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Method for preparing 3-fluorine-4 morpholinyl phenylamine

A technology of morpholinoaniline and morpholinobenzene, which is applied in the field of preparation of pharmaceutical intermediates, can solve the problems of complex post-treatment of fluorine-containing wastewater and high price, and achieve the effects of low price, less environmental pollution, and reduced production costs

Active Publication Date: 2010-03-03
SUZHOU JINGYE MEDICINE & CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] (1) The price of 3,4-difluoronitrobenzene is relatively expensive, about 200,000 yuan / ton;
[0005] (2) In the morpholine substitution reaction in this route, the reaction leaving group is fluoride ion, and the post-treatment of fluorine-containing wastewater is more complicated

Method used

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  • Method for preparing 3-fluorine-4 morpholinyl phenylamine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] (1) Add 100ml of water, 1.44g (0.04mol) of hydrochloric acid with a mass fraction of 36% and 22.3g (0.4mol) of iron powder in a 250ml reaction bottle equipped with a dropping and reflux device, slowly add o-fluorine dropwise under reflux Add 14.1g (0.1mol) of nitrobenzene, reflux for 2 hours after addition, cool at 50°C, add 100ml of toluene, filter, wash the filter cake once with 20ml of toluene, and discard the iron sludge. The layers were separated, and the aqueous layer was extracted once with 50 ml of toluene. The toluene layers were combined, concentrated under reduced pressure, and rectified to obtain 10 g of o-fluoroaniline, with a yield of 90%.

[0029] (2) Dissolve 66g (0.6mol) of o-fluoroaniline obtained in step (1) in 300ml of ethylene glycol, then add 99g (0.92mol) of anhydrous sodium carbonate, and dropwise add 127.5g (0.9mol) of di Chloroethyl ether, dropwise, stirred at 150°C for 5 hours to complete the reaction, cooled at 50°C, extracted with 2×100ml to...

Embodiment 2

[0033] (1) Add 20g (0.142mol) o-fluoronitrobenzene, 130ml methanol, and 1g Raney nickel into a 200ml autoclave, adjust the hydrogen pressure to 20 atmospheres, and stir at room temperature for 10 hours to complete the reaction. The reaction solution was obtained by filtration, and the filtrate was concentrated under reduced pressure and rectified to obtain 14.2 g of an oily substance. The yield was 90%.

[0034] (2) According to the method for preparing o-fluoro-morpholinylbenzene in step (2) of Example 1, ethylene glycol is replaced with diethylene glycol dimethyl ether solvent to obtain 86g of o-fluoro-morpholinylbenzene with a yield of 80 %.

[0035] (3) According to the method for preparing o-fluoro-morpholinyl nitrobenzene according to step (3) of Example 1, the concentrated nitric acid with a mass fraction of 68% was replaced with fuming nitric acid with a mass fraction of 98%, to obtain 57.7g of solid, with a yield of 85% .

[0036] (4) Add 50 g (0.22 mol) of 3-fluor...

Embodiment 3

[0038] (1) According to the catalytic hydrogenation reduction method of the second step (1) of the embodiment, the Raney nickel is replaced with palladium carbon.

[0039] (2) According to the method for preparing o-fluoro-morpholinylbenzene in step (2) of Example 1, anhydrous sodium carbonate was replaced with anhydrous potassium carbonate to obtain 80 g of o-fluoro-morpholinylbenzene with a yield of 74.3%.

[0040] (3) Same as embodiment one step (3).

[0041] (4) With embodiment two steps (4).

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Abstract

The invention belongs to a method for preparing pharmaceutical intermediate, and discloses a method for preparing 3-fluorine-4 morpholinyl phenylamine, comprising the steps: (1) reducing o-fluoro-nitrobenzene to obtain o-fluoroaniline; (2) adding the o-fluoroaniline and deacidifying agent into organic solvent, and slowly adding disubstituted ethyl ether into a reaction system at the temperature of100-150 DEG C and then stirring at the temperature of 100-200 DEG C to react for preparing o-fluoro-morpholinyl benzene; (3) taking nitric acid with the mass percent of 65-98% as nitrating agent andacetic acid as solvent, and leading the o-fluoro-morpholinyl benzene obtained in the step (2) to have nitration reaction to obtain 3-fluorine-4 morpholinyl nitrobenzene; (4) reducing the 3-fluorine-4morpholinyl nitrobenzene obtained in the step (3) and obtaining the 3-fluorine-4 morpholinyl phenylamine. As the method takes the o-fluoro-nitrobenzene as initial reactant, the price of the raw materials is low, and the production cost can be reduced. Meanwhile, no waste water containing fluorine is generated in the preparation process of the method, so that the method has little environmental pollution and is environment-friendly.

Description

technical field [0001] The present invention relates to a preparation method of a pharmaceutical intermediate, in particular to a preparation method of the key intermediate 3-fluoro-4morpholinoaniline for the preparation of the oxazolidinone antibacterial agent Linezolid Background technique [0002] Linezolid is a new type of oxazolidinone antibacterial agent. Although there are many synthetic routes of linezolid reported at home and abroad, 3-fluoro-4morpholinoaniline is a necessary intermediate for the synthesis. [0003] The preparation method of 3-fluoro-4 morpholino aniline, is to adopt 3 in the prior art, and 4-difluoronitrobenzene is raw material, through morpholine substitution and nitro reduction (referring to: [1]: Steven JB, Douglas KH, Michael RB, et al.J Med Chem, 1996, 39 (3): 673-679. [2]: China Medicinal Chemistry, February 2003, total 51 phase), the method of the two-step synthetic route There are two disadvantages: [0004] (1) The price of 3,4-difluoron...

Claims

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Application Information

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IPC IPC(8): C07D295/135
Inventor 沈建伟吴和明朱崇泉
Owner SUZHOU JINGYE MEDICINE & CHEM
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