Patent Description:
(<NUM>-fluoro-<NUM>,<NUM>-dihydrobenzofuran-<NUM>-yl)methylamine is an important intermediate compound that can be used to synthesize important drugs and agricultural chemicals. At present, the main literature reports, including international applications <CIT> and <CIT>, adopt the following route to synthesize and prepare (<NUM>-fluoro-<NUM>,<NUM>-dihydrobenzofuran-<NUM>-yl)methylamine:
<CHM>.

In the above synthetic route, <NUM>-bromo-<NUM>-fluorophenol is used as the starting material to react with <NUM>-bromo-<NUM>,<NUM>-diethoxyethane to obtain <NUM>-bromo-<NUM>-(<NUM>,<NUM>-diethoxyethoxy)-<NUM>-fluorobenzene (A5. <NUM>), and then PPA cyclization reaction is carried out to obtain <NUM>-bromo-<NUM>-fluorobenzofuran (A5.2a and its regioisomer A5.2b), which is then reacted with Zn(CN)<NUM>, Pd(PPh<NUM>)<NUM> to obtain <NUM>-fluorobenzofuran-<NUM>-carbonitrile (A5. <NUM>), and then hydrogenation reduction and amino protection are carried out simultaneously to obtain tert-butyl ((<NUM>-fluoro-<NUM>,<NUM>-dihydrobenzofuran-<NUM>-yl)methyl) carbamate (A5. <NUM>), and the last step is to remove the amino protecting group to obtain (<NUM>-fluoro-<NUM>,<NUM>-dihydrobenzofuran-<NUM>-yl)methylamine (A5). When the inventors reproduced this route, it was found that this route had many defects, for example: the cyclization reaction would produce positional isomers (A5.2a and A5.2b). Since the positional isomers have the same molecular weight and little difference in polarity, the positional isomer impurities are difficult to remove by purification, and multiple column chromatography separations would be necessary. In addition, zinc cyanide and the catalyst Pd(PPh<NUM>)<NUM> need to be added during the cyanidation process. Zinc cyanide can absorb carbon dioxide in moist air, generate zinc carbonate and release hydrocyanic acid, which is highly toxic and may release toxic gases and vapors during decomposition. The catalyst Pd(PPh<NUM>)<NUM> is also easy to remain. Furthermore, the post-treatments of the four steps in the above route require column chromatography to conduct separation and purification. Therefore, this reaction route is relatively cumbersome, the raw material reagents are highly toxic and expensive, and the post-treatments require multiple column chromatography purifications, so it is not suitable for industrial production.

Therefore, there is an urgent need in the prior art for a preparation method of (<NUM>-fluoro-<NUM>,<NUM>-dihydrobenzofuran-<NUM>-yl)methanamine with simple operation, cheap and easy-to-obtain raw materials, environment-friendly and simple post-treatment.

In view of the above-mentioned problems in the prior art, the present invention provides a preparation method of (<NUM>-fluoro-<NUM>,<NUM>-dihydrobenzofuran-<NUM>-yl)methylamine, which has the advantages of suitable reaction steps, simple operation, low cost and easy availability of reaction raw materials, environmental friendliness, simple post-treatment, and high yield. The overall route of the preparation method can be found in the following Scheme <NUM> (the following compound numbers refer to the compound numbers listed in Scheme <NUM>):
<CHM>
<CHM>.

In one aspect, the present invention provides a preparation method of (<NUM>-fluoro-<NUM>,<NUM>-dihydrobenzofuran-<NUM>-yl)methylamine or a salt thereof, which comprises the following reaction steps:.

In one embodiment, the above step <NUM>) is carried out by slowly adding a bromination reagent dropwise to a mixture of <NUM>-fluoro-<NUM>-methylphenol (<NUM>) and a reaction solvent, and optionally has one or more of the following features:.

In one embodiment, the above step <NUM>) is carried out by performing O-alkylation reaction between <NUM>-bromo-<NUM>-fluoro-<NUM>-methylphenol (<NUM>) and <NUM>-bromo-<NUM>,<NUM>-diethoxyethane (<NUM>) in the presence of a base and a reaction solvent, and optionally has one or more of the following features:.

In one embodiment, the above step <NUM>) is carried out by adding <NUM>-bromo-<NUM>-(<NUM>,<NUM>-diethoxyethoxy)-<NUM>-fluoro-<NUM>-toluene (<NUM>) dropwise to a mixture of polyphosphoric acid and a reaction solvent, and optionally has one or more of the following features:.

In one embodiment, the above step <NUM>) is carried out by brominating <NUM>-bromo-<NUM>-fluoro-<NUM>-methylbenzofuran (<NUM>) in the presence of a reaction solvent, a peroxide initiator and a bromination reagent, and optionally has one or more of the following features:.

In one embodiment, the above azidation in step <NUM>) is carried out by reacting an azide with <NUM>-bromo-<NUM>-fluoro-<NUM>-methylbenzofuran (<NUM>) in water and a reaction solvent, and optionally has one or more of the following features:.

In one embodiment, the above hydrogenation in step <NUM>) is carried out by hydrogenating <NUM>-bromo-<NUM>-fluoro-<NUM>-azidomethyl-benzofuran (<NUM>) under pressure in the presence of a catalyst, and optionally has one or more of the following features:.

In one embodiment, the above ammonolysis in step <NUM>) is carried out in an ammonia-alcohol solution, and optionally has one or more of the following features:.

The reaction temperature is room temperature or ambient temperature; and/or
the reaction time is <NUM>-<NUM>.

In one embodiment, the above hydrogenation in step <NUM>) is carried out by hydrogenating <NUM>-bromo-<NUM>-(aminomethyl)-<NUM>-fluorobenzofuran (<NUM>) under pressure in the presence of a catalyst, and optionally has one or more of the following features:.

In one embodiment, the salt of (<NUM>-fluoro-<NUM>,<NUM>-dihydrobenzofuran-<NUM>-yl)methylamine is selected from inorganic acid salts and organic acid salts. In one embodiment, the inorganic acid salts are selected from hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate and phosphate, and the like; and the organic acid salts are selected from acetate, propionate, glycollate, <NUM>-hydroxypropionate, pamoate, <NUM>-oxopropionate, oxalate, malonate, succinate, <NUM>-butenedioate, maleate, methanesulfonate, ethanesulfonate, benzenesulfonate and toluenesulfonic acid. In a preferred embodiment, the salt of (<NUM>-fluoro-<NUM>,<NUM>-dihydrobenzofuran-<NUM>-yl)methylamine is selected from hydrobromide.

In another aspect, the present invention provides the following compounds: <NUM>-fluoro-<NUM>-methylphenol (<NUM>), <NUM>-bromo-<NUM>-fluoro-<NUM>-methylphenol (<NUM>), <NUM>-bromo-<NUM>-( <NUM>,<NUM>-diethoxyethoxy)-<NUM>-fluoro-<NUM>-toluene (<NUM>), <NUM>-bromo-<NUM>-fluoro-<NUM>-methylbenzofuran (<NUM>), <NUM>-bromo-<NUM>-( bromomethyl)-<NUM>-fluorobenzofuran (<NUM>), <NUM>-bromo-<NUM>-fluoro-<NUM>-azidomethyl-benzofuran (<NUM>) and/or <NUM>-bromo-<NUM>-(aminomethyl )-<NUM>-fluorobenzofuran (<NUM>), and their use as intermediates for the preparation of (<NUM>-fluoro-<NUM>,<NUM>-dihydrobenzofuran-<NUM>-yl)methylamine or a salt thereof.

The preparation method of the present invention includes, but not limited to, the following advantages:.

The specific details of the preparation method of the present invention are illustrated in the following sections. It should be understood that, the illustrative description is only to facilitate those skilled in the art to better understand and practice the present invention. Those skilled in the art can adjust and/or modify one or more details in combination with the conventional practice in the chemical field.

Hereinafter, each step will be illustrated with reference to the above Scheme <NUM> and the preparation method.

<NUM>-fluoro-<NUM>-methylphenol is mixed with a reaction solvent and the temperature is lowered to - <NUM> to -<NUM>. A bromination reagent is slowly added dropwise, and the dropping time is controlled within <NUM>-<NUM> to prevent the rapid dropping rate from producing polysubstituted bromide, and the reaction system is monitored after the dropwise addition is over. After the reaction is over, the unreacted bromination reagent can be treated by adding at least one of saturated sodium thiosulfate and water, saturated sodium thiosulfate and saturated sodium bicarbonate, and saturated sodium bisulfite and water, or a mixture thereof, and then adding dichloromethane, and adopting the conventional post-treatment method in the art.

In one embodiment, the bromination reagent is selected from at least one of bromine, phosphorus oxybromide, phosphorus pentabromide, phosphorus tribromide, dibromotrialkylphosphine, dibromodiphenylphosphine, NBS, and dibromohydantoin; preferably bromine, phosphorus oxybromide, and NBS.

In one embodiment, the molar ratio of <NUM>-fluoro-<NUM>-methylphenol to the bromination reagent is <NUM>:(<NUM>-<NUM>), more preferably <NUM>:(<NUM>-<NUM>).

In one embodiment, the reaction solvent is selected from at least one of chlorinated alkanes, ethers, C<NUM>-C<NUM> alcohols, acetonitrile, and DMF, preferably chlorinated alkanes, and more preferably dichloromethane, chloroform, and dichloroethane.

In one embodiment, the reaction time is preferably <NUM>-<NUM>.

A reaction solvent, <NUM>-bromo-<NUM>-fluoro-<NUM>-methylphenol, <NUM>-bromo-<NUM>,<NUM>-diethoxyethane and a base are mixed to perform the O-alkylation reaction. The reaction system is heated to <NUM>-<NUM>, and the reaction time is <NUM>-<NUM>. After the reaction is over, the reaction system is monitored, and water and methyl tert-butyl ether are sequentially added, and a conventional post-treatment method in the art is adopted for the treatment.

In one embodiment, the molar ratio of <NUM>-bromo-<NUM>-fluoro-<NUM>-methylphenol to <NUM>-bromo-<NUM>,<NUM>-diethoxyethane is <NUM>:(<NUM>-<NUM>) , more preferably <NUM>: (<NUM>-<NUM>).

In one embodiment, the molar ratio of <NUM>-bromo-<NUM>-fluoro-<NUM>-methylphenol to the base is <NUM>:(<NUM>-<NUM>), more preferably <NUM>:(<NUM>-<NUM>).

In one embodiment, the base is selected from inorganic base or organic base, and the inorganic base is selected from at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate, and the organic base is selected from at least one of pyridine, triethylamine, diisopropylethylamine, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide, and DBU, or a mixture thereof.

In one embodiment, the reaction solvent is selected from at least one of DMF, acetonitrile, DMSO, toluene, or xylene, or a mixture thereof.

In one embodiment, the reaction temperature is preferably <NUM>-<NUM>, and the reaction time is preferably <NUM>-<NUM>.

Polyphosphoric acid (PPA) and a reaction solvent are heated to <NUM>-<NUM>, and a mixture system of <NUM>-bromo-<NUM>-(<NUM>,<NUM>-diethoxyethoxy)-<NUM>-fluoro-<NUM>-toluene and a reaction solvent is slowly added dropwise. The reaction system is heated to <NUM>-<NUM> and the reaction time is <NUM>-<NUM>. After the reaction is over, the reaction system is monitored, water and hexane are added sequentially, and a conventional post-treatment method in the art is adopted for the treatment.

In one embodiment, the molar ratio of <NUM>-bromo-<NUM>-(<NUM>,<NUM>-diethoxyethoxy)-<NUM>-fluoro-<NUM>-toluene to PPA is <NUM>: (<NUM>-<NUM>), preferably <NUM>: (<NUM>-<NUM>).

In one embodiment, the reaction solvent is at least one of toluene and xylene, or a mixture thereof.

<NUM>-bromo-<NUM>-fluoro-<NUM>-methylbenzofuran, a reaction solvent, a peroxide initiator and a bromination reagent are added sequentially, and the reaction system is heated to <NUM>-<NUM>° C. and reacted for <NUM>-<NUM> in an inert environment. After the reaction is over, the reaction system is monitored, water and ethyl acetate are added, and a conventional post-treatment method in the art is adopted for the treatment.

In one embodiment, the reaction solvent is selected from at least one of chlorinated alkanes, ethers, C<NUM>-C<NUM> alcohols, acetonitrile, ethyl acetate, and DMF; more preferably dichloromethane, chloroform, dichloroethane, carbon tetrachloride, and ethyl acetate.

In one embodiment, the peroxide initiator is selected from at least one of acyl peroxides, hydroperoxides, dialkyl peroxides, and peroxide-esters, and is more preferably selected from benzoyl peroxide, lauroyl peroxide, cumyl hydroperoxide, tert-butyl hydroperoxide, di-tert-butyl peroxide, dicumyl peroxide, tert-butyl peroxybenzoate; and tert-butyl peroxypivalate.

In one embodiment, the bromination reagent is selected from at least one of bromine, phosphorus oxybromide, phosphorus pentabromide, phosphorus tribromide, dibromotrialkylphosphine, dibromodiphenylphosphine, NBS, and dibromohydantoin; preferably bromine, NBS and dibromohydantoin.

In one embodiment, the inert environment is selected from nitrogen and argon.

In one embodiment, the molar ratio of <NUM>-bromo-<NUM>-fluoro-<NUM>-methylbenzofuran to the peroxide initiator is <NUM>: (<NUM>-<NUM>), more preferably <NUM>: (<NUM>-<NUM>).

In one embodiment, the molar ratio of <NUM>-bromo-<NUM>-fluoro-<NUM>-methylbenzofuran to the brominating reagent is <NUM>: (<NUM>-<NUM>), more preferably <NUM>: (<NUM>-<NUM>).

Water, an azide and a reaction solvent are added sequentially, and stirred evenly at <NUM>-<NUM>, <NUM>-bromo-<NUM>-(bromomethyl)-<NUM>-fluorobenzofuran is gradually add, and stirred at <NUM>-<NUM> for <NUM>-<NUM>. After the reaction is over, the reaction system is monitored, water and methyl tert-butyl ether are added, and a conventional post-treatment method in the art is adopted for the treatment.

In one embodiment, the azide is selected from sodium azide and potassium azide.

In one embodiment, the molar ratio of <NUM>-bromo-<NUM>-(bromomethyl)-<NUM>-fluorobenzofuran to the azide is <NUM>: (<NUM>-<NUM>), more preferably <NUM>: (<NUM>-<NUM>).

In one embodiment, the reaction temperature is <NUM>-<NUM>, and the reaction time is <NUM>-<NUM>.

In one embodiment, the reaction solvent is at least one of chlorinated alkanes, ethers, C<NUM>-C<NUM> alcohols, acetonitrile, DMF, ethyl acetate, DMSO, and ketone solvents; more preferably DMF, acetonitrile, acetone, <NUM>-methylbutanone.

In an autoclave, a reaction solvent, a catalyst and <NUM>-bromo-<NUM>-fluoro-<NUM>-azidomethyl-benzofuran are sequentially added. After nitrogen replacement, the hydrogen gas is pressurized to <NUM>-3Mpa, and the reaction is heated to <NUM>-<NUM> for <NUM>-<NUM>. After the reaction is over, the reaction system is monitored, the catalyst is filtered, and a conventional post-treatment method in the art is adopted for the treatment.

In one embodiment, the reaction solvent is selected from common solvents such as C<NUM>-C<NUM> alcohols, ethers, chlorinated alkanes; and more preferably methanol, ethanol.

In one embodiment, the catalyst is selected from a palladium catalyst or Raney nickel, more preferably a palladium catalyst, and the mass ratio of <NUM>-bromo-<NUM>-fluoro-<NUM>-azidomethyl-benzofuran to the catalyst is (<NUM>-<NUM>):<NUM>, more preferably <NUM>:<NUM>.

<NUM>-bromo-<NUM>-bromomethyl-<NUM>-fluorobenzofuran is dissolved in tetrahydrofuran and the resulting solution is dropped into a homemade or commercially available high-concentration ammonia-methanol solution at -<NUM>. The system is sealed and reacted under stirring.

In one embodiment, the reaction temperature is room temperature or ambient temperature, and the reaction time is <NUM>-<NUM>.

In an autoclave, a reaction solvent, a catalyst and <NUM>-bromo-<NUM>-(aminomethyl)-<NUM>-fluorobenzofuran are sequentially added. After nitrogen replacement, the hydrogen gas is pressurized to <NUM>-3Mpa, and the reaction is heated to <NUM>-<NUM> for <NUM>-<NUM>. After the reaction is over, the reaction system is monitored, the catalyst is filtered, and a conventional post-treatment method in the art is adopted for the treatment.

In one embodiment, the catalyst is selected from a palladium catalyst or Raney nickel, more preferably a palladium catalyst, and the mass ratio of <NUM>-bromo-<NUM>-(aminomethyl)-<NUM>-fluorobenzofuran to the catalyst is (<NUM>-<NUM>):<NUM>, more preferably <NUM>:<NUM>.

In the following examples, the compounds used were commercially available or obtained by self-made methods.

The solution of <NUM>-fluoro-<NUM>-methylphenol (<NUM>, <NUM> mol) in <NUM> of dichloromethane was cooled to -<NUM>, and kept at -<NUM>, and Br<NUM> (<NUM>, <NUM> mol) was added dropwise. The reaction lasted for <NUM> hours, and the reaction was monitored and no reaction material remained. <NUM> of saturated Na<NUM>S<NUM>O<NUM> solution and <NUM> of water were added, and the reaction liquid was slowly warmed to room temperature and separated. The aqueous phase was extracted with dichloromethane (<NUM>*<NUM>), and the organic layers were combined. After post-treatment and concentration, <NUM> of product was obtained, which was slurried with n-hexane to obtain <NUM> of product with a yield of <NUM>%.

Nuclear magnetic data: <NUM>H NMR (<NUM>, CDCl<NUM>, ppm): δ7. <NUM> (d, <NUM>), <NUM> (d, <NUM>), <NUM> (s, <NUM>).

To a solution of <NUM>-bromo-<NUM>-fluoro-<NUM>-methylphenol (<NUM>, <NUM> mol) in <NUM> of DMF was added potassium carbonate (<NUM>, <NUM> mol) and <NUM>-bromo-<NUM>,<NUM>-diethoxy ethane (<NUM>, <NUM> mol). The mixture was heated to <NUM> and reacted for <NUM>. The reaction was monitored and no reaction material remained. The reaction was cooled to room temperature; the mixture was poured into <NUM> of water, and then extracted with methyl tert-butyl ether (<NUM>*<NUM>). The combined organic phase was washed with <NUM> of water and <NUM> of brine, dried and concentrated to obtain <NUM> of crude product.

Nuclear magnetic data: <NUM>H NMR (<NUM>, CDCl<NUM>, ppm): δ <NUM> (d, <NUM>), <NUM> (d, <NUM>), <NUM> (t, <NUM>), <NUM> (d, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (t, <NUM>).

The mixture of polyphosphoric acid (<NUM>, <NUM> mol) in <NUM> of toluene was heated to <NUM>, and the solution of <NUM>-bromo-<NUM>-(<NUM>,<NUM>-diethoxyethoxy)-<NUM>-fluoro-<NUM>-toluene (<NUM>, <NUM> mol) in <NUM> of toluene was added dropwise. The reaction was heated to <NUM> for <NUM>. The reaction was monitored and no reaction material remained. The reaction was then cooled to room temperature and poured into <NUM> of water, and extracted with n-hexane (<NUM>*<NUM>). The combined organic phase was washed with <NUM> of water and <NUM> of brine, dried and concentrated to obtain <NUM> of crude product, which was then mixed with <NUM> of silica gel and washed with petroleum ether to obtain <NUM> of product, and the two-step yield of Examples <NUM>-<NUM> was <NUM>%.

Nuclear magnetic data: <NUM>H NMR (<NUM>, CDCl<NUM>, ppm): δ7. <NUM> (s, <NUM>), <NUM> (d, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

<NUM>-bromo-<NUM>-fluoro-<NUM>-methylbenzofuran (<NUM>, <NUM> mol), <NUM> of ethyl acetate, and then benzoyl peroxide (<NUM>, <NUM> mol) and NBS (<NUM> , <NUM> mol) were added sequentially. The flask was ventilated <NUM> times, then heated to <NUM> and reacted under nitrogen for <NUM> hours. The reaction was monitored and no reaction material remained. The reaction was cooled to room temperature, and poured into <NUM> of water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (<NUM>*<NUM>). The combined organic phase was washed with <NUM> of water and <NUM> of brine, dried and concentrated to obtain <NUM> of crude product, which was refined with methanol-n-hexane to obtain <NUM> of product, with a yield of <NUM>%.

Nuclear magnetic data: <NUM>H NMR (<NUM>, CDCl<NUM>, ppm): δ <NUM> (s, <NUM>), <NUM> (d, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

<NUM> of water, <NUM> of sodium azide (<NUM> mol, <NUM> eq) and <NUM> of acetone were added sequentially. The mixture was stirred at room temperature, and <NUM>-bromo-<NUM>-(bromomethyl)-<NUM>-fluorobenzofuran (<NUM>, <NUM> mol) was gradually added. The reaction was stirred at room temperature for <NUM> hours. The reaction was monitored and no reaction material remained. The reaction was added with <NUM> of water, and extracted with methyl tert-butyl ether (<NUM>*<NUM>). The combined organic phase was washed with water and brine, dried and concentrated to obtain <NUM> of product with a yield of <NUM>%.

<NUM> of methanol, <NUM> of <NUM>% Pd/C, and <NUM> of <NUM>-bromo-<NUM>-fluoro-<NUM>-azidomethylbenzofuran were added to an autoclave. After nitrogen replacement three times, the hydrogen gas was pressurized to <NUM> Mpa. The mixture was heated to <NUM> and reacted for <NUM> hours. After the reaction was over, the catalyst was filtered, and the filtrate was concentrated to obtain <NUM> of product in the form of hydrobromide, with a yield of <NUM>%.

Nuclear magnetic data: <NUM>H NMR (<NUM>, CDCl<NUM>, ppm): δ <NUM> (t, <NUM>), <NUM> (dd, <NUM>), <NUM> (t, <NUM>), <NUM> (s, <NUM>), <NUM> (t, <NUM>).

<NUM> of <NUM>-bromo-<NUM>-bromomethyl-<NUM>-fluorobenzofuran was dissolved in <NUM> of tetrahydrofuran and the resulting solution was dropped into 10N ammonia-methanol solution. After the addition, the reaction liquid was sealed and stirred overnight at room temperature, and concentrated. The crude product was slurried with <NUM> of ethyl acetate, filtered, and dried to obtain <NUM> of white solid product with a yield of <NUM>%.

Nuclear magnetic data: <NUM>H NMR (<NUM>, CDCl<NUM>, ppm): δ8. <NUM> (d, <NUM>), <NUM> (d, <NUM>), <NUM> (d, <NUM>), <NUM> (s, <NUM>).

Reference is made to the operation in Example <NUM> for pressurized hydrogenation to obtain the product.

Claim 1:
A preparation method of (<NUM>-fluoro-<NUM>,<NUM>-dihydrobenzofuran-<NUM>-yl)methylamine or a salt thereof, which comprises the following reaction steps:
<NUM>) Taking <NUM>-fluoro-<NUM>-methylphenol as the starting material, and brominating it at a reaction temperature of -<NUM> to -<NUM> for a reaction time of <NUM>-<NUM> to obtain <NUM>-bromo-<NUM>-fluoro-<NUM>-methylphenol;
<NUM>) Performing O-alkylation reaction between <NUM>-bromo-<NUM>-fluoro-<NUM>-methylphenol and <NUM>-bromo-<NUM>,<NUM>-diethoxyethane at a reaction temperature is <NUM>-<NUM> for a reaction time of <NUM>-<NUM> to obtain <NUM>-bromo-<NUM>-(<NUM>,<NUM>-diethoxyethoxy)-<NUM>-fluoro-<NUM>-toluene;
<NUM>) Cyclizing <NUM>-bromo-<NUM>-(<NUM>,<NUM>-diethoxyethoxy)-<NUM>-fluoro-<NUM>-toluene to obtain <NUM>-bromo-<NUM>-fluoro-<NUM>-methylbenzofuran;
<NUM>) Brominating <NUM>-bromo-<NUM>-fluoro-<NUM>-methylbenzofuran to obtain <NUM>-bromo-<NUM>-(bromomethyl)-<NUM>-fluorobenzofuran;
<NUM>) Preparing (<NUM>-fluoro-<NUM>,<NUM>-dihydrobenzofuran-<NUM>-yl)methylamine or a salt thereof using the following two-step reaction in any one of <NUM> or <NUM>:
<NUM>) Aziding <NUM>-bromo-<NUM>-(bromomethyl)-<NUM>-fluorobenzofuran in the presence of an azide, at a reaction temperature of <NUM>-<NUM> for a reaction time of <NUM>-<NUM>, to obtain <NUM>-bromo-<NUM>-fluoro-<NUM>-azidomethyl-benzofuran, which is then hydrogenated, at a reaction temperature of <NUM>-<NUM> for a reaction time of <NUM>-<NUM>, to obtain (<NUM>-fluoro-<NUM>,<NUM>-dihydrobenzofuran-<NUM>-yl)methylamine or a salt thereof; or
<NUM>) Ammonolyzing <NUM>-bromo-<NUM>-(bromomethyl)-<NUM>-fluorobenzofuran, at a reaction temperature of -<NUM>-<NUM> for a reaction time of <NUM>-<NUM>, to obtain <NUM>-bromo-<NUM>-(aminomethyl)-<NUM>-fluorobenzofuran, which is then hydrogenated, at a reaction temperature of <NUM>-<NUM> for a reaction time of <NUM>-<NUM>, to obtain (<NUM>-fluoro-<NUM>,<NUM>-dihydrobenzofuran-<NUM>-yl)methylamine or a salt thereof.