A kind of synthetic method of deuterium-labeled retinoic acid glucuronide

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 glucuronide retinoyl glucuronide retinoid which has not been found. The synthesis method of acylphenol amines and other problems, to achieve the effect of excellent anti-tumor activity, less side effects, and simple and easy-to-obtain reagents

Active Publication Date: 2019-11-08
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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  • A kind of synthetic method of deuterium-labeled retinoic acid glucuronide
  • A kind of synthetic method of deuterium-labeled retinoic acid glucuronide
  • A kind of synthetic method of deuterium-labeled retinoic acid glucuronide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Preparation of compound 3:

[0044]

[0045] Into a 100ml round bottom flask, add 4-nitrophenol-D sequentially 4 (2.25g, 15.7mmol), 16.9ml of dry pyridine and 3.94ml of acetic anhydride, the reaction was heated to 90 degrees in an oil bath and stirred for 2 hours, the reaction solution was brown. After TLC shows that the reaction of the raw materials is complete, cool to room temperature (18 degrees), spin-dry the pyridine, add 20ml of water, stir, precipitate a large amount of solids, filter with suction, wash with an appropriate amount of water, drain, and place in a vacuum desiccator to dry overnight. The product compound 3 (2.88 g, off-white solid). The yield was 98.95%.

[0046] Preparation of compound 4:

[0047]

[0048] Into a 100ml round-bottomed flask were sequentially added the prepared compound 3 (2.88g, 15.5mmol), 43.2ml methanol, the raw materials were not easily soluble, weighed and added 0.43g Pd / C in sequence under the protection of nitrogen, the reaction wa...

Embodiment 2

[0064] Preparation of compound 3:

[0065]

[0066] Into a 100ml round bottom flask, add 4-nitrophenol-D sequentially 4 (3g, 20.9mmol), 30ml of dry pyridine and 6ml of acetic anhydride, the reaction was heated to 100°C in an oil bath and stirred for 1 hour, the reaction solution was brown. After TLC shows that the reaction of the raw materials is complete, cool to room temperature (20 degrees), spin-dry the pyridine, add 50ml of water, stir, precipitate a large amount of solids, filter with suction, wash with an appropriate amount of water, drain, and place in a vacuum desiccator to dry overnight. Product compound 3 (3.0 g, off-white solid). The yield was 77.30%.

[0067] Preparation of compound 4:

[0068]

[0069] Into a 150ml round-bottomed flask were sequentially added the prepared compound 3 (3g, 16.2mmol), 60ml of methanol, the raw materials were not easily soluble, under the protection of nitrogen, weighed and added 0.6g Pd / C successively, reacted with hydrogen, at room temp...

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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 specifically relates to a method for synthesizing deuterium-labeled glucuronide retinoyl amine. Background technique [0002] The aliases of tretinoin are fenretinide, fenretinide, p-hydroxyaniline and all-trans-N-(4-hydroxyphenyl) retinoic acid. Retinoyl phenamide can increase the level of reactive oxygen species in cells, can induce apoptosis of human hepatocellular carcinoma cells in vitro, and has good anti-tumor activity. The molecular weight is 391.55, the molecular formula is C26H33NO2, and the structural formula is as follows: [0003] [0004] Glucuronide retinoic acid is a metabolite of retinoic acid in vivo and may also have good anti-tumor activity. It has better water solubility and is more conducive to absorption, so the effect may be better. This requires further clinical trials on glucuronide retinoyl amine. The structural formula of glucuron...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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