Synthesis method of 5-(2, 3-difluoro-6-methoxybenzyloxy)-2-fluoro-4-methoxyaniline

Abstract

The embodiment of the invention discloses a synthesis method of 5-(2, 3-difluoro-6-methoxybenzyloxy)-2-fluoro-4-methoxyaniline, and belongs to the technical field of organic synthesis. The invention relates to a synthesis method of 5-(2, 3-difluoro-6-methoxybenzyloxy)-2-fluoro-4-methoxyaniline, 4-fluoro-2-bromophenol is used as an initial raw material, and Ullmann methoxylation reaction, phenolic hydroxyl protection reaction, nitration reaction, hydrolysis reaction, alkylation reaction and reduction reaction are sequentially carried out. The synthetic route is reasonable in design, raw materials are cheap and easy to obtain, reaction conditions are mild, post-treatment is simple and convenient (column chromatography is not needed), the total yield is good, and the method is suitable for large-scale production and has remarkable industrial application value.

Description

TECHNICAL FIELD

[0001] The embodiment of the present application relates to the technical field of chemical synthesis, in particular to a synthesis method of 5-(2,3-difluoro-6-methoxybenzyloxy)-2-fluoro-4-methoxyaniline. BACKGROUND

[0002] 5-(2,3-difluoro-6-methoxybenzyloxy)-2-fluoro-4-methoxyaniline (CAS No.: 935287-59-5) is the core intermediate of the marketed drug linzagolix choline salt. On June 17, 2022, ObsEva SA announced that the European Commission (EC) has granted marketing authorization for the oral GnRH antagonist (linzagolix) for the treatment of moderate to severe uterine fibroid (UF) symptoms in women of childbearing age (18 years old and above).

[0003] The current synthesis method of this intermediate depends on expensive starting materials such as 4-fluoro-2-methoxyphenol (Org. Process Res. Dev. 2025, 29, 146-154; CN 116496180A), which has problems such as high production cost and difficulty in industrialization. SUMMARY

[0004] Therefore, the embodiment of the present application provides a synthesis method of 5-(2,3-difluoro-6-methoxybenzyloxy)-2-fluoro-4-methoxyaniline which is safe, economical and suitable for industrial production.

[0005] In order to achieve the above-mentioned purpose, the embodiment of the present application provides the following technical scheme:

[0006] A synthesis method of 5-(2,3-difluoro-6-methoxybenzyloxy)-2-fluoro-4-methoxyaniline, taking 4-fluoro-2-bromophenol as a starting material, sequentially performing Ullmann methoxylation reaction, phenolic hydroxyl protection reaction, nitration reaction, hydrolysis reaction, alkylation reaction and reduction reaction;

[0007] The synthesis route of the 5-(2,3-difluoro-6-methoxybenzyloxy)-2-fluoro-4-methoxyaniline is as follows:

[0008]

[0009] Further, the Ullmann methoxylation reaction is carried out in the presence of a ligand, a catalyst, an acid binding agent and a solvent;

[0010] The ligand is oxalyl diamide or oxalyl diphenylamine;

[0011] The catalyst is CuI;

[0012] the acid-binding agent is potassium tert-butoxide;

[0013] the solvent is methanol;

[0014] the molar ratio of the 4-fluoro-2-bromophenol, the ligand, the catalyst, the acid-binding agent is 1:0.1:0.08-0.1:2.5;

[0015] the temperature of the Ullmann methoxylation reaction is 70-75℃.

[0016] further, the phenolic hydroxyl protection reaction is carried out in the presence of nitrobenzoic acid, EDCI, DMAP and a solvent;

[0017] the solvent is dichloromethane;

[0018] the molar ratio of the intermediate SM-1, nitrobenzoic acid, EDCI, DMAP is 1:1.2-1.3:1.5-1.6:0.1-0.15;

[0019] the temperature of the phenolic hydroxyl protection reaction is 20-25℃.

[0020] further, the nitration reaction is carried out in the presence of concentrated sulfuric acid and sodium nitrate;

[0021] the molar ratio of the intermediate SM-2 and sodium nitrate is 1:1.05-1.1, and the mass-volume ratio of the intermediate SM-2 and concentrated sulfuric acid is 10g:50-55mL;

[0022] the process of the nitration reaction is: adding the intermediate SM-2 into concentrated sulfuric acid, cooling to 0℃, then slowly adding sodium nitrate in batches, controlling the reaction temperature not to exceed 5℃, and keeping 0℃ after adding.

[0023] further, the hydrolysis reaction is carried out in the presence of lithium hydroxide monohydrate and a solvent;

[0024] the solvent is a mixture of MeOH, THF, H2O in a volume ratio of 2:2:1;

[0025] the molar ratio of the intermediate SM-3 and lithium hydroxide monohydrate is 1:2-2.1;

[0026] the temperature of the hydrolysis reaction is 20-25℃.

[0027] further, the alkylation reaction is carried out in the presence of 2,3-difluoro-6-methoxybenzyl bromide, sodium carbonate and a solvent;

[0028] the solvent is DMF;

[0029] The molar ratio of the intermediate SM-4, 2,3-difluoro-6-methoxybenzyl bromide and sodium carbonate is 1:1.2-1.3:1.5-1.8;

[0030] The temperature of the alkylation reaction is 20-25℃.

[0031] Further, the reduction reaction is carried out in the presence of NiBr2, NaBH4 and a solvent;

[0032] The solvent is a mixture of THF and MeOH in a volume ratio of 1:1;

[0033] The molar ratio of the intermediate SM-6, NiBr2 and NaBH4 is 1:0.04-0.06:2.5-3.0;

[0034] The temperature of the reduction reaction is 0-5℃.

[0035] The embodiment of the present application has the following advantages:

[0036] The synthetic route of the present application is rationally designed, the raw materials are cheap and easy to obtain, the reaction conditions are mild, the post-treatment is simple (no need for column chromatography), the total yield is good, it is suitable for scale-up production, and has significant industrial application value. BRIEF DESCRIPTION OF DRAWINGS

[0037] In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings needed to be used in the embodiments or the prior art description will be briefly introduced below. Obviously, the drawings in the following description are only exemplary, and other drawings can be obtained by the provided drawings without creative labor for those skilled in the art.

[0038] Figure 1 The H NMR spectrum of the intermediate SM-4 provided by the present application is as follows: 1 H NMR spectrum;

[0039] Figure 2 The H NMR spectrum of the intermediate SM-4 provided by the present application is as follows: 13 C NMR spectrum;

[0040] Figure 3 The liquid chromatogram of the intermediate SM-4 provided by the present application is as follows:

[0041] Figure 4 The H NMR spectrum of the intermediate SM-5 provided by the present application is as follows: 1 H NMR spectrum;

[0042] Figure 5 The H NMR spectrum of the intermediate SM-5 provided by the present application is as follows: 13 C NMR spectrum;

[0043] Figure 6 Liquid chromatogram of the intermediate SM-5 provided in the present application;

[0044] Figure 7 Liquid chromatogram of the intermediate SM-6 provided in the present application; 1 HNMR spectrum;

[0045] Figure 8 HNMR spectrum of the target product TM provided in the present application; 13 C NMR spectrum;

[0046] Figure 9 Liquid chromatogram of the intermediate SM-6 provided in the present application;

[0047] Figure 10 HNMR spectrum of the target product TM provided in the present application; 1 HNMR spectrum of the target product TM provided in the present application;

[0048] Figure 11 C NMR spectrum of the target product TM provided in the present application; 13 C NMR spectrum of the target product TM provided in the present application;

[0049] Figure 12 Liquid chromatogram of the target product TM provided in the present application. DETAILED DESCRIPTION

[0050] The present application will be described in greater detail by way of specific embodiments, which should not be considered as limiting the scope of the application. It should be apparent to those skilled in the art that many more embodiments can be created without departing from the inventive concept disclosed and enabled herein. The embodiments described below are merely given as examples of the application and are not intended to limit the application in any way. Accordingly, the application is not limited to the embodiments described herein, which are merely given by way of example. It is furthermore understood that features of the disclosed embodiments can be combined with each other, unless otherwise indicated.

[0051] 2,3-Difluoro-6-methoxybenzyl bromide (denoted as intermediate SM-5) can be purchased commercially or synthesized according to the literature Organic Process Research & Development 2008, 12, 1293-1298. The present application synthesizes intermediate SM-5 according to the above-mentioned literature.

[0052] Example 1

[0053] The present example provides a method for synthesizing 5-(2,3-difluoro-6-methoxybenzyloxy)-2-fluoro-4-methoxyaniline, comprising the following steps:

[0054] (1) Synthesis of intermediate SM-1

[0055] Dissolve 4-fluoro-2-bromophenol (R, 200.0 g, 1.0 eq) in methanol (2.0 L, 10 V), add oxalyl bisphenylamine (25.2 g, 0.1 eq) and CuI (20.0 g, 0.1 eq), then add potassium tert-butoxide (294.0 g, 2.5 eq) in batches, exchange three times under nitrogen protection, heat to reflux reaction (70-75 °C). Monitor the reaction completion by HPLC (about 5 h), filter with celite, concentrate, dissolve with 5 V of ethyl acetate, wash with 2 V of 5% citric acid three times, dry the ethyl acetate phase, concentrate, and obtain intermediate SM-1 (125.0 g, yield 84%, purity 94.55%) as a dark liquid.

[0056] (2) Synthesis of intermediate SM-2

[0057] Add intermediate SM-1 (120.5 g, 1.0 eq) to DCM (1.25 L, 10 V), add p-nitrobenzoic acid (176.0 g, 1.2 eq), EDCI (253.0 g, 1.5 eq) and DMAP (11.0 g, 0.1 eq) respectively, and stir the reaction at room temperature (25 °C) for 30 min. After the reaction is completed by TLC and HPLC, wash with water, wash with saturated sodium chloride, dry and concentrate to obtain intermediate SM-2 (250.6 g, yield 98.0%, purity 98.26%) as a white solid.

[0058] (3) Synthesis of intermediate SM-3

[0059] Add intermediate SM-3 (100.0 g, 1.0 eq) to concentrated sulfuric acid (500.0 mL, 5 V), cool to 0 °C, then slowly add sodium nitrate (32.0 g, 1.1 eq) in batches, control the reaction temperature not to exceed 5 °C, and keep the reaction at 0 °C for 10 min after completion. After the disappearance of the raw material is monitored by TLC and HPLC, slowly add the reaction system to ice water, precipitate the product, filter and dry to obtain intermediate SM-3 (106.1 g, yield 92.0%, purity 95.5%) as a yellow solid.

[0060] (4) Synthesis of intermediate SM-4

[0061] Add SM-3 (106.1 g, 1.0 eq) to a mixed solvent of MeOH / THF / H2O = 2 / 2 / 1 (10 V), add lithium hydroxide monohydrate (25.6 g, 2.0 eq), and stir the reaction at room temperature (25 °C) for 30 min. After the reaction is completed by TLC and HPLC, concentrate to remove most of the organic solvent, add water, extract with ethyl acetate, combine the ethyl acetate phases, dry, concentrate, and obtain intermediate SM-4 (56.7 g, yield 99.87%, purity 99%) as a yellow solid.

[0062] (5) Synthesis of intermediate SM-6

[0063] Dissolve intermediate SM-4 (180 g, 0.96 mol) in DMF (2.47 L), then add intermediate SM-5 (272 g, 1.15 mol) and sodium carbonate (152 g, 1.44 mol) to the reaction solution. After addition, stir the reaction at room temperature (25 °C) for 8 h. Monitor the reaction completion by UPLC. Dilute with water 5 L, extract with ethyl acetate 3 times, combine, dry and concentrate to obtain intermediate SM-6 (327.9 g, yield 99.5%, purity 99.34%) as a yellow solid.

[0064] (6) Synthesis of target product TM

[0065] Dissolve intermediate SM-6 (300 g, 0.87 mol) in THF / MeOH = 1 / 1 (2.4 L), then add NiBr2(9.56 g, 43.73 mmol) to the reaction solution. Cool to 0 °C, and slowly add NaBH4(94.66 g, 2.5 mol) to the reaction solution in batches. After addition, stir the reaction at 0 °C for 2 h. Monitor the reaction completion by UPLC. Filter with celite, concentrate to remove the solvent, heat 2 V of ethyl acetate to 70 °C until dissolved, then add 5 V of petroleum ether dropwise. Allow to cool to room temperature to recrystallize. Obtain target product 5-(2,3-difluoro-6-methoxybenzyloxy)-2-fluoro-4-methoxyaniline (251 g, yield 92.1%, purity 99.78%) as a gray solid.

[0066] Example 2

[0067] This example provides a method for synthesizing 5-(2,3-difluoro-6-methoxybenzyloxy)-2-fluoro-4-methoxyaniline, which is different from Example 1 in that:

[0068] (1) Synthesis of intermediate SM-1

[0069] Dissolve 4-fluoro-2-bromophenol (R, 200.0 g, 1.0 eq) in methanol (2.0 L, 10 V), then add oxalic diamide (9.2 g, 0.1 eq) and CuI (20.0 g, 0.1 eq). Then add potassium tert-butoxide (294.0 g, 2.5 eq) in batches. After addition, exchange the gas three times under nitrogen protection, and heat to reflux reaction. Monitor the reaction completion by HPLC (about 5 h), filter with celite, and concentrate. Dissolve in 5 V of ethyl acetate, wash with 2 V of 5% citric acid three times, dry the ethyl acetate phase, concentrate, and obtain intermediate SM-1 (122.0 g, yield 82%, purity 99.25%) as a dark liquid.

[0070] Comparative Example 1

[0071] This comparative example provides a method for synthesizing 5-(2,3-difluoro-6- methoxybenzyloxy)-2-fluoro-4-methoxyaniline, which is different from Example 1 in that,

[0072] (1) Synthesis of intermediate SM-1

[0073] Dissolve 4-fluoro-2-bromophenol (R, 200.0 g, 1.0 eq) in methanol (200 mL, 10V), add oxalyl bisphenylamine (25.2 g, 0.1 eq) and CuI (10.0 g, 0.05 eq), then add potassium tert-butoxide (294.0 g, 2.5 eq) in batches, and after adding, exchange the air three times under nitrogen protection, and heat to reflux (70-75°C). Monitor the reaction completion by HPLC (about 15 h), filter with celite, and concentrate. Dissolve in 5V of ethyl acetate, wash with 2V of 5% citric acid three times, dry the ethyl acetate phase, and concentrate to obtain intermediate SM-1 (97.3 g, yield 65.4%, purity 88.25%) as a dark liquid.

[0074] Comparative Example 2

[0075] This comparative example provides a method for synthesizing 5-(2,3-difluoro-6- methoxybenzyloxy)-2-fluoro-4-methoxyaniline, which is different from Example 1 in that,

[0076] (6) Synthesis of target product TM

[0077] Dissolve intermediate SM-6 (300 g, 0.87 mol) in THF:MeOH = 1:1 (2.4 L), then add NiBr2 (19.12 g, 87.46 mmol) to the reaction solution, cool to 0°C, and slowly add NaBH4 (105.3 g, 3.045 mol) to the reaction solution in batches, after adding, stir the reaction solution at 0°C for 1 h, monitor the reaction completion by UPLC, filter with celite, concentrate to remove the solvent, and recrystallize using ethyl acetate and petroleum ether to obtain the target product 5-(2,3-difluoro-6-methoxybenzyloxy)-2-fluoro-4-methoxyaniline (191.3 g, yield 70.2%, purity 92.40%) as a gray solid.

[0078] Although the present application has been described in detail in the foregoing description with general principles and specific embodiments, some modifications or improvements can be made on the basis of the present application, which is obvious to those skilled in the art. Therefore, these modifications or improvements made on the basis of not deviating from the spirit of the present application, all belong to the scope of the present application claimed.

Claims

1. A method for synthesizing 5-(2,3-difluoro-6-methoxybenzyloxy)-2-fluoro-4-methoxyaniline, characterized in that, Starting with 4-fluoro-2-bromophenol, the reaction proceeds sequentially with Ullmann methoxylation, phenolic hydroxyl protection, nitration, hydrolysis, alkylation, and reduction. The synthetic route for 5-(2,3-difluoro-6-methoxybenzyloxy)-2-fluoro-4-methoxyaniline is as follows:

2. The method for synthesizing 5-(2,3-difluoro-6-methoxybenzyloxy)-2-fluoro-4-methoxyaniline according to claim 1, characterized in that, The Ullman methoxylation reaction is carried out in the presence of ligands, catalysts, acid-binding agents, and solvents; The ligand is oxalyl diamine or oxalyl diphenylamine; The catalyst is CuI; The acid-binding agent is potassium tert-butoxide; The solvent is methanol; The molar ratio of 4-fluoro-2-bromophenol, ligand, catalyst, and acid-binding agent is 1:0.1:0.08 to 0.1:2.5; The temperature for the Ullman methoxylation reaction is 70–75 °C.

3. The method for synthesizing 5-(2,3-difluoro-6-methoxybenzyloxy)-2-fluoro-4-methoxyaniline according to claim 1, characterized in that, The phenolic hydroxyl protection reaction was carried out in the presence of nitrobenzoic acid, EDCI, DMAP, and a solvent. The solvent is dichloromethane; The molar ratio of the intermediate SM-1, nitrobenzoic acid, EDCI, and DMAP is 1:1.2-1.3:1.5-1.6:0.1-0.15; The temperature for the phenolic hydroxyl protection reaction is 20–25 °C.

4. The method for synthesizing 5-(2,3-difluoro-6-methoxybenzyloxy)-2-fluoro-4-methoxyaniline according to claim 1, characterized in that, The nitration reaction is carried out in the presence of concentrated sulfuric acid and sodium nitrate. The molar ratio of intermediate SM-2 to sodium nitrate is 1:1.05-1.1, and the mass-to-volume ratio of intermediate SM-2 to concentrated sulfuric acid is 10g:50-55mL. The nitration process is as follows: intermediate SM-2 is added to concentrated sulfuric acid, the temperature is lowered to 0°C, and then sodium nitrate is slowly added in batches, controlling the reaction temperature to not exceed 5°C. After the addition is complete, the reaction is maintained at 0°C.

5. The method for synthesizing 5-(2,3-difluoro-6-methoxybenzyloxy)-2-fluoro-4-methoxyaniline according to claim 1, characterized in that, The hydrolysis reaction is carried out in the presence of lithium hydroxide monohydrate and a solvent; The solvent is a mixture of MeOH, THF, and H2O in a volume ratio of 2:2:

1. The molar ratio of intermediate SM-3 to lithium hydroxide monohydrate is 1:2 to 2.1; The hydrolysis reaction is carried out at a temperature of 20–25°C.

6. The method for synthesizing 5-(2,3-difluoro-6-methoxybenzyloxy)-2-fluoro-4-methoxyaniline according to claim 1, characterized in that, The alkylation reaction was carried out in the presence of 2,3-difluoro-6-methoxybenzyl bromide, sodium carbonate, and a solvent; The solvent is DMF; The molar ratio of the intermediate SM-4, 2,3-difluoro-6-methoxybenzyl bromide, and sodium carbonate is 1:1.2-1.3:1.5-1.

8. The alkylation reaction is carried out at a temperature of 20–25 °C.

7. The method for synthesizing 5-(2,3-difluoro-6-methoxybenzyloxy)-2-fluoro-4-methoxyaniline according to claim 1, characterized in that, The reduction reaction is carried out in the presence of NiBr2, NaBH4 and solvent; The solvent is a mixture of THF and MeOH in a volume ratio of 1:

1. The molar ratio of the intermediate SM-6, NiBr2, and NaBH4 is 1:0.04~0.06:2.5~3.0; The reduction reaction is carried out at a temperature of 0–5 °C.

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