CN101565352A

CN101565352A - Preparation method of 2-fluoronaphthalene

Info

Publication number: CN101565352A
Application number: CNA200910084946XA
Authority: CN
Inventors: 郑国钧; 郭方超; 徐光辉; 恽海顺
Original assignee: JIANGSU HUADA CHEMICAL GROUP CO Ltd; Beijing University of Chemical Technology
Current assignee: JIANGSU HUADA CHEMICAL GROUP CO Ltd; Beijing University of Chemical Technology
Priority date: 2009-06-05
Filing date: 2009-06-05
Publication date: 2009-10-28

Abstract

The invention discloses a preparation method of 2-fluoronaphthalene. The preparation method comprises the following steps: (1) 2-naphthol and para-toluene sulfochloride (or para-toluenesulfonic acid) react to produce para-toluenesulfonic acid-2-naphthyl; and (2) under the catalysis of tertiary amine bidentate ligand and metallic copper, the para-toluenesulfonic acid-2-naphthyl obtained from the step (1) reacts in an aprotic solvent with high boiling point so as to prepare the 2-fluoronaphthalene. The invention introduces fluorine atoms on a benzene ring, avoids use of dangerous toxic materials of diazoimido compounds and the like, has easy obtaining of materials and simple operation and is applicable to industrial production.

Description

The preparation method of 2-fluoronaphthalene

Technical field:

The present invention relates to the preparation method of 2-fluoronaphthalene.

Background technology:

The 2-fluoronaphthalene is the pharmaceutical intermediate that a kind of development in recent years is got up.Hydrogen atom on the aromatic nucleus is substituted with fluorine atom, discover that the aromatic compound that fluorine atom replaces has good biological activity, it has active compound and usually uses on medicine and agricultural.

In the prior art, fluoridation can pass through iodine atom, bromine atoms, chlorine atom and nitro and fluorine atom exchanges realization, carries out with the form of nucleophilic substitution.About the fluoro-reaction of the aromatic ring of passivation, known fluorination reagent price is often relatively more expensive, and technology is immature, and productive rate is lower.

Chinese patent application CN99109523.5 has reported the synthetic of a class naphthalene derivatives, it is characterized in that using alkyl lithium reagents, makes metal reagent, fluoridizes by the effect realization of fluorizating agent, and severe reaction conditions is difficult for industrialization; In addition, Chinese patent application CN200610028433.3 has reported the synthetic of 1-fluoronaphthalene, is that thermolysis obtained the 1-fluoronaphthalene after raw material generated diazonium salt with the naphthalidine, and this method generates dangerous virulent triazo-compound, and higher to equipment requirements; U.S. Pat 20060074261 has reported and has used cupric fluoride to prepare the method for 2-fluoronaphthalene as the halogen-fluorine exchange process of fluorination reagent that this method catalyzer costs an arm and a leg.

Summary of the invention:

The preparation method who the purpose of this invention is to provide a kind of 2-fluoronaphthalene, this method synthetic route is short, and the reaction desired raw material is with low cost, can access productive rate and steady quality preferably.

The invention provides a kind of method of the 2-of preparation fluoronaphthalene, the employing beta naphthal is a raw material, generate tosic acid-2-naphthalene ester with toluene sulfonyl chloride reaction, again with inorganic fluoride under the effect of metallic copper and tertiary amine bitooth ligand, reaction makes target compound 2-fluoronaphthalene in sprotic high boiling solvent.

Method of the present invention comprises the following steps:

1), beta naphthal, Tosyl chloride or tosic acid, basic catalyst and solvent were reacted 6～18 hours under 10～100 degree reactions, wherein the mol ratio of beta naphthal, Tosyl chloride or tosic acid, basic catalyst is 1: 1～3: 2～6, generates intermediate tosic acid-2-naphthalene ester;

2), add the salt acid elution in the crude product intermediate that step 1) is obtained, 50 degree heating added ethyl acetate extraction after 2 hours, were washed till neutrality, and dry back concentrates that removing desolvates obtains pure product tosic acid-2-naphthalene ester;

3), under the nitrogen protection, with step 2) tosic acid-2-naphthalene ester of obtaining and part and copper powder and fluorochemical and sprotic solvent obtained reactant in 2～8 hours in 100～200 degree reactions; With respect to tosic acid-2-naphthalene ester, described part molar equivalent is 1～2, and the copper powder molar equivalent is 2～5, and the fluorochemical molar equivalent is 3～5; Part is selected from N, N, N ', N '-Tetramethyl Ethylene Diamine (TMEDA), N, N, N ', N '-tetraethylethylenediamine (TEEDA), N, N, N ', N '-tetramethyl-para-phenylene diamine (TMPD) or N, N, N ', N '-tetraethyl-Ursol D (TEPD), fluorochemical is selected from Potassium monofluoride, Sodium Fluoride or silver fluoride, and solvent is selected from tetramethylene sulfone, HMPA, N-N-methyl-2-2-pyrrolidone N-or diglyme;

4), add the mixed solvent of entry and normal hexane in the reactant with step 3), filter the refining 2-fluoronaphthalene that obtains in extraction back.

Step 1) neutral and alkali catalyzer is organic bases or mineral alkali, and organic bases is sodium alkoxide, triethylamine, diethylamine, tri-n-butylamine or tripropylamine; Mineral alkali is sodium hydroxide, potassium hydroxide, hydrated barta, calcium hydroxide, magnesium hydroxide, yellow soda ash, sodium bicarbonate, salt of wormwood or saleratus; Reaction solvent is selected from methylene dichloride, trichloromethane, tetracol phenixin, hexane, hexanaphthene, ethyl acetate, sherwood oil or tetrahydrofuran (THF).

The present invention has following advantage:

1, preparation tosic acid-2-naphthalene ester reaction conditions gentleness, purifying easily.

2, adopting the catalytic inorganic fluoride of copper is fluorizating agent, and cost of material is cheap, and is simple to operate, and reaction is easy to control.

3, products obtained therefrom purity height has reached the purity requirement of pharmaceutical intermediate.

Embodiment:

Below each embodiment further set forth the present invention, should be understood that these embodiment only are used to the present invention is described and are not used in to limit the scope of the invention.

Embodiment 1

With 15.6g (0.11mol) beta naphthal, 40g (0.19mol) Tosyl chloride, 20ml (0.25mol) pyridine and 50ml anhydrous tetrahydro furan join in the reaction flask, about 24 hours of room temperature reaction.TLC adds 1N hydrochloric acid 50ml after detecting raw material, 50 degree heating 2 hours, and cooled and filtered is removed solid insoluble, add the 40ml ethyl acetate extraction three times, merge organic phase, after organic phase was washed till neutrality with saturated sodium carbonate, salt solution, dry precipitation got white solid 30g (0.1mol).

Solid 30g (0.1mol) with the last step obtains adds anhydrous HMPA 100ml, copper powder 15g (0.24mol), Potassium monofluoride 13.9g (0.24mol), 26.2ml (0.15mol) exsiccant TMEDA, 170 degree reactions 6 hours.After being cooled to room temperature, add 120ml water and 40ml normal hexane, solid is gone out in filtration, the saturated common salt water washing of normal hexane layer, again with merging behind the 40ml n-hexane extraction water, the crude product of precipitation is through the refining (sherwood oil: ethyl acetate=20: 1), obtain colorless oil (product purity＞99%) of too short silicagel column.

Embodiment 2

With 15.6g (0.11mol) beta naphthal, 32.7g (0.19mol) tosic acid, 20ml (0.25mol) pyridine and 50ml trichloromethane join in the reaction flask, about 24 hours of room temperature reaction.TLC adds 1N sodium hydroxide 50ml after detecting raw material, stirring at room 2 hours, cooled and filtered is removed solid insoluble, add the 40ml ethyl acetate extraction three times, merge organic phase, after organic phase was washed till neutrality with saturated sodium bicarbonate, salt solution, dry precipitation got white solid 28g (0.094mol).

Solid 28g (0.094mol) with the last step obtains adds anhydrous HMPA 100ml, copper powder 15g (0.24mol), Sodium Fluoride 13.6g (0.24mol), 28.5ml (0.15mol) exsiccant TEEDA, 170 degree reactions 6 hours.After being cooled to room temperature, add 120ml water and 40ml normal hexane, solid is gone out in filtration, the saturated common salt water washing of normal hexane layer, again with merging behind the 40ml n-hexane extraction water, the crude product of precipitation is through the refining (sherwood oil: ethyl acetate=20: 1), obtain colorless oil (product purity＞99%) of too short silicagel column.

Embodiment 3

White solid 19g (0.064mol) with embodiment 2 obtains adds anhydrous HMPA 80ml, copper powder 10g (0.16mol), silver fluoride 32.5g (0.25mol), 20.3ml (0.25mol) exsiccant TMPD, 170 degree reactions 6 hours.After being cooled to room temperature, add 90ml water and 30ml normal hexane, solid is gone out in filtration, the saturated common salt water washing of normal hexane layer, again with merging behind the 30ml n-hexane extraction water, the crude product of precipitation is through the refining (sherwood oil: ethyl acetate=20: 1), obtain colorless oil (product purity＞99%) of too short silicagel column.

Embodiment 4

With the white solid 19g (0.064mol) that embodiment 2 obtains, add N-N-methyl-2-2-pyrrolidone N-80ml, copper powder 10g (0.16mol), silver fluoride 32.5g (0.25mol), 20.3ml (0.25mol) exsiccant TEPD, 170 degree reactions 6 hours.After being cooled to room temperature, add 100ml water and 30ml normal hexane, solid is gone out in filtration, the saturated common salt water washing of normal hexane layer, again with merging behind the 30ml n-hexane extraction water, the crude product of precipitation is through the refining (sherwood oil: ethyl acetate=20: 1), obtain colorless oil (product purity＞99.5%) of too short silicagel column.

Embodiment 5

White solid 19g (0.064mol) with embodiment 2 obtains adds diglyme 100ml, copper powder 10g (0.16mol), silver fluoride 32.5g (0.25mol), 20.3ml (0.25mol) exsiccant TEEDA, 170 degree reactions 6 hours.After being cooled to room temperature, add 100ml water and 40ml normal hexane, solid is gone out in filtration, the saturated common salt water washing of normal hexane layer, again with merging behind the 30ml n-hexane extraction water, the crude product of precipitation is through the refining (sherwood oil: ethyl acetate=20: 1), obtain colorless oil (product purity＞99.2%) of too short silicagel column.

Claims

1, the preparation method of 2-fluoronaphthalene is characterized in that, may further comprise the steps:

3), under the nitrogen protection, with step 2) tosic acid-2-naphthalene ester of obtaining and part and copper powder and fluorochemical and sprotic solvent obtained reactant in 2～8 hours in 100～200 degree reactions; With respect to tosic acid-2-naphthalene ester, described part molar equivalent is 1～2, and the copper powder molar equivalent is 2～5, and the fluorochemical molar equivalent is 3～5; Part is selected from N, N, N ', N '-Tetramethyl Ethylene Diamine, N, N, N ', N '-tetraethylethylenediamine, N, N, N ', N '-tetramethyl-para-phenylene diamine or N, N, N ', N '-tetraethyl-Ursol D, fluorochemical is selected from Potassium monofluoride, Sodium Fluoride or silver fluoride, and sprotic solvent is selected from tetramethylene sulfone, HMPA, N-N-methyl-2-2-pyrrolidone N-or diglyme;

2, the preparation method of 2-fluoronaphthalene according to claim 1 is characterized in that: with step 1) neutral and alkali catalyzer is organic bases or mineral alkali, and organic bases is sodium alkoxide, triethylamine, diethylamine, tri-n-butylamine or tripropylamine; Mineral alkali is sodium hydroxide, potassium hydroxide, hydrated barta, calcium hydroxide, magnesium hydroxide, yellow soda ash, sodium bicarbonate, salt of wormwood or saleratus; Reaction solvent is selected from methylene dichloride, trichloromethane, tetracol phenixin, hexane, hexanaphthene, ethyl acetate, sherwood oil or tetrahydrofuran (THF).