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

Abstract

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

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

technical field

The present invention relates to a synthesis method of 3,4-difluoro-2-((phenylthio)methyl)benzoic acid.

Background technique

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.

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:

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 discloses another synthetic method of this intermediate:

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.

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.

SUMMARY OF THE INVENTION

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.

The specific operation steps are as follows:

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.

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.

Detailed ways:

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.

Example 1: Preparation of 2-bromomethyl-3,4-difluorobenzoic acid

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%.

Example 2: Preparation of 2-bromomethyl-3,4-difluorobenzoic acid

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%.

Example 3: Preparation of 3,4-difluoro-2-((phenylthio)methyl)benzoic acid

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%.

Example 4: Preparation of 3,4-difluoro-2-((phenylthio)methyl)benzoic acid

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.

Example 5: Preparation of 3,4-difluoro-2-((phenylthio)methyl)benzoic acid

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%.

Example 6: Preparation of 3,4-difluoro-2-((phenylthio)methyl)benzoic acid

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% .

Description of the drawings: Figure 1 is a hydrogen NMR spectrum of 3,4-difluoro-2-((phenylthio)methyl)benzoic acid

Figure 2 is a high performance liquid phase diagram of 3,4-difluoro-2-((phenylthio)methyl)benzoic acid.

Claims (10)

1. a synthetic method of 3,4-difluoro-2-((phenylthio) methyl) benzoic acid, synthetic route is:

The specific operations are as follows: 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; 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; 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. 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. 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. 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. 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. 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. 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. 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. 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. 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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