A kind of synthetic method of 2-fluoro-3-nitrobenzoic acid

Abstract

The present invention relates to a method for synthesizing an important pharmaceutical intermediate 2-fluoro-3-nitrobenzoic acid. The method uses 2-methyl-6-nitroaniline as a raw material, undergoes diazotization and chlorination reactions to generate 2-chloro-3-nitrotoluene, and then undergoes a chlorine-fluorine exchange reaction to prepare 2-fluoro-3-nitrotoluene; and finally, an oxidation reaction is performed to prepare the target product 2-fluoro-3-nitrobenzoic acid. The present invention has great advantages over the existing technology for preparing 2-fluoro-3-nitrobenzoic acid, mainly in that the process yield is high, the raw materials are cheap and readily available, the cost is greatly reduced, and it is suitable for industrial production.

Description

Technical Field

[0001] The invention relates to a method for synthesizing 2-fluoro-3-nitrobenzoic acid, an important pharmaceutical intermediate. Background Art

[0002] 2-Fluoro-3-nitrobenzoic acid (Formula 1) is an important pharmaceutical intermediate and one of the main synthetic raw materials for the BRAF inhibitor Dabrafenib. The traditional process for preparing 2-fluoro-3-nitrobenzoic acid is mainly to directly nitrate 2-fluorotoluene and then oxidize it to obtain 2-fluoro-3-nitrobenzoic acid. The reaction formula is as follows:

[0003]

[0004] The process route has poor selectivity and a very low reaction yield (<10%), so the cost remains high, resulting in relatively high market competition pressure and environmental pressure. At present, there has been no report on a new method for industrial production of 2-fluoro-3-nitrobenzoic acid. Therefore, exploring and improving a new industrial process route to synthesize 2-fluoro-3-nitrobenzoic acid with high yield and low cost has practical and important economic significance. Summary of the invention

[0005] The purpose of the present invention is to provide an industrial synthesis method for an important pharmaceutical intermediate 2-fluoro-3-nitrobenzoic acid, which mainly solves the technical problems of poor selectivity, low yield and high cost of the existing synthesis method. In order to achieve the technical purpose of the present invention, the technical solution provided by the present invention is:

[0006] First, a method for synthesizing 2-fluoro-3-nitroalkylbenzene is provided, wherein 2-chloro-3-nitroalkylbenzene is prepared by a chlorine-fluorine exchange reaction.

[0007]

[0008] Wherein, R is an alkyl group. Preferably, R is a methyl group.

[0009] The reaction temperature is 100°C to 150°C, and preferably, the reaction temperature is 130°C.

[0010] Furthermore, the present invention provides a method for synthesizing 2-fluoro-3-nitrobenzoic acid, comprising the following steps:

[0011] (1) Using 2-methyl-6-nitroaniline as a raw material, diazotization and chlorination reactions are performed to generate 2-chloro-3-nitrotoluene;

[0012] (2) 2-chloro-3-nitrotoluene is subjected to a chlorine-fluorine exchange reaction to prepare 2-fluoro-3-nitrotoluene;

[0013] (3) 2-Fluoro-3-nitrotoluene is oxidized to obtain 2-fluoro-3-nitrobenzoic acid.

[0014] As a preferred technical solution, the diazotization and chlorination reaction described in step (1) is as follows: 2-methyl-6-nitroaniline is dissolved in a mixed solution of water and concentrated hydrochloric acid, and a 25-35% by weight sodium nitrite aqueous solution is added dropwise at 0-10° C. The obtained diazonium salt solution is mixed with a concentrated hydrochloric acid solution of cuprous chloride for reaction, and then subjected to steam distillation and reduced pressure distillation in sequence to obtain 2-chloro-3-nitrotoluene. The reaction can be carried out in a microchannel continuous reactor.

[0015] As a preferred technical solution, the chlorine-fluorine exchange reaction in step (2) is as follows: 2-chloro-3-nitrotoluene is dissolved in a non-protonic polar solvent, a fluorinating agent and a catalyst are added, and the reaction is carried out at 130° C. to prepare 2-fluoro-3-nitrotoluene.

[0016] As a preferred technical solution, the oxidation reaction described in step (3) is: 2-fluoro-3-nitrotoluene is reacted at 15-30° C. for 1-5 hours under the action of an oxidant, and recrystallized in ice water to prepare 2-fluoro-3-nitrobenzoic acid.

[0017] The oxidant is potassium permanganate, sodium dichromate or potassium dichromate.

[0018] As a further preferred technical solution, the aprotic polar solvent in the chloro-fluorine exchange reaction in step (2) is dimethyl sulfoxide, sulfolane, N,N-dimethylformamide or N,N-dimethylacetamide.

[0019] As a further preferred technical solution, the fluorinating agent in the chlorine-fluorine exchange reaction in step (2) is selected from potassium fluoride, sodium fluoride, cesium fluoride or silver fluoride.

[0020] As a further preferred technical solution, the catalyst in the chlorine-fluorine exchange reaction in step (2) is selected from any two of the following compound combinations: 18-crown ether-6, polyethylene glycol, butyltriphenylphosphonium bromide, tetrakis[tris(dimethylamino)phosphoranylideneamino]phosphorus fluoride, bis(triphenylphosphine)ammonium chloride, tetrakis(diethylamino)phosphorus bromide, trihexyltetradecylphosphonium tetrafluoroborate, choline chloride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide, benzyltriethylammonium chloride, benzyltriethylammonium bromide, dodecyltrimethylammonium chloride, tetradecyltrimethylammonium chloride, hexadecyltrimethylammonium bromide, tetramethylammonium chloride, tetraethylammonium chloride, trioctylmethylammonium chloride, tetrabutylammonium fluoride or tetramethylammonium fluoride.

[0021] As a further preferred technical solution, the molar ratio of 2-chloro-3-nitrotoluene, fluorinating agent and catalyst in the chlorine-fluorine exchange reaction of step (2) is 1-1.5:1.5-2.5:0.1-0.5.

[0022] The entire synthetic route is shown in the following reaction formula:

[0023]

[0024] Beneficial effects of the present invention: The method for synthesizing 2-fluoro-3-nitrobenzoic acid provided by the present invention, in step (1), 2-chloro-3-nitrotoluene is prepared by using a continuous reactor. Compared with the prior art, the reaction time is shortened from the traditional several hours to less than 1 hour, which significantly improves the reaction efficiency, and can be operated under milder conditions, reducing the reaction cost, making it safer and easier to control; the chlorine-fluorine exchange reaction in step (2) uses a preferred combined catalyst, which improves the selectivity of the reaction and has a high product yield. The preferred reaction temperature is 130° C., which can meet the requirements for industrial implementation and is suitable for large-scale industrial synthesis. In the prior art reported in literature and patents, the reaction temperature is usually above 180° C., which is difficult to implement in industry. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 This is a simplified diagram of microchannel continuous reaction. DETAILED DESCRIPTION

[0026] The following will further non-restrictive explanation of the technical solution of the present invention in combination with several specific embodiments. Obviously, the protection scope of the present invention is not limited to the embodiments, and other embodiments of the present invention made by those skilled in the art all fall within the protection scope of the present invention.

[0027] Embodiment 1:

[0028] Synthesis of 2-chloro-3-nitrotoluene:

[0029] like Figure 1The present synthesis uses a microchannel continuous reaction device, including an injection pump 1, an injection pump 2, a micro mixer 3, a microchannel reactor 4, and a receiver 5, wherein the injection pump 1 and the injection pump 2 are connected to the micro mixer 3 in parallel, and the micro mixer 3, the microchannel reactor 4, and the receiver 5 are connected in series in sequence through pipelines. The inner diameter of the coil of the microchannel reactor 4 is 0.5 mm. 2-Methyl-6-nitroaniline (45.0 g, 0.30 mol) was dissolved in a mixed solution of water (100 mL) and concentrated hydrochloric acid (100 mL), cooled to 0°C, and a 25% sodium nitrite aqueous solution (100 mL) was added dropwise, and the obtained diazonium salt solution was added to syringe pump 1; cuprous chloride (50.0 g, 0.50 mol) was added to concentrated hydrochloric acid (130 mL) to obtain a concentrated hydrochloric acid solution of cuprous chloride, which was added to syringe pump 2; the flow rate of syringe pump 1 and syringe pump 2 was 1.5 mL / min, the reaction temperature of the microchannel reactor was 35°C, the reaction volume was 15 mL, and the diazonium salt solution and the concentrated hydrochloric acid solution of cuprous chloride were injected into the microchannel reaction device through the syringe pump for mixed reaction; the outflowing reaction liquid was collected, and a crude product was obtained by steam distillation, and a light yellow oily substance 2-chloro-3-nitrotoluene (48.2 g) was collected by reduced pressure distillation, with a yield of 95%. 1 H NMR (400MHz, CDCl3): δ7.58 (d, J=8.0Hz, 1H), 7.44 (d, J=8.0Hz, 1H), 7.29 (t, J=8.0Hz, 1H), 2.46 (s, 3H).

[0030] Embodiment 2:

[0031] Synthesis of 2-fluoro-3-nitrotoluene:

[0032] 2-Chloro-3-nitrotoluene (48.0 g, 0.28 mol) was dissolved in dimethyl sulfoxide (500 mL), potassium fluoride (25.0 g, 0.43 mol), butyltriphenylphosphine bromide (6.0 g, 15 mmol) and 18-crown ether-6 (4.0 g, 15 mmol) were added, the temperature was raised to 130°C for reaction, the temperature was lowered to room temperature, water was added with stirring, and 2-fluoro-3-nitrotoluene (38.5 g) was obtained by steam distillation with a yield of 89%. 1 H NMR (400MHz, CDCl3): δ7.83-7.88(m,1H),7.48-7.52(m,1H),7.17-7.21(m,1H),2.39(s,1H).

[0033] Embodiment 3:

[0034] Synthesis of 2-fluoro-3-nitrobenzoic acid:

[0035] 2-Fluoro-3-nitrotoluene (38.0 g, 0.245 mol) was dissolved in ethanol (400 mL) and water (200 mL), and potassium permanganate (77.0 g, 0.49 mol) was added. The reaction mixture was reacted at 30°C for 1 h, filtered, and the filtrate was evaporated under reduced pressure to remove the organic solvent. Water was added to the residue with stirring, and the temperature was raised to dissolve. The temperature was lowered to below 0°C for recrystallization to obtain 2-fluoro-3-nitrobenzoic acid (41.1 g) with a yield of 91%. 1 H NMR (400MHz, DMSO-d6): δ13.85 (br s, 1H), 8.33 (t, J = 7.3 Hz, 1H), 8.20 (t, J = 6.8 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H).

[0036] Embodiment 4:

[0037] Synthesis of 2-chloro-3-nitrotoluene:

[0038] The microchannel continuous reaction device is the same as in Example 1. 2-Methyl-6-nitroaniline (58.0 g, 0.38 mol) was dissolved in a mixed solution of water (125 mL) and concentrated hydrochloric acid (125 mL), cooled to 5°C, and a 30% aqueous sodium nitrite solution (125 mL) was added dropwise. The obtained diazonium salt solution was added to syringe pump 1; cuprous chloride (63.0 g, 0.64 mol) was added to concentrated hydrochloric acid (180 mL) to obtain a concentrated hydrochloric acid solution of cuprous chloride, which was added to syringe pump 2; the flow rate of syringe pump 1 and syringe pump 2 was 1.5 mL / min, The reaction temperature of the microchannel reactor is 35°C, the reaction volume is 15 mL, and the diazonium salt solution and the concentrated hydrochloric acid solution of cuprous chloride are injected into the microchannel reaction device through a syringe pump for mixed reaction; the outflowing reaction liquid is collected, and the crude product is obtained by steam distillation. After reduced pressure distillation, a light yellow oily product 2-chloro-3-nitrotoluene (62.0 g) is collected, and the yield is 95%.

[0039] Embodiment 5:

[0040] Synthesis of 2-fluoro-3-nitrotoluene:

[0041] 2-Chloro-3-nitrotoluene (62.0 g, 0.36 mol) was dissolved in cyclohexane sulfone (800 mL), and sodium fluoride (30.0 g, 0.72 mol), benzyltriethylammonium chloride (24.0 g, 0.11 mol) and polyethylene glycol (18.0 g) were added. The temperature was raised to 130°C for reaction, then cooled to room temperature, water was added with stirring, and 2-fluoro-3-nitrotoluene (50.5 g) was obtained by steam distillation with a yield of 90%.

[0042] Embodiment 6:

[0043] Synthesis of 2-fluoro-3-nitrobenzoic acid:

[0044] 2-Fluoro-3-nitrotoluene (50.0 g, 0.32 mol) was dissolved in isopropanol (600 mL) and water (300 mL), and sodium dichromate (150.0 g, 0.57 mol) was added. The reaction mixture was reacted at 25°C for 3 h, filtered, and the filtrate was evaporated under reduced pressure to remove the organic solvent. Water was added to the residue with stirring, and the temperature was raised to dissolve. The temperature was lowered to below 0°C for recrystallization to obtain 2-fluoro-3-nitrobenzoic acid (57.3 g) with a yield of 96%.

[0045] Embodiment 7:

[0046] Synthesis of 2-chloro-3-nitrotoluene:

[0047] The microchannel continuous reaction device is the same as in Example 1. 2-Methyl-6-nitroaniline (105.0 g, 0.69 mol) was dissolved in a mixed solution of water (210 mL) and concentrated hydrochloric acid (210 mL), cooled to 10°C, and a 35% sodium nitrite aqueous solution (210 mL) was added dropwise. The obtained diazonium salt solution was added to syringe pump 1; cuprous chloride (115.0 g, 1.16 mol) was added to concentrated hydrochloric acid (350 mL) to obtain a concentrated hydrochloric acid solution of cuprous chloride, which was added to syringe pump 2; the flow rate of syringe pump 1 and syringe pump 2 was 1.5 mL / min, The reaction temperature of the microchannel reactor is 35° C., the reaction volume is 15 mL, and the diazonium salt solution and the concentrated hydrochloric acid solution of cuprous chloride are injected into the microchannel reaction device through a syringe pump for mixed reaction; the outflowing reaction liquid is collected, and the crude product is obtained by steam distillation. After reduced pressure distillation, a light yellow oily product 2-chloro-3-nitrotoluene (116.0 g) is collected, and the yield is 98%.

[0048] Embodiment 8:

[0049] Synthesis of 2-fluoro-3-nitrotoluene:

[0050] 2-Chloro-3-nitrotoluene (116.0 g, 0.68 mol) was dissolved in N,N-dimethylformamide (1200 mL), and cesium fluoride (250.0 g, 1.65 mol), bis(triphenylphosphine)ammonium chloride (190.0 g, 0.33 mol) and polyethylene glycol (150.0 g) were added. The temperature was raised to 130°C for reaction, then cooled to room temperature, water was added with stirring, and 2-fluoro-3-nitrotoluene (92.0 g) was obtained by steam distillation with a yield of 88%.

[0051] Embodiment 9:

[0052] Synthesis of 2-fluoro-3-nitrobenzoic acid:

[0053] 2-Fluoro-3-nitrotoluene (92.0 g, 0.59 mol) was dissolved in acetonitrile (1000 mL) and water (500 mL), and potassium dichromate (210.0 g, 0.71 mol) was added. The reaction mixture was reacted at 15°C for 5 h, filtered, and the filtrate was evaporated under reduced pressure to remove the organic solvent. Water was added to the residue with stirring, and the temperature was raised to dissolve. The temperature was lowered to below 0°C for recrystallization to obtain 2-fluoro-3-nitrobenzoic acid (102.5 g) with a yield of 93%.

Claims

1. A method for synthesizing 2-fluoro-3-nitrobenzoic acid, comprising the following steps: (1) Using 2-methyl-6-nitroaniline as a raw material, diazotization and chlorination reactions are performed to generate 2-chloro-3-nitrotoluene; (2) 2-chloro-3-nitrotoluene is subjected to a chlorine-fluorine exchange reaction to prepare 2-fluoro-3-nitrotoluene; (3) 2-fluoro-3-nitrotoluene is oxidized to obtain 2-fluoro-3-nitrobenzoic acid; in, In step (1), 2-chloro-3-nitrotoluene is prepared by continuous microchannel reaction; the chlorine-fluorine exchange reaction described in step (2) is as follows: 2-chloro-3-nitrotoluene is dissolved in a non-protonic polar solvent, a fluorinating agent and a catalyst are added, and the reaction is carried out at 130° C. to prepare 2-fluoro-3-nitrotoluene; the oxidation reaction described in step (3) is as follows: 2-fluoro-3-nitrotoluene is dissolved in an alcohol solvent, a nitrile solvent, water or a mixed solvent thereof, an oxidant potassium permanganate, sodium dichromate or potassium dichromate is added, the reaction is carried out at 15-30° C. for 1-5 hours, and the reaction is recrystallized in ice water to obtain 2-fluoro-3-nitrobenzoic acid.

2. A method for synthesizing 2-fluoro-3-nitrobenzoic acid according to claim 1, characterized in that: The diazotization and chlorination reaction described in step (1) is as follows: 2-methyl-6-nitroaniline is dissolved in a mixed solution consisting of water and concentrated hydrochloric acid, a 25-35% by weight sodium nitrite aqueous solution is added dropwise at 0-10° C., the obtained diazonium salt solution is mixed with a concentrated hydrochloric acid solution of cuprous chloride for reaction, and then subjected to steam distillation and reduced pressure distillation in sequence to prepare 2-chloro-3-nitrotoluene.

3. The synthesis method according to claim 1, characterized in that The aprotic polar solvent in the chloro-fluorine exchange reaction is dimethyl sulfoxide, sulfolane, N,N-dimethylformamide or N,N-dimethylacetamide.

4. The synthesis method according to claim 1, characterized in that The fluorinating agent in the chlorine-fluorine exchange reaction is selected from potassium fluoride, sodium fluoride, cesium fluoride or silver fluoride.

5. The synthesis method according to claim 1, characterized in that The catalyst in the chlorine-fluorine exchange reaction is selected from any two of the following compound combinations: 18-crown ether-6, polyethylene glycol, butyltriphenylphosphonium bromide, tetrakis[tris(dimethylamino)phosphoranylideneamino]phosphonium fluoride, bis(triphenylphosphine)ammonium chloride, tetrakis(diethylamino)phosphonium bromide, trihexyltetradecylphosphonium tetrafluoroborate, choline chloride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide, benzyltriethylammonium chloride, benzyltriethylammonium bromide, dodecyltrimethylammonium chloride, tetradecyltrimethylammonium chloride, hexadecyltrimethylammonium bromide, tetramethylammonium chloride, tetraethylammonium chloride, trioctylmethylammonium chloride, tetrabutylammonium fluoride or tetramethylammonium fluoride.

6. The synthesis method according to claim 1, characterized in that The molar ratio of 2-chloro-3-nitrotoluene, fluorinating agent and catalyst in the chlorine-fluorine exchange reaction is 1-1.5:1.5-2.5:0.1-0.5.

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