Preparation method of (5-fluoro-2, 3-dihydrobenzofuran-4-yl) methylamine hydrochloride

Abstract

The invention provides a preparation method of (5-fluoro-2, 3-dihydrobenzofuran-4-yl) methylamine hydrochloride, the (5-fluoro-2, 3-dihydrobenzofuran-4-yl) methylamine hydrochloride is a compound as shown in a formula a, and the preparation method comprises the following steps: adding a compound b into an acid solution to remove Boc protecting groups to obtain a compound a, and adding a compound b into a reaction kettle to obtain a compound b; according to the preparation method, an eight-step synthesis route is provided, the (5-fluoro-2, 3-dihydrobenzofuran-4-yl) methylamine hydrochloride is prepared through the eight-step reaction of formylation, deprotection, substitution, upper protection, ring closing, deprotection, ammonification and deprotection, dangerous equipment such as a highly toxic reagent, an expensive palladium catalyst and high-pressure hydrogenation is not used in the whole reaction process, and the preparation method is simple and convenient to operate and easy to implement. The yield of each step is higher than that of the prior art.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and in particular relates to a method for preparing (5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamine hydrochloride. Background Art

[0002] PcG (polycomb group) proteins, as an epigenetic modification system, are responsible for cell differentiation during development through transcriptional repression. In mammals, PcG proteins are part of two major transcriptional repression complexes, polycomb repressive complexes 1 and 2 (PRC1 and PRC2). PRC2 contains histone methyltransferase activity, which can promote chromatin remodeling and transcriptional silencing through trimethylation at H3K27Me3. Dysregulation of PRC2 activity is closely related to human cancers, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and epithelioid sarcoma that have been discovered. Therefore, scientists are making great efforts to develop small molecule inhibitors to regulate the activity of PRC2, and such inhibitors are a hot topic in the field of medicine.

[0003] In the prior art, patent document WO2017 / 221100 proposes the following synthesis method, and the specific synthesis route is shown in Route 1:

[0004]

[0005] This route has the following technical problems: the starting materials are expensive, polyphosphoric acid PPA is used, and cyanide, precious metal palladium catalyst, and hydrogenation pressure vessel are required. The pilot-scale operation is unsafe, post-processing is difficult, and the positional isomer intermediates produced are difficult to separate and purify.

[0006] Chinese patent ZL201911308456.3 proposes the following synthesis method, and the specific synthesis route is shown in Route 2:

[0007]

[0008] This route has the following technical problems: first, the overall yield is low, especially in the third step, the aldehyde formylation reaction, the yield is only about 20%; second, the last step uses zinc powder for high-temperature reduction, which is unsafe to produce and difficult to carry out pilot-scale production. The low yield leads to high material costs.

[0009] In summary, the prior art has the following defects: 1) the use of highly toxic reagents, high reaction risk; 2) low reaction yield. Therefore, it is necessary to develop a more effective preparation method of PRC2 inhibitor ((5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamine hydrochloride) to facilitate the development of PRC2 inhibitors. Summary of the invention

[0010] In view of this, the present invention aims to overcome the defects in the prior art and provides a method for preparing (5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamine hydrochloride.

[0011] To achieve the above object, the technical solution of the present invention is achieved as follows:

[0012] A method for preparing (5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamine hydrochloride, wherein the (5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamine hydrochloride is a compound as shown in formula a, comprising the following steps:

[0013] Compound b is added to an acidic solution to remove the Boc protecting group to obtain compound I, namely:

[0014]

[0015] Preferably, the acidic solution is one or more of a hydrogen chloride / ethyl acetate solution, a hydrogen chloride / dioxane solution, and a hydrogen chloride / isopropanol solution; more preferably, it is a hydrogen chloride / ethyl acetate solution, and the molar ratio of the compound b to the acidic solution is (1.0-2.0):(3.0-20.0); preferably, the reaction temperature is -10 to 0°C, and the reaction time is 5 to 40 hours.

[0016] Preferably, the preparation method of compound b comprises the following steps:

[0017] Compound c is dissolved in the first solvent, and tert-butyl carbamate, acid and silane are added to undergo an amination reaction to obtain compound b, namely:

[0018]

[0019] Preferably, the first solvent is one or more of dichloromethane, tetrahydrofuran, and acetonitrile; more preferably dichloromethane; the silane is one or more of triethylsilane, diphenylchlorosilane, and phenyldimethylsilane, more preferably triethylsilane; the acid is one or more of trifluoroacetic acid, tri(pentafluorophenyl)borane, and boron trifluoride ether; more preferably trifluoroacetic acid; the molar ratio of compound c, tert-butyl carbamate, acid, and silane is (1.0-2.0): (2.0-4.0): (1.0-4.0): (1.0-4.0), preferably, the reaction temperature is 0-10°C, and the reaction time is 10-48h.

[0020] Preferably, the preparation method of compound 3 comprises the following steps:

[0021] Compound e is dissolved in a second solvent, and a metal organic reagent is added to undergo a cyclization reaction to obtain compound d. Compound d is dissolved in a third solvent, and a hydrochloric acid aqueous solution is added to react to obtain compound c, namely:

[0022]

[0023] Preferably, the second solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydrofuran / hexane; more preferably tetrahydrofuran; the first metal organic reagent is one or more of Grignard reagents such as n-butyl lithium n-hexane solution and isopropyl magnesium chloride, more preferably n-butyl lithium n-hexane solution; preferably, the molar ratio of the compound e to the metal organic reagent is (1.0-2.0): (1.0-2.0); preferably, the reaction temperature is -90 to -60°C, more preferably -70±5°C; preferably, the reaction time is 0.5-10h.

[0024] Preferably, the third solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydrofuran / hexane; more preferably tetrahydrofuran; preferably, the molar ratio of compound d to hydrochloric acid is (1.0-2.0): (2.0-5.0); preferably, the reaction temperature is -50 to -40°C; preferably, the reaction time is 1.0-10h.

[0025] Preferably, the preparation method of compound e comprises the following steps:

[0026] Compound f is dissolved in the fourth solvent, and the first catalyst and ethylene glycol are added to undergo condensation reaction to obtain compound e, namely:

[0027]

[0028] Preferably, the fourth solvent is one or more of toluene, xylene, and cyclohexane, more preferably toluene; the first catalyst is one or more of p-toluenesulfonic acid, triethyl orthoformate, and iodine, more preferably p-toluenesulfonic acid; the molar ratio of the compound f, ethylene glycol, and the catalyst is (1.0-2.0): (2.0-10.0): (0.05-0.3); preferably, the reaction temperature is gradually increased to an internal temperature of 100-120°C and an external temperature of 120-140°C.

[0029] Preferably, the preparation method of compound f comprises the following steps:

[0030] Compound g is dissolved in the fifth solvent, and a base and 1,2-dibromoethane are added to undergo a substitution reaction to obtain compound f, namely:

[0031]

[0032] Preferably, the fifth solvent is one or more of acetonitrile, N,N-dimethylformamide, and dichloromethane, more preferably acetonitrile; the base is one or more of potassium carbonate, sodium hydroxide, and lithium hydride, more preferably potassium carbonate; the molar ratio of the compound g, the base and 1,2-dibromoethane is (1.0-2.0): (1.0-3.0): (5.0-15.0); preferably, the reaction temperature is gradually increased to an internal temperature of 50 to 90°C.

[0033] Preferably, the preparation method of compound g comprises the following steps:

[0034] Compound h is dissolved in the sixth solvent, and boron tribromide is added to carry out a demethylation reaction to obtain compound g, namely:

[0035]

[0036] Preferably, the sixth solvent is one or more of dichloromethane, dichloroethane, and toluene, more preferably dichloromethane; the molar ratio of compound 8 to boron tribromide is (1.0-2.0): (1.5-5.0); preferably, the reaction temperature is -10 to 0°C; preferably, the reaction time is 1.0-10.0h.

[0037] Preferably, the preparation method of compound 8 comprises the following steps:

[0038] Compound i is dissolved in the seventh solvent, lithium diisopropylamide is added to react, and then added to the third catalyst to continue the reaction to obtain an intermediate, and the intermediate is added to a hydrolysis solution for hydrolysis to obtain compound h, namely:

[0039]

[0040] Preferably, the seventh solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and n-hexane; the third catalyst is one or more of N,N-dimethylformamide, ethyl formate, and N-formylpiperidine, more preferably N,N-dimethylformamide; the hydrolysis solution is one or more of hydrochloric acid aqueous solution, ammonium chloride aqueous solution, and citric acid aqueous solution, more preferably hydrochloric acid aqueous solution; the molar ratio of compound i, lithium diisopropylamide, the third catalyst, and the hydrolysis solution is (1.0-2.0): (1.0-4.0): (1.5-4.0): (1.0-5.0); preferably, the reaction temperature is -90 to -60°C, more preferably -70±5°C; preferably, the reaction time is 1.0-10.0h.

[0041] Preferably, the preparation method of compound a comprises the following steps:

[0042]

[0043] Compared with the prior art, the present invention has the following advantages:

[0044] The preparation method of (5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamine hydrochloride of the present invention provides an 8-step synthesis route, and (5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamine hydrochloride is prepared through 8 steps of reaction, namely, formylation, deprotection, substitution, upper protection, cyclization, deprotection, amination, and deprotection. No highly toxic reagents, expensive palladium catalysts, high-pressure hydrogenation and other dangerous equipment are used in the overall reaction process, and the yield of each step is higher than the existing technical level; the technical route is novel, the operation is simple, the purification is easy, and the product is suitable for large-scale industrial production. DETAILED DESCRIPTION

[0045] Unless otherwise defined, the technical terms used in the following examples have the same meanings as those generally understood by those skilled in the art to which the present invention belongs. The test reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the experimental methods, unless otherwise specified, are all conventional methods.

[0046] The present invention is described in detail below in conjunction with embodiments.

[0047] Example 1

[0048] (1) Preparation of compound h

[0049]

[0050] Add THF (600mL, 6vol) and diisopropylamine (67.9g, 1.375eq) to reaction bottle 1, dissolve, complete the addition, replace with nitrogen 3 times, control the temperature to -20 to -30°C, and drop 2.5M n-butyl lithium n-hexane solution (243.9mL, 1.25eq) into the reaction system. Complete the addition, keep warm and stir for 30min. Add compound i (100g, 1.0eq) to reaction bottle 2, add THF (600mL, 6vol) and replace with nitrogen 3 times after the addition. The system is a transparent clear liquid, and the temperature is controlled to -70±5°C.

[0051] Control the temperature to -70±5℃, add reaction bottle 1 dropwise to reaction bottle 2, there is obvious heat release in the early stage, and the addition is completed, and the reaction is kept warm for 1h. Add DMF (71.3g, 2.0eq) and react for 2h. Add 6N hydrochloric acid aqueous solution (1000mL, 10vol) to reaction bottle 3, and control the temperature to 0-5℃ in dry ice ethanol external bath. Add reaction bottle 2 dropwise to reaction bottle 3, add and return to room temperature, extract with ethyl acetate (1000mL, 10vol)*3, combine the organic phases, add 10% sodium sulfate (700mL, 7vol)*4 to wash (DMF residue), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure at 40℃ until no fraction flows out. Compound h is obtained as a yellow solid product 96.6g, with a yield of 85%.

[0052] 1 H NMR (CDCl3, 400MHz) δ10.380~10.379(s,1H), 7.265~7.063(m,2H), 3.925(s,3H). GCMS=234.00.

[0053] (2) Preparation of compound g

[0054]

[0055] Add DCM (1255 mL, 13.8 vol) to the reaction bottle, start stirring, add compound h (90.93 g, 1.0 eq), replace with nitrogen 3 times, stir until dissolved, cool to -10 to 0 ° C, and drop boron tribromide solution (224.83 g, 2.3 eq) into the reaction system. After addition, remove the cooling and return to room temperature. Keep warm for 3 hours.

[0056] The system was temperature controlled to 0±5°C, H2O (2273 mL, 25 vol) was added dropwise to quench, DCM (909.3 mL, 10 vol) was added to extract and separate, and the aqueous phase was extracted with EA (909.3, 10 vol)*2 times. All organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 40°C until there was no fraction to obtain compound g as a yellow solid (86.65 g, yield 100%).

[0057] 1 H NMR (CDCl3, 400MHz) δ10.331~10.329(s,1H), 7.281~7.246(m,1H), 7.138~7.091(m,1H), 5.924~5.304(s,1H). GCMS=219.00.

[0058] (3) Preparation of compound f

[0059]

[0060] Add acetonitrile (683.7mL, 8vol), compound g (85.46g, 1.0eq) to the reaction bottle in sequence, stir until dissolved, add potassium carbonate (70.1g, 1.3eq), add 1,2-dibromoethane (667.1g, 9.1eq), replace with nitrogen 3 times, gradually increase the temperature to 80±3℃, keep warm and stir overnight. Return to room temperature and filter, rinse the filter cake with 10vol acetonitrile, collect the filtrate, and concentrate under reduced pressure at 40℃ until no fraction flows out to obtain compound f as a yellow solid (114.5g, yield 90%).

[0061] 1 H NMR (CDCl3, 400MHz) δ10.369~10.367(s,1H), 7.263~7.110(m,2H), 4.367~4.336(m,2H), 3.714~3.683(m,2H). GCMS=326.00.

[0062] (4) Preparation of compound e

[0063]

[0064] Add toluene (890 mL, 10 vol) and compound f (89.03 g, 1.0 eq) to the reaction bottle, stir to dissolve, add TsOH (4.7 g, 0.1 eq), add ethylene glycol (84.77 g, 5.0 eq), purge with nitrogen, increase the temperature gradually to 120°C internal temperature, increase the external temperature to 130°C, reflux vigorously to remove water, and keep stirring for 3 h.

[0065] The disappearance of the starting material was monitored by TLC, developed with n-hexane:ethyl acetate (5:1), and colored at 254 nm.

[0066] The system was stopped from heating and returned to room temperature, and concentrated under reduced pressure at 55°C until no fraction flowed out to obtain a yellow solid crude product. Sodium bicarbonate aqueous solution (446mL, 5vol) and EA (890mL, 10vol)*2 were added for extraction, and the organic phases were combined, dried, concentrated and filtered to obtain a yellow solid crude product of compound e. MTBE (267mL, 3vol) was added to the crude product and slurried at room temperature for 60min, filtered, and the filter cake was rinsed with MTBE (89mL, 1vol). Dry in a 40°C forced air drying oven to constant weight to obtain an off-white solid (80.8g, yield 80%).

[0067] 1H NMR (CDCl3, 400MHz) δ7.261~7.016(m,1H), 6.991~6.902(m,1H), 6.393~6.3 90(s,1H), 4.311~4.230(m,4H), 4.086~4.032(m,2H), 3.677~3.645(m,2H). GCMS=370.00.

[0068] (5) Preparation of compound c

[0069]

[0070] Add THF (1235.2mL, 18.8vol) and compound e (65.7g, 1.0eq) to the reaction bottle, stir and dissolve, the system is a colorless transparent clear liquid, and replace with nitrogen 3 times. Control the temperature at -70±5℃, add 2.5M n-butyl lithium hexane solution (88.8mL, 1.25eq) to the system, and there is obvious heat release during the addition. After the addition, keep the reaction for 1h and the reaction is over. Cool the system to -50~-40℃, add dropwise to 0~10℃ 2N HCl aqueous solution (5vol), after the reaction is completed, add saturated sodium bicarbonate aqueous solution to the system to adjust pH=7-8. Add EA (328.5mL, 5vol)*2 to extract and separate. Dry and filter the organic phase, and concentrate under reduced pressure at 40℃ until no fraction flows out to obtain a crude yellow oil of compound c. Purify by wet loading column chromatography (Hex:EA=100:1~50:1). The eluate was concentrated under reduced pressure to obtain an off-white solid (20.64 g, yield 70%).

[0071] 1 H NMR (CDCl3, 400MHz) δ10.398 (s, 1H), 7.274~6.918 (m, 2H), 4.666~4.622 (m, 2H), 3.548~3.504 (m, 2H). GCMS=166.00.

[0072] (6) Preparation of compound b

[0073]

[0074] Add DCM (294.8mL, 10vol), compound c (37.3g, 1.0eq) to the reaction bottle, stir to dissolve, add triethylsilane (61.9g, 3.0eq), tert-butyl carbamate (10.46g, 2.0eq), after addition, replace with nitrogen three times, control the temperature at 0-10℃ and stir for 30min. Control the temperature at 0-10℃, add trifluoroacetic acid (40.47g, 2.0eq) dropwise to the reaction system, and no obvious heat release is observed during the addition. After addition, remove the cooling and heat to T=30℃. Keep the reaction warm for 24h. Add H2O (294.8mL, 10vol) to the reaction system, add DCM (147.4mL, 5vol)*2 to extract, combine the organic phases, dry and filter. Concentrate under reduced pressure at 40℃ until no fraction flows out. Compound b is obtained as a yellow solid (60g, 100%).

[0075] 1 H NMR (DMSO-d6, 400MHz) δ7.25 (bs, 1H), 6.88 ~ 6.84 (m, 1H), 6.65 ~ 6.1 (m, 1H), 4.53 (t, 2H), 4.12 (d, 1H), 3.21 (t, 2H), 1.38 (s, 1H). LCMS[M+1]=268.46.

[0076] (7) Preparation of compound a

[0077]

[0078] Add compound b (37.3 g, 1.0 eq) to the reaction flask, add 4M HCl / EA (186.5 mL, 5 vol) to dissolve, and control the temperature of ice brine to -10-0°C. Keep warm and stir overnight. Add H2O (373 mL, 10 vol) to the reaction system, add EA (5 vol, 186.5 mL)*2 to extract and separate. Discard the organic phase. Add saturated sodium bicarbonate aqueous solution to the aqueous phase to adjust the pH to 7-8, add EA (186.5 mL, 5 vol)*2 to extract, collect the organic phase, dry it with anhydrous sodium sulfate, filter, and concentrate under reduced pressure at 40°C until no fraction flows out to obtain a yellow crude oil of compound a. Control the temperature to -10-0°C, add 4M HCl / EA (186.5 mL, 5 vol) to the crude product, keep warm and stir for 10 h, filter, collect the filter cake, and obtain an off-white solid (23.03 g, yield: 81%).

[0079] 1H NMR (DMSO-d6, 400MHz) δ 8.66 (bs, 3H), 7.01 ~ 6.97 (m, 1H), 6.80 ~ 6.77 (m, 1H), 4.57 (t, 2H), 3.94 (bs, 2H), 3.43 (t, 2H). LCMS[M+1]=168.53.

[0080] Example 2

[0081] (1) Preparation of compound h

[0082]

[0083] Add 2-MeTHF (600 mL, 6 vol) and diisopropylamine (54.3 g, 1.10 eq) to reaction bottle 1, dissolve, replace with nitrogen 3 times, control the temperature to -20 to -30 ° C, and add 2.5 M n-butyl lithium n-hexane solution (195.2 mL, 1.00 eq) dropwise to the reaction system. After addition, stir at this temperature for 30 min.

[0084] Compound i (100 g, 1.0 eq) was added to reaction bottle 2, and 2-MeTHF (600 mL, 6 vol) was added. The nitrogen atmosphere was replaced three times after the addition. The system was a transparent liquid and the temperature was controlled to -80±5°C.

[0085] The temperature was controlled to -80±5°C, and reaction flask 1 was added dropwise to reaction flask 2. There was obvious heat release in the early stage, and after the addition was completed, the reaction was kept warm for 1 hour. Ethyl formate (54.2 g, 1.5 eq) was added and the reaction was continued for 10 hours.

[0086] Add 6N ammonium chloride aqueous solution (1000mL, 10vol) to reaction flask 3, and control the temperature to 0-5°C with dry ice ethanol external bath. Add reaction flask 2 dropwise to reaction flask 3, return to room temperature, extract with ethyl acetate (1000mL, 10vol)*3, combine the organic phases, add 10% sodium sulfate (700mL, 7vol)*4 for washing (DMF residue), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure at 40°C until no fraction flows out. Compound h is obtained as a yellow solid product of 96.6g, with a yield of 85%.

[0087] (2) Preparation of compound g

[0088]

[0089] Add dichloroethane (1255mL, 13.8vol) to the reaction bottle, start stirring, add compound h (90.93g, 1.0eq), replace with nitrogen 3 times, stir until dissolved, cool to -10 to 0℃, and drop boron tribromide solution (146.61g, 1.5eq) into the reaction system. After addition, remove cooling and return to room temperature. Keep warm for 10h.

[0090] The system was temperature controlled to 0±5°C, H2O (2273 mL, 25 vol) was added dropwise to quench, DCM (909.3 mL, 10 vol) was added to extract and separate, and the aqueous phase was extracted with EA (909.3, 10 vol)*2 times. All organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 40°C until there was no fraction to obtain compound g as a yellow solid (86.65 g, yield 100%).

[0091] (3) Preparation of compound f

[0092]

[0093] Add DMF (683.7 mL, 8 vol) and compound g (85.46 g, 1.0 eq) to the reaction flask in sequence, stir until dissolved, add sodium hydroxide (15.6 g, 1.0 eq), add 1,2-dibromoethane (366.5 g, 5.0 eq), replace with nitrogen 3 times, gradually increase the temperature to 55±5°C, keep warm and stir overnight. Return to room temperature and filter, rinse the filter cake with 10 vol acetonitrile, collect the filtrate, and concentrate under reduced pressure at 40°C until no fraction flows out to obtain compound f as a yellow solid (114.5 g, yield 90%).

[0094] (4) Preparation of compound e

[0095]

[0096] Add xylene (890 mL, 10 vol) and compound f (89.03 g, 1.0 eq) to the reaction bottle, stir to dissolve, add triethyl orthoformate (2.4 g, 0.05 eq), add ethylene glycol (33.88 g, 2.0 eq), purge with nitrogen, increase the temperature gradually to 100°C internal temperature, increase the external temperature to 130°C, reflux vigorously to separate water, and keep stirring for 3 h.

[0097] The disappearance of the starting material was monitored by TLC, developed with n-hexane:ethyl acetate (5:1), and colored at 254 nm.

[0098] The system was stopped from heating and returned to room temperature, and concentrated under reduced pressure at 55°C until no fraction flowed out to obtain a yellow solid crude product. Sodium bicarbonate aqueous solution (446mL, 5vol) and EA (890mL, 10vol)*2 were added for extraction, and the organic phases were combined, dried, concentrated and filtered to obtain a yellow solid crude product of compound e. MTBE (267mL, 3vol) was added to the crude product and slurried at room temperature for 60min, filtered, and the filter cake was rinsed with MTBE (89mL, 1vol). Drying in a 40°C forced air drying oven to constant weight gave an off-white solid (80.8g, yield 80%).

[0099] (5) Preparation of compound c

[0100]

[0101] Add 2-MeTHF (1235.2mL, 18.8vol) and compound e (65.7g, 1.0eq) to the reaction bottle, stir and dissolve, the system is a colorless transparent clear liquid, and replace with nitrogen 3 times. Control the temperature at -70±5℃, add 2.5M n-butyl lithium n-hexane solution (142mL, 2.0eq) to the system, and there is obvious heat release during the addition. After the addition, keep the reaction warm for 0.5h and the reaction is over. Cool the system to -50~-40℃, add dropwise to 0~10℃ 2N HCl aqueous solution (5vol), after the reaction is completed, add saturated sodium bicarbonate aqueous solution to the system to adjust pH=7-8. Add EA (328.5mL, 5vol)*2 to extract and separate. Dry and filter the organic phase, and concentrate under reduced pressure at 40℃ until no fraction flows out to obtain a crude yellow oil of compound c. Purification was performed by wet loading column chromatography (Hex:EA=100:1-50:1). The eluate was concentrated under reduced pressure to obtain an off-white solid (20.64 g, yield 70%).

[0102] (6) Preparation of compound b

[0103]

[0104] Add THF (373mL, 10vol), compound c (37.3g, 1.0eq) to the reaction bottle, stir to dissolve, add diphenylchlorosilane (49.1g, 1.0eq), tert-butyl carbamate (10.46g, 2.0eq), after addition, replace with nitrogen three times, control the temperature at 0-10℃ and stir for 30min. Control the temperature at 0-10℃, add tri(pentafluorophenyl)borane (114.9g, 1.0eq) to the reaction system, and no obvious heat release is observed during the addition. After addition, remove the cooling and heat to T=30℃. Keep the reaction warm for 10h. Add H2O (373mL, 10vol) to the reaction system, add DCM (186.5mL, 5vol)*2 to extract, combine the organic phases, dry and filter. Concentrate under reduced pressure at 40℃ until no fraction flows out, and obtain compound b as a yellow solid (60g, 100%).

[0105] (7) Preparation of compound a

[0106]

[0107] Add compound b (37.3 g, 1.0 eq) to the reaction flask, add 4M hydrogen chloride / dioxane solution (105 mL, 2.8 vol) to dissolve, and control the temperature of ice brine to -10-0°C. Keep warm and stir overnight. Add H2O (373.3 mL, 10 vol) to the reaction system, add EA (5 vol, 186.5 mL)*2 to extract and separate. Discard the organic phase. Add saturated sodium bicarbonate aqueous solution to the aqueous phase to adjust the pH to 7-8, add EA (186.5 mL, 5 vol)*2 to extract, collect the organic phase, dry it with anhydrous sodium sulfate, filter, and concentrate under reduced pressure at 40°C until no fraction flows out to obtain a yellow crude oil of compound a. Control the temperature to -10-0°C, add 4M HCl / EA (186.5 mL, 5 vol) to the crude product, keep warm and stir for 5 h, filter, collect the filter cake, and obtain an off-white solid (23.03 g, yield: 81%).

[0108] Example 3

[0109] (1) Preparation of compound h

[0110]

[0111] Add THF (600 mL, 6 vol) and diisopropylamine (108.6 g, 2.2 eq) to reaction bottle 1, dissolve, replace with nitrogen 3 times, control the temperature to -20 to -30 ° C, and add 2.5 M n-butyl lithium n-hexane solution (390.2 mL, 2.0 eq) dropwise to the reaction system. After addition, stir at this temperature for 30 min.

[0112] Compound i (100 g, 1.0 eq) was added to reaction bottle 2, and n-hexane (600 mL, 6 vol) was added. After the addition, the nitrogen was replaced three times. The system was a transparent liquid, and the temperature was controlled to -80±5°C.

[0113] The temperature was controlled to -80±5°C, and reaction flask 1 was added dropwise to reaction flask 2. There was obvious heat release in the early stage, and after the addition was completed, the reaction was kept warm for 1 hour. N-formylpiperidine (110.4 g, 2.0 eq) was added and the reaction was continued for 1 hour.

[0114] Add 6N citric acid aqueous solution (1000mL, 10vol) to reaction flask 3, and control the temperature to 0-5°C with dry ice ethanol external bath. Add reaction flask 2 dropwise to reaction flask 3, return to room temperature, extract with ethyl acetate (1000mL, 10vol)*3, combine the organic phases, add 10% sodium sulfate (700mL, 7vol)*4 for washing (DMF residue), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure at 40°C until no fraction flows out. Compound h is obtained as a yellow solid product of 96.6g with a yield of 85%.

[0115] (2) Preparation of compound g

[0116]

[0117] Add toluene (1255mL, 13.8vol) to the reaction flask, start stirring, add compound h (90.93g, 1.0eq), replace with nitrogen 3 times, stir until dissolved, cool to -10 to 0°C, and drop boron tribromide solution (244.4g, 2.5eq) into the reaction system. After addition, remove cooling and return to room temperature. Keep warm for 1h.

[0118] The system was temperature controlled to 0±5°C, H2O (2273 mL, 25 vol) was added dropwise to quench, DCM (909.3 mL, 10 vol) was added to extract and separate, and the aqueous phase was extracted with EA (909.3, 10 vol)*2 times. All organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 40°C until there was no fraction to obtain compound g as a yellow solid (86.65 g, yield 100%).

[0119] (3) Preparation of compound f

[0120]

[0121] DCM (683.7 mL, 8 vol) and compound g (85.46 g, 1.0 eq) were added to the reaction flask in sequence, stirred until dissolved, lithium hydride (4.7 g, 1.5 eq) was added, 1,2-dibromoethane (550.2 g, 7.5 eq) was added, nitrogen was replaced 3 times, the temperature was gradually increased to 70 ± 5 ° C, and the temperature was kept and stirred overnight. Return to room temperature and filter, the filter cake was rinsed with 10 vol acetonitrile, the filtrate was collected, and the reduced pressure was concentrated at 40 ° C until no fraction flowed out to obtain compound f as a yellow solid (114.5 g, yield 90%).

[0122] (4) Preparation of compound e

[0123]

[0124] Add cyclohexane (890 mL, 10 vol) and compound f (89.03 g, 1.0 eq) to the reaction bottle, stir to dissolve, add iodine (10.4 g, 0.15 eq), add ethylene glycol (84.77 g, 5.0 eq), purge with nitrogen, increase the temperature gradually to 100°C internal temperature, increase the external temperature to 140°C, reflux vigorously to remove water, and keep stirring for 3 h.

[0125] The disappearance of the starting material was monitored by TLC, developed with n-hexane:ethyl acetate (5:1), and colored at 254 nm.

[0126] The system was stopped from heating and returned to room temperature, and concentrated under reduced pressure at 55°C until no fraction flowed out to obtain a yellow solid crude product. Sodium bicarbonate aqueous solution (446mL, 5vol) and EA (890mL, 10vol)*2 were added for extraction, and the organic phases were combined, dried, concentrated and filtered to obtain a yellow solid crude product of compound e. MTBE (267mL, 3vol) was added to the crude product and slurried at room temperature for 60min, filtered, and the filter cake was rinsed with MTBE (89mL, 1vol). Dry in a 40°C forced air drying oven to constant weight to obtain an off-white solid (80.8g, yield 80%).

[0127] (5) Preparation of compound c

[0128]

[0129] Add tetrahydrofuran / hexane (1235.2mL, 18.8vol) and compound e (65.7g, 1.0eq) to the reaction bottle, stir and dissolve, the system is a colorless transparent clear liquid, and replace with nitrogen 3 times. Control the temperature at -80±5℃, add 2.0M isopropylmagnesium chloride (177.6mL, 2.0eq) to the system, and there is obvious heat release during the addition. After the addition, keep the reaction for 10h and the reaction is over. Cool the system to -50~-40℃, add dropwise to 0~10℃ 2N HCl aqueous solution (5vol), after the reaction is completed, add saturated sodium bicarbonate aqueous solution to the system to adjust pH=7-8. Add EA (328.5mL, 5vol)*2 to extract and separate. Dry and filter the organic phase, and concentrate under reduced pressure at 40℃ until no fraction flows out to obtain a crude yellow oil of compound c. Purification was performed by wet loading column chromatography (Hex:EA=100:1-50:1). The eluate was concentrated under reduced pressure to obtain an off-white solid (20.64 g, yield 70%).

[0130] (6) Preparation of compound b

[0131]

[0132] Add ACN (373mL, 10vol), compound c (37.3g, 1.0eq) to the reaction bottle, stir to dissolve, add phenyldimethylsilane (61.2g, 2.0eq), tert-butyl carbamate (52.6g, 2.0eq), after addition, replace with nitrogen three times, control the temperature at 0-10℃ and stir for 30min. Control the temperature at 0-10℃, add boron trifluoride ether (63.7g, 2.0eq) dropwise to the reaction system, and no obvious heat release is observed during the addition. After addition, remove the cooling and heat to T=30℃. Keep the reaction warm for 48h. Add H2O (373mL, 10vol) to the reaction system, add DCM (186.5mL, 5vol)*2 to extract, combine the organic phases, dry and filter. Concentrate under reduced pressure at 40℃ until no fraction flows out. Compound b is obtained as a yellow solid (60g, 100%).

[0133] (7) Preparation of compound a

[0134]

[0135] Add compound b (37.3 g, 1.0 eq) to the reaction flask, add 4M hydrogen chloride / isopropanol solution (348.8 mL, 9.3 vol) to dissolve, and control the temperature of ice brine to -10-0°C. Keep warm and stir overnight. Add H2O (373.3 mL, 10 vol) to the reaction system, add EA (5 vol, 186.5 mL)*2 to extract and separate. Discard the organic phase. Add saturated sodium bicarbonate aqueous solution to the aqueous phase to adjust the pH to 7-8, add EA (186.5 mL, 5 vol)*2 to extract, collect the organic phase, dry it with anhydrous sodium sulfate, filter, and concentrate under reduced pressure at 40°C until no fraction flows out, and obtain compound a as a yellow crude oil. Control the temperature to -10-0°C, add 4M HCl / EA (186.5 mL, 5 vol) to the crude product, keep warm and stir for 40 h, filter, collect the filter cake, and obtain an off-white solid (23.03 g, yield: 81%).

[0136] The above description is only a preferred embodiment of the present invention and is not intended to limit the invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing (5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamine hydrochloride, characterized in that: The (5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamine hydrochloride is a compound as shown in formula a, comprising the following steps: Compound b is added to an acidic solution to remove the Boc protecting group to obtain compound a, namely:

2. The preparation method according to claim 1, characterized in that: The acidic solution is one or more of a hydrogen chloride / ethyl acetate solution, a hydrogen chloride / dioxane solution, and a hydrogen chloride / isopropanol solution; more preferably a hydrogen chloride / ethyl acetate solution, and the molar ratio of the compound b to the acidic solution is (1.0-2.0):(3.0-20.0); preferably, the reaction temperature is -10 to 0°C, and the reaction time is 5 to 40 hours.

3. The preparation method according to claim 2, characterized in that: The preparation method of the compound 2 comprises the following steps: Compound c is dissolved in the first solvent, and tert-butyl carbamate, acid and silane are added to undergo an amination reaction to obtain compound b, namely: Preferably, the first solvent is one or more of dichloromethane, tetrahydrofuran, and acetonitrile; more preferably dichloromethane; the silane is one or more of triethylsilane, diphenylchlorosilane, and phenyldimethylsilane, more preferably triethylsilane; the acid is one or more of trifluoroacetic acid, tri(pentafluorophenyl)borane, and boron trifluoride ether; more preferably trifluoroacetic acid; the molar ratio of compound c, tert-butyl carbamate, acid, and silane is (1.0-2.0): (2.0-4.0): (1.0-4.0): (1.0-4.0), preferably, the reaction temperature is 0-10°C, and the reaction time is 10-48h.

4. The preparation method according to claim 3, characterized in that: The preparation method of compound 3 comprises the following steps: Compound e is dissolved in a second solvent, and a metal organic reagent is added to undergo a cyclization reaction to obtain compound d. Compound d is dissolved in a third solvent, and a hydrochloric acid aqueous solution is added to react to obtain compound c, namely: Preferably, the second solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and tetrahydrofuran / hexane; more preferably tetrahydrofuran; the first metal organic reagent is one or more of n-butyl lithium n-hexane solution and isopropyl magnesium chloride, more preferably n-butyl lithium n-hexane solution; preferably, the molar ratio of the compound e to the metal organic reagent is (1.0-2.0): (1.0-2.0); preferably, the reaction temperature is -90 to -60°C, more preferably -70±5°C; preferably, the reaction time is 0.5-10h.

5. The preparation method according to claim 4, characterized in that: The third solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and tetrahydrofuran / hexane; more preferably tetrahydrofuran; preferably, the molar ratio of compound d to hydrochloric acid is (1.0-2.0): (2.0-5.0); preferably, the reaction temperature is -50 to -40°C; preferably, the reaction time is 1.0-10h.

6. The preparation method according to claim 5, characterized in that: The preparation method of the compound e comprises the following steps: Compound f is dissolved in the fourth solvent, and the first catalyst and ethylene glycol are added to undergo condensation reaction to obtain compound e, namely: Preferably, the fourth solvent is one or more of toluene, xylene, and cyclohexane, more preferably toluene; the first catalyst is one or more of p-toluenesulfonic acid, triethyl orthoformate, and iodine, more preferably p-toluenesulfonic acid; the molar ratio of the compound f, ethylene glycol, and the catalyst is (1.0-2.0): (2.0-10.0): (0.05-0.3); preferably, the reaction temperature is gradually increased to an internal temperature of 100-120°C and an external temperature of 120-140°C.

7. The preparation method according to claim 6, characterized in that: The preparation method of the compound f comprises the following steps: Compound g is dissolved in the fifth solvent, and a base and 1,2-dibromoethane are added to undergo a substitution reaction to obtain compound f, namely: Preferably, the fifth solvent is one or more of acetonitrile, N,N-dimethylformamide, and dichloromethane, more preferably acetonitrile; the base is one or more of potassium carbonate, sodium hydroxide, and lithium hydride, more preferably potassium carbonate; the molar ratio of the compound g, the base and 1,2-dibromoethane is (1.0-2.0): (1.0-3.0): (5.0-15.0); preferably, the reaction temperature is gradually increased to an internal temperature of 50 to 90°C.

8. The preparation method according to claim 7, characterized in that: The preparation method of compound g comprises the following steps: Compound h is dissolved in the sixth solvent, and boron tribromide is added to carry out a demethylation reaction to obtain compound g, namely: Preferably, the sixth solvent is one or more of dichloromethane, dichloroethane, and toluene, more preferably dichloromethane; the molar ratio of compound h to boron tribromide is (1.0-2.0): (1.5-5.0); preferably, the reaction temperature is -10 to 0°C; preferably, the reaction time is 1.0-10.0h.

9. The preparation method according to claim 8, characterized in that: The preparation method of the compound h comprises the following steps: Compound i is dissolved in the seventh solvent, lithium diisopropylamide is added to react, and then added to the third catalyst to continue the reaction to obtain an intermediate, and the intermediate is added to a hydrolysis solution for hydrolysis to obtain compound h, namely: Preferably, the seventh solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and n-hexane; the third catalyst is one or more of N,N-dimethylformamide, ethyl formate, and N-formylpiperidine, more preferably N,N-dimethylformamide; the hydrolysis solution is one or more of hydrochloric acid aqueous solution, ammonium chloride aqueous solution, and citric acid aqueous solution, more preferably hydrochloric acid aqueous solution; the molar ratio of compound i, lithium diisopropylamide, the third catalyst, and the hydrolysis solution is (1.0-2.0): (1.0-4.0): (1.5-4.0): (1.0-5.0); preferably, the reaction temperature is -90 to -60°C, more preferably -70±5°C; preferably, the reaction time is 1.0-10.0h.

10. The preparation method according to claim 1, characterized in that: The preparation method of compound a comprises the following steps:

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