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Process for selectively protecting baccatin derivative and its application in synthesizing tartrialkane

A technology for derivatives and hydroxytaxanes, which is applied in the field of selective protection of baccatin derivatives and its application in the synthesis of taxanes, which can solve the problems of narrow application fields and valuable purification

Inactive Publication Date: 2006-03-08
SOC DETUD & DE RES & DEV & INGIE PHARMA SERIPHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Under conditions of using alkali metal alkoxides as intermediates at very low temperatures, it is possible to avoid this secondary reaction, but for industrial synthesis, it would lead to new double disadvantage of
[0014] 2 / The susceptibility of alkylsilyl ethers to acidic conditions limits the possibility of using acidic reagents in later synthetic steps, thus narrowing the field of application of this protecting group
[0015] 3 / The known susceptibility of alkylsilyl ethers to hydroxyl-containing solvents such as water and alcohols makes it impossible to use these solvents for recrystallization for this series of compounds, but these systems are invaluable for purification of this series of compounds , which is another significant disadvantage
[0016] 4 / When using industrial chromatography to purify intermediates with silyl ethers, due to partial decomposition, it is practically impossible to allow the use of this purification technique from the point of view of obtaining high-value, high-purity pharmaceutical raw materials look is precious

Method used

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  • Process for selectively protecting baccatin derivative and its application in synthesizing tartrialkane
  • Process for selectively protecting baccatin derivative and its application in synthesizing tartrialkane
  • Process for selectively protecting baccatin derivative and its application in synthesizing tartrialkane

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0106] 7-O-(2,2,2-Trichlorobutoxycarbonyl)-10-deacetylbaccatin III

[0107] Within 50 minutes, at 40°C under an inert atmosphere, to stirred 500mg (0.919mmol) 10-deacetylbaccatin III and 0.19g (1.29mmol) 4-pyrrolidin-1-ylpyridine in 5mL To the solution in anhydrous dichloromethane was added a solution of 0.26 g (1.10 mmol) 2,2,2-trichloro-tert-butoxycarbonyl chloride in 2 mL of dichloromethane. After an additional 1 hour of reaction, cooled to ambient temperature, the organic solution was washed with 2% aqueous hydrochloric acid (5 mL), then permeated water (2 x 5 mL), dried over magnesium sulfate, and concentrated under reduced pressure. After chromatographic purification of the crude product on silica gel (15-40 μm) (elution: cyclohexane / ethyl acetate, 60 / 40), 7-O-(2,2,2-trichloro-tert-butyl Oxycarbonyl)-10-deacetylbaccatin III (Yield = 89%).

[0108] The product obtained has the following properties:

[0109] -RMN 1 H 400MHz (CDCl 3 )(δppm): 8,10(2H,d,J=7,3Hz); 7,62(1H...

Embodiment 2

[0111] 7-O-(2,2,2-Trichlorobutoxycarbonyl)-baccatin III

[0112] At ambient temperature and under an inert atmosphere, to stirred 260mg (0.347mmol) 7-O-(2,2,2-trichloro-tert-butoxycarbonyl)-10-deacetylbaccatin III and 127.5mg ( Add 50 μL (0.695 mmol) of acetyl chloride to a solution of 1.04 mmol) 4-dimethylaminopyridine in 2.5 mL of anhydrous dichloromethane. After 1 hour of reaction at ambient temperature, the organic phase is washed with 2% aqueous hydrochloric acid until pH = 6 is obtained, dried over magnesium sulfate and concentrated under reduced pressure. After chromatographic purification of the resulting residue on silica gel (15-40 μm) (elution: cyclohexane / ethyl acetate, 6 / 4), 7-O-(2,2,2-trichloro-tert-butyl Oxycarbonyl)-Baccatin III (Yield = 96%).

[0113] The product obtained has the following properties:

[0114] -RMN 1 H 400MHz(CDCl3)(δppm): 8,10(2H,d,J=7,6Hz); 7,61(1H,t,J=7,4Hz); 7,48(2H,t,J=7 ,7Hz); 6,52(1H,s); 5,65(1H,d,J=6,9Hz); 5,39(1H,dd,J=10,4 and 7,...

Embodiment 3

[0115] Example 3 (comparative example)

[0116] 7-O-Trichloroethoxycarbonyl-10-deacetylbaccatin III

[0117] Within 40 minutes, at 40°C under an inert atmosphere, to stirred 500mg (0.919mmol) 10-deacetylbaccatin III and 0.19g (1.29mmol) 4-pyrrolidin-1-ylpyridine in 5mL To the solution in dry dichloromethane was added a solution of 0.152 mL (1.10 mmol) trichloroethoxycarbonyl chloride in 2 mL of dichloromethane. After an additional 1 hour of reaction, cool down to ambient temperature, wash the organic solution with 2% hydrochloric acid (5 mL), wash with permeated water (2×5 mL), dry over magnesium sulfate, and concentrate under reduced pressure (HPLC analysis, Yield = 57%). After chromatographic purification of the crude product on silica gel (15-40 μm) (elution: cyclohexane / ethyl acetate, 60 / 40), 7-O-trichloroethoxycarbonyl-10-deacetyl was obtained as white powder Baccatin III.

[0118] The product obtained has the following properties:

[0119] -RMN 1 H 400MHz (CDCl ...

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Abstract

This invention concerns a method for selective protection of 7-hydroxyl baccatin derivatives using substituted alkoxycarbonyl groups more encumbered than trichloroethoxycarbonyl, the intermediates obtained, and their use in the preparation of taxanes suitable for medicinal purposes.

Description

[0001] This application was submitted on December 27, 1996, the application number is 96199356.1, and the divisional application of the patent application titled "Method for Selective Protection of Baccatin Derivatives and Its Application in the Synthesis of Taxanes" . technical field [0002] The invention relates to a novel intermediate for semi-synthesizing taxanes and a preparation method thereof Background technique [0003] Taxanes are a class of natural substances whose diterpene backbone is generally esterified with β-amino acid side chains derived from N-alkanoyl- or N-aroyl-phenyl-isoserine, which are known as anticancer agents. Including dozens of taxanes isolated from Taxus species, such as PACLITAXEL represented by the following general formulas 1 and 2 (R1=Ac, R2=Ph, R3=R4=H) , cephalomannine, its deacetylated derivative at the 10-position, or baccatin (derivative without side chain). [0004] [0005] [0006...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D305/14C07F7/18C07D413/12
CPCC07F7/188C07D305/14C07F7/1856C07F7/1804
Inventor L·查恩泰劳普B·查维尤C·科宾R·德哈尔S·利古恩A·拉米A·莱兹J·P·罗宾
Owner SOC DETUD & DE RES & DEV & INGIE PHARMA SERIPHARM