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Synthesis of tolvaptan degradation derivative

A technology of tolvaptan and its derivatives, which is applied in the field of synthesis of tolvaptan degraded derivatives, achieving the effects of simple experimental operation, reasonable route design, and cheap raw materials

Active Publication Date: 2021-08-17
TLC NANJING PHARMA RANDD CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There is no report about the preparation method of this tolvaptan degradation derivative

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  • Synthesis of tolvaptan degradation derivative
  • Synthesis of tolvaptan degradation derivative
  • Synthesis of tolvaptan degradation derivative

Examples

Experimental program
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Effect test

Embodiment 1

[0031] Such as figure 1 Shown, a kind of synthetic method of tolvaptan degradation derivative comprises the following steps:

[0032] Step (1): Preparation of Compound II

[0033] Take 3.0 g of raw material I and dissolve in 30 mL of toluene, then add 1.67 g of concentrated sulfuric acid, react at 110 ° C, and monitor the completion of the reaction by TLC. The reaction solution was washed with saturated aqueous sodium bicarbonate solution, then directly concentrated and evaporated to dryness, and purified by column chromatography to obtain 2.5 g of compound II with a yield of 87.8%.

[0034]

[0035] Step (2): Preparation of Compound III

[0036] Take 2.5g of compound II and dissolve it in 50mL of methanol, add 1.04g of hydrogen peroxide, after a period of reaction, TLC shows that the reaction is complete. Sodium sulfite solution was added under ice-cooling to quench the remaining oxidant, methanol was concentrated, the aqueous phase was extracted with ethyl acetate, and...

Embodiment 2

[0048] Such as figure 1 Shown, a kind of synthetic method of tolvaptan degradation derivative comprises the following steps:

[0049] Step (1): Preparation of Compound II

[0050] Take 9.0 g of raw material I and dissolve it in 90 mL of toluene, then add 5 g of concentrated sulfuric acid, react at 110 ° C, and monitor the completion of the reaction by TLC. The reaction solution was washed with saturated aqueous sodium bicarbonate solution, then directly concentrated and evaporated to dryness, and purified by column chromatography to obtain 7.47 g of compound II with a yield of 87.5%.

[0051]

[0052] Step (2): Preparation of Compound III

[0053] Take 7.3g of compound II and dissolve it in 120mL of methanol, add 2.5g of hydrogen peroxide, after a period of reaction, TLC shows that the reaction is complete. Add sodium sulfite solution under ice bath to quench the remaining oxidant, concentrate to remove methanol, extract the aqueous phase with ethyl acetate, and concentr...

Embodiment 3

[0065] Such as figure 1 Shown, a kind of synthetic method of tolvaptan degradation derivative comprises the following steps:

[0066] Step (1): Preparation of Compound II

[0067] Take 45.0g of raw material I and dissolve in 270mL of toluene, then add 15.03g of concentrated sulfuric acid, react at 110°C, and monitor the completion of the reaction by TLC. The reaction solution was washed with saturated aqueous sodium bicarbonate solution, then directly concentrated and evaporated to dryness, and purified by column chromatography to obtain 37.23 g of compound II with a yield of 87.2%;

[0068]

[0069] Step (2): Preparation of Compound III

[0070] Take 37.0g of Compound II and dissolve it in 720mL of methanol, add 14.98g of hydrogen peroxide, after a period of reaction, TLC shows that the reaction is complete. Sodium sulfite solution was added under an ice bath to quench the remaining oxidant, methanol was concentrated, the aqueous phase was extracted with ethyl acetate, ...

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Abstract

The invention discloses a synthesis method of a tolvaptan degradation derivative, and belongs to the field of biological medicines. The preparation method comprises the following steps: by taking a compound I as a raw material, dehydrating to form double bonds, oxidizing the double bonds into epoxy, reducing the epoxy into hydroxyl, introducing a methyl group by using a methylation reagent, and finally removing p-toluenesulfonyl to obtain a target molecule. The whole route is reasonable in design, raw materials are cheap and easy to obtain, and the optimal reaction condition and molar ratio are preferably obtained through a large number of screening experiments. The whole process is simple to operate, and the synthesized target molecule can be used as a derivative standard substance in tolvaptan detection and analysis, and has important application value.

Description

technical field [0001] The invention belongs to the field of biomedicine, and in particular relates to a method for synthesizing a degraded derivative of tolvaptan. Background technique [0002] Tolvaptan: Tolvaptan, chemical name N-[4-[(7-Chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl)carbonyl]-3-methylphenyl ]-2-methylbenzamide, trade name Samsca, tolvaptan was developed by Otsuka Pharm in Japan, and was approved by the US FDA in 2009. It is another approved product after mozavaptan Oral arginine vasopressin V for the treatment of hyponatremia 2 receptor antagonists. It is used to treat hyponatremia caused by congestive heart failure, cirrhosis, and syndrome of inappropriate antidiuretic hormone secretion. Tolvaptan is the world's first oral putan drug. Clinical studies have shown that it is better tolerated than other anti-heart failure drugs, does not need to restrict water intake during treatment, has mild adverse reactions, and has broad application prosp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D223/16
CPCC07D223/16
Inventor 吕冠宝李南南胡永铸刘春
Owner TLC NANJING PHARMA RANDD CO LTD
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