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Preparation method for difluoromethyl-substituted sulfoaryl sulfonate

A technology of difluoromethyl and sulfonate, which is applied in the direction of organic chemistry, and can solve problems such as the preparation method of thioaryl sulfonate lacking difluoromethyl substitution

Active Publication Date: 2018-01-05
SHANGHAI INST OF ORGANIC CHEMISTRY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The technical problem to be solved by the present invention is to provide a difluoromethyl-substituted thioaryl sulfonate in order to overcome defects such as the lack of preparation methods for difluoromethyl-substituted thioaryl sulfonates in the prior art. Preparation method of acid ester

Method used

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  • Preparation method for difluoromethyl-substituted sulfoaryl sulfonate
  • Preparation method for difluoromethyl-substituted sulfoaryl sulfonate
  • Preparation method for difluoromethyl-substituted sulfoaryl sulfonate

Examples

Experimental program
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Effect test

Embodiment 1

[0054] The preparation of embodiment 1 difluoromethyl substituted benzylthiol

[0055]

[0056] The preparation of difluoromethyl-substituted benzylthiol can be carried out in any of the following ways.

[0057] Method 1 Add n-hexane (1500mL) into a three-necked flask, place it in a -78°C cold bath for stirring, and slowly introduce chlorodifluoromethane (ClCF 2 H, F-22, 750mmol), NaOH (50g, 1250mmol), tris (3,6-dioxaheptyl) amine (TDA-1, 8.1g, 25mmol) and benzyl mercaptan ( 62.1g, 500mmol), and then slowly raised to 60°C and reacted under dry ice-acetone condensation for 2-4h. The reaction solution was filtered, subjected to desolvation under reduced pressure, and separated by flash silica gel column chromatography to obtain 53 g of light pink oily liquid with a yield of 61%. The hydrogen spectrum showed a purity greater than 98%.

[0058] Method 2 Add KOH (168g, 3000mmol), acetonitrile / water (1400mL, 1:1) and benzyl mercaptan (18.6g, 150mmol) into a three-neck flask, st...

Embodiment 2

[0060] Embodiment 2 Preparation of thiodifluoromethylphenylsulfonate

[0061]

[0062] The preparation of thiodifluoromethylphenyl sulfonate can be prepared by any of the following methods.

[0063] Method 1: Add 98mLCl to the three-necked flask 2 / CHCl 3 solution (1.232mol / L, 120mmol), the flask was placed in a -10°C cold bath and stirred, and the difluoromethyl-substituted benzylthiol (20.9g, 120mmol) prepared in Example 1 was added, and the reaction was carried out for 1h (using 19 F NMR for monitoring). Under a cooling bath at -10°C, sodium phenylsulfinate (19.7 g, 120 mmol) was added rapidly, and then raised to room temperature for reaction. The reaction solution was filtered, subjected to desolvation under reduced pressure, and separated by flash silica gel column chromatography to obtain 19.4 g of a yellow oily liquid with a yield of 72%. The hydrogen spectrum showed a purity greater than 98%.

[0064] Method 2: Add 98mLCl to the three-necked flask 2 / CHCl 3 so...

Embodiment 3

[0071] Example 3 4-Methylthiodifluoromethylarylsulfonate

[0072]

[0073] Add 16.3mLCl to the 50mL sealed tube 2 / CHCl 3 solution (1.232mol / L, 20mmol), the flask was placed in a -10°C cold bath and stirred, and difluoromethyl-substituted benzylthiol 2 (3.48g, 20mmol) was added, and the reaction was carried out for 1h (using 19 F NMR for monitoring). Under a cooling bath at -10°C, sodium 4-methylphenylsulfinate (20 mmol) was added rapidly, and then raised to room temperature for 10 h. The reaction solution was filtered, subjected to desolvation under reduced pressure, and separated by flash silica gel column chromatography to obtain 3.42 g of the corresponding product with a yield of 72%. The hydrogen spectrum showed that the purity was greater than 98%.

[0074] 4-Methylthiodifluoromethylarylsulfonate: 1 H NMR (400MHz, CDCl 3 ,293K,TMS)δ7.47(d,J=8.0Hz,2H),7.16(d,J=8.0Hz,2H),6.80(t,J=56.0Hz,1H),2.35(s,3H)ppm : 19 F NMR (375MHz, CDCl 3 )δ-93.5 (d, J = 56.3Hz, 2F) ppm...

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Abstract

The invention discloses a preparation method for difluoromethyl-substituted sulfoaryl sulfonate. The preparation method comprises a step of subjecting a compound as show in a formula 2 which is described in the specification or a salt thereof and difluoromethanesulfonyl chloride to difluoromethylthiolation in an organic solvent so as to obtain a compound as show in a formula 3 which is described in the specification, wherein the organic solvent is one or more selected from a group consisting of a chloralkane organic solvent, a chlorinated aromatic hydrocarbon organic solvent, an aromatic hydrocarbon organic solvent and a nitrile organic solvent . The preparation method of the invention has the advantages of a wide scope of applicable substrates, mild reaction conditions, a high reaction conversion rate, high yield, high product purity and good industrial production prospects.

Description

technical field [0001] The invention relates to a preparation method of difluoromethyl-substituted thioarylsulfonate. Background technique [0002] In the fields of medicine and pesticides, fluorine-containing and fluoroalkyl functional groups are an important structural unit. The introduction of fluorine functional groups can effectively increase the metabolic stability of drugs, and at the same time improve fat solubility, which can better penetrate cell membranes and improve drug efficiency. effect. [0003] Difluoromethylthio (SCF 2 H) is a member of fluoroalkyl, which has important applications in the fields of medicine and pesticides, and has become a research hotspot for chemists in recent years. On the one hand, SCF 2 Compared with other fluorine-containing groups, H has smaller electron-withdrawing properties and poorer stability. These characteristics show advantages in the special selectivity of drugs and shorter biological metabolism; on the other hand, SCF 2...

Claims

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Application Information

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IPC IPC(8): C07C381/04C07D333/34C07D213/71C07D215/36C07D263/58C07D277/78C07D209/30
Inventor 沈其龙吕龙朱佃虎
Owner SHANGHAI INST OF ORGANIC CHEMISTRY - CHINESE ACAD OF SCI
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