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Deuterated difluoromethyl substituted sulfo-aryl sulfonate as well as preparation method and application thereof

A technology of difluoromethyl and sulfonate, which is applied to the preparation of sulfides, organic chemical methods, chemical instruments and methods, etc., can solve the problems that the deuteration of four types of substrates cannot be realized, and achieve high deuteration ratio, The effect of high yield

Pending Publication Date: 2022-03-08
南京贝塔生物科学有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In literature PhSO 2 SCF 2 H: A Shelf-Stable, Easily Scalable Reagent for RadicalDifluoromethylthiolation[J]. Angew. Chem. Int. Ed. 2016, 55, 15807-15811. and Synthesis of Difluoromethylthioesters from Aldehydes[J]. In 2018, 57, 1663-1667., Shen Qilong's research group disclosed the reagent PhSO 2 SCF 2 The experimental method of H applied to four kinds of drug substrates reflects the excellent reaction performance of this kind of reagents, but the deuteration of the corresponding four kinds of substrates cannot be realized

Method used

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  • Deuterated difluoromethyl substituted sulfo-aryl sulfonate as well as preparation method and application thereof
  • Deuterated difluoromethyl substituted sulfo-aryl sulfonate as well as preparation method and application thereof
  • Deuterated difluoromethyl substituted sulfo-aryl sulfonate as well as preparation method and application thereof

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Experimental program
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Effect test

Embodiment 1

[0052] Under the condition of nitrogen protection at room temperature, add 25ml of anhydrous diethyl ether as a solvent into a 100mL reaction flask, add 1.3g of sodium hydride (mass purity 60%) and stir well; the ice bath keeps the temperature of the mixture at 0-5 o C, slowly add 3.7g benzyl mercaptan, rise to normal temperature and continue to react for 3h after adding; o C, and slowly add 20mL of NaOH heavy aqueous solution with a mass concentration of 10% and stir evenly, add 9.2g of bromodifluoromethyl diethyl phosphate after 5min, and continue the reaction for 5h; let stand, and extract and separate the upper layer with 50mL ethyl acetate Liquid, after vacuum drying, 5.4g of BnSCF with a purity of about 92% was obtained 2 D, yield 95%.

[0053] Ice bath (0~5 oC ) conditions, add 40mL of Cl with a concentration of 0.6mol / L to the 100mL reaction flask 2 Chloroform solution, and 3.5g BnSCF 2 D (purity about 92%), rose to normal temperature and continued to react for 5h,...

Embodiment 2

[0055] Under nitrogen protection at room temperature, 120ml of anhydrous ether was added to a 500mL reaction flask as a solvent, 6.6g of sodium hydride (purity 60%) was added and stirred evenly; the temperature of the mixture was kept at 0-5 o C, slowly add 18.6g benzyl mercaptan, rise to normal temperature after addition and continue to react for 3h; ice bath makes the reaction solution temperature drop to 0~5 o C, and slowly add 100mL of NaOH heavy aqueous solution with a mass concentration of 10% and stir evenly, add 46.1g of bromodifluoromethyl diethyl phosphate after 5min, and continue the reaction for 5h; let stand, extract and separate the upper layer of oily liquid, and vacuum dry Afterwards, 27.1g of BnSCF with a purity of about 92% was obtained 2 D, the yield is 95%.

[0056] Ice bath (0~5 oC ) conditions, add 250mL of Cl with a concentration of 0.5mol / L to the 500mL reaction flask 2 Chloroform solution, and 18.3g BnSCF 2 D (purity about 92%), rose to normal temp...

Embodiment 3

[0058] Under nitrogen protection at room temperature, 300ml of anhydrous ether was added to a 1000mL reaction flask as a solvent, 17.6g of sodium hydride (purity 60%) was added and stirred evenly; the temperature of the mixture was kept at 0-5 o C, slowly add 49.6g benzyl mercaptan, rise to normal temperature and continue to react for 3h after adding; o C, and slowly add 200mL of NaOH heavy aqueous solution with a mass concentration of 10% and stir evenly, add 123g of diethyl bromodifluoromethyl phosphate after 5min, and continue the reaction for 5h; let stand, extract and separate the upper layer of oily liquid, and vacuum dry Get 69g of BnSCF with a purity of about 92% 2 D, the yield is 91%.

[0059] Ice bath (0~5 oC ) conditions, add 600mL of Cl with a concentration of 0.7mol / L to a 1000mL reaction flask 2 Chloroform solution, and 66.6g BnSCF 2 D (purity about 92%), rose to normal temperature and continued to react for 5h, after which the reaction bottle was placed in a...

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Abstract

The invention discloses deuterated difluoromethyl substituted sulfo aryl sulfonate as well as a preparation method and application thereof, and belongs to the technical field of organic synthesis. The preparation method mainly comprises the following steps: preparing an intermediate product BnSCF2D; and preparing a PhSO2SCF2D reagent: adding a chloroform solution of Cl2 into a reaction bottle, placing at 0-5 DEG C, adding quantitative BnSCF2D, heating to normal temperature, continuing to react for 2-6 hours, cooling the system temperature to 0-5 DEG C, adding quantitative sodium benzenesulfinate, heating to normal temperature, continuing to react for 10 hours, and separating the product through column chromatography after the reaction is finished. The deuterated difluoromethylthio reagent disclosed by the invention can be used for synthesizing 'SCF2D' drug molecules, and different types of deuterated difluoromethylthio drugs can be obtained through a more direct method.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a deuterated difluoromethyl-substituted thioarylsulfonate and a preparation method and application thereof. Background technique [0002] Since D has a greater relative atomic mass than H, making the C–D bond more stable (6–9 times) than the C–H bond, deuteration of the C–H bond may drastically alter the metabolic and pharmacokinetic properties of drug candidates. Deuteration technology has been widely used in various fields such as organic synthesis, drug metabolism, nuclear magnetic resonance analysis and drug development. In recent years, researchers have conducted in-depth research on deuterated drugs. In 2017, the FDA approved the first deuterated drug, deuterated tetrabenazine (Austedo), which greatly promoted the development of deuterated synthetic methods. SCF 2 H is a potential replacement for lipophilic OH or NH substitutes, some containing SCF ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C381/04C07C319/14C07C323/03C07B59/00
CPCC07C381/04C07B59/001C07C319/14C07B2200/05C07C323/03
Inventor 易文斌胡春洋陆国平张志国
Owner 南京贝塔生物科学有限公司