WO2008116388A1

WO2008116388A1 - A preparation process for taxol, baccatin and derivatives thereof

Info

Publication number: WO2008116388A1
Application number: PCT/CN2008/000594
Authority: WO
Inventors: Ling Yang; Yanyan Zhang; Guangbo Ge
Original assignee: Dalian Institute Of Chemical Physics, Chinese Academy Of Sciences
Priority date: 2007-03-27
Filing date: 2008-03-26
Publication date: 2008-10-02
Also published as: CN101274923A; CN101274923B

Abstract

A process for preparing taxol, baccatin and derivatives thereof. In the process, C(10) hydroxy group of 10-deacetyl baccatin is selectively acylated with anhydride in the presence of metal nitrate catalyst. When a side chain is presented at C(13) and a hydroxy group is presented at C(2'), by this process C(10) and C(2') hydroxy groups are selectively acylated. The resulted taxanes are important intermediates for the preparation of taxol and derivatives thereof.

Description

Method for preparing paclitaxel, baccatin III and its derivatives

Field of practice

The present invention relates to a process for the preparation of paclitaxel, baccatin III and derivatives thereof. In particular, it relates to a method for selectively acylating a C (10) hydroxyl group on a 10-deacetyl-baccaridine by a one-step reaction under the catalytic condition of a metal element nitrate, when the docetaxel contains a side at the C (13) position. The chain and the C(2') position contains a free hydroxyl group 0, and the 10-deacetyl-taxane compound can be converted into a taxane simultaneously acylated with a C(10) and C(2') hydroxyl group by the method. The prepared taxane can be used as an important intermediate for the preparation of paclitaxel and its analogues. Technology

Paclitaxel (formula 111, 1) and docetaxel (Dacetaxel) are currently widely used as clinical first-line drugs for the treatment of different types of tumors.

In the form of paclitaxel and 10-deacetyl-paclitaxel IV -10- deacetyl-baccarin III, through the extraction of Taxus, plant cell culture, biosynthesis, fungal fermentation and chemical semi-synthesis, etc. Acetyl-taxanes, a common feature of these materials is that they all have a 10-deacetyl-baccarin III (10-DAB, formula IV) core structure, which is acylated by its C(10) hydroxyl group. Bacastin III and its derivatives are available, while 10-deacetyl-paclitaxel (Formula 111, 2) and its analogs are in the C(1), C(7), C(10), C(2,) positions. The taxane's steroid compound containing a plurality of hydroxyl groups and selectively acylating hydroxyl groups at the C(10) and C(2') positions can be used as an important intermediate for semi-synthetic paclitaxel and other taxanes. At present, the work in this area is mainly concentrated in the following aspects: (-) acylation The C(10) hydroxyl group of 10-DAB

Denis et al. (J. Am. Chem. Soc., 1988, 110, pp. 5917) in the case of pyridine as an acid scavenger, TEC1 is used to protect the C(7) hydroxyl group, and then acetyl chloride is used to complete the C. (10) Acetylation of a hydroxyl group to give 7-O-TES-baccaridine III.

Cravelle et al. (Tetrahedron Letters, 1988, 39, pp. 4263) used the Methyleniminium salt as the acylating agent to obtain the baccatin III by a single step reaction of 10-DAB acetylation.

Holton et al. (Tetrahedron Letters, 1998, 39, pp. 2883) found that in the presence of a metal halide or triflate, for 10-deacetylbaccatin III or C (2' The paclitaxel in which the hydroxyl group is protected, the hydroxyl group at the C(10) position may be selectively acylated with respect to the hydroxyl group at the C(7) position. (CN125196C, WO 1999/009021, US6706896).

Damen et al. (Tetrahedron Letters, 1998, 39, pp. 6081) found that 10-DAB can be selectively acetylated to bacatein by the use of acetic anhydride under the catalysis of a rare earth triflate. If other anhydrides, by selective acylation of 10-DAB in the C (10) position hydroxyl group, various derivatives can be obtained (EP0875508, US5874595, JP10298171) _o but research work in the above two are not related to a Group IIIB The problem of selective acylation of the C(10) hydroxyl group by the nitrate of the metal element as a catalyst for the acylation reaction. At the same time, there is no mention of the acylation between the C(2') and C(7) hydroxyl groups and the C(2,) and €(10) hydroxyl groups when the free hydroxyl group is present at the C(2':) position. The selectivity issue.

Sisti et al. (US 5,914,411) dissolved 10-deacetylbaccatin III in a THF reaction system, adding a lithium salt such as LiCl, adding TEA as an acid scavenger, and using acetyl chloride as an acylating agent. Sexually got the Baccarat III. In its subsequent patent (US6048990, US6066749), he also extended the method to selectively acetylate the C(10) hydroxyl group to obtain C (2' M stand-up after the C(T) hydroxyl group is protected. Hydroxyl protected paclitaxel.

Kant et al. (Tetrahedron Letters, 1994, 35, pp. 5543) dissolve 7-O-TES- 10-DAB in THF and use n-BuLi or LiHMDS to activate C (10M hydroxyl group, using acetyl chloride) As the acylating agent, 7-O-TES-baccatin was obtained selectively. A series of taxane C (10) derivatives were synthesized in the same manner using other acid chlorides as acylating agents.

(b) acylation 10-deacetyl-paclitaxel (alkane) C (10) hydroxyl group

Rao et al. (J. Heterocycl. Chem., 1997, 34, pp. 675) oxidatively cleave 10-xylyl-7-xylose-paclitaxel C(7) xylenyl using periodate, using pyridine After acetylating the hydroxyl group at the C(10) and C(2') positions with acetic anhydride as an acylating agent, the residual group at the C(7) position is removed using benzoquinone to obtain C(2' a hydroxyacetylated paclitaxel, which is then dissolved in methanol to selectively remove the C(2') acetyl group under low concentration of dimethylamine to obtain paclitaxel (US5200534; US5367086) _o

Chattopad yay et al. (US5856532) will obtain a 10-deacetyl taxane compound, which will protect the C(7) and C(2,) hydroxyl groups of the C, and then acetylate the C (10) hydroxyl group. The desilicon ether protecting group gives the desired product.

Fang et al. (Chemical Letters, 8(10), 1997, pp. 847) found that the hydroxyl group at the C(7) position of 7-Table-10-deacetyl-paclitaxel is pyridine, acetyl chloride. Hard to be acetylated. Therefore, they protected the C(2,) hydroxyl group with triethylchlorosilane, acetylated the C(10) hydroxyl group, and then removed the C(2') silyl ether protecting group to obtain 7-epi-paclitaxel.

Tang Dingning et al. (CN1640871A, WO2005/073209) found that when the reaction system contains rare earth chloride, rare earth hydroxide, rare earth oxychloride, or a double salt of a rare earth element, acetic anhydride can be used to acetylate C (10). And C (2, M hydroxy group, to obtain C(2,) hydroxyacetylated paclitaxel.

The development of 10-deacetyl-taxane compounds of the present invention involves one-step selective acylation reaction process. Since the nitrate of the lanthanum metal element is oxidizing, it has rarely been used as a catalyst for the acylation reaction. The present inventors examined the effect of the catalyst and the anhydride on the 10-DAB C(1). ), selective acylation between multiple hydroxyl groups at C(7), C(10). At the same time, under the reaction conditions, we have a relationship between 10-deacetyl-paclitaxel and its analogs at the C(1), C7), C(10), C(2') positions. The acylation activity was also investigated. Disclosure of invention

It is an object of the present invention to provide a method for selectively acylating a hydroxyl group at the c(io) position of 10-deacetyl-baccarine in, and a 10-deacetyl-paclitaxel having a side chain at the C(13) position (: A method for preparing a hydroxyacylated paclitaxel or other docetaxel at a C(2') and C(10) position, based on the product, by selectively hydrolyzing a C(2') acyl group in one step, Paclitaxel and other C (10M hydroxyacylated taxane derivatives are available).

In order to achieve the above object, the present invention provides a method for preparing paclitaxel, baccarin III and derivatives thereof, which is characterized in that:

- the reaction system contains a catalytic equivalent of a metal element nitrate as a catalyst;

^: ~~ Using a anhydride of not less than 1 mole of substrate equivalent as an acylating agent, a 10-deacetyl-taxane compound having the following structural formula (Formula I) is treated:

Wherein R1 is a H, — OT, an OSi (T) 3 or an OCOT; R2 and R3 are the same or different and are a T or an OT; wherein T is H, C1 to C20 is a linear, branched or cyclic type a hydrocarbon group, an aryl group, an aralkyl group, or a substituent of the above three hydrocarbon groups, the substituent including a hydroxyl group, a C1 to C8 decyloxy group, an acetal, a ketal, a halogen, a nitro group and an amino group;

- The reaction is carried out in an inert organic solvent.

The specific implementation of the present invention is carried out by using a nitrate of a lanthanide metal element as a catalyst, mixing with a raw material 10-deacetyl-baccatin in an inert organic solvent, and under the condition of an acid anhydride as an acylating agent, these catalysts can be used. The C (10) hydroxyl group is selectively activated such that it is selectively acylated. When the taxane contains a side chain at the C(13) position and a free hydroxyl group at the C(2') position, the catalyst can also activate the C(2') hydroxyl group, thereby obtaining a C(10) position and a C (2' position. A docetaxel in which the hydroxyl group is acylated. At the same time, when C (1) When the C (7) hydroxyl group is protected or substituted by another group, the C(10) and C(2,) hydroxyl groups can also be acylated by the method of the present invention, and the obtained taxane compound can be obtained. As an important intermediate for the preparation of xanthanol and its derivatives.

The 10-deacetyl-docetaxel involved in the present invention has the following structural formula (Formula I):

Wherein R1 is an H, — OT, an OSi (T) 3 or an OCOT; R2 and R3 may be the same or different and are a T or an OT; wherein T is H, C1 to C20 is linear, branched or a cyclic hydrocarbon group, an aryl group, an aryl fluorenyl group, and a substituent of the above three hydrocarbon groups, the substituent including a hydroxyl group, a C1 to C8 decyloxy group, an acetal, a ketal, a halogen, a nitro group and an amino group;

0X-,

x ₄ -c-ox _:

In particular, the acetal and ketal moieties referred to herein have the structural formula ^χ 3 , wherein XI,

Χ2, Χ3, Χ4 represents hydrogen or a hydrocarbyl group, and the hydrocarbyl group may be substituted by any substituent as defined herein, and the moiety may include an acetal or ketal made from a saccharide or a substituted saccharide such as glucose or xylose ( Koppaka V. RaoJ. Heterocyclic Chem. 34, 676 (1997)), when this moiety is introduced into the taxane of the present invention as a protecting group for the C(7) hydroxy group, the XI or X2 generation refers to the taxane moiety.

The selective acylation reaction is preferably carried out in an ether solvent such as tetrahydrofuran, diethyl ether or the like. However, a reaction can also occur in a good solvent of docetaxel such as dichloromethane, chloroform or ethyl acetate, except that the reaction time is slightly extended. The reaction system is preferably a solvent which is strictly water-removing. When the moisture in the system exceeds a certain amount, the reaction rate can be lowered, and even the reaction cannot be carried out.

The catalyst used in this selective acylation reaction is derived from the nitrate of the steroid metal element in the periodic table. Preferred are cerium nitrate, cerium nitrate, cerium nitrate, cerium nitrate, cerium nitrate, cerium nitrate, cerium nitrate, cerium nitrate.

The acylating agent which can be used in the selective acylation reaction includes various acid anhydrides such as acetic anhydride, chloroacetic anhydride, propionic anhydride, methacrylic anhydride, benzoic anhydride, etc., and the structure of the acid anhydride has a structural formula

And wherein R' is a linear, branched or cyclic hydrocarbon group of C1 to C20, an aryl group, and a halogenated product of the above three hydrocarbon groups.

The selective acylation reaction proceeds smoothly at room temperature, but proper temperature rise facilitates the equilibrium of the reaction as quickly as possible, and is generally preferably carried out at -80 ° C to 100 ° C. The selective acylation reaction process and the chemical reaction formula of the present invention are as shown in Formula IV and Formula V:

Formula VI

Where R', Rl, R2, R3 are defined as before.

The taxane starting material which can be used in the selective acylation reaction may be a natural product source of 10-deacetyl-baccarin III having a hydroxyl group at the C(1), C(7), C(10) position and In C(1), C(7), C(10), C(2, M, a 10-deacetyl-paclitaxel (alkane) compound monomer or a mixture thereof having a hydroxyl group. Meanwhile, via biosynthesis, The taxane having a hydroxyl group at the above position obtained by chemical semi-synthesis or total synthesis means can also be selectively acylated with C(10) and C(2' M-hydroxyl groups by the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is the LC-MS spectrum of 10-deacetyl-bakacitin III, the negative ion signal of 10-deacetyl-bakacitin III: [M-H]- at m/z 543.0;

Figure 2 shows the LC-MS spectrum of Baccatin ,, the negative ion signal of Bacaster III: [M-H]- at m/z 585.2;

Figure 3 is an LC-MS spectrum of 10-deacetyl-paclitaxel, an anion signal of 10-deacetyl-paclitaxel: [M-H]- at m/z 810.4;

Figure 4 is an LC-MS spectrum of 2,-0-acetyl-paclitaxel, an anion signal of 2,-0-acetyl-paclitaxel: [M-H]- at m/z 894.9;

Figure 5 shows the LC-MS spectrum of paclitaxel, the negative ion signal of paclitaxel: [MH]- at m/z 852.3; Dendrobium stone stone stone - -6- 3⁄4Π 肖3⁄4Ππ 3⁄4Π肖肖3⁄4π肖3⁄4 -.

Acidic acid acid

Figure 6 is the LC-MS spectrum of 10-deacetyl- cephalosporin, the negative ion signal of 10-deacetyl- cephalosporin: [MH]-at 788.3 m/z _;

Figure 7 is an LC-MS spectrum of cephalosporin, the negative ion signal of cephalosporin: [M-H]-at 830.4 m/z;

Figure 8 is an LC-MS spectrum of 10-deacetyl-7-xylose-paclitaxel, an anion signal of 10-deacetyl-7-xylose-paclitaxel: [MH]-at 942.5 m/z _; Best way

The following examples are intended to further illustrate the invention and are not intended to limit the scope thereof.

Example 1 Nitrate catalyzed acetylation using various lanthanide metal elements 10-deacetyl-bakaciting III Preparation of baccarin III

Weigh 10 mg of 10-deacetyl-bakathione (content 98%, LC-MS spectrum shown in Figure 1) in 1 ml of the reaction solvent, add the catalytic equivalent of the nitrate of the lanthanide metal, and mix well. , was slowly added dropwise to about 3 equivalents of acetic anhydride, stirred at room temperature, TLC detection after the completion of the reaction, the reaction was quenched with saturated NaHCO ₃ solution. After the reaction, the solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated and evaporated to give the carbazide III (the LC-MS spectrum is shown in Fig. 2). The various catalysts, catalyst amounts, reaction solvents, reaction times and yields used are shown in Table 1.

Table 1 Nitrate-catalyzed acetylation of various lanthanide metal elements 10-deacetyl-bakacitine III ^ catalyst ~~ catalyst amount (equiv) reaction solvent ~~ reaction time (h) ~~ yield (%)

0.2 THF 3 >98

1 CHC13 36 83

0.1 THF 1.5 >98

0.1 dioxane 2.5 >98

0.5 THF 3 >98

0.5 CH2C12 36 77

0.2 EtOAc 26 70

0.1 THF 1 >98

0.1 ether 5 >98

0.1 THF: chloroform (1:1) 1 >98 Example 2 Nitrate-catalyzed acetylation using various steroidal metal elements 10-Deacetyl-paclitaxel to prepare paclitaxel

Weigh 10 mg of 10-deacetyl-paclitaxel (content 62%, LC-MS spectrum shown in Figure 3) dissolved in 1 ml of reaction solvent, add catalytic equivalent of nitrate of lanthanum metal element, mix well, slowly drip adding about 5 equivalents of acetic anhydride, stirred at room temperature, TLC detection after the completion of the reaction, the reaction was quenched with saturated NaHC0 ₃ solution. After the reaction, the solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated, and then evaporated to give 2,0-acetyl- paclitaxel (see Figure 4 for LC-MS). Various catalysts used, Stone stone stone stone 5 stone stone Xiao Xiao Xiao Xiao 3⁄4π 肖肖肖肖

Catalyst acid acid acid

The amount of hydrazine, the reaction solvent, the reaction time and the yield are shown in Table 2.

Weigh 2,-0-acetyl-paclitaxel (content 55%, LC-MS spectrum see Figure 4) lOOmg. Dissolve in 1ml of THF, slowly add 1ml of 30% hydrogen peroxide, then add 50mg of Na2HPO4, stir at room temperature for 3h, TLC detection reaction After completion, the reaction was quenched by the addition of a saturated sodium thiosulfate solution. After the reaction, the solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then evaporated and evaporated to give a mixture of 96 mg (yield: 49%, yield: 89.7%, LC-MS spectrum, see Figure 5).

Table 2 Nitrate-catalyzed acetylation of various Group IIIB metal elements 10-deacetyl-paclitaxel

"~ Catalyst ~" Catalyst (equiv) Reaction solvent ~~Reaction time (h) ~"Yield (%)

0.5 oxygen >98

0.5 >98

0.3 3 >98

Hexachloro τ Τ Τ

0.2 ξ £ H H H 12 78

No F F F

0.5 3 >98

0.5 CH2C12 36 70

0.5 EtOAc 28 65

0.3 ether >98

0.2 EtOAc 10 80

0.1 THF: chloroform (1:1) >9: Example 3 Preparation of cephalosporin from 10-deacetyl- cephalosporin

Weigh 10 g of 10-deacetyl-tacrosinine (content 85%, LC-MS spectrum shown in Figure 6), dissolve in 5 ml of tetrahydrofuran, add O.lg cerium nitrate and mix well, slowly add 0.5 ml. Acetic anhydride was reacted at room temperature for 3 hours, and 25 ml of a saturated NaHCO 3 solution was added to quench the reaction. After the reaction, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated. This was dissolved in 5 ml of tetrahydrofuran, 2.5 ml of hydrogen peroxide (concentration: 30%) was added, and 100 mg of sodium citrate was added thereto, and the solution was sufficiently dissolved at room temperature. After the TLC reaction was completed, the reaction was quenched by the addition of a saturated sodium thiosulfate solution. The solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated. The LC-MS spectrum is shown in Figure 7). Example 4 Preparation of paclitaxel from 10-deacetyl-7-xylose-paclitaxel

Weigh 10 g of 10-deacetyl-7-xylose-paclitaxel (content 90%, LC-MS spectrum shown in Figure 8), dissolve in 30 ml methanol/water (4:1), add 1.0 g high iodine After sodium and 3 ml of 0.5]Vi sulfuric acid, the reaction was carried out for 3 hours at room temperature. The reaction was quenched by the addition of water (30 mL). Dissolve it in 10 ml of tetrahydrofuran, add O.lg cerium nitrate, mix well, slowly add 0.3 ml of acetic anhydride, react at room temperature for 1.5 hours, complete the reaction by TLC, add 15 ml of saturated NaHC03 solution to quench the reaction, extract with ethyl acetate. Liquid, Dry over anhydrous sodium sulfate and vacuum to give a white solid. It was dissolved in 20 ml of methanol/water (4:1), 3 ml of acetic acid and 0.5 ml of phenylhydrazine were added, and the reaction was carried out for 3 hours at 50 Torr, and the reaction was quenched by adding 50 ml of water, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. , vacuum distillation gave 0.92 g of a white solid. This was dissolved in 5 ml of tetrahydrofuran, 2.5 ml of hydrogen peroxide (concentration: 30%) was added, 100 mg of disodium hydrogen phosphate was added thereto, and after fully dissolved, the reaction was carried out at 0 C for 5 hours, and the reaction was quenched by adding a saturated sodium thiosulfate solution. The solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated. The spectrum is shown in Figure 5). Example 5 Selective acylation of 10-deacetyl-bakacaine πκ ιο) hydroxyl group with cerium nitrate

Weigh 100 mg of 10-deacetyl-baccarin III (content 98%, LC-MS spectrum shown in Figure 1), dissolve in 1 ml of THF, mix well with 5 mg of lanthanum nitrate, add 1.5 equivalents of anhydride, stir at room temperature. The reaction was completely detected by TLC, and the reaction was quenched by adding 5 ml of a saturated NaHC03 solution. After the reaction, the reaction mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to give white solids (yield of the obtained product, the various acid anhydrides used, reaction time, temperature and yield as shown in Table 3).

Table 3 Selective acylation of cerium nitrate 10-deacetyl-bakacaine mc(io) hydroxyl group

10- OP acyl-10DAB

temperature reflex

P acyl anhydride reaction time (h) yield (%)

Benzoyl benzoic anhydride 40 5 >98

Hexanoyl hexanoic anhydride 40 3 >98 chloroacetyl chloroacetic anhydride 0 1 87

Propionyl propionic anhydride 5 1.5 >98 methyl propyl methacrylate 30 3 95 Example 6 Selective acylation of 10-deacetyl-paclitaxel C (10) and C (2,) hydroxyl groups with cerium nitrate 10-100 mg of deacetyl-paclitaxel (content 62%, LC-MS spectrum shown in Figure 3), dissolved in 1 ml of THF, 10 mg of cerium nitrate was thoroughly mixed, 3 equivalents of anhydride was added, and stirred at room temperature. The reaction was completely detected by TLC, and the reaction was quenched by adding 5 ml of a saturated NaHC03 solution. After the reaction, the reaction mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to give a white solid.

2',10-O-P acyl-10-deacetyl-paclitaxel

Reaction temperature reaction time yield

P acyl anhydride (°c) (h) (%)

Propionyl propionic anhydride 30 3 >98

Hexanoyl hexanoic anhydride 40 3 >98

Methacryloyl methacrylic anhydride 50 1.5 >98

Benzoyl benzoic anhydride 50 2 >98

Chloroacetyl chloroacetic anhydride 0 2 >98 Example 7 Preparation of 10-O-propionyl-polyene paclitaxel from docetaxel

A sample of docetaxel (content 98%) was weighed, 100 mg, dissolved in 1 ml of tetrahydrofuran, and 10 mg of cerium nitrate was added thereto, and then mixed with propionic anhydride, and reacted at 20 ° C for 1.5 hours, and 5 ml of a saturated NaHC03 solution was added to quench the reaction. After the reaction, the mixture was extracted with ethyl acetate. The substance is dissolved in 1 ml of THF, and added with 1 ml of 30% hydrogen peroxide solution, 200 mg of sodium citrate, and reacted at room temperature for 5 hours. The mixture is extracted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated to dryness to give 97 mg of l0-O-propionyl- Taxol (content 95%, yield 87.9%). Example 8 Preparation of 10-O-benzoyl- 10-deacetyl-7-0-TES-paclitaxel from 10-deacetyl-7-0-TES-paclitaxel

Weigh 500 mg of 10-deacetyl-7-0-TES-paclitaxel (content 80%), dissolve it in 5 ml of tetrahydrofuran, add 10 mg of cerium nitrate, mix well, add 0.5 g of benzoic anhydride, and react for 3 hours at 50 Torr. The reaction was quenched by adding 15 ml of a saturated NaHC03 solution. After the reaction, the solution was treated with ethyl acetate. The extract was dried over anhydrous sodium sulfate and evaporated. This material was dissolved in 3 ml of THF, 3 ml of 30% hydrogen peroxide solution and 500 mg of sodium tartrate. After reacting for 3 h at room temperature, the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. This material was subjected to silica gel column chromatography to give 10-O-benzoyl-10-deacetyl-7-0- TES- paclitaxel 0.41 g (yield: 85%, yield: 83.3%). Example 9 Preparation of 2",3"-bisbromo- cephalosporin from 2",3"-dibromo-3-deacetyl-tacrosinine

Weigh 50 mg of 2", 3"-dibromo-10-deacetyl- cephalosporin (content 90%), dissolve in 1 ml of tetrahydrofuran, add 5 mg of lanthanum nitrate, mix well, and slowly add 0.1 ml of acetic anhydride. The reaction was carried out for 2 hours at room temperature, and 1 ml of a saturated NaHC03 solution was added to quench the reaction. The reaction mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated. It was dissolved in 1 ml of tetrahydrofuran, added with 1 ml of hydrogen peroxide (concentration: 30%), and 50 mg of sodium citrate was added thereto, and dissolved at room temperature. After 5 hours, the reaction was completely detected by TLC, and the reaction was quenched by the addition of a saturated sodium thiosulfate solution. The mixture was extracted with EtOAc (EtOAc)EtOAc. %, yield 70.5%). Industrial applicability

The present invention relates to a process for the preparation of paclitaxel, baccarin III and derivatives thereof. In the method, a nitrate of a metal element is used as a reaction catalyst, and under the condition of an acid anhydride as an acylating agent, a hydroxyl group at the C(10) position on the 10-deacetyl-baccarine 111 can be selectively acylated. When the taxane contains a side chain at the C(13) position and a free hydroxyl group at the C(2') position, the C(2') and C(10) hydroxyl groups can be simultaneously acylated using the present method. The obtained taxane compound can be used as an important intermediate for preparing paclitaxel and its derivatives.

Claims

Rights request

A method for preparing paclitaxel, baccarin III and derivatives thereof, characterized in that: - a reaction system containing a catalytic equivalent of a metal element nitrate as a catalyst;

- treating a 10-deacetyl-taxane compound having the following formula (Formula I) using an acid anhydride of not less than 1 mole of substrate equivalent as an acylating agent:

Wherein R1 is a Ή, an OT, — OSi (T) 3 or an OCOT; R2 and R3 are the same or different and are a T or an OT; wherein T is H, C1 to C20 is a linear, branched or cyclic type a hydrocarbon group, an aryl group, an aralkyl group, or a substituent of the above three hydrocarbon groups, the substituent including a hydroxyl group, a C1 to C8 decyloxy group, an acetal, a ketal, a halogen, a nitro group and an amino group;

- The reaction is carried out in an inert organic solvent. '

2. A method for preparing paclitaxel, baccaline and its derivatives according to claim 1, wherein: the taxane starting material is a 10-cyanyl group having a hydroxyl group at the C(10) position derived from a natural product. - Bacaster III or a 10-deacetyl-paclitaxel compound monomer or a mixture thereof having a hydroxyl group at the C(2') and C(10) positions, or via biosynthesis, chemical semi-synthesis or total synthesis A taxane having a hydroxyl group at the above position obtained by means.

A method of preparing paclitaxel, baccaline III and derivatives thereof according to claim 1, wherein the catalyst is a nitrate of a Group IIIB metal element.

4. The preparation according to claim 3 Taxol, Baccatin III, and derivatives ^thereof,: characterized in that: said catalyst is selected from scandium nitrate, ytterbium nitrate, erbium nitrate, lanthanum nitrate, cerium nitrate, rubidium nitrate, Barium nitrate, barium nitrate.

5. A method of preparing paclitaxel, baccarin III and derivatives thereof according to claim 1,

0 〇

The acid anhydride has a structural formula R^o^', wherein R' is a straight chain or a branch of ci to _C20 . A chain or cyclic hydrocarbon group, an aryl group, or a halogenated product of the above three hydrocarbon groups.

6. Process for the preparation of paclitaxel, baccatin HI and derivatives thereof according to claim 1, characterized in that the inert organic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, ethyl acetate, dioxane, chloroform, dichloro One or more mixed systems of formazan.

A method for preparing paclitaxel, baccaline III and derivatives thereof according to claim 1, wherein the reaction temperature is from -80 ° C to 100 ° C.