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Side chain C-3 position-modified taxane analogs and preparation method thereof

A taxane and side chain technology, applied in the field of paclitaxel analogs and their synthesis, can solve the problems of low natural content, low water solubility, drug resistance, etc., and achieve the effect of reducing toxic and side effects

Inactive Publication Date: 2016-02-03
SHANGHAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are few reports on paclitaxel analogues for the treatment of liver cancer, and its natural content is low, collection is limited, water solubility is extremely low, and there are still a series of problems such as drug resistance, toxicity and side effects

Method used

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  • Side chain C-3 position-modified taxane analogs and preparation method thereof
  • Side chain C-3 position-modified taxane analogs and preparation method thereof
  • Side chain C-3 position-modified taxane analogs and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1: Preparation of compound 3’-n- to prepare method of toluene-7,9,10- to remove acetyl-1-1-dehrotic hydroxybaka Pavilion VI. The structural format of this compound is:

[0027]

[0028] A.1-Demoba Kaica Pavilion VI1 (419mg, 0.6mmol) is dissolved in 20ml95%alcohol, adds 10ml water combination, and stir at room temperature for 15 hours.Use 0.2N dilute hydrochloric acid to neutralize, ethyl acetate extract, organic phase to wash three times with saturated saline, dry sodium sodium sulfate, and reduce the solvents with decompression.Cross-products with methanol and orthopedane heavy crystals, which are colorless transparent crystals 7,9,10,13-four-de-acetyl-1-oxygenbaca Pavilion VI2 is 227mg, and the yield is 87%;

[0029] B.Compound 2 (239mg, 0.5 mmol) dissolved in 18ml dichlorobial and 1.5ml methanol. After completely dissolving, add 2,2-di oxygenyl propylene (0.4ml, 2.0mmol), stir well, and add Montk10 to 24mg.Stir at room temperature for 0.5 hours; decompression d...

Embodiment 2

[0039] Example 2: Preparation of compounds 3’-n-benzenesulfraogl-7,9,10- to remove acetyl-1-1-dehrotic hydroxybaka Pavilion VI. The structure of the compound is:

[0040]

[0041] Methods Sedow Example 1:

[0042] 6b: 1 HNMR (500MHz ,CDCL 3 ) Δ (ppm): 3.24 (s, 1H), 3.77 (s, 3H), 4.38 (d, D, J = 2.3Hz, 1H), 4.91 (DD, J = 2.39.6Hz, 1H), 5.58 (D, J = 9.8Hz, 1H), 7.14-7.15 (m, 2H), 7.20 (T, T, J = 3.3Hz, 3H), 7.33 (T, J = 7.8Hz, 2H), 7.44 (T, J = 8.0Hz, 1H), 7.67 (D, J = 7.2Hz, 2H); 13 C-NMR (125MHz, CDCL 3 ) Δ (PPM): 22.10,27.79,52.93,59.42,67.61,68.66,744,107.87,126.83,126.27,128.64,137.35,140.54,172.39.

[0043] 7b: 1 HNMR (500MHz , CDCL 3 ) Δ (ppm): 3.24 (s, 1H), 3.77 (s, 3H), 4.38 (d, D, J = 2.3Hz, 1H), 4.91 (DD, J = 2.39.6Hz, 1H), 5.58 (D, J = 9.8Hz, 1H), 7.14-7.15 (m, 2H), 7.20 (T, T, J = 3.3Hz, 3H), 7.33 (T, J = 7.8Hz, 2H), 7.44 (T, J = 8.0Hz, 1H), 7.67 (D, J = 7.2Hz, 2H); 13 C-NMR (125MHz, CDCL 3 ) Δ (PPM): 27.03,28.84,52.64,65.17,81.74,102.55,127.44,127.65, 128.12, 1328,13...

Embodiment 3

[0047] Example 3: Preparation of compound 3’-N-Preparation method of dehuminyl-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-deodba-1-1-deodiabenyl-1.

[0048]

[0049] Methods Same Example 1:

[0050] 6C: 1 HNMR (500MHz, CDCL 3 ) Δ (ppm): 3.68 (s, 1H), 3.79 (s, 3H), 4.38 (d, D, J = 2.2Hz, 1H), 4.88 (DD, J = 2.39.8Hz, 1H), 6.36 (D, J = 9.8Hz, 1H), 7.13 (D, J = 1.2Hz, 2H), 7.19 (D, J = 3.0Hz, 1H), 7.37 (s, 1H), 7.38-7.41 (m, 3H), 7.46 (D, J = 6.8Hz, 1H); 13 CNMR (125MHz, CDCL 3

[0051] 7C: 1 HNMR (500MHz, CDCL 3 ) Δ (ppm): 1.80 (s, 3H), 1.87 (s, 3H), 3.72 (s, 3H), 4.52 (d, D, J = 5.4Hz, 1H), 5.18 (D, J = 5.4Hz, 1H), 7.13-7.17 (m, 4H), 7.19-7.22 (m, 1H), 7.27-7.34 (m, 4H); 13 CNMR (125MHz, CDCL 3 ) Δ (PPM): 27.20,28.59,52.70,65.11,81.69,100.64,127.26,127.81,128.23,128.95,137.22,139.84,170.26;

[0052] 8C: 1 HNMR (500MHz, CDCL 3 ) Δ (ppm): 1.24 (s, 3H), 1.27 (s, 3H), 1.54 (s, 6H), 1.69 (s, 3H), 1.81 (s, 3H), 1.88 (s, 6H), 1.94 (S, 3H), 2.00 (D, J = 8.8Hz, 1H), 2.06 (D, J= 11.2Hz, 1H), 2....

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Abstract

The invention relates to side chain C-3 position-modified taxane analogs and a preparation method thereof. The structural formula of the analogs can be found in the specification, wherein R is methyl phenyl, phenyl, bromophenyl, thienyl, benzene and tetrahydrofuran, methoxyphenyl, fluoro-phenyl, four methyl phenyl, naphthyl, p-nitrophenyl, furyl, trifluoromethyl, quinolyl, methyl quinoline, pyridyl and the like; R1 is hydrogen or hydrogen. According to the side chain C-3 position-modified taxane analogs and the preparation method thereof, various types of substituent groups are introduced to the 13th position of 1-dehydroxybaccatin VI taxane, a ring skeleton and a necessary functional group of taxanes are maintained, the compound of the type is enriched, the obtained compound has anticancer biological activity of natural taxol, and the side chain C-3 position-modified taxane analogs have certain application prospect on the aspect of lowering the toxic and side effect of the natural taxol; meanwhile, a quite significant foundation is laid for research of the active structure-activity relationship of the compound of the type.

Description

Technical field [0001] The invention involves a paclitaxel analog and its synthesis method.Especially involved a side chain C-3 ˊ -N transformed pacane analges and their preparation methods. technical background [0002] Paclitaxol (TAXOL) is a new type of anticancer drug with unique anti -cancer activity from the genus Taxus plant.The structure is as follows: [0003] [0004] Its structure is novel, unique in action, strong activity, and widely spectrum. It has been clinically proved that paclitaxel is a special effect of treating breast cancer, uterine cancer, pancreatic cancer, and colon cancer.At the end of 1992, it was officially approved by the FDA of the United States as a new drug for the treatment of ovarian and uterine cancer. It is currently one of the best anti -tumor drugs internationally recognized internationally.However, there are few reports on the treatment of liver cancer treatment literature on the treatment of liver cancer, and its natural content is low, ...

Claims

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Application Information

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IPC IPC(8): C07D305/14C07D413/12C07D407/12C07D409/14C07D409/12A61P35/00
CPCC07D305/14C07D407/12C07D409/12C07D409/14C07D413/12
Inventor 林海霞徐培佩邱卫清崔永梅李青峰王子潇
Owner SHANGHAI UNIV
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