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Preparation method for N-difluoromethylthiophthalimide compound

A technology of difluoromethylthio-o- and difluoromethylthio, which is applied in the field of preparing N-difluoromethylthio-phthalimide compounds, and can solve the problem of harsh reaction conditions, low conversion rate, and inapplicability to industrial production And other issues

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

AI Technical Summary

Problems solved by technology

[0038] The technical problem to be solved by the present invention is to overcome the cumbersome steps, complicated operation, harsh reaction conditions, narrow scope of substrate application, low yield, low conversion rate, etc. It is not suitable for defects such as industrial production, but provides a method for preparing N-difluoromethylthio-phthalimide compounds

Method used

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  • Preparation method for N-difluoromethylthiophthalimide compound
  • Preparation method for N-difluoromethylthiophthalimide compound
  • Preparation method for N-difluoromethylthiophthalimide compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Example 1 N-difluoromethylthio-phthalimide 3

[0069]

[0070] 1) Preparation of difluoromethyl-substituted benzylthiol 2

[0071] method one,

[0072] Add n-hexane (1500mL) into the three-necked flask, place it in a -78°C cold bath and stir, slowly pass through chlorodifluoromethane (F-22, 750mmol), add NaOH (50g, 1250mmol) at -78°C, three (3,6-dioxaheptyl)amine (TDA-1, 8.1g, 25mmol) and benzyl mercaptan (62.1g, 500mmol) were reacted slowly at 60°C for 2-4h under dry ice-acetone condensation. 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%.

[0073] Method Two,

[0074] Add KOH (168g, 3000mmol), acetonitrile / water (1400mL, 1:1) and benzyl mercaptan (18.6g, 150mmol) into a three-necked flask, stir in a cold bath at -78°C, and add bromodifluorophosphoric acid...

Embodiment 2

[0083] Example 2 N-difluoromethylthio-4-nitro-phthalimide 3

[0084]

[0085] 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 difluoromethyl-substituted benzylthiol 2 (20.9g, 120mmol) was added, and the reaction was carried out for 1h (using 19 F NMR for monitoring). Under a cooling bath at -10°C, 4-nitrophthalimide potassium salt (27.6 g, 120 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 19.7 g of a white solid with a yield of 60%. The hydrogen spectrum showed that the purity was greater than 98%.

[0086]

[0087] N-difluoromethylthio-4-nitrophthalimide (N-(difluoromethylthio)-4-nitrophthalimide): 1 H NMR (400MHz, CDCl 3 ,293K,TMS)δ8.82(d,J=5.2Hz,1H),8.74(dd,J=8.2,1.8Hz,1H),8.24(d,J=8.2Hz,1H),6.80(t,J ...

Embodiment 3

[0088] Example 3 N-trifluoromethylthio-phthalimide

[0089]

[0090] Method 1: At 0°C, add CF into 1,2-dichloroethane of o-benzimide potassium salt (3.7g, 20mmol) 3 SCl gas, then react the reaction solution at room temperature (25°C) for 7h (with a reflux condenser at -20°C), filter after the reaction, and recrystallize the filtrate to obtain 0.5g of a white solid with a yield of 10 %, the hydrogen spectrum shows that the purity is greater than 98%.

[0091] Method 2: At 0°C, add CF into 1,2-dichloroethane of o-benzimide potassium salt (3.7g, 20mmol) 3 SCl gas, then the reaction solution was reacted at 90-100°C for 7h (with a -20°C reflux condenser), after the reaction was completed, it was cooled to room temperature, filtered, and the filtrate was precipitated and recrystallized to obtain 3.2g of a white solid. The yield is 65%, and the hydrogen spectrum shows that the purity is greater than 98%.

[0092] N-(trifluoromethylthio)phthalimide: 1 H NMR (400MHz, CDCl 3 )δ8...

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Abstract

The invention discloses a preparation method for a N-difluoromethylthiophthalimide compound. The preparation method comprises a step of subjecting difluoromethanesulfonyl chloride and a compound as show in a formula 1 which is described in the specification to difluoromethylthiolation in an organic solvent so as to obtain the N-difluoromethylthiophthalimide compound as show in a formula 3 which isdescribed in the specification. The preparation method of the invention has the advantages of simple operation, few steps, a wide scope of applicable substrates, mild reaction conditions, a high reaction conversion rate, high yield, low cost and suitability for industrial production.

Description

technical field [0001] The invention relates to a method for preparing N-difluoromethylthio o-phenylimide compounds. Background technique [0002] In the field 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 the lipid solubility of drugs, which can better penetrate cell membranes and improve Efficacy. [0003] Difluoromethylthio (SCF 2 H) is a member of the fluoroalkyl group, which has important applications in the fields of medicine and pesticides, and is becoming a research hotspot for chemists in recent years. On the one hand, SCF 2 Compared with other fluorine-containing groups, H has less electron-withdrawing properties and poorer stability, and these properties show advantages in specific drug selectivity and shorter biological metabolism; on the other hand, SCF 2 H...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/48
Inventor 沈其龙吕龙朱佃虎
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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