or the like.
  • a reaction can also occur in a good solvent of docetaxel such as methylene chloride, chloroform or ethyl acetate, except that the reaction time is slightly extended.
  • the system for the selective acetylation reaction in the first step is preferably a solvent which strictly removes water, and when the amount of water in the system exceeds a certain amount, the reaction rate can be lowered, and even the reaction cannot be performed.
  • Figure 1 is an LC-MS spectrum of 10-deacetyl-paclitaxel, an anion signal of 10-deacetyl-paclitaxel: [M-H]- at m/z 810.4;
  • Figure 2 is an LC-MS spectrum of 2,-0-acetyl-paclitaxel, a negative ion signal of 2,-0-acetyl-paclitaxel: [M-H]- at m/z 894.9;
  • Figure 3 is the LC-MS spectrum of paclitaxel, the negative ion signal of paclitaxel: [MH]- at m/z 852.3;
  • Figure 4 is an LC-MS spectrum of 10-deacetyl- cephalosporin, an anion signal of 10-deacetyl- cephalosporin: [MH]-at 788.3 m/z;
  • Figure 5 is the LC-MS spectrum of cephalosporin, the negative ion signal of cephalosporin: [M-H]-at 830.4m/z;
  • Figure 6 is an LC-MS spectrum of 10-deacetyl-7-xylose-paclitaxel, an anion signal of 10-deacetyl-7-xylose-paclitaxel: [M-H]-at 942.5 m/ Z;
  • Example 1 Catalytic acetylation using a variety of steroid metal element salts 10-Deacetyl-paclitaxel Preparation of paclitaxel
  • paclitaxel LC-MS spectrum is shown in Fig. 3).
  • the various catalysts used, the amount of catalyst, the reaction solvent, the acetylation reaction time and the yield of the final product paclitaxel are shown in Table 1.
  • Table 1 uses a variety of steroidal metal element salts to catalyze acetylation 10-deacetyl-paclitaxel to prepare paclitaxel. Amount of catalyst acetylation Paclitaxel
  • the present invention relates to a "one-pot process" suitable for industrial applications for the preparation of paclitaxel and its derivatives.
  • the method uses a 10-deacetyl-taxane compound containing a hydroxyl group at the C(2') and C(10) positions as a raw material, and is selectively acetylated with acetic anhydride under the catalysis of a metal element salt. (2' M and C (10) hydroxyl groups, followed by the addition of peroxides and basic substances in the reaction system, selective hydrolysis of the acetyl group at the C (2':) position, resulting in C (10) a hydroxyacetylated taxane compound.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Epoxy Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Procédé monotope de fabrication de taxol et de dérivés de taxol convenant pour des applications industrielles. Les groupes hydroxy (C10) et (C2') de 10-déacétyltaxane sont acétylés sélectivement avec de l'anhydride acétique en présence de sels métalliques. Ensuite, par adjonction de peroxyde et d'une substance alcaline au système de réaction, de l'acétyle (C2') est sélectivement hydrolisé et donne du taxane acétylé (C10).
PCT/CN2008/000593 2007-03-27 2008-03-26 Procédé de fabrication de taxol et de dérivés de taxol WO2008116387A1 (fr)

Applications Claiming Priority (2)

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CN200710010742.2 2007-03-27
CN2007100107422A CN101274924B (zh) 2007-03-27 2007-03-27 一种制备紫杉醇及其衍生物的方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101508645B (zh) * 2009-03-23 2012-05-23 浙江工业大学 一种二乙酰大黄酸的制备方法
CN101863861A (zh) * 2009-04-16 2010-10-20 山东靶点药物研究有限公司 一种简便高效地制备紫杉醇类似物Larotaxel的方法
CN102516207B (zh) * 2011-12-19 2014-10-08 河南省科学院化学研究所有限公司 一种利用7-木糖10-去乙酰基紫杉烷制备紫杉醇的方法
CN109651303A (zh) * 2018-12-12 2019-04-19 福建紫杉园生物有限公司 一种利用10-脱乙酰基紫杉醇合成紫杉醇的工艺

Citations (5)

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Publication number Priority date Publication date Assignee Title
US5629433A (en) * 1994-07-18 1997-05-13 Hauser, Inc. Selective process for the deacylation and deacetylation of taxol and taxanes
EP1285920A1 (fr) * 2001-07-31 2003-02-26 Florida State University Research Foundation, Inc. Taxanes substitués par ester en C10 utilisés comme agents anticancereux
WO2004007473A1 (fr) * 2002-07-15 2004-01-22 Cipla Limited Procede de preparation de paclitaxel
CN1205196C (zh) * 1997-08-18 2005-06-08 佛罗里达州立大学 选择性衍生紫杉烷的方法
CN1303077C (zh) * 2004-01-16 2007-03-07 桂林晖昂生化药业有限责任公司 合成紫杉烷的制备工艺

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WO2004033442A2 (fr) * 2002-10-09 2004-04-22 Chatham Biotec Ltd. Nouveaux taxanes, leurs modes d'utilisation et leurs procedes de preparation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5629433A (en) * 1994-07-18 1997-05-13 Hauser, Inc. Selective process for the deacylation and deacetylation of taxol and taxanes
CN1205196C (zh) * 1997-08-18 2005-06-08 佛罗里达州立大学 选择性衍生紫杉烷的方法
EP1285920A1 (fr) * 2001-07-31 2003-02-26 Florida State University Research Foundation, Inc. Taxanes substitués par ester en C10 utilisés comme agents anticancereux
WO2004007473A1 (fr) * 2002-07-15 2004-01-22 Cipla Limited Procede de preparation de paclitaxel
CN1303077C (zh) * 2004-01-16 2007-03-07 桂林晖昂生化药业有限责任公司 合成紫杉烷的制备工艺

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
QUN Y.Z. ET AL.: "Deacetylation of paclitaxel and other taxanes", TETRAHEDRON LETTERS, vol. 36, no. 12, 1995, pages 2001 - 2004 *

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CN101274924A (zh) 2008-10-01

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