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Synthesis and resolution methods of N-[4-(1-aminoethyl)-2,6-difluorophenyl]methanesulfonamide

A technology of methanesulfonamide and difluorophenyl, which is applied in the field of synthesis and resolution of N-[4--2,6-difluorophenyl]methanesulfonamide, can solve the problems of undiscovered compounds and achieve the product The effect of high purity and reaction yield, simple operation, and low production cost

Active Publication Date: 2019-04-12
CHANGZHOU SUNLIGHT PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] No literature reports on the synthesis and resolution of the above compound [that is, N-[4-(1-aminoethyl)-2,6-difluorophenyl]methanesulfonamide] have been found so far

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1）

[0035] This example is the synthetic method of N-[4-(1-aminoethyl)-2,6-difluorophenyl]methanesulfonamide, specifically as follows:

[0036] ①Add 276g of potassium carbonate (2.0mol), 114g of methanesulfonamide (1.2mol) and 700mL of DMSO into a 2L four-necked reaction flask, stir and heat up to 110-120°C, keep it warm for 4 hours, then add 140g of 3 , 4,5-trifluoroacetophenone (0.8mol), continue to react for 4h, cool down to 40-50°C, and filter.

[0037] ② Transfer the filtrate to another 2L four-neck reaction flask, add 112g of hydroxylamine hydrochloride (1.6mol), raise the temperature to 40-50°C for 8 hours, and adjust the pH to 7-8 with ammonia water.

[0038] ③Transfer the reaction system into another 2L four-necked reaction flask, add 14g, 10wt% Raney nickel, pass through hydrogen at 0.1-0.2MPa after replacement, keep warm at 40-50°C for 4 hours, adjust the pH to 3 with acetic acid , filtered to remove Raney nickel, the filtrate was adjusted to pH=9 with 25wt% ammonia wa...

（ example 6）

[0042] This example is the synthetic method of N-[4-(1-aminoethyl)-2,6-difluorophenyl]methanesulfonamide, specifically as follows:

[0043] ①Add 2.76kg of potassium carbonate (20mol), 1.14kg of methanesulfonamide (12mol) and 7L of DMSO into a 20L reactor, stir and heat up to 110-120°C, keep it warm for 4 hours, then add 1.4kg of 3, 4,5-Trifluoroacetophenone (8mol), continue to react for 4h, then cool down to 40-50°C, and filter.

[0044] ② Transfer the filtrate to another 20L reactor, add 1.12kg of hydroxylamine hydrochloride (16mol), heat up to 40-50°C for 8 hours, and adjust the pH to 7-8 with ammonia water.

[0045] ③Transfer the reaction system into a 20L hydrogenation kettle, add 140g, 10wt% Raney nickel, pass through hydrogen at 0.1-0.2MPa after replacement, keep warm at 40-50°C for 4 hours, adjust the pH to 3 with acetic acid, filter and remove Raney nickel, the filtrate was adjusted to pH=9 with 25wt% ammonia water, a large amount of solids were precipitated, filtered...

Embodiment 1）

[0047] This embodiment is the resolution method of N-[4-(1-aminoethyl)-2,6-difluorophenyl]methanesulfonamide, specifically as follows:

[0048] ①Add 20g of N-[4-(1-aminoethyl)-2,6-difluorophenyl]methanesulfonamide racemate (80mmol) and 200mL of water into the reaction device, raise the temperature to reflux, and Add 2.43g of D-mandelic acid (16mmol) in 5 batches at a time, and finish adding in about 2 hours. After adding, keep warm and reflux for 1 hour, the solid part dissolves, then cool down to 40-50°C [that is, the resolution temperature], and keep warm for reaction 2h, filtered, and the filtrate was set aside.

[0049] ②Put the filter cake obtained in step ① and 100mL of water into the reaction device, raise the temperature to reflux, add 1.22g of D-mandelic acid (8mmol) in 5 batches for the second time, and finish adding in about 2 hours. After adding, keep warm and reflux React for 1 hour, then cool down to 40-50°C, keep warm for 2 hours, filter, and the filtrate is se...

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PUM

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Abstract

The invention discloses synthesis and resolution methods of N-[4-(1-aminoethyl)-2,6-difluorophenyl]methanesulfonamide. The synthesis method comprises the steps of conducting a reaction on 3,4,5-TRIFLUOROACETOPHENONE and methanesulfonamide to obtain N-(4-acetyl-2,6-difluorophenyl)methanesulfonamide, then conducting a reaction on the N-(4-acetyl-2,6-difluorophenyl)methanesulfonamide and hydroxylamine hydrochloride to obtain N-[4-(hydroxyaminoethyl)-2,6-difluorophenyl]methanesulfonamide, and finally conducting catalytic hydrogenation. The resolution method adopsts D-mandelic acid and the like asa resolution agent, adopts water and the like as a solvent, and the resolution temperature is 40 to 50 DEG C. The synthesis method of the invention has simple operation, low production cost, less environmental pollution, and high product purity and reaction yield, and is suitable for industrial large-scale production. The resolution method of the present invention can finally obtain higher resolution yield and product optical purity by selecting a suitable resolution agent, solvent and temperature, especially an addition mode of the resolutio agent.

Description

technical field [0001] The invention belongs to the technical field of vanilloid receptor antagonists, and specifically relates to a synthesis and resolution method of N-[4-(1-aminoethyl)-2,6-difluorophenyl]methanesulfonamide. Background technique [0002] Vanillin is a class of natural and synthetic compounds characterized by the presence of vanillyl (4-hydroxy-3-methoxybenzyl) or functionally equivalent groups. The vanilloid receptor (VR-1), whose function is regulated by such compounds, has been extensively studied. [0003] Vanilloid receptors are members of the transient receptor potential (TRP) superfamily. Members of this superfamily are nonvoltage-activated cation channel proteins that play important roles in sensory physiology to vasodilation and male reproduction. [0004] Chinese patent document CN102137851A discloses a new compound as a vanilloid receptor antagonist, its general formula is as follows: [0005] . [0006] (R)-N-[4-(1-aminoethyl)-2,6-difluoro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C303/44C07C311/08
CPCC07B2200/07C07C303/36C07C303/40C07C303/44C07C311/08
Inventor 胡国宜胡锦平鲁炜高永清李喜龙
Owner CHANGZHOU SUNLIGHT PHARMA
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