Synthesis method of 1-(2-amino-4-fluoro-5-methoxyphenyl)-1-acetone

Abstract

The invention discloses a synthesis method of 1-(2-amino-4-fluoro-5-methoxyphenyl)-1-acetone, which comprises the following steps: by taking 3-fluoro-4-methoxyaniline as a starting material, sequentially carrying out bromination reaction, nucleophilic substitution reaction of amino, nucleophilic substitution reaction and Boc removal reaction to obtain the 1-(2-amino-4-fluoro-5-methoxyphenyl)-1-acetone. The method has the advantages of mild reaction conditions, low cost, easily available raw materials, repeated use of dichloromethane and tetrahydrofuran as solvents, improvement of the utilization rate of the raw materials, reduction of resource waste and reduction of pollution.

Description

Technical Field

[0001] The invention belongs to the field of chemical pharmacy, and specifically relates to a method for synthesizing 1-(2-amino-4-fluoro-5-methoxyphenyl)-1-acetone. Background Art

[0002] 1-(2-amino-4-fluoro-5-methoxyphenyl)-1-acetone is an important organic compound, which plays an important role in the fields of pharmacy and chemistry. However, the traditional synthesis method (taking the part involved in patent CN1114608 as an example) is to add the anhydrous dichloromethane solution of 3-fluoro-4-methoxyaniline to boron trichloride to obtain a pink suspension and stir for five minutes, then drip propionitrile and aluminum chloride for several times, then obtain the target product by heating to reflux, hydrochloric acid hydrolysis, cooling, filtering, washing, extraction, drying and purification. The propionitrile that this route needs to use is highly toxic and easily carcinogenic chemicals, which is harmful to the experimenter, has a large damage to the experimental equipment, has a long reaction time, has a high energy consumption, and has a relatively expensive raw material, a low yield, and an excessively high cost of industrialized production, and the specific route is as follows.

[0003] Summary of the invention

[0004] In view of the shortcomings of the prior art, the present invention provides a method for synthesizing 1-(2-amino-4-fluoro-5-methoxyphenyl)-1-acetone, using 3-fluoro-4-methoxyaniline as a starting material, and sequentially undergoing bromination reaction, amino nucleophilic substitution reaction, nucleophilic substitution reaction, and Boc removal reaction to obtain a target product. The method has mild reaction conditions, low cost, and readily available raw materials, and solvents such as dichloromethane and tetrahydrofuran can be repeatedly used, thereby improving the utilization rate of raw materials, reducing resource waste, and reducing pollution.

[0005] The method for synthesizing 1-(2-amino-4-fluoro-5-methoxyphenyl)-1-acetone of the present invention comprises the following steps:

[0006] Step 1: Take a suitable three-necked flask, add 3-fluoro-4-methoxyaniline thereto, then dissolve it with DCM, then add Na2CO3 to neutralize the generated acid, control the reaction temperature at 0°C, then slowly add Br2, control the reaction time at 1h, filter the resulting mixed solution, extract it with water and saturated NaHSO4 solution, collect the organic phase and spin dry it, purify it using a chromatographic column method, flush out impurities with PE:EA=30:1, then flush out the product with PE:EA=20:1 and spin dry it to obtain 2-bromo-5-fluoro-4-methoxyaniline.

[0007] Step 2: Take a suitable three-necked flask, protect with nitrogen, add 2-bromo-5-fluoro-4-methoxyaniline thereto, then dissolve it with DCM, then add triethylamine, DMAP, and di-tert-butyl dicarbonate, react at room temperature for 10 hours, filter the resulting mixed solution, extract with water and saturated NaCl solution, collect the organic phase and evaporate to dryness, and purify it by column chromatography, use PE:EA system, flush out the product with PE:EA=15:1 and evaporate to obtain N-Boc-2-bromo-5-fluoro-4-methoxyaniline carbamate.

[0008] Step 3: Take a suitable three-necked flask, use nitrogen protection, add N-Boc-2-bromo-5-fluoro-4-methoxyaniline carbamate, then dissolve it with THF, add n-Bntyllithium at a temperature of -50°C and react for 2 hours, then add N-methoxy-N-methyl-propionamide and react for 2 hours, turn off the heating temperature until it returns to about 25°C, extract the resulting mixed solution with saturated NH4Cl solution, collect the organic phase and purify it using a chromatographic column method, use a PE:EA system, use PE:EA=30:1 to flush out impurities, use PE:EA=20:1 to flush out the product, and then rotary evaporate to obtain N-Boc-5-fluoro-4-methoxy-2-propionylphenylcarbamate.

[0009] Step 4: Take a suitable three-necked flask, add N-Boc-5-fluoro-4-methoxy-2-propionylphenylcarbamate thereto, then dissolve it with DCM, add HCl-dioxane at a temperature of 30°C and react for 4 hours, spin-dry the reaction solution, add saturated NaHCO3 solution and EA for extraction, and spin-dry the resulting organic phase, dissolve it with methanol, reverse the phase and purify it using a chromatographic column method, use a DCM:MeOH system, flush out the product with DCM:MeOH=1:1 and then freeze-dry to obtain 1-(2-amino-4-fluoro-5-methoxyphenyl)-1-propanone.

[0010] In step 1, the mass ratio of 3-fluoro-4-methoxyaniline to Br2 is 1:0.9-1, the volume ratio of 3-fluoro-4-methoxyaniline to ethylene dichloride is 1:15-20, and the mass ratio of 3-fluoro-4-methoxyaniline to Na2CO3 is 1:2.5-3.

[0011] In step 1, saturated NaHSO4 solution is used to remove excess Br2.

[0012] In step 2, the mass ratio of 2-bromo-5-fluoro-4-methoxyaniline to di-tert-butyl dicarbonate is 1:1.4-1.6, the mass ratio of 2-bromo-5-fluoro-4-methoxyaniline to triethylamine is 1:2.5-3, the mass ratio of 2-bromo-5-fluoro-4-methoxyaniline to DMAP is 0.1-0.2, and the volume ratio of 2-bromo-5-fluoro-4-methoxyaniline to DCM is 10-15.

[0013] In step 3, the volume ratio of N-Boc-2-bromo-5-fluoro-4-methoxyaniline carbamate to n-Bntyllithium is 1:0.3-0.5, the mass ratio of N-Boc-2-bromo-5-fluoro-4-methoxyaniline carbamate to N-methoxy-N-methyl-propionamide is 1:2, and the volume ratio of N-Boc-2-bromo-5-fluoro-4-methoxyaniline carbamate to THF is 1:3-4.

[0014] In step 3, the concentration of the hydrochloric acid solution is 20%.

[0015] In step 3, the saturated NH4Cl solution is used to remove excess butyl lithium.

[0016] In step 4, the volume ratio of N-Boc-5-fluoro-4-methoxy-2-propionylphenylcarbamate to HCl-dioxane is 1:2, and the volume ratio of N-Boc-5-fluoro-4-methoxy-2-propionylphenylcarbamate to DCM is 1:4-5.

[0017] In step 4, saturated NaHCO3 solution is used to neutralize the acid, and water is used to remove the generated salt.

[0018] The synthetic route of the present invention is as follows:

[0019]

[0020] The synthesis method of the invention uses 3-fluoro-4-methoxyaniline as a starting material, and sequentially undergoes bromination reaction, amino nucleophilic substitution reaction, nucleophilic substitution reaction, and Boc removal reaction to obtain the 1-(2-amino-4-fluoro-5-methoxyphenyl)-1-propanone. The reaction conditions are simple, the reaction process is safe, the raw materials are cheap and easily available, the solvent can be repeatedly used, the total yield is high, and the product purity is high. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 LC-MS spectrum of the product.

[0022] Figure 2 H NMR spectrum of the product. DETAILED DESCRIPTION

[0023] The technical solution of the present invention is further illustrated by specific embodiments below. These embodiments are only for illustration and are not intended to be limiting.

[0024] Embodiment 1:

[0025] The synthesis method of 1-(2-amino-4-fluoro-5-methoxyphenyl)-1-acetone in this embodiment comprises the following steps:

[0026] 1. Synthesis of 2-bromo-5-fluoro-4-methoxyaniline

[0027]

[0028] 10 g of 3-fluoro-4-methoxyaniline and 100 L of dichloroethane were put into a 250 mL three-necked flask, stirred evenly, and then 29 g of Na2CO3 was added. The temperature was controlled below 0°C with ethanol and dry ice, and 11.5 g of Br2 was slowly added dropwise thereto. The reaction was kept below 0°C for 1 hour. An appropriate amount of saturated NaHSO4 was added to the reaction solution to remove excess Br2. After extraction, the obtained organic phase was purified by column chromatography (PE:EA system), and impurities were flushed out with PE:EA=30:1, and the product was flushed out with PE:EA=20:1 to obtain 14.4 g of 2-bromo-5-fluoro-4-methoxyaniline with a yield of 92% and a HPLC purity of 98.5%.

[0029] 2. Synthesis of N-Boc-2-bromo-5-fluoro-4-methoxyaniline carbamate

[0030]

[0031] Under nitrogen protection, 150 mL of dichloromethane was added to a 250 mL three-necked flask, 10 g of N-Boc-2-bromo-5-fluoro-4-methoxyaniline carbamate was added, and then 14.9 g of di-tert-butyl dicarbonate, 14 g of TEA and 0.55 g of DMAP were slowly added. After the addition was completed, the temperature was controlled to be 25° C. and stirred for 10 h. The resulting reaction solution was extracted with H2O and saturated NaCl solution, the organic phase was collected and spin-dried, and the obtained organic phase was purified by column chromatography (PE:EA system), and the product was flushed out with PE:EA=20:1 to obtain 13.2 g of N-Boc-2-bromo-5-fluoro-4-methoxyaniline carbamate, with a yield of 91% and an HPLC purity of 99.6%.

[0032] 3. Synthesis of N-Boc-5-fluoro-4-methoxy-2-propionylphenylcarbamate

[0033]

[0034] Under nitrogen protection, 10g N-Boc-2-bromo-5-fluoro-4-methoxyaniline carbamate was added to a 250mL three-necked flask, dissolved with 100mL tetrahydrofuran, and the temperature was controlled below -50°C with dry ice and ethanol, and 3mL n-Butyllithium was added. After reacting for 2h, 7.5g propionamide was slowly added dropwise, and the temperature was stopped after the addition, and the reaction was stirred for 2h. The resulting reaction was extracted with a saturated NH4Cl solution, and the resulting organic phase was purified by a chromatographic column method (PE: EA system), and impurities were flushed out with PE: EA = 30: 1, and the product was flushed out with PE: EA = 20: 1, and the mixture was collected and spin-dried to obtain 8.2g N-Boc-5-fluoro-4-methoxy-2-propionylphenyl carbamate, with a yield of 88% and a HPLC purity of 99.1%.

[0035] 4. Synthesis of 1-(2-amino-4-fluoro-5-methoxyphenyl)-1-propanone

[0036]

[0037] Under nitrogen protection, 10 g of N-Boc-5-fluoro-4-methoxy-2-propionylphenyl carbamate was added to a 100 mL three-necked flask, dissolved with 40 mL of DCM, and slowly added with 20 mL of HCl-Dioxane after the solid was dissolved, and reacted at 30 degrees Celsius for 4 hours. The resulting reaction solution was spin-dried, EA and saturated NaHCO3 were added for extraction, and all 1 was flushed out, collected and freeze-dried to obtain 5.6 g of 1-(2-amino-4-fluoro-5-methoxyphenyl)-1-acetone, with a yield of 85% and a HPLC purity of 99.8%.

[0038] 1 H NMR (400MHz, DMSO-d6) δ7.41(d,J=9.7Hz,1H),7.10(s,2H),6.60(d,J=13.7Hz,1H),3.78(s,3H),2.96(q,J=7.2Hz,2H),1.06(t,J=7.2Hz,3H).

[0039] Embodiment 2:

[0040] The synthesis method of 1-(2-amino-4-fluoro-5-methoxyphenyl)-1-acetone in this embodiment comprises the following steps:

[0041] 1. Synthesis of 2-bromo-5-fluoro-4-methoxyaniline

[0042]

[0043] 10g of 3-fluoro-4-methoxyaniline and 100mL of dichloroethane were added to a 250mL three-necked flask, stirred evenly, and then 29g of Na2CO3 was added. The temperature was controlled below 0°C with ethanol and dry ice, and 12.5g of Br2 was slowly added dropwise, and the reaction was kept below 0°C for 1h. An appropriate amount of saturated NaHSO4 was added to the reaction solution to remove excess Br2. After extraction, the obtained organic phase was purified by chromatographic column method (PE:EA system), and impurities were flushed out with PE:EA=30:1, and the product was flushed out with PE:EA=20:1. 15g of 2-bromo-5-fluoro-4-methoxyaniline was obtained, with a yield of 96% and a HPLC purity of 98.2%.

[0044] 2. Synthesis of N-Boc-2-bromo-5-fluoro-4-methoxyaniline carbamate

[0045]

[0046] Under nitrogen protection, 150 mL of dichloromethane was added to a 250 mL three-necked flask, 10 g of N-Boc-2-bromo-5-fluoro-4-methoxyaniline carbamate was added, and then 16.8 g of di-tert-butyl dicarbonate, 14 g of TEA, and 0.55 g of DMAP were slowly added. After the addition, the temperature was controlled to 25 ° C and stirred for 10 hours. The resulting reaction solution was extracted with H2O and saturated NaCl solution, and the organic phase was collected and spin-dried. The obtained organic phase was purified by column chromatography (PE: EA system), and the product was flushed out with PE: EA = 20: 1. 13.67 g of N-Boc-2-bromo-5-fluoro-4-methoxyaniline carbamate was obtained, with a yield of 94% and a HPLC purity of 98.4%.

[0047] 3. Synthesis of N-Boc-5-fluoro-4-methoxy-2-propionylphenylcarbamate

[0048]

[0049] Under nitrogen protection, 10g N-Boc-2-bromo-5-fluoro-4-methoxyaniline carbamate was added to a 250mL three-necked flask, dissolved with 100mL tetrahydrofuran, and the temperature was controlled below -50°C with dry ice and ethanol. 3mL n-Butyllithium was added, and 7.5g propionamide was slowly added dropwise after the reaction for 2h. After the addition, the temperature was stopped and the reaction was stirred for 2h. The resulting reaction was extracted with a saturated NH4Cl solution, and the resulting organic phase was purified by a chromatographic column method (PE: EA system), and impurities were flushed out with PE: EA = 30: 1, and the product was flushed out with PE: EA = 20: 1. Collect and spin dry to obtain 8.4g N-Boc-5-fluoro-4-methoxy-2-propionylphenyl carbamate, with a yield of 90% and a HPLC purity of 97.8%.

[0050] 4. Synthesis of 1-(2-amino-4-fluoro-5-methoxyphenyl)-1-propanone

[0051]

[0052] Under nitrogen protection, 10 g of N-Boc-5-fluoro-4-methoxy-2-propionylphenyl carbamate was added to a 100 mL three-necked flask, dissolved with 40 mL of DCM, and slowly added with 20 mL of HCl-Dioxane after the solid was dissolved, and reacted at 30 degrees Celsius for 4 hours. The resulting reaction solution was spin-dried, EA and saturated NaHCO3 were added for extraction, and all 1 was flushed out of the product, collected and freeze-dried to obtain 5.7 g of 1-(2-amino-4-fluoro-5-methoxyphenyl)-1-acetone, with a yield of 86% and a HPLC purity of 99.1%.

[0053] 1 H NMR (400MHz, DMSO-d6) δ7.41(d,J=9.7Hz,1H),7.10(s,2H),6.60(d,J=13.7Hz,1H),3.78(s,3H),2.96(q,J=7.2Hz,2H),1.06(t,J=7.2Hz,3H).

[0054] Embodiment 3:

[0055] The synthesis method of 1-(2-amino-4-fluoro-5-methoxyphenyl)-1-acetone in this embodiment comprises the following steps:

[0056] 1. Synthesis of 2-bromo-5-fluoro-4-methoxyaniline

[0057]

[0058] 10g of 3-fluoro-4-methoxyaniline and 100mL of dichloroethane were added to a 250mL three-necked flask, stirred evenly, and then 29g of Na2CO3 was added. The temperature was controlled below 0°C with ethanol and dry ice, and 11.5g of Br2 was slowly added dropwise, and the reaction was kept below 0°C for 1h. An appropriate amount of saturated NaHSO4 was added to the reaction solution to remove excess Br2. After extraction, the obtained organic phase was purified by chromatographic column method (PE:EA system), and impurities were flushed out with PE:EA=30:1, and the product was flushed out with PE:EA=20:1. 14.0g of 2-bromo-5-fluoro-4-methoxyaniline was obtained, with a yield of 90% and a HPLC purity of 97.7%.

[0059] 2. Synthesis of N-Boc-2-bromo-5-fluoro-4-methoxyaniline carbamate

[0060]

[0061] Under nitrogen protection, 150 mL of dichloromethane was added to a 250 mL three-necked flask, 10 g of N-Boc-2-bromo-5-fluoro-4-methoxyaniline carbamate was added, and then 14.9 g of di-tert-butyl dicarbonate, 13.7 g of TEA, and 0.55 g of DMAP were slowly added. After the addition, the temperature was controlled to 25 ° C and stirred for 10 hours. The resulting reaction solution was extracted with H2O and saturated NaCl solution, and the organic phase was collected and spin-dried. The obtained organic phase was purified by column chromatography (PE: EA system), and the product was flushed out with PE: EA = 20: 1. 14 g of N-Boc-2-bromo-5-fluoro-4-methoxyaniline carbamate was obtained, with a yield of 96% and an HPLC purity of 98.1%.

[0062] 3. Synthesis of N-Boc-5-fluoro-4-methoxy-2-propionylphenylcarbamate

[0063]

[0064] Under nitrogen protection, 10g N-Boc-2-bromo-5-fluoro-4-methoxyaniline carbamate was added to a 250mL three-necked flask, dissolved with 100mL tetrahydrofuran, and the temperature was controlled below -50°C with dry ice and ethanol. 3mL n-Butyllithium was added, and 8g propionamide was slowly added dropwise after the reaction for 2h. After the addition, the temperature was stopped and the reaction was stirred for 2h. The obtained reaction was extracted with saturated NH4Cl solution, and the obtained organic phase was purified by chromatographic column method (PE: EA system), and impurities were flushed out with PE: EA = 30: 1, and the product was flushed out with PE: EA = 20: 1. Collect and spin dry to obtain 8.75g N-Boc-5-fluoro-4-methoxy-2-propionylphenyl carbamate, with a yield of 94% and a HPLC purity of 97.8%.

[0065] 4. Synthesis of 1-(2-amino-4-fluoro-5-methoxyphenyl)-1-propanone

[0066]

[0067] Under nitrogen protection, 10g of N-Boc-5-fluoro-4-methoxy-2-propionylphenylcarbamate was added to a 100mL three-necked flask, dissolved with 40mL of DCM, and slowly added with 25mL of HCl-Dioxane after the solid was dissolved, and reacted at 30 degrees Celsius for 4h. The resulting reaction solution was spin-dried, EA and saturated NaHCO3 were added for extraction, and all 1 was flushed out of the product, collected and freeze-dried to obtain 6.1g of 1-(2-amino-4-fluoro-5-methoxyphenyl)-1-acetone, with a yield of 92% and a HPLC purity of 97.5%.

[0068] 1H NMR (400MHz, DMSO-d6) δ7.41(d,J=9.7Hz,1H),7.10(s,2H),6.60(d,J=13.7Hz,1H),3.78(s,3H),2.96(q,J=7.2Hz,2H),1.06(t,J=7.2Hz,3H).

[0069] The following conclusions can be drawn from the above examples 1-3:

[0070] 1. When synthesizing 2-bromo-5-fluoro-4-methoxyaniline, an excess of Br2 should be added to enable 3-fluoro-4-methoxyaniline to react fully, thereby increasing the yield of 2-bromo-5-fluoro-4-methoxyaniline.

[0071] 2. When synthesizing N-Boc-2-bromo-5-fluoro-4-methoxyaniline carbamate, an excess of di-tert-butyl dicarbonate should be added to enable 2-bromo-5-fluoro-4-methoxyaniline to fully react, thereby increasing the yield of N-Boc-2-bromo-5-fluoro-4-methoxyaniline carbamate.

[0072] 3. When synthesizing N-Boc-5-fluoro-4-methoxy-2-propionylphenylcarbamate, an excess of N-methoxy-N-methyl-propionamide should be added to enable N-Boc-2-bromo-5-fluoro-4-methoxyanilinecarbamate to fully react, thereby increasing the yield of N-Boc-5-fluoro-4-methoxy-2-propionylphenylcarbamate.

[0073] 4. When synthesizing 1-(2-amino-4-fluoro-5-methoxyphenyl)-1-propanone, an excess of HCl-dioxane should be added to enable N-Boc-5-fluoro-4-methoxy-2-propionylphenylcarbamate to react fully, thereby increasing the yield of 1-(2-amino-4-fluoro-5-methoxyphenyl)-1-propanone.

[0074] The invention discloses a method for synthesizing 1-(2-amino-4-fluoro-5-methoxyphenyl)-1-acetone, wherein 3-fluoro-4-methoxyaniline is used as a starting material, and the 1-(2-amino-4-fluoro-5-methoxyphenyl)-1-acetone is obtained by sequentially undergoing a bromination reaction, a nucleophilic substitution reaction of an amino group, a nucleophilic substitution reaction, and a de-Boc reaction. The method has mild reaction conditions, low cost, and readily available raw materials, and solvents such as dichloromethane and tetrahydrofuran can be repeatedly used, thereby improving the utilization rate of raw materials, reducing resource waste, and reducing pollution.

[0075] The above description is only a preferred embodiment of the present invention. It should be pointed out that a person skilled in the art can make several improvements without departing from the principle of the present invention. These improvements are also considered to be within the protection scope of the present invention.

Claims

1. A method for synthesizing 1-(2-amino-4-fluoro-5-methoxyphenyl)-1-acetone, characterized in that: Using 3-fluoro-4-methoxyaniline as the starting material, the target product is obtained through bromination reaction, amino nucleophilic substitution reaction, nucleophilic substitution reaction, and Boc removal reaction in sequence. The synthetic route is as follows:

2. The synthesis method according to claim 1, characterized in that The steps include: Step 1: Add 3-fluoro-4-methoxyaniline to the reactor, dissolve it with DCM, then add Na2CO3 to neutralize the generated acid, control the reaction temperature at 0°C, slowly add Br2 dropwise, control the reaction time at 1h, filter the resulting mixed solution, extract it with water and saturated NaHSO4 solution, collect the organic phase and spin dry it, and purify it by column chromatography to obtain 2-bromo-5-fluoro-4-methoxyaniline; Step 2: In a nitrogen atmosphere, 2-bromo-5-fluoro-4-methoxyaniline was added to a reactor, dissolved with DCM, and then triethylamine, DMAP, and di-tert-butyl dicarbonate were added. The mixture was reacted at room temperature for 10 h. The obtained mixed solution was filtered, extracted with water and saturated NaCl solution, and the organic phase was collected and evaporated to dryness, and purified by column chromatography to obtain N-Boc-2-bromo-5-fluoro-4-methoxyaniline carbamate; Step 3: Under nitrogen protection, N-Boc-2-bromo-5-fluoro-4-methoxyaniline carbamate was added to the reactor, dissolved in THF, and n-Bntyllithium was added at -50°C for 2h, and then N-methoxy-N-methyl-propionamide was added for 2h. The system was restored to room temperature, and the obtained mixed solution was extracted with a saturated NH4Cl solution. The organic phase was collected and purified by column chromatography to obtain N-Boc-5-fluoro-4-methoxy-2-propionylphenylcarbamate; Step 4: Add N-Boc-5-fluoro-4-methoxy-2-propionylphenylcarbamate to the reactor, dissolve it with DCM, add HCl-dioxane at 30°C and react for 4 hours, spin-dry the reaction solution, add saturated NaHCO3 solution and EA for extraction, spin-dry the obtained organic phase, dissolve it with methanol, reverse the phase and purify it using a chromatographic column method to obtain 1-(2-amino-4-fluoro-5-methoxyphenyl)-1-propanone.

3. The synthesis method according to claim 2, characterized in that: In step 1, the mass ratio of 3-fluoro-4-methoxyaniline to Br2 is 1:0.9-1, and the mass ratio of 3-fluoro-4-methoxyaniline to Na2CO3 is 1:2.5-3.

4. The synthesis method according to claim 2, characterized in that: In step 2, the mass ratio of 2-bromo-5-fluoro-4-methoxyaniline to di-tert-butyl dicarbonate is 1:1.4-1.6, the mass ratio of 2-bromo-5-fluoro-4-methoxyaniline to triethylamine is 1:2.5-3, and the mass ratio of 2-bromo-5-fluoro-4-methoxyaniline to DMAP is 0.1-0.

2.

5. The synthesis method according to claim 2, characterized in that: In step 3, the volume ratio of N-Boc-2-bromo-5-fluoro-4-methoxyaniline carbamate to n-Bntyllithium is 1:0.3-0.5, and the mass ratio of N-Boc-2-bromo-5-fluoro-4-methoxyaniline carbamate to N-methoxy-N-methyl-propionamide is 1:

2.

6. The synthesis method according to claim 2, characterized in that: In step 4, the volume ratio of N-Boc-5-fluoro-4-methoxy-2-propionylphenylcarbamate to HCl-dioxane is 1:2.

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