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Synthesis of a Degraded Derivative of Tolvaptan

A technology for tolvaptan and derivatives is applied in the field of synthesis of tolvaptan degradation derivatives, and achieves the effects of simple experimental operation, reasonable route design, and cheap raw materials

Active Publication Date: 2022-06-10
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

Method used

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  • Synthesis of a Degraded Derivative of Tolvaptan
  • Synthesis of a Degraded Derivative of Tolvaptan
  • Synthesis of a Degraded Derivative of Tolvaptan

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] as Figure 1 As shown, a method of synthesis of tolvaptan degraded derivatives, comprising the following steps:

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

[0033] Take 3.0g of raw material I. dissolved in 30mL of toluene, and then add 1.67g of concentrated sulfuric acid, 110 °C reaction, TLC monitoring reaction end. The reaction solution was washed with saturated sodium bicarbonate aqueous solution, and then directly concentrated and steamed dry, and column chromatography was purified to give 2.5g of compound II., with a yield of 87.8%.

[0034]

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

[0036] Take 2.5g of compound II. dissolved in 50mL of methanol, add 1.04g of hydrogen peroxide, after a period of reaction, TLC showed that the reaction was complete. Under the ice bath, sodium sulfite solution was added to quench the remaining oxidant, methanol was concentrated, and the aqueous phase was extracted with ethyl acetate to concentrate 2.40g of compound III., with a ...

Embodiment 2

[0048] as Figure 1 As shown, a method of synthesis of tolvaptan degraded derivatives, comprising the following steps:

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

[0050]Take 9.0g of raw material I. dissolved in 90mL of toluene, and then add 5g of concentrated sulfuric acid, 110 °C reaction, TLC monitoring the end of the reaction. The reaction solution was washed with saturated sodium bicarbonate aqueous solution, and then directly concentrated and steamed dry, and column chromatography was purified to obtain 7.47g of compound II., with a yield of 87.5%.

[0051]

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

[0053] Take 7.3g of compound II. dissolved in 120mL of methanol, add 2.5g of hydrogen peroxide, after a period of reaction, TLC showed that the reaction was complete. Under the ice bath, sodium sulfite solution was added to quench the remaining oxidant, methanol was concentrated, and ethyl acetate was extracted in the aqueous phase to give 6.98g of compound III., NMR ex...

Embodiment 3

[0065] as Figure 1 As shown, a method of synthesis of tolvaptan degraded derivatives, comprising the following steps:

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

[0067] Take 45.0g of raw material I. dissolved in 270mL of toluene, and then add 15.03g of concentrated sulfuric acid, 110 °C reaction, TLC monitoring reaction end. The reaction solution was washed with saturated sodium bicarbonate aqueous solution, and then directly concentrated and steamed dry, and column chromatography was purified to give 37.23g of compound II., with a yield of 87.2%;

[0068]

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

[0070] Take 37.0g of compound II. dissolved in 720mL of methanol, add 14.98g of hydrogen peroxide, after a period of reaction, TLC showed that the reaction was complete. Under the ice bath, sodium sulfite solution was added to quench the remaining oxidant, methanol was concentrated, and the aqueous phase was extracted with ethyl acetate, concentrated to give 35.40g of compou...

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Abstract

The invention discloses a method for synthesizing a degraded derivative of tolvaptan, which belongs to the field of biomedicine. In the present invention, compound I is used as a raw material to form a double bond through dehydration, then oxidize the double bond to epoxy, reduce the epoxy to hydroxyl, introduce a methyl group with a methylating agent, and finally remove the p-toluenesulfonyl group to obtain the target molecule . The whole route of the invention is designed reasonably, the raw materials are cheap and easy to obtain, and the best reaction conditions and molar ratios are obtained through optimization 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 in the detection and analysis of tolvaptan, which has important application value.

Description

Technical field [0001] The present invention belongs to the biomedical field, specifically relates to a method of synthesizing a degraded derivative of Tolvaptan. Background [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, Tovaptan by Otsuka Pharm, Japan Research and development, approved by the US FDA in 2009, is another approved marketing after mozavaptam oral arginine vasopressin V for the treatment of hyponatremia 2 Receptor antagonists. It is used to treat hyponatremia caused by congestive heart failure, cirrhosis of the liver, and syndrome of abnormal antidiuretic hormone secretion. Tovatriptan is the world's first oral putan drug. Clinical studies have shown that it is well tolerated compared with other anti-heart failure drugs, it is not necessary to limit the intake of water in treatment, adverse reactions are mild, and the application prospects a...

Claims

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Application Information

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Patent Type & Authority Patents(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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