Synthesis and resolution 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 High purity and reaction yield, less environmental pollution, and low production cost

Active Publication Date: 2021-03-09
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, finish adding in about 2 hours, keep warm and reflux for 1 hour, the solid part dissolves, then cool down to 40-50°C [that is, the resolution temperature], 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, add it in about 2 hours, keep warm and reflux after adding React for 1 hour, then cool down to 40-50°C, keep warm for 2 hours, filter, and the filtrate is set aside.

[0050] ③Repeat the abo...

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PUM

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Abstract

The invention discloses a synthesis and resolution method of N-[4-(1-aminoethyl)-2,6-difluorophenyl]methanesulfonamide. The synthesis method comprises 3,4,5-trifluorobenzene Ethanone reacts with methanesulfonamide to obtain N-(4-acetyl-2,6-difluorophenyl) methanesulfonamide, and then reacts with hydroxylamine hydrochloride to obtain N-[4-(hydroxylaminoethyl)-2, 6‑difluorophenyl] methanesulfonamide, finally obtained by catalytic hydrogenation. The resolving agent adopted in the resolution method is D-mandelic acid, etc., the solvent used is water, etc., and the resolution temperature is 40-50°C. The synthesis method of the invention has simple operation, low production cost, less environmental pollution, high product purity and high reaction yield, and is suitable for large-scale industrial production. In the resolution method of the present invention, a higher resolution yield and optical purity can be finally obtained by selecting a suitable resolution agent, solvent, resolution temperature, especially the addition method of the resolution 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 Patents(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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