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Medicine intermediate 2,6-difluoro-3-morpholinophenyl methylamine and preparation method thereof

A technology of morpholine phenylmethylamine and difluorobenzonitrile, which is applied in the field of pharmaceutical intermediate 2,6-difluoro-3-morpholine phenylmethylamine and its preparation, can solve the problems of difficult scale-up production, high cost and high production cost. Low efficiency and other problems, to achieve the effect of easy control and operation, cheap price and wide source of raw materials

Inactive Publication Date: 2017-04-26
LANZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method requires the use of relatively expensive palladium catalysts and phosphine ligands, and has defects such as low yield and difficult to scale up production.

Method used

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  • Medicine intermediate 2,6-difluoro-3-morpholinophenyl methylamine and preparation method thereof
  • Medicine intermediate 2,6-difluoro-3-morpholinophenyl methylamine and preparation method thereof
  • Medicine intermediate 2,6-difluoro-3-morpholinophenyl methylamine and preparation method thereof

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preparation example Construction

[0024] A preparation method of pharmaceutical intermediate 2,6-difluoro-3-morpholine phenylmethylamine, comprising the steps of:

[0025] Dissolve 5g of 2,6-difluorobenzonitrile II in 15.0mL of concentrated sulfuric acid, add 6.0mL of concentrated nitric acid at -10°C,

[0026]

[0027] After the addition, the reaction was continued at 20°C for 5 hours. After cooling, it was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and evaporated to remove the solvent under reduced pressure to obtain the nitrated product III.

[0028] 2) Dissolve 6.0 g of the nitration product III obtained in the previous step in 50.0 mL of isopropanol, add 34 g of ammonium chloride aqueous solution with a mass concentration of 40%, and iron powder (6.0 g) successively, and react at a temperature of 80° C. for 10 hours.

[0029]

[0030] After cooling, the insoluble matter was removed by filtration, the organic phase was washed successively with water and saturated b...

Embodiment 2

[0038] A preparation method of a pharmaceutical intermediate 2,6-difluoro-3-morpholine phenylmethylamine, comprising the following steps, the reaction formula is shown in formula 3 to formula 6:

[0039] 1) Dissolve 7.5g of 2,6-difluorobenzonitrile II in 23.0mL of concentrated sulfuric acid, add 18.0mL of concentrated nitric acid at 0°C, continue the reaction at 25°C for 3 hours after the addition, cool with dichloro Extract with methane, dry over anhydrous sodium sulfate, filter, evaporate the solvent under reduced pressure to obtain the nitrated product III.

[0040] 2) Dissolve 8.0 g of the nitrated product III obtained in the previous step in 80.0 mL of isopropanol, add 60 g of ammonium chloride aqueous solution and iron powder (13.0 g) with a mass ratio of 40% in sequence, and react at a temperature of 90° C. for 8 hours. After cooling, the insoluble matter was removed by filtration, the organic phase was washed successively with water and saturated brine, dried over anhy...

Embodiment 3

[0044] A preparation method of a pharmaceutical intermediate 2,6-difluoro-3-morpholine phenylmethylamine, comprising the following steps, the reaction formula is shown in formula 3 to formula 6:

[0045]1) Dissolve 10.0g of 2,6-difluorobenzonitrile II in 40.0mL of concentrated sulfuric acid, add 30.0mL of concentrated nitric acid at 5°C, continue the reaction at 35°C for 2 hours after the addition, cool with dichloro Extract with methane, dry over anhydrous sodium sulfate, filter, evaporate the solvent under reduced pressure to obtain the nitrated product III.

[0046] 2) Dissolve 11.0 g of the nitration product III obtained in the previous step in 130.0 mL of isopropanol, add 90 g of ammonium chloride aqueous solution with a mass concentration of 40%, and iron powder (20.0 g) successively, and react at a temperature of 110° C. for 6 hours, After cooling, the insoluble matter was removed by filtration, the organic phase was washed successively with water and saturated brine, d...

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Abstract

The invention discloses a medicine intermediate 2,6-difluoro-3-morpholinophenyl methylamine and a preparation method thereof. The compound is represented by the formula 1. The preparation method of the compound comprises the steps of taking 2,6-difluorocyanophenyl as a starting raw material, carrying out nitrification, nitroreduction, morpholine ring formation and nitro group reduction and other conversions to obtain the target product. The used method has the advantages of wide raw material sources, low price, easy control and operation of the preparation process and the like. The obtained product can be used for preparing HIV integrase inhibitors and drugs for treating age-related macular degeneration.

Description

technical field [0001] The invention relates to a pharmaceutical intermediate 2,6-difluoro-3-morpholine phenylmethylamine and a preparation method thereof, that is, a compound having the structure shown in formula 1 and a preparation method thereof. [0002] Background technique [0003] Multi-substituted benzylamines have important applications in the pharmaceutical industry because the amino groups in them can serve as reaction sites for amidation and reductive amination. Studies have shown that the simultaneous introduction of morpholine and fluorine substituents into the benzene ring of polysubstituted benzylamines can improve the solubility and metabolic kinetics of the drug. For example, the antibacterial drug Linezolid3 contains morpholine and fluorine-substituted benzene ring structural units; an HIV integrase inhibitor reported in 2005 also contains this structural unit. Therefore, polyfluorinated morpholine phenylmethylamine derivatives can be used as important...

Claims

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Application Information

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IPC IPC(8): C07D295/135
CPCC07D295/135
Inventor 李立奇张元
Owner LANZHOU UNIVERSITY
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