CN110790690A - A kind of synthetic method of 3,4-difluoro-2-((phenylthio)methyl)benzoic acid - Google Patents

A kind of synthetic method of 3,4-difluoro-2-((phenylthio)methyl)benzoic acid Download PDF

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CN110790690A
CN110790690A CN201911123930.5A CN201911123930A CN110790690A CN 110790690 A CN110790690 A CN 110790690A CN 201911123930 A CN201911123930 A CN 201911123930A CN 110790690 A CN110790690 A CN 110790690A
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郑子建
田晒校
徐广宇
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Hunan Normal University
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Abstract

本发明公开了一种巴洛沙韦关键中间体即3,4‑二氟‑2‑((苯硫基)甲基)苯甲酸的制备方法。本发明以3,4‑二氟‑2‑甲基苯甲酸为原料与偶氮二异丁腈(AIBN)和N‑溴代琥珀酰亚胺(NBS)在四氯化碳溶液中回流反应得到2‑溴甲基‑3,4‑二氟苯甲酸,然后与苯硫酚钠或者与二苯二硫醚反应得到3,4‑二氟‑2‑((苯硫基)甲基)苯甲酸。该方法合成只需两步就能得到目标产物,原料易得,后处理简便,产率高。The invention discloses a preparation method of 3,4-difluoro-2-((phenylthio)methyl)benzoic acid, a key intermediate of baloxavir. In the present invention, 3,4-difluoro-2-methylbenzoic acid is used as raw material to react with azobisisobutyronitrile (AIBN) and N-bromosuccinimide (NBS) in carbon tetrachloride solution to obtain 2-bromomethyl-3,4-difluorobenzoic acid, then react with sodium thiophenate or diphenyl disulfide to obtain 3,4-difluoro-2-((phenylthio)methyl)benzoic acid . The synthesis method of the method can obtain the target product in only two steps, the raw materials are readily available, the post-processing is simple and the yield is high.

Description

一种3,4-二氟-2-((苯硫基)甲基)苯甲酸的合成方法A kind of synthetic method of 3,4-difluoro-2-((phenylthio)methyl)benzoic acid

技术领域technical field

本发明涉及3,4-二氟-2-((苯硫基)甲基)苯甲酸的合成方法。The present invention relates to a synthesis method of 3,4-difluoro-2-((phenylthio)methyl)benzoic acid.

背景技术Background technique

流行性感冒是呼吸道受流感病毒急性感染后所致的一种疾病,其症状包括发烧、精神萎靡、流涕等。抗病毒药可用于季节性流感的预防和治疗,目前有包括M2(金刚胺与金刚乙胺)和神经氨酸酶抑制剂(奥司他韦与扎那米韦)等药物用于流感的化学预防,有效率为70-90%。巴洛沙韦(Baloxavir marboxil)是一款创新的Cap依赖型核酸内切酶抑制剂,也是世上少数可以抑制流感病毒增殖的新药。对比通常的感冒药,这项疗法的优势在于生效快,疗效持续时间长,用药量少。Influenza is a disease caused by acute infection of the respiratory tract by influenza virus, and its symptoms include fever, lethargy, and runny nose. Antiviral drugs can be used for the prevention and treatment of seasonal influenza, and currently there are drugs including M2 (amantadine and rimantadine) and neuraminidase inhibitors (oseltamivir and zanamivir) for influenza chemistries Prevention, the effective rate is 70-90%. Baloxavir marboxil is an innovative Cap-dependent endonuclease inhibitor and one of the few new drugs in the world that can inhibit the proliferation of influenza virus. Compared with the usual cold medicine, the advantage of this therapy is that it takes effect quickly, the effect lasts for a long time, and the dosage is small.

目前关于巴洛沙韦关键中间体3,4-二氟-2-((苯硫基)甲基)苯甲酸的相关报道只有两条,其中WO2017221869公开了一种合成方法:At present, there are only two relevant reports on baloxavir key intermediate 3,4-difluoro-2-((phenylthio)methyl)benzoic acid, wherein WO2017221869 discloses a synthetic method:

Figure 437329DEST_PATH_IMAGE001
Figure 437329DEST_PATH_IMAGE001

此方法第一步用到正丁基锂(n-BuLi),试剂易燃,操作需非常小心,且反应需在-40℃下进行。该路线实际操作中因区域选择性问题导致产品纯化麻烦。The first step of this method uses n-butyllithium (n-BuLi), the reagent is flammable, the operation needs to be very careful, and the reaction needs to be carried out at -40 °C. In the actual operation of this route, product purification is troublesome due to the problem of regioselectivity.

CN109721585公开了该中间体的另一种合成方法:CN109721585 discloses another synthetic method of this intermediate:

Figure 823310DEST_PATH_IMAGE002
Figure 823310DEST_PATH_IMAGE002

此路线第一步需要使用溴化氢,第三步需要惰性气体保护并在-35℃反应。该路线相较于专利WO2017221869的方法,操作简便,但需三步反应才能合成得到,且原料2,3-二氟-6-溴苯甲醇不易商业化获得。The first step of this route requires the use of hydrogen bromide, and the third step requires the protection of inert gas and the reaction at -35 °C. Compared with the method of patent WO2017221869, this route is easy to operate, but requires three-step reaction to be synthesized, and the raw material 2,3-difluoro-6-bromobenzyl alcohol is not easily obtained commercially.

鉴于近年来流感发病率逐年提升,流感病毒抗药性不断增强,抗流感药物也越来越受到科学家的关注,因此实现一条更安全、便捷、高效、低成本的合成3,4-二氟-2-((苯硫基)甲基)苯甲酸的路线是十分必要的。In view of the increasing incidence of influenza in recent years, the increasing resistance of influenza viruses, and the increasing attention of scientists on anti-influenza drugs, a safer, more convenient, efficient and low-cost synthetic 3,4-difluoro-2 The route of -((phenylthio)methyl)benzoic acid is quite necessary.

发明内容SUMMARY OF THE INVENTION

针对现有技术存在的上述问题,我们设计了一条原料便宜易得,步骤简便,收率高的反应路线。该路线只需要两步反应就能得到产物,反应路线不涉及低温、惰性气体保护等不便要求,后处理简便,产率高,且原料3,4-二氟-2-甲基苯甲酸是合成ATP竞争性的mTOR选择性抑制剂XL388的重要中间体,它亦可由3,4-二氟甲苯通过一步反应方便制得。In view of the above problems existing in the prior art, we have designed a reaction route with cheap and easily available raw materials, simple steps and high yield. This route only needs two-step reaction to obtain the product, the reaction route does not involve inconvenient requirements such as low temperature and inert gas protection, the post-processing is simple and the yield is high, and the raw material 3,4-difluoro-2-methylbenzoic acid is synthesized An important intermediate of XL388, an ATP-competitive mTOR-selective inhibitor, which can also be easily prepared by one-step reaction from 3,4-difluorotoluene.

具体操作步骤如下:The specific operation steps are as follows:

步骤1:将3,4-二氟-2-甲基苯甲酸、偶氮二异丁腈和N-溴代琥珀酰亚胺在室温下加入到四氯化碳溶液中,开启搅拌,升温回流(60-80℃),反应2-12h后,停止反应,减压除去溶剂,将残余物加入乙酸乙酯和水,分液,乙酸乙酯用水洗数次,饱和食盐水洗涤,无水硫酸钠干燥,减压除去溶剂,得到2-溴甲基-3,4-二氟苯甲酸。Step 1: Add 3,4-difluoro-2-methylbenzoic acid, azobisisobutyronitrile and N-bromosuccinimide to the carbon tetrachloride solution at room temperature, turn on stirring, heat up and reflux (60-80°C), after 2-12 hours of reaction, the reaction was stopped, the solvent was removed under reduced pressure, the residue was added with ethyl acetate and water, and the layers were separated. Dry over sodium and remove the solvent under reduced pressure to give 2-bromomethyl-3,4-difluorobenzoic acid.

步骤2:方法一:将2-溴甲基-3,4-二氟苯甲酸与苯硫酚钠在室温下混合,加入有机溶液A,室温搅拌2-6h后停止反应,加入有机溶剂B和水,有机溶剂B用水洗涤数次,饱和食盐水洗涤,无水硫酸钠干燥,加入少量活性炭室温搅拌10min,过滤,滤液减压抽除溶剂,得到3,4-二氟-2-((苯硫基)甲基)苯甲酸。方法二:将二苯二硫醚加入双口瓶中,充氮气,加入还原剂C和溶剂D或者加入还原剂C、碱和溶剂D,升温至30-80℃回反应10-30min,再加入2-溴甲基-3,4-二氟苯甲酸,继续反应2-6h,TLC跟踪反应完毕后,反应液加入有机溶剂E和氢氧化钠溶液萃取,将氢氧化钠溶液用盐酸溶液和乙酸乙酯萃取,干燥减压抽除有机溶剂,得到3,4-二氟-2-((苯硫基)甲基)苯甲酸。Step 2: Method 1: Mix 2-bromomethyl-3,4-difluorobenzoic acid and sodium thiophenate at room temperature, add organic solution A, stir at room temperature for 2-6 hours, and stop the reaction, add organic solvent B and Water, organic solvent B was washed several times with water, washed with saturated brine, dried over anhydrous sodium sulfate, added with a small amount of activated carbon and stirred at room temperature for 10 min, filtered, and the filtrate was vacuumed to remove the solvent to obtain 3,4-difluoro-2-((benzene thio)methyl)benzoic acid. Method 2: Add diphenyl disulfide into a double-necked bottle, fill with nitrogen, add reducing agent C and solvent D or add reducing agent C, alkali and solvent D, heat up to 30-80 ° C and react for 10-30 min, then add 2-Bromomethyl-3,4-difluorobenzoic acid, continue to react for 2-6h, after the completion of TLC tracking reaction, the reaction solution is added with organic solvent E and sodium hydroxide solution for extraction, and the sodium hydroxide solution is extracted with hydrochloric acid solution and acetic acid Ethyl ester extraction, drying and vacuum extraction to remove the organic solvent to obtain 3,4-difluoro-2-((phenylthio)methyl)benzoic acid.

具体实施方式:Detailed ways:

下面结合具体实施例对本发明作进一步说明,但本发明的保护范围并不限于此。The present invention will be further described below with reference to specific embodiments, but the protection scope of the present invention is not limited thereto.

实施例1:2-溴甲基-3,4-二氟苯甲酸的制备Example 1: Preparation of 2-bromomethyl-3,4-difluorobenzoic acid

在25ml单口烧瓶中加入3,4-二氟-2-甲基苯甲酸(0.500g,2.905mmol)、N-溴代琥珀酰亚胺(0.517g,2.905mmol)、偶氮二异丁腈(0.050g,0.304mmol)、四氯化碳10ml,80℃回流反应2h,TLC跟踪至反应完毕。冷却反应液,减压抽除溶剂得到白色固体,固体溶于30ml乙酸乙酯,水洗(20mlx2),饱和食盐水20ml洗涤,无水硫酸钠干燥,减压抽除乙酸乙酯,得到2-溴甲基-3,4-二氟苯甲酸0.711g,收率为97.5%。3,4-Difluoro-2-methylbenzoic acid (0.500g, 2.905mmol), N-bromosuccinimide (0.517g, 2.905mmol), azobisisobutyronitrile ( 0.050 g, 0.304 mmol), 10 ml of carbon tetrachloride, refluxed at 80°C for 2 h, followed by TLC until the completion of the reaction. The reaction solution was cooled, and the solvent was removed under reduced pressure to obtain a white solid. The solid was dissolved in 30 ml of ethyl acetate, washed with water (20 ml×2), washed with 20 ml of saturated brine, dried over anhydrous sodium sulfate, and the ethyl acetate was removed under reduced pressure to obtain 2-bromo Methyl-3,4-difluorobenzoic acid 0.711 g, yield 97.5%.

实施例2:2-溴甲基-3,4-二氟苯甲酸的制备Example 2: Preparation of 2-bromomethyl-3,4-difluorobenzoic acid

在25ml单口烧瓶中加入3,4-二氟-2-甲基苯甲酸(0.500g,2.905mmol)、N-溴代琥珀酰亚胺(0.550g,3.090mmol)、偶氮二异丁腈(0.050g,0.304mmol)、四氯化碳10ml,70℃回流反应5h,TLC跟踪至反应完毕,冷却反应液,减压抽除溶剂得白色固体,固体溶于30ml乙酸乙酯,水洗涤(20mlx2),饱和食盐水20ml洗涤,无水硫酸钠干燥,减压抽除乙酸乙酯,得到2-溴甲基-3,4-二氟苯甲酸0.707g,收率为97.0%。3,4-Difluoro-2-methylbenzoic acid (0.500g, 2.905mmol), N-bromosuccinimide (0.550g, 3.090mmol), azobisisobutyronitrile ( 0.050g, 0.304mmol), 10ml of carbon tetrachloride, refluxed at 70°C for 5h, followed by TLC until the reaction was completed, cooled the reaction solution, and removed the solvent under reduced pressure to obtain a white solid. The solid was dissolved in 30ml of ethyl acetate and washed with water (20ml×2 ), washed with 20 ml of saturated brine, dried over anhydrous sodium sulfate, and removed ethyl acetate under reduced pressure to obtain 0.707 g of 2-bromomethyl-3,4-difluorobenzoic acid with a yield of 97.0%.

实施例3:3,4-二氟-2-((苯硫基)甲基)苯甲酸的制备Example 3: Preparation of 3,4-difluoro-2-((phenylthio)methyl)benzoic acid

在25ml单口烧瓶中加入2-溴甲基-3,4-二氟苯甲酸(0.200g,0.797mmol)、苯硫酚钠(0.110g,0.832mmol)、乙酸乙酯6ml,室温下搅拌4h,加入乙酸乙酯25ml,水洗(20mlx2),饱和食盐水洗(20ml),加入10mg活性炭,常温搅拌10min后过滤,滤液加入无水硫酸钠干燥,减压抽除溶剂,得到3,4-二氟-2-((苯硫基)甲基)苯甲酸176mg,收率为78.8%。2-Bromomethyl-3,4-difluorobenzoic acid (0.200g, 0.797mmol), sodium thiophenate (0.110g, 0.832mmol) and 6ml of ethyl acetate were added to a 25ml one-necked flask, and stirred at room temperature for 4h, 25ml of ethyl acetate was added, washed with water (20mlx2), washed with saturated brine (20ml), added with 10mg of activated carbon, stirred at room temperature for 10min, filtered, the filtrate was dried by adding anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 3,4-difluoro- 2-((phenylthio)methyl)benzoic acid 176 mg, yield 78.8%.

实施例4:3,4-二氟-2-((苯硫基)甲基)苯甲酸的制备Example 4: Preparation of 3,4-difluoro-2-((phenylthio)methyl)benzoic acid

在25ml单口烧瓶中加入2-溴甲基-3,4-二氟苯甲酸(0.200g,0.797mmol)、苯硫酚钠(0.106g,0.802mmol)、丙酮6ml,室温下搅拌4h,加入乙酸乙酯25ml,水洗(20mlx2),饱和食盐水洗(20ml),加入10mg活性炭,常温搅拌10min后过滤,滤液加入无水硫酸钠干燥,减压抽除溶剂,得到3,4二氟-2-((苯硫基)甲基)苯甲酸183mg,收率为81.9%,本发明采用核磁共振法对3,4-二氟-2-((苯硫基)甲基)苯甲酸进行表征,见说明书附图1。HPLC纯度为99.35%,其液相图见附图2。2-Bromomethyl-3,4-difluorobenzoic acid (0.200g, 0.797mmol), sodium thiophenate (0.106g, 0.802mmol) and 6ml of acetone were added to a 25ml single-necked flask, stirred at room temperature for 4h, and acetic acid was added 25ml of ethyl ester, washed with water (20mlx2), washed with saturated brine (20ml), added 10mg of activated carbon, stirred at room temperature for 10min and filtered, the filtrate was dried by adding anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 3,4-difluoro-2-( (Phenylthio)methyl)benzoic acid 183mg, the yield is 81.9%, the present invention adopts nuclear magnetic resonance method to characterize 3,4-difluoro-2-((phenylthio)methyl)benzoic acid, see description Figure 1. The HPLC purity is 99.35%, and its liquid phase diagram is shown in accompanying drawing 2.

实施例5:3,4-二氟-2-((苯硫基)甲基)苯甲酸的制备Example 5: Preparation of 3,4-difluoro-2-((phenylthio)methyl)benzoic acid

在25ml双口瓶中加入二苯二硫醚0.348g(1.59mmol)和硼氢化钠0.110g(2.91mmol),室温置换氮气三次,加入乙醇10ml,升温至70℃回流反应30min后,加入2-溴甲基-3,4-二氟苯甲酸0.760g(3.03mmol),反应四小时,冷却至室温,反应液中加入1mol/L氢氧化钠溶液(30ml)和乙酸乙酯(50ml),分液,再用1mol/L氢氧化钠溶液洗涤有机相(30mlx2次),合并碱液,用12mol/L浓盐酸溶液(约7ml)调节pH至3-4,乙酸乙酯萃取(25mlx3次),合并乙酸乙酯,无水硫酸钠干燥,减压除去溶剂,得到3,4-二氟-2-((苯硫基)甲基)苯甲酸0.647g,收率76.2%。Add 0.348g (1.59mmol) of diphenyl disulfide and 0.110g (2.91mmol) of sodium borohydride to a 25ml double-necked bottle, replace nitrogen three times at room temperature, add 10ml of ethanol, warm up to 70°C and reflux for 30min, add 2- 0.760g (3.03mmol) of bromomethyl-3,4-difluorobenzoic acid was reacted for four hours, cooled to room temperature, 1mol/L sodium hydroxide solution (30ml) and ethyl acetate (50ml) were added to the reaction solution, and the mixture was separated Then, wash the organic phase with 1mol/L sodium hydroxide solution (30ml×2 times), combine the lye, adjust the pH to 3-4 with 12mol/L concentrated hydrochloric acid solution (about 7ml), extract with ethyl acetate (25ml×3 times), The ethyl acetate was combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 0.647 g of 3,4-difluoro-2-((phenylthio)methyl)benzoic acid with a yield of 76.2%.

实施例6:3,4-二氟-2-((苯硫基)甲基)苯甲酸的制备Example 6: Preparation of 3,4-difluoro-2-((phenylthio)methyl)benzoic acid

在25ml双口瓶中加入二苯二硫醚0.870g(3.98mmol),室温置换氮气三次,加入8ml四氢呋喃,硼氢化钠0.275g(7.27mmol)、氢氧化钠0.916g和水10ml,升温至70℃回流反应5min后,加入2-溴甲基-3,4-二氟苯甲酸2.00g(7.97mmol),反应四小后,反应液中加入1mol/L氢氧化钠溶液(30ml)和乙酸乙酯(50ml),分液,再用1mol/L氢氧化钠溶液洗涤有机相(30mlx2次),合并碱液,用12mol/L浓盐酸溶液(约7ml)调节pH至3-4,乙酸乙酯萃取(25mlx3次),合并乙酸乙酯,无水硫酸钠干燥,减压除去溶剂,得到3,4-二氟-2-((苯硫基)甲基)苯甲酸2.149g,收率96.2%。Add 0.870g (3.98mmol) of diphenyl disulfide to a 25ml two-necked bottle, replace nitrogen three times at room temperature, add 8ml of tetrahydrofuran, 0.275g (7.27mmol) of sodium borohydride, 0.916g of sodium hydroxide and 10ml of water, heat up to 70 After 5 minutes of reflux reaction at ℃, 2.00 g (7.97 mmol) of 2-bromomethyl-3,4-difluorobenzoic acid was added. After 4 hours of reaction, 1 mol/L sodium hydroxide solution (30 ml) and ethyl acetate were added to the reaction solution. Ester (50ml), separated, then washed the organic phase with 1mol/L sodium hydroxide solution (30ml×2 times), combined the lye, adjusted pH to 3-4 with 12mol/L concentrated hydrochloric acid solution (about 7ml), ethyl acetate Extraction (25ml×3 times), combined ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 2.149g of 3,4-difluoro-2-((phenylthio)methyl)benzoic acid, yield 96.2% .

附图说明:图1是 3,4-二氟-2-((苯硫基)甲基)苯甲酸核磁氢谱Description of the drawings: Figure 1 is a hydrogen NMR spectrum of 3,4-difluoro-2-((phenylthio)methyl)benzoic acid

图2是3,4-二氟-2-((苯硫基)甲基)苯甲酸高效液相图。Figure 2 is a high performance liquid phase diagram of 3,4-difluoro-2-((phenylthio)methyl)benzoic acid.

Claims (10)

1.一种3,4-二氟-2-((苯硫基)甲基)苯甲酸的合成方法,合成路线为:1. a synthetic method of 3,4-difluoro-2-((phenylthio) methyl) benzoic acid, synthetic route is:
Figure 230389DEST_PATH_IMAGE001
Figure 230389DEST_PATH_IMAGE001
具体操作如下:The specific operations are as follows: 步骤1:将3,4-二氟-2-甲基苯甲酸、偶氮二异丁腈和N-溴代琥珀酰亚胺在室温下加入到四氯化碳溶液中,开启搅拌,升温回流(60-80℃),反应2-12h后,停止反应,减压除去溶剂,将残余物中加入乙酸乙酯和水,分液,乙酸乙酯层用水洗数次,饱和食盐水洗涤,无水硫酸钠干燥,减压除去溶剂,得到2-溴甲基-3,4-二氟苯甲酸;Step 1: Add 3,4-difluoro-2-methylbenzoic acid, azobisisobutyronitrile and N-bromosuccinimide to the carbon tetrachloride solution at room temperature, turn on stirring, heat up and reflux (60-80 ℃), after the reaction for 2-12 h, the reaction was stopped, the solvent was removed under reduced pressure, ethyl acetate and water were added to the residue, and the layers were separated. Dry over sodium sulfate, and remove the solvent under reduced pressure to obtain 2-bromomethyl-3,4-difluorobenzoic acid; 步骤2:方法一:将2-溴甲基-3,4-二氟苯甲酸与苯硫酚钠在室温下混合,加入有机溶剂A,室温搅拌2-6h后停止反应,加入有机溶剂B和水,分液,有机层用水洗涤数次,饱和食盐水洗涤,无水硫酸钠干燥,加入少量活性炭室温搅拌10min,过滤,滤液减压抽除溶剂,得到3,4-二氟-2-((苯硫基)甲基)苯甲酸;Step 2: Method 1: Mix 2-bromomethyl-3,4-difluorobenzoic acid and sodium thiophenate at room temperature, add organic solvent A, stir at room temperature for 2-6 h, stop the reaction, add organic solvent B and Water, separated, the organic layer was washed several times with water, washed with saturated brine, dried over anhydrous sodium sulfate, added with a small amount of activated carbon and stirred at room temperature for 10 min, filtered, and the filtrate was vacuumed to remove the solvent to obtain 3,4-difluoro-2-( (phenylthio)methyl)benzoic acid; 方法二:将二苯二硫醚加入双口瓶中,氮气保护下,加入还原剂C和溶剂D或者加入还原剂C、碱和溶剂D,升温至30-80℃反应10-30min,再加入2-溴甲基-3,4-二氟苯甲酸,继续反应2-6h,TLC跟踪反应完毕后,反应液加入有机溶剂E和氢氧化钠溶液萃取分液,水相用盐酸中和后用乙酸乙酯萃取,干燥后减压抽除有机溶剂,得到3,4-二氟-2-((苯硫基)甲基)苯甲酸。Method 2: Add diphenyl disulfide into a double-necked bottle, under nitrogen protection, add reducing agent C and solvent D or add reducing agent C, alkali and solvent D, heat up to 30-80 ℃ and react for 10-30min, then add 2-Bromomethyl-3,4-difluorobenzoic acid, continue to react for 2-6h, after the completion of TLC tracking reaction, organic solvent E and sodium hydroxide solution are added to the reaction solution for extraction and separation, and the aqueous phase is neutralized with hydrochloric acid and then used After extraction with ethyl acetate, after drying, the organic solvent was removed under reduced pressure to obtain 3,4-difluoro-2-((phenylthio)methyl)benzoic acid.
2.根据权利要求1所述的一种3,4-二氟-2-((苯硫基)甲基)苯甲酸的合成方法,其特征在于,在步骤(1)中,回流温度在60-80℃之间,回流时间在2-12h之间。2. the synthetic method of a kind of 3,4-difluoro-2-((phenylthio) methyl) benzoic acid according to claim 1, is characterized in that, in step (1), reflux temperature is at 60 ℃ Between -80℃, the reflux time is between 2-12h. 3.根据权利要求1所述的一种3,4-二氟-2-((苯硫基)甲基)苯甲酸的合成方法,其特征在于,在步骤(1)中,3,4-二氟-2-甲基苯甲酸、N-溴代琥珀酰亚胺和偶氮二异丁腈物质的量之比为1:1:0.05-0.2。3. the synthetic method of a kind of 3,4-difluoro-2-((phenylthio) methyl) benzoic acid according to claim 1, is characterized in that, in step (1), 3,4- The ratio of the amounts of difluoro-2-methylbenzoic acid, N-bromosuccinimide and azobisisobutyronitrile species was 1:1:0.05-0.2. 4.根据权利要求1所述的一种3,4-二氟-2-((苯硫基)甲基)苯甲酸的合成方法,其特征在于,在步骤(2)中,所述有机溶剂A为丙酮、乙酸乙酯、二氯甲烷等有机溶剂。4. the synthetic method of a kind of 3,4-difluoro-2-((phenylthio) methyl) benzoic acid according to claim 1, is characterized in that, in step (2), described organic solvent A is an organic solvent such as acetone, ethyl acetate, and dichloromethane. 5.根据权利要求1所述的一种3,4-二氟-2-((苯硫基)甲基)苯甲酸的合成方法,其特征在于,在步骤(2)中,所述有机溶剂B可为乙酸乙酯、甲苯、二氯甲烷等。5. the synthetic method of a kind of 3,4-difluoro-2-((phenylthio) methyl) benzoic acid according to claim 1, is characterized in that, in step (2), described organic solvent B can be ethyl acetate, toluene, dichloromethane and the like. 6.根据权利要求1所述的一种3,4-二氟-2-((苯硫基)甲基)苯甲酸的合成方法,其特征在于,在步骤(2)中,2-溴甲基-3,4-二氟苯甲酸与苯硫酚钠的物质的量之比为1:1-1.5。6. the synthetic method of a kind of 3,4-difluoro-2-((phenylthio) methyl) benzoic acid according to claim 1, is characterized in that, in step (2), 2-bromomethyl The substance amount ratio of base-3,4-difluorobenzoic acid to sodium thiophenolate is 1:1-1.5. 7.根据权利要求1所述的一种3,4-二氟-2-((苯硫基)甲基)苯甲酸的合成方法,其特征在于,在步骤(2)中,2-溴甲基-3,4-二氟苯甲酸与苯硫酚钠的反应时间为2-6h。7. the synthetic method of a kind of 3,4-difluoro-2-((phenylthio) methyl) benzoic acid according to claim 1, is characterized in that, in step (2), 2-bromomethyl The reaction time of base-3,4-difluorobenzoic acid and sodium thiophenolate is 2-6h. 8.根据权利要求1所述的一种3,4-二氟-2-((苯硫基)甲基)苯甲酸的合成方法,其特征在于,在步骤(2)中,所用还原剂C为硼氢化钠;溶剂D可为乙醇、四氢呋喃、甲苯、1,4-二氧六环、N,N-二甲基甲酰胺、乙腈、水的一种或两种以上混合物;碱为氢氧化钠、氢氧化锂、氢氧化钾中的一种或两种以上混合物。8. the synthetic method of a kind of 3,4-difluoro-2-((phenylthio) methyl) benzoic acid according to claim 1, is characterized in that, in step (2), used reducing agent C It is sodium borohydride; solvent D can be one or more mixtures of ethanol, tetrahydrofuran, toluene, 1,4-dioxane, N,N-dimethylformamide, acetonitrile, and water; the base is hydroxide One or more mixtures of sodium, lithium hydroxide and potassium hydroxide. 9.根据权利要求1所述的一种3,4-二氟-2-((苯硫基)甲基)苯甲酸的合成方法,其特征在于,在步骤(2)中,2-溴甲基-3,4-二氟苯甲酸与二苯二硫醚物质的量之比为1:0.4-0.6;二苯二硫醚与碱、还原剂的物质的量之比为1:0.5-2:0.5-2。9. the synthetic method of a kind of 3,4-difluoro-2-((phenylthio) methyl) benzoic acid according to claim 1, is characterized in that, in step (2), 2-bromomethyl The ratio of the amount of base-3,4-difluorobenzoic acid to diphenyl disulfide is 1:0.4-0.6; the ratio of diphenyl disulfide to alkali and reducing agent is 1:0.5-2 : 0.5-2. 10.根据权利要求1所述的一种3,4-二氟-2-((苯硫基)甲基)苯甲酸的合成方法,其特征在于,在步骤(2)中,2-溴甲基-3,4-二氟苯甲酸与二苯二硫醚的反应可因还原剂的不同而不加入碱,如还原剂为硼氢化钠时可以不用加碱。10. the synthetic method of a kind of 3,4-difluoro-2-((phenylthio) methyl) benzoic acid according to claim 1, is characterized in that, in step (2), 2-bromomethyl For the reaction of base-3,4-difluorobenzoic acid and diphenyl disulfide, alkali may not be added due to different reducing agents. For example, when the reducing agent is sodium borohydride, alkali may not be added.
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