A method for synthesizing compound 3-amino-2-fluoro-6-methylbenzoic acid methyl ester

Abstract

The invention discloses a method for synthesizing a compound 3-amino-2-fluoro-6-methylbenzoic acid methyl ester, characterized in that the raw material 1-(2-fluoro-4-methylphenyl)-2,5-dimethyl-1H-pyrrole is first converted into an intermediate compound 3-(2,5-dimethyl-1H-pyrrole-1-yl)-2-fluoro-6-methylbenzoic acid methyl ester, and then converted into a target compound 3-amino-2-fluoro-6-methylbenzoic acid methyl ester. The synthetic route weakens the activity of the amino group by protecting the amino group, and then uses a lithium reagent to extract the hydrogen on the ester group, and the target product can be accurately positioned to avoid the generation of isomers, while also solving the problem of steric hindrance and poor insertion of carbonyl, and then the target product can be easily obtained by a conventional deprotection method; finally a synthetic route of a compound 3-amino-2-fluoro-6-methylbenzoic acid methyl ester with high yield, low cost and suitable for process amplification is obtained.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a method for synthesizing a compound, 3-amino-2-fluoro-6-methylbenzoic acid methyl ester. Background Art

[0002] Methyl benzoate compounds are an important class of organic compounds, which are widely used in many fields such as synthesis, pesticides, and medicine. For example, methyl 5-bromo-2-fluoro-4-methylbenzoate is used as a key intermediate in the synthesis of tetrazole compounds in patent WO2019 / 213244, which inhibit apoptosis signal-regulating kinase 1 (ASK1) associated with autoimmune diseases, neurodegenerative diseases, inflammatory diseases, chronic kidney diseases, and cardiovascular diseases; in patent WO2014 / 159559, it is used to synthesize compounds with anti-hepatitis C virus (HCV) activity; in patent WO2023 / 150681, it is used to synthesize RAF kinase inhibitors. Methyl 5-bromo-3-fluoro-2-methylbenzoate is also used as a key intermediate in the synthesis of new macrocyclic LRRK2 kinase inhibitors in patent WO2021 / 224320, which can treat diseases affected or regulated by LRRK2 kinase activity, such as neurological diseases, including Parkinson's disease and Alzheimer's disease, as well as heart disease or inflammatory diseases, such as Crohn's disease; in patent WO2022 / 086828, it is used in the synthesis of triazole pyridine compounds as receptor-interacting protein kinase 1 (RIPK1) inhibitors. Methyl benzoate compounds have great application potential in drug development.

[0003] Among these compounds, methyl 3-amino-2-fluoro-6-methylbenzoate is an important molecular building block. For example, it is used in the synthesis of glucocorticoid receptor agonists in patent WO2022 / 204108, which can be used to treat autoimmune and inflammatory diseases such as atopic dermatitis and rheumatoid arthritis.

[0004] In the prior art, the synthetic route of the compound 3-amino-2-fluoro-6-methylbenzoic acid methyl ester, due to the particularity of its own structure, the groups contained in it are all positional. Whether it is obtained by nitration of the amino group or by directly adding halogen, the basic isomers are obtained. If the method of halogen insertion into carbonyl is used, it cannot react due to the problem of steric hindrance and is difficult to achieve. Summary of the invention

[0005] In view of the shortcomings of the synthesis method of the compound 3-amino-2-fluoro-6-methylbenzoic acid methyl ester in the above-mentioned prior art, the present invention provides a synthesis method of the compound 3-amino-2-fluoro-6-methylbenzoic acid methyl ester. The entire synthesis method has the advantages of low cost, ideal yield and process scale-up potential.

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

[0007] A method for synthesizing a compound 3-amino-2-fluoro-6-methylbenzoic acid methyl ester, wherein a raw material compound 1 (1-(2-fluoro-4-methylphenyl)-2,5-dimethyl-1H-pyrrole) is first converted into an intermediate compound 2 (3-(2,5-dimethyl-1H-pyrrol-1-yl)-2-fluoro-6-methylbenzoic acid methyl ester), and compound 2 is then converted into a target compound 3 (3-amino-2-fluoro-6-methylbenzoic acid methyl ester), and the synthesis route is as follows:

[0008]

[0009] Further, the synthesis method of the compound 3-amino-2-fluoro-6-methylbenzoic acid methyl ester comprises the following steps:

[0010] (1) Add 2,2,6,6-tetramethylpiperidine to organic solvent I, cool to -40°C to -10°C under inert gas protection, slowly drop n-butyl lithium, and stir for 20-40 minutes; then cool to -80°C to -50°C, dissolve raw material 1, i.e. 1-(2-fluoro-4-methylphenyl)-2,5-dimethyl-1H-pyrrole, in organic solvent II, and slowly drop it into the above reaction solution, and stir for 0.5-2 hours; then slowly drop dimethyl carbonate, and stir for 1-5 hours. After the reaction is completed, the reaction solution is post-treated to obtain compound 2, i.e. 3-(2,5-dimethyl-1H-pyrrol-1-yl)-2-fluoro-6-methylbenzoic acid methyl ester.

[0011] (2) Compound 2 is added to organic solvent III and water, and then hydroxylamine hydrochloride and triethylamine are added, heated to reflux, and reacted for 10-40 hours. After the reaction is completed, the reaction solution is post-treated to obtain compound 3, namely methyl 3-amino-2-fluoro-6-methylbenzoate.

[0012] Furthermore, in step (1), the post-treatment process includes: after the reaction is completed, adding a saturated aqueous solution of ammonium chloride, extracting with an organic solvent IV, combining the organic phases, washing the organic phases, drying, and spin-drying to obtain compound 2, namely 3-(2,5-dimethyl-1H-pyrrol-1-yl)-2-fluoro-6-methylbenzoic acid methyl ester.

[0013] Furthermore, in step (1), the inert gas is one or more of nitrogen or argon.

[0014] Furthermore, in step (1), the organic solvent I is one or more of n-heptane, cyclohexane, tetrahydrofuran, toluene, or 1,4-dioxane.

[0015] Furthermore, in step (1), the organic solvent II is one or more of n-heptane, cyclohexane, tetrahydrofuran, toluene, or 1,4-dioxane.

[0016] Furthermore, in step (1), the mass volume ratio of the compound 1 to the organic solvent I is 1:(5-40) in g / mL.

[0017] Furthermore, in step (1), the mass volume ratio of the compound 1 to the organic solvent II is 1:(5-40) in g / mL.

[0018] Furthermore, in step (1), the molar ratio of the raw material 1 to 2,2,6,6-tetramethylpiperidine is 1.0:(1.0-2.0).

[0019] Furthermore, in step (1), the molar ratio of the raw material 1 to n-butyl lithium is 1.0:(1.0-1.5).

[0020] Furthermore, in step (1), the molar ratio of the raw material 1 to dimethyl carbonate is 1.0:(1.0-2.0).

[0021] Furthermore, in step (1), the organic solvent IV is one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, or dichloroethane.

[0022] Furthermore, in step (2), the post-treatment process includes: after the reaction is completed, the reaction solution is cooled to room temperature, added to ice water, extracted with an organic solvent V, the organic phases are combined, the organic phases are washed, dried, and spin-dried to obtain compound 3, namely 3-amino-2-fluoro-6-methylbenzoic acid methyl ester.

[0023] Furthermore, in step (2), the organic solvent III is one or more of ethanol, methanol or tert-butanol.

[0024] Furthermore, in step (2), the mass volume ratio of the compound 2 to the organic solvent III is 1:(5-40) in g / mL.

[0025] Furthermore, in step (2), the molar ratio of compound 2 to hydroxylamine hydrochloride is 1.0:(10.0-20.0).

[0026] Furthermore, in step (2), the molar ratio of compound 2 to triethylamine is 1.0:(2.0-6.0).

[0027] Furthermore, in step (2), the organic solvent V is one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, or dichloroethane.

[0028] Compared with the prior art, the beneficial technical effects of the present invention are:

[0029] The present invention provides a method for synthesizing a compound 3-amino-2-fluoro-6-methylbenzoic acid methyl ester, wherein the raw material 1-(2-fluoro-4-methylphenyl)-2,5-dimethyl-1H-pyrrole is first converted into an intermediate compound 3-(2,5-dimethyl-1H-pyrrole-1-yl)-2-fluoro-6-methylbenzoic acid methyl ester, and then converted into a target compound 3-amino-2-fluoro-6-methylbenzoic acid methyl ester. The synthetic route weakens the activity of the amino group by protecting the amino group, and then uses a lithium reagent to extract hydrogen to form an ester group, so that the target product can be accurately positioned to avoid the formation of isomers, and the problem of large steric hindrance and difficulty in inserting carbonyl is also solved. The target product can be easily obtained by a conventional deprotection method; finally, a synthetic route of the compound 3-amino-2-fluoro-6-methylbenzoic acid methyl ester with high yield, low cost, and suitable for process amplification is obtained. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 This is the H NMR spectrum of compound 3 (methyl 3-amino-2-fluoro-6-methylbenzoate) in Example 1. DETAILED DESCRIPTION

[0031] In order to make the technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings of the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the described embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. Unless otherwise defined, the technical terms or scientific terms used herein should be the common meanings understood by people with general skills in the field to which the present invention belongs.

[0032] Unless otherwise specified in the following examples, all reagents and materials used were commercially available.

[0033] A method for synthesizing a compound 3-amino-2-fluoro-6-methylbenzoic acid methyl ester, wherein a raw material compound 1 (1-(2-fluoro-4-methylphenyl)-2,5-dimethyl-1H-pyrrole) is first converted into an intermediate compound 2 (3-(2,5-dimethyl-1H-pyrrol-1-yl)-2-fluoro-6-methylbenzoic acid methyl ester), and compound 2 is then converted into a target compound 3 (3-amino-2-fluoro-6-methylbenzoic acid methyl ester), and the synthesis route is as follows:

[0034]

[0035] The technical solution of the present invention is further explained below by way of embodiments.

[0036] Example 1

[0037] In this example, the compound 3-amino-2-fluoro-6-methylbenzoic acid methyl ester was synthesized by the following steps:

[0038] (1) 2,2,6,6-tetramethylpiperidine (180.69 g, 1.28 mol, 1.30 eq) was added to tetrahydrofuran (2.0 L), and the temperature was lowered to -20°C under nitrogen protection. N-butyl lithium (2.50 M in cyclohexane, 472.30 mL, 1.18 mol, 1.20 eq) was slowly added dropwise, and stirred for 30 minutes; the temperature was then lowered to -65°C, and the raw material 1, i.e., 1-(2-fluoro-4-methylphenyl)-2,5-dimethyl-1H-pyrrole (200.00 g, 983.96 mmol, 1.00 eq) was dissolved in tetrahydrofuran (2.0 L), and the mixture was slowly added dropwise to the above reaction solution, and stirred for 1 hour; dimethyl carbonate (106.36 g, 1.18 mol, 1.20 eq) was then slowly added dropwise, and the reaction was stirred for 2 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (2.0 L) was added, extracted with ethyl acetate three times (1.0 L×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain compound 2, i.e., 3-(2,5-dimethyl-1H-pyrrol-1-yl)-2-fluoro-6-methylbenzoic acid methyl ester (weight 249.20 g, purity 98%, yield 95%).

[0039] (2) Compound 2 (200.00 g, 765.41 mmol, 1.00 eq) was added to ethanol (1.5 L) and water (0.5 L), and then hydroxylamine hydrochloride (797.81 g, 11.48 mol, 15.00 eq) and triethylamine (309.82 g, 3.06 mol, 4.00 eq) were added, heated to reflux, and reacted for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, added to ice water, and extracted with ethyl acetate 3 times (2.0 L × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain compound 3, i.e., methyl 3-amino-2-fluoro-6-methylbenzoate (weight 133.60 g, purity 98%, yield 93%).

[0040] The H NMR spectrum of the obtained compound 3 (methyl 3-amino-2-fluoro-6-methylbenzoate) is as follows: Figure 1 The characterization data are as follows:

[0041] 1H NMR (400MHz, CDCl3) δ6.76 (dt, J = 16.4, 8.2Hz, 2H), 3.93 (s, 3H), 2.27 (s, 3H).

[0042] Embodiments 2 to 14

[0043] Examples 2 to 14 are the same as Example 1, except that the 2,2,6,6-tetramethylpiperidine, n-butyl lithium, dimethyl carbonate, organic solvent I in reaction step (1), and the hydroxylamine hydrochloride, triethylamine, organic solvent III in reaction step (2) are adjusted, as shown in Table 1.

[0044] Through Examples 1 to 14, the effects of various reaction conditions on the reaction yield during the synthesis of intermediate compound 2 (3-(2,5-dimethyl-1H-pyrrol-1-yl)-2-fluoro-6-methylbenzoic acid methyl ester) and target compound 3 (3-amino-2-fluoro-6-methylbenzoic acid methyl ester) were investigated, and the results are shown in Table 1.

[0045] Table 1

[0046]

[0047]

[0048] Comparing Examples 1-3, when the molar ratio of compound 1:2,2,6,6-tetramethylpiperidine is 1.0:1.3, the reaction effect is already very good.

[0049] Comparing Examples 1, 4-5, when the molar ratio of compound 1: n-butyl lithium is 1.0:1.2, the reaction effect is already very good.

[0050] Comparing Examples 1, 6-7, when the molar ratio of compound 1: dimethyl carbonate is 1.0:1.2, the reaction effect is already very good.

[0051] Comparing Examples 1, 8-9, when the molar ratio of compound 2:hydroxylamine hydrochloride is 1.0:15.0, the reaction effect is already very good.

[0052] Comparing Examples 1, 10-11, when the molar ratio of compound 2:triethylamine is 1.0:4.0, the reaction effect is already very good.

[0053] Comparing Examples 1, 12-13, tetrahydrofuran, cyclohexane or toluene were used as solvents, and the reaction was able to obtain compound 2 in high yield, among which tetrahydrofuran was more effective as solvent.

[0054] Comparing Examples 1 and 14, the product can be obtained in high yield in both ethanol and methanol solvents, and ethanol is more effective as a solvent.

[0055] The above is only a preferred embodiment of the present invention, and the present invention is not limited to the above embodiments. It is understood that other improvements and changes directly derived or associated by those skilled in the art without departing from the spirit and concept of the present invention should be considered to be included in the protection scope of the present invention.

Claims

1. A method for synthesizing a compound 3-amino-2-fluoro-6-methylbenzoic acid methyl ester, characterized in that: The raw material 1-(2-fluoro-4-methylphenyl)-2,5-dimethyl-1H-pyrrole is first converted into the intermediate compound 3-(2,5-dimethyl-1H-pyrrol-1-yl)-2-fluoro-6-methylbenzoic acid methyl ester, and then converted into the target compound 3-amino-2-fluoro-6-methylbenzoic acid methyl ester. The synthetic route is as follows:

2. The method for synthesizing a compound according to claim 1, 3-amino-2-fluoro-6-methylbenzoic acid methyl ester, characterized in that: The synthesis method comprises the following steps: (1) adding 2,2,6,6-tetramethylpiperidine to an organic solvent (I), cooling to -40°C to -10°C under inert gas protection, slowly adding n-butyl lithium dropwise, and stirring for 20-40 minutes; then cooling to -80°C to -50°C, dissolving the raw material (1), i.e. 1-(2-fluoro-4-methylphenyl)-2,5-dimethyl-1H-pyrrole, in an organic solvent (II), and slowly adding dropwise to the above reaction solution, and stirring for (0.5-2) hours; then slowly adding dropwise dimethyl carbonate, stirring for reaction for (1-5) hours, and after the reaction is completed, the reaction solution is post-treated to obtain compound (2), i.e. 3-(2,5-dimethyl-1H-pyrrol-1-yl)-2-fluoro-6-methylbenzoic acid methyl ester; (2) Compound (2) is added to an organic solvent (III) and water, and then hydroxylamine hydrochloride and triethylamine are added, and the mixture is heated to reflux and reacted for (10-40) hours. After the reaction is completed, the reaction solution is post-treated to obtain compound (3), namely methyl 3-amino-2-fluoro-6-methylbenzoate.

3. The method for synthesizing a compound according to claim 2, 3-amino-2-fluoro-6-methylbenzoic acid methyl ester, characterized in that: In step (1), the post-treatment process includes: after the reaction is completed, adding a saturated aqueous solution of ammonium chloride, extracting with an organic solvent (IV), combining the organic phases, washing the organic phases, drying, and spin-drying to obtain compound (2), namely 3-(2,5-dimethyl-1H-pyrrol-1-yl)-2-fluoro-6-methylbenzoic acid methyl ester.

4. The method for synthesizing a compound according to claim 2, 3-amino-2-fluoro-6-methylbenzoic acid methyl ester, characterized in that: In step (1), the inert gas is one or more of nitrogen or argon; In step (1), the organic solvent I is one or more of n-heptane, cyclohexane, tetrahydrofuran, toluene, or 1,4-dioxane; In step (1), the organic solvent II is one or more of n-heptane, cyclohexane, tetrahydrofuran, toluene and 1,4-dioxane.

5. The method for synthesizing a compound according to claim 2, 3-amino-2-fluoro-6-methylbenzoic acid methyl ester, characterized in that: In step (1), the mass volume ratio of the compound (1) to the organic solvent (I) is 1:5-40 g / mL; In step (1), the mass volume ratio of the compound (1) to the organic solvent (II) is 1:5-40 g / mL; In step (1), the molar ratio of the raw material (1) to 2,2,6,6-tetramethylpiperidine is 1.0:(1.0-2.0); In step (1), the molar ratio of the raw material (1) to n-butyl lithium is 1.0:(1.0-1.5); In step (1), the molar ratio of the raw material (1) to dimethyl carbonate is 1.0:(1.0-2.0).

6. The method for synthesizing a compound according to claim 2, methyl 3-amino-2-fluoro-6-methylbenzoate, characterized in that: In step (1), the organic solvent (IV) is one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, or dichloroethane.

7. The method for synthesizing a compound according to claim 2, 3-amino-2-fluoro-6-methylbenzoic acid methyl ester, characterized in that: In step (2), the post-treatment process includes: after the reaction is completed, the reaction solution is cooled to room temperature, added to ice water, extracted with an organic solvent (V), the organic phases are combined, the organic phases are washed, dried, and spin-dried to obtain compound 3, namely 3-amino-2-fluoro-6-methylbenzoic acid methyl ester.

8. The method for synthesizing a compound according to claim 2, methyl 3-amino-2-fluoro-6-methylbenzoate, characterized in that: In step (2), the organic solvent (III) is one or more of ethanol, methanol or tert-butanol.

9. The method for synthesizing a compound according to claim 2, methyl 3-amino-2-fluoro-6-methylbenzoate, characterized in that: In step (2), the mass volume ratio of the compound (2) to the organic solvent (III) is 1:(5-40) g / mL; In step (2), the molar ratio of the compound (2) to hydroxylamine hydrochloride is 1.0:(10.0-20.0); In step (2), the molar ratio of the compound (2) to triethylamine is 1.0:(2.0-6.0).

10. The method for synthesizing a compound 3-amino-2-fluoro-6-methylbenzoic acid methyl ester according to claim 2, characterized in that: In step (2), the organic solvent (V) is one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, or dichloroethane.

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