WO2008074178A1 - A new semisynthetic process of pacutaxel - Google Patents
A new semisynthetic process of pacutaxel Download PDFInfo
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- WO2008074178A1 WO2008074178A1 PCT/CN2006/003150 CN2006003150W WO2008074178A1 WO 2008074178 A1 WO2008074178 A1 WO 2008074178A1 CN 2006003150 W CN2006003150 W CN 2006003150W WO 2008074178 A1 WO2008074178 A1 WO 2008074178A1
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- ketal
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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 invention relates to a novel semi-synthetic method of the anticancer drug paclitaxel. Background technique
- Paclitaxel is considered to be the most effective anticancer drug ever discovered by humans and is extracted from the genus Taxus.
- the extraction of paclitaxel from plants has not been possible due to its low content and the extraction of plants belonging to national conservation plants. Since the discovery of paclitaxel, its all-in-one achievement has become the synthetic target of many chemists. Due to the complex structure of paclitaxel, its fully synthetic route is long and the yield is low.
- Semi-synthesis is relatively easy. Semi-synthesis mainly uses 10-deacetylbaccatin III and paclitaxel C13 side chain as raw materials. The chemical semi-synthesis method of paclitaxel not only helps to protect scarce plant resources, but also has great significance and huge economic benefits for expanding its clinical application and reducing treatment costs.
- paclitaxel The strategy for semi-synthesis of paclitaxel is to dock with protected bacatein and chiral side chains and then deprotect to obtain paclitaxel as follows:
- the side chain synthesis step is lengthy and the reagents used are expensive and cost prohibitive.
- the present invention employs a third type of chiral side chain: 3-phenylisoserine type.
- the invention has the following features: 1. Using different novel chiral side chains, the protected buckhaming III can be prepared by 10-deacetylbaccatin III extracted from the leaves of the yew, and the docking reaction condition is mild, at 0 ⁇ Reaction between 40 ° C for 1 ⁇ 12 h ; 2. Using a clever strategy to flip the 2 '' position of the C13 position side chain to get the correct configuration.
- the process of the invention is suitable for industrial production.
- the synthetic route of the present invention is as follows:
- the R1 protecting group is a hydroxy protecting group such as tert-butyldimethylsilyl (TBS), triethylsilyl (TES), ethoxyethyl (EE), tetrahydropyran (THP), trichloroethyl Oxycarbonyl (Troc), methoxymethyl (MOM), etc.
- R2 protecting group is a hydroxy protecting group such as TBS, TES, EE, THP, Troc, MOM, etc.
- R3 is H; or R2, R3 are ketal protection
- the ketal may be, for example, an anisyl ketal, an acetone ketal, or the like; and the dehydrating agent may be a thionyl chloride, a phosphorus pentachloride, a trifluoromethanesulfonic anhydride, a Vi lsmeier reagent or the like.
- the invention condenses the protected bicalatin 111 (1) and the novel chiral side chain (2) under the action of cyclohexyl carbodiimide (DCC) / 4-dimethylaminopyridine (DMAP) to obtain a compound ( 3), removing the side chain protection to obtain the compound (4), dehydration while completing the side chain 2, chiral inversion to obtain the compound (5), and finally hydrolyzing the oxazoline to obtain the compound (6), removing the 7-position protection Paclitaxel (Taxol) was obtained.
- DCC cyclohexyl carbodiimide
- DMAP 4-dimethylaminopyridine
Abstract
A new semisynthetic process for preparing taxol by condensing the synthetical C-13 side chain precursor of 2-epipaclitaxel with protected baccatin III. The resulted paclitaxel is completely the same as that from the Yew in configuration.
Description
种紫杉醇半合成的新方法 技术领域 New method for semi-synthesis of paclitaxel
本发明涉及抗癌药紫杉醇的半合成新方法。 背景技术 The invention relates to a novel semi-synthetic method of the anticancer drug paclitaxel. Background technique
紫杉醇被认为是迄今人类发现的最有效的抗癌药，是从红豆杉属 植物中提取出来的。由于其含量很低且所提取的植物属于国家保护植 物， 从植物中提取紫杉醇已无法进行。 自紫杉醇被发现以来， 其全合 成就成为众多化学家的合成目标。 由于紫杉醇结构复杂， 其全合成路 线长， 产率低。 而其半合成则相对容易的多。 半合成主要采用 10-脱 乙酰巴卡亭 III和紫杉醇 C13侧链为原料。开展紫杉醇的化学半合成 方法，不仅有利于保护稀缺的植物资源，而且对扩大其在临床的运用， 降低治疗成本都有重大意义和巨大的经济效益。 Paclitaxel is considered to be the most effective anticancer drug ever discovered by humans and is extracted from the genus Taxus. The extraction of paclitaxel from plants has not been possible due to its low content and the extraction of plants belonging to national conservation plants. Since the discovery of paclitaxel, its all-in-one achievement has become the synthetic target of many chemists. Due to the complex structure of paclitaxel, its fully synthetic route is long and the yield is low. Semi-synthesis is relatively easy. Semi-synthesis mainly uses 10-deacetylbaccatin III and paclitaxel C13 side chain as raw materials. The chemical semi-synthesis method of paclitaxel not only helps to protect scarce plant resources, but also has great significance and huge economic benefits for expanding its clinical application and reducing treatment costs.
紫杉醇的半合成采取的策略是：用保护的巴卡亭 ΠΙ和手性侧链 对接， 然后脱保护得到紫杉醇， 如下所示： The strategy for semi-synthesis of paclitaxel is to dock with protected bacatein and chiral side chains and then deprotect to obtain paclitaxel as follows:
从现有的已发表的专利和文献（例如： US 5175315; EP 400971； European J. Org. Chem, 1999, 121； J. Am. Chem. Soc, 1994, 116 ( 14)： 1579〜1602) 来看， 迄今为止， 半合成紫杉醇所采用的手性
From existing published patents and literature (eg: US 5175315; EP 400971; European J. Org. Chem, 1999, 121; J. Am. Chem. Soc, 1994, 116 (14): 1579~1602) Look, to date, the chirality of semi-synthetic paclitaxel
第一类 2R, 35-苯基异丝氨酸型 第二类 37?, 45- β -内酰胺型 无论采用哪类手性侧链， 其手性构型都是和紫杉醇的一样， 而该 两类侧链的合成步骤冗长， 所用试剂价格昂贵， 成本过高。 The first type of 2R, 35-phenyl isoserine type, the second type of 37?, 45-β-lactam type, regardless of the chiral side chain, the chiral configuration is the same as that of paclitaxel. The side chain synthesis step is lengthy and the reagents used are expensive and cost prohibitive.
发明内容 Summary of the invention
本发明则采用第三类手性侧链：
3 -苯基异丝 氨酸型。 The present invention employs a third type of chiral side chain: 3-phenylisoserine type.
本发明的特点在于： 1.采用不同的新型手性侧链， 保护的巴卡亭 III可以用从红豆杉枝叶中提取的 10-去乙酰巴卡亭 III制备， 对接 反应条件温和，在 0〜40°C之间反应 1〜12 h; 2.采用巧妙的策略对 C13位侧链 2 '' 位的构型进行翻转得到正确的构型。 本发明方法适合 于工业化生产。 The invention has the following features: 1. Using different novel chiral side chains, the protected buckhaming III can be prepared by 10-deacetylbaccatin III extracted from the leaves of the yew, and the docking reaction condition is mild, at 0~ Reaction between 40 ° C for 1~12 h ; 2. Using a clever strategy to flip the 2 '' position of the C13 position side chain to get the correct configuration. The process of the invention is suitable for industrial production.
本发明的合成路线如下图：
The synthetic route of the present invention is as follows:
本发明用保护的巴卡亭 111 (1)和新型手性侧链 (2)在环己垸碳二 亚胺（DCC) /4—二甲基氨基吡啶（DMAP)作用下缩合制得化合物（3)， 脱除侧链的保护得到化合物 (4)， 脱水的同时完成侧链 2， 位手性的 翻转得到化合物 (5)， 最后水解恶唑啉得到化合物 (6)， 脱除 7位保护 得到紫杉醇 (Taxol)。
T N2006/003150 为了便于理解本发明，特列举以下实施例。其作用应被理解为是 对本发明的诠释而绝非对本发明的任何形式的限制。 The invention condenses the protected bicalatin 111 (1) and the novel chiral side chain (2) under the action of cyclohexyl carbodiimide (DCC) / 4-dimethylaminopyridine (DMAP) to obtain a compound ( 3), removing the side chain protection to obtain the compound (4), dehydration while completing the side chain 2, chiral inversion to obtain the compound (5), and finally hydrolyzing the oxazoline to obtain the compound (6), removing the 7-position protection Paclitaxel (Taxol) was obtained. T N2006/003150 In order to facilitate the understanding of the present invention, the following examples are specifically enumerated. It is to be understood that the invention is not to be construed as limiting the invention.
具体实施方式 detailed description
实施例 1 Example 1
50克化合物 la和 50克化合物 2a加入甲苯 5000毫升， 加入 1 克 D AP和 50克 DCC， 加热到 80度搅拌 S小时后反应完全， 过滤， 减压蒸去甲苯， 剩余物柱层析， 得到 65克化合物 3a。得率： 86.4%。 lH NMR (500 MHz, C6D6) δ： 8.35 (dd, J=6.8, 2.8 Hz, 2H) , 7.83 (br d, J=7.1 Hz, 2H), 7.50 (d, J=7.3 Hz, 1H)， 7.42 (s， 1H), 7.40 —7.32 (m， 2H), 7.30—7.15 (m, 7H)， 7.00 (t, J=7.3 Hz, 1H)， 6.95 (s, 1H)， 6.90- 6.85 (m, 4H), 6.60 (br t, J=9.2 Hz, 1H), 6.12 (d, J-6.9 Hz, 1H)， 5.97 (br s, 1H)， 5.45 (s, 2H) 5.01 (d， J=8.3 Hz, 1H)， 4.90 (dd, J=11.4， 6.8 Hz, 1H), 4.80 (br s, 1H), 4.44 (d， J=8.6 Hz, 1H), 4.40 (d, J=8.6 Hz, 1H)， 4.28 (d， J=6.9 Hz, 1H), 3.35 (s， 3H), 2.80— 2.70 (m, 1H), 2.56 (s, 3H), 2.54 (dd, J=15.2, 9.2 Hz, 1H), 2.42 (dd, J=15.2, 9.2 Hz, 1H) , 2.30—2.18 (m， 1H)， 2.13 (s, 3H)， 2.08 (s' 3H), 1.95 (s, 3H), 1.83 (br s, 1H)， 1.35 (s, 3H), 1.23 (s, 3H). 50 g of compound la and 50 g of compound 2a were added to 5000 ml of toluene, 1 g of D AP and 50 g of DCC were added, and the mixture was heated to 80 ° C and stirred for S hours, the reaction was completed, filtered, toluene was evaporated under reduced pressure, and the residue was purified by column chromatography. 65 g of compound 3a. Yield: 86.4%. lH NMR (500 MHz, C 6 D 6 ) δ: 8.35 (dd, J = 6.8, 2.8 Hz, 2H), 7.83 (br d, J = 7.1 Hz, 2H), 7.50 (d, J = 7.3 Hz, 1H ), 7.42 (s, 1H), 7.40 - 7.32 (m, 2H), 7.30 - 7.15 (m, 7H), 7.00 (t, J = 7.3 Hz, 1H), 6.95 (s, 1H), 6.90- 6.85 ( m, 4H), 6.60 (br t, J=9.2 Hz, 1H), 6.12 (d, J-6.9 Hz, 1H), 5.97 (br s, 1H), 5.45 (s, 2H) 5.01 (d, J= 8.3 Hz, 1H), 4.90 (dd, J=11.4, 6.8 Hz, 1H), 4.80 (br s, 1H), 4.44 (d, J=8.6 Hz, 1H), 4.40 (d, J=8.6 Hz, 1H ), 4.28 (d, J=6.9 Hz, 1H), 3.35 (s, 3H), 2.80— 2.70 (m, 1H), 2.56 (s, 3H), 2.54 (dd, J=15.2, 9.2 Hz, 1H) , 2.42 (dd, J=15.2, 9.2 Hz, 1H), 2.30-2.18 (m, 1H), 2.13 (s, 3H), 2.08 (s' 3H), 1.95 (s, 3H), 1.83 (br s, 1H), 1.35 (s, 3H), 1.23 (s, 3H).
实施例 2
Example 2
65克化合物 3a溶于 1000毫升无水乙醇中，加入 2N的稀盐酸 50 毫升， 室温搅拌过夜， 用饱和碳酸氢钠中和至中性， 蒸去溶剂， 剩余 物柱层析， 得到 50克化合物 4a。 得率： 85.7%。 65 g of the compound 3a was dissolved in 1000 ml of absolute ethanol, and 50 ml of 2N diluted hydrochloric acid was added thereto, stirred at room temperature overnight, neutralized to neutral with saturated sodium hydrogencarbonate, and the solvent was evaporated. 4a. Yield: 85.7%.
Ή匪 R (500 MHz, C6D6) δ： 8.50 (d， J=8.5 Hz, 1H) , 8.46 (d, J=6.6 Hz, 1H)， 7.63 (d, J=7.3 Hz, 1H), 7.56 - 7.50 (m, 2H)， 7.35 - 7.21 (m, 6H), 7.10 (t， J=7.3 Hz, 1H), 7.03 - 6.97 (m, 2H) , 6.85 (d， J=9.2 Hz, 1H), 6.64 (s, 1H)， 6.56 (dd， J=9.2, 8.9 Hz, 1H), 6.18 (dd, J二 9.2， 2.1 Hz, 1H)， 6.06 (d, J=6.9 Hz, 1H)， 5.55 (s, 2H), 4.99 (cld, J=7.6, 1.9 Hz, 1H), 4.80 — 4.75 (m, 1H), 4.74 (dd, J=4.6, 2.1 Hz, 1H), 4.49 (s, 2H)， 4.12 (d， J=6.9 Hz, 1H)， 3.56 (d， J=4.6 Hz, 1H), 2.90 (d, J=4.0 Hz, 1H)， 2.73 (dd, J=15.7, 8.9 Hz, 1H)， 2.71 - 2.65 (m, 1H), 2.64 (dd, ]=15.7, 9.2 Hz, 1H)， 2.25— 2.16 (m, 1H), 2.23 (s， 3H)， 2.05 (s， 3H), 2.02 (s, 3H)， 1.85 (s, 3H), 1.74 (s, 1H), 1.17 (s, 3H), 1.14 (s， 3H) . Ή匪R (500 MHz, C 6 D 6 ) δ: 8.50 (d, J=8.5 Hz, 1H), 8.46 (d, J=6.6 Hz, 1H), 7.63 (d, J=7.3 Hz, 1H), 7.56 - 7.50 (m, 2H), 7.35 - 7.21 (m, 6H), 7.10 (t, J=7.3 Hz, 1H), 7.03 - 6.97 (m, 2H) , 6.85 (d, J=9.2 Hz, 1H) , 6.64 (s, 1H), 6.56 (dd, J=9.2, 8.9 Hz, 1H), 6.18 (dd, J 2 9.2, 2.1 Hz, 1H), 6.06 (d, J=6.9 Hz, 1H), 5.55 ( s, 2H), 4.99 (cld, J=7.6, 1.9 Hz, 1H), 4.80 — 4.75 (m, 1H), 4.74 (dd, J=4.6, 2.1 Hz, 1H), 4.49 (s, 2H), 4.12 (d, J=6.9 Hz, 1H), 3.56 (d, J=4.6 Hz, 1H), 2.90 (d, J=4.0 Hz, 1H), 2.73 (dd, J=15.7, 8.9 Hz, 1H), 2.71 - 2.65 (m, 1H), 2.64 (dd, ]=15.7, 9.2 Hz, 1H), 2.25— 2.16 (m, 1H), 2.23 (s, 3H), 2.05 (s, 3H), 2.02 (s, 3H) ), 1.85 (s, 3H), 1.74 (s, 1H), 1.17 (s, 3H), 1.14 (s, 3H).
实施例 3 Example 3
50克化合物 4a溶于 500毫升二氯甲烷中， 冷却到 -45度， 小心 滴加三氟甲磺酸酐 15克， 加毕慢慢升温至室温搅拌过夜， 用饱和碳 酸氢钠中和至中性， 蒸去溶剂，剩余物柱层析，得到 40克化合物 5a。 得率： 80.0%。 50 g of compound 4a was dissolved in 500 ml of dichloromethane, cooled to -45 °C, and 15 g of trifluoromethanesulfonic anhydride was carefully added dropwise, and the mixture was slowly warmed to room temperature and stirred overnight, neutralized with saturated sodium bicarbonate until neutral. The solvent was distilled off, and the residue was subjected to column chromatography to yield 40 g of Compound 5a. Yield: 80.0%.
Ή NMR (500 MHz, COCh) δ： 8,25 (d， J=8.4 Hz, 1H〉， 8.15 (d, J=6.5 Hz, 1H)， 7.43 (d, J=7.1 Hz, 1H) , 7.26 - 7.20 (m, 2H), 7.15 - 7.09 (m, 6H)f 7.00 (t， J=7.1 Hz, 1H) , 6.93 - 6.90 (m, 2H) , 6.65 (s, 1H), 6.58 (dd, J=9.4, 8.7 Hz, 1H), 6.15 (dd, J=9.4, 2.3 Hz, 1H) , 6.08 (d, J=6.8 Hz, 1H)， 5.58 (s， 2H)， 4.96 (dd, J=7.5, 1.8 Hz, 1H)， 4.82 - 4.77 (m, 1H), 4.72 (dd, J=4.5, 2.1 Hz, 1H), 4.45 (s， 2H)， 4.10 (d， J=6.7 Hz, 1H)， 2.94 (d, J=4.1 Hz, 1H) , 2.75 (dd, J=15.6, 8.7 Hz, 1H), 2.70— 2.63 (m, 1H), 2.60 (dd, J=15.6, 9.0 Hz, 1H)， 2.28 - 2.19 (m, 1H)， 2.20 (s, 3H)， 2.04 (s, 3H), 2.02 (s, 3H), 1.87 (s, 3H)， 1.75 (s, 1H), 1.18 (s, 3H), 1.16 (s, 3H) NMR NMR (500 MHz, COCh) δ: 8,25 (d, J=8.4 Hz, 1H>, 8.15 (d, J=6.5 Hz, 1H), 7.43 (d, J=7.1 Hz, 1H), 7.26 - 7.20 (m, 2H), 7.15 - 7.09 (m, 6H) f 7.00 (t, J=7.1 Hz, 1H), 6.93 - 6.90 (m, 2H), 6.65 (s, 1H), 6.58 (dd, J= 9.4, 8.7 Hz, 1H), 6.15 (dd, J=9.4, 2.3 Hz, 1H), 6.08 (d, J=6.8 Hz, 1H), 5.58 (s, 2H), 4.96 (dd, J=7.5, 1.8 Hz, 1H), 4.82 - 4.77 (m, 1H), 4.72 (dd, J=4.5, 2.1 Hz, 1H), 4.45 (s, 2H), 4.10 (d, J=6.7 Hz, 1H), 2.94 (d , J=4.1 Hz, 1H), 2.75 (dd, J=15.6, 8.7 Hz, 1H), 2.70— 2.63 (m, 1H), 2.60 (dd, J=15.6, 9.0 Hz, 1H), 2.28 - 2.19 ( m, 1H), 2.20 (s, 3H), 2.04 (s, 3H), 2.02 (s, 3H), 1.87 (s, 3H), 1.75 (s, 1H), 1.18 (s, 3H), 1.16 (s , 3H)
4 4
40克化合物 5a溶于 1000毫升无水乙醇中，加入 2N的稀盐酸 50 毫升， 室温搅拌过夜， 用饱和碳酸氢钠中和至弱碱性， 搅拌过夜， 蒸 去溶剂， 剩余物加入醋酸 500毫升、 水 50毫升、 锌粉 50克， 加热回
流一小时， 冷却后用饱和碳酸氢钠中和到中性， 旋去溶剂， 剩余物柱 层析， 得到 20克紫杉醇， 为白色固体。 经核磁旋光等检测， 和天然 紫杉醇一样。 得率： 60.4%。 40 g of compound 5a was dissolved in 1000 ml of absolute ethanol, added with 2N of dilute hydrochloric acid 50 ml, stirred at room temperature overnight, neutralized with saturated sodium bicarbonate to weakly basic, stirred overnight, evaporated, and evaporated. 50 ml of water, 50 g of zinc powder, heated back After flowing for one hour, it was neutralized to neutrality with saturated sodium hydrogencarbonate, and the solvent was evaporated, and the residue was subjected to column chromatography to obtain 20 g of paclitaxel as a white solid. It is detected by nuclear magnetic rotation and the like, and is the same as natural paclitaxel. Yield: 60.4%.
m. p. 213-216 。 C m. p. 213-216. C
IR (KBr)： 3482, 1732， 1653 cm"; IR (KBr): 3482, 1732, 1653 cm";
[a ] D25: -49.2。 [a] D 25 : -49.2.
Ή NMR (CDC13) 500M) δ： 8.12 (d, J二 7.9 Hz, 2H), 7.71 (d， J=7.9 Hz, 2H) , 7.58 (t， J二 7.2 Hz, 1H), 7.53 (m， 5H), 7.40— 7.30 (m, 5H)， 6.98 (d, J=8.7Hz， 1H), 6.25〈s， 1H), 6.18 (bt, J二 8.9Hz, 1H), 5.75 (dd， J=8.7, 2.6Hz, 1H), 5.63 (d, J=7. lHz, 1H), 4.92 (bd， J=8.8Hz, 1H), 4.75 (d, J二 2.1Hz, 1H)， 4.36 (dd, J=10.5, 6.7 Hz, 1H), 4.29 (d， J=8.4 Hz, 1H)， 4.17 (d, J=8.3Hz, 1H), 3.76 (d, J=7.0 Hz., 1H), 3.54 (bs, 1H)， 2.51 (ddd, J=15.3, 9.5, 5.8Hz， 1H), 2.43 (bs, 1H)， 2.35 (s， 1H)， 2.33 (dd, J=15.3, 8.7Hz， 1H), 2.27 (dd, J=15.3, 8.7Hz， 1H), 2.25 (s, 3H), 2.20 (s， 3H), 1.90-1.85 (m, 1H), 1.75 (s, 3H), 1.65 (s, 3H), 1.20 (s, 3H), 1.11 (s, 3H)； ^匪！^ (CdC , 125M) δ 203.5, 172.6, 171.2, 170.3, 167.1, 167.0, 142.1， 137.8, 133.6, 133.6, 133.0, 132.0, 130.2, 129.1, 129.0, 128.8， 128.7, 128.4, 127.1， 127.0, 84.4, 81.0， 79.0, 76.4, 75.4 , 74.8, 73.3， 72.3, 72.2, 58.6, 55.0， 45.6, 43.1, 35.6, 35.6, 26.8, 22.6, 21,8， 20.9, 14.9, 9.5.
NMR NMR (CDC1 3) 500M) δ: 8.12 (d, J 7.9 Hz, 2H), 7.71 (d, J=7.9 Hz, 2H), 7.58 (t, J 7.2 Hz, 1H), 7.53 (m, 5H), 7.40— 7.30 (m, 5H), 6.98 (d, J=8.7Hz, 1H), 6.25<s, 1H), 6.18 (bt, J=8.9Hz, 1H), 5.75 (dd, J=8.7 , 2.6Hz, 1H), 5.63 (d, J=7. lHz, 1H), 4.92 (bd, J=8.8Hz, 1H), 4.75 (d, J two 2.1Hz, 1H), 4.36 (dd, J= 10.5, 6.7 Hz, 1H), 4.29 (d, J=8.4 Hz, 1H), 4.17 (d, J=8.3Hz, 1H), 3.76 (d, J=7.0 Hz., 1H), 3.54 (bs, 1H) ), 2.51 (ddd, J = 15.3, 9.5, 5.8 Hz, 1H), 2.43 (bs, 1H), 2.35 (s, 1H), 2.33 (dd, J = 15.3, 8.7 Hz, 1H), 2.27 (dd, J=15.3, 8.7Hz, 1H), 2.25 (s, 3H), 2.20 (s, 3H), 1.90-1.85 (m, 1H), 1.75 (s, 3H), 1.65 (s, 3H), 1.20 (s , 3H), 1.11 (s, 3H); ^匪! ^ (CdC , 125M) δ 203.5, 172.6, 171.2, 170.3, 167.1, 167.0, 142.1, 137.8, 133.6, 133.6, 133.0, 132.0, 130.2, 129.1, 129.0, 128.8, 128.7, 128.4, 127.1, 127.0, 84.4, 81.0 , 79.0, 76.4, 75.4, 74.8, 73.3, 72.3, 72.2, 58.6, 55.0, 45.6, 43.1, 35.6, 35.6, 26.8, 22.6, 21,8, 20.9, 14.9, 9.5.
Claims
1、 一种抗肿瘤药物紫杉醇的半合成新方法， 其特征在于， 所述 的方法包括如下步骤： A new method for semi-synthesis of an antitumor drug paclitaxel, characterized in that the method comprises the following steps:
(1)式 1表示的保护的巴卡亭 III与式 2表示的 2—表紫杉醇 C -13侧链前体对接， 得到式 3表示的化合物； (1) The protected bicalatin III represented by Formula 1 is docked with the 2-epitaxel C-13 side chain precursor represented by Formula 2 to obtain a compound represented by Formula 3;
(2) 式 3表示的化合物脱除保护基得到式 4表示的化合物； (2) The compound represented by Formula 3 is deprotected to give a compound represented by Formula 4;
(3) 式 4表示的化合物在缩水试剂的作用下脱水后得到式 5表 示的化合物，此脱水过程中化合物 4的 2' 位手性同时发生构型翻转; (3) The compound represented by Formula 4 is dehydrated by the action of a shrinking agent to obtain a compound represented by Formula 5, and the 2'-position chirality of Compound 4 is simultaneously reversed in the dehydration process;
(4) 式 5表示的化合物水解， 得到紫杉醇。 (4) The compound represented by Formula 5 is hydrolyzed to obtain paclitaxel.
2、 根据权利要求 1所述的方法， 其特征在于， 所述式 2表示的化 合物环化为式 2a表示的化合物再发生反应。
δ
3、 根据权利要求 1所述的方法， 其特征在于， 所述 R,或 R2是羟 基保护基， 所述 是^ 2. The method according to claim 1, wherein the compound represented by Formula 2 is cyclized to react with the compound represented by Formula 2a. δ 3. The method according to claim 1, wherein the R or R 2 is a hydroxy protecting group, and the
4、 根据权利要求 1所述的方法， 其特征在于， 所述 或 R2是缩 酮保护基， 所述！^是^ 4. The method according to claim 1, wherein the or R 2 is a ketal protecting group, the! ^是^
5、 根据权利要求 3所述的方法， 其特征在于， 所述羟基保护基选 自叔丁基二甲基硅、 三乙基硅、 乙氧基乙基、 四氢吡喃、 三氯乙基氧 羰基或者甲氧甲基。 5. The method according to claim 3, wherein the hydroxy protecting group is selected from the group consisting of tert-butyldimethylsilyl, triethylsilyl, ethoxyethyl, tetrahydropyran, trichloroethyl Oxycarbonyl or methoxymethyl.
6、 根据权利要求 4所述的方法， 其特征在于， 所述缩酮保护基是 对茴香基缩酮或者丙酮基缩酮。 6. The method according to claim 4, wherein the ketal protecting group is a p-anis ketal or an acetone ketal.
7、 根据权利要求 1所述的方法， 其特征在于， 所述缩合试剂是二 氯亚砜、五氯化磷、三氟甲磺酸酐、 Vi lsmeier试剂中的一种或几种。
7. The method according to claim 1, wherein the condensation reagent is one or more of thionyl chloride, phosphorus pentachloride, trifluoromethanesulfonic anhydride, and Vi lsmeier reagent.
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| PCT/CN2006/003150 WO2008074178A1 (en) | 2006-11-23 | 2006-11-23 | A new semisynthetic process of pacutaxel |
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| PCT/CN2006/003150 WO2008074178A1 (en) | 2006-11-23 | 2006-11-23 | A new semisynthetic process of pacutaxel |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011134067A1 (en) * | 2010-04-29 | 2011-11-03 | 6570763 Canada Inc. | Novel amino acid molecule and uses thereof |
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| US5686623A (en) * | 1992-10-30 | 1997-11-11 | Rhone-Poulenc Rorer, S.A. | Method for preparing taxane derivatives |
| CN1646512A (en) * | 2002-04-12 | 2005-07-27 | 因德纳有限公司 | A semi-synthetic process for the preparation of N debenzoylpaclitaxel |
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| US5686623A (en) * | 1992-10-30 | 1997-11-11 | Rhone-Poulenc Rorer, S.A. | Method for preparing taxane derivatives |
| CN1646512A (en) * | 2002-04-12 | 2005-07-27 | 因德纳有限公司 | A semi-synthetic process for the preparation of N debenzoylpaclitaxel |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2011134067A1 (en) * | 2010-04-29 | 2011-11-03 | 6570763 Canada Inc. | Novel amino acid molecule and uses thereof |
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