CN101007795B - Synthetic method of paclitaxel and docetaxel - Google Patents

Abstract

The invention provides a synthetic method of paclitaxel and docetaxel, which uses 10-DAB III as an intermediate, first selectively protects the C-7 hydroxyl group, then acylates or protects the C-10 hydroxyl group, and then uses the protected side chain The acid is coupled with the C-13 hydroxyl group, and finally the protecting group is removed by hydrolysis to obtain the target compound paclitaxel or docetaxel. The inventive method overcomes the shortcoming that several protecting groups exist at present, develops a kind of new protecting group---imidazolylthiocarbonyl; In order to avoid the formation of C-2' epimerization and severe reaction conditions, synthesized 2 -Monosubstituted-1,3-oxazolidine type side chain acid; reasonable design, low price of reagents, few reaction steps and mild reaction conditions. The method of the invention provides favorable conditions for the industrial production of paclitaxel. At the same time, it provides a new way for the synthesis of docetaxel.

Description

Synthetic method of paclitaxel and docetaxel

technical field

The invention belongs to compound synthesis, and mainly relates to the synthesis method of anticancer drugs paclitaxel and docetaxel.

Background technique

Paclitaxel (trade name Taxol, Formula Ia) is a taxane diterpenoid isolated from Taxus plants. Its novel structure, unique anti-cancer mechanism, remarkable anti-cancer effect and broad anti-cancer spectrum are considered to be one of the best anti-cancer drugs discovered so far. After the United States, paclitaxel as a first-line anticancer drug has been approved for marketing in more than 40 countries. However, the lack of paclitaxel supply greatly limits its clinical application. At present, the main source of medicinal paclitaxel is to extract and isolate from the bark of the natural Taxus genus. However, due to the small number of plants in this genus, slow growth, low content, and rather difficult extraction, it is impossible to meet the growing clinical needs in the long run.

Docetaxel (Docetaxel, trade name Taxotere, Formula Ib) is a chemically modified derivative of the new anticancer drug paclitaxel, and its antitumor effect and side effects are significantly better than paclitaxel. Clinically, docetaxel has been used as a chemotherapeutic drug in the treatment of breast cancer, lung cancer, gastric cancer and esophageal cancer, etc., with good effect and less side effects. However, the supply of docetaxel is far from meeting the demand of the market.

In recent years, the chemical total synthesis of paclitaxel has been successful, but the synthetic route is complicated and the cost is too high, so it is only of research significance and has no commercial value. In comparison, the chemical semi-synthesis of paclitaxel is a preparation method with practical value, so it is particularly important.

Semi-synthetic studies generally use 10-deacetylbaccatin (10-deacetylbaccatin III, 10-DAB III), which is similar in structure to the macrocycle of paclitaxel, as an intermediate, and is prepared by docking with the side chain of paclitaxel or docetaxel. Get paclitaxel or docetaxel. 10-DAB III can be extracted from the needles of the genus Taxus with a high yield, which provides sufficient guarantee for the semi-synthesis of paclitaxel and docetaxel.

Generally speaking, the semi-synthetic route of paclitaxel and docetaxel using 10-DAB III as a precursor includes the following steps:

(1) Selective protection of hydroxyl groups at C-7 and C-10

There are four hydroxyl groups in the molecular structure of 10-DAB III (Formula II), which are located at C-1, 7, 10 and 13 respectively. The reactivity of these hydroxyl groups is different, and the order of reactivity from fast to slow is C-7>C-10>C-13>C-1. In addition, the C-7 hydroxyl group is extremely prone to epimerization under basic conditions. Therefore, the protecting group of the C-7 hydroxyl group must be selectively protected and deprotected under mild reaction conditions. In the semi-synthetic study of paclitaxel, four groups have been reported as C-7 hydroxyl protecting groups: triethylsilyl (TES), trichloroethoxycarbonyl (Troc), trichloroacetyl and chlorine Acetyl. Wherein, triethylsilyl is the most commonly used protecting group, yet in the reaction of C-7 hydroxyl protection, its optimum reaction condition is to need the expensive triethylsilyl of large excess (20 times equimolar quantity); Trichloroethoxycarbonyl is used as C-7 hydroxyl protecting group, because this group has almost no selectivity to the reaction of C-7 and C-10 two hydroxyl groups, so it needs several more steps of reaction in the process of obtaining paclitaxel in synthesis, in addition When protecting and deprotecting the C-7 hydroxyl group, severe reaction conditions are required (Tetrahedron Letters, 1992, pp5185-5188); the patent US6130336 adopts the method of adding trichloroacetyl protecting group intermittently to selectively protect the C-7 hydroxyl group ; As for the chloroacetyl group, due to its low reactivity selectivity, strict quantification conditions are required in the reaction.

After the C-7 hydroxyl group is protected, the C-10 hydroxyl group is acylated to obtain the 7-hydroxyl protected baccatin III; Protection can give 10-deacetylbaccatin III with 7,10-hydroxyl protection.

(2) Selective docking of the protected phenylisoserine side chain (C13 side chain) with the C-13 hydroxyl group

Since the C-13 hydroxyl group in the baccatin molecule is located in the concave area of the hemispherical taxane skeleton, it is difficult for the blocked C-13 hydroxyl group to undergo esterification with the side chain acid, so this step is a step in the synthesis process. key. In order to improve the yield of esterification and reduce the formation of by-products, the side chain of phenylisoserine is usually properly protected. There are three types of C-13 side chains commonly used for protection: linear type, four-membered ring β-lactam type and five-membered ring oxazolidine type.

(3) Deprotection of the side chain and the two parts of baccatin

In the deprotection process, it is often necessary to carry out the side chain and baccatin step by step, and at the same time, the N-protecting group of the side chain will also be removed. Obviously, if the side chain and bacatine can be simultaneously deprotected in one step reaction, and the N-protecting group can be retained, the synthesis process of paclitaxel and docetaxel will be greatly simplified.

Contents of the invention

The purpose of the present invention is to provide a new synthetic method for semi-synthetic paclitaxel and docetaxel, which uses 10-DABIII as an intermediate to selectively protect the C-7 hydroxyl group, and then acylate or protect the C-10 hydroxyl group. , and then use the protected side chain acid to couple with the C-13 hydroxyl group, and finally hydrolyze and remove the protecting group to obtain the target compound paclitaxel or docetaxel.

The synthetic method of semi-synthetic paclitaxel and docetaxel provided by the present invention is specifically realized through the following steps:

(1) 10-deacetylbaccatin (10-DAB III, compound II) reacts with compound (III) in a solvent to obtain compound (IV).

or

代表杂环基。Wherein R ₃ -represents aliphatic group and aromatic group; X-represents halogen group and hydroxyl group;

represents a heterocyclic group.

The above is the reaction formula for preparing compound (IV). The compound (III) used in this step reaction can be an acyl halide compound or a heterocyclic compound, usually an aromatic acyl halide or an aromatic heterocyclic compound, such as thio Carbonyldiimidazole. The reaction temperature can be between -78-100°C, usually at room temperature, and the yield is 65-85%. The solvent used can be an ether solvent, such as 1,4-dioxane, dimethoxyethane, tetrahydrofuran, etc.; it can also be an aromatic solvent, such as benzene, toluene, xylene, etc.; it can also be chlorinated Solvents, such as dichloromethane, dichloroethane, chloroform, etc., usually use chloroform. The resulting product (IV) can be purified by recrystallization, such as ethyl acetate-n-hexane; flash silica gel column chromatography can also be performed.

(2) Compound (IV) reacts with an acetylating reagent in a solvent to obtain compound (Va); compound (IV) reacts with reagents such as chloroacetyl chloride in a solvent to protect the C-10 hydroxyl group to obtain compound (Vb ).

代表杂环基。Here R ₂ -represents acetyl, chloroacetyl, trichloroethoxycarbonyl, benzyloxycarbonyl, trichloroacetyl; R ₃ -represents aliphatic, aromatic;

represents a heterocyclic group.

The above is the reaction formula for preparing compound (V). The acetylating reagent used in this step reaction can be acetyl chloride, acetic anhydride, glacial acetic acid, etc., usually using acetyl chloride or acetic anhydride; used for C-10 hydroxyl protection. The reagent can be chloroacetyl chloride, trichloroethoxycarbonyl chloride, benzyloxycarbonyl chloride, trichloroacetyl chloride. The acid scavenger used is some weak bases, such as pyridine, triethylamine, piperidine, etc. The reaction temperature can be between -78°C and 100°C, usually between 0°C and 30°C. The solvent used can be an ether solvent, such as tetrahydrofuran, etc.; it can also be a chlorinated solvent, such as methylene chloride, chloroform, etc., or it can be pyridine, which is usually pyridine. Both recrystallization and flash column chromatography are available purification methods.

(3) The C-13 hydroxyl in compound (Va) and the protected side chain acid (VIa) carry out esterification coupling in a solvent in the presence of a base to obtain compound (VIIa); C-13 in compound (Vb) The hydroxyl group and the protected side chain acid (VIb) are esterified and coupled in a solvent in the presence of a base to obtain compound (VIIb).

代表杂环基。Here R ₁ -represents phenyl, tert-butoxy; R ₂ -represents acetyl, chloroacetyl, trichloroethoxycarbonyl, benzyloxycarbonyl, trichloroacetyl; R ₃ -represents aliphatic, aromatic base:

represents a heterocyclic group.

Above-mentioned is the reaction formula of preparing compound (VII), and the alkali used in this step reaction comprises two parts: a part is condensing agent carbonyl imides, as dicyclohexyl carbonyl imide (DCC), diiso Propyl carbonyl imide (DIC), etc.; the other part is an activator, such as 4-dimethylaminopyridine, etc. The optional solvent can be an ether solvent, such as 1,4-dioxane, dimethoxyethane, tetrahydrofuran, etc.; it can be an aromatic solvent, such as benzene, toluene, xylene, etc.; it can be a chlorinated solvent, Such as dichloromethane, dichloroethane, chloroform, etc.; it can also be an amide solvent, such as dimethylformamide, dimethylacetamide, etc.; it can also be a combination of them, such as benzene-tetrahydrofuran, toluene-dichloromethane wait. The reaction temperature of this step can be controlled between -78°C and 100°C, usually between 0°C and 30°C. The crude product of the obtained product (VII) can be purified by flash column chromatography, or directly enter the next reaction without purification.

(4) Compound (VIIa) carries out a one-step reaction under acidic conditions to remove the C-7 protecting group and the oxazole ring protecting group to obtain the target product paclitaxel (Ia); compound (VIIb) carries out a one-step reaction under acidic conditions to remove C -7 protecting group, C-10 protecting group and oxazole ring protecting group, obtain target product docetaxel (Ib).

代表杂环基。Here R ₁ -represents phenyl, tert-butoxy; R ₂ -represents acetyl, chloroacetyl, trichloroethoxycarbonyl, benzyloxycarbonyl, trichloroacetyl; R ₃ -represents aliphatic, aromatic base;

represents a heterocyclic group.

The above is the reaction formula for preparing the target compound paclitaxel and docetaxel. The weak acid used in this step reaction can be an organic acid, such as formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, etc.; it can also be an aqueous solution of an inorganic acid , such as dilute hydrochloric acid, dilute sulfuric acid, phosphoric acid, etc.; it can also be a combination of them, such as p-toluenesulfonic acid-dilute hydrochloric acid, trifluoroacetic acid-acetic acid, etc. The reaction temperature can be between -78°C and 100°C, usually at room temperature. The optional solvent can be water, tetrahydrofuran, dioxane, acetonitrile, methanol, ethanol, etc. The resulting crude product can be purified by column chromatography.

The new method for synthesizing paclitaxel provided by the invention has the following characteristics: (1) Overcome the shortcomings of several protecting groups at present, and develop a new protecting group——imidazolylthiocarbonyl. (2) In order to avoid the formation of C-2' epimerization and severe reaction conditions, a 2-monosubstituted-1,3-oxazolidine type side chain acid was synthesized. (3) The design is reasonable, the reagents used are cheap, the reaction steps are few, and the reaction conditions are mild. The method of the invention provides favorable conditions for the industrial production of paclitaxel. At the same time, the invention provides a new way for the synthesis of docetaxel.

Detailed ways

The present invention will be further described below through embodiment.

Example 1: Preparation of 7-(imidazolyl)thiocarbonyloxy-10-deacetylbaccatin-III(IV)

Dissolve 1.25g (2.3mmol) of 10-deacetylbaccatin-III into 110mL of anhydrous chloroform, add 0.82g (4.6mmol) of 1,1'-thiocarbonyldiimidazole under stirring at room temperature, and continue stirring, the system is Bright yellow and transparent, TLC monitors the reaction process. After the reaction, it was diluted with chloroform, and washed with water and saturated sodium chloride solution successively. Dry over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. The concentrate was purified by recrystallization from ethyl acetate-n-hexane to obtain 1.24 g (72.6%) of compound IV as a white solid. mp145-148°C; IR(KBr)v: 3445, 1717, 1245cm ^-1 ; ¹ HNMR (400MHz, DMSO-d ₆ ) δ: 8.31(s, 1H), 8.05(d, J=7.2Hz, 2H), 7.69(m, 1H), 7.67(s, 1H), 7.58(t, J ₁ =8.0Hz, J2=7.2Hz, 2H), 7.09(s, 1H), 6.11(t, J ₁ =9.2Hz, J ₂ =8.4Hz, 1H), 5.51(d, J=6.8Hz, 1H), 5.29(d, J=4.4Hz, 1H), 5.24(s, 1H), 5.18(s, 1H), 5.02(d, J=9.2Hz, 1H), 4.63(s, 1H), 4.46(s, 1H), 4.14(s, 2H), 4.04(d, J=6.8Hz, 1H), 2.73(m, 1H), 2.25( s, 3H), 2.21(m, 2H), 1.94(s, 3H), 1.90(m, 1H), 1.85(s, 3H), 0.96(s, 3H), 0.94(s, 3H); ¹³ CNMR( 100MHz, DMSO-d6)δ: 209.23, 182.74, 169.99, 165.29, 141.88, 136.91, 134.40, 133.28, 130.76, 130.11, 129.53(2C), 128.69(2C), 118.56, 82.70, 81.856, 76 74.69, 74.39, 69.95, 55.38, 46.16, 42.27, 39.09, 31.21, 26.57, 22.14, 20.07, 14.79, 11.22; LRMS calcd for C ₃₃ H ₃₈ N ₂ O ₁₀ S[M] ⁺ 654.2, found 654.4.

Example 2: Preparation of 7-(imidazolyl)thiocarbonyloxy-baccatin-III(V)

1.11g (1.7mmol) of compound IV was dissolved in 15mL of anhydrous pyridine, nitrogen was blown, stirred, 3.3ml (34mmol) of acetic anhydride was added dropwise, and stirring was continued at room temperature for 24h. Add an equal volume of ethyl acetate and water, stir, let stand to separate layers, extract the aqueous phase twice with ethyl acetate, combine the organic phases, wash with saturated copper sulfate solution until pyridine is completely removed, and then successively water and saturated chlorine NaCl solution for washing. Dry over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. The concentrate was purified by flash column chromatography (eluent: ethyl acetate-cyclohexane, volume ratio: 3:4) to obtain 0.97 g (71.7%) of compound V as a white solid. mp241-244°C; IR(KBr)v: 3466, 1722, 1236cm ^-1 ; ¹ HNMR (400MHz, DMSO-d ₆ ) δ: 8.15(s, 1H), 8.04(d, J=7.2Hz, 2H), 7.69(t, J1=7.2Hz, _J2 =8.0Hz, 1H), 7.59(t, J=7.6Hz, 2H), 7.54(s, 1H), 7.03(s, 1H), 6.16(s, 1H ), 6.12(m, 1H), 5.49(d, J=7.2Hz, 1H), 5.44(d, J=4.4Hz, 1H), 5.05(d, J=5.2Hz, 1H), 4.65(s, 2H ), 4.13(s, 2H), 3.95(d, J=7.2Hz, 1H), 2.86(m, 1H), 2.25(s, 3H), 2.19(m, 2H), 1.95(s, 6H), 1.86 (m, 1H), 1.84(s, 3H), 0.98(s, 6H); ¹³ CNMR (100MHz, DMSO-d ₆ ): 202.69, 183.07, 170.12, 168.47, 165.25, 146.25, 136.85, 133.39, 130.36, 130.06 , 129.99, 129.59(2C), 128.76(2C), 118.47, 82.69, 81.35, 79.46, 76.76, 75.51, 75.25, 74.01, 66.00, 55.51, 46.66, 42.44, 39.10, 31.09, 25.34, 20.25 , 11.22; LRMS calcdfor C ₃₅ H ₄₀ N ₂ O ₁₁ S[M] ⁺ 696.2, found 696.5.

Example 3: 13-(2'-phenyl-4'-p-methoxyphenyl N-benzoyl-oxazolidine-1-carbonyloxy)-7-(imidazolyl)thiocarbonyloxy - Preparation of baccatin-III (VIIa)

Dissolve 0.77g (1.1mmol) of compound V into 120mL of anhydrous toluene and dichloromethane (volume ratio is 2:1), add 1.33g (3.3mmol) of compound VIa, 40.3mg (0.33mmol) N, N '-Dimethylaminopyridine (DMAP), after stirring for 10 min, 340 mg (1.65 mmol) of dicyclohexylcarbonyl imide (DCC) was added, and the system became turbid after a while. Stirring was continued at room temperature, and the reaction progress was detected by TLC. After the reaction was completed, the turbidity was filtered off, diluted with ethyl acetate, and washed with saturated ammonium chloride solution, sodium bicarbonate solution and sodium chloride solution in sequence. Dry over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. The concentrate was purified by flash column chromatography (eluent: ethyl acetate-cyclohexane, volume ratio: 1:2) to obtain 1.02 g (75%) of compound VIIa as a white solid. mp157-161°C; IR(KBr)v: 3428, 1726, 1653, 1245 cm ^-1 ; ¹ HNMR (400MHz, DMSO-d ₆ ) δ: 8.18(s, 1H), 8.02(d, J=7.2Hz, 2H), 7.69(t, J ₁ =7.6Hz, J ₂ =7.2Hz, 1H), 7.59(t, J=7.6Hz, 2H), 7.56(s, 1H), 7.44-7.26(m, 12H), 7.04(s, 1H), 6.96(d, J=8.0Hz, 2H), 6.63(s, 1H), 6.20(s, 1H), 6.17-6.11(m, 2H), 5.58(d, J=6.8Hz , 1H), 5.51(s, 1H), 5.16(s, 1H), 5.09(s, 1H), 5.03(d, J=9.2Hz, 1H), 4.12(s, 2H), 3.95(d, J= 7.2Hz, 1H), 3.78(s, 3H), 2.84(m, 1H), 2.38(m, 1H), 2.25(m, 1H), 2.14(s, 3H), 1.99(s, 3H), 1.96( s, 3H), 1.87 (s, 3H), 1.86 (m, 1H), 1.16 (s, 3H), 1.03 (s, 3H); ¹³ CNMR (100MHz, DMSO-d ₆ ) δ: 202.03, 183.02, 170.39 , 169.35, 169.32, 168.39, 165.13, 159.59 (2c), 156.58, 140.14, 139.08, 136.86, 135.79, 133.53, 132.62, 130.39, 129.58 (2C), 129.74, 128.52 (2C), 128.74, 128.52 (2C), 128.5.52 (28.74, 128.52 (28.74, 128.52 (28.74). , 128.22(2C), 127.91, 126.84(2C), 126.49(2C), 118.46, 113.63(2C), 90.14, 82.60, 82.11, 80.99, 79.65, 76.66, 75.23, 74.65, 73.84, 70.93, 65.56, 5 , 47.48, 43.01, 35.15, 31.02, 25.30, 21.60, 21.10, 20.23, 14.18, 11.21; LRMS calcd for C ₅₉ H ₅₉ N ₃ O ₁₅ S[M] ⁺ 1081.3, found 1081.0.

Embodiment 4: the preparation of paclitaxel (Ia)

0.82g (0.76mmol) of compound VIIa was dissolved in 30mL of methanol, and 145mg (0.84mmol) of p-toluenesulfonic acid was added under stirring at room temperature. After reacting for 3 hours, 10mL of 0.1N hydrochloric acid aqueous solution was added, and the reaction progress was detected by TLC. After the reaction was completed, it was diluted with ethyl acetate, and then washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution in sequence. Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is purified by flash column chromatography (eluent: ethyl acetate-cyclohexane, volume ratio: 1:1) to obtain 0.56 g (67%) of white solid compound Ia . mp206-209°C; ¹ HNMR (400MHz, DMSO-d ₆ ) δ: 8.89(d, J=8.8Hz, 1H), 7.99(d, J=9.2Hz, 1H), 7.97(d, J=8.0Hz, 2H), 7.88(d, J=8.4Hz, 2H), 7.73-7.36(m, 9H), 7.22(d, J=8.4Hz, 1H), 6.29(s, 1H), 6.17(d, J=7.6 Hz, 1H), 5.89(t, J ₁ =8.8Hz, J ₂ =9.2Hz, 1H), 5.42-5.40(m, 2H), 4.92-4.90(m, 2H), 4.70(s, 1H), 4.58 (t, _J1 = 7.6Hz, _J2 = 8.4Hz, 1H), 4.41 (d, J = 4.0Hz, 2H), 4.11-4.09 (m, 1H), 3.61 (d, J = 7.6Hz, 1H) , 2.32(m, 1H), 2.22(s, 3H), 2.12(m, 1H), 2.11(s, 3H), 1.88(m, 2H), 1.79(s, 3H), 1.50(s, 3H), 1.07(s, 3H), 1.05(s, 3H); LRMS calcd for C ₄₇ H ₅₁ NO ₁₄ [M] ⁺ 853.3, found 853.0.

Example 5: Preparation of 7-(phenyl)thiocarbonyloxy-10-desacetylbaccatin-III(IV)

Dissolve 1.25g (2.3mmol) of 10-deacetylbaccatin-III into 110mL of anhydrous chloroform, add 0.64g (4.6mmol) of thiobenzoic acid under stirring at room temperature, continue stirring, and monitor the reaction progress by TLC. After the reaction, it was diluted with chloroform, and washed with water and saturated sodium chloride solution successively. Dry over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. The concentrate was purified by ethyl acetate-n-hexane recrystallization to obtain compound IV.

Example 6: Preparation of 7-(phenyl)thiocarbonyloxy-10-trichloroacetyl-10-desacetylbaccatin-III(V)

Dissolve 1.13g (1.7mmol) of compound IV in 15mL of anhydrous pyridine, blow nitrogen gas, stir, add dropwise 6.18g (34mmol) of trichloroacetyl chloride, and continue stirring at room temperature for 24h. Add an equal volume of ethyl acetate and water, stir, let stand to separate layers, extract the aqueous phase twice with ethyl acetate, combine the organic phases, wash with saturated copper sulfate solution until pyridine is completely removed, and then successively water and saturated chlorine NaCl solution for washing. Dry over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. The concentrate was purified by flash column chromatography (eluent: ethyl acetate-cyclohexane, volume ratio: 3:4) to obtain compound V.

Example 7: 13-(2'-phenyl-4'-p-methoxyphenyl-N-tert-butoxycarbonyl-oxazolidine-1-carbonyloxy)-7-(phenyl)thiocarbonyl Preparation of Oxy-10-trichloroacetyl-10-desacetylbaccatin-III(VIIb)

Dissolve 0.89g (1.1mmol) of compound V into 120mL of anhydrous toluene and dichloromethane (2:1 by volume), and add 1.32g (3.3mmol) of compound VIb under stirring, 40.3mg (0.33mmol) N'N '-Dimethylaminopyridine (DMAP), after stirring for 10 min, 340 mg (1.65 mmol) of dicyclohexylcarbonyl imide (DCC) was added, and the system became turbid after a while. Stirring was continued at room temperature, and the reaction progress was detected by TLC. After the reaction was completed, the turbidity was filtered off, diluted with ethyl acetate, and washed with saturated ammonium chloride solution, sodium bicarbonate solution and sodium chloride solution in sequence. Dry over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. The concentrate was purified by flash column chromatography (eluent: ethyl acetate-cyclohexane, volume ratio: 1:2) to obtain compound VIIb.

Embodiment 8: the preparation of docetaxel (Ib)

0.91g (0.76mmol) of compound VIIb was dissolved in 30mL of methanol, and 145mg (0.84mmol) of p-toluenesulfonic acid was added under stirring at room temperature. After reacting for 3h, 10mL of 0.1N hydrochloric acid aqueous solution was added, and the reaction progress was detected by TLC. After the reaction was completed, it was diluted with ethyl acetate, and then washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution in sequence. Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is purified by flash column chromatography (eluent: ethyl acetate-cyclohexane, volume ratio: 1:1) to obtain compound Ib.

Claims (6)

1. the synthetic method of taxol or Docetaxel, general structure is:

It is characterized in that realizing by following steps:

(1) 10-deacetylate crust card booth II and compound III are reacted in solvent; obtain compound IV; wherein compound III is acetyl halide compound or heterogeneous ring compound; temperature of reaction is at-78～100 ℃; solvent for use is selected ether solvent, aromatic solvent or chlorinated solvent for use; products therefrom IV passes through the method purifying of recrystallization, or carries out quick purification by silica gel column chromatography, and reaction formula is:

Or

Wherein compound III is

R ₃-be fatty group or aromatic base, X-is halogen radical or hydroxyl,

Be heterocyclic radical;

(2) compound IV and acetylation reagent react in solvent; obtain compound Va; or compound IV and chloroacetyl chloride reagent react in solvent; the C-10 hydroxyl protected obtain compound Vb; used acetylation reagent is selected Acetyl Chloride 98Min., diacetyl oxide or glacial acetic acid for use, and the used reagent of C-10 hydroxyl protection is selected for use chloroacetyl chloride, trichlorine ethoxy dicarbonyl chloride, benzyloxy dicarbonyl chloride or trichoroacetic chloride, and temperature of reaction is-78～100 ℃; the same step of the purification process of product (1), reaction formula is:

R wherein ₃-be fatty group or aromatic base, Be heterocyclic radical;

(3) the side-chain acid VIa of C-13 hydroxyl among the compound Va and protection carries out the esterification coupling in solvent in the presence of alkali; obtain compound VI Ia; the C-13 hydroxyl among the compound Vb and the side-chain acid VIb of protection carry out the esterification coupling in solvent in the presence of alkali; obtain compound VI Ib; wherein used alkali comprises condensing agent carbonyl imide class and activator; solvent is selected the ether solvent for use; aromatic solvent; chlorinated solvent; amide solvent or their combination; the temperature of reaction is-78～100 ℃; the purifying of product VII adopts rapid column chromatography; or directly enter next step, reaction formula is:

R wherein ₃-be fatty group or aromatic base,

Be heterocyclic radical, compound VI a, VIb are

(4) compound VI Ia carries out under acidic conditions that single step reaction removes the C-7 protecting group Ji oxazole ring protection base; obtain target product taxol Ia; compound VI Ib carries out single step reaction and removes C-7 protecting group, C-10 protecting group Ji oxazole ring protection base under acidic conditions; obtain target product Docetaxel Ib; organic acid, inorganic aqueous acid or their combination are selected in used acid for use; temperature of reaction is at-78～100 ℃; the solvent of selecting for use is water, tetrahydrofuran (THF), dioxane, acetonitrile, methyl alcohol or ethanol; products therefrom is through column chromatography purification, and reaction formula is:

R wherein ₁-be phenyl or tert.-butoxy, R ₂-be ethanoyl, chloracetyl, trichlorine ethoxycarbonyl acyl, benzyloxy carbonyl acyl group or tribromo-acetyl base, R ₃-be fatty group or aromatic base,

Be heterocyclic radical.

2. the synthetic method of taxol according to claim 1 or Docetaxel is characterized in that: the R in the step (1) in the used compound III ₃-be aromatic base, X-is a halogen radical.

3. the synthetic method of taxol according to claim 1 or Docetaxel is characterized in that: used acetylation reagent is selected Acetyl Chloride 98Min. or diacetyl oxide for use in the step (2), and temperature of reaction is selected 0～30 ℃ for use.

4. the synthetic method of taxol according to claim 1 or Docetaxel, it is characterized in that: condensing agent carbonyl imide class is selected dicyclohexyl carbonyl imide or di-isopropyl carbonyl imide for use in the step (3), activator is selected the 4-Dimethylamino pyridine for use, and temperature of reaction is selected 0～30 ℃ for use.

5. the synthetic method of taxol according to claim 1 or Docetaxel is characterized in that: the combination solvent of selecting for use in the step (3) is benzene-tetrahydrofuran (THF) or toluene-methylene dichloride.

6. the synthetic method of taxol according to claim 1 or Docetaxel is characterized in that: used composite acid is selected toluenesulphonic acids-dilute hydrochloric acid or trifluoroacetic acid-acetate for use in the step (4).