CN113024384A - Synthesis method of 2-fluoro-3-nitrobenzoic acid intermediate raw material - Google Patents
Synthesis method of 2-fluoro-3-nitrobenzoic acid intermediate raw material Download PDFInfo
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Abstract
The invention discloses a synthesis method of a 2-fluoro-3-nitrobenzoic acid intermediate raw material. The invention provides a novel synthetic route, and an important medical intermediate can be quickly and conveniently prepared from cheap and easily-obtained raw materials. The process method comprises the steps of starting from o-methyl phenol, selectively generating a key intermediate 2-methyl-6-nitrophenol through nitration reaction, generating 2-chloro-3-nitrotoluene through hydroxyl chlorination, generating 2-fluoro-3-nitrotoluene through fluoro reaction, and finally oxidizing methyl to generate 2-fluoro-3-nitrobenzoic acid under the action of an oxidant. The process has high yield and is suitable for large-scale production.
Description
Technical Field
The invention relates to synthesis of 2-fluoro-3-nitrobenzoic acid, in particular to a synthesis method of a 2-fluoro-3-nitrobenzoic acid intermediate raw material.
Background
The 2-fluoro-3-nitrobenzoic acid is light yellow solid, is slightly soluble in water, is a common intermediate raw material, and is widely applied to the synthesis of benzene sulfonamide thiazole medicaments, quinolone derivatives, active biological enzymes and other medicaments (ZL 201010264912.1; ZL 200910078771.1; WO 2009137391; ACS Med. chem. Lett.,2013,4, 1059-. At present, the synthesis process of 2-fluoro-3-nitrobenzoic acid is reported at home and abroad, and 2-fluorotoluene is mainly taken as a raw material (ZL 200610147128.6, Tetrahedron Letters,2006,47, 4933-. The method mainly adopts the following synthetic route (shown as I), 2-fluorotoluene is taken as a raw material and is directly nitrified under the condition of sulfuric acid/nitric acid to obtain 2-fluoro-3-nitrotoluene, then potassium permanganate or chromium trioxide is used for oxidation to obtain a target product, namely 2-fluoro-3-nitrobenzoic acid, and the total yield is about 15%. In the method, the dosage of the nitric acid is 1.15-1.75 equivalent of the raw material, and the dosage of the sulfuric acid is 40-60% of the nitric acid. The key point of the method is that in the first step of direct nitration, a plurality of nitration products can appear, which causes difficulty in intermediate separation, and in the whole reaction route, the yield of the target product is low, thus greatly increasing the cost of the intermediate raw material.
2-fluorotoluene is used as a raw material, is firstly oxidized into 2-fluorobenzoic acid, and then is subjected to nitration reaction, so that a mixture of 2-fluoro-3-nitrobenzoic acid and 2-fluoro-5-nitrobenzoic acid (shown as II) is obtained, and a target product is obtained by rectification under reduced pressure or recrystallization separation (Journal of Organic Chemistry,1990, 55, 3415-17; Synthetic Communications,2016,46,1619 and 1624; e-EROS Encyclopedia of Reagents for Organic Synthesis). The method has the advantages that only two products can be obtained during nitration, the separation operation is simpler, but the nitration reaction rate is reduced, and because fluorine atoms and nitro groups are passivating groups, the reaction conditions are more severe, and the industrial production is not facilitated.
Disclosure of Invention
Aiming at the technical problems, the invention provides a synthesis method of a 2-fluoro-3-nitrobenzoic acid intermediate raw material, which can reduce the raw material cost and improve the yield. The method starts from cheaper raw material o-methylphenol, prepares 2-methyl-nitrophenol by nitration of nitrate/p-toluenesulfonic acid, converts hydroxyl into chlorine atom by chlorination, converts the chlorine atom into fluorine atom under the action of cesium fluoride, and finally obtains the target product 2-fluoro-3-nitrobenzoic acid (shown as III) by oxidation. The total yield can be improved to more than 40 percent while the cost of raw materials is reduced. On the other hand, the whole reaction path avoids the use of strong acid, and each step of intermediate separation is simple and easy to operate.
The technical scheme of the invention is as follows:
a synthetic method of a 2-fluoro-3-nitrobenzoic acid intermediate raw material comprises the following steps:
(1) taking o-methylphenol as a raw material, and preparing 2-methyl-6-nitrophenol by nitration under the action of nitrate and p-toluenesulfonic acid;
(2) chloridizing the 2-methyl-6-nitrophenol obtained in the step (1) to obtain 2-chloro-3-nitrotoluene;
(3) under the action of cesium fluoride, 2-chloro-3-nitrotoluene reacts to obtain 2-fluoro-3-nitrotoluene;
(4) oxidizing the 2-fluoro-3-nitrotoluene to obtain a target product 2-fluoro-3-nitrobenzoic acid.
Further, in the step (1), the ratio of o-methylphenol: the molar ratio of the nitrate is 1: 1-1: 2, and the dosage of the p-toluenesulfonic acid is 1 mol% -3 mol%.
Further, in the step (1), the nitrate is Ni (NO)3)2、Co(NO3)2、Fe(NO3)3、Cu(NO3)2、Zn(NO3)2、Mn(NO3)2In the presence of an iso-transition metal nitrateEither one of them.
Further, in the step (1), the nitration is carried out under the reflux condition for 5-10 minutes.
Further, in the step (2), the chlorination reaction is carried out at C6H5POCl2And Cl2Or C6H5POCl2And PCl5Under the conditions of (1), wherein n (2-methyl-6-nitrophenol): n (C)6H5POCl2):n(Cl2) 1:0.3:3 to 1:1:10, n (2-methyl-6-nitrophenol): n (C)6H5POCl2):n(Cl2) The chlorination reaction is carried out at the temperature of 100-160 ℃ for 3-10 hours, wherein the ratio of the chlorination reaction to the chlorination reaction is 1:0.3: 3-1: 1: 5.
Further, in the step (3), the reaction temperature is 50-80 ℃, and the reaction time is 8-48 hours.
Further, in the step (4), the oxidation reaction is carried out in the presence of potassium permanganate or chromium trioxide, the temperature of the oxidation reaction is 80-100 ℃, and the time is 4-12 hours.
The invention has the beneficial effects that:
(1) the o-methyl phenol adopted by the invention is low in price, so that the raw material cost can be effectively reduced, the yield can be obviously improved, and the total yield can be up to more than 40%.
(2) The whole reaction path of the invention avoids the use of strong acid, is more environment-friendly, and the separation of the intermediate in each step is simple and easy to operate.
Detailed Description
The present invention will be described in further detail with reference to specific examples, but the present invention is not limited thereto.
Example 1
1.1 Synthesis of intermediate 2-methyl-6-nitrophenol
10.8g of o-methylphenol (100mmol) and 18.3g of Co (NO) were weighed out3)2(100mmol), 0.21g of TsOH (1.2 mol%) inA250 mL reaction flask was charged with 100mL acetone (. gtoreq.97% analytically pure) and refluxed for 8 minutes. After the reaction is finished, cooling to room temperature, and removing the acetone under reduced pressure; the product is washed by water to obtain 14.84g of light yellow crystals, the yield is 97%, and the chromatographic purity is more than or equal to 98%.1H NMR(400MHz,CDCl3)δ7.83(s,1H),7.28(s,1H),6.96(s,1H),5.0(s,1H),2.35(s,3H)。
1.2 Synthesis of intermediate 2-chloro-3-nitrotoluene
14.84g (97mmol) of 2-methyl-6-nitrophenol obtained in step 1, 6.44g C6H5POCl2(33mmol)，66.56g PCl5(320mmol) was added to a 250mL round bottom flask, slowly heated to 160 deg.C, stirred for 5 hours, followed by TLC until completion, and evaporated in vacuo to remove POCl3. The reaction solution was poured into an ice-water mixture and saturated Na was added2CO3The solution was neutralized and extracted with 50mL of a 3X ethyl acetate solution. The organic phase was washed 3 times with water and with anhydrous Na2SO4And (5) drying. Distilling under reduced pressure to remove ethyl acetate to obtain crude product, further recrystallizing and purifying to obtain 13.32g of product, wherein the yield is 80%, and the chromatographic purity is more than or equal to 99%.1H NMR(400MHz,CDCl3)δ7.94(s,1H),7.39(s,1H),7.28(s,1H),2.35(s,3H)。
1.3 Synthesis of intermediate 2-fluoro-3-nitrotoluene
Into a 250mL round-bottomed flask were successively added 13.32g of 2-chloro-3-nitrotoluene (77.6mmol) and 17.69g of CsF (116.4mmol), and 100mL of acetonitrile was added as a solvent to conduct a reaction at 80 ℃ for 16 hours. After the reaction is finished, carrying out suction filtration to remove insoluble substances; concentrating the filtrate under reduced pressure to remove the solvent; the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate 2: 1) to give 9.86g of a pale yellow liquid, yield 82%, and chromatographic purity ≥ 98%.1H NMR(400MHz,CDCl3)δ7.98(s,1H),7.43(s,1H),7.17(s,1H),2.35(s,3H)。
1.4 Synthesis of the target Compound 2-fluoro-3-nitrobenzoic acid
To a 250mL round bottom flask were added 9.86g of 2-fluoro-3-nitrotoluene (64.9mmol), 4.67g of KOH (64.9mmol), and 100mL of distilled water in that order, and the mixture was heated to boiling. Potassium permanganate (20.51g,129.8mmol) was added portionwise with stirring and the reaction was continued for 4 h. Filtering, acidifying the filtrate with concentrated hydrochloric acid until pH is 1-2, filtering, pouring the filtrate into an appropriate amount of ice water mixture, cooling to separate out crystals, filtering, and recrystallizing the solid with distilled water to obtain yellow crystals, namely 8.16g of 2-fluoro-3-nitrobenzoic acid, wherein the yield is 68% and the chromatographic purity is more than or equal to 99%.1H NMR(400MHz,CDCl3)δ11.0(s,1H),8.50(s,2H),7.50(s,1H)。
After four-step reaction, 8.16g of 2-fluoro-3-nitrobenzoic acid is obtained altogether, the theoretical yield is 15.52g, and the yield is 41%.
Example 2
1.1 Synthesis of intermediate 2-methyl-6-nitrophenol
10.8g of o-methylphenol (100mmol) and 18.3g of Ni (NO) were weighed out3)2(100mmol), 0.21g TsOH (1.2 mol%) in a 250mL reaction flask, 100mL acetone (analytically pure ≧ 97%) was added, and the reaction was refluxed for 5-10 minutes. After the reaction is finished, cooling to room temperature, and removing the acetone under reduced pressure; the product is washed by water to obtain 14.84g of light yellow crystals, the yield is 97%, and the chromatographic purity is more than or equal to 98%.
1.2 Synthesis of intermediate 2-chloro-3-nitrotoluene
14.84g (97mmol) of 2-methyl-6-nitrophenol obtained in step 1, 6.44g C6H5POCl2(33mmol)，66.56g PCl5(320mmol) was added to a 250mL round bottom flask, slowly heated to 160 deg.C, stirred for 5 hours, followed by TLC until completion, and evaporated in vacuo to remove POCl3. The reaction solution was poured into an ice-water mixture and saturated Na was added2CO3The solution was neutralized and extracted with 50mL of a 3X ethyl acetate solution. The organic phase was washed 3 times with water and with anhydrous Na2SO4And (5) drying. Distilling under reduced pressure to remove ethyl acetate to obtain crude product, further recrystallizing and purifying to obtain 13.32g of product, wherein the yield is 80%, and the chromatographic purity is more than or equal to 99%.
1.3 Synthesis of intermediate 2-fluoro-3-nitrotoluene
Into a 250mL round-bottomed flask were successively added 13.32g of 2-chloro-3-nitrotoluene (77.6mmol) and 17.69g of CsF (116.4mmol), and 100mL of acetonitrile was added as a solvent to conduct a reaction at 80 ℃ for 14 to 20 hours. After the reaction is finished, carrying out suction filtration to remove insoluble substances; concentrating the filtrate under reduced pressure to remove the solvent; the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate 2: 1) to give 9.86g of a pale yellow liquid, yield 82%, and chromatographic purity ≥ 98%.
1.4 Synthesis of the target Compound 2-fluoro-3-nitrobenzoic acid
To a 250mL round bottom flask were added 9.86g of 2-fluoro-3-nitrotoluene (64.9mmol), 4.67g of KOH (64.9mmol), and 100mL of distilled water in that order, and the mixture was heated to 80 ℃. Potassium permanganate (20.51g,129.8mmol) was added portionwise with stirring and the reaction was continued for 12 h. Filtering, acidifying the filtrate with concentrated hydrochloric acid until pH is 1-2, filtering, pouring the filtrate into an appropriate amount of ice water mixture, cooling to separate out crystals, filtering, and recrystallizing the solid with distilled water to obtain yellow crystals, namely 8.16g of 2-fluoro-3-nitrobenzoic acid, wherein the yield is 68% and the chromatographic purity is more than or equal to 99%.
After four-stage reaction, 8.16g of 2-fluoro-3-nitrobenzoic acid are obtained in total, the theoretical yield being 15.52g and the yield being 41%.
Example 3
1.1 Synthesis of intermediate 2-methyl-6-nitrophenol
10.8g of o-methylphenol (100mmol) and 24.2g of Fe (NO) were weighed out3)3(100mmol), 0.17g TsOH (1.0 mol%) in a 250mL reaction flask, 100mL acetone (analytically pure ≧ 97%) was added, and the reaction was refluxed for 5-10 minutes. After the reaction is finished, cooling to room temperature, and removing the acetone under reduced pressure; the product is washed with water to obtain 14.68g of light yellow crystals, the yield is 96%, and the chromatographic purity is more than or equal to 98%.
1.2 Synthesis of intermediate 2-chloro-3-nitrotoluene
14.68g (96mmol) of 2-methyl-6-nitrophenol obtained in step 1 and 8.95g C6H5PCl2(50mmol) was added to a 250mL round bottom flask and slowly heated to 160 ℃ with 34.08g Cl2(480mmol) through the reaction solution, stirring the reaction solution for 5 hours, tracking the reaction by TLC until the reaction is finished, and removing POCl by vacuum evaporation3. The reaction solution was poured into an ice-water mixture and saturated Na was added2CO3The solution was neutralized and extracted with 50mL of a 3X ethyl acetate solution. The organic phase was washed 3 times with water and with anhydrous Na2SO4And (5) drying. Distilling under reduced pressure to remove ethyl acetate to obtain crude product, further recrystallizing and purifying to obtain 13.95g of product, wherein the yield is 85%, and the chromatographic purity is more than or equal to 99%.
1.3 Synthesis of intermediate 2-fluoro-3-nitrotoluene
13.95g of 2-chloro-3-nitrotoluene (81.6mmol) and 14.88g of CsF (97.9mmol) were sequentially added to a 250mL round-bottomed flask, and 100mL of acetonitrile was added thereto to react at 50 ℃ for 24 to 48 hours. After the reaction is finished, carrying out suction filtration to remove insoluble substances; concentrating the filtrate under reduced pressure to remove the solvent; the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate: 2: 1) to obtain 10.12g of a pale yellow liquid, yield 80%, and chromatographic purity ≥ 98%.
1.4 Synthesis of the target Compound 2-fluoro-3-nitrobenzoic acid
To a 250mL round bottom flask were added 10.12g of 2-fluoro-3-nitrotoluene (65.2mmol), 4.67g of KOH (64.9mmol), and 100mL of distilled water in that order, and the mixture was heated to 100 ℃. Potassium permanganate (20.51g,129.8mmol) was added portionwise with stirring and the reaction was continued for 12 h. Filtering, acidifying the filtrate with concentrated hydrochloric acid until pH is 1-2, filtering, pouring the filtrate into an appropriate amount of ice water mixture, cooling to separate out crystals, filtering, and recrystallizing the solid with distilled water to obtain yellow crystal 2-fluoro-3-nitrobenzoic acid 8.44g, with yield 70% and chromatographic purity not less than 99%.
After four-stage reaction, 8.44g of 2-fluoro-3-nitrobenzoic acid are obtained in total, the theoretical yield being 15.52g and the yield being 43%.
Example 4
1.1 Synthesis of intermediate 2-methyl-6-nitrophenol
10.8g of o-methylphenol (100mmol) and 37.6g of Cu (NO) were weighed out3)2(200mmol), 0.51g TsOH (3.0 mol%) in a 250mL reaction flask, 100mL acetone (analytically pure ≧ 97%) was added, and the reaction was refluxed for 5-10 minutes. After the reaction is finished, cooling to room temperature, and removing the acetone under reduced pressure; simple water washing to obtain 14.99g of light yellow crystals with the yield of 98 percent,the chromatographic purity is more than or equal to 98 percent.
1.2 Synthesis of intermediate 2-chloro-3-nitrotoluene
14.99g (98mmol) of 2-methyl-6-nitrophenol obtained in step 1 and 17.54g C6H5PCl2(98mmol) was charged into a 250mL round-bottom flask, slowly heated to 160 ℃ and 69.58g of Cl2(980mmol) is added into the reaction solution, the reaction is stirred for 5 hours, the TLC tracking reaction is carried out until the reaction is finished, and POCl is removed by vacuum evaporation3. The reaction solution was poured into an ice-water mixture and saturated Na was added2CO3The solution was neutralized and extracted with 50mL of a 3X ethyl acetate solution. The organic phase was washed 3 times with water and with anhydrous Na2SO4And (5) drying. Distilling under reduced pressure to remove ethyl acetate to obtain crude product, further recrystallizing and purifying to obtain 13.57g of product, wherein the yield is 81%, and the chromatographic purity is more than or equal to 99%.
1.3 Synthesis of intermediate 2-fluoro-3-nitrotoluene
Into a 250mL round-bottomed flask were successively added 13.57g of 2-chloro-3-nitrotoluene (79.4mmol) and 14.88g of CsF (97.9mmol), and 100mL of acetonitrile was added to dissolve the mixture, followed by reaction at 80 ℃ for 12 hours. After the reaction is finished, carrying out suction filtration to remove insoluble substances; concentrating the filtrate under reduced pressure to remove the solvent; the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate ═ 2: 1) to give 10.09g of a pale yellow liquid, the yield was 82%, and the chromatographic purity was 98% or more.
1.4 Synthesis of the target Compound 2-fluoro-3-nitrobenzoic acid
To a 250mL round bottom flask were added 10.09g of 2-fluoro-3-nitrotoluene (65.11mmol), 4.67g of KOH (64.9mmol), and 100mL of distilled water in that order, and the mixture was heated to 100 ℃. While stirring, chromium trioxide (13.0g,130mmol) was added in portions and the reaction was continued with stirring for 12 h. Filtering, acidifying the filtrate with concentrated hydrochloric acid until pH is 1-2, filtering, pouring the filtrate into an appropriate amount of ice water mixture, cooling to separate out crystals, filtering, and recrystallizing the solid with distilled water to obtain yellow crystal 2-fluoro-3-nitrobenzoic acid 9.03g, with yield of 75% and chromatographic purity of 99% or more.
After four-stage reaction, 9.03g of 2-fluoro-3-nitrobenzoic acid are obtained in total, the theoretical yield being 15.52g and the yield being 46%.
Example 5
1.1 Synthesis of intermediate 2-methyl-6-nitrophenol
10.8g of o-methylphenol (100mmol) and 18.9g of Zn (NO) were weighed3)2(100mmol), 0.21g TsOH (1.2 mol%) in a 250mL reaction flask, 100mL acetone (analytically pure,. gtoreq.97%) was added, and the reaction was refluxed for 8 minutes. After the reaction is finished, cooling to room temperature, and removing the acetone under reduced pressure; the product is washed by water to obtain 14.84g of light yellow crystals, the yield is 97%, and the chromatographic purity is more than or equal to 98%.
1.2 Synthesis of intermediate 2-chloro-3-nitrotoluene
14.84g (97mmol) of 2-methyl-6-nitrophenol obtained in step 1, 6.44g C6H5POCl2(33mmol)，100.88g PCl5(485mmol) was added to a 250mL round bottom flask, slowly heated to 160 deg.C, stirred for 5 hours, followed by TLC until completion, and evaporated in vacuo to remove POCl3. The reaction solution was poured into an ice-water mixture and saturated Na was added2CO3The solution was neutralized and extracted with 50mL of a 3X ethyl acetate solution. The organic phase was washed 3 times with water and with anhydrous Na2SO4And (5) drying. Distilling under reduced pressure to remove ethyl acetate to obtain crude product14.10g of product is obtained by one-step recrystallization and purification, the yield is 85 percent, and the chromatographic purity is more than or equal to 99 percent.
1.3 Synthesis of intermediate 2-fluoro-3-nitrotoluene
To a 250mL round-bottomed flask were added 14.10g of 2-chloro-3-nitrotoluene (82.5mmol) and 17.69g of CsF (116.4mmol) in this order, and 100mL of acetonitrile was added as a solvent, followed by reaction at 80 ℃ for 24 hours. After the reaction is finished, carrying out suction filtration to remove insoluble substances; concentrating the filtrate under reduced pressure to remove the solvent; the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate 2: 1) to give 13.02g of a pale yellow liquid, yield 84%, and chromatographic purity ≥ 98%.
1.4 Synthesis of the target Compound 2-fluoro-3-nitrobenzoic acid
Into a 250mL round bottom flask were added 13.02g of 2-fluoro-3-nitrotoluene (69.3mmol), 4.67g of KOH (64.9mmol), and 100mL of distilled water in that order, and heated to boiling. Potassium permanganate (20.51g,129.8mmol) was added portionwise with stirring and the reaction was continued for 4 h. Filtering, acidifying the filtrate with concentrated hydrochloric acid until pH is 1-2, filtering, pouring the filtrate into an appropriate amount of ice water mixture, cooling to separate out crystals, filtering, and recrystallizing the solid with distilled water to obtain yellow crystal 2-fluoro-3-nitrobenzoic acid 8.97g, with yield of 70% and chromatographic purity of 99% or more.
After four-step reaction, 8.97g of 2-fluoro-3-nitrobenzoic acid is obtained altogether, the theoretical yield is 15.52g, and the yield is 45%.
Claims (7)
1. A synthetic method of a 2-fluoro-3-nitrobenzoic acid intermediate raw material is characterized by comprising the following steps:
(1) taking o-methylphenol as a raw material, and preparing 2-methyl-6-nitrophenol by nitration under the action of nitrate and p-toluenesulfonic acid;
(2) chloridizing the 2-methyl-6-nitrophenol obtained in the step (1) to obtain 2-chloro-3-nitrotoluene;
(3) under the action of cesium fluoride, 2-chloro-3-nitrotoluene reacts to obtain 2-fluoro-3-nitrotoluene;
(4) oxidizing the 2-fluoro-3-nitrotoluene to obtain a target product 2-fluoro-3-nitrobenzoic acid.
2. The synthesis method according to claim 1, wherein in step (1), the ratio of o-methylphenol: the molar ratio of the nitrate is 1: 1-1: 2, and the dosage of the p-toluenesulfonic acid is 1 mol% -3 mol%.
3. The synthesis method according to claim 1, wherein in the step (1), the nitrate is Ni (NO)3)2、Co(NO3)2、Fe(NO3)3、Cu(NO3)2、Zn(NO3)2、Mn(NO3)2And the like.
4. The synthesis method according to claim 1, wherein in the step (1), the nitration is carried out under reflux conditions for 5 to 10 minutes.
5. The synthesis method according to claim 1, wherein in the step (2), the chlorination reaction is carried out at C6H5POCl2And Cl2Or C6H5POCl2And PCl5Under the conditions of (1), wherein n (2-methyl-6-nitrophenol): n (C)6H5POCl2):n(Cl2) 1:0.3:3 to 1:1:10, n (2-methyl-6-nitrophenol): n (C)6H5POCl2):n(Cl2) The chlorination reaction is carried out at the temperature of 100-160 ℃ for 3-10 hours, wherein the ratio of the chlorination reaction to the chlorination reaction is 1:0.3: 3-1: 1: 5.
6. The synthesis method according to claim 1, wherein in the step (3), the reaction temperature is 50-80 ℃ and the reaction time is 8-48 hours.
7. The synthesis method according to claim 1, wherein in the step (4), the oxidation reaction is carried out in the presence of potassium permanganate or chromium trioxide, and the temperature of the oxidation reaction is 80-100 ℃ and the time is 4-12 hours.
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| CN113717053A (en) * | 2021-09-02 | 2021-11-30 | 合肥利夫生物科技有限公司 | Synthesis method of key intermediate of tyrosine kinase inhibitor |
| CN115322102A (en) * | 2022-08-30 | 2022-11-11 | 老河口华辰化学有限公司 | Synthetic method for producing 2-fluoro-3-nitrobenzoic acid from 2-chloro-3-nitrotoluene |
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