CN110078633B - Preparation method of 4-fluoro-3-methoxy-5-methylaniline hydrochloride - Google Patents
Preparation method of 4-fluoro-3-methoxy-5-methylaniline hydrochloride Download PDFInfo
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Abstract
The invention discloses a preparation method of 4-fluoro-3-methoxy-5-methylaniline hydrochloride, belonging to the field of organic synthesis. A preparation method of 4-fluoro-3-methoxy-5-methylaniline hydrochloride comprises the following synthetic route:
the preparation method of the 4-fluoro-3-methoxy-5-methylaniline hydrochloride takes cheap and easily obtained 5-bromo-2-fluorotoluene as a starting material, obtains the 4-fluoro-3-methoxy-5-methylaniline hydrochloride through 5 steps of reaction, has convenient process operation, low cost, safety, high total yield and environmental friendliness, is suitable for industrial production, and has wide application prospect.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of 4-fluoro-3-methoxy-5-methylaniline hydrochloride.
Background
In 2012, Hui Li, Santa Clara, CA (US) et al used 2-fluoro-3-methylphenol as a starting material to prepare 4-fluoro-3-methoxy-5-methylaniline hydrochloride (see US 2012/28923; (2012); (A1) English) through 4 steps of reactions. Although the method has less process steps, the initial raw materials are not easy to synthesize, the price is high, the reaction conditions are harsh, and the three wastes are huge. Particularly, the first bromination, the third nitration and the fourth reaction are carried out in an autoclave, so that the reaction risk coefficient is high, the production discharge capacity is large, and the environmental pollution is easily caused.
Disclosure of Invention
Aiming at the problems, the invention provides a preparation method of 4-fluoro-3-methoxy-5-methylaniline hydrochloride, which has the advantages of easily obtained raw materials, low cost, convenient and safe process operation, high total yield and environmental friendliness.
The technical scheme adopted by the invention is as follows:
a preparation method of 4-fluoro-3-methoxy-5-methylaniline hydrochloride comprises the following synthetic route:
further, a preparation method of the 4-fluoro-3-methoxy-5-methylaniline hydrochloride comprises the following steps:
s1, sequentially adding 5-bromo-2-fluorotoluene and diisopropylamine into a three-necked bottle filled with an organic solvent, dropwise adding a cyclohexane solution dissolved with butyllithium into the three-necked bottle at 0 ℃, cooling the system to-50 to-80 ℃ after dropwise adding, reacting for 1-2 hours, dropwise adding a tetrahydrofuran solution of trimethyl borate or isopropyl borate into the reaction system, and continuing to react for 2-4 hours after dropwise adding; after the reaction is finished, carrying out water quenching reaction, separation, extraction and concentration to obtain 5-bromo-2-fluoro-3-methylphenylboronic acid;
s2, dissolving the 5-bromo-2-fluoro-3-methylphenylboronic acid in an organic solvent, cooling the system to 0-10 ℃, then dropwise adding an oxidant, heating the system to room temperature in a nitrogen atmosphere to react for 5-10 hours after dropwise adding is finished, and carrying out acid quenching reaction, separation, extraction and concentration after the reaction is finished to obtain 5-bromo-2-fluoro-3-methylphenol;
s3, dissolving the 5-bromo-2-fluoro-3-methylphenol in an organic solvent, then adding an alkali solution, dropwise adding dimethyl sulfate or methyl iodide or methanol in a nitrogen atmosphere, raising the temperature of the system to 60-80 ℃ after dropwise adding is finished, reacting for 1-2 hours, cooling the temperature of the system to room temperature after the reaction is finished, and then carrying out water quenching reaction, separation, extraction and concentration to obtain 5-bromo-2-fluoro-3-methyl anisole;
s4, dissolving the 5-bromo-2-fluoro-3-methylanisole in methanolamine, adding a catalyst, heating the system to 40-60 ℃ in a nitrogen atmosphere, reacting for 2-5 hours, cooling the system to room temperature after the reaction is finished, and performing water quenching reaction, separation, extraction and concentration to obtain 4-fluoro-3-methoxy-5-methylaniline;
s5, dissolving the 4-fluoro-3-methoxy-5-methylaniline in methanol or ethanol, then adding hydrogen chloride or a hydrogen chloride ethanol solution, heating the system to 60-80 ℃ under a nitrogen atmosphere, refluxing the reaction body for 1-2 h, cooling the system to room temperature after the reaction is finished, dropwise adding methyl tert-butyl ether into the system while stirring, and then filtering and drying to obtain the 4-fluoro-3-methoxy-5-methylaniline hydrochloride.
Further, the molar ratio of 5-bromo-2-fluoro-toluene, butyllithium, diisopropylamine, trimethyl borate, or isopropyl borate in S1 is 1: 1.0-1.5: 1.0-1.5: 1.0 to 1.5.
Further, in the S2, the oxidant is hydrogen peroxide, sodium hypochlorite or sodium hypobromite.
Further, the molar ratio of the 5-bromo-2-fluoro-3-methylbenzeneboronic acid to the oxidizing agent in the S2 is 1: 2.0 to 5.0.
Further, the mole ratio of the 5-bromo-2-fluoro-3-methylphenol, the dimethyl sulfate or the methyl iodide or the methanol in the S3 is 1: 1.0 to 2.
Further, the mass ratio of the 5-bromo-2-fluoro-3-methylanisole to the catalyst in the S4 is 1: 0.01 to 0.1.
Further, the organic solvent in S1 is at least one of tetrahydrofuran, diethyl ether, methyl tert-butyl ether, and toluene; the mass ratio of the organic solvent to the 5-bromo-2-fluoro-toluene is 5-10: 1.
Further, the organic solvent in S2 is at least one of tetrahydrofuran, dichloromethane, dioxane, and methyl tert-butyl ether; the mass ratio of the organic solvent to the 5-bromo-2-fluoro-3-methylbenzeneboronic acid is 5-10: 1.
Further, the organic solvent in S3 is at least one of tetrahydrofuran, dioxane, and DMF; the mass ratio of the organic solvent to the 5-bromo-2-fluoro-3-methylphenol is 5-10: 1.
Specifically, the extracting agent used for extraction is one or two of methyl tert-butyl ether, ethyl acetate and dichloromethane; the alkali solution in the S3 is at least one of sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide solution; the catalyst in the S4 is manganese, iron, nickel, zinc, copper, palladium, rhodium, cesium, platinum, ruthenium or cobalt and a complex compound or a complex compound thereof; the mass ratio of methanolamine or ethanol to 5-bromo-2-fluoro-3-methylanisole in S4 is 0.6-1: 1; the mass ratio of the methanol or the ethanol to the 4-fluoro-3-methoxy-5-methylaniline in the S5 is 5-10: 1.
The invention has the beneficial effects that: the preparation method of the 4-fluoro-3-methoxy-5-methylaniline hydrochloride takes cheap and easily obtained 5-bromo-2-fluorotoluene as a starting material, obtains the 4-fluoro-3-methoxy-5-methylaniline hydrochloride through 5 steps of reaction, has convenient process operation, low cost, safety, high total yield and environmental friendliness, is suitable for industrial production, and has wide application prospect.
Drawings
FIG. 15 nuclear magnetic resonance spectrum of bromo-2-fluoro-3-methylphenol;
FIG. 25 shows the nuclear magnetic resonance spectrum of bromo-2-fluoro-3-methylanisole;
FIG. 34 nuclear magnetic resonance spectrum of fluoro-3-methoxy-5-methylaniline;
FIG. 44-fluoro-3-methoxy-5-methylaniline hydrochloride.
Detailed Description
The embodiments of the present invention can be obtained by different substitutions in specific ranges based on the above technical solutions, and therefore, the following embodiments are only preferred embodiments of the embodiments, and any technical substitutions made by the above technical solutions are within the protection scope of the present invention.
Example 1
A preparation method of 4-fluoro-3-methoxy-5-methylaniline hydrochloride comprises the following steps:
preparation of S1.5-bromo-2-fluoro-3-methylphenylboronic acid
Sequentially adding 5-bromo-2-fluorotoluene (50g, 1.0eq) and diisopropylamine (26.7g, 1eq) into a three-neck flask containing tetrahydrofuran (500g), dropwise adding a cyclohexane (100g) solution of butyllithium (16.92g, 1eq) at 0 ℃, cooling the system to-65 ℃ after dropwise adding, reacting for 2 hours, dropwise adding a tetrahydrofuran (100g) solution of isopropyl borate (49.77g, 1.3eq) into the reaction system, and continuing to react for 3 hours after dropwise adding. After the reaction was completed, water was slowly added to the reaction system, the organic phase was separated, the product was extracted from the aqueous phase with methyl tert-butyl ether (500g), the organic phase was concentrated to dryness, and column chromatography (PE: MTBE ═ 20:1) was performed to obtain 5-bromo-2-fluoro-3-methylphenylboronic acid in yield: 85 percent.
Preparation of S2.5-bromo-2-fluoro-3-methylphenol
Dissolving 5-bromo-2-fluoro-3-methylphenylboronic acid (50g, 1.0eq) in tetrahydrofuran (500g), cooling to 5 ℃, slowly adding hydrogen peroxide (45g, 3.0eq) dropwise into the reaction system, after dropwise addition, heating the system to room temperature under a nitrogen atmosphere to react for 7 hours, after the reaction is finished, slowly adding hydrochloric acid into the reaction system, then extracting an organic phase with methyl tert-butyl ether (250g), concentrating the organic phase to dryness, and performing column chromatography (PE: MTBE 20:1) to obtain 5-bromo-2-fluoro-3-methylphenol, wherein the yield is as follows: 80 percent.
Preparation of S3.5-bromo-2-fluoro-3-methylanisole
Dissolving 5-bromo-2-fluoro-3-methylphenol (50g, 1.0eq) in DMF (250g), then adding potassium hydroxide solution (27.3g, 2.0eq), under nitrogen atmosphere, further adding methyl iodide (32.5g, 1.0eq) dropwise, after the dropwise addition is finished, raising the temperature of the system to 70 ℃, reacting for 2h, after the reaction of the raw materials is finished, cooling the system to room temperature, adding water into the system for quenching reaction, extracting an organic phase with methyl tert-butyl ether (500g), separating the organic phase, concentrating the organic phase to dryness, and performing column chromatography (PE: MTBE 20:1) to obtain 5-bromo-2-fluoro-3-methyl anisole, wherein the yield is: 75 percent.
S4.4-fluoro-3-methoxy-5-methylaniline preparation
Dissolving 5-bromo-2-fluoro-3-methylanisole (50g, 1.0eq) in methanolamine solution (30g, 2.0eq), adding catalyst rhodium (2.5g), raising the temperature of the system to 50 ℃ under nitrogen atmosphere, reacting for 2 hours, cooling the system to room temperature after the reaction is finished, adding water into the system for quenching reaction, extracting an organic phase with methyl tert-butyl ether (100g), concentrating the organic phase to dryness, and performing column chromatography (PE: MTBE 20:1) to obtain 4-fluoro-3-methoxy-5-methylaniline, wherein the yield is as follows: 90 percent.
S5.4-fluoro-3-methoxy-5-methylanilide hydrochloride
Dissolving 4-fluoro-3-methoxy-5-methylaniline (50g, 1.0eq) in ethanol (250g), then adding a hydrogen chloride ethanol solution (40g, 2.0eq), raising the temperature of the system to 70 ℃ under a nitrogen atmosphere, carrying out reflux reaction for 2h, cooling the system to room temperature after the reaction is finished, adding methyl tert-butyl ether (250g) into the system while stirring, separating out a large amount of solid, stirring for a plurality of minutes, filtering, and drying to obtain 4-fluoro-3-methoxy-5-methylaniline hydrochloride, wherein the yield is as follows: 89 percent.
Example 2
A preparation method of 4-fluoro-3-methoxy-5-methylaniline hydrochloride comprises the following steps:
preparation of S1.5-bromo-2-fluoro-3-methylphenylboronic acid
Adding 5-bromo-2-fluorotoluene (50g, 1.0eq) and diisopropylamine (40.15g, 1.5eq) into a three-neck flask containing tetrahydrofuran (500g) in sequence, dropwise adding a cyclohexane (100g) solution of butyllithium (25.38g, 1.5eq) at 0 ℃, cooling the system to-65 ℃ after dropwise adding, reacting for 2h, dropwise adding a tetrahydrofuran (100g) solution of isopropyl borate (74.65g, 1.5eq) into the reaction system, and continuing to react for 3h after dropwise adding. After the reaction was completed, water was slowly added to the reaction system, the organic phase was separated, the product was extracted from the aqueous phase with methyl tert-butyl ether (500g), the organic phase was concentrated to dryness, and column chromatography (PE: MTBE ═ 20:1) was performed to obtain 5-bromo-2-fluoro-3-methylphenylboronic acid in yield: 75 percent.
Preparation of S2.5-bromo-2-fluoro-3-methylphenol
Dissolving 5-bromo-2-fluoro-3-methylphenylboronic acid (50g, 1.0eq) in tetrahydrofuran (500g), cooling to 5 ℃, slowly adding hydrogen peroxide (75g, 5.0eq) dropwise into the reaction system, after dropwise addition, heating the system to room temperature under a nitrogen atmosphere to react for 7 hours, after the reaction is finished, slowly adding hydrochloric acid into the reaction system, then extracting an organic phase with methyl tert-butyl ether (250g), concentrating the organic phase to dryness, and performing column chromatography (PE: MTBE 20:1) to obtain 5-bromo-2-fluoro-3-methylphenol, wherein the yield is as follows: 80 percent.
Preparation of S3.5-bromo-2-fluoro-3-methylanisole
Dissolving 5-bromo-2-fluoro-3-methylphenol (50g, 1.0eq) in DMF (250g), then adding potassium hydroxide solution (27.3g, 2.0eq), under a nitrogen atmosphere, further adding methyl iodide (48.75g, 1.5eq) dropwise, after the dropwise addition is finished, raising the temperature of the system to 70 ℃, reacting for 2 hours, after the reaction of the raw materials is finished, cooling the system to room temperature, adding water into the system for quenching reaction, extracting an organic phase with methyl tert-butyl ether (500g), separating the organic phase, concentrating the organic phase to dryness, and performing column chromatography (PE: MTBE 20:1) to obtain 5-bromo-2-fluoro-3-methyl anisole, wherein the yield is as follows: 89 percent.
S4.4-fluoro-3-methoxy-5-methylaniline preparation
Dissolving 5-bromo-2-fluoro-3-methylanisole (50g, 1.0eq) in methanolamine solution (30g, 2.0eq), adding palladium catalyst (0.5g), raising the temperature of the system to 50 ℃ under nitrogen atmosphere, reacting for 2 hours, cooling the system to room temperature after the reaction is finished, adding water into the system for quenching reaction, extracting an organic phase with methyl tert-butyl ether (100g), concentrating the organic phase to dryness, and performing column chromatography (PE: MTBE 20:1) to obtain 4-fluoro-3-methoxy-5-methylaniline, wherein the yield is as follows: 80 percent.
S5.4-fluoro-3-methoxy-5-methylanilide hydrochloride
Dissolving 4-fluoro-3-methoxy-5-methylaniline (50g, 1.0eq) in ethanol (250g), then adding a hydrogen chloride ethanol solution (40g, 2.0eq), raising the temperature of the system to 70 ℃ under a nitrogen atmosphere, carrying out reflux reaction for 2h, cooling the system to room temperature after the reaction is finished, adding methyl tert-butyl ether (250g) into the system while stirring, separating out a large amount of solid, stirring for a plurality of minutes, filtering, and drying to obtain 4-fluoro-3-methoxy-5-methylaniline hydrochloride, wherein the yield is as follows: 82 percent.
The nuclear magnetic detection result of the 5-bromo-2-fluoro-3-methylphenol is as follows:1h NMR (400MHz, (CD3)2SO): δ 6.91(1H, s),6.86(1H, s),2.17(3H, s), as shown in fig. 1.
The nuclear magnetic detection result of the 5-bromo-2-fluoro-3-methylanisole is as follows:1h NMR (400MHz, (CD3)2 SO). delta.7.15 (1H, s),7.03(1H, s),3.82(3H, s),2.19(3H, s) as shown in FIG. 2.
The nuclear magnetic detection result of the 4-fluoro-3-methoxy-5-methylaniline is as follows: the nuclear magnetic detection result of the 4-fluoro-3-methoxy-5-methylaniline is as follows: 1H NMR (400MHz, (CD3)2 SO). delta.7.00 (1H, s),6.82(1H, s),3.82(3H, s),2.23(3H, s), as shown in FIG. 3.
The nuclear magnetic detection result of the 4-fluoro-3-methoxy-5-methylaniline hydrochloride is as follows:1h NMR (400MHz, (CD3)2 SO). delta.7.00 (1H, s),6.82(1H, s),3.82(3H, s),2.23(3H, s) as shown in FIG. 4.
Claims (10)
1. The preparation method of the 4-fluoro-3-methoxy-5-methylaniline hydrochloride is characterized in that the synthetic route is as follows:
2. the process for producing 4-fluoro-3-methoxy-5-methylaniline hydrochloride according to claim 1, comprising the steps of:
s1, sequentially adding 5-bromo-2-fluorotoluene and diisopropylamine into a three-necked bottle filled with an organic solvent, dropwise adding a cyclohexane solution dissolved with butyllithium into the three-necked bottle at 0 ℃, cooling the system to-50 to-80 ℃ after dropwise adding, reacting for 1-2 hours, dropwise adding a tetrahydrofuran solution of trimethyl borate or isopropyl borate into the reaction system, and continuing to react for 2-4 hours after dropwise adding; after the reaction is finished, carrying out water quenching reaction, separation, extraction and concentration to obtain 5-bromo-2-fluoro-3-methylphenylboronic acid;
s2, dissolving the 5-bromo-2-fluoro-3-methylphenylboronic acid in an organic solvent, cooling the system to 0-10 ℃, then dropwise adding an oxidant, heating the system to room temperature in a nitrogen atmosphere to react for 5-10 hours after dropwise adding is finished, and carrying out acid quenching reaction, separation, extraction and concentration after the reaction is finished to obtain 5-bromo-2-fluoro-3-methylphenol;
s3, dissolving the 5-bromo-2-fluoro-3-methylphenol in an organic solvent, then adding an alkali solution, dropwise adding dimethyl sulfate or methyl iodide or methanol in a nitrogen atmosphere, raising the temperature of the system to 60-80 ℃ after dropwise adding is finished, reacting for 1-2 hours, cooling the temperature of the system to room temperature after the reaction is finished, and then carrying out water quenching reaction, separation, extraction and concentration to obtain 5-bromo-2-fluoro-3-methyl anisole;
s4, dissolving the 5-bromo-2-fluoro-3-methylanisole in methanolamine, adding a catalyst, heating the system to 40-60 ℃ in a nitrogen atmosphere, reacting for 2-5 hours, cooling the system to room temperature after the reaction is finished, and performing water quenching reaction, separation, extraction and concentration to obtain 4-fluoro-3-methoxy-5-methylaniline;
s5, dissolving the 4-fluoro-3-methoxy-5-methylaniline in methanol or ethanol, then adding hydrogen chloride or a hydrogen chloride ethanol solution, heating the system to 60-80 ℃ under a nitrogen atmosphere, refluxing the reaction body for 1-2 h, cooling the system to room temperature after the reaction is finished, dropwise adding methyl tert-butyl ether into the system while stirring, and then filtering and drying to obtain the 4-fluoro-3-methoxy-5-methylaniline hydrochloride.
3. The method of claim 2, wherein the molar ratio of 5-bromo-2-fluoro-toluene, butyllithium, diisopropylamine, trimethyl borate, or isopropyl borate in S1 is 1: 1.0-1.5: 1.0-1.5: 1.0 to 1.5.
4. The method for preparing 4-fluoro-3-methoxy-5-methylaniline hydrochloride as in claim 2, wherein the oxidant in S2 is hydrogen peroxide, sodium hypochlorite or sodium hypobromite.
5. The method of claim 2, wherein the molar ratio of 5-bromo-2-fluoro-3-methylphenylboronic acid to oxidant in S2 is 1: 2.0 to 5.0.
6. The method of claim 2, wherein the molar ratio of 5-bromo-2-fluoro-3-methylphenol, dimethyl sulfate, methyl iodide or methanol in S3 is 1: 1.0 to 2.
7. The method for preparing 4-fluoro-3-methoxy-5-methylaniline hydrochloride according to claim 2, wherein the mass ratio of 5-bromo-2-fluoro-3-methylanisole to the catalyst in S4 is 1: 0.01 to 0.1.
8. The method for preparing 4-fluoro-3-methoxy-5-methylaniline hydrochloride according to claim 2, wherein the organic solvent in S1 is at least one of tetrahydrofuran, diethyl ether, methyl tert-butyl ether and toluene; the mass ratio of the organic solvent to the 5-bromo-2-fluoro-toluene is 5-10: 1.
9. The method for preparing 4-fluoro-3-methoxy-5-methylaniline hydrochloride according to claim 2 wherein said organic solvent in S2 is at least one of tetrahydrofuran, dichloromethane, dioxane and methyl tert-butyl ether; the mass ratio of the organic solvent to the 5-bromo-2-fluoro-3-methylbenzeneboronic acid is 5-10: 1.
10. The method of claim 2, wherein the organic solvent of S3 is at least one of tetrahydrofuran, dioxane, and DMF; the mass ratio of the organic solvent to the 5-bromo-2-fluoro-3-methylphenol is 5-10: 1.
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