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Synthesizing method of deuterium-labeled glucuronide fenretinide

A technology of retinoyl glucuronide and synthesis method, which is applied in the field of synthesis of deuterium-labeled retinoyl glucuronide, and can solve the problem of retinoyl glucuronide that has not been found. To solve problems such as the synthesis method of acylphenamides, achieve the effects of excellent antitumor activity, simple and easy-to-obtain reagents, and reasonable synthesis process design

Active Publication Date: 2017-07-25
TLC NANJING PHARMA RANDD CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] There is no report on the synthesis method of retinoyl glucuronide and deuterium-labeled retinoic acid glucuronide in China

Method used

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  • Synthesizing method of deuterium-labeled glucuronide fenretinide
  • Synthesizing method of deuterium-labeled glucuronide fenretinide
  • Synthesizing method of deuterium-labeled glucuronide fenretinide

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Preparation of Compound 3:

[0044]

[0045] To a 100ml round bottom flask, add 4-nitrophenol-D in sequence 4 (2.25g, 15.7mmol), 16.9ml of dry pyridine and 3.94ml of acetic anhydride, the reaction was heated to an oil bath at 90°C and stirred for 2 hours, and the reaction solution was brown. After TLC showed that the raw materials had reacted completely, cooled to room temperature (18 degrees), spin-dried pyridine, added 20ml of water, stirred, a large amount of solids were precipitated, filtered with suction, washed with an appropriate amount of water, drained, and dried overnight in a vacuum dryer to obtain Product Compound 3 (2.88 g, off-white solid). Yield 98.95%.

[0046] Preparation of Compound 4:

[0047]

[0048] In a 100ml round bottom flask, add the prepared compound 3 (2.88g, 15.5mmol) and 43.2ml methanol successively. The raw materials are not easily soluble. Weigh and add 0.43g Pd / C successively under nitrogen protection, and react with hydrogen ga...

Embodiment 2

[0064] Preparation of compound 3:

[0065]

[0066] To a 100ml round bottom flask, add 4-nitrophenol-D in sequence 4 (3g, 20.9mmol), 30ml of dry pyridine and 6ml of acetic anhydride, the reaction temperature was raised to 100°C in an oil bath and stirred for 1 hour, the reaction solution was brown. After TLC showed that the raw materials had reacted completely, cooled to room temperature (20 degrees), spin-dried pyridine, added 50ml of water, stirred, a large amount of solids were precipitated, filtered with suction, washed with an appropriate amount of water, drained, and dried overnight in a vacuum dryer to obtain Product Compound 3 (3.0 g, off-white solid). Yield 77.30%.

[0067] Preparation of compound 4:

[0068]

[0069] In a 150ml round bottom flask, add the prepared compound 3 (3g, 16.2mmol) successively, 60ml methanol, the raw material is not easily soluble, weigh and add 0.6g Pd / C successively under the protection of nitrogen, react hydrogen, at room tempera...

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Abstract

The invention discloses a synthesizing method of deuterium-labeled glucuronide fenretinide. The synthesizing method comprises the following steps of 4-nitrophenol-D4 is used as a deuterium-labeled initiating matter, and six-step reaction is performed, so as to obtain the deuterium-labeled glucuronide fenretinide-D4. The synthesizing method has the advantages that the optimum preparation steps and reaction conditions are screened by a large amount of experiments, the whole technological design is reasonable, and the operability is strong; for the prepared deuterium-labeled glucuronide fenretinide, the purity can reach 98% or above, the yield rate can reach 70% or above, and the isotope abundance is greater than 99%. The prepared deuterium-labeled glucuronide fenretinide can be used as a deuterium-labeled metabolite of fenretinide, a test and contrast sample is provided for the study of metabolism mechanism of fenretinide and the anti-tumor mechanism, and the important application value is realized.

Description

technical field [0001] The invention belongs to the technical field of synthesis of isotope-labeled drug metabolites, and in particular relates to a synthesis method of deuterium-labeled retinoic acid glucuronide. Background technique [0002] The aliases of retinoic acid amine are fenretinide, phenretinamine, retinoic acid p-hydroxyaniline and all-trans-N-(4-hydroxyphenyl) retinoic acid. Retinoic acid can increase the level of intracellular reactive oxygen species, induce apoptosis of human hepatocellular carcinoma cells in vitro, and has good antitumor activity. The molecular weight is 391.55, the molecular formula is C26H33NO2, and the structural formula is as follows: [0003] [0004] Retinoic acid glucuronide is an in vivo metabolite of retinoic acid, which may also have good antitumor activity. It is more water-soluble and more conducive to absorption, so the effect may be better. This requires further clinical trials of retinoic acid glucuronide. The structura...

Claims

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Application Information

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IPC IPC(8): C07H15/203C07H1/00
CPCC07H1/00C07H15/203
Inventor 杨石张东东陈国雨张池王忠义徐一鸣
Owner TLC NANJING PHARMA RANDD CO LTD
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