Synthesis method of flutomi ester compound

Abstract

The invention belongs to the technical field of medicinal chemistry, and discloses a synthesis method of a flutomil compound, which comprises the following steps: (1) taking 4-fluoromethylbenzylamine and dihydroxy acetone as raw materials, and reacting with potassium thiocyanate in an acidic acetonitrile solution to synthesize an intermediate A; (2) carrying out oxidative desulfurization on the intermediate A and 2-6eq of peroxidant sodium nitrite in an acidic solvent to prepare an intermediate B; (3) further oxidizing the intermediate B into an intermediate C; and (4) reacting the intermediate C in the reaction mixed solution with n-heterocyclic carbene under a DBU alkaline condition to generate an active intermediate, and then degrading the active intermediate into the flutomi ester compound. The synthesis route is high in atom utilization rate, simple in post-treatment, free of high temperature and high heat in the reaction process, less in reaction waste liquid and low in environmental protection pressure, and compared with original literature patents, the reaction steps are few, reagents are cheap, and the process route is easy to implement, economical and efficient.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry technology, and particularly relates to a method for synthesizing a flutoxamate compound. Background Technology

[0002] There are few reported synthetic routes for flutomidate. It is usually synthesized using the same method as the patented route for etomidate, as shown in the following synthetic route 1. That is, the raw material I is condensed with ethyl bromoacetate to synthesize intermediate II, which is then formylated in formic acid solution using a water separator. The resulting oily substance is converted into an enol sodium salt in methanol solution with sodium methoxide, and then cyclized with potassium thiocyanate in acidic ethanol solution to synthesize a mercaptoimidazole. The target compound is obtained by desulfurization with hydrogen peroxide. The entire process route is complicated. The intermediates are all oily substances. Even a slight incomplete reaction of the raw material will cause difficulties in the later separation. The use of hydrogen peroxide for desulfurization also leaves an explosion hazard in the process route.

[0003]

[0004] Furthermore, Merck (WO2014 / 4416) uses a second method to synthesize the intermediate aldehyde, as shown in synthetic route 2 below. This method uses hydrogen peroxide for desulfurization (200g starting material, 388ml hydrogen peroxide, 3 molar equivalents), which also poses safety risks. The intermediate aldehyde is then reacted with manganese dioxide in the presence of sodium cyanide or TMSCN, followed by ethanol reflux to obtain etomidate, etc. This route uses highly toxic compounds, putting pressure on environmental protection. Summary of the Invention

[0005] To address the aforementioned technical deficiencies in existing flutotomycin synthesis processes, this invention proposes a method for synthesizing flutotomycin compounds by improving experimental conditions, avoiding the use of easily explosive or highly toxic raw materials, and simplifying operational steps and separation methods.

[0006] To achieve the above objectives, the present invention adopts the following technical solution:

[0007] A method for synthesizing a flutoxamid compound, comprising the following steps:

[0008] (1) Using 1-(4-fluorophenyl)-1-ethylamine and acetone alcohol as raw materials, (1-(1-(4-fluorophenyl)ethyl)-2-mercapto-1H-imidazol-4-yl)methanol was synthesized by reacting potassium thiocyanate with acidic acetonitrile solution at 45-70℃.

[0009] (2) (1-(1-(4-fluorophenyl)ethyl)-2-mercapto-1H-imidazol-4-yl)methanol was oxidized and desulfurized in an acidic solvent with 2-6 eq of sodium nitrite peroxidant at 10-60℃ to obtain (1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-4-yl)methanol;

[0010] (3) Further oxidize (1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-4-yl)methanol to intermediate 1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-4-carboxaldehyde;

[0011] (4) The 1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-4-carbene in the reaction mixture of step (3) reacts with the nitrogen heterocyclic carbene under DBU alkaline conditions to directly generate the flutomidate compound in ethanol solvent.

[0012] Preferably, the specific process of step (1) is as follows:

[0013] 1-(4-fluorophenyl)-1-ethylamine was added dropwise to 30% hydrochloric acid, and the temperature was controlled below 20°C. The resulting mixture was added to acetonitrile, and acetic acid and acetone alcohol were added at once. The mixture would automatically cool down.

[0014] Then add potassium thiocyanate (KSCN), heat to 45°C under nitrogen protection, stop heating, stir, and the reaction temperature will rise to 65°C within 2 hours. After the exothermic reaction is completed, heat to 65°C and react overnight.

[0015] The reaction solution was cooled to 40°C, ice water was added, and the mixture was stirred for 0.5 h. The mixture was then filtered and washed with water to obtain a solid. The solid was washed with ethyl acetate, collected, and dried to obtain the intermediate (1-(1-(4-fluorophenyl)ethyl)-2-mercapto-1H-imidazol-4-yl)methanol.

[0016] Preferably, in step (2), the acidic solvent is acetic acid or a mixture of acetic acid + tetrahydrofuran, acetic acid + dichloromethane, acetic acid + ethyl acetate, or acetic acid + water, with a mixed solvent ratio of 2:1 to 1:2.

[0017] Preferably, the specific process of step (2) is as follows:

[0018] Acetic acid was added to tetrahydrofuran and stirred. Then, intermediate (1-(1-(4-fluorophenyl)ethyl)-2-mercapto-1H-imidazol-4-yl)methanol was added. A sodium nitrite aqueous solution with an equivalent concentration of 2N was added dropwise using a peristaltic pump. After about 24 hours of dropwise addition, the reaction was carried out for another 24 hours.

[0019] After the reaction was confirmed to be complete by TLC, ammonia was added under ice bath cooling, the solid was filtered, washed with ethyl acetate, and dried to obtain intermediate B (1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-4-yl)methanol.

[0020] Preferably, in step (3), the peroxidant used in the oxidation reaction is one or more of manganese dioxide, pyridinium dichromate (PDC), pyridinium chlorochromate (PCC), or N-chlorosuccinimide (NCS), and the amount used is 2-6 molar equivalents of (1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-4-yl)methanol.

[0021] Preferably, in step (3), the solvent used in the oxidation reaction is one or more of dichloromethane, methanol, and tetrahydrofuran.

[0022] Preferably, the specific process of step (3) is as follows:

[0023] The intermediate (1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-4-yl)methanol was added to dichloromethane and stirred. Active manganese dioxide was added and stirred overnight at room temperature. The reaction was detected by TLC to be complete, and the intermediate 1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-4-carboxaldehyde was generated.

[0024] Preferably, in step (4), the nitrogen-containing heterocyclic carbene is 1-butyl-3-methylimidazolium tetrafluoroborate, 1,4-dimethyl-1,2,4-triazolium iodide, 1,4-diethyl-1,2,4-triazolium iodide, or 4-(4-(methoxycarbonyl)benzyl)-1-methyl-1H-1,2,4-triazolium bromide. One or more of them.

[0025] Preferably, in step (4), the amount of the nitrogen-containing heterocyclic carbene is 0.1-1 molar equivalent of 1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-4-carboxaldehyde, and the amount of DBU is 1.0-2.0 molar equivalent of 1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-4-carboxaldehyde.

[0026] More preferably, in step (4), the amount of the nitrogen heterocyclic carbene is 0.2 molar equivalents of 1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-4-carbaldehyde, and the amount of DBU is 1.2 molar equivalents of 1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-4-carbaldehyde.

[0027] Preferably, the specific process of step (4) is as follows:

[0028] The oxidizing agent was filtered off from the reaction mixture after the reaction in step (3) was completed. The solid was washed with a solvent of DCM:MEOH ratio of 10:1. The filtrate was dried by rotary evaporation to obtain an oily substance.

[0029] The resulting oily substance was added to ethyl acetate, washed twice with water, washed once with saturated brine, evaporated to dryness, and then anhydrous sodium sulfate was added. The mixture was extracted with methyl tert-butyl ether, evaporated to dryness, and then purified by slurrying with methyl tert-butyl ether to obtain flutomidate compound.

[0030] The present invention adopts the above technical solution and has the following technical effects compared with the prior art:

[0031] (1) The synthesis route of this invention has high atom utilization, simple post-processing, no need for high temperature and heat in the reaction process, less reaction waste liquid, and less environmental pressure. Compared with the original literature patent, it has fewer reaction steps, cheaper reagents, and the process route is easy to implement, making it economical and efficient.

[0032] (2) This invention optimizes the desulfurization reaction conditions and finds the optimal feed ratio to make it suitable for kilogram-level feed, thereby maximizing economic benefits;

[0033] (3) This invention is the first to utilize the intermediate aldehyde to react with carbene reagent under DBU alkaline conditions to directly generate flutomidate compound in ethanol solvent, which improves the reaction conversion rate, simplifies the operation, and successfully explores a kilogram-scale process route.

[0034] (4) This invention improves the safety and production efficiency of the synthesis process by improving experimental conditions, avoiding the use of easily explosive or highly toxic raw materials, simplifying operation steps and separation methods. Attached Figure Description

[0035] Figure 1 The NMR spectrum of the intermediate (1-(1-(4-fluorophenyl)ethyl)-2-mercapto-1H-imidazol-4-yl)methanol obtained in Example 1 of this invention is shown below.

[0036] Figure 2 The NMR spectrum of the intermediate (1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-4-yl)methanol obtained in Example 2 of this invention is shown below.

[0037] Figure 3 The NMR spectrum of the target product flutotomycin compound obtained in Example 4 of this invention is shown below.

[0038] Figure 4 The NMR spectrum of metoprolol methyl ester prepared in Example 5 of this invention is shown below.

[0039] Figure 5 The NMR spectrum of fluoxetine prepared in Example 6 of this invention is shown. Detailed Implementation

[0040] This invention addresses the technical deficiencies of existing synthetic routes 1 and 2 for flutotropite compounds by improving experimental conditions, avoiding the use of easily explosive or highly toxic raw materials, and simplifying operational steps and separation methods, thereby providing a synthetic method for flutotropite compounds. Specifically, it includes the following steps:

[0041] (1) Using structural formulas Using 1-(4-fluorophenyl)-1-ethylamine and 1,3-dihydroxyacetone as raw materials, potassium thiocyanate was reacted with the 1-ethylamine in an acidic acetonitrile solution at 45-70℃ to synthesize the following structural formula: The compound (1-(1-(4-fluorophenyl)ethyl)-2-mercapto-1H-imidazol-4-yl)methanol;

[0042] (2) The structural formula is The compound was subjected to oxidative desulfurization in an acidic solvent with 2-6 eq of sodium nitrite peroxide at 10-60 °C to obtain the compound with the following structural formula: The compound (1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-4-yl)methanol;

[0043] (3) The above structural formula is The compound is further oxidized to form a structure with the following structural formula: The intermediate 1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-4-carboxaldehyde;

[0044] (4) Under DBU alkaline conditions, 1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-4-carben in the reaction mixture of step (3) reacts with nitrogen heterocyclic carbene to directly generate fluorotomylate compound in ethanol solvent.

[0045] In summary, the main synthetic route of the flutomidate compound disclosed in this invention is as follows:

[0046]

[0047] The present invention will now be described in detail and specifically through specific embodiments to enable a better understanding of the invention. However, the following embodiments do not limit the scope of the invention.

[0048] Unless otherwise specified, the conditions in the examples are as per standard conditions or the manufacturer's recommendations. Reagents or instruments whose manufacturers are not specified are all commercially available products.

[0049] In the following examples, unless otherwise specified, all operations were performed at room temperature; and unless otherwise specified, all purities are HPLC purities.

[0050] Example 1: Preparation of intermediate (1-(1-(4-fluorophenyl)ethyl)-2-mercapto-1H-imidazol-4-yl)methanol

[0051] The synthetic route for (1-(1-(4-fluorophenyl)ethyl)-2-mercapto-1H-imidazol-4-yl)methanol is shown below:

[0052]

[0053] The specific synthesis process is as follows: 2 kg of 4-fluoromethylbenzylamine was added dropwise to 1.65 L of 30% hydrochloric acid, with the temperature controlled below 20°C, and the mixture was thoroughly mixed. 9 L of acetonitrile was added to the resulting mixture, followed by the simultaneous addition of 1.65 L of acetic acid and 1.487 kg of acetone alcohol. The mixture automatically cooled. Then, 1.603 kg of potassium thiocyanate (KSCN) was added, and the mixture was heated to 45°C under nitrogen protection. Heating was stopped, and the mixture was stirred. The reaction temperature rose to 65°C within 2 hours. After the exothermic reaction, the temperature was maintained at 65°C and the reaction proceeded overnight. The reaction solution was cooled to 40°C, transferred to a 25 L container, and 5 L of ice water was added. The mixture was stirred for 0.5 h, filtered, and washed with water to obtain a solid. The solid was washed with 6 L of ethyl acetate, collected, and dried to obtain 2 kg of intermediate A. The NMR spectrum of intermediate A is shown below. Figure 1 As shown.

[0054] Example 2: Preparation of intermediate (1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-4-yl)methanol

[0055] The synthetic route for (1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-4-yl)methanol is shown below:

[0056]

[0057] The specific synthesis process is as follows: 3.2 L of acetic acid was added to 3.2 L of tetrahydrofuran solution and stirred until homogeneous. Then, 1.5 kg of intermediate A was added, followed by dropwise addition of a 2N sodium nitrite aqueous solution (prepared by adding 2.35 kg of sodium nitrite to 12.4 L of water to a concentration of 2N) using a peristaltic pump. The addition was carried out for approximately 24 hours, followed by a further 24 hours of reaction. After TLC detection showed complete reaction, 3.2 L of ammonia was added under ice bath cooling. The solid was filtered, washed with 6 L of ethyl acetate, and dried to obtain 1.11 kg of intermediate B, with a yield of 84.8%. The NMR spectrum of intermediate B is shown below. Figure 2 As shown.

[0058] Example 3: Preparation of intermediate 1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-4-carboxaldehyde

[0059]

[0060] The specific synthesis process is as follows: 1 kg of intermediate B is added to 8 L of dichloromethane and stirred evenly. Then 2 kg of active manganese dioxide is added and stirred overnight at room temperature until the reaction is complete as detected by TLC. After removing the solvent by vacuum filtration and depressurization, intermediate 1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-4-carboxaldehyde is quantitatively generated.

[0061] Example 4: Preparation method of flutotomycin compound

[0062] The synthetic route for this flutotomycin compound is shown below:

[0063]

[0064] The specific synthesis process is as follows: 2 kg of activated manganese dioxide was added to the reaction mixture of Example 3, followed by 102 g of methyltriazole iodide salt. Nitrogen gas was then introduced for protection, and 829 g of DBU was added dropwise. The mixture was stirred overnight at room temperature, and TLC was used to confirm the completeness of the reaction. The reaction mixture was transferred to a 30 L container, the manganese dioxide was filtered off, and the solid was washed with a mixed solvent of DCM:MEOH at a volume ratio of 10:1. The filtrate was then evaporated to dryness. The resulting oily substance was then added to 8 L of ethyl acetate, washed twice with water, and once with saturated brine. The mixture was evaporated to dryness, and anhydrous sodium sulfate was added. The mixture was extracted with methyl tert-butyl ether, evaporated to dryness, and the methyl tert-butyl ether was slurried to obtain 964 g of product C, flutomidate compound, with a yield of 81%. The NMR spectrum of intermediate C is shown below. Figure 3 As shown.

[0065] Comparative Example 1: Preparation of Flutomidate Compound

[0066] The synthetic route for this flutotomycin compound is shown below:

[0067]

[0068] The specific synthesis process is as follows: Following the reaction mixture prepared in Example 3, 2 kg of activated manganese dioxide, 0.25 kg of TMSCN, and 1 kg of TBAF were added sequentially, and the reaction was allowed to proceed overnight. TLC analysis showed the reaction was incomplete, so another 2 kg of activated manganese dioxide, 0.25 kg of TMSCN, and 0.43 kg of TBAF were added, and the mixture was stirred overnight at room temperature. TLC analysis confirmed the reaction was complete. The reaction mixture was transferred to a 30 L container, and the manganese dioxide was filtered off. The solid was washed with a solvent containing DCM:MEOH at a volume ratio of 10:1, and the filtrate was evaporated to dryness. The resulting oily substance was added to 8 L of ethyl acetate, washed twice with water, and once with saturated brine. The mixture was evaporated to dryness, and anhydrous sodium sulfate was added. The mixture was extracted with methyl tert-butyl ether, evaporated to dryness, and the methyl tert-butyl ether was slurried to obtain 700 g of the product, flutoimidyl ester, with a yield of 58.8%.

[0069] Example 5: Preparation of metoprolol compound

[0070] Similar to Examples 1, 2, 3, and 4, α-methylphenethylamine hydrochloride was used as the starting material to finally obtain the target compound metomethyl ester, whose NMR spectrum is shown below. Figure 4 As shown. The synthetic route for this metoprolol methyl ester is as follows:

[0071]

[0072] Example 6 Preparation of flutropane compound

[0073] The synthetic route for this fluoxetine compound is shown below:

[0074]

[0075] The specific synthesis process is as follows: Following the reaction mixture of the aldehyde prepared in Example 3, 2 kg of active manganese dioxide was added, followed by 100 g of methyltriazole iodide. Nitrogen gas was then introduced for protection, and 830 g of DBU was added dropwise. The mixture was stirred overnight at room temperature, and TLC was used to confirm the completeness of the reaction. The reaction mixture was transferred to a 30 L container, and the manganese dioxide was filtered off. The solid was washed with a mixed solvent with a DCM:MEOH volume ratio of 10:1, and the filtrate was evaporated to dryness. The resulting oily substance was then added to 8 L of ethyl acetate, washed twice with water, and once with saturated brine. The mixture was evaporated to dryness, and anhydrous sodium sulfate was added. The mixture was extracted with methyl tert-butyl ether, evaporated to dryness, and the methyl tert-butyl ether was slurried to obtain 980 g of the product, fluoxetine methyl ester, with a yield of 86.9%. Its NMR spectrum is shown below. Figure 5 As shown.

[0076] The specific embodiments of the present invention have been described in detail above, but they are merely examples, and the present invention is not limited to the specific embodiments described above. For those skilled in the art, any equivalent modifications and substitutions to the present invention are also within the scope of the present invention. Therefore, all equivalent transformations and modifications made without departing from the spirit and scope of the present invention should be covered within the scope of the present invention.

Claims

1. A method of synthesizing a compound of flutamide, characterized by, Comprising the following steps: (1) 1-(4-fluorophenyl)-1-ethylamine and dihydroxyacetone as raw materials, reaction with potassium thiocyanate in acidic acetonitrile solution at 45-70℃ to cyclize (1-(1-(4-fluorophenyl) ethyl)-2-mercapto-1H-imidazol-4-yl) methanol; (2) (1-(1-(4-fluorophenyl) ethyl)-2-mercapto-1H-imidazol-4-yl) methanol is oxidized with 2-6 eq of peroxidation agent sodium nitrite in an acidic solvent at 10-60℃ to produce (1-(1-(4-fluorophenyl) ethyl)-1H-imidazol-4-yl) methanol; (3) (1-(1-(4-fluorophenyl) ethyl)-1H-imidazol-4-yl) methanol is further oxidized to intermediate 1-(1-(4-fluorophenyl) ethyl)-1H-imidazol-4-carboxaldehyde; (4) 1-(1-(4-fluorophenyl) ethyl)-1H-imidazol-4-carboxaldehyde in the reaction mixture of step (3) is reacted with azacyclic carbene under DBU basic conditions to directly form flutramide compound in ethanol solvent.

2. The method of synthesis of flutomicin compound according to claim 1, characterized in that, The specific process of step (1) is: 1-(4-fluorophenyl)-1-ethylamine is added dropwise into 30% hydrochloric acid, the temperature is controlled below 20℃, the obtained mixture is added into acetonitrile, acetic acid and propanol are added at one time, the mixture is automatically cooled; Then potassium thiocyanate (KSCN) is added, heated to 45℃ under nitrogen protection, heating is stopped, stirring is carried out, the reaction temperature is increased to 65℃ within 2h, after the heat release is over, heating is added to 65℃ overnight; The reaction solution is cooled to 40℃, ice water is added, stirring is carried out for 0.5h, filtration is carried out and water washing is carried out to obtain solid, the solid is washed with ethyl acetate, the solid is collected and dried to obtain intermediate (1-(1-(4-fluorophenyl) ethyl)-2-mercapto-1H-imidazol-4-yl) methanol.

3. The method of synthesis of flutomicin compound according to claim 1, characterized by, In step (2), the acidic solvent is acetic acid or a mixed solvent of acetic acid + tetrahydrofuran, acetic acid + dichloromethane, acetic acid + ethyl acetate, acetic acid + water, the proportion of the mixed solvent is 2:1-1:

2.

4. The process for the synthesis of flutamide compound as claimed in claim 1, wherein, The specific process of step (2) is: Acetic acid is added into tetrahydrofuran and stirred, after the intermediate (1-(1-(4-fluorophenyl) ethyl)-2-mercapto-1H-imidazol-4-yl) methanol is added, 2N sodium nitrite aqueous solution is added dropwise by peristaltic pump, after about 24h of dropwise addition, reaction is carried out for another 24h; After TLC detection of complete reaction, ammonia is added under ice bath cooling, solid is filtered, washed with ethyl acetate, dried to obtain intermediate (1-(1-(4-fluorophenyl) ethyl)-1H-imidazol-4-yl) methanol.

5. The method of synthesis of flutamide compound as claimed in claim 1, wherein, In step (3), the peroxidation agent used in the oxidation reaction is one or several of manganese dioxide, pyridine heavy chromate (PDC), pyridine chlorochromate (PCC) or N-chlorosuccinimide (NCS), the amount is 2-6 mol eq of (1-(1-(4-fluorophenyl) ethyl)-1H-imidazol-4-yl) methanol.

6. The method of synthesis of flutamide compound as claimed in claim 1, wherein, In step (3), the solvent used in the oxidation reaction is one or several of dichloromethane, methanol, tetrahydrofuran.

7. The method of synthesis of flutamide compound as claimed in claim 1, wherein, The specific process of step (3) is: The intermediate (1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-4-yl)methanol was stirred in dichloromethane, activated manganese dioxide was added, and the mixture was stirred at room temperature overnight. TLC indicated that the reaction was complete, and the intermediate 1-(1-(4-fluorophenyl)ethyl)-1H-imidazole-4-carboxaldehyde was formed.

8. The method of synthesis of flutamide compound as claimed in claim 1, wherein, In step (4), the carbene is 1-butyl-3-methylimidazolium tetrafluoroborate, 1,4-dimethyl-1,2,4-triazolium iodide, 1,4-diethyl-1,2,4-triazolium iodide, 4-(4-(methoxycarbonyl)benzyl)-1-methyl-1H-1,2,4triazolium bromide one or more of the following:

9. The method of synthesis of flutamide compound as claimed in claim 1, wherein, In step (4), the amount of the azacycle carbine used was 0.1-1 mole equivalent of 1-(1-(4-fluorophenyl)ethyl)-1H-imidazole-4-carboxaldehyde, and the amount of the DBU used was 1.0-2.0 mole equivalent of 1-(1-(4-fluorophenyl)ethyl)-1H-imidazole-4-carboxaldehyde.

10. The method of synthesis of flutamide compound as claimed in claim 1, wherein, The specific process of step (4) was as follows: The reaction mixture in which the reaction in step (3) was complete was filtered to remove the oxidant, and the solid was washed with a solvent of DCM:MEOH=10:

1. The filtrate was spin-dried to obtain an oil. The obtained oil was added to ethyl acetate, washed with water twice, washed with saturated brine once, spin-dried, added with anhydrous sodium sulfate, and the mixture was extracted with methyl tert-butyl ether. The mixture was spin-dried, and then purified by slurry with methyl tert-butyl ether to obtain the flutamide compound.

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