A process for the preparation of 7-formyl-2,3-dihydrobenzofuran-4-carbonitrile

Abstract

The application belongs to the field of pharmaceutical chemistry, and specifically discloses a preparation method of 7-formyl-2,3-dihydrobenzofuran-4-carbonitrile, which comprises the following steps: coupling reaction of a compound shown in formula VI with cyanogen under the action of a palladium catalyst to generate a compound shown in formula VII. The method provided by the application is low in cost, good in safety, high in yield, and suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry and relates to a method for preparing 7-formyl-2,3-dihydrobenzofuran-4-carbamate. Background Technology

[0002] The 2,3-dihydrobenzofuran ring is an important structural unit widely found in various pharmacologically active natural products. Numerous reports have been published on the synthesis of the 2,3-dihydrobenzofuran ring, such as CN108329285A, CN111253355A, and CN114591278A. However, there are few reports on efficient methods for preparing 4- and 7-dihydrobenzofuran compounds from simple and inexpensive raw materials.

[0003] To introduce substituents at the 4 and 7 positions of 2,3-dihydrobenzofuran, as described in CN113480534A, 5-bromo-2-methylphenol was used as a starting material. After nucleophilic substitution with 2-bromo-1,1-diethoxyethane, it was cyclized with polyphosphoric acid to generate 4-bromo-7-methylbenzofuran. Then, it was coupled with cuprous cyanide to introduce a cyano group to generate 7-methylbenzofuran-4-nitrile. However, in subsequent experiments, the applicant attempted to reduce the furan ring to obtain a 2,3-dihydrobenzofuran ring with substituents at the 4 and 7 positions, but this attempt failed under various conditions, possibly due to the formation of a large conjugated system between the cyano group and the benzofuran ring.

[0004]

[0005] In addition, a prior application has provided a method for preparing 7-formyl-2,3-dihydrobenzofuran-4-carbonitrile: using 4-amino-5-chloro-2,3-dihydro-1-benzofuran-7-carboxylic acid as the starting material, after methylation, dehalogenation is carried out under palladium-carbon pressure hydrogenation, followed by diazotization with tert-butyl nitrite, and then reaction with cuprous bromide to introduce halogen. Then, a coupling reaction is carried out with cuprous cyanide at high temperature, further reduced to an alcohol under the action of lithium borohydride, and finally oxygenated with Desmartin reagent to generate 7-formyl-2,3-dihydrobenzofuran-4-carbonitrile. However, the starting material cost is high, which is not conducive to large-scale production.

[0006]

[0007] Therefore, there is a need for a safer, more economical, and industrially viable route to synthesize 7-formyl-2,3-dihydrobenzofuran-4-carbamate. 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-carbamate, which addresses the shortcomings of the prior art.

[0009] To solve the above-mentioned technical problems, the present invention discloses the following technical solution:

[0010] First aspect This invention discloses a compound as shown in Formula VI;

[0011]

[0012] Among them, R1 and R2 are independently selected from C 1-6 Alkyl, C 1-6 Alkyl group or H; preferably, R1 and R2 are each independently selected from C 1-4 Alkyl, C 1-4 Alkyl group or H; more preferably, R1 and R2 are each independently selected from C 1-2 Alkyl, C 1-2 Alkoxy, or H.

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

[0014]

[0015] Second aspect The present invention discloses a method for preparing the compound shown in the first aspect VI above, comprising the following steps:

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

[0017] (2) The compound shown in formula V undergoes a reduction reaction under the action of a reducing agent to produce the compound shown in formula VI;

[0018]

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

[0020] In step (2), the reducing agent is sodium bis(methoxyethoxy)aluminum hydride modified by a modifying agent; preferably, the modifying agent includes N-methylpiperazine and / or cis-2,6-dimethylmorpholine, more preferably 2,6-dimethylmorpholine; preferably, the molar ratio of the compound shown in Formula IV, sodium bis(methoxyethoxy)aluminum hydride, and the modifying agent is 1:0.9-7.5:1.1-6.6, more preferably 1:1.2-5:1.4-4.4, and even more preferably 1:1.5-2.5:1.8-2.2; preferably, the modifying solvent is an organic solvent, more preferably toluene; preferably, the feed ratio of the compound shown in Formula IV to the solvent is 1g:3- 81 mL, preferably 1 g: 4-27 mL, more preferably 1 g: 5-9 mL; preferably, the modification involves adding sodium bis(methoxyethoxy)aluminum hydride and the remaining solvent to a mixed solution of the modifier and a portion of the solvent, wherein the portion 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 modification temperature is -15 to 20°C, preferably -10 to 15°C, more preferably -5 to 10°C.

[0021] In step (2), the reduction reaction is carried out by adding a solution containing a reducing agent to a solution containing a compound of formula V; the solvents in both the solution containing the reducing agent and the solution containing the compound of formula V are 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 was adjusted to between 0 and 1, stirred for 0.5 h, allowed to stand and separated, retaining the organic phase; 90-150 mL of toluene was added to the aqueous phase and stirred for 0.5 h, allowed to stand and separated, retaining the organic phase; the organic phases were combined and washed sequentially with 200-400 mL of 5% sodium bicarbonate aqueous solution, 200-400 mL of purified water, and 200-400 mL of saturated NaCl aqueous solution, retaining the organic phase; N-methylpyrrolidone (240-60 mL) was added to the organic phase, and the mixture was concentrated under reduced pressure at 40-70 °C until no obvious droplets fell from the condenser receiver to obtain the compound shown in Formula VI.

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

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

[0024] (ii) The compound shown in formula III undergoes a hydrolysis reaction under the action of a strong acid to obtain the compound shown in formula IV.

[0025]

[0026] In step (i), the strong base is any one or a combination of several of n-butyllithium, sec-butyllithium, tert-butyllithium, and diisopropylaminolithium, preferably diisopropylaminolithium; preferably, the molar ratio of the compound represented by Formula II to the strong base is 1:0.8-3, more preferably 1:1.0-2.25, and even 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, more preferably 1:2.4-8, and even more preferably 1:3-4; preferably, the solvent for the reaction is an organic solvent, preferably tetrahydrofuran; preferably, the feed ratio of the compound represented by Formula II to the solvent is 1g:8-32mL, more preferably 1g:10-24mL, and even more preferably 1g:8-32mL. The preferred step is 1g:12-16mL; preferably, a strong base is added to the mixture of the compound shown in Formula II and the solvent, a first stirring is performed, 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, more preferably 1.5-2.5M; preferably, the temperature at which the strong base is added to the reaction system is -115 to -35℃, preferably -105 to -45℃, more preferably -95 to -55℃; 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 0.6-4 h, more preferably 0.8-3.5 h, and even more preferably 1-3 h; preferably, the concentration of the ethylene oxide solution is 1.2-12 M, more preferably 1.6-8 M, and even more preferably 2-4 M; preferably, the temperature at which the ethylene oxide is added to the reaction system is -115 to -35 °C, more preferably -105 to -45 °C, and even more preferably -95 to -65 °C; preferably, the second stirring time is 0.1-1.5 h, more preferably 0.3-1 h, and even more preferably 0.5-1 h; Preferably, the heating rate of the ring-opening and ring-closing reactions is 6-75℃ / h, more preferably 8-50℃ / h, and even more preferably 10-25℃ / h; preferably, the temperature is raised to 5-65℃, more preferably 10-55℃, and even more preferably 15-45℃; preferably, after the reaction is completed, the temperature is lowered to -5-25℃, and saturated ammonium chloride solution (400-800mL) is added dropwise to the reaction solution for quenching, the temperature is raised to 25-45℃ and stirred for 0.5h, and the solution is concentrated under reduced pressure at 25-45℃ until no liquid flows out from the condenser end. n-Heptane (200-400mL) is added to the reaction solution and stirred for 0.5h, the solution is allowed to stand and separated, retaining the organic phase; n-Heptane (200-400mL) is added to the aqueous phase and stirred for 0.5h.After 5 hours of settling, allow the mixture to stand and separate the liquids, retaining the organic phase. Add 200-400 mL of n-heptane and 20-40 g of diatomaceous earth to the aqueous phase, stir for 0.5 hours, filter, allow to stand and separate the liquids, retaining the organic phase. Combine the organic phases and concentrate under reduced pressure to dryness 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%, more preferably concentrated hydrochloric acid with a mass concentration of 32%-42%; preferably, the ratio of the compound shown in Formula II to the strong acid is 1g:0.6-6mL, preferably 1g:0.8-4mL, more preferably 1g:1-2mL; preferably, the solvent for the reaction is any one or a combination of toluene, n-heptane, ethyl acetate, and dichloromethane, preferably toluene; preferably, the solvent for the reaction is... The ratio of compound to solvent is 1g:2.5-100mL, preferably 1g:3-20mL, and more preferably 1g:3.5-4mL; preferably, the reaction temperature is 5-55℃, preferably 10-45℃, and more preferably 15-35℃; preferably, after the reaction is completed, methyl tert-butyl ether (80-160mL) is slowly added dropwise to the reaction solution. After the addition is complete, the temperature is lowered to 0-10℃ and stirred for 6 hours, filtered, and the filter cake is dried under vacuum; methyl tert-butyl ether (80-120mL) is added to the filter cake, the temperature is raised to 30-50℃ and stirred and slurryed for 1-3 hours, the temperature is lowered to -5-15℃ and stirred for 1-3 hours, filtered, and dried under vacuum at 30-50℃ 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 in 0.5-4.5 hours.

[0028] In step (i), the preparation method of the compound shown in Formula II includes: the compound shown in Formula I undergoes an esterification reaction in the presence of di-tert-butyl dicarbonate, 4-dimethylaminopyridine and tert-butanol to obtain the compound shown in Formula II;

[0029]

[0030] 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 feed ratio of the compound of Formula I to tert-butanol is 1g:2-10mL, preferably... The ratio of the compound of Formula I to the solvent is 1g:2.5-7.5mL, more preferably 1g:3-5mL; preferably, the solvent for the reaction is an organic solvent, preferably tetrahydrofuran; preferably, the ratio of the compound of 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 mixture of the compound of Formula I, 4-dimethylaminopyridine, tert-butanol and the solvent; preferably, the di-tert-butyl dicarbonate... The ditert-butyl dicarbonate is added to the reaction system in batches; preferably, the temperature at which the ditert-butyl dicarbonate is added to the reaction system is 5–45°C, more preferably 10–40°C, and even more preferably 15–35°C; preferably, the reaction temperature is 45–85°C, more preferably 50–80°C, and even more preferably 55–75°C; preferably, after the reaction is completed, the temperature is lowered to 15–30°C, ethyl acetate (600–1000 mL) and 5% sodium bicarbonate aqueous solution (1000–2000 mL) are added to the reaction solution and stirred for 15–35 min, allowed to stand and separate, retaining the organic phase; ethyl acetate (400–600 mL) is added to the aqueous phase and stirred for 15–35 min, allowed to stand and separate, retaining the organic phase; after combining the organic phases, they are washed sequentially with 5% citric acid aqueous solution (800–1200 mL), 5% sodium bicarbonate aqueous solution (400–600 mL), and saturated NaCl aqueous solution (400–600 mL), retaining the organic phase, and concentrated and dried under reduced pressure to constant weight to obtain the compound shown in Formula II.

[0031] Third aspect The present invention discloses the use of the compound shown in Formula VI as an intermediate; preferably, the compound shown in Formula VI is used as an intermediate to prepare dihydrobenzofuran compounds; preferably, the dihydrobenzofuran compounds include the compound shown in Formula VII;

[0032]

[0033] Among them, the compound shown in formula VI undergoes a coupling reaction with a cyano group under a palladium catalyst to generate the compound shown in formula VII;

[0034]

[0035] The palladium catalyst is [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride (Pd(dppf)Cl2), [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (Pd(dppf)Cl2·CH2Cl2), and methane sulfonate (2-di-tert-butylphosphine-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)(tBuXPhos Pd Any one or more combinations of G3), preferably [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex and / or methane sulfonate (2-di-tert-butylphosphine-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), more preferably [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex; preferably, the molar ratio of the palladium catalyst to the compound shown in Formula IV is 0.01-0.08:1, more preferably 0.01-0.06:1, more preferably 0.02-0.04:1; preferably, The solvent for the coupling reaction is any one or a combination of several 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 further includes anhydrous sodium carbonate and potassium ferrocyanide; preferably, the molar ratio of the anhydrous sodium carbonate, potassium ferrocyanide, and the compound shown in Formula IV is 0.3-4.5:0.06-0.6:1, more preferably 0.4-3.1:0.08-0.4:1, and more preferably 0.5-1.5:0.1-0.2:1; Preferably, the coupling reaction temperature is 80-140℃, more preferably 90-130℃, and even more preferably 100-120℃; Preferably, after the reaction is completed, the temperature is lowered to 60-90℃, toluene (200-400mL) and purified water (200-400mL) are added to the reaction solution, stirred for 20-40min, pre-coated with diatomaceous earth (40-80g) and filtered, washed with toluene (80-120mL), the filtrate is allowed to stand and separated, retaining the organic phase; toluene (100-200mL) is added to the aqueous phase, stirred at 60-90℃ for 20-40min, allowed to stand and separated, retaining the organic phase; the organic phases are combined, 10% sodium chloride aqueous solution (200-400mL) is added, stirred at 60-90℃ for 20-40min, allowed to stand and separated, Retain the organic phase; add 200-400 mL of 10% sodium chloride aqueous solution to the organic phase and stir at 60-90 °C for 30-50 min, allow to stand and separate, retaining the organic phase; add 70-110 g of silica gel to the organic phase and stir at 60-90 °C for 50-70 min, pre-coat filter with silica gel (40-80 g), wash with dichloromethane (400-800 mL), distill the filtrate under reduced pressure at 30-60 °C until approximately 150-350 mL of material remains, heat the remaining filtrate to 60-90 °C and stir, add 400-600 mL of n-heptane dropwise to the filtrate, continue stirring for 0.5-1.5 h after the addition is complete, slowly cool to -5-15 °C and stir for 0.5-1.5 h, filter, and dry 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 in this invention includes 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 this invention can be a commercially available reagent, requires no 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 use of pressurized hydrogenation, which makes the reaction safer.

[0041] (3) This invention provides a new method for preparing the compound 7-formyl-2,3-dihydrobenzofuran-4-carbamate, thus providing a basis for the application of 4- and 7-position-double-substituted 2,3-dihydrobenzofuran compounds in drug synthesis. At the same time, the method is low in cost, safe, and has a high yield, making it suitable for large-scale industrial production. Attached Figure Description

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

[0043] Figure 1 The image shows the 1H NMR spectrum of compound 2 obtained in Example 1.

[0044] Figure 2 The image shows the carbon NMR spectrum of compound 2 obtained in Example 1.

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

[0046] Figure 4 The image shows the 1H NMR spectrum of compound 3 obtained in Example 1.

[0047] Figure 5 The image shows the carbon NMR spectrum of compound 3 obtained in Example 1.

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

[0049] Figure 7 The image shows the 1H NMR spectrum of compound 4 obtained in Example 1.

[0050] Figure 8 The image shows the carbon NMR spectrum of compound 4 obtained in Example 1.

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

[0052] Figure 10 The image shows the 1H NMR spectrum of compound 5 obtained in Example 1.

[0053] Figure 11 The image shows the carbon NMR spectrum of compound 5 obtained in Example 1.

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

[0055] Figure 13 The image shows the 1H NMR spectrum of compound 6 obtained in Example 1.

[0056] Figure 14 The image shows the carbon NMR spectrum of compound 6 obtained in Example 1.

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

[0058] Figure 16 The image shows the 1H NMR spectrum of compound 7 obtained in Example 1.

[0059] Figure 17 The image shows the carbon NMR spectrum of compound 7 obtained in Example 1.

[0060] Figure 18 This is a high-resolution mass spectrum of compound 7 obtained in Example 1. Detailed Implementation

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

[0062] In this embodiment of the invention, the term "controlling internal temperature" refers to the reaction internal temperature.

[0063] In the embodiments of this invention, the percentages representing concentration are all mass percentages unless otherwise specified.

[0064] Unless otherwise specified, the solvent for the diisopropylaminolithium solution described in this invention is a tetrahydrofuran solution or a tetrahydrofuran / n-hexane mixed solution.

[0065] Example 1

[0066] Synthesis of compound 2:

[0067]

[0068] Add 800 mL of THF, 400 mL of tert-butanol, 100 g of 4-bromo-2-fluorobenzoic acid, and 5.58 g of 4-dimethylaminopyridine to a 3000 mL three-necked flask and stir at 25 ± 5 °C. Add 318.89 g of ditert-butyl dicarbonate to the reaction solution in portions. After the addition is complete, slowly raise the temperature to 65 ± 5 °C and react for 4 h. After the reaction is complete, lower the temperature to 25 ± 5 °C and add 800 mL of ethyl acetate and 5% sodium bicarbonate solution to the reaction solution. The aqueous phase (1500 mL) was stirred for 25 min, allowed to stand, and separated, retaining the organic phase. Ethyl acetate (500 mL) was added to the aqueous phase and stirred for 25 min, then allowed to stand and separated, retaining the organic phase. The combined organic phases were washed sequentially with 5% citric acid aqueous solution (1000 mL), 5% sodium bicarbonate aqueous solution (500 mL), and saturated NaCl aqueous solution (500 mL), retaining the organic phase. The mixture was concentrated under reduced pressure and dried to constant weight to obtain a yellow or orange-yellow liquid compound 2, which can be directly used for the next step. The 1H NMR spectrum, 1C NMR spectrum, and high-resolution mass spectrum of compound 2 are shown below. Figures 1-3 As 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 560 mL of dry THF and 40 g of compound 2 to a 1000 mL three-necked flask, purge with nitrogen three times, and cool to -85 to -65 °C. Slowly add 100 mL of 2.0 M diisopropylaminolithium solution to the reaction solution. After addition, maintain the internal temperature between -85 and -65 °C and stir for 2 h. Slowly add 170 mL of 3.0 M ethylene oxide tetrahydrofuran solution to the reaction solution. After addition, maintain the internal temperature between -85 and -65 °C and stir for 1 h. Slowly increase the internal temperature to 30 ± 5 °C at a rate of 15–20 °C / h to carry out the reaction. After the reaction is complete, cool to 0–20 °C and add dropwise... Quenching was performed with 600 mL of saturated ammonium chloride solution. The mixture was heated to 35 ± 5 °C and stirred for 0.5 h. The solution was then concentrated under reduced pressure at 35 ± 5 °C until no liquid flowed out from the condenser. 300 mL of n-heptane was added to the reaction mixture and stirred for 0.5 h. The mixture was allowed to stand and separated, retaining the organic phase. 300 mL of n-heptane was added to the aqueous phase and stirred for 0.5 h. The mixture was allowed to stand and separated, retaining the organic phase. 300 mL of n-heptane and 30 g of diatomaceous earth were added to the aqueous phase and stirred for 0.5 h. After filtration, the mixture was allowed to stand and separated, retaining the organic phase. The organic phases were combined and concentrated under reduced pressure at 50 ± 5 °C until dry to obtain a yellow or orange-yellow liquid compound 3, which can be directly used for the next step. The 1H NMR spectrum, 1C NMR spectrum, and high-resolution mass spectrum of compound 3 are shown below. Figures 4-6 As 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 from the previous step were added to a 1000 mL three-necked flask. The mixture was stirred at 25 ± 5 °C for 2 h. After the reaction was complete, methyl tert-butyl ether (120 mL) was slowly added dropwise to the reaction solution (1-4 h). After the addition was complete, the mixture was cooled to 0–10 °C and stirred for 6 h. The mixture was then filtered, and the filter cake was dried under vacuum. The filter cake was transferred to a 500 mL three-necked flask, and methyl tert-butyl ether (120 mL) was added. The mixture was heated to 40 ± 5 °C and stirred for 2 h. The mixture was then cooled to 0–10 °C and stirred for 2 h. After filtration, the mixture was dried under vacuum at 40 ± 5 °C to obtain approximately 16.09 g of a pale yellow solid, compound 4. The overall yield of the three steps was approximately 45.28%. The 1H NMR spectrum, 1C NMR spectrum, and high-resolution mass spectrum of compound 4 are shown below. Figures 7-9 As 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 calculated 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. The mixture was purged with nitrogen three times, heated to 65 ± 5 °C, and refluxed for 4 h. After the reaction was completed, the temperature was lowered to 35 ± 5 °C, and toluene (300 mL) was added to the reaction solution. The mixture was concentrated under reduced pressure at 35 ± 5 °C until almost no liquid flowed out from the condenser end. The temperature was lowered to 0–10 °C and stirred. A 5% sodium bicarbonate aqueous solution was added to the reaction solution to adjust the pH of the aqueous phase to 7–8. The mixture was stirred for 20 min, allowed to stand, and separated, retaining the organic phase. Toluene (120 mL) was added to the aqueous phase and stirred for 0.5 h. The mixture was allowed to stand and separated, retaining the organic phase. The organic phases were combined, and a saturated sodium chloride solution (150 mL) was added to the organic phase. The mixture was stirred for 0.5 h, allowed to stand, and separated, retaining the organic phase. The organic phase was concentrated under reduced pressure at 55 ± 5 °C until no obvious water was found in the condenser receiver, yielding a toluene solution of compound 5, which can be directly used in the next step. The proton NMR spectrum, carbon NMR spectrum, and high-resolution mass spectrum of compound 5 are shown below. Figures 10-12 As 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, purge with nitrogen three times, start stirring, cool to -10±5℃, and control the internal temperature at -10±5℃. Add dropwise 70% sodium bis(methoxyethoxy)aluminum hydride toluene solution (71.31 g, diluted with 60 mL of toluene) to the reaction solution. After the addition is complete, slowly raise the temperature to 0±5℃ and stir for 2 h to prepare the modified Red-Al toluene solution.

[0093] Add the toluene solution of compound 5 from the previous step to a 1000 mL three-necked flask, purge with nitrogen three times, start stirring, cool to -10±5℃, and control the internal temperature at -10±5℃. Add the modified Red-Al toluene solution dropwise to the reaction solution. After the addition is complete, slowly raise the temperature to 0±5℃ and stir for 2 hours. After the reaction is complete, adjust the pH of the aqueous phase to between 0 and 1 with 25% dilute sulfuric acid solution, stir for 0.5 hours, let stand and separate the liquids, retaining the organic phase. Add 120 mL of toluene to the aqueous phase and stir for 0.5 hours. Let stand and separate the liquids, retaining the organic phase. Combine the organic phases and wash them sequentially with 5% sodium bicarbonate aqueous solution (300 mL), purified water (300 mL), and saturated NaCl aqueous solution (300 mL), retaining the organic phase. Add N-methylpyrrolidone (300 mL) to the organic phase and concentrate under reduced pressure at 55±5℃ until no obvious droplets fall from the condenser to obtain the N-methylpyrrolidone solution of compound 6, which can be directly used in the next step. The 1H NMR spectrum, 1C NMR spectrum, and high-resolution mass spectrum of compound 6 are shown below. Figures 13-15 As 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 calculated value: [C9H8O2Br+H] + 226.9708, measured value: 226.97000.

[0097] Synthesis of compound 7:

[0098]

[0099] Add the N-methylpyrrolidone solution of compound 6 from the previous step to a 1000 mL three-necked flask, along with anhydrous sodium carbonate (13.14 g), potassium ferrocyanide (13.70 g), and [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (3.04 g). Purge the solution with nitrogen three times, start stirring, and heat to 110±5℃ for 3 h. After the reaction, cool to 75±5℃, add toluene (300 mL) and purified water (300 mL) to the reaction solution, stir for 30±5 min, pre-coat the filter with diatomaceous earth (60 g), wash with toluene (100 mL), allow the filtrate to stand and separate, retaining the organic phase; add toluene (150 mL) to the aqueous phase, stir at 75±5℃ for 30±5 min, allow to stand and separate, retaining the organic phase; combine the organic phases, add 10%... 300 mL of sodium chloride aqueous solution was stirred at 75±5 °C for 30 min, allowed to stand and separated, retaining the organic phase; 300 mL of 10% sodium chloride aqueous solution was added to the organic phase and stirred at 75±5 °C for 30 min, allowed to stand and separated, retaining the organic phase; 90 g of silica gel was added to the organic phase and stirred at 75±5 °C for 60 min, pre-coated and filtered using silica gel (60 g), washed with dichloromethane (600 mL), and the filtrate was distilled under reduced pressure at 45±5 °C until about 200-300 mL of material remained. 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 complete, stirring was continued for 1 h, the temperature was slowly lowered to 0-10 °C and stirred for 1 h, filtered, and dried under vacuum at 40±5 °C to obtain about 8.12 g of pale yellow solid compound 7. The overall yield of the three steps was about 37.84%. The proton NMR spectrum, carbon NMR spectrum, and high-resolution mass spectrum of compound 7 are shown below. Figures 16-18 As 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 calculated value: [C 10 H7O2N-H] +172.03985, Measured value: 172.03894.

[0103] Example 2

[0104] Synthesis of compound 2:

[0105]

[0106] Add 600 mL of THF, 300 mL of tert-butanol, 100 g of 4-bromo-2-fluorobenzoic acid, and 6.7 g of 4-dimethylaminopyridine to a 3000 mL three-necked flask and stir at 20 ± 5 °C. Add 358.75 g of ditert-butyl dicarbonate to the reaction solution in portions. After the addition is complete, slowly raise the temperature to 60 ± 5 °C and react for 5 h. After the reaction is complete, lower the temperature to 20 ± 5 °C and add 600 mL of ethyl acetate and 5% sodium bicarbonate solution to the reaction solution. Stir the aqueous phase (2000 mL) for 35 min, allow it to stand and separate the liquids, retaining the organic phase; add ethyl acetate (600 mL) to the aqueous phase and stir for 35 min, allow it to stand and separate the liquids, retaining the organic phase; after combining the organic phases, wash them sequentially with 5% citric acid aqueous solution (800 mL), 5% sodium bicarbonate aqueous solution (400 mL), and saturated NaCl aqueous solution (400 mL), retaining the organic phase, concentrate and dry under reduced pressure to constant weight to obtain yellow or orange-yellow liquid compound 2, which can be directly used for the next step of feeding.

[0107] Synthesis of compound 3:

[0108]

[0109] Add 480 mL of dry THF and 40 g of compound 2 to a 1000 mL three-necked flask, purge with nitrogen three times, and cool to -95 to -75 °C. Slowly add 116 mL of 1.5 M diisopropylaminolithium solution to the reaction solution. After addition, maintain the internal temperature between -95 and -75 °C and stir for 3 h. Slowly add 218 mL of 2.0 M ethylene oxide tetrahydrofuran solution to the reaction solution. After addition, maintain the internal temperature between -95 and -75 °C and stir for 1.5 h. Slowly increase the internal temperature to 20 ± 5 °C at a rate of 10–20 °C / h to carry out the reaction. After the reaction is complete, cool to -5 to -15 °C and add... Quenching was performed by adding 400 mL of saturated ammonium chloride solution. The mixture was heated to 30 ± 5 °C and stirred for 0.5 h. The mixture was then concentrated under reduced pressure at 30 ± 5 °C until no liquid flowed out from the condenser. 200 mL of n-heptane was added to the reaction mixture and stirred for 0.5 h. The mixture was allowed to stand and separated, retaining the organic phase. 400 mL of n-heptane was added to the aqueous phase and stirred for 0.5 h. The mixture was allowed to stand and separated, retaining the organic phase. 400 mL of n-heptane and 20 g of diatomaceous earth were added to the aqueous phase and stirred for 0.5 h. The mixture was filtered and allowed to stand and separated, retaining the organic phase. The organic phases were combined and concentrated under reduced pressure at 60 ± 5 °C until dry to obtain a yellow or orange-yellow liquid compound 3, which can be directly used for the next step of feeding.

[0110] Synthesis of compound 4:

[0111]

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

[0113] Synthesis of compound 5:

[0114]

[0115] Add compound 4 (30g), methanol (300mL), and 98wt% concentrated sulfuric acid (6.39g) to a 1000mL three-necked flask. Purge with nitrogen three times, heat to 60±5℃ and reflux for 3h. After the reaction, cool to 40±5℃ and add toluene (400mL) to the reaction solution. Concentrate under reduced pressure at 40±5℃ until almost no liquid flows out from the condenser end. Cool to 0-10℃ and stir. Add 5% sodium bicarbonate aqueous solution to the reaction solution to adjust the pH of the aqueous phase to 7-8, stir for 10min, let stand and separate, retaining the organic phase. Add toluene (90mL) to the aqueous phase and stir for 0.5h. Let stand and separate, retaining the organic phase. Combine the organic phases, add saturated sodium chloride solution (120mL) to the organic phase, stir for 0.5h, let stand and separate, retaining the organic phase. Concentrate the organic phase under reduced pressure at 50±5℃ until there is no obvious water in the condenser receiver to obtain a toluene solution of compound 5, which can be directly used in the next process.

[0116] Synthesis of compound 6:

[0117]

[0118] Add 25.49 g of cis-2,6-dimethylmorpholine and 120 mL of toluene to a 500 mL three-necked flask. Purge the solution with nitrogen three times, start stirring, and cool to -15 ± 5 °C. While maintaining the internal temperature at -15 ± 5 °C, add dropwise 70% sodium bis(methoxyethoxy)aluminum hydride toluene solution (52.18 g, diluted with 30 mL of toluene). After the addition is complete, slowly raise the temperature 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 from the previous step to a 1000 mL three-necked flask, purge with nitrogen three times, start stirring, cool to -15±5℃, and control the internal temperature at -15±5℃. Add the modified Red-Al toluene solution dropwise to the reaction solution. After the addition is complete, slowly raise the temperature to -5±5℃ and stir for 2 hours. After the reaction is complete, adjust the pH of the aqueous phase to between 0 and 1 with 25% dilute sulfuric acid solution, stir for 0.5 hours, let stand and separate the liquids, retaining the organic phase. Add 150 mL of toluene to the aqueous phase and stir for 0.5 hours. Let stand and separate the liquids, retaining the organic phase. Combine the organic phases and wash them sequentially with 5% sodium bicarbonate solution (400 mL), purified water (400 mL), and saturated NaCl solution (400 mL), retaining the organic phase. Add N-methylpyrrolidone (240 mL) to the organic phase and concentrate under reduced pressure at 45±5℃ until no obvious droplets fall from the condenser 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 from the previous step to a 1000 mL three-necked flask, along with anhydrous sodium carbonate (19.71 g), potassium ferrocyanide (9.13 g), and [1,1-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (4.05 g). Purge the solution with nitrogen three times, start stirring, and heat to 105±5℃ for 3 h. After the reaction, cool to 85±5℃, add toluene (200 mL) and purified water (200 mL) to the reaction solution, stir for 20 min, pre-coat the filter with diatomaceous earth (80 g), wash with toluene (120 mL), allow the filtrate to stand and separate, retaining the organic phase; add toluene (200 mL) to the aqueous phase, stir at 85±5℃ for 40 min, allow to stand and separate, retaining the organic phase; combine the organic phases, add 10% sodium chloride solution. The organic phase was separated from the organic phase by stirring at 85±5℃ for 20 min, allowing it to stand. 200 mL of 10% sodium chloride aqueous solution was added to the organic phase and stirred at 85±5℃ for 20 min. The mixture was allowed to stand and separated, retaining the organic phase. 70 g of silica gel was added to the organic phase and stirred at 85±5℃ for 50 min. The mixture was pre-coated and filtered using silica gel (40 g). It was washed with dichloromethane (800 mL). The filtrate was distilled under reduced pressure at 35±5℃ until approximately 150–250 mL of material remained. The remaining filtrate was heated to 85±5℃ and stirred. 600 mL of n-heptane was added dropwise to the filtrate. After the addition was complete, stirring continued for 0.5 h. The mixture was then slowly cooled to -5–5℃ and stirred for 0.5 h. After filtration, the mixture was dried under vacuum at 35±5℃ to obtain approximately 7.56 g of a pale yellow solid compound 7. The overall yield of the three steps was approximately 35.23%.

[0123] Example 3

[0124] Synthesis of compound 2:

[0125]

[0126] Add 1000 mL of THF, 500 mL of tert-butanol, 100 g of 4-bromo-2-fluorobenzoic acid, and 4.46 g of 4-dimethylaminopyridine to a 3000 mL three-necked flask and stir at 30 ± 5 °C. Add 279.03 g of ditert-butyl dicarbonate to the reaction solution in portions. After the addition is complete, slowly raise the temperature to 70 ± 5 °C and react for 3 h. After the reaction is complete, lower the temperature to 25 ± 5 °C and add 1000 mL of ethyl acetate and 5% sodium bicarbonate solution to the reaction solution. The solution (1000 mL) was stirred for 15 min, allowed to stand and separated, retaining the organic phase; ethyl acetate (400 mL) was added to the aqueous phase and stirred for 15 min, allowed to stand and separated, retaining the organic phase; after combining the organic phases, the mixture was washed sequentially with 5% citric acid aqueous solution (1200 mL), 5% sodium bicarbonate aqueous solution (600 mL), and saturated NaCl aqueous solution (600 mL), retaining the organic phase, 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.

[0127] Synthesis of compound 3:

[0128]

[0129] Add 640 mL of dry THF and 40 g of compound 2 to a 1000 mL three-necked flask, purge with nitrogen three times, and cool to -75 to -55 °C. Slowly add 87 mL of 2.5 M diisopropylaminolithium solution to the reaction solution. After addition, maintain the internal temperature between -75 and -55 °C and stir for 1 h. Slowly add 145 mL of 4.0 M ethylene oxide tetrahydrofuran solution to the reaction solution. After addition, maintain the internal temperature between -75 and -55 °C and stir for 0.5 h. Slowly increase the internal temperature to 40 ± 5 °C at a rate of 15–25 °C / h to carry out the reaction. After the reaction is complete, cool to 5–25 °C and add dropwise to the reaction solution. Quenching was performed with 800 mL of saturated ammonium chloride solution, and the mixture was heated to 40 ± 5 °C and stirred for 0.5 h. The mixture was then concentrated under reduced pressure at 35 ± 5 °C until no liquid flowed out from the condenser. 400 mL of n-heptane was added to the reaction solution and stirred for 0.5 h. The mixture was allowed to stand and separated, retaining the organic phase. 200 mL of n-heptane was added to the aqueous phase and stirred for 0.5 h. The mixture was allowed to stand and separated, retaining the organic phase. 200 mL of n-heptane and 40 g of diatomaceous earth were added to the aqueous phase and stirred for 0.5 h. The mixture was filtered and allowed to stand and separated, retaining the organic phase. The organic phases were combined and concentrated under reduced pressure at 40 ± 5 °C until dry to obtain a yellow or orange-yellow liquid compound 3, which can be directly used for the next step of feeding.

[0130] Synthesis of compound 4:

[0131]

[0132] Toluene (140 mL), trifluoroacetic acid (40 mL), and the concentrate of compound 3 from the previous step were added to a 1000 mL three-necked flask. The mixture was stirred at 30 ± 5 °C for 3 h. After the reaction was completed, methyl tert-butyl ether (80 mL) was slowly added dropwise to the reaction mixture for 1.5–4.5 h. After the addition was complete, the mixture was cooled to 0–10 °C and stirred for 6 h. The mixture was then filtered, and the filter cake was dried under vacuum. The filter cake was transferred to a 500 mL three-necked flask, and methyl tert-butyl ether (80 mL) was added. The mixture was heated to 45 ± 5 °C and stirred for 3 h. The mixture was then cooled to 5–15 °C and stirred for 3 h. After filtration, the mixture was dried under vacuum at 45 ± 5 °C to obtain approximately 15.32 g of a pale yellow solid compound 4. The overall yield of the three steps was approximately 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. The mixture was purged with nitrogen three times, heated to 70 ± 5 °C, and refluxed for 5 h. After the reaction was completed, the temperature was lowered to 30 ± 5 °C, and toluene (200 mL) was added to the reaction solution. The mixture was concentrated under reduced pressure at 30 ± 5 °C until almost no liquid flowed out from the condenser end. The temperature was lowered to 0–10 °C and stirred. A 5% sodium bicarbonate aqueous solution was added to the reaction solution to adjust the pH of the aqueous phase to 7–8. The mixture was stirred for 30 min, allowed to stand, and separated, retaining the organic phase. Toluene (150 mL) was added to the aqueous phase and stirred for 0.5 h. The mixture was allowed to stand and separated, retaining the organic phase. The organic phases were combined, and a saturated sodium chloride solution (180 mL) was added to the organic phase. The mixture was stirred for 0.5 h, allowed to stand, and separated, retaining the organic phase. The organic phase was concentrated under reduced pressure at 60 ± 5 °C until no obvious water was found in the condenser receiver, yielding 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, purge with nitrogen three times, start stirring, cool to -10±5℃, and control the internal temperature at -10±5℃. Add 70% sodium bis(methoxyethoxy)aluminum hydride toluene solution (87 g, diluted with 90 mL of toluene) dropwise to the reaction solution. After the addition is complete, slowly raise the temperature to 5±5℃ and stir for 2 h to prepare the modified Red-Al toluene solution.

[0139] Add the toluene solution of compound 5 from the previous step to a 1000 mL three-necked flask, purge with nitrogen three times, start stirring, cool to -10±5℃, and control the internal temperature at -10±5℃. Add the modified Red-Al toluene solution dropwise to the reaction solution. After the addition is complete, slowly raise the temperature to 5±5℃ and stir for 2 hours. After the reaction is complete, adjust the pH of the aqueous phase to between 0 and 1 with 25% dilute sulfuric acid solution, stir for 0.5 hours, let stand and separate the liquids, retaining the organic phase. Add 90 mL of toluene to the aqueous phase and stir for 0.5 hours. Let stand and separate the liquids, retaining the organic phase. Combine the organic phases and wash them sequentially with 5% sodium bicarbonate aqueous solution (200 mL), purified water (200 mL), and saturated NaCl aqueous solution (200 mL), retaining the organic phase. Add N-methylpyrrolidone (360 mL) to the organic phase and concentrate under reduced pressure at 65±5℃ until no obvious droplets fall from the condenser 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 from the previous step to a 1000 mL three-necked flask, along with anhydrous sodium carbonate (6.57 g), potassium ferrocyanide (18.30 g), and [1,1-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (2.03 g). Purge the solution with nitrogen three times, start stirring, and heat to 115±5℃ for 3 h. After the reaction, cool to 65±5℃, add toluene (400 mL) and purified water (400 mL) to the reaction solution, stir for 40 min, pre-coat the filter with diatomaceous earth (40 g), wash with toluene (80 mL), allow the filtrate to stand and separate, retaining the organic phase; add toluene (100 mL) to the aqueous phase, stir at 65±5℃ for 20 min, allow to stand and separate, retaining the organic phase; combine the organic phases, add 10% sodium chloride solution. The organic phase was separated from the organic phase by stirring at 65±5℃ for 40 min, allowing it to stand. 400 mL of 10% sodium chloride aqueous solution was added to the organic phase and stirred at 65±5℃ for 40 min. The mixture was allowed to stand and separated, retaining the organic phase. 110 g of silica gel was added to the organic phase and stirred at 65±5℃ for 70 min. The mixture was pre-coated and filtered using silica gel (80 g). It was washed with dichloromethane (400 mL). The filtrate was distilled under reduced pressure at 55±5℃ until approximately 250–350 mL of material remained. The remaining filtrate was heated to 65±5℃ and stirred. 400 mL of n-heptane was added dropwise to the filtrate. After the addition was complete, stirring continued for 1.5 h. The mixture was then slowly cooled to 5–15℃ and stirred for another 1.5 h. After filtration, the mixture was dried under vacuum at 45±5℃ to obtain approximately 7.21 g of a pale yellow solid compound 7. The overall yield of the three steps was approximately 33.6%.

[0143] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

Claims

1. A compound, characterized in that, As shown in formula VI; wherein R1, R2are independently selected from C 1-2 alkyl, C 1-2 alkoxy, or H.

2. The compound of claim 1, wherein The compound is shown as formula 6; 3. A process for the preparation of a compound according to claim 1, characterized in that, The method comprises the following steps: (1) esterification of the compound shown as formula IV with an alcohol compound under the action of sulfuric acid to obtain a compound shown as formula V; (2) reduction of the compound shown as formula V under the action of a reducing agent to obtain a compound shown as formula VI; The preparation method of the compound shown as formula IV comprises: (i) nucleophilic ring-opening and ring-closing reaction of the compound shown as formula II with ethylene oxide under the action of a strong base to obtain a compound shown as formula III; (ii) hydrolysis of the compound shown as formula III under the action of a strong acid to obtain a compound shown as formula IV; The preparation method of the compound shown as formula II comprises: esterification of the compound shown as formula I under the action of di-tert-butyl dicarbonate, 4-dimethylaminopyridine and tert-butyl alcohol to obtain a compound shown as formula II; 4. The production method according to claim 3, characterized by, In step (1), the sulfuric acid is concentrated sulfuric acid with a mass concentration of 90%-99%, the alcohol compound is C1-C10 hydroxy alcohol, the molar ratio of the compound shown as formula IV to sulfuric acid is 1:0.3-4.5, the feeding amount ratio of the compound shown as formula IV to the alcohol compound is 1g:6-60mL, and the esterification reaction is carried out at a temperature of 35-95°C.

5. The preparation method according to claim 4, characterized in that, In step (1), the sulfuric acid is concentrated sulfuric acid with a mass concentration of 98%, the alcohol compound is C1-C5 hydroxy alcohol, the molar ratio of the compound shown as formula IV to sulfuric acid is 1:0.4-3, the feeding amount ratio of the compound shown as formula IV to the alcohol compound is 1g:8-40mL, and the esterification reaction is carried out at a temperature of 45-85°C.

6. The production method according to claim 5, characterized by, In step (1), the alcohol compound is methanol, the molar ratio of the compound shown as formula IV to sulfuric acid is 1:0.5-1.5, the feeding amount ratio of the compound shown as formula IV to the alcohol compound is 1g:10-20mL, and the esterification reaction is carried out at a temperature of 55-75°C.

7. The preparation method according to claim 3, characterized in that, In step (2), the reducing agent is sodium bis(methoxyethoxy)aluminum hydride modified by a modified reagent; the molar ratio of the compound shown as formula IV, sodium bis(methoxyethoxy)aluminum hydride and the modified reagent is 1:0.9-7.5:1.1-6.6; the modified solvent is an organic solvent; and the feeding amount ratio of the compound shown as formula IV to the solvent is 1g:3-81mL.

8. The production method according to claim 7, characterized by, The modified reagent comprises N-methylpiperazine and / or or cis-2,6-dimethylmorpholine; the molar ratio of the compound shown as formula IV, sodium bis(methoxyethoxy)aluminum hydride and the modified reagent is 1:1.2-5:1.4-4.4; the modified solvent is toluene; and the feeding amount ratio of the compound shown as formula IV to the solvent is 1g:4-27mL.

9. The production method according to claim 8, characterized by, The molar ratio of the compound shown as formula IV, sodium bis(methoxyethoxy)aluminum hydride and the modified reagent is 1:1.5-2.5:1.8-2.2; and the feeding amount ratio of the compound shown as formula IV to the solvent is 1g:5-9mL.

10. The method of claim 7, wherein, The modification is adding sodium bis(methoxyethoxy)aluminum hydride and the rest of the solvent to the mixed solution of the modifier and part of the solvent, and the part of the solvent is 60%-90% of the total solvent volume; the temperature of adding sodium bis(methoxyethoxy)aluminum hydride into the reaction system is-30-5℃; the temperature of the modification is-15-20℃.

11. The method of claim 10, wherein, The part of the solvent is 63.3%-85% of the total solvent volume 63.3%-85% of the total solvent volume, the temperature of adding sodium bis(methoxyethoxy)aluminum hydride into the reaction system is-25-0℃, and the temperature of the modification is-10-15℃.

12. The method of claim 11, wherein, The part of the solvent is 66.7%-80% of the total solvent volume 66.7%-80% of the total solvent volume, the temperature of adding sodium bis(methoxyethoxy)aluminum hydride into the reaction system is-20--5℃, and the temperature of the modification is-5-10℃.

13. The preparation method according to claim 3, characterized in that, In step (2), the reduction reaction is adding a solution containing a reducing agent to a solution containing a compound shown in formula V to carry out the reduction reaction; the solvents in the solution containing the reducing agent and the solution containing the compound shown in formula V are both organic solvents; the temperature of adding the reducing agent into the reaction system is-30-5℃; and the temperature of the reduction reaction is-20-5℃.

14. The method of claim 13, wherein, The solvents in the solution containing the reducing agent and the solution containing the compound shown in formula V are both toluene; the temperature of adding the reducing agent into the reaction system is-25-0℃; and the temperature of the reduction reaction is-15-0℃.

15. The method of claim 14, wherein, The temperature of adding the reducing agent into the reaction system is-20--5℃; and the temperature of the reduction reaction is-10--5℃.

16. The preparation method according to claim 3, characterized in that, In step (i), the strong base is any one or a combination of n-butyllithium, sec-butyllithium, tert-butyllithium and diisopropylamino lithium; the molar ratio of the compound shown in formula II to the strong base is 1:0.8-3; the molar ratio of the compound shown in formula II to ethylene oxide is 1:1.8-12; the solvent of the reaction is an organic solvent; and the feeding amount ratio of the compound shown in formula II to the solvent is 1g:8-32mL.

17. The preparation method according to claim 3, characterized in that, In step (i), the strong base is diisopropylamino lithium, the molar ratio of the compound shown in formula II to the strong base is 1:1.0-2.25, the molar ratio of the compound shown in formula II to ethylene oxide is 1:2.4-8, the solvent of the reaction is tetrahydrofuran, and the feeding amount ratio of the compound shown in formula II to the solvent is 1g:10-24mL.

18. The method of claim 17, wherein, In step (i), the molar ratio of the compound shown in formula II to the strong base is 1:1.2-1.5, the molar ratio of the compound shown in formula II to ethylene oxide is 1:3-4, and the feeding amount ratio of the compound shown in formula II to the solvent is 1g:12-16mL.

19. The method of claim 18, wherein, In step (i), the strong base is added to the mixed system of the compound shown in formula II and the solvent, and then the first stirring is carried out, followed by adding ethylene oxide and then the second stirring, and then the reaction is carried out by increasing the temperature; and the reaction is carried out in an inert gas atmosphere.

20. The method of claim 19, wherein, The strong base is added to the reaction system in the form of a strong base solution; the concentration of the strong base solution is 0.9-7.5 M; the temperature of the strong base added to the reaction system is -115 to -35 ℃; the oxirane is added to the reaction system in the form of an oxirane solution; the concentration of the oxirane solution is 1.2-12 M; the temperature of the oxirane added to the reaction system is -115 to -35 ℃; the rate of temperature increase of the ring-opening and ring-closing reaction is 6-75 ℃ / h; and the temperature is increased to 5-65 ℃.

21. The method of claim 20, wherein, The concentration of the strong base solution is 1.2-5 M, the temperature of the strong base added to the reaction system is -105 to -45 ℃, the concentration of the oxirane solution is 1.6-8 M, the temperature of the oxirane added to the reaction system is -105 to -45 ℃, the rate of temperature increase of the ring-opening and ring-closing reaction is 8-50 ℃ / h, and the temperature is increased to 10-55 ℃.

22. The method of claim 21, wherein, The concentration of the strong base solution is 1.5-2.5 M, the temperature of the strong base added to the reaction system is -95 to -55 ℃, the concentration of the oxirane solution is 2-4 M, the temperature of the oxirane added to the reaction system is -95 to -65 ℃, the rate of temperature increase of the ring-opening and ring-closing reaction is 10-25 ℃ / h, and the temperature is increased to 15-45 ℃.

23. The preparation method according to claim 3, characterized in that, In step (ii), the strong acid is any one or a combination of sulfuric acid, hydrochloric acid and trifluoroacetic acid; the sulfuric acid is concentrated sulfuric acid with a mass concentration of 90%-99%; the hydrochloric acid is concentrated hydrochloric acid with a mass concentration of 24%-63%; the use amount ratio of the compound of formula II to the strong acid is 1 g:0.6-6 mL; the reaction solvent is any one or a combination of toluene, n-heptane, ethyl acetate and dichloromethane; the feeding amount ratio of the compound of formula II to the solvent is 1 g:2.5-100 mL; and the reaction temperature is 5-55 ℃.

24. The method of claim 23, wherein, The sulfuric acid is concentrated sulfuric acid with a mass concentration of 98%, the hydrochloric acid is concentrated hydrochloric acid with a mass concentration of 28%-52.5%, the use amount ratio of the compound of formula II to the strong acid is 1 g:0.8-4 mL, the feeding amount ratio of the compound of formula II to the solvent is 1 g:3-20 mL, and the reaction temperature is 10-45 ℃.

25. The method of claim 24, wherein, The hydrochloric acid is concentrated hydrochloric acid with a mass concentration of 32%-42%, the use amount ratio of the compound of formula II to the strong acid is 1 g:1-2 mL, the feeding amount ratio of the compound of formula II to the solvent is 1 g:3.5-4 mL, and the reaction temperature is 15-35 ℃.

26. The method of claim 3, wherein, In the preparation method of the compound shown in formula II, the molar ratio of the compound shown in formula I to di-tert-butyl dicarbonate is 1:2-6; the molar ratio of the compound shown in formula I to 4-dimethylaminopyridine is 1:0.048-0.36; the feeding amount ratio of the compound shown in formula I to tert-butyl alcohol is 1g:2-10mL; the solvent of the reaction is an organic solvent; the feeding amount ratio of the compound shown in formula I to the solvent is 1g:4-20mL; di-tert-butyl dicarbonate is added to the mixed system of the compound shown in formula I, 4-dimethylaminopyridine, tert-butyl alcohol and the solvent; the temperature of adding di-tert-butyl dicarbonate into the reaction system is 5-45℃; and the temperature of the reaction is 45-85℃.

27. The method of claim 26, wherein, In the preparation method of the compound shown in formula II, the molar ratio of the compound shown in formula I to di-tert-butyl dicarbonate is 1:2.4-4.8, the molar ratio of the compound shown in formula I to 4-dimethylaminopyridine is 1:0.064-0.24, the feeding amount ratio of the compound shown in formula I to tert-butyl alcohol is 1g:2.5-7.5mL, the solvent of the reaction is tetrahydrofuran, the feeding amount ratio of the compound shown in formula I to the solvent is 1g:5-15mL, the temperature of adding di-tert-butyl dicarbonate into the reaction system is 10-40℃, and the temperature of the reaction is 50-80℃.

28. The method of claim 3, wherein, In the preparation method of the compound shown in formula II, the molar ratio of the compound shown in formula I to di-tert-butyl dicarbonate is 1:2.8-3.6, the molar ratio of the compound shown in formula I to 4-dimethylaminopyridine is 1:0.08-0.12, the feeding amount ratio of the compound shown in formula I to tert-butyl alcohol is 1g:3-5mL, the feeding amount ratio of the compound shown in formula I to the solvent is 1g:6-10mL, the temperature of adding di-tert-butyl dicarbonate into the reaction system is 15-35℃, and the temperature of the reaction is 55-75℃.

29. Use of a compound as claimed in claim 1 of formula VI ###0007### VI for the preparation of a compound of formula VII ###0008### VII as an intermediate. The compound shown in formula VI is coupled with cyanogen under the action of a palladium catalyst to generate the compound shown in formula VII; wherein R1, R2are independently selected from C 1-2 alkyl, C 1-2 alkoxy, or H.

30. The use according to claim 29, characterized in that, The palladium catalyst is any one or a combination of several of [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex and methane sulfonate (2-di-tert-butylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II); the molar ratio of the palladium catalyst to the compound shown in formula IV is 0.01-0.08:1; the solvent of the coupling reaction is any one or a combination of several of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile and water; the coupling reaction further comprises anhydrous sodium carbonate and potassium ferrocyanide; the molar ratio of the anhydrous sodium carbonate, potassium ferrocyanide and the compound shown in formula IV is 0.3-4.5:0.06-0.6:1; and the temperature of the coupling reaction is 80-140℃.

31. The use according to claim 30, wherein The molar ratio of the palladium catalyst to the compound of formula IV is 0.01-0.06:1, the molar ratio of the anhydrous sodium carbonate, potassium ferrocyanide and the compound of formula IV is 0.4-3.1:0.08-0.4:1, and the temperature of the coupling reaction is 90-130°C.

32. The use according to claim 31, characterized in that, The molar ratio of the palladium catalyst to the compound of formula IV is 0.02-0.04:1, the molar ratio of the anhydrous sodium carbonate, potassium ferrocyanide and the compound of formula IV is 0.5-1.5:0.1-0.2:1, and the temperature of the coupling reaction is 100-120°C.

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