9,10-dihydroxy-1-deoxy-taxol analogue and preparation method thereof

A paclitaxel analog, dihydroxyl technology, applied in drug combination, organic chemistry, antitumor drugs, etc., can solve the problems of limited collection, toxic and side effects, drug resistance, etc., and achieve the effect of improving water solubility

Inactive Publication Date: 2015-06-10
SHANGHAI UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, its natural content is very small, its collection is limited, its water solubility is extremely low, and there are problems such as drug resistance and toxic side effects. Therefore, the research on new resources of paclitaxel and its analogues has attracted much attention. Diterpene components (Taxoids) as the precursor semi-synthesis of paclitaxel and its derivatives is one of the main ways to solve the shortage of resources and improve the comprehensive performance

Method used

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  • 9,10-dihydroxy-1-deoxy-taxol analogue and preparation method thereof
  • 9,10-dihydroxy-1-deoxy-taxol analogue and preparation method thereof
  • 9,10-dihydroxy-1-deoxy-taxol analogue and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Embodiment 1: The preparation method of compound 3'-N-p-toluoyl-(7,9,10)-trideacetyl-1-dehydroxy-paclitaxel analogue, the structural formula of this compound is:

[0026]

[0027] A. 1-Deshydroxybaccatin VI1 (419 mg, 0.6 mmol) was dissolved in 20 mL of 95% ethanol, 10 mL of hydrazine hydrate was added, and stirred at room temperature for 15 hours. Neutralize with 0.2N dilute hydrochloric acid, extract with ethyl acetate, wash the organic phase three times with saturated brine, dry over anhydrous sodium sulfate, and evaporate the solvent under reduced pressure. The crude product was recrystallized from methanol and n-hexane to obtain 227 mg of colorless transparent crystal 7,9,10,13-tetradeacetyl-1-deoxybaccatin VI2 with a yield of 87%;

[0028] B.B. Compound 2 (239mg, 0.5mmol) was dissolved in 18mL of dichloromethane and 1.5mL of methanol, after it was completely dissolved, 2,2-dimethoxypropane (0.4mL, 2.0mmol) was added, stirred evenly, and then Mont K10 was added f...

Embodiment 2

[0038] Example 2: The preparation method of the compound 3'-N-p-methoxybenzoyl-(7,9,10)-trisdeacetyl-1-dehydroxy-paclitaxel analogue, the structural formula of the compound is:

[0039]

[0040] 8b

[0041] The method is the same as implementation example 1:

[0042] 5b: 1 HNMR (CDCl 3, 500MHz) δ(ppm): 3.85(s, 3H), 3.87(s, 3H), 4.65(s, 1H), 5.74(d, J=9.5Hz, 1H), 6.94(d, J=8.4Hz, 3H ), 7.32(t, J=15.5Hz, 1H), 7.38(t, J=15.4Hz, 2H), 7.47(d, J=8.3Hz, 2H), 7.76(d, J=8.5Hz, 2H); 13 C-NMR (125MHz, CDCl 3 )δ (ppm): 29.70, 53.29, 54.81, 55.44, 73.31, 113.84, 126.27, 126.89, 127.91, 128.54, 128.75, 128.93, 138.86, 162.71, 166.38, 173.43;

[0043] 6b: 1 HNMR (CDCl 3, 500MHz)δ(ppm):3.77(s,3H),3.82(s,6H),4.86(d,J=3.3Hz),5.47(br,1H),6.72(d,J=9.4Hz,2H), 6.87(d, J=9.3Hz, 2H), 6.94(br, 1H), 7.29-7.35(m, 6H), 7.48(br, 2H); 13 C-NMR (125MHz, CDCl 3 )δ (ppm): 14.43, 52.27, 55.29, 113.50, 127.03, 127.69, 128.01, 128.69, 128.73, 129.30, 130.08, 159.88, 161.61, 170.53;

[0044] 7b: 1 ...

Embodiment 3

[0046] Example 3: The preparation method of the compound 3'-N-p-hexylbenzoyl-(7,9,10)-trisdeacetyl-1-dehydroxy-paclitaxel analogue, the structural formula of the compound is:

[0047]

[0048] The method is the same as implementation example 1:

[0049] 5c: 1 HNMR (CDCl 3, 500MHz) δ (ppm): 1.26 (t, J = 15Hz, 3H), 2.70 (q, J = 39.3Hz, 2H), 3.76 (s, 3H), 4.10 (d, J = 4.4Hz, 1H), 4.63 (s,1H),5.77(d,J=9.6Hz,1H),7.20(d,J=6.5Hz,2H),7.26-7.36(m,4H),7.45(d,J=7.7Hz,2H) ,7.71(d,J=7.3Hz,2H),8.02(d,J=7.3Hz,1H); 13 C-NMR (125MHz, CDCl 3 )δ (ppm): 15.33, 28.78, 53.04, 55.11, 73.46, 126.98, 127.34, 127.79, 127.94, 128.05, 128.63, 130.30, 131.32, 148.45, 167.27, 173.42;

[0050] 6c: 1 HNMR (CDCl 3, 500MHz) δ (ppm): 1.20 (t, J = 15.5Hz, 3H), 2.62 (q, J = 24.4Hz, 2H), 3.82 (s, 3H), 3.83 (s, 3H), 4.10 (d, J =4.4Hz,1H),4.88(s,1H),5.47(br,1H),6.87(d,J=8.8Hz,2H),6.92(br,1H),7.07(d,J=9.4Hz,2H ), 7.26(d, J=8.4Hz, 3H), 7.31-7.34(m, 3H), 7.45(m, 2H); 13 C-NMR (125MHz, CDCl 3 )δ (ppm): 14....

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Abstract

The invention relates to a 9,10-dihydroxy-1-deoxy-taxol analogue and a preparation method thereof. The structural formula of the analogue is shown in the specification, wherein R is methylphenyl, methoxyphenyl, propylphenyl, ethylphenyl, fluorophenyl, methyl chlorophenyl, bromophenyl, furyl, thienyl or benzofuranyl. The 9,10-dihydroxy-1-deoxy-taxol analogue has exposed hydroxyls on sites 7, 9 and 10, so that the water solubility of compounds can be greatly improved; various substituents are located on a side chain on a site 13, so that the compounds are enriched, and a very important foundation is laid for the authentication of structure-activity relationship of the compounds.

Description

technical field [0001] The invention relates to a doxytaxel analogue and a synthesis method thereof. Particularly related to a side chain C-N-3 , Modified 9,10-dihydroxy-1-deoxypaclitaxel analogs and methods for their preparation. technical background [0002] Paclitaxol (trade name: Taxol) is a new type of anticancer drug isolated from Taxus plants with unique anticancer activity. Its structure is as follows: [0003] [0004] It has a novel structure, a unique mechanism of action, strong activity, and a broad spectrum of action. It has been clinically proven that paclitaxel is a specific drug for the treatment of various cancers such as breast cancer, uterine cancer, pancreatic cancer, and colon cancer. At the end of 1992, it was officially approved by the US FDA as a new drug for the treatment of ovarian cancer and uterine cancer. It is one of the best anti-tumor drugs recognized internationally in recent years. However, its natural content is very small, its colle...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D305/14C07D407/12C07D409/12A61P35/00
CPCC07D305/14C07D407/12C07D409/12
Inventor 李青峰林海霞崔永梅徐培佩
Owner SHANGHAI UNIV
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