Preparation method of 7-formyl-2, 3-dihydrobenzofuran-4-carbonitrile

Abstract

The invention belongs to the field of medicinal chemistry, and particularly discloses a preparation method of 7-formyl-2, 3-dihydrobenzofuran-4-carbonitrile, which comprises the following steps: carrying out coupling reaction on a compound as shown in a formula VI and cyano under the action of a palladium catalyst to generate a compound as shown in a formula VII. The method provided by the invention is low in cost, good in safety, relatively high in yield and suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry and relates to a method for preparing 7-formyl-2,3-dihydrobenzofuran-4-carbonitrile. Background Art

[0002] The 2,3-dihydrobenzofuran ring is an important structural unit widely present in a variety of pharmacologically active natural products. There have been a large number of reports on the synthesis of 2,3-dihydrobenzofuran rings, such as CN108329285A, CN111253355A, CN114591278A, etc. However, there are few reports on the efficient preparation of 4- and 7-dihydrobenzofuran compounds using simple and inexpensive raw materials.

[0003] In order to introduce substituents at the 4- and 7-positions of 2,3-dihydrobenzofuran, as described in CN113480534A, 5-bromo-2-methylphenol is used as a raw material, and after nucleophilic substitution with 2-bromo-1,1-diethoxyethane, cyclization is performed under the action of polyphosphoric acid to generate 4-bromo-7-methylbenzofuran, and then cyano group is introduced by coupling with cuprous cyanide to generate 7-methylbenzofuran-4-carbonitrile. However, in the subsequent experimental process, the applicant wanted to reduce the furan ring by reduction reaction to obtain a 2,3-dihydrobenzofuran ring with substituents at the 4- and 7-positions, but failed under various conditions, which may be related to the formation of a large conjugated system between the cyano group and the benzofuran ring.

[0004]

[0005] In addition, the prior application has provided a method for preparing 7-formyl-2,3-dihydrobenzofuran-4-carbonitrile: 4-amino-5-chloro-2,3-dihydro-1-benzofuran-7-carboxylic acid is used as the starting material, after methylation, it is dehalogenated under palladium carbon pressure hydrogenation, then diazotized with tert-butyl nitrite, reacted with cuprous bromide to introduce halogen, then coupled with cuprous cyanide at high temperature, further reduced to alcohol under the action of lithium borohydride, and finally oxidized with Dess-Martin reagent to generate 7-formyl-2,3-dihydrobenzofuran-4-carbonitrile. However, the cost of the starting material is high, which is not conducive to large-scale production.

[0006]

[0007] Therefore, it is necessary to provide a safer, more economical and more suitable method for industrial production to synthesize 7-formyl-2,3-dihydrobenzofuran-4-carbonitrile. Summary of the invention

[0008] Purpose of the invention: The technical problem to be solved by the present invention is to provide a method for preparing 7-formyl-2,3-dihydrobenzofuran-4-carbonitrile in view of the shortcomings of the prior art.

[0009] In order to solve the above technical problems, the present invention discloses the following technical solutions:

[0010] First aspect , the present invention discloses a compound as shown in Formula VI;

[0011]

[0012] Wherein, R1 and R2 are independently selected from C 1-6 Alkyl, C 1-6 Preferably, R1 and R2 are independently selected from C 1-4 Alkyl, C 1-4 Alkoxy, or H; further preferably, R1, R2 are independently selected from C 1-2 Alkyl, C 1-2 Alkoxy, or H.

[0013] In some embodiments, the compound represented by Formula VI is represented by Formula 6;

[0014]

[0015] Second aspect The present invention discloses a method for preparing the compound represented by the first aspect of formula VI, comprising the following steps:

[0016] (1) the compound represented by formula IV undergoes an esterification reaction with an alcohol compound under the action of sulfuric acid to obtain a compound represented by formula V;

[0017] (2) the compound represented by formula V undergoes a reduction reaction under the action of a reducing agent to generate a compound represented by formula VI;

[0018]

[0019] In step (1), the sulfuric acid is concentrated sulfuric acid with a mass concentration of 90%-99%, preferably concentrated sulfuric acid with a mass concentration of 98%; preferably, the alcohol compound is C1-C10 hydroxy alcohol, preferably C1-C5 hydroxy alcohol, preferably methanol; preferably, the molar ratio of the compound represented by formula IV to sulfuric acid is 1:0.3-4.5, preferably 1:0.4-3, and more preferably 1:0.5-1.5; preferably, the feed ratio of the compound represented by formula IV to the alcohol compound is 1g:6-60mL, preferably 1g:8-40mL, and more preferably 1g:10-20mL; preferably, the temperature of the esterification reaction is 35-95°C, preferably 45-85°C, and more preferably 55-75°C; preferably After the reaction is completed, the temperature is lowered to 25-45°C, toluene (200-400mL) is added to the reaction solution, and the mixture is concentrated under reduced pressure at 25-45°C until substantially no liquid flows out of the condenser end; the temperature is lowered to 0-10°C and stirred, a 5% aqueous sodium bicarbonate solution is added to the reaction solution to adjust the pH of the aqueous phase to 7-8, the mixture is stirred for 10-30min, the mixture is allowed to stand for separation, and the organic phase is retained; toluene (90-150mL) is added to the aqueous phase and stirred for 0.5h, the mixture is allowed to stand for separation, and the organic phase is retained; the organic phases are combined, a saturated sodium chloride solution (90-180mL) is added to the organic phase, the mixture is stirred for 0.5h, the mixture is allowed to stand for separation, and the organic phase is retained; the organic phase is concentrated under reduced pressure at 45-65°C until there is no obvious water in the condensation receiver part, and the compound represented by formula V is obtained.

[0020] In step (2), the reducing agent is obtained by modifying sodium bis(methoxyethoxy)aluminum hydride with a modifying agent; preferably, the modifying agent includes N-methylpiperazine and / or cis-2,6-dimethylmorpholine, preferably 2,6-dimethylmorpholine; preferably, the molar ratio of the compound represented by formula IV, sodium bis(methoxyethoxy)aluminum hydride and the modifying agent is 1:0.9-7.5:1.1-6.6, preferably 1:1.2-5:1.4-4.4, and further preferably 1:1.5-2.5:1.8-2.2; preferably, the modified solvent is an organic solvent, preferably toluene; preferably, the feed ratio of the compound represented by formula IV to the solvent is 1 g:3 g. 81mL, preferably 1g: 4-27mL, more preferably 1g: 5-9mL; preferably, the modification is to add sodium bis(methoxyethoxy)aluminum hydride and the remaining solvent to a mixed solution of the modifier and part of the solvent, the part of the solvent is 60%-90% of the total solvent volume, preferably 63.3%-85%, more preferably 66.7%-80%; preferably, the temperature at which the sodium bis(methoxyethoxy)aluminum hydride is added to the reaction system is -30 to 5°C, preferably -25 to 0°C, more preferably -20 to -5°C; preferably, the temperature of the modification is -15 to 20°C, preferably -10 to 15°C, more preferably -5 to 10°C.

[0021] In step (2), the reduction reaction is to add a solution containing a reducing agent to a solution containing a compound represented by formula V for a reduction reaction; the solvents in the solution containing a reducing agent and the solution containing a compound represented by formula V are both organic solvents, preferably toluene; preferably, the temperature at which the reducing agent is added to the reaction system is -30 to 5°C, preferably -25 to 0°C, and more preferably -20 to -5°C; preferably, the temperature of the reduction reaction is -20 to 5°C, preferably -15 to 0°C, and more preferably -10 to -5°C; preferably, after the reaction is completed, the aqueous phase is adjusted with a 25% dilute sulfuric acid aqueous solution The pH value is adjusted to between 0 and 1, stirred for 0.5 h, allowed to stand for separation, and the organic phase is retained; 90-150 mL of toluene is added to the aqueous phase, stirred for 0.5 h, allowed to stand for separation, and the organic phase is retained; the organic phases are combined, and washed with 5% aqueous sodium bicarbonate solution (200-400 mL), purified water (200-400 mL), and saturated aqueous NaCl solution (200-400 mL) in sequence, and the organic phase is retained; N-methylpyrrolidone (240-60 mL) is added to the organic phase, and the mixture is concentrated under reduced pressure at 40-70° C. until no obvious droplets fall from the condensation receiver to obtain the compound represented by formula VI.

[0022] In step (1), the preparation method of the compound represented by formula IV comprises:

[0023] (i) the compound represented by formula II undergoes nucleophilic ring-opening and ring-closing reaction with ethylene oxide under the action of a strong base to obtain the compound represented by formula III;

[0024] (ii) the compound represented by formula III undergoes hydrolysis reaction under the action of a strong acid to obtain a compound represented by formula IV;

[0025]

[0026] In step (i), the strong base is any one or a combination of n-butyl lithium, sec-butyl lithium, tert-butyl lithium and lithium diisopropylamide, preferably lithium diisopropylamide; preferably, the molar ratio of the compound represented by formula II to the strong base is 1:0.8-3, preferably 1:1.0-2.25, and more preferably 1:1.2-1.5; preferably, the molar ratio of the compound represented by formula II to ethylene oxide is 1:1.8-12, preferably 1:2.4-8, and more preferably 1:3-4; preferably, the solvent of the reaction is an organic solvent, preferably tetrahydrofuran; preferably, the feeding amount ratio of the compound represented by formula II to the solvent is 1g:8-32mL, preferably 1g:10-24mL, and further preferably 1g:10-24mL. The step is preferably 1g: 12-16mL; preferably, a strong base is added to the mixed system of the compound represented by formula II and the solvent, a first stirring is performed, and then ethylene oxide is added, a second stirring is performed, and the temperature is increased to react; preferably, the reaction is carried out under an inert gas atmosphere; preferably, the strong base is added to the reaction system in the form of a strong base solution; the solvent of the strong base solution is a tetrahydrofuran solution, or a mixture of tetrahydrofuran and n-hexane; preferably, the concentration of the strong base solution is 0.9-7.5M, preferably 1.2-5M, and more preferably 1.5-2.5M; preferably, the temperature at which the strong base is added to the reaction system is -115 to -35°C, preferably -105 to -45°C, and more preferably -95 to -55°C; preferably , the ethylene oxide is added to the reaction system in the form of an ethylene oxide solution; the solvent of the ethylene oxide solution is a tetrahydrofuran solution, or a mixture of tetrahydrofuran and n-hexane; preferably, the first stirring time is 0.6-4h, preferably 0.8-3.5h, and more preferably 1-3h; preferably, the concentration of the ethylene oxide solution is 1.2-12M, preferably 1.6-8M, and more preferably 2-4M; preferably, the temperature at which the ethylene oxide is added to the reaction system is -115 to -35°C, preferably -105 to -45°C, and more preferably -95 to -65°C; preferably, the second stirring time is 0.1-1.5h, preferably 0.3-1h, and more preferably 0.5-1h; Preferably, the heating rate of the ring-opening and ring-closing reactions is 6-75°C / h, preferably 8-50°C / h, and more preferably 10-25°C / h; preferably, the temperature is raised to 5-65°C, preferably 10-55°C, and more preferably 15-45°C; preferably, after the reaction is completed, the temperature is lowered to -5-25°C, a saturated ammonium chloride solution (400-800mL) is added dropwise to the reaction solution for quenching, the temperature is raised to 25-45°C and stirred for 0.5h, the reaction solution is concentrated under reduced pressure at 25-45°C until no liquid flows out of the condenser end, n-heptane (200-400mL) is added to the reaction solution and stirred for 0.5h, the solution is allowed to stand for separation, and the organic phase is retained; n-heptane (200-400mL) is added to the aqueous phase and stirred for 0.5h, stand and separate, retain the organic phase; add n-heptane (200-400mL) and diatomaceous earth (20-40g) to the aqueous phase, stir for 0.5h, filter and stand to separate, retain the organic phase; combine the organic phases, and concentrate to dryness under reduced pressure at 35-65°C to obtain the compound shown in formula III.

[0027] In step (ii), the strong acid is any one or a combination of sulfuric acid, hydrochloric acid and trifluoroacetic acid, preferably trifluoroacetic acid; preferably, the sulfuric acid is concentrated sulfuric acid with a mass concentration of 90%-99%, preferably concentrated sulfuric acid with a mass concentration of 98%; preferably, the hydrochloric acid is concentrated hydrochloric acid with a mass concentration of 24%-63%, preferably concentrated hydrochloric acid with a mass concentration of 28%-52.5%, and more preferably concentrated hydrochloric acid with a mass concentration of 32%-42%; preferably, the amount ratio of the compound represented by formula II to the strong acid is 1g:0.6-6mL, preferably 1g:0.8-4mL, and more preferably 1g:1-2mL; preferably, the solvent of the reaction is any one or a combination of toluene, n-heptane, ethyl acetate and dichloromethane, preferably toluene; preferably, the compound represented by formula II The feeding ratio of the compound to the solvent is 1g:2.5-100mL, preferably 1g:3-20mL, and more preferably 1g:3.5-4mL; preferably, the reaction temperature is 5-55°C, preferably 10-45°C, and more preferably 15-35°C; preferably, after the reaction is completed, methyl tert-butyl ether (80-160mL) is slowly added dropwise to the reaction solution, and after the addition is completed, the temperature is lowered to 0-10°C and stirred for 6h, filtered, and the filter cake is drained; methyl tert-butyl ether (80-120mL) is added to the filter cake, the temperature is raised to 30-50°C, stirred and slurried for 1-3h, the temperature is lowered to -5-15°C, stirred for 1-3h, filtered, and vacuum dried at 30-50°C to obtain the compound shown in formula IV; preferably, methyl tert-butyl ether is slowly added dropwise to the reaction solution, and the addition is completed for 0.5-4.5h.

[0028] In step (i), the preparation method of the compound represented by formula II comprises: subjecting the compound represented by formula I to an esterification reaction under the action of di-tert-butyl dicarbonate, 4-dimethylaminopyridine and tert-butyl alcohol to obtain the compound represented by formula II;

[0029]

[0030] Wherein, the molar ratio of the compound represented by formula I to di-tert-butyl dicarbonate is 1:2-6, preferably 1:2.4-4.8, and more preferably 1:2.8-3.6; preferably, the molar ratio of the compound represented by formula I to 4-dimethylaminopyridine is 1:0.048-0.36, preferably 1:0.064-0.24, and more preferably 1:0.08-0.12; preferably, the feeding amount ratio of the compound represented by formula I to tert-butyl alcohol is 1g:2-10mL, preferably 1g:2.5-7.5mL, more preferably 1g:3-5mL; preferably, the solvent of the reaction is an organic solvent, preferably tetrahydrofuran; preferably, the feeding ratio of the compound represented by formula I to the solvent is 1g:4-20mL, preferably 1g:5-15mL, preferably 1g:6-10mL; preferably, di-tert-butyl dicarbonate is added to the mixed system of the compound represented by formula I, 4-dimethylaminopyridine, tert-butyl alcohol and solvent; preferably, the di-tert-butyl dicarbonate preferably, the temperature of adding di-tert-butyl dicarbonate to the reaction system is 5-45°C, preferably 10-40°C, and more preferably 15-35°C; preferably, the reaction temperature is 45-85°C, preferably 50-80°C, and more preferably 55-75°C; preferably, after the reaction is completed, the temperature is lowered to 15-30°C, ethyl acetate (600-1000mL) and 5% sodium bicarbonate aqueous solution (1000-2000mL) are added to the reaction solution, stirred for 15-35min, allowed to stand for separation, and the organic phase is retained; ethyl acetate (400-600mL) is added to the aqueous phase, stirred for 15-35min, allowed to stand for separation, and the organic phase is retained; after the organic phases are combined, 5% citric acid aqueous solution (800-1200mL), 5% sodium bicarbonate aqueous solution (400-600mL), and saturated NaCl aqueous solution (400-600mL) are used to wash in sequence, the organic phase is retained, and it is concentrated and dried under reduced pressure to constant weight to obtain the compound shown in formula II.

[0031] The third aspect The present invention discloses the use of the compound represented by formula VI in the first aspect as an intermediate; preferably, the compound represented by formula VI is used as an intermediate for preparing dihydrobenzofuran compounds; preferably, the dihydrobenzofuran compounds include compounds represented by formula VII;

[0032]

[0033] Wherein, the compound represented by formula VI undergoes coupling reaction with cyano group under palladium catalyst to generate the compound represented by formula VII;

[0034]

[0035] The palladium catalyst is [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (Pd(dppf)Cl2), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (Pd(dppf)Cl2·CH2Cl2) and methanesulfonate (2-di-tert-butylphosphine-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (tBuXPhos Pd G3) is any one or a combination of several, preferably [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex and / or methanesulfonate (2-di-tert-butylphosphine-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II), and further preferably [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex; preferably, the molar ratio of the palladium catalyst to the compound represented by formula IV is 0.01-0.08:1, preferably 0.01-0.06:1, and further preferably 0.02-0.04:1; preferably, The solvent of the coupling reaction is any one or a combination of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile and water, preferably any one of N-methylpyrrolidone, acetonitrile and water, and more preferably N-methylpyrrolidone; preferably, the coupling reaction also includes anhydrous sodium carbonate and potassium ferrocyanide; preferably, the molar ratio of anhydrous sodium carbonate, potassium ferrocyanide and the compound represented by formula IV is 0.3-4.5:0.06-0.6:1, preferably 0.4-3.1:0.08-0.4:1, and more preferably 0.5-1.5:0.1-0.2:1; preferably, the temperature of the coupling reaction is 80-140°C, preferably 90-130°C, and more preferably 100-120°C; preferably, after the reaction is completed, the temperature is lowered to 60-90°C, toluene (200-400mL) and purified water (200-400mL) are added to the reaction solution, stirred for 20-40min, diatomaceous earth (40-80g) is used for pre-coating filtration, and toluene (80-120mL) is used for washing, and the filtrate is allowed to stand for separation, and the organic phase is retained; toluene (100-200mL) is added to the aqueous phase, stirred at 60-90°C for 20-40min, allowed to stand for separation, and the organic phase is retained; the organic phases are combined, 10% sodium chloride aqueous solution (200-400mL) is added, stirred at 60-90°C for 20-40min, allowed to stand for separation, The organic phase is retained; 10% sodium chloride aqueous solution (200-400mL) is added to the organic phase and stirred at 60-90°C for 30-50min, the mixture is allowed to stand for separation, and the organic phase is retained; silica gel (70-110g) is added to the organic phase, and the mixture is stirred at 60-90°C for 50-70min, silica gel (40-80g) is used for pre-coating filtration, and the mixture is washed with dichloromethane (400-800mL), and the filtrate is distilled under reduced pressure at 30-60°C until about 150-350mL of the remaining material is distilled, and the remaining filtrate is heated to 60-90°C and stirred, and n-heptane (400-600mL) is added dropwise to the filtrate, and after the dripping is completed, the mixture is stirred for 0.5-1.5h, and the mixture is slowly cooled to -5-15°C and stirred for 0.5-1.5h, filtered, and dried under vacuum at 30-50°C to obtain the compound shown in Formula VII.

[0036] The method for preparing the compound represented by formula VII of the present invention comprises the following synthetic route:

[0037]

[0038] Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0039] (1) The starting material 4-bromo-2-fluorobenzoic acid used in the present invention can be a commercial reagent, does not require special treatment, and is inexpensive. Compared with the starting material 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid in the preparation method of the intermediate in the applicant's previous patent, the price is reduced by 14 times, and it can be prepared in large quantities by a simple method.

[0040] (2) The preparation method of the present invention avoids the step of pressurized hydrogenation, thereby increasing the safety factor of the reaction.

[0041] (3) The present invention provides a new preparation method for the compound 7-formyl-2,3-dihydrobenzofuran-4-carbonitrile, thereby providing a basis for the application of 2,3-dihydrobenzofuran compounds with disubstituted 4- and 7-positions in drug synthesis. At the same time, the method has low cost, good safety, high yield, and is suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] The present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments, and the above and / or other advantages of the present invention will become more clear.

[0043] Figure 1 This is the H NMR spectrum of compound 2 obtained in Example 1.

[0044] Figure 2 This is the NMR carbon spectrum of compound 2 obtained in Example 1.

[0045] Figure 3 This is the high-resolution mass spectrum of compound 2 obtained in Example 1.

[0046] Figure 4 This is the H NMR spectrum of compound 3 obtained in Example 1.

[0047] Figure 5 This is the NMR carbon spectrum of compound 3 obtained in Example 1.

[0048] Figure 6 This is the high-resolution mass spectrum of compound 3 obtained in Example 1.

[0049] Figure 7 This is the H NMR spectrum of compound 4 obtained in Example 1.

[0050] Figure 8 This is the NMR carbon spectrum of compound 4 obtained in Example 1.

[0051] Fig. 9 This is the high-resolution mass spectrum of compound 4 obtained in Example 1.

[0052] Fig.10 This is the H NMR spectrum of compound 5 obtained in Example 1.

[0053] Fig.11 This is the NMR carbon spectrum of compound 5 obtained in Example 1.

[0054] Fig.12 This is the high-resolution mass spectrum of compound 5 obtained in Example 1.

[0055] Fig.13 This is the H NMR spectrum of compound 6 obtained in Example 1.

[0056] Fig.14 This is the NMR carbon spectrum of compound 6 obtained in Example 1.

[0057] Fig.15 This is the high-resolution mass spectrum of compound 6 obtained in Example 1.

[0058] Fig.16 This is the H NMR spectrum of compound 7 obtained in Example 1.

[0059] Fig.17 This is the NMR carbon spectrum of compound 7 obtained in Example 1.

[0060] Fig.18 This is the high-resolution mass spectrum of compound 7 obtained in Example 1. DETAILED DESCRIPTION

[0061] The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and materials described are commercially available unless otherwise specified.

[0062] The term "controlling the internal temperature" in the embodiments of the present invention refers to the internal temperature of the reaction.

[0063] In the embodiments of the present invention, the percentages expressed in % are by mass unless otherwise specified.

[0064] The lithium diisopropylamide solution described in the present invention, unless otherwise specified, is made of a solvent of tetrahydrofuran solution or a tetrahydrofuran / n-hexane mixed solution.

[0065] Example 1

[0066] Synthesis of compound 2:

[0067]

[0068] THF (800 mL), tert-butyl alcohol (400 mL), 4-bromo-2-fluorobenzoic acid (100 g), and 4-dimethylaminopyridine (5.58 g) were added to a 3000 mL three-necked flask and stirred at 25±5°C. Di-tert-butyl dicarbonate (318.89 g) was slowly added to the reaction solution in portions. After the addition was completed, the temperature was slowly raised to 65±5°C for reaction for 4 h. After the reaction was completed, the temperature was lowered to 25±5°C. Ethyl acetate (800 mL) and 5% sodium bicarbonate aqueous solution were added to the reaction solution. The mixture was stirred with ethyl acetate (1500 mL) for 25 min, allowed to stand for separation, and the organic phase was retained; the aqueous phase was added with ethyl acetate (500 mL) and stirred for 25 min, allowed to stand for separation, and the organic phase was retained; after the organic phases were combined, they were washed with 5% citric acid aqueous solution (1000 mL), 5% sodium bicarbonate aqueous solution (500 mL), and saturated NaCl aqueous solution (500 mL) in sequence, and the organic phase was retained, and concentrated and dried under reduced pressure to constant weight to obtain a yellow or orange-yellow liquid compound 2, which can be directly used for the next step of feeding. The H NMR spectrum, C NMR spectrum, and high-resolution mass spectrum of compound 2 are shown as follows: Figure 1-Figure 3 shown.

[0069] 1 H NMR (400MHz, d6-DMSO): δ7.77-7.73(t,1H), δ7.69-7.66(dd,J1=10.44Hz, J2=1.84Hz, 1H), δ7.54-7.52(dd,J1=8.40Hz, J1=1.60Hz, 1H), δ1.53(s,9H).

[0070] 13 C-NMR (400MHz, d6-DMSO): δ162.48, δ162.44, δ162.42, δ159.81, δ133.46, δ133.45, δ128 .32, δ128.28, δ127.23, δ127.13, δ121.00, δ120.74, δ119.70, δ119.60, δ82.48, δ28.17,.

[0071] HR-ESI(+): Theoretical calculated value: [C 11 H 12 BrFO2-Br+2CH3CN+Na] + 301.1328, measured value: 301.14091.

[0072] Synthesis of compound 3:

[0073]

[0074] Add dry THF (560 mL) and compound 2 (40 g) to a 1000 mL three-necked flask, replace with nitrogen 3 times, cool to -85 to -65 ° C, slowly drop 2.0 M lithium diisopropylamide solution (100 mL) into the reaction solution, control the internal temperature between -85 and -65 ° C and stir for 2 h; slowly drop 3.0 M ethylene oxide tetrahydrofuran solution (170 mL) into the reaction solution, control the internal temperature between -85 and -65 ° C and stir for 1 h; control the internal temperature to slowly rise to 30 ± 5 ° C at a heating rate of 15 to 20 ° C / h to react; after the reaction is completed, cool to 0 to 20 ° C, drop the reaction solution Add saturated ammonium chloride solution (600mL) to quench, heat to 35±5℃ and stir for 0.5h, concentrate under reduced pressure at 35±5℃ until no liquid flows out of the condenser, add n-heptane (300mL) to the reaction solution and stir for 0.5h, stand and separate, and retain the organic phase; add n-heptane (300mL) to the aqueous phase, stir for 0.5h, stand and separate, and retain the organic phase; add n-heptane (300mL) and diatomaceous earth (30g) to the aqueous phase, stir for 0.5h, stand and separate after filtering, and retain the organic phase; combine the organic phases, and concentrate under reduced pressure at 50±5℃ to dryness to obtain a yellow or orange-yellow liquid compound 3, which can be directly used for the next step. The NMR hydrogen spectrum, NMR carbon spectrum and high-resolution mass spectrum of compound 3 are shown as follows: Figure 4-Figure 6 shown.

[0075] 1 H NMR (400MHz, d6-DMSO): δ7.47-7.45(d,J=8.48Hz,1H), δ7.08-7.06(d,J=8.52Hz,1H), δ4.70-4.66(t,2H), δ3.20-3.16(t,2H), δ1.50(s,9H).

[0076] 13 C-NMR (400MHz, d6-DMSO): δ163.55, δ160.67, δ131.33, δ131.17, δ123.65, δ123.19, δ113.75, δ81.04, δ71.92, δ30.72, δ28.30.

[0077] HR-ESI(+): Theoretical calculated value: [C 13 H 15 O3Br-CH3] + 284.0048, measured value: 283.99121.

[0078] Synthesis of compound 4:

[0079]

[0080] Toluene (150 mL), trifluoroacetic acid (60 mL), and the concentrate of compound 3 in the previous step were added to a 1000 mL three-necked flask, and stirred at 25±5°C for 2 h. After the reaction was completed, methyl tert-butyl ether (120 mL) was slowly added dropwise to the reaction solution (1-4 h). After the addition was completed, the temperature was lowered to 0-10°C and stirred for 6 h, filtered, and the filter cake was drained; the filter cake was transferred to a 500 mL three-necked flask, methyl tert-butyl ether (120 mL) was added, the temperature was raised to 40±5°C, stirred and slurried for 2 h, the temperature was lowered to 0-10°C, stirred for 2 h, filtered, and vacuum dried at 40±5°C to obtain about 16.09 g of light yellow solid compound 4, with a total yield of about 45.28% in the three steps. The H NMR spectrum, C NMR spectrum, and high-resolution mass spectrum of compound 4 are shown as follows: Figure 7-Figure 9 shown.

[0081] 1 H NMR (400MHz, d6-DMSO): δ12.80(s,1H), δ7.53-7.50(d,J=8.48Hz,1H), δ7.10-7.08(d,J=8.44Hz,1H), δ4.70-4.66(t,2H), δ3.22-3.18(t,2H).

[0082] 13 C-NMR (400MHz, d6-DMSO): δ165.92, δ160.87, δ131.62, δ131.33, δ123.77, δ123.25, δ113.10, δ71.88, δ30.72.

[0083] HR-ESI(+): Theoretical calculation value: [C9H7O3Br+H] + 242.9657, measured value: 242.96490.

[0084] Synthesis of compound 5:

[0085]

[0086] Compound 4 (30 g), methanol (450 mL), and 98 wt% concentrated sulfuric acid (12.78 g) were added to a 1000 mL three-necked flask, and the mixture was replaced with nitrogen three times. The mixture was heated to 65±5°C and refluxed for 4 h. After the reaction, the mixture was cooled to 35±5°C, toluene (300 mL) was added to the reaction solution, and the mixture was concentrated under reduced pressure at 35±5°C until almost no liquid flowed out of the condenser end; the mixture was cooled to 0-10°C and stirred, 5% aqueous sodium bicarbonate solution was added to the reaction solution to adjust the pH of the aqueous phase to 7-8, stirred for 20 min, allowed to stand for separation, and the organic phase was retained; toluene (120 mL) was added to the aqueous phase and stirred for 0.5 h, allowed to stand for separation, and the organic phase was retained; the organic phases were combined, a saturated sodium chloride solution (150 mL) was added to the organic phase, stirred for 0.5 h, allowed to stand for separation, and the organic phase was retained; the organic phase was concentrated under reduced pressure at 55±5°C until there was no obvious water in the condensation receiver part to obtain a toluene solution of compound 5, which can be directly used in the next step. The H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrum of compound 5 are shown in Figure 10-12 shown.

[0087] 1 H NMR (400MHz, d6-DMSO): δ7.54-7.52(d,J=8.48Hz,1H), δ7.12-7.10(d,J=8.52Hz,1H), δ4.72-4.68(t,2H), δ3.79(s,3H), δ3.23-3.18(t,2H).

[0088] 13 C-NMR (400MHz, d6-DMSO): δ165.01, δ160.68, δ131.56, δ131.30, δ124.29, δ123.47, δ111.90, δ72.10, δ52.32, δ30.71.

[0089] HR-ESI(+): Theoretical calculated value: [C 10 H9O3Br+H] + 256.9813, measured value: 256.98056.

[0090] Synthesis of compound 6:

[0091]

[0092] Add cis-2,6-dimethylmorpholine (29.16 g) and toluene (150 mL) to a 500 mL three-necked flask, replace with nitrogen three times, start stirring, cool to -10±5°C, control the internal temperature at -10±5°C, add 70% sodium bis(methoxyethoxy)aluminum hydride toluene solution (71.31 g, diluted with 60 mL toluene) dropwise to the reaction solution, slowly heat to 0±5°C and stir for 2 h to prepare the modified Red-Al toluene solution.

[0093] Add the toluene solution of compound 5 in the previous step to a 1000mL three-necked flask, replace with nitrogen 3 times, start stirring, cool to -10±5°C, control the internal temperature at -10±5°C, add the modified Red-Al toluene solution to the reaction solution, slowly heat to 0±5°C and stir for 2h, after the reaction, adjust the pH of the aqueous phase to between 0 and 1 with 25% dilute sulfuric acid aqueous solution, stir for 0.5h, stand for separation, and retain the organic phase; add 120mL toluene to the aqueous phase and stir for 0.5h, stand for separation, and retain the organic phase; combine the organic phases, wash with 5% sodium bicarbonate aqueous solution (300mL), purified water (300mL), and saturated NaCl aqueous solution (300mL) in sequence, and retain the organic phase; add N-methylpyrrolidone (300mL) to the organic phase, concentrate under reduced pressure at 55±5°C until no obvious droplets fall from the condensation receiver to obtain the N-methylpyrrolidone solution of compound 6, which can be directly used in the next step. The H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrum of compound 6 are shown in Figure 13-Figure 15 shown.

[0094] 1 H NMR (400MHz, d6-DMSO): δ10.05 (s, 1H), δ7.45-7.43 (d, J = 8.44Hz, 1H), δ7.18-7.16 (d, J = 8.40Hz, 1H), δ4.80-4.76 (t, 2H), δ3.24-3.20 (t, 2H).

[0095] 13 C-NMR (400MHz, d6-DMSO): δ188.24, δ162.27, δ131.79, δ128.68, δ126.00, δ124.06, δ118.55, δ73.06, δ30.33.

[0096] HR-ESI(+): Theoretical calculation value: [C9H8O2Br+H] + 226.9708, measured value: 226.97000.

[0097] Synthesis of compound 7:

[0098]

[0099] Add the N-methylpyrrolidone solution of compound 6 in the previous step to a 1000mL three-necked flask, add anhydrous sodium carbonate (13.14g), potassium ferrocyanide (13.70g), [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (3.04g), replace with nitrogen 3 times, start stirring, heat to 110±5℃ for reaction for 3h, cool to 75±5℃ after the reaction, add toluene (300mL) and purified water (300mL) to the reaction solution, stir for 30±5min, use diatomaceous earth (60g) for pre-coating filtration, wash with toluene (100mL), let the filtrate stand for separation, and retain the organic phase; add toluene (150mL) to the aqueous phase, stir at 75±5℃ for 30±5min, let stand for separation, and retain the organic phase; combine the organic phases, add 10% Sodium chloride aqueous solution (300 mL) was stirred at 75±5°C for 30 min, allowed to stand for separation, and the organic phase was retained; 10% sodium chloride aqueous solution (300 mL) was added to the organic phase and stirred at 75±5°C for 30 min, allowed to stand for separation, and the organic phase was retained; silica gel (90 g) was added to the organic phase and stirred at 75±5°C for 60 min, silica gel (60 g) was used for pre-coating filtration, and the mixture was washed with dichloromethane (600 mL), and the filtrate was distilled under reduced pressure at 45±5°C until about 200-300 mL of the remaining material was obtained, the remaining filtrate was heated to 75±5°C and stirred, and n-heptane (500 mL) was added dropwise to the filtrate. After the addition was completed, stirring was continued for 1 h, the temperature was slowly lowered to 0-10°C and stirred for 1 h, filtered, and dried in vacuo at 40±5°C to obtain about 8.12 g of light yellow solid compound 7, with a total yield of about 37.84% in three steps. The H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrum of compound 7 are shown in Figure 16-Figure 18 shown.

[0100] 1 H NMR (400MHz, d6-DMSO): δ10.13(s,1H), δ7.66-7.64(d,J=8.04Hz,1H), δ7.38-7.36(d,J=8.08Hz,1H), δ4.85-4.81(t,2H), δ3.46-3.42(t,2H).

[0101] 13 C-NMR (400MHz, d6-DMSO): δ188.59, δ162.06, δ136.43, δ128.06, δ123.55, δ121.74, δ117.03, δ113.30, δ73.97, δ28.43.

[0102] HR-ESI(-): Theoretical calculation value: [C 10 H7O2N-H] +172.03985, measured value: 172.03894.

[0103] Example 2

[0104] Synthesis of compound 2:

[0105]

[0106] THF (600 mL), tert-butyl alcohol (300 mL), 4-bromo-2-fluorobenzoic acid (100 g), and 4-dimethylaminopyridine (6.7 g) were added to a 3000 mL three-necked flask and stirred at 20±5°C. Di-tert-butyl dicarbonate (358.75 g) was slowly added to the reaction solution in portions. After the addition was completed, the temperature was slowly raised to 60±5°C for reaction for 5 h. After the reaction was completed, the temperature was lowered to 20±5°C. Ethyl acetate (600 mL) and 5% sodium bicarbonate aqueous solution were added to the reaction solution. The mixture was stirred for 35 min with ethyl acetate (600 mL) added to the aqueous phase, stirred for 35 min, allowed to stand for separation, and the organic phase was retained; after the organic phases were combined, they were washed with 5% citric acid aqueous solution (800 mL), 5% sodium bicarbonate aqueous solution (400 mL), and saturated NaCl aqueous solution (400 mL) in sequence, and the organic phase was retained and concentrated and dried under reduced pressure to constant weight to obtain a yellow or orange-yellow liquid compound 2, which can be directly used for the next step.

[0107] Synthesis of compound 3:

[0108]

[0109] Add dry THF (480 mL) and compound 2 (40 g) to a 1000 mL three-necked flask, replace with nitrogen 3 times, cool to -95 to -75 ° C, slowly drop 1.5 M lithium diisopropylamide solution (116 mL) into the reaction solution, control the internal temperature between -95 and -75 ° C and stir for 3 h; slowly drop 2.0 M ethylene oxide tetrahydrofuran solution (218 mL) into the reaction solution, control the internal temperature between -95 and -75 ° C and stir for 1.5 h; control the internal temperature to slowly rise to 20 ± 5 ° C at a heating rate of 10 to 20 ° C / h to react; after the reaction is completed, cool to -5 to 15 ° C, add 2.0 M ethylene oxide tetrahydrofuran solution (218 mL) into the reaction solution, control the internal temperature between -95 and -75 ° C and stir for 1.5 h; control the internal temperature to slowly rise to 20 ± 5 ° C at a heating rate of 10 to 20 ° C / h to react; after the reaction is completed, cool to -5 to 15 ° C, add 2.0 M ethylene oxide tetrahydrofuran solution (218 mL) into the reaction solution, control the internal temperature between -95 and -75 ° C and stir for 1.5 h; Saturated ammonium chloride solution (400 mL) was added dropwise for quenching, the temperature was raised to 30±5°C and stirred for 0.5 h, and the mixture was concentrated under reduced pressure at 30±5°C until no liquid flowed out of the condenser end. n-heptane (200 mL) was added to the reaction solution and stirred for 0.5 h, and the mixture was allowed to stand for separation, and the organic phase was retained; n-heptane (400 mL) was added to the aqueous phase, and the mixture was stirred for 0.5 h, and the mixture was allowed to stand for separation, and the organic phase was retained; n-heptane (400 mL) and diatomaceous earth (20 g) were added to the aqueous phase, and the mixture was stirred for 0.5 h. After filtering, the mixture was allowed to stand for separation, and the organic phase was retained; the organic phases were combined and concentrated under reduced pressure at 60±5°C to dryness to obtain a yellow or orange-yellow liquid compound 3, which can be directly used for the next step.

[0110] Synthesis of compound 4:

[0111]

[0112] Toluene (160 mL), trifluoroacetic acid (80 mL), and the concentrate of compound 3 in the previous step were added to a 1000 mL three-necked flask, and the mixture was stirred at 20±5°C for 1 h. After the reaction, methyl tert-butyl ether (160 mL) was slowly added dropwise to the reaction solution (0.5-3.5 h). After the addition was completed, the mixture was cooled to 0-10°C and stirred for 6 h. The mixture was filtered and the filter cake was drained. The filter cake was transferred to a 500 mL three-necked flask, methyl tert-butyl ether (160 mL) was added, the mixture was heated to 35±5°C and stirred for 1 h. The mixture was cooled to -5-5°C and stirred for 1 h. The mixture was filtered and dried in vacuo at 35±5°C to obtain about 15.55 g of light yellow solid compound 4 with a total yield of about 43.76% for the three steps.

[0113] Synthesis of compound 5:

[0114]

[0115] Compound 4 (30 g), methanol (300 mL), and 98 wt% concentrated sulfuric acid (6.39 g) were added to a 1000 mL three-necked flask, and the mixture was replaced with nitrogen three times. The mixture was heated to 60±5°C and refluxed for reaction for 3 h. After the reaction, the mixture was cooled to 40±5°C, toluene (400 mL) was added to the reaction solution, and the mixture was concentrated under reduced pressure at 40±5°C until almost no liquid flowed out of the condenser end; the mixture was cooled to 0-10°C and stirred, 5% aqueous sodium bicarbonate solution was added to the reaction solution to adjust the pH of the aqueous phase to 7-8, stirred for 10 min, allowed to stand for separation, and the organic phase was retained; toluene (90 mL) was added to the aqueous phase and stirred for 0.5 h, allowed to stand for separation, and the organic phase was retained; the organic phases were combined, a saturated sodium chloride solution (120 mL) was added to the organic phase, stirred for 0.5 h, allowed to stand for separation, and the organic phase was retained; the organic phase was concentrated under reduced pressure at 50±5°C until there was no obvious water in the condensation receiver part to obtain a toluene solution of compound 5, which can be directly used in the next step.

[0116] Synthesis of compound 6:

[0117]

[0118] Add cis-2,6-dimethylmorpholine (25.49 g) and toluene (120 mL) to a 500 mL three-necked flask, replace with nitrogen three times, start stirring, cool to -15±5°C, control the internal temperature at -15±5°C, add 70% sodium bis(methoxyethoxy)aluminum hydride toluene solution (52.18 g, diluted with 30 mL toluene) dropwise to the reaction solution, slowly heat to 0±-5°C and stir for 2 h to prepare the modified Red-Al toluene solution.

[0119] Add the toluene solution of compound 5 in the previous step to a 1000mL three-necked flask, replace with nitrogen 3 times, start stirring, cool to -15±5°C, control the internal temperature at -15±5°C, add the modified Red-Al toluene solution to the reaction solution, slowly heat to -5±5°C and stir for 2h, after the reaction, adjust the pH of the aqueous phase to between 0 and 1 with 25% dilute sulfuric acid aqueous solution, stir for 0.5h, stand for separation, and retain the organic phase; add 150mL of toluene to the aqueous phase and stir for 0.5h, stand for separation, and retain the organic phase; combine the organic phases, wash with 5% sodium bicarbonate aqueous solution (400mL), purified water (400mL), and saturated NaCl aqueous solution (400mL) in sequence, and retain the organic phase; add N-methylpyrrolidone (240mL) to the organic phase, concentrate under reduced pressure at 45±5°C until no obvious droplets fall from the condensation receiver to obtain the N-methylpyrrolidone solution of compound 6, which can be directly used in the next step.

[0120] Synthesis of compound 7:

[0121]

[0122] Add the N-methylpyrrolidone solution of compound 6 in the previous step to a 1000mL three-necked flask, add anhydrous sodium carbonate (19.71g), potassium ferrocyanide (9.13g), [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (4.05g), replace with nitrogen 3 times, start stirring, heat to 105±5℃ for reaction for 3h, cool to 85±5℃ after the reaction, add toluene (200mL) and purified water (200mL) to the reaction solution, stir for 20min, use diatomaceous earth (80g) for pre-coating filtration, wash with toluene (120mL), let the filtrate stand for separation, and retain the organic phase; add toluene (200mL) to the aqueous phase, stir at 85±5℃ for 40min, let stand for separation, and retain the organic phase; combine the organic phases, add 10% sodium chloride aqueous solution liquid (200 mL), stirred at 85±5°C for 20 min, allowed to stand for separation, and the organic phase was retained; 10% sodium chloride aqueous solution (200 mL) was added to the organic phase, stirred at 85±5°C for 20 min, allowed to stand for separation, and the organic phase was retained; silica gel (70 g) was added to the organic phase, stirred at 85±5°C for 50 min, silica gel (40 g) was used for pre-coating filtration, and the mixture was washed with dichloromethane (800 mL), and the filtrate was distilled under reduced pressure at 35±5°C until about 150 to 250 mL of the remaining material was obtained, the remaining filtrate was heated to 85±5°C and stirred, and n-heptane (600 mL) was added dropwise to the filtrate. After the dripping was completed, stirring was continued for 0.5 h, the temperature was slowly lowered to -5 to 5°C and stirred for 0.5 h, filtered, and dried in vacuo at 35±5°C to obtain about 7.56 g of light yellow solid compound 7, with a total yield of about 35.23% in three steps.

[0123] Example 3

[0124] Synthesis of compound 2:

[0125]

[0126] THF (1000 mL), tert-butyl alcohol (500 mL), 4-bromo-2-fluorobenzoic acid (100 g), and 4-dimethylaminopyridine (4.46 g) were added to a 3000 mL three-necked flask and stirred at 30±5°C. Di-tert-butyl dicarbonate (279.03 g) was slowly added to the reaction solution in portions. After the addition was completed, the temperature was slowly raised to 70±5°C for reaction for 3 h. After the reaction was completed, the temperature was lowered to 25±5°C. Ethyl acetate (1000 mL) and 5% sodium bicarbonate solution were added to the reaction solution. The solution (1000 mL) was stirred for 15 min, allowed to stand for separation, and the organic phase was retained; ethyl acetate (400 mL) was added to the aqueous phase and stirred for 15 min, allowed to stand for separation, and the organic phase was retained; after the organic phases were combined, they were washed with 5% citric acid aqueous solution (1200 mL), 5% sodium bicarbonate aqueous solution (600 mL), and saturated NaCl aqueous solution (600 mL) in sequence, and the organic phase was retained, concentrated and dried under reduced pressure to constant weight to obtain a yellow or orange-yellow liquid compound 2, which can be directly used for the next step.

[0127] Synthesis of compound 3:

[0128]

[0129] Add dry THF (640 mL) and compound 2 (40 g) to a 1000 mL three-necked flask, replace with nitrogen 3 times, cool to -75 to -55 ° C, slowly drop 2.5 M lithium diisopropylamide solution (87 mL) into the reaction solution, control the internal temperature between -75 and -55 ° C and stir for 1 h; slowly drop 4.0 M ethylene oxide tetrahydrofuran solution (145 mL) into the reaction solution, control the internal temperature between -75 and -55 ° C and stir for 0.5 h; control the internal temperature to slowly rise to 40 ± 5 ° C at a heating rate of 15 to 25 ° C / h to react; after the reaction is completed, cool to 5 to 25 ° C, drop the reaction solution Add saturated ammonium chloride solution (800 mL) for quenching, raise the temperature to 40±5°C and stir for 0.5 h, concentrate under reduced pressure at 35±5°C until no liquid flows out of the condenser, add n-heptane (400 mL) to the reaction solution and stir for 0.5 h, let stand and separate, and retain the organic phase; add n-heptane (200 mL) to the aqueous phase, stir for 0.5 h, let stand and separate, and retain the organic phase; add n-heptane (200 mL) and diatomaceous earth (40 g) to the aqueous phase, stir for 0.5 h, filter and let stand and separate, and retain the organic phase; combine the organic phases, concentrate under reduced pressure at 40±5°C to dryness to obtain a yellow or orange-yellow liquid compound 3, which can be directly used for the next step.

[0130] Synthesis of compound 4:

[0131]

[0132] Toluene (140 mL), trifluoroacetic acid (40 mL), and the concentrate of compound 3 in the previous step were added to a 1000 mL three-necked flask, and the mixture was stirred at 30±5°C for 3 h. After the reaction, methyl tert-butyl ether (80 mL) was slowly added dropwise to the reaction solution (1.5-4.5 h). After the addition was completed, the mixture was cooled to 0-10°C and stirred for 6 h. The mixture was filtered and the filter cake was drained. The filter cake was transferred to a 500 mL three-necked flask, methyl tert-butyl ether (80 mL) was added, the mixture was heated to 45±5°C and stirred for 3 h. The mixture was cooled to 5-15°C and stirred for 3 h. The mixture was filtered and dried in vacuo at 45±5°C to obtain about 15.32 g of light yellow solid compound 4 with a total yield of about 43.11%.

[0133] Synthesis of compound 5:

[0134]

[0135] Compound 4 (30 g), methanol (600 mL), and 98 wt% concentrated sulfuric acid (19.17 g) were added to a 1000 mL three-necked flask, and the mixture was replaced with nitrogen three times. The mixture was heated to 70±5°C and refluxed for reaction for 5 h. After the reaction, the mixture was cooled to 30±5°C, toluene (200 mL) was added to the reaction solution, and the mixture was concentrated under reduced pressure at 30±5°C until almost no liquid flowed out of the condenser end; the mixture was cooled to 0-10°C and stirred, 5% sodium bicarbonate aqueous solution was added to the reaction solution to adjust the pH of the aqueous phase to 7-8, stirred for 30 min, allowed to stand for separation, and the organic phase was retained; toluene (150 mL) was added to the aqueous phase and stirred for 0.5 h, allowed to stand for separation, and the organic phase was retained; the organic phases were combined, a saturated sodium chloride solution (180 mL) was added to the organic phase, stirred for 0.5 h, allowed to stand for separation, and the organic phase was retained; the organic phase was concentrated under reduced pressure at 60±5°C until there was no obvious water in the condensation receiver part to obtain a toluene solution of compound 5, which can be directly used in the next step.

[0136] Synthesis of compound 6:

[0137]

[0138] Add cis-2,6-dimethylmorpholine (30.59 g) and toluene (180 mL) to a 500 mL three-necked flask, replace with nitrogen three times, start stirring, cool to -10±5°C, control the internal temperature at -10±5°C, add 70% sodium bis(methoxyethoxy)aluminum hydride toluene solution (87 g, diluted with 90 mL toluene) dropwise to the reaction solution, slowly heat to 5±5°C and stir for 2 h to prepare the modified Red-Al toluene solution.

[0139] Add the toluene solution of compound 5 in the previous step to a 1000mL three-necked flask, replace with nitrogen 3 times, start stirring, cool to -10±5℃, control the internal temperature at -10±5℃, add the modified Red-Al toluene solution to the reaction solution, slowly heat to 5±5℃ and stir for 2h, after the reaction, adjust the pH of the aqueous phase to between 0 and 1 with 25% dilute sulfuric acid aqueous solution, stir for 0.5h, stand for separation, and retain the organic phase; add 90mL toluene to the aqueous phase and stir for 0.5h, stand for separation, and retain the organic phase; combine the organic phases, wash with 5% sodium bicarbonate aqueous solution (200mL), purified water (200mL), and saturated NaCl aqueous solution (200mL) in sequence, and retain the organic phase; add N-methylpyrrolidone (360mL) to the organic phase, concentrate under reduced pressure at 65±5℃ until no obvious droplets fall from the condensation receiver to obtain the N-methylpyrrolidone solution of compound 6, which can be directly used in the next step.

[0140] Synthesis of compound 7:

[0141]

[0142] Add the N-methylpyrrolidone solution of compound 6 in the previous step to a 1000mL three-necked flask, add anhydrous sodium carbonate (6.57g), potassium ferrocyanide (18.30g), [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (2.03g), replace with nitrogen 3 times, start stirring, heat to 115±5℃ for reaction for 3h, cool to 65±5℃ after the reaction, add toluene (400mL) and purified water (400mL) to the reaction solution, stir for 40min, use diatomaceous earth (40g) for pre-coating filtration, wash with toluene (80mL), let the filtrate stand for separation, and retain the organic phase; add toluene (100mL) to the aqueous phase, stir at 65±5℃ for 20min, let stand for separation, and retain the organic phase; combine the organic phases, add 10% sodium chloride aqueous solution liquid (400 mL), stirred at 65±5°C for 40 min, allowed to stand for separation, and the organic phase was retained; 10% sodium chloride aqueous solution (400 mL) was added to the organic phase, stirred at 65±5°C for 40 min, allowed to stand for separation, and the organic phase was retained; silica gel (110 g) was added to the organic phase, stirred at 65±5°C for 70 min, silica gel (80 g) was used for pre-coating filtration, and the mixture was washed with dichloromethane (400 mL), and the filtrate was distilled under reduced pressure at 55±5°C until about 250-350 mL of the remaining material was obtained, the remaining filtrate was heated to 65±5°C and stirred, and n-heptane (400 mL) was added dropwise to the filtrate. After the addition was completed, stirring was continued for 1.5 h, the temperature was slowly lowered to 5-15°C and stirred for 1.5 h, filtered, and dried in vacuo at 45±5°C to obtain about 7.21 g of light yellow solid compound 7, with a total yield of about 33.6% in the three steps.

[0143] The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A compound, characterized in that As shown in formula VI; Wherein, R1 and R2 are independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, or H.

2. The compound according to claim 1, characterized in that R1 and R2 are independently selected from C 1-4 Alkyl, C 1-4 Preferably, R1 and R2 are independently selected from C 1-2 Alkyl, C 1-2 Alkoxy, or H.

3. The compound according to claim 1, characterized in that The compound is shown in Formula 6; 4. The method for preparing the compound according to claim 1, characterized in that: The following steps are involved: (1) the compound represented by formula IV undergoes an esterification reaction with an alcohol compound under the action of sulfuric acid to obtain a compound represented by formula V; (2) the compound represented by formula V undergoes a reduction reaction under the action of a reducing agent to generate a compound represented by formula VI; 5. The preparation method according to claim 4, characterized in that: In step (1), preferably, the sulfuric acid is concentrated sulfuric acid with a mass concentration of 90%-99%, preferably concentrated sulfuric acid with a mass concentration of 98%; preferably, the alcohol compound is C1-C10 hydroxy alcohol, preferably C1-C5 hydroxy alcohol, preferably methanol; preferably, the molar ratio of the compound represented by formula IV to sulfuric acid is 1:0.3-4.5, preferably 1:0.4-3, and more preferably 1:0.5-1.5; preferably, the feed ratio of the compound represented by formula IV to the alcohol compound is 1g:6-60mL, preferably 1g:8-40mL, and more preferably 1g:10-20mL; preferably, the temperature of the esterification reaction is 35-95°C, preferably 45-85°C, and more preferably 55-75°C; Preferably, in step (2), the reducing agent is sodium bis(methoxyethoxy)aluminum hydride modified by a modifying agent; preferably, the modifying agent comprises N-methylpiperazine and / or cis-2,6-dimethylmorpholine, preferably 2,6-dimethylmorpholine; preferably, the molar ratio of the compound represented by formula IV, sodium bis(methoxyethoxy)aluminum hydride and the modifying agent is 1:0.9-7.5:1.1-6.6, preferably 1:1.2-5:1.4-4.4, and further preferably 1:1.5-2.5:1.8-2.2; preferably, the modified solvent is an organic solvent, preferably toluene; preferably, the feed ratio of the compound represented by formula IV to the solvent is 1 g: 3-81mL, preferably 1g:4-27mL, more preferably 1g:5-9mL; preferably, the modification is to add sodium bis(methoxyethoxy)aluminum hydride and the remaining solvent to a mixed solution of the modifier and part of the solvent, the part of the solvent is 60%-90% of the total solvent volume, preferably 63.3%-85%, more preferably 66.7%-80%; preferably, the temperature at which the sodium bis(methoxyethoxy)aluminum hydride is added to the reaction system is -30 to 5°C, preferably -25 to 0°C, more preferably -20 to -5°C; preferably, the temperature of the modification is -15 to 20°C, preferably -10 to 15°C, more preferably -5 to 10°C; Preferably, the reduction reaction is to add a solution containing a reducing agent to a solution containing the compound represented by formula V for a reduction reaction; the solvents in the solution containing the reducing agent and the solution containing the compound represented by formula V are both organic solvents, preferably toluene; preferably, the temperature at which the reducing agent is added to the reaction system is -30 to 5°C, preferably -25 to 0°C, and further preferably -20 to -5°C; preferably, the temperature of the reduction reaction is -20 to 5°C, preferably -15 to 0°C, and further preferably -10 to -5°C.

6. The preparation method according to claim 4, characterized in that: The preparation method of the compound represented by formula IV comprises: (i) the compound represented by formula II undergoes nucleophilic ring-opening and ring-closing reaction with ethylene oxide under the action of a strong base to obtain the compound represented by formula III; (ii) the compound represented by formula III undergoes hydrolysis reaction under the action of a strong acid to obtain a compound represented by formula IV; 7. The preparation method according to claim 6, characterized in that: In step (i), the strong base is any one or a combination of n-butyl lithium, sec-butyl lithium, tert-butyl lithium and lithium diisopropylamide, preferably lithium diisopropylamide; preferably, the molar ratio of the compound represented by formula II to the strong base is 1:0.8-3, preferably 1:1.0-2.25, and more preferably 1:1.2-1.5; preferably, the molar ratio of the compound represented by formula II to ethylene oxide is 1:1.8-12, preferably 1:2.4-8, and more preferably 1:3- 4; preferably, the solvent of the reaction is an organic solvent, preferably tetrahydrofuran; preferably, the feeding ratio of the compound represented by formula II to the solvent is 1g:8-32mL, preferably 1g:10-24mL, and more preferably 1g:12-16mL; preferably, a strong base is added to the mixed system of the compound represented by formula II and the solvent, a first stirring is performed, and then ethylene oxide is added, a second stirring is performed, and the temperature is raised to react; preferably, the reaction is carried out under an inert gas atmosphere; preferably, the strong base is added to the reaction system in the form of a strong base solution; preferably, the concentration of the strong base solution is 0.9-7.5M, preferably 1.2-5M, and more preferably 1.5-2.5M; preferably, the temperature at which the strong base is added to the reaction system is -115 to -35°C, preferably -105 to -45°C, and more preferably -95 to -55°C; preferably, the ethylene oxide is added to the reaction system in the form of an ethylene oxide solution; preferably, the concentration of the ethylene oxide solution is 1.2-12M, preferably ... Preferably, the temperature at which ethylene oxide is added to the reaction system is -115 to -35°C, preferably -105 to -45°C, and more preferably -95 to -65°C; Preferably, the heating rate of the ring-opening and ring-closing reactions is 6 to 75°C / h, preferably 8 to 50°C / h, and more preferably 10 to 25°C / h; Preferably, the temperature is raised to 5 to 65°C, preferably 10 to 55°C, and more preferably 15 to 45°C; Preferably, in step (ii), the strong acid is any one or a combination of sulfuric acid, hydrochloric acid and trifluoroacetic acid, preferably trifluoroacetic acid; preferably, the sulfuric acid is concentrated sulfuric acid with a mass concentration of 90%-99%, preferably concentrated sulfuric acid with a mass concentration of 98%; preferably, the hydrochloric acid is concentrated hydrochloric acid with a mass concentration of 24%-63%, preferably concentrated hydrochloric acid with a mass concentration of 28%-52.5%, and further preferably concentrated hydrochloric acid with a mass concentration of 32%-42%; preferably, the amount ratio of the compound represented by formula II to the strong acid is 1g:0.6 -6mL, preferably 1g:0.8-4mL, further preferably 1g:1-2mL; preferably, the solvent of the reaction is any one or a combination of toluene, n-heptane, ethyl acetate and dichloromethane, preferably toluene; preferably, the feed ratio of the compound represented by formula II to the solvent is 1g:2.5-100mL, preferably 1g:3-20mL, further preferably 1g:3.5-4mL; preferably, the reaction temperature is 5-55°C, preferably 10-45°C, further preferably 15-35°C.

8. The preparation method according to claim 6, characterized in that: The preparation method of the compound represented by formula II comprises: subjecting the compound represented by formula I to an esterification reaction under the action of di-tert-butyl dicarbonate, 4-dimethylaminopyridine and tert-butyl alcohol to obtain the compound represented by formula II; Preferably, the molar ratio of the compound of formula I to di-tert-butyl dicarbonate is 1:2-6, preferably 1:2.4-4.8, and more preferably 1:2.8-3.6; preferably, the molar ratio of the compound of formula I to 4-dimethylaminopyridine is 1:0.048-0.36, preferably 1:0.064-0.24, and more preferably 1:0.08-0.12; preferably, the feeding amount ratio of the compound of formula I to tert-butyl alcohol is 1g:2-10mL, preferably 1g:2.5-7.5mL, and more preferably 1g:3-5mL; preferably, the solvent of the reaction is an organic solvent, preferably tetrahydrofuran; preferably, the feeding ratio of the compound represented by formula I to the solvent is 1g:4-20mL, preferably 1g:5-15mL, preferably 1g:6-10mL; preferably, di-tert-butyl dicarbonate is added to the mixed system of the compound represented by formula I, 4-dimethylaminopyridine, tert-butyl alcohol and solvent; preferably, the temperature of adding di-tert-butyl dicarbonate to the reaction system is 5-45°C, preferably 10-40°C, and more preferably 15-35°C; preferably, the reaction temperature is 45-85°C, preferably 50-80°C, and more preferably 55-75°C.

9. Use of the compound of formula VI as claimed in claim 1 as an intermediate; preferably, the compound of formula VI is used as an intermediate for preparing dihydrobenzofuran compounds; preferably, the dihydrobenzofuran compounds include compounds of formula VII; 10. The use according to claim 9, characterized in that: The compound represented by formula VI undergoes a coupling reaction with a cyano group in the presence of a palladium catalyst to generate a compound represented by formula VII; Preferably, the palladium catalyst is any one or a combination of [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride, [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex and methanesulfonate (2-di-tert-butylphosphine-2', 4', 6'-tri-i-propyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II), preferably [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex and / or methanesulfonate (2-di-tert-butylphosphine-2', 4', 6'-tri-i-propyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II), and further preferably [1,1- Bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex; preferably, the palladium catalyst is a compound of formula IV The molar ratio of the compounds is 0.01-0.08:1, preferably 0.01-0.06:1, and more preferably 0.02-0.04:1; preferably, the solvent for the coupling reaction is any one or a combination of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile and water, preferably any one of N-methylpyrrolidone, acetonitrile and water, and more preferably N-methylpyrrolidone; preferably, The coupling reaction also includes anhydrous sodium carbonate and potassium ferrocyanide; preferably, the molar ratio of the anhydrous sodium carbonate, potassium ferrocyanide and the compound represented by formula IV is 0.3-4.5:0.06-0.6:1, preferably 0.4-3.1:0.08-0.4:1, and more preferably 0.5-1.5:0.1-0.2:1; preferably, the temperature of the coupling reaction is 80-140°C, preferably 90-130°C, and more preferably 100-120°C.

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