阅读说明：本技术 一种合成1-氧代-1,3-二氢-3-羟基苯并呋喃-5-甲酸的方法 (A method of synthesis 1- oxo -1,3- dihydro-3-hydroxy benzofuran -5- formic acid ) 是由 席福贵 董智云 范建凤 赵三虎 张佳琪 董芝彤 于 2019-08-30 设计创作，主要内容包括：本发明公开了一种合成1-氧代-1,3-二氢-3-羟基苯并呋喃-5-甲酸的方法,该合成方法包括：取2,5-二卤甲苯、冰醋酸、醋酸酐、浓硫酸混合,加入三氧化铬氧化反应制得2,5-二卤-二乙酸基甲基苯,2,5-二卤-二乙酸基甲基苯经钯催化剂催化制得4-卤-3-甲酰基苯甲酸,4-卤-3-甲酰基苯甲酸再经钯催化剂催化制得1-氧代-1,3-二氢-3-羟基苯并呋喃-5-甲酸。本发明的制备方法对仪器设备要求简单,原料易得,便于规模化制备,经济效益好,产物产率较高,反应后处理简单。(The invention discloses a kind of synthesis 1- oxos -1; the method of 3- dihydro-3-hydroxy benzofuran -5- formic acid; the synthetic method includes: to take 2; 5- halogeno toluene, glacial acetic acid, acetic anhydride, concentrated sulfuric acid mixing; chromium trioxide oxidation reaction is added and is made 2; 5- dihalo--diacetoxyl methylbenzene; 2; 5- dihalo--via palladium-catalyzed dose of diacetoxyl methylbenzene, which is catalyzed, is made 4- halogen -3- formylbenzoate; 4- halogen -3- formylbenzoate is catalyzed obtained 1- oxo -1,3- dihydro-3-hydroxy benzofuran -5- formic acid for via palladium-catalyzed dose again.Preparation method of the invention requires simply instrument and equipment, and raw material is easy to get, and is convenient for large-scale preparation, and good in economic efficiency, products collection efficiency is higher, and post-reaction treatment is simple.)

1. a kind of method of synthesis 1- oxo -1,3- dihydro-3-hydroxy benzofuran -5- formic acid, which is characterized in that including as follows Step:

(1) it takes 2,5- halogeno toluene to be added into the mixed liquor of glacial acetic acid, acetic anhydride and the concentrated sulfuric acid, it is anti-that chromium trioxide oxidation is added Answer, obtain reaction solution, reaction solution is added and is stirred into ice water to there is light green precipitating, ultrasonic vibration, filter and spend from Sub- water washing, the light green solid after being dried are dissolved with organic solvent one, are filtered after ultrasonic vibration, are obtained 2,5- dihalo-- Diacetoxyl methylbenzene；

(2) by 2,5- dihalo--diacetoxyl methylbenzene protection gas protection under with palladium catalyst, Phosphine ligands, organic solvent two, Water and alkali mixing, are reacted under carbon monoxide environment, remove organic solvent two after reaction, are adjusted pH value to 1-4, are taken out Filter, is washed with deionized water, is dried to obtain 4- halogen -3- formylbenzoate；

(3) by 4- halogen -3- formylbenzoate protection gas protection under with palladium catalyst, Phosphine ligands, organic solvent two, water and Alkali mixing, is reacted under carbon monoxide environment, removes organic solvent two after reaction, and adjusting pH value to 1-4 filters, 1- oxo -1,3- dihydro-3-hydroxy benzofuran -5- formic acid is obtained by extraction by organic solvent three after washing with deionized water.

2. a kind of preparation method of 1- oxo -1,3- dihydro-3-hydroxy benzofuran -5- formic acid according to claim 1, It is characterized in that, glacial acetic acid described in step (1), acetic anhydride, the concentrated sulfuric acid and 2, the molar ratio of 5- halogeno toluene is 21-25:13- 15:5-8:1；

The molar ratio of the chromium trioxide and 2,5- halogeno toluene is 3-5:1；

The mass ratio of the reaction solution and ice water is 1:5.

3. a kind of side for synthesizing 1- oxo -1,3- dihydro-3-hydroxy benzofuran -5- formic acid according to claim 1 or 2 Method, which is characterized in that 2,5- halogeno toluene described in step (1) is 2,5- dichlorotoleune or 2,5- dibromomethylbenzene；

The organic solvent one is any one of petroleum ether, n-hexane or hexamethylene.

4. a kind of method of synthesis 1- oxo -1,3- dihydro-3-hydroxy benzofuran -5- formic acid according to claim 1, It is characterized in that, the temperature of mixed liquor is 0-5 DEG C when chromium trioxide being added in the step (1)；

The oxidizing reaction temperature is 23-25 DEG C, time 2-24h.

5. a kind of method of synthesis 1- oxo -1,3- dihydro-3-hydroxy benzofuran -5- formic acid according to claim 1, It is characterized in that, protection gas described in step (2) and/or step (3) is any of nitrogen, argon gas or neon；

The palladium catalyst is palladium chloride, palladium acetate, tetra-triphenylphosphine palladium, bis- (the diphenylphosphine) -1,1'- dinaphthalenes of 2,2'-] dichloro Change palladium, chlorine (1,5- cyclo-octadiene) methyl palladium (II), bis- (dicyclohexyl amine) acid chlorides (II), three (two benzal-base acetone) two Palladium, double focusing chlorination two (2- methylallyl) palladium it is any；

The Phosphine ligands be bis- (the diphenylphosphine) -9,9- xanthphos of 4,5-, (bromination triphenyl phosphoniums) bis- to two methylene benzene, (Lvization triphenyl phosphoniums) bis- to two methylene benzene, two (1- naphthalene) phosphonium chlorides, three (4- aminomethyl phenyl) phosphine oxides or four triphenylphosphines One of；

The organic solvent two is any mixing mixed with water with the volume ratio of 10:1 in tetrahydrofuran or dimethyl sulfoxide Solvent；

The alkali is any of trimethylamine, triethylamine or sodium carbonate.

6. a kind of method of synthesis 1- oxo -1,3- dihydro-3-hydroxy benzofuran -5- formic acid according to claim 5, It is characterized in that, 2,5- dihalo--diacetoxyl methylbenzene, palladium catalyst and Phosphine ligands described in step (2) and/or step (3) Molar ratio be 1:0.05:0.1；

The additional amount of the organic solvent two is that 20mL organic solvent two is added in every 1g 2,5- dihalo--diacetoxyl methylbenzene；

When the alkali is trimethylamine or triethylamine, the volume ratio with water is 1:1, when the alkali is sodium carbonate, the mass ratio with water For 1:2.

7. a kind of side for synthesizing 1- oxo -1,3- dihydro-3-hydroxy benzofuran -5- formic acid according to claim 5 or 6 Method, which is characterized in that in the step (2) and/or step (3), carbon monoxide environment is by being filled with carbon monoxide gas after evacuating Body 5min is obtained；

The reaction temperature is 65-110 DEG C, reaction time 1.5-4h, and in reaction process, every 30min is filled with one time one oxidation Carbon gas 5min；

The operation for adjusting pH value to 1-4 is the salt acid for adjusting pH value with 10% to 1-4.

8. a kind of method of synthesis 1- oxo -1,3- dihydro-3-hydroxy benzofuran -5- formic acid according to claim 7, It is characterized in that, removing the operation of organic solvent two in step (2) and/or step (3) are as follows: when organic solvent two is tetrahydrofuran When, revolving is added 10 times that water is diluted to raw water volume after removing organic solvent two；

When organic solvent two is dimethyl sulfoxide, pH value is adjusted to 10-12, with organic molten with highly basic weak solution after being diluted with water Agent four is washed three times.

9. a kind of preparation method of 1- oxo -1,3- dihydro-3-hydroxy benzofuran -5- formic acid according to claim 8, It is characterized in that, the highly basic weak solution is the sodium hydroxide or potassium hydroxide solution that concentration is 2mol/L；

The organic solvent four is any one of ethyl acetate, ether, dichloromethane or chloroform.

10. a kind of preparation side of 1- oxo -1,3- dihydro-3-hydroxy benzofuran -5- formic acid according to claim 1 Method, which is characterized in that dry operation described in step (2) is 60 DEG C of dry 8-12h；

Organic solvent three described in step (3) is ethyl acetate or methylene chloride.

Technical field

The present invention relates to a kind of methods of synthesis 1- oxo -1,3- dihydro-3-hydroxy benzofuran -5- formic acid, and belonging to has Machine synthesizes field.

Background technique

Terephthaldehyde's acids compound is a kind of important dyestuff, drug and chemical intermediate.In multi-functional metal The synthesis field of organic frame (Metal-Organic frameworks, MOFs) has potential application.To benzene two The pre- modification that the side position of formic acid carries out organic active functional group is a kind of common research strategy, and new functional group is especially chemically The introducing of the active group of matter is to this kind of new material bring new property.

BaogangWang et al. reported 3 1- oxo -1,3- dihydrobenzo furans containing different substituents in 2014 It mutters the synthesis of -5- formic acid formic acid, wherein the yield of 1- oxo -1,3- dihydro-3-hydroxy benzofuran -5- formic acid is 20%, is closed It is as follows at route:

With 2,5- dibromo benzaldehyde for raw material in the work of Stephen J.D. in 2016, in palladium acetate, the bis- (hexichol of 4,5- Base phosphine) it synthesizes under the conditions of -9,9- xanthphos and carbon monoxide etc., the isomers of 2- formoxyl terephthalic acid (TPA), road Line is as follows:

The synthesis of 1- oxo -1,3- dihydro-3-hydroxy benzofuran -5- formic acid is reported at present, it is domestic not yet at Ripe method and related patents.

Summary of the invention

In view of this, the present invention provides a kind of synthesis 1- oxo -1,3- dihydro-3-hydroxy benzofuran -5- formic acid Method is that raw material dexterously together by multistep kind reaction bonded by testing meticulously, is opened with cheap 2,5- halogeno toluene Issue a kind of synthetic route of new 1- oxo -1,3- dihydro-3-hydroxy benzofuran -5- formic acid.

Specifically, the present invention adopts the following technical scheme:

A kind of preparation method of 1- oxo -1,3- dihydro-3-hydroxy benzofuran -5- formic acid, includes the following steps:

(1) it takes 2,5- halogeno toluene to be added into the mixed liquor of glacial acetic acid, acetic anhydride and the concentrated sulfuric acid, is added three at 0-5 DEG C Chromium oxide, 23-25 DEG C of (preferably 25 DEG C) oxidation reaction 2-24h, obtains reaction solution, by reaction solution with reaction solution: ice water 1:5-10 Volume ratio be added and stirred into ice water to there is light green precipitating, ultrasonic vibration is filtered and is washed with deionized, done Light green solid after dry is washed with organic solvent one, is filtered after ultrasonic vibration, is obtained 2,5- dihalo--diacetoxyl methylbenzene；

(2) by 2,5- dihalo--diacetoxyl methylbenzene protection gas protection under with palladium catalyst, Phosphine ligands, You Jirong Agent two, water and alkali mixing, are filled with CO gas 5min and obtain carbon monoxide environment, under carbon monoxide environment after evacuation 65-110 DEG C of reaction 1.5-4h, in reaction process, every 30min is filled with a CO gas 5min, removes after reaction Organic solvent two is filtered, is washed with deionized water, 60 DEG C of dry 8-12h obtain 4- with 10% salt acid for adjusting pH value to 1-4 Halogen -3- formylbenzoate；

(3) by the bromo- 3- formylbenzoate of 4- protection gas protection under with palladium catalyst, Phosphine ligands, organic solvent two, Water and alkali mixing, are filled with CO gas 5min and obtain carbon monoxide environment after evacuation, the 65-110 under carbon monoxide environment DEG C reaction 6-12h, in reaction process, every 30min is filled with a CO gas 5min, removes organic solvent after reaction Two, with 10% salt acid for adjusting pH value to 1-4, filters, extracted after being washed with deionized water by ethyl acetate or methylene chloride To 1- oxo -1,3- dihydro-3-hydroxy benzofuran -5- formic acid.

By taking 2,5- dibromomethylbenzene as an example, route of the present invention is as follows:

The beneficial effects of the present invention are:

(1) reaction obtains 1- oxo -1,3- dihydro-3-hydroxy benzofuran -5- formic acid with higher yield, after reaction Reason is simple, and washing, extraction and filtering is only needed just to obtain pure target product；

(2) method therefor synthesizes simple, raw material and is easy to get, and is convenient for large-scale preparation；

(3) selecting method requires instrument and equipment simple, there is very big advantage in reaction cost, good in economic efficiency.

Further, 2,5- halogeno toluene is 2,5- dichlorotoleune or 2,5- dibromomethylbenzene in step (1)；

Organic solvent one is any one of petroleum ether, n-hexane or hexamethylene；

Protection gas is any of nitrogen, argon gas or neon in step (2) and/or step (3)；

Palladium catalyst is palladium chloride, palladium acetate, tetra-triphenylphosphine palladium, [bis- (the diphenylphosphine) -1,1'- dinaphthalenes of 2,2'-] two Palladium chloride, chlorine (1,5- cyclo-octadiene) methyl palladium (II), bis- (dicyclohexyl amine) acid chlorides (II), three (two benzal-base acetone) Two palladiums, double focusing chlorination two (2- methylallyl) palladium it is any；

Phosphine ligands be bis- (the diphenylphosphine) -9,9- xanthphos of 4,5-, (bromination triphenyl phosphoniums) bis- to two methylene benzene, (Lvization triphenyl phosphoniums) bis- to two methylene benzene, two (1- naphthalene) phosphonium chlorides, three (4- aminomethyl phenyl) phosphine oxides or four triphenylphosphines One of；

Organic solvent two is any mixing mixed with water with the volume ratio of 10:1 in tetrahydrofuran or dimethyl sulfoxide Solvent；

Alkali is any of trimethylamine, triethylamine or sodium carbonate.

It is that raw material is easy to get using above-mentioned further beneficial effect, the reaction time is short, and post-processing is simple, does not need spy Different means of purification.

Further, glacial acetic acid, acetic anhydride, the concentrated sulfuric acid and 2 in step (1), the molar ratio of 5- halogeno toluene are 21-25:13- 15:5-8:1；

The molar ratio of chromium trioxide and 2,5- halogeno toluene is 3-5:1；

2,5- dihalo--diacetoxyl methylbenzene, the molar ratio of palladium catalyst and Phosphine ligands in step (2) and/or step (3) For 1:0.05-0.2:0.1；

The additional amount of organic solvent two is that 20mL organic solvent two is added in every 1g 2,5- dihalo--diacetoxyl methylbenzene；

When alkali is trimethylamine or triethylamine, the volume ratio with water is 1:1, when the alkali is sodium carbonate, the mass ratio with water For 2:1.

It is further had the beneficial effect that using above-mentioned, reduce the generation of by-product, the reaction time is short, and post-processing is simple, no Need special means of purification.

Further, step (2) and/or the middle operation for removing organic solvent two of step (3) are as follows: when organic solvent two is tetrahydro When furans, revolving is added 10 times that water is diluted to original volume after removing organic solvent two；

When organic solvent two is dimethyl sulfoxide, pH value is adjusted to 10-12, to have with highly basic weak solution after being diluted with water Solvent four is washed three times, wherein highly basic weak solution is the sodium hydroxide or potassium hydroxide solution that concentration is 2mol/L；It is organic molten Agent four is any one of ethyl acetate, ether, dichloromethane or chloroform.

Detailed description of the invention

Fig. 1 is the nuclear magnetic resonance spectroscopy spectrogram of 2- formoxyl terephthalic acid (TPA) obtained in the embodiment of the present invention 1；

Fig. 2 is the nuclear-magnetism of 1- oxo -1,3- dihydro-3-hydroxy benzofuran -5- formic acid obtained in the embodiment of the present invention 1 The hydrogen that resonates composes spectrogram.

Specific embodiment

Following will be combined with the drawings in the embodiments of the present invention, and technical solution in the embodiment of the present invention carries out clear, complete Site preparation description, it is clear that described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.It is based on Embodiment in the present invention, it is obtained by those of ordinary skill in the art without making creative efforts every other Embodiment shall fall within the protection scope of the present invention.

In the examples below, bis- (diphenylphosphine) -9,9- xanthphos of 4,5-, to the bis- (brominations three of two methylene benzene Ben Ji Phosphonium), (Lvization triphenyl phosphoniums) bis- to two methylene benzene, two (1- naphthalene) phosphonium chlorides, three (4- aminomethyl phenyl) phosphine oxides or four Triphenylphosphine (97%, splendid remote chemical science and technology limited Company)；Palladium chloride, palladium acetate, tetra-triphenylphosphine palladium, 2,2'- bis- (two Phenylphosphine) -1,1'- dinaphthalene] palladium chloride, chlorine (1,5- cyclo-octadiene) methyl palladium (II), bis- (dicyclohexyl amine) acid chlorides (II), Three (two benzal-base acetone) two palladiums, double focusing chlorination two (2- methylallyl) palladium (98%, Arkpharm)；2,5- dibromo first Benzene (70%, EAP Chem company)；Acetic anhydride, chromium trioxide (analyzing pure, Chinese medicines group chemical reagent)；Concentrated sulfuric acid H₂SO₄(day Yong great chemical reagent Co., Ltd, Jinshi City)；Glacial acetic acid, Anhydrous potassium carbonate (analyze pure, Tianjin great Mao chemical reagent factory)；Tetrahydro Furans, petroleum ether, n-hexane, ethyl acetate, methylene chloride, anhydrous sodium sulfate (analyze pure, Tianjin North Star Founder chemical reagent work)；N, Dinethylformamide (99.5%, analyze pure, Tianjin Yong great chemical reagent Co., Ltd)；Hydrochloric acid HCl (98%, Dongguan City Qiao Ke Chemical Co., Ltd.)；Anhydrous methanol, triethylamine, sodium hydroxide, sodium chloride, dimethyl sub-maple (analyze pure, Tianjin Shen Safe chemical reagent Science and Technology Ltd.).

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