Method for synthesizing 1H-furo[3,2-B]imidazo[4,5-D]pyridine compounds

Abstract

A method is provided for synthesizing 1H-furo[3,2-b]imidazo[4,5-d]pyridine compounds, comprising the steps of reacting compound 1 with compound 2 in a solvent in the presence of a base to obtain compound 3, subjecting compound 3 to a reduction reaction to obtain compound 4, and subjecting compound 4 to a ring-closing reaction with compound 5 or compound 5′ to obtain compound 6 or a hydrate thereof, where R is methyl or ethyl, optionally substituted by hydroxyl, and X═O or CH 2 The method for synthesizing 1H-furo[3,2-b]imidazo[4,5-d]pyridine compounds has the advantages of high yield, less impurities, easy to control, and reduced costs. The method is simple and convenient to operate, and suitable for industrial scale. [Formula 1] JPEG2024546195000092.jpg59159

Description

[Technical field]

[0001] The present invention relates to the field of pharmaceutical synthesis, and in particular to a method for synthesizing 1H-furo[3,2-b]imidazo[4,5-d]pyridine compounds. [Background technology]

[0002] The 1H-furo[3,2-b]imidazo[4,5-d]pyridine compounds are highly selective JAK1 and TYK2 inhibitors that selectively inhibit the activity of one or more protein kinases compared to other related kinases. They are therefore expected to be used in the treatment of diseases mediated by the selectively inhibited kinase(s) while avoiding the adverse side effects associated with the inhibition of other kinases, for example for the treatment of disorders associated with the activity of JAK1 / TYK2, such as autoimmune or inflammatory diseases or disorders, and cancers or tumors or disorders.

[0003] The methods for synthesizing such compounds in the prior art have problems of high cost and complicated operation, so that the methods are not suitable for industrial scale (WO 2018 / 067422 A1, WO 2020 / 244348 A1, and WO 2020 / 244349 A1). In view of this, there is a need to develop a method for synthesizing 1H-furo[3,2-b]imidazo[4,5-d]pyridine compounds that has the advantages of high yield, less impurities, easy control, cost reduction, and simple operation, and thus is suitable for industrial scale. Summary of the Invention

[0004] In view of the above problems existing in the prior art, the object of the present invention is to provide a method for synthesizing 1H-furo[3,2-b]imidazo[4,5-d]pyridine compounds, which reduces the cost, is simple and convenient to operate, and is therefore suitable for industrial scale.

[0005] In order to achieve the above objectives, the technical solutions adopted by the present invention are as follows:

[0006] The method for synthesizing 1H-furo[3,2-b]imidazo[4,5-d]pyridine compounds (hereinafter referred to as "Synthetic Route 1") comprises the steps of:

[0007] [ka] reacting compound 1 with compound 2 or a hydrochloride salt of compound 2 in a solvent in the presence of a base to obtain compound 3;

[0008] [ka] subjecting compound 3 to a reduction reaction to obtain compound 4 or a hydrochloride salt of compound 4;

[0009] [ka] and subjecting compound 4 or the hydrochloride of compound 4 to a closing reaction with compound 5 or compound 5' to obtain compound 6 or a hydrate of compound 6, wherein R is methyl or ethyl, which is optionally substituted by hydroxyl, preferably R is 1-hydroxyethyl, X is CH or O, and the hydrate is preferably a monohydrate.

[0010] According to an embodiment of the present invention, in step 1, The base is an organic base other than N,N'-diisopropylamine, in which case the organic base is preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or the base is an inorganic base, in which case the inorganic base is preferably sodium carbonate (Na2CO3), potassium carbonate (KHCO3), or sodium bicarbonate (NaHCO3), more preferably sodium bicarbonate (NaHCO3), or the base is N,N'-diisopropylamine.

[0011] The solvent is ethanol and / or acetonitrile, preferably ethanol or a mixed solvent of ethanol and acetonitrile, in which case the volume ratio of acetonitrile to ethanol (mL / mL or L / L) is 1:0.8 to 1:1.2, preferably 1:1; the ratio of compound 1 to compound 2 is 1:0.8 to 1:1.2, for example, 1:0.8, 1:0.9, 1:1, 1:1.01, 1:1.05, 1:1.1, and 1:1.2; When compound 2 is in the form of a hydrochloride salt, the molar ratio of compound 1 to base is 1:2 to 1:2.5, preferably 1:2.1 to 1:2.3, more preferably 1:2.2 to 1:2.25, and most preferably 1:2.2 to 1:2.23; When compound 2 is in a salt-free form, the molar ratio of compound 1 to base is 1:1 to 1:1.5, preferably 1:1.1 to 1:1.3; The mass-to-volume ratio (g / mL) of compound 1 to the solvent is 1:9 to 1:10; The reaction of step 1 is optionally carried out under protection of an inert gas (such as nitrogen); The reaction is carried out at a temperature of 50-80° C. and lasts for 16-22 hours. After the reaction is completed, the reaction solution is cooled, stirred, filtered, and the filter cake is washed and dried to obtain compound 3 (for example, after the reaction is completed, the reaction solution is cooled to 20-30°C, water is added to the solution, and the solution is stirred at 20-30°C for 0.5-2 hours, then cooled to 0-15°C, stirred at 0-15°C for 2-4 hours, then filtered, and the filter cake is washed and dried to obtain compound 3).

[0012] According to an embodiment of the present invention, in step 2, The reducing agent used in the reduction reaction is a nitro reducing agent other than H2 / Pd, The reducing agent used in the reduction reaction is Fe / acetic acid, or B2(OH)4, or SnCl2, When the reducing agent is Fe / acetic acid, the solvent used in the reduction reaction is acetonitrile, the molar ratio of Fe to compound 3 is 1:6 to 1:9, the molar ratio of acetic acid to compound 3 is 1:12 to 1:14, and the mass-to-volume ratio (g / mL) of the solvent to compound 3 is 1:4 to 1:10, preferably 1:5 to 1:9; When the reducing agent is B2(OH)4, the solvent used in the reduction reaction is a mixed solvent of water and methanol, the volume ratio of methanol to water (mL / mL or L / L) is 1:1 to 9:1, preferably 3:1 to 5:1, more preferably 4:1, the molar ratio of B2(OH)4 to compound 3 is 1:3 to 1:5, preferably 1:3.5, the mass-to-volume ratio of the solvent to compound 3 (g / mL) is 1:4 to 1:10, preferably 1:5 to 1:9, and B2(OH)4 is added in small portions; When the reducing agent is SnCl2, the solvent used in the reduction reaction is ethyl acetate, the molar ratio of SnCl2 to compound 3 is 1:2 to 1:9, preferably 1:3 to 1:6, and the mass-to-volume ratio (g / mL) of the solvent to compound 3 is 1:4 to 1:20, preferably 1:5 to 1:15; When the reducing agent is B2(OH)4, 4,4'-bipyridine is optionally added; The reaction of step 2 is optionally carried out under protection of an inert gas (such as nitrogen); The reaction is carried out at a temperature of 15 to 90°C and lasts for 1 to 18 hours. When the reducing agent is Fe / acetic acid, after the reaction is completed, the reaction solution is filtered before cooling and rinsed with hot acetonitrile. The pH is adjusted to about 6 with sodium citrate solution (e.g., the pH is adjusted to 6), and then the pH is adjusted to 8-9 with K3PO4 solution (e.g., 30% K3PO4 solution). After concentration, celite, water, and ethyl acetate are added to the reaction solution, the solution is filtered, and the layers are separated. The resulting aqueous phase is extracted with ethyl acetate, and the resulting organic phases are combined and washed with aqueous sodium citrate solution and saturated saline, respectively. Silica gel and anhydrous sodium sulfate are added, the solution is filtered, washed with ethyl acetate, and concentrated. Methyl tert-butyl ether is added, and the precipitate is filtered and dried to obtain compound 4, When the reducing agent is B2(OH)4, the temperature is lowered to 35-45°C after the reaction is completed. Part of the solvent is concentrated under reduced pressure, then the temperature is lowered to 0-10°C, the reaction solution is stirred and filtered. The filter cake is rinsed with dichloromethane, and the filtrate is collected. Sodium bicarbonate is added in small portions and stirred at 20-30°C. The system is allowed to settle, then the organic phase is separated, and the aqueous phase is extracted with dichloromethane. The obtained organic phases are combined and dried with anhydrous sodium sulfate. Hydrogen chloride in ethanol solution is added dropwise at 15-25°C, and stirred at a temperature maintained at 15-25°C. Ethyl acetate is added dropwise at 15-25°C, and stirred at a temperature maintained at 15-25°C. The mixture is filtered, then the filter cake is rinsed with ethyl acetate and dried to obtain compound 4 hydrochloride, When the reducing agent is SnCl2, the temperature is lowered to room temperature after the reaction is completed. Sodium bicarbonate is added in an ice bath, and then the reaction solution is stirred and filtered. The filter cake is rinsed with ethyl acetate, and the filtrate is collected and washed three times with saturated aqueous sodium bicarbonate solution. The resulting organic phases are combined and washed three times with saturated brine, and then the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain compound 4.

[0013] According to an embodiment of the present invention, in step 3,

[0014] Compound 5 is R-lactic acid ( [ka] ) and compound 5' is acetic acid or acetic anhydride; The ring closure reaction is carried out in a solvent, the solvent being toluene, dioxane, acetic acid, methylcyclohexane, or acetic anhydride; When compound 4 is subjected to a ring-closing reaction with R-lactic acid, the molar ratio of compound 4 to R-lactic acid is 1:4 to 1:30, preferably 1:4 to 1:20, more preferably 1:4 to 1:10, and the mass-to-volume ratio (g / mL) of compound 4 to the solvent is 1:1.5 to 1:40, preferably 1:1.5 to 1:30, more preferably 1:1.5 to 1:15; When compound 4 is subjected to a ring-closing reaction with acetic anhydride or acetic acid, acetic anhydride or acetic acid acts as a reaction reagent and a solvent at the same time, and the mass-to-volume ratio (g / mL) of compound 4 to acetic anhydride or acetic acid is 1:1 to 1:10, preferably 1:2 to 1:5; An acid catalyst is optionally added in the ring-closing reaction of compound 4 with compound 5 or compound 5′, in which case the acid catalyst is preferably methanesulfonic acid; In the ring-closing reaction between compound 4 and compound 5′, when the reaction reagent / solvent is acetic anhydride, acetic acid (AcOH) or sodium acetate (NaOAc) is optionally added; In the ring-closing reaction between compound 4 and compound 5′, when the reaction reagent / solvent is acetic acid, sodium acetate (NaOAc) is optionally added; The reaction is carried out at a temperature of 80 to 120° C. and continues for 5 to 24 hours, preferably 16 to 18 hours. After the reaction is completed, the reaction solution is cooled and extracted, the pH is adjusted to 7-10, and the resulting solid is dried to obtain compound 6 or a hydrate of compound 6.

[0015] According to an embodiment of the invention, the present invention provides a method for the synthesis of a 1H-furo[3,2-b]imidazo[4,5-d]pyridine compound (using "Synthetic Route 1" used to synthesize compounds 6A, 6C or a hydrate thereof, preferably a monohydrate), the method comprising: Step 1:

[0016] [ka] reacting compound 1 with compound 2 or compound 2 hydrochloride in a solvent in the presence of a base to obtain compound 3; Step 2:

[0017] [ka] subjecting compound 3 to a reduction reaction to obtain compound 4 or compound 4 hydrochloride; Step 3:

[0018] [ka] and subjecting compound 4 or compound 4 hydrochloride to a ring-closing reaction with R-lactic acid to obtain compounds 6A and 6C, or hydrates thereof.

[0019] According to an embodiment of the present invention, in the method for synthesizing compounds 6A and 6C or their hydrates, step 1 and step 2 are as described above, and in step 3, the ring-closing reaction is carried out in a solvent, the solvent being toluene, dioxane, or methylcyclohexane, preferably toluene or methylcyclohexane, more preferably methylcyclohexane; The molar ratio of compound 4 to R-lactic acid is 1:4 to 1:30, preferably 1:4 to 1:20, more preferably 1:4 to 1:10, and most preferably 1:5 to 1:7. the mass-to-volume ratio (g / mL) of compound 4 to the solvent is 1:1.5 to 1:40, preferably 1:1.5 to 1:30, more preferably 1:1.5 to 1:15, and most preferably 1:1.5 to 1:5; The reaction is refluxed in a Dean-Stark apparatus at 87-110 °C for 5-24 h. After the reaction is completed, methanol is added and the methanol layer is separated. Sodium hydroxide solution is added with stirring. Hydrochloric acid is added dropwise to adjust the pH to about 7. The solvent is removed under reduced pressure and water is added with stirring. The solid is filtered, washed with water and dried to obtain compound 6A or 6C (for example, in the process of synthesizing compound 6A, after the reaction is completed, methanol is added, the reaction solution is cooled to 20-30 ° C, methanol is added (for example, 3 times the volume), the resulting mixture is stirred and layer separated to obtain the methanol layer. The methanol layer is cooled to -10-0 ° C, sodium hydroxide solution is added, stirred, and hydrochloric acid is added dropwise to adjust the pH to 7, then the solvent is removed under reduced pressure, water is added, and the resulting system is stirred, filtered, washed with water and dried to obtain compound 6A).

[0020] According to an embodiment of the present invention, the present invention provides a method for synthesizing a 1H-furo[3,2-b]imidazo[4,5-d]pyridine compound for synthesizing compound 6B or 6D (using synthetic route 1), the method comprising: Step 1:

[0021] [ka] reacting compound 1 with compound 2 or compound 2 hydrochloride in a solvent in the presence of a base to obtain compound 3; Step 2:

[0022] [ka] subjecting compound 3 to a reduction reaction to obtain compound 4 or compound 4 hydrochloride; Step 3:

[0023] [ka] subjecting compound 4 or compound 4 hydrochloride to a ring-closing reaction with acetic anhydride and / or acetic acid to obtain compound 6B or compound 6D.

[0024] According to an embodiment of the present invention, in the method for synthesizing compound 6B or 6D, step 1 and step 2 are as described above, and in step 3, When compound 4 is subjected to a ring-closing reaction with acetic anhydride, acetic acid or sodium acetate is optionally added, and the molar ratio of compound 4 to acetic acid is 1:0.1 to 1:0.5, preferably 1:0.2 to 1:0.3, for example 1:0.2; and the molar ratio of compound 4 to sodium acetate is 1:0.2 to 1:1, preferably 1:0.4 to 1:0.8, for example 1:0.5; When compound 4 is subjected to a ring-closing reaction with acetic acid, sodium acetate is optionally added, and the molar ratio of compound 4 to sodium acetate is 1:1 to 1:3, preferably 1:1.5 to 1:2.5, for example 1:2; When compound 4 is subjected to a ring-closing reaction with acetic anhydride, the mass-to-volume ratio of compound 4 to acetic anhydride is 1:2 to 1:5, preferably 1:3; When compound 4 is subjected to a ring-closing reaction with acetic acid, the mass-to-volume ratio of compound 4 to acetic acid is 1:3 to 1:8, preferably 1:5; The reaction is carried out at a temperature of 80 to 120° C., preferably 90 to 110° C., and lasts for 12 to 24 hours, preferably 12 to 18 hours; After the reaction is completed, methyl tert-butyl ether is added to the reaction solution, and the resulting system is stirred evenly and filtered. The filter cake is dissolved in a mixed solvent of water and dichloromethane, and an aqueous NaOH solution is added dropwise to adjust the pH to 7-10. The resulting solution is separated into layers. The resulting aqueous layer is then extracted with dichloromethane, and the resulting organic phases are combined, dried over anhydrous Na2SO4, filtered, and concentrated. Ethanol and water are added to the system with stirring. The obtained system is filtered, and then the filter cake is dried to obtain compound 6B or 6D. (For example, in the reaction of synthesizing compound 6B, after the reaction is completed, the reaction solution is added with methyl tert-butyl ether, stirred evenly at 0-10°C, filtered, and the filter cake is dissolved in the mixed solvent of water and dichloromethane, and 10% NaOH aqueous solution is added dropwise to adjust pH to 7-10. The obtained solution is separated into layers. Then, the obtained aqueous layer is extracted with dichloromethane, and the obtained organic phase is combined, dried with anhydrous Na2SO4, filtered, and concentrated. Ethanol is added, and the obtained system becomes transparent at 45-55°C. The solution is cooled to 0-10°C for precipitation, and then water is added with stirring. The mixture is filtered, and the filter cake is dried to obtain compound 6B.)

[0025] According to an embodiment of the invention, the invention further provides a method for synthesizing compound 1, the method comprising: Step 1-1:

[0026] [ka] reacting compound 1-1 with triphenylphosphine to obtain compound 1-2; Step 1-2:

[0027] [ka] reacting compound 1-2 with ethyl formate to obtain compound 1-3; Step 1-3:

[0028] [ka] subjecting compound 1-3 to a demethylation and acetalization reaction to obtain compound 1-4; Step 1-4:

[0029] [ka] subjecting compound 1-4 to a ring-closing reaction under acidic conditions to obtain compound 1-5;

[0030] [ka] subjecting compound 1-5 to a nitration reaction to obtain compound 1-6; Step 1-6:

[0031] [ka] subjecting compound 1-6 to a chloro substitution reaction to obtain compound 1.

[0032] According to an embodiment of the present invention, the method of synthesizing compound 1 preferably comprises: In step 1-1,

[0033] [ka] Sodium carbonate is added all at once to a mixture of compound 1-1, toluene, and water. The resulting mixture is stirred at room temperature and the layers are separated. The resulting aqueous phase is extracted with toluene, and the resulting organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. Triphenylphosphine is added to the filtrate, and the resulting system is heated in a Dean-Stark apparatus to 110-120°C (preferably 108-115°C) for 14-20 hours (preferably 16-18 hours). The reaction is cooled to 20-30°C, filtered, rinsed with toluene, and the wet product is then dried under reduced pressure to give compound 1-2.

[0034] In step 1-2,

[0035] [ka] A mixture of compound 1-2 and dimethyl sulfoxide is cooled to 18-25°C, alkali metal tert-butoxide is added at once, the temperature is controlled at 20-35°C, and then the reaction solution is added and stirred at room temperature for 1-2 hours. Ethyl formate is added dropwise, and the resulting system is stirred at 40-50°C for 8-12 hours, and then cooled to room temperature. An organic solvent and water are added, and the resulting system is extracted and separated into layers. The resulting organic phase is washed with water, and the pH is adjusted to 5-6 with hydrochloric acid, and the layers are separated. The resulting aqueous phase is extracted with an organic solvent, and the adjusted pH is adjusted to 8 or more with a base, and the layers are separated. The resulting aqueous phase is extracted with an organic solvent, and the resulting organic phases are combined, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 1-3.

[0036] In steps 1-3,

[0037] [ka] The mixture of compound 1-3 and dichloromethane is cooled to 10-20°C, and boron tribromide is added dropwise at 20-30°C. After stirring the reaction solution at 20-30°C for 1-1.5 hours, the reaction solution is quenched by adding ethanol dropwise at 10-35°C, and the resulting mixture is stirred for 0.5-2.5 hours. The solvent is removed under reduced pressure, then ethanol is added, and the solvent is removed under reduced pressure. The system is cooled to 15-20°C, and an ethanol solution of sodium ethoxide is added dropwise. The temperature is controlled at 15-30°C, and the dropwise addition is stopped until the pH is 5-6. The reaction solution is filtered and rinsed with ethanol. The ethanol solution of sodium ethoxide is added dropwise to the filtrate at 15-30°C, and the dropwise addition is stopped until the pH of the material is 8-9. The solvent is removed under reduced pressure, and methyl tert-butyl ether is added. The resulting system is cooled to 5-15°C, stirred for 0.5-1 h, and filtered. The filter cake is rinsed with methyl tert-butyl ether and dried to give compound 1-4.

[0038] In steps 1-4,

[0039] [ka] Benzoyl chloride is added dropwise to the dichloromethane solution of compound 1-4 at 0-10°C. The resulting system is stirred at 0-10°C for 1-1.5 hours. The reaction solution is added dropwise to concentrated sulfuric acid at 15-25°C and stirred at 15-25°C for 0.5-1.5 hours. The reaction solution is added dropwise to water, controlling the temperature not to exceed 25°C during the dropwise addition. The resulting mixture is filtered, and the filtrate is added dropwise to ammonia water (adjusting the pH to 7-8), stirred for 0.5-1 hour, and filtered. The filter cake is rinsed with water and dried to obtain compound 1-5.

[0040] In steps 1-5,

[0041] [ka] Nitric acid is added dropwise to the mixture of acetic acid and acetic anhydride, and the temperature is controlled at 15-30°C while dropping. The reaction solution is stirred evenly at 20-30°C after dropping. The mixed solution of acetic acid, acetic anhydride, and nitric acid is added dropwise to the acetic acid solution of compound 1-5. The temperature is controlled at 110-120°C during dropping. The reaction solution is stirred at 110-120°C for 1-1.5 hours. The reaction solution is cooled to 20-30°C and methyl tert-butyl ether is added. The resulting system is stirred evenly and filtered. The filter cake is rinsed with methyl tert-butyl ether and dried to obtain compound 1-6.

[0042] In steps 1-6,

[0043] [ka] Phosphorus oxychloride is added dropwise to a mixture of compound 1-6, N,N-dimethylformamide, and toluene, and the resulting mixture is stirred at 35-75°C for 1-2 hours. The reaction solution is then cooled to room temperature, and the toluene is removed. Dichloromethane and 10% aqueous potassium carbonate or 5% aqueous sodium bicarbonate are added, and the resulting system is separated into layers. The resulting organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the solvent is removed to obtain compound 1.

[0044] According to an embodiment of the present invention, in step 1-1, In a mixture of compound 1-1, toluene, and water, the mass-to-volume ratio (g / mL) of compound 1-1 to toluene and water is 1:5 to 1:6, and the volume ratio of toluene to water is 8:1 to 9:1; The molar ratio of compound 1-1 to sodium carbonate is 1:1.1 to 1:1.2; The molar ratio of compound 1-1 to triphenylphosphine is 1:1.1 to 1:1.2; The reaction of step 1-1 is optionally carried out under protection of an inert gas (such as nitrogen).

[0045] According to an embodiment of the present invention, in step 1-2, the alkali metal tert-butoxide is potassium tert-butoxide or sodium tert-butoxide; The base used to adjust the pH is aqueous ammonia or sodium carbonate. The organic solvent used for extraction is methyl tert-butyl ether or ethyl acetate. The mass to volume ratio of compound 1-2 to dimethyl sulfoxide is 1:3 to 1:5; the molar ratio of compound 1-2 to alkali metal tert-butoxide is 1:1.05 to 1:1.15, preferably 1:1.1; The molar ratio of compound 1-2 to ethyl formate is 1:4 to 1:5; The reaction of step 1-2 is optionally carried out under protection of an inert gas (such as nitrogen).

[0046] According to an embodiment of the present invention, in step 1-3, The mass to volume ratio (g / mL) of compound 1-3 to dichloromethane is 1:6 to 1:10; the molar ratio of compound 1-3 to boron tribromide is 1:2.0 to 1:3.5, preferably 1:2.5 to 1:3.2; The reactions of steps 1-3 are optionally carried out under the protection of an inert gas (such as nitrogen).

[0047] According to an embodiment of the present invention, in steps 1-4, The mass to volume ratio (g / mL) of compound 1-4 to concentrated sulfuric acid is 1:2 to 1:5; The mass to volume ratio (g / mL) of compound 1-4 to dichloromethane is 1:25 to 1:26; The molar ratio of compound 1-4 to benzoyl chloride is 1:1.5 to 1:2.5, preferably 1:2.

[0048] According to an embodiment of the present invention, in steps 1-5, In the acetic acid solution of the compound 1-5, the mass ratio of the compound 1-5 to acetic acid is 1:9 to 1:11, preferably 1:10; The mass ratio of compound 1-5 to acetic acid in the mixed solution of acetic acid, acetic anhydride, and nitric acid is 1:3 to 1:5; the molar ratio of compound 1-5 to acetic anhydride is 1:2 to 1:5, preferably 1:2.6 to 1:4.2; the molar ratio of compound 1-5 to nitric acid is 1:2 to 1:5, preferably 1:2.5 to 1:4.0; The reactions of steps 1-5 are optionally carried out under the protection of an inert gas (such as nitrogen).

[0049] According to an embodiment of the present invention, in steps 1-6, The molar ratio of compound 1-6 to N,N-dimethylformamide is 1:1 to 1:1.2; The mass to volume ratio of toluene in compound 1-6 is 1:9 to 1:11, preferably 1:10; The molar ratio of compound 1-6 to phosphorus oxychloride is 1:1.8 to 1:2.2, preferably 1:2; The reactions of steps 1-6 are optionally carried out under the protection of an inert gas (such as nitrogen).

[0050] According to an embodiment of the present invention, when compound 2 is compound 2a, the present invention further provides a method for synthesizing compound 2a hydrochloride, the method comprising:

[0051] [ka] subjecting compound 2-1 to a ring-closing reaction under the catalysis of sodium methoxide to obtain compound 2-2;

[0052] [ka] reacting compound 2-2 with hydrochloric acid to obtain compound 2a hydrochloride.

[0053] According to an embodiment of the present invention, the method for synthesizing N,N compound 2a hydrochloride preferably comprises: In step 2-1,

[0054] [ka] The methanol solution of sodium methoxide is added dropwise to the mixture of compound 2-1 and tetrahydrofuran, and the temperature of the system is controlled at 0-10°C during the dropwise addition. The system is stirred at 20-30°C for 3-8 hours. After the reaction is completed, ammonium chloride solution is added dropwise to the reaction solution at 15-25°C to adjust the pH to 7-8. The resulting mixture is extracted with methyl tert-butyl ether, washed with sodium chloride solution, dried with anhydrous sodium sulfate, cooled to 0-10°C, filtered, and then the filter cake is dried to obtain compound 2-2.

[0055] In step 2-2,

[0056] [ka] A solution of hydrogen chloride in ethanol is added dropwise to a mixture of compound 2-2 and dichloromethane. The reaction is stirred at 20-25° C. for 4-8 hours. The reaction mixture is cooled to 0-5° C. and filtered, and the filter cake is then rinsed with dichloromethane and dried to give compound 2a hydrochloride.

[0057] According to an embodiment of the present invention, in step 2-1, The mass-to-volume ratio (g / mL) of compound 2-1 to tetrahydrofuran is 1:10 to 1:12, preferably 1:10 to 1:11; The molar ratio of compound 2-1 to sodium methoxide in the methanol solution is 1:0.2 to 1:0.3, preferably 1:0.25; The reaction of step 2-1 is optionally carried out under protection of an inert gas (such as nitrogen).

[0058] According to an embodiment of the present invention, in step 2-2, The mass to volume ratio of compound 2-2 to dichloromethane is 1:5 to 1:7, preferably 1:6; The molar ratio of compound 2-2 to hydrogen chloride in the ethanol solution is 1:2 to 1:5, preferably 1:3; The reaction of step 2-2 is optionally carried out under protection of an inert gas (such as nitrogen).

[0059] According to an embodiment of the present invention, the present invention provides another method for synthesizing 1H-furo[3,2-b]imidazo[4,5-d]pyridine compounds (hereinafter referred to as "synthetic route 2" for synthesizing compounds 6A and 6B), which comprises: Step 1A:

[0060] [ka] reacting compound 1 with cis-trans isomer mixture 7 in a solvent in the presence of a base to obtain cis-trans isomer mixture 8; Step 2A:

[0061] [ka] subjecting the cis-trans isomer mixture 8 to a reduction reaction to obtain a cis-trans isomer mixture 9 or mixture 9 hydrochloride; Step 3A:

[0062] [ka] subjecting cis-trans isomer mixture 9 or mixture 9 hydrochloride to a ring-closing reaction with compound 5 or compound 5' to obtain mixture 10 or a hydrate of mixture 10, wherein R is methyl or ethyl, which is optionally substituted by hydroxyl, preferably R is methyl or 1-hydroxyethyl, and the hydrate of mixture 10 is a monohydrate of mixture 10; Step 4A:

[0063] [ka] and subjecting mixture 10 or a hydrate of mixture 10 to an isomer conversion reaction under basic conditions to obtain compound 6 or a hydrate of compound 6, wherein the hydrate of compound 6 is preferably a monohydrate of compound 6.

[0064] According to an embodiment of the present invention, in synthetic route 2, steps 1A, 2A and 3A follow steps 1, 2 and 3 of synthetic route 1. In step 4A, the reaction is carried out under basic conditions, and the base is an alkoxide base, preferably an alkali metal C 1~6 An alkoxide, more preferably potassium tert-butoxide.

[0065] According to an embodiment of the present invention, the present invention provides another method for synthesizing compound 6A, including step 1A, step 2A, step 3A, and step 4A, in which steps 1A, 2A, and 3A are according to the method described in steps 1, 2, and 3 (synthetic route 1) for preparing compound 6A above, Step 1A:

[0066] [ka] reacting compound 1 with cis-trans isomer mixture 7 in a solvent in the presence of a base to obtain cis-trans isomer mixture 8; Step 2A:

[0067] [ka] subjecting the cis-trans isomer mixture 8 to a reduction reaction to obtain a cis-trans isomer mixture 9 or mixture 9 hydrochloride; Step 3A:

[0068] [ka] subjecting the cis-trans isomer mixture 9 or the hydrochloride salt of mixture 9 to a ring-closing reaction with R-lactic acid to obtain mixture 6Aa or a hydrate of mixture 6Aa; Step 4A:

[0069] [ka] and subjecting the mixture 6Aa or a hydrate of the mixture 6Aa to an isomer conversion reaction under basic conditions to obtain a hydrate of the compound 6A. The base is preferably an alkoxide base, preferably an alkali metal C 1~6 The alkoxide, more preferably potassium tert-butoxide, and the hydrate of compound 6A is preferably the monohydrate of compound 6A.

[0070] According to an embodiment of the present invention, in a method for synthesizing compound 6A by steps 1A to 4A, in step 4A, The reaction is carried out in a solvent, preferably tetrahydrofuran; the molar ratio of the mixture 6Aa to the base is 1:0.05 to 1:0.2, preferably 1:0.1 to 1:0.2; The reaction is carried out at room temperature. After the reaction is complete, dilute hydrochloric acid is added to adjust the pH to 6-7, and the solvent is removed by rotary evaporation. Water is added to the reaction solution, and the resulting system is stirred, filtered, and washed with water. The filter cake is collected and dried at 50 °C to obtain the hydrate of compound 6A.

[0071] According to an embodiment of the present invention, the present invention provides another method for synthesizing compound 6B, including step 1A, step 2A, step 3A and step 4A, wherein steps 1A, 2A and 3A are according to the method described in steps 1, 2 and 3 (synthetic route 1) for preparing compound 6B above, Step 1A:

[0072] [ka] reacting compound 1 with cis-trans isomer mixture 7 in a solvent in the presence of a base to obtain cis-trans isomer mixture 8; Step 2A:

[0073] [ka] subjecting the cis-trans isomer mixture 8 to a reduction reaction to obtain a cis-trans isomer mixture 9 or mixture 9 hydrochloride;

[0074] [ka] subjecting the cis-trans isomer mixture 9 or the hydrochloride salt of mixture 9 to a ring-closing reaction with acetic anhydride and / or acetic acid to obtain mixture 6Ba; Step 4A:

[0075] [ka] The mixture 6Ba is subjected to an isomer conversion reaction under basic conditions to obtain compound 6B. The base is an alkoxide base, preferably an alkali metal C 1~6 An alkoxide, more preferably potassium tert-butoxide.

[0076] According to an embodiment of the present invention, in a method for synthesizing compound 6B in steps 1A to 4A, in step 4A, The reaction is carried out in a solvent, preferably tetrahydrofuran; the molar ratio of the mixture 6Ba to the base is 1:0.05 to 1:0.2, preferably 1:0.1 to 1:0.2; The reaction is carried out at room temperature. After the reaction is complete, dilute hydrochloric acid is added to adjust the pH to 6-7, and the solvent is removed by rotary evaporation. Water is added to the reaction solution, and the resulting system is stirred, filtered, and washed with water. The filter cake is collected and dried at 50 °C to obtain compound 6B.

[0077] The present application further relates to a mixture of formula 8 (cis-trans isomer mixture 8),

[0078] [ka] or a mixture of Formula 8, wherein the mixture of Formula 8 comprises a compound of Formula 3a and a compound of Formula 8A.

[0079] [ka]

[0080] The present application further relates to a mixture of formula 9 (cis-trans isomer mixture 9),

[0081] [ka] or a mixture of formula 9, the mixture of formula 9 comprising a compound of formula 4a and a compound of formula 9A.

[0082] [ka]

[0083] The present application further provides compounds of formula 6Aa (mixture 6Aa):

[0084] [ka] or a hydrate of the mixture of formula 6Aa, or a salt of the mixture of formula 6Aa, wherein the mixture of formula 6Aa comprises a compound of formula 6A and a compound of formula 6Ab.

[0085] [ka]

[0086] The present application relates to a mixture of formula 6Ba (mixture 6Ba),

[0087] [ka] or a salt of a mixture of formula 6Ba, the mixture of formula 6Ba comprising a compound of formula 6B and a compound of formula 6Bb.

[0088] [ka] .

[0089] Beneficial effects The method for synthesizing 1H-furo[3,2-b]imidazo[4,5-d]pyridine compounds of the present invention has the advantages of high yield, low impurities, easy control, and low cost. The method is simple, convenient to operate, and suitable for industrial scale. [Brief description of the drawings]

[0090] [Figure 1] FIG. 1 is a 1H NMR spectrogram of compound 1 prepared in Example 6 of the present invention. [Diagram 2] FIG. 2 is an LCMS spectrogram of compound 1 prepared in Example 6 of the present invention. [Diagram 3] FIG. 3 is a 1H NMR spectrogram of compound 2a prepared in Example 8 of the present invention. [Figure 4] FIG. 4 is a HPLC spectrogram derived from TsCl of compound 2a prepared in Example 8 of the present invention. [Diagram 5] FIG. 5 is an HPLC spectrogram derived from Nα-(2,4-dinitro-5-fluorophenyl)-L-valinamide, compound 2a, prepared in Example 8 of the present invention. [Figure 6] FIG. 6 is a 1H NMR spectrogram of compound 6A prepared by Method A of Example 13 of the present invention. [Figure 7] FIG. 7 is an HPLC spectrogram of compound 6A prepared by Method A of Example 13 of the present invention. [Figure 8]FIG. 8 is an HPLC spectrogram of isomers of compound 6A prepared by Method A of Example 13 of the present invention. [Figure 9] FIG. 9 is a 1H NMR spectrogram of compound 6B prepared by Method A of Example 15 of the present invention. [Figure 10] FIG. 10 is an HPLC spectrogram of compound 6B prepared by Method A of Example 15 of the present invention. [Figure 11] FIG. 11 is a 1H NMR spectrogram of the tartrate salt of compound 6B prepared in Example 16 of the present invention. [Figure 12] FIG. 12 is an HPLC spectrogram of the tartrate salt of compound 6B prepared in Example 16 of the present invention. [Figure 13] FIG. 13 is an HPLC spectrogram of Compound 1 prepared in Example 6 of the present invention. [Figure 14] FIG. 14 is a 1H NMR spectrogram of compound 6C prepared in Example 14 of the present invention. [Figure 15] FIG. 15 is a TGA spectrogram of compound 6A prepared in Example 13 of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0091] The sources of key materials for the following examples are given in the table below.

[0092] [Table 1] JPEG2024546195000049.jpg238159

[0093] [Testing and inspection methods for compound 1] Test method 1 device: Agilent 1200 High Performance Liquid Chromatograph or similar liquid chromatograph Chromatography column: Poroshell 120 EC-C18 (4.6 x 50 mm x 2.7 μm) method: The area normalization method was used for the test. The chromatographic analysis conditions were as follows. Flow rate: 1.0ml / min Column temperature: 30℃ Detector: UV (210 nm) Post run: 1 minute

[0094] [Table 2]

[0095] Test method 2 Karl Fischer Moisture Test: According to the operating procedure of the moisture determination method, about 0.2-0.5 g of the test sample of compound 1 was weighed, and the result was accurate to 0.1 mg. The test sample was added to the titration cup of the titrator for measurement. The result was recorded. The test sample was determined twice in parallel by the same method, and the average value of the two results was taken as the moisture content of the test sample, and the result was recorded to one decimal place.

[0096] Test method 3 Gas chromatograph such as Shimadzu GC-2014C or similar Gas column: HP-5 30m x 320μm x 0.25μm column. Column temperature: 40°C, hold for 3 min, heat to 260°C at 10°C / min, hold for 2 min Injector temperature: 230℃ Detector temperature: 260℃ Airflow: 400mL / min Hydrogen flow rate: 40mL / min Tail blow nitrogen: 25ml / min Chromatography column flow rate (nitrogen): 1 mL / min

[0097] Test method 4 Drying loss: A test sample of evenly mixed compound 1 (if the sample is a relatively large crystal, it needs to be quickly crushed to particles of about 2 mm) was taken, and 1-2 grams of the sample was accurately weighed and placed in a dry, flat-shaped weighing bottle with a stopper under the same conditions as the sample. The weighing bottle was first weighed when the weighing bottle was empty, and then the bottle cup was placed on top after the sample was added, and then the total weight was weighed. The weighing bottle was gently shaken in parallel to spread the sample as evenly as possible, so that the thickness of the sample did not exceed 5 mm. The weighing bottle containing the sample was placed in a drying oven at a constant temperature and reduced pressure (the bottle cap was removed and placed in the dryer), and dried at 50 ° C for 4 hours at -0.09 to -0.1 MPa. The dried sample in the oven was covered with a bottle cap immediately after drying, transferred to the dryer, cooled to room temperature, and then weighed. Drying loss calculation formula Loss on drying = (W1~W2) / W1×100%. W1 was the sample weight before drying and W2 was the sample weight after drying.

[0098] Methods for detecting the final product of compound 1 1. Appearance The product was placed under natural light for visual inspection. 2. Detection By using nuclear magnetic resonance spectroscopy with CDCl3 as the solvent, USP <761> Detection was performed by an external unit according to the method described above. 3. Purity and Related Substances Equipment and Devices

[0099] [Table 3] reagent

[0100] [Table 4] Sample information

[0101] [Table 5] Chromatography conditions

[0102] [Table 6]

[0103] [Detection method of compound 2a]

[0104] Determination of compound 2a by GC chromatographic detection

[0105] [Table 7] Method for determining the HPLC purity and de value of the final product of compound 2a

[0106] [Table 8] JPEG2024546195000057.jpg47159 Method for determining the ee value of the final product of compound 2a

[0107] [Table 9]

[0108] [Detection method of compounds 3a, 4a, and 6A]

[0109] Detection method 1

[0110] [Table 10]

[0111] Detection method 2

[0112] [Table 11] JPEG2024546195000061.jpg86159

[0113] Detection method 3

[0114] [Table 12]

[0115] Detection method 4

[0116] [Table 13]

[0117] [Method for detecting compound 6B and the tartrate salt of compound 6B] Chromatograph: Agilent 1260 high performance liquid chromatograph. Column model: Waters XBridge C18 250mm×4.6mm×5μm. Mobile phase A: 20 mM dipotassium hydrogen phosphate aqueous solution Mobile phase B: Methanol gradient:

[0118] [Table 14] Column temperature: 40℃ Sample room temperature: room temperature Flow rate: 1mL / min Injection volume: 5μL Run Time: 50 minutes Test sample concentration: Approximately 1 mg / mL Detection wavelength: UV 230nm.

[0119] The present invention is further illustrated below with reference to the following examples, which do not constitute a limitation or restriction to the scope of the invention. EXAMPLES

[0120] [Example 1: Preparation of Compound 1-2] 2-Chloromethyl-3,4-dimethoxypyridinium hydrochloride (250 kg, 1.0 equiv.) was added to reaction vessel 1 under the protection of nitrogen, followed by toluene (1050 kg) and drinking water (150 kg). The reaction solution was stirred and cooled to 20-25°C. Sodium carbonate (68.8 kg, 0.58 equiv.) was added in one portion, the temperature in the vessel was controlled below 30°C, and then the reaction solution was stirred for 0.5 hours. The system was allowed to stand for 20 minutes and the layers were separated. The upper organic phase was saved, and the lower aqueous phase was transferred to reaction vessel 2 and extracted with toluene (435 kg), and the organic phases were combined in reaction vessel 1. The aqueous phase was extracted again with toluene (225 kg), the lower aqueous phase was discarded, and the organic phases were combined in reaction vessel 1. The combined organic phases were washed with saturated saline (204 kg) and dried over anhydrous sodium sulfate (150 kg). The filtrate obtained after filtration was transferred to reaction vessel 3, and the obtained solid was rinsed with toluene (50 kg). Triphenylphosphine (350 kg, 1.2 equivalents) was added to reaction vessel 3, the system was stirred, the internal temperature was heated to 108-115 °C, and the reaction solution was refluxed in a Dean-Stark apparatus for 18 hours. After the reaction was completed, the material in reaction vessel 3 was cooled to 20-30 °C. The material was centrifuged, and the obtained solid was rinsed with toluene (100 kg). The wet product was dried with a double cone, the temperature of the hot water in the jacket was 50-60 °C, and the vacuum degree was less than -0.090 Mpa until the water was less than 0.2%. The product was collected, packaged in a double-layer PE bag, and placed in a fiberboard drum (yield: 489.8 kg, yield: 97.4%, HPLC purity: 99.8%).

[0121] Example 2: Preparation of Compounds 1-3 Compound 1-2 (489.8 kg, 1.0 equiv.) and dimethyl sulfoxide (1614.2 kg, 3V) were added to reaction vessel 1, stirred, and then cooled to 20-25°C. Sodium tert-butoxide (114.9 kg, 1.1 equiv.) was added in one portion, and the resulting system was heated to 25-32°C after the addition. The reaction solution was stirred for 1.5 hours while maintaining the temperature at 25-32°C. Ethyl formate (397.8 kg, 5.0 equiv.) was added dropwise to reaction vessel 1, reaction vessel 1 was heated to 40-50°C, and the temperature of the reaction solution was maintained at 40-50°C and stirred for 8 hours. After the reaction was completed, reaction vessel 1 was cooled to a temperature below 25°C. The reaction mixture was extracted with ethyl acetate (1320.7 kg, 3 V) and drinking water (1467.4 kg, 3 V), the resulting organic layer was separated, and the resulting aqueous phase was extracted twice with ethyl acetate. The organic phases were combined and washed with water (978.3 kg). Water (1467.4 kg) was added to the organic phase, and hydrochloric acid (108.7 kg) was added dropwise to adjust the pH to 5-6. The organic phase was separated and washed with water (250.0 kg), the aqueous phases were combined, and extracted twice with ethyl acetate (1320.2 kg). Ethyl acetate (1320.7 kg, 3 V) and sodium carbonate (54.0 kg) were added to the aqueous phase all at once to adjust the pH to 8 or higher. The organic phase was separated, and the resulting aqueous phase was extracted with ethyl acetate (880.4 kg, 2 V). The combined organic phase was washed with saturated brine (341.3 kg), dried over anhydrous sodium sulfate (217.4 kg), filtered under vacuum, and rinsed with ethyl acetate (81.5 kg). The filtrate was collected and the solvent was removed. The residue was triturated with n-heptane (337.0 kg) and centrifuged. The resulting solid was rinsed with n-heptane (76.0 kg) and dried to give compound 1-3 (yield: 202.0 kg, yield: 88.8%, and HPLC purity: 97.3%).

[0122] Example 3: Preparation of Compounds 1-4 Compound 1-3 (200.0 kg, 1.0 equiv.) and dichloromethane (1431.0 kg, 6 V) were added to reaction vessel 1 under the protection of nitrogen, and the temperature of the material in the reaction vessel was maintained at 15-20°C. Boron tribromide (600.0 kg, 2.5 equiv.) was added, and the temperature of the material in the reaction vessel was maintained at 20-30°C. After the addition, the reaction solution was stirred for 1 hour while maintaining the temperature at 20-30°C. At 15-30°C, under the protection of nitrogen, the mixed solution in reaction vessel 1 was slowly dripped into reaction vessel 2 containing ethyl alcohol (1422.0 kg, 10 V). The reaction system was stirred for 2 hours while maintaining the temperature at 30-35°C. The solvent was removed under reduced pressure to 1600 L. Ethyl alcohol (570.0 kg 4 V) was added twice to the resulting solution, and it was concentrated to a volume of 1,600 L after each addition. The temperature was controlled at 15-30°C and 18% sodium ethoxide in ethanol solution (1367.0 kg) was added to adjust the pH to 5-6. The solid was separated and rinsed with absolute ethanol (143.0 kg, 1 V). To the mother liquor, 18% sodium ethoxide in ethanol (1378.4 kg) was added to adjust the pH to 8-9. The solvent was removed under reduced pressure and methyl tert-butyl ether (540.0 kg, 4 V) was added. The solid was separated, rinsed with methyl tert-butyl ether (135.0 kg, 1 V) and dried to give compound 1-4 (yield: 170 kg, yield: 78.3%, and HPLC purity: 97.9%).

[0123] Example 4: Preparation of Compounds 1-5 Benzoyl chloride (214.6 kg, 2.0 equiv.) was slowly added dropwise to a dichloromethane solution (3271.0 kg, 25.5 V) containing compound 1-4 (170.0 kg, 1.0 equiv.) at 0-10 °C. The reaction solution was stirred at 0-10 °C for 1 h. The reaction solution was slowly added dropwise to a reaction vessel containing sulfuric acid (1518.0 kg, 4.85 V) at 15-25 °C, and the resulting mixture was stirred for 1 h. The reaction solution was quenched with water (850.0 kg, 5 V) at 0-10 °C. The solid was separated and rinsed with water (85.0 kg, 0.5 V), the mother liquor was cooled to 0-10 °C, and aqueous ammonia (1841.3 kg) was added dropwise to adjust the pH to 7-8. The mixture was stirred at 53-57 °C for 0.5 h, then cooled to 20-25 °C. The solid was separated and rinsed with water (170.0 kg, 1V). The solid thus obtained was dried to give compound 1-5 (yield: 92.7 kg, yield: 91.7%, and HPLC purity: 98.3%).

[0124] [Example 5: Preparation of Compounds 1-6] Nitric acid (52.5 kg) was added dropwise to reaction vessel 1 containing acetic acid (141.0 kg) and acetic anhydride (89.25 kg) at 15-30 °C and stirred at 20-30 °C for 0.5 h. The mixture was slowly added dropwise to an acetic acid solution (450.0 kg, 10 V) containing compound 1-5 (45.0 kg, 1.0 equiv.) at a temperature of 113-116 °C over 2 h under the protection of nitrogen, and the temperature was kept at 112-117 °C. The mixture was stirred for 1 h while maintaining the temperature at 112-117 °C. After cooling to 20-30 °C, methyl tert-butyl ether (337.5 kg, 10 V) was added and the mixture was stirred for 0.5 h. The solid was separated and rinsed with methyl tert-butyl ether (100.8 kg, 3 V). The solid thus obtained was dried to give compound 1-6 (yield: 44.4 kg, yield: 74.0%, and HPLC purity: 94.7%).

[0125] Example 6: Preparation of Compound 1 Phosphorus oxychloride (72.8 kg, 1.2 equiv.) was added dropwise to a N,N-dimethylformamide solution (214.2 kg, 3.0 W) containing compound 1-6 (71.8 kg) at 15-25 °C under the protection of nitrogen. The reaction mixture was stirred at 38-43 °C for 1 h and then cooled to 15-20 °C. The reaction solution was quenched by dropwise addition of water (714.0 kg, 10 W) and the reaction solution was stirred for 1 h while maintaining the temperature at 20-30 °C. The solid was separated, rinsed with water (214.2 kg, 3 W), and then stirred in dichloromethane (1224.0 kg, 13 V) for 15 min. 5% aqueous sodium bicarbonate solution (357.0 kg) and Celite (35.7 kg) were added and the mixture was stirred for 0.5 h. The solid was separated and rinsed with dichloromethane (195.3 kg, 2 V). The filtrate was collected. The dichloromethane layer was separated and the aqueous layer was extracted with dichloromethane (474.3 kg, 5 V). The dichloromethane layers were combined, washed with saturated brine (485.5 kg), dried with anhydrous sodium sulfate (107.0 kg, 1.5 W) for 1 h, filtered, and rinsed with dichloromethane (188.7 kg, 2 V). The filtrate was collected and activated carbon (7.0 kg, 0.1 W) was added. The resulting mixture was stirred at 20-30 °C for 1 h, filtered, and rinsed with dichloromethane (93.8 kg, 1 V). The solvent was removed and n-heptane (242.8 kg, 5 V) was added for trituration. The separated solid was rinsed with n-heptane (47.9 kg, 1V) and dried to give compound 1 (yield: 62.2 kg, yield: 78.5%, and HPLC purity: 99.96%). 1 The 1 H NMR spectrogram is shown in FIG. 1, the LCMS spectrogram is shown in FIG. 2, and the HPLC spectrogram is shown in FIG.

[0126] [Example 7: Preparation of compound 2-2] A methanolic solution of sodium methoxide (19.18 kg, 0.25 equiv.) and tetrahydrofuran (91.1 kg, 1.0 V) was added to a tetrahydrofuran solution (911.4 kg, 10 V) containing compound 2-1 (102.4 kg, 1.0 equiv.) at 0-5°C. The reaction was stirred at 20-25°C for 4-8 h. The reaction was monitored by GC and HPLC until the starting material was below 1.0%. The temperature was reduced to 15-20°C and an aqueous solution of ammonium chloride (13.3 kg, 0.13 V) (5.69 kg, 0.25 equiv.) was added to the reaction, the pH was adjusted to 7-8, and the temperature was maintained at 15-25°C. Methyl tert-butyl ether (166.7 kg, 2.2 V) and 20% sodium chloride solution (61.4 kg sodium chloride, 0.6 W and 245.8 kg drinking water, 2.4 W) were added to the mixture solution, respectively. The organic phase was separated, the aqueous phase was extracted with methyl tert-butyl ether (75.8 kg, 1 V), and the organic phases were combined. The organic phase was washed with 30% aqueous sodium chloride solution (43.0 kg, 0.42 W sodium chloride solid, 100.4 kg, 0.98 W drinking water), and then separated. The aqueous phase was extracted with methyl tert-butyl ether (75.8 kg, 1 V). The organic phases were combined, and anhydrous sodium sulfate (51.2 kg, 0.5 W) and activated charcoal (10.24 kg, 0.1 W) were added. The mixture was filtered and rinsed with methyl tert-butyl ether (41.0 kg, 0.4 W). The filtrate was collected, concentrated, and methyl tert-butyl ether (227.3 kg, 3.0 V) was added. The mixture was ground at 50-55° C. for 2 h and slowly cooled to 0-10° C. The solid thus obtained was filtered, collected, and dried to obtain compound 2-2 (yield: 43.2 kg, yield: 42.2%). Quality standards for compound 2-2: Appearance: off-white solid, Purity (GC): 96.0%, Maximum content of unknown single impurity: 1.6%, and Moisture: 0.0%.

[0127] Example 8: Preparation of compound 2a hydrochloride Compound 2-2 (43.21 kg, 1.0 equivalent) and dichloromethane (192 kg, 6V) were added to the reaction vessel R01, the resulting system was cooled to 0-5°C, and then 35% hydrogen chloride in ethanol solution (hydrochloride: 19.3 kg, anhydrous ethyl alcohol: 35.9 kg) was added dropwise. After the dropwise addition, the system was heated to 20-25°C, and the temperature was maintained for 4-8 hours. Upon detection by TLC and GC, the system was cooled to 0-5°C after the content of raw material compound 2-2 was below 1.0%. The system was centrifuged to obtain the wet product of hydrochloride of compound 2a, and then the wet product was rinsed with dichloromethane (32.0 kg, 1V), centrifuged and dried. The double cone jacket was heated to 55-65 °C, and the obtained material was dried under vacuum at a vacuum degree of -0.095 MPa or less for 12 h to obtain compound 2a hydrochloride (yield: 28.96 kg, yield: 91.2%). 1 The 1 H NMR spectrogram is shown in FIG. 3, the HPLC spectrogram derived from TsCl is shown in FIG. 4, and the HPLC spectrogram derived from Nα-(2,4-dinitro-5-fluorophenyl)-L-valinamide is shown in FIG. Quality standards of compound 2a hydrochloride: Appearance: white solid, purity (HPLC from TsCl): 99.8%, de value (HPLC from TsCl): 99.8%, e.g. value (HPLC from Nα-(2,4-dinitro-5-fluorophenyl)-L-valinamide): 99.9%, maximum content of single impurity: 0.2%, and moisture: 0.1%.

[0128] Example 9: Preparation of compound 3a Method A Absolute ethanol (110.6 kg, 5V), acetonitrile (109.2 kg, 5V), compound 1 (27.97 kg, 1.0 equiv.), and compound 2a hydrochloride (25.07 kg, 1.0 equiv.) were pumped into a 1000 L reaction vessel (R01), and then N,N-diisopropylethylamine (40.0 kg, 2.2 equiv.) was pumped into the mixture under the protection of nitrogen. The reaction solution was reacted at 50-60°C for 16 hours, and a sample was tested by HPLC until compound 1 was below 1.0%. The reaction solution was cooled to 20-30°C, and water (560 kg, 20V) was added dropwise at 20-30°C. After the dropwise addition, the reaction solution was continuously stirred for 1.0 hour while maintaining the temperature at 20-30°C. The material was stirred at 0-5°C for 2 h, then centrifuged and the filter cake was rinsed once with a mixed solvent of acetonitrile and water (pre-cooled at 0-10°C, 25 kg acetonitrile + 56 kg water). The filter cake was dried in a vacuum oven at 45-55°C to give compound 3a (yield: 37.51 kg, moisture: 0.03%, yield: 88.1%). Method B Ethanol (1.9 L), compound 1 (200 g, 1.0 equiv.), compound 2a hydrochloride (179.7 g, 1.01 equiv.), and sodium bicarbonate (188 g, 2.23 equiv.) were added to a flask under nitrogen atmosphere. The reaction solution was reacted at 70-80°C for 16 hours. The reaction solution was cooled to 20-30°C, and water (2.9 L) was added slowly. The resulting mixture was stirred for 2 hours and cooled to 5-15°C. The mixture was stirred for 4 hours while maintaining the temperature at 5-15°C, and filtered. The filter cake was eluted with water and ethanol (600 mL, water / ethanol=1:2) and dried to obtain compound 3a as a yellow solid (yield: 286.9 g, yield: 94%). Method C Compound 3a was prepared by the same preparation method as in Method B, except that the added base was different from that in Method B, the added base was sodium carbonate (2.2 equiv.), and the amount of compound 3a detected by HPLC was 72%. Method D Compound 3a was prepared by the same preparation method as in Method B, except that the added base was different from that in Method B, the added base was potassium bicarbonate (2.2 equiv.), and the amount of compound 3a detected by HPLC was 83%. Method E Anhydrous ethanol (1 mL), acetonitrile (1 mL), compound 1 (200 mg, 1.0 equivalent), compound 2a hydrochloride (179 mg, 1.0 equivalent), and 1,8-diazabicyclo[5.4.0]undec-7-ene (339 mg, 2.2 equivalent) were added to a 40 mL flask and reacted at 55° C. for 16 hours. The reaction solution was then cooled to room temperature, concentrated, and separated by column chromatography to obtain compound 3a (yield: 198 mg, yield: 65.1%).

[0129] Example 10: Preparation of compound 3b Under a nitrogen atmosphere, ethanol (27 mL), compound 1 (2.84 g, 1.0 equiv.), compound 2b (2-(trans-4-aminocyclohexyl)acetonitrile, 2 g, 1.01 equiv.), and sodium bicarbonate (1.44 g, 1.2 equiv.) were added to a flask and reacted at 75° C. for 16 hours. The reaction solution was cooled to 20-30° C., water (30 mL) was slowly added, and the resulting system was stirred for 2 hours and filtered. The filter cake was eluted with water and ethanol (6 mL, water / ethanol=1:2) and dried to obtain compound 3b as a yellow solid (yield: 3.694 g, yield: 86%).

[0130] [Example 11: Preparation of Compound 4a / Compound 4a Hydrochloride] Method A Under nitrogen protection, acetonitrile (264 kg, 9 V), acetic acid (90 kg, 12 equiv.), and compound 3a (37.43 kg, 1.0 equiv.) were added to a 1000 L glass-lined reactor. Iron powder (41.17 kg, 6.0 equiv.) was added in one portion at 60-70 °C and stirred for 1 h while maintaining the temperature at 60-70 °C. Iron powder (14 kg, 2.02 equiv.) and acetic acid (10 kg, 1.34 equiv.) were added again until the reaction was complete. The reaction solution was cooled to 30-40 °C, filtered, and eluted with hot acetonitrile (50-60 °C, 176 kg, 6 V). A 30% aqueous solution of sodium citrate (164.56 kg sodium citrate, 5.15 eq., 380 kg water) was added to the filtrate at 10-25 °C until the pH was 6, then a 30% aqueous solution of potassium phosphate (224.46 kg potassium phosphate, 8.5 eq., and 522 kg water) was added until the pH was 8. After vacuum distillation, ethyl acetate (167.8 kg, 5 V) and water (112 kg, 3 V) were added. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (101 kg, 3 V). The organic phases were combined and then washed with a 20% aqueous solution of sodium citrate (water, 60 kg, and sodium citrate, 15 kg, 0.47 eq.) and a 15% aqueous solution of sodium chloride (water, 61.3 kg, and sodium chloride, 10.8 kg). Anhydrous sodium sulfate (41.5 kg) and silica gel (5.23 kg) were added and the resulting mixture was stirred for 30 min. The mixture was filtered and rinsed with ethyl acetate (67 kg). After distillation under reduced pressure, 30 kg of isopropanol was added to the system and evaporated to dryness under reduced pressure, then another 30 kg of isopropanol was added and evaporated to dryness under reduced pressure. 101.15 kg of isopropanol was added and the system thus obtained was stirred at 80 ° C to dissolve and obtain a clear solution. After dissolving until transparent, the reaction solution was slowly cooled to 0-10 ° C and stirred for 2 hours. The solid thus obtained was separated, and the filter cake was washed with 18.72 kg of isopropanol and dried to obtain compound 4a (21.15 kg, yield: 55%). The content of isopropanol was 12.65%. Method B Compound 3a (210 g, 1.0 eq.), water (840 mL), and methanol (210 mL) were added to the reaction flask, and the temperature was raised to 65-75°C with stirring. Then, hypoboric acid (218 g, 3.5 eq., 7 additions) was added in one portion at 65-75°C, and the reaction was carried out overnight. A sample was taken for detection (more hypoboric acid was added until the reaction was complete). After the reaction was completed, the reaction solution was cooled to 35-45°C, a portion of the solvent was concentrated under reduced pressure, and the temperature was lowered to 0-10°C. The system thus obtained was stirred for 1-2 hours and filtered. The filter cake was eluted with 1000 mL of dichloromethane, the filtrate was collected, sodium bicarbonate (105 g) was added in one portion at 20-30°C, the system was stirred for 1 hour with the temperature maintained at 20-30°C, and the system was allowed to stand for 0.5 hours. The organic phase obtained was separated and the aqueous phase obtained was extracted with dichloromethane (660 mL x 3). The organic phases thus obtained were combined and dried over anhydrous sodium sulfate (210 g). Hydrochloric acid in ethanol solution (230 mL, 30%) was added dropwise at 15-25°C and the resulting system was stirred for 8 hours while maintaining the temperature at 15-25°C. Ethyl acetate (1050 mL) was added dropwise at 15-25°C and the resulting system was stirred for 1 hour while maintaining the temperature at 15-25°C and then filtered. The filter cake was eluted with ethyl acetate (420 mL) and dried in a vacuum drying oven at 30-40 °C to obtain compound 4a hydrochloride, i.e., 2-((2R,5S)-5-(6-aminofuro[3,2-b]pyridin-7-ylamino)tetrahydro-2H-pyran-2-yl)acetonitrile hydrochloride (yield: 232.8 g, yield: 85.3%). Method C At room temperature, compound 3a (1.00 g, 3.31 mmol), 4,4'-bipyridine (2.58 mg, 0.0165 mmol), and solvent DMF (20 mL) were added to a 50 mL multi-neck flask. The mixture was purged with nitrogen three times while stirring, and B2(OH)4 (0.89 g, 9.92 mmol) was added. The mixture was reacted at 15-25 °C for 5 h. The reaction solution was detected by HPLC. After compound 3a was completely consumed, the reaction was stopped and 200 mL of water was added. The resulting system was extracted five times with ethyl acetate (50 mL each), washed with 100 mL of saturated saline, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was further separated by column chromatography using dichloromethane and methanol (30:1 (v / v)) to obtain compound 4a, with a yield of 44.4%. Method D Ethyl acetate (2mL), compound 3a (198mg, 1.0eq), and stannous chloride (373mg, 3.0eq) were added to a reaction flask and reacted at 85°C for 3 hours, then cooled to room temperature. Sodium bicarbonate was added in an ice bath, and the resulting system was stirred and filtered. The filter cake was rinsed with 2mL of ethyl acetate. The filtrate was collected and washed three times with saturated aqueous sodium bicarbonate. The organic phases were combined and then washed three times with saturated brine. The organic phases thus obtained were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 4a (yield: 123mg, yield: 69%).

[0131] Example 12: Preparation of compound 4b Compound 3b (3.69 g, 1.0 equiv.), water (14.8 mL), and methanol (3.7 mL) were added to a reaction flask and the temperature was raised to 65-75 °C with stirring. Hypoboric acid (4.51 g, 4.1 equiv., 4 additions) was added in one portion and the mixture was reacted at 65-75 °C overnight. After the reaction was complete, the reaction solution was cooled to 20-30 °C. Sodium bicarbonate (1.85 g) was added in one portion and the mixture was stirred at 20-30 °C for 0.5 h. The organic phase was separated and the aqueous phase was extracted with dichloromethane (10 mL x 3), then the resulting organic phases were combined, washed with water (10 mL x 3) and saturated brine (10 mL x 3), dried over anhydrous sodium sulfate (3.7 g), filtered, and concentrated to give compound 4b (yield: 3.02 g, 90.9% yield).

[0132] Example 13: Preparation of compound 6A Method A R-Lactic acid (30.5 kg, 5.0 equiv., isomer content: 0.25%), compound 4a (21.14 kg, 1.0 equiv.), and methylcyclohexane (37.0 kg) were added to a 300 L reaction vessel R01, the resulting system was stirred and heated to reflux at 87.2-101 °C for 5 h using a Dean-Stark apparatus, and then a sample was taken for in-process control. After the reaction was completed, steam heating was stopped, methanol (43.8 kg, 3 V) was slowly added dropwise to the reaction vessel R01, and the system was cooled to 20-30 °C. The reaction solution was allowed to settle for layer separation. The lower layer was separated, and methanol (29.6 kg, 2 V) was added. Sodium hydroxide solution (25.3 kg water, and 10.9 kg sodium hydroxide) was added dropwise at -10-0 °C, and the material was reacted under a temperature maintained at -10-0 °C until the HPLC detection result was qualified. Hydrochloric acid (4.81 kg concentrated hydrochloric acid + 45.03 kg water) was added dropwise to adjust the pH to 7. After the solvent was removed under vacuum, water (277.5 kg, 15V) was added. The resulting mixture was stirred for 1 hour and then centrifuged. The filter cake was washed with water (55.5 kg, 3V). The resulting wet product was placed in 185 kg water. The mixture was stirred at about 30°C for 2 hours, centrifuged, washed with 30 kg water, and dried to obtain crude product of compound 6A. HPLC purity of compound 6A: 97.24%; HPLC content of compound 6A isomers: 1.95%; water content: 5.2%. Purified compound 6A: A mixture of 20.49 kg of crude product of compound 6A, 116 kg of isopropanol, and 50 kg of water was stirred and refluxed to dissolve and clarify. The system was cooled to -5~5°C, stirred for 3 hours while maintaining the temperature at -5~5°C, and centrifuged. The filter cake was rinsed once with mixed solvent (rinsed once with isopropanol (12 kg) and water (5 kg), pre-cooled to 0~10°C) to obtain the first recrystallized compound 6A. HPLC purity of compound 6A: 99.03%; and HPLC content of isomers of compound 6A: 1.03%. Recrystallization (107.16 kg of isopropanol, and 45.36 kg of water) was carried out again to obtain the second recrystallized compound 6A. HPLC purity of compound 6A: 99.66%; HPLC content of isomers of compound 6A: 0.43%. 87.7 kg of methanol and 1.2 kg of activated carbon were added to 17.1 kg of wet product of compound 6A, and the resulting system was refluxed with stirring for 1 hour. The mixture was pressure filtered (through a polished filter) and rinsed with 13.5 kg of methanol. The solvent was removed under reduced pressure. 13.5 kg of isopropanol was added, and then the solvent was removed again under reduced pressure. Recrystallization was carried out by the same recrystallization method as above. Compound 6A was obtained after drying (Compound 6A was characterized as the monohydrate of compound 6A, and its thermogravimetric analysis (TGA) thermogram is shown in Figure 15. The TGA thermogram shows a weight loss of 5.353% when heated from 25 °C to 133 °C, which corresponds to the weight loss of one molecule of water), yield: 14.76 kg, water: 5.2%, isopropanol remaining: 0.0405%. HPLC purity of compound 6A: 99.94%; HPLC content of isomers of compound 6A: 0.21%; Yield: 66.2%. 1 The 1 H NMR spectrogram is shown in FIG. 6, the HPLC spectrogram of compound 6A is shown in FIG. 7, and the HPLC spectrogram of an isomer of compound 6A is shown in FIG. Method B Except for the following differences from Method A, compound 6A was prepared by the same preparation method as Method A, the amount of compound 4a was 1 g, the reaction solvent was 1,4-dioxane (6 mL), and R-lactic acid (20 equivalents) and methanesulfonic acid (2 g) were added. HPLC: 91.1%; HPLC after sodium hydroxide hydrolysis: 98.2%. Method C Except for the following differences from Method A, compound 6A was prepared by the same preparation method as Method A, the amount of compound 4a was 1 g, the reaction solvent was 1,4-dioxane (10 mL), R-lactic acid (30.2 equiv.) was added, and the reaction solution was heated at 95-105 °C for 16 h. HPLC: 70%, HPLC after sodium hydroxide hydrolysis: 99.6%, chiral purity: 99.0%. Method D Except for the following differences from Method A, compound 6A was prepared by the same preparation method as Method A, the amount of compound 4a was 10 g, the reaction solvent was toluene (75 mL), and the reaction solution was heated at 108-113 °C for 10 h. HPLC: 97%, chiral purity: 96%.

[0133] Example 14: Preparation of compound 6C R-Lactic acid (1.66 g, 5.0 equiv.), compound 4b (1 g, 1.0 equiv.), and methylcyclohexane (5.25 g) were added to the reaction flask, and the reaction mixture was refluxed at 110° C. with stirring for 24 h. The reaction was cooled to 20-30° C., and methanol was added. The resulting mixture was allowed to settle for layer separation. The resulting upper organic phase was discarded, and the resulting lower layer was collected. Sodium hydroxide solution (1.2 g water, and 0.52 g sodium hydroxide) was added dropwise in an ice bath, and the mixture was stirred for 0.5 h. Hydrochloric acid (0.23 g concentrated hydrochloric acid + 2.15 g water) was added dropwise to adjust the pH to 7. The solution was concentrated under reduced pressure, water was added, and the resulting system was stirred for 0.5 h and filtered. The filter cake was dried to obtain compound 6C (yield: 0.984 g, 82%). 1 The 1 H NMR spectrogram is shown in FIG.

[0134] Example 15: Preparation of compound 6B Method A Compound 4a hydrochloride (200 g) and acetic anhydride (600 mL) were combined in a reaction vessel, stirred and heated at 90° C. for 12 h. The reaction solution was cooled to 0-10° C. and methyl tert-butyl ether (2 L) was added. The mixture was stirred at 0-10° C. for 1 h and filtered. The filter cake was rinsed with methyl tert-butyl ether (400 mL) and then placed in water (600 mL) and stirred. Dichloromethane was added. Sodium hydroxide (10% aqueous solution) was added in one portion at 15-25° C. to adjust the pH to 7-9. After allowing the system to stand for 0.5 h, the resulting organic phase was separated and the resulting aqueous phase was extracted with dichloromethane three times (600 mL). The organic phases were combined, dried over anhydrous sodium sulfate (200 g) and filtered. The filtrate was concentrated to 400 mL at 30-40° C. and ethanol (400 mL) was added. The resulting solution was concentrated under reduced pressure to 400 mL, and ethanol (400 mL) was added again. The mixture was concentrated under reduced pressure to 600 mL, heated to 45-55 °C, and stirred until the compound was dissolved and clear. The mixture was cooled to 0-10 °C, and water (2 L) was added dropwise slowly over about 1 h. The mixture was stirred at 0-10 °C for 1 h and filtered. The filter cake was eluted with aqueous ethanol (400 mL, ethanol:water = 1:5) and dried in a vacuum oven at 35-45 °C to obtain compound 6B, i.e., 2-((2R,5S)-5-(2-methyl-1H-furo[3,2-b]imidazo[4,5-d]pyridin-1-yl)tetrahydro-2H-pyran-2-yl)acetonitrile (yield: 134.6 g, and yield: 89%). 1 H NMR (400MHz, chloroform-d) δ8.96(s,1H),7.90(d,J=2.3Hz,1H),7.17(d,J=2.3Hz,1H),4.61- 4.48(m,1H),4.33(t,J=11.1Hz,1H),4.11-3.99(m,2H),2.78(dd,J=12.6,4.2Hz,1H),2.73 (s, 3H),2.70 (t,J=5.2 Hz, 2H),2.30-2.06(m,2H),1.93-1.78(m,1H). 1 The 1 H NMR spectrogram is shown in FIG. 9, and the HPLC spectrogram is shown in FIG. Method B Compound 6B was prepared by the same preparation method as Method A, except for the following differences from Method A: the amount of compound 4a hydrochloride was 0.5g, the reagent / solvent was acetic acid (2.5mL), the temperature was controlled at 100-110°C, and the reaction time was 23h. HPLC: 26%. Method C Compound 6B was prepared by the same preparation method as Method A, except for the following differences from Method A: the amount of compound 4a hydrochloride was 0.5 g, the reagent / solvent was acetic acid (2.5 mL), sodium acetate (0.24 g, 2 eq.) was added, and the reaction time was 23 h. HPLC: 93%. Method D Compound 6B was prepared by the same preparation method as Method A, except for the following differences from Method A: acetic acid (0.2 eq.) was added to the system, and the reaction time was 18 h. HPLC: 99%. Method E Compound 6B was prepared by the same preparation method as Method A, except for the following differences from Method A: sodium acetate (0.5 eq.) was added to the system, and the reaction time was 18 h. HPLC: 99%.

[0135] Example 16: Preparation of L-tartrate of compound 6B Compound 6B (100 g) and acetone (500 mL) were combined in a reaction vessel and heated at 40-50 °C with stirring for 1 h until a clear solution was obtained. A solution of L-tartaric acid (30 g) in acetone (1 L) was added and the resulting system was stirred at 40-50 °C for 4 h. The solution was cooled to 15-25 °C, stirred for 1 h, then cooled to 0-10 °C and stirred for 1 h. The reaction solution was filtered. The filter cake was eluted with acetone (500 mL) and dried in a vacuum oven at 45-55 °C for 24 h to obtain the L-tartrate salt of compound 6B (yield: 122.3 g, yield: 81%). 1H NMR(400MHz,DMSO-d6)δ8.80(s,1H),8.31(d,J=2.3Hz,1H),7.24(d,J=2.2Hz,1H),4.65- 4.57(m,1H),4.33(s,1H),4.20-4.08(m,2H),3.95-3.88(m,1H),3.06-2.76(m,2H),2.71 (s,3H),2.57-2.47(m,1H),2.21-2.14(m,1H),2.03-1.97(m,1H),1.81-1.66(m,1H). 1 The 1 H NMR spectrogram is shown in FIG. 11, and the HPLC spectrogram is shown in FIG.

[0136] [Example 17: Preparation of cis-trans isomer mixture 8] Cis-trans isomer mixture 7 (25.1 g, cis:trans = 1:1.7, 1.01 equiv.), compound 1 (28 g, 1.0 equiv.), absolute ethanol (210 g, 9.5 V), and sodium bicarbonate (54.9 g, 4.5 equiv.) were combined in a reaction flask and heated at 70-80 °C for 6-10 h. After the temperature was cooled to room temperature (20-30 °C), 20 V of water was added dropwise. The resulting mixture was stirred for 0.5-1.0 h and stirred at 0-10 °C for an additional 0.5-1.0 h. The mixture was filtered and the filter cake was rinsed with 4 V of water (20-25 °C). The filter cake was ground in 5 V of water at 20-25 °C for 0.5-1.0 h. The mixture was filtered and rinsed with 4 V of water (20-25 °C). The wet product was dried at 50° C. to give a cis-trans isomer mixture 8 (41.9 g, yield: 98%, purity: 97.9%, and water: 0.26%, compound 8A: compound 3a = 1: 1.7).

[0137] [Example 18: Preparation of cis-trans isomer mixture 9] Cis-trans isomer mixture 8 (19 g, 1.0 equiv), water (76 g, 4 V), and methanol (15.0 g, 1 V) were mixed and heated to 60-70 °C. Hypoboric acid (20 g, 1.0 equiv + 1.0 equiv + 1.0 equiv + 0.5 equiv) was added in one portion, and the reaction mixture was heated at 70-80 °C for 1-3 h. The reaction was stopped when mixture 8 was 1% or less. The reaction solution was cooled to 45 °C and concentrated under reduced pressure to 4-5 V (this process is mainly to remove some of the methanol). The reaction solution was cooled to 0-10 °C, stirred for 1.0 h, and filtered under reduced pressure. The filter cake was eluted with 6 V of DCM, and then sodium bicarbonate (35.43 g, 0.5 W) was added to the filtrate with stirring. After stirring for 0.5-1.0 h, the aqueous layer was extracted four times with 3 V of DCM each. The resulting organic phases were combined, dried over 1W anhydrous sodium sulfate, and filtered. The filtrate was concentrated to 2V DCM, and 10V TBME was slowly added dropwise below 30°C. The resulting mixture was mechanically stirred for 1-2 hours, cooled to 1-10°C, and held for 1-2 hours. The mixture was filtered under reduced pressure and dried at 50°C to obtain cis-trans isomer mixture 9 (12.77g, yield: 74.64%, purity: 98.9%, water: 0.79%, and compound 9A: compound 4a = 1: 1.4).

[0138] Example 19: Preparation of Mixture 6Aa R-Lactic acid (13.2 g, 5 equiv.), cis-trans isomer mixture 9 (8 g, 1 equiv.), and methylcyclohexane (20 g) were combined and refluxed in a Dean-Stark apparatus until the IPC: isomeric intermediate amide was less than 3%. 24 mL of methanol was added dropwise and the reaction solution was cooled to room temperature. The methanol layer was separated and 15 mL of methanol was added. The reaction solution was cooled to less than 0°C and an aqueous solution of sodium hydroxide (4.72 g of sodium hydroxide and 11 g of water) was added dropwise and the resulting mixture was stirred until the reaction was complete. Dilute hydrochloric acid was added dropwise to adjust the pH to 7-8. The solvent was removed and 120 mL of water was added. The mixture was filtered. The resulting wet product was placed in 120 ml of water, stirred for 2 h, filtered, and dried at 50°C to give 5 g of solid. The filtrates were combined, extracted with dichloromethane (100 ml x 3), and concentrated to give 3.5 g of a solid. The solids were combined to give a mixture 6Aa (8.5 g, yield: 88.6%, compound 6Ab: compound 6A = 1:2).

[0139] Example 20: Preparation of compound 6A Mixture 6Aa (6.5 g) and potassium tert-butoxide solution (0.39 g, 10.5 mL tetrahydrofuran) were combined and stirred until isomer 6Ab was less than 2.85%. Dilute hydrochloric acid was added to adjust the pH to 6-7. The solvent was removed by rotary evaporation and 98 mL of water was added. The resulting mixture was stirred for 2 hours, filtered, and washed with water (20 ml x 2). The filter cake was collected and dried at 50 °C to obtain compound 6A (5.35 g). 5 g of compound 6A, 28.3 g of isopropanol, and 12 g of water were refluxed to obtain a clear solution. The reaction solution was cooled below 5 °C for 3 hours, filtered, and washed with mixed solvent to obtain 4.35 g of wet product. 28.3 g of isopropanol and 12 g of water were added to the wet product and refluxed to obtain a clear solution. The reaction solution was cooled to less than 5° C. for 3 hours and filtered to obtain compound 6A (3.5 g, purity: 99.62%, isomers: 0.49%, yield: 54%). 1 The 1 H NMR spectrogram is shown in FIG.

Claims

1. 1. A method for synthesizing a 1H-furo[3,2-b]imidazo[4,5-d]pyridine compound, comprising: Step 1: 【Chemistry 1】 reacting compound 1 with compound 2 or compound 2 hydrochloride in a solvent in the presence of a base to obtain compound 3; Step 2: 【Chemistry 2】 subjecting the compound 3 to a reduction reaction to obtain compound 4 or compound 4 hydrochloride; Step 3: 【Transformation 3】 subjecting compound 4 or compound 4 hydrochloride to a ring-closure reaction with compound 5 or compound 5′ to obtain compound 6 or a hydrate of compound 6, wherein R is methyl or ethyl, and said methyl or ethyl is optionally substituted by hydroxyl, preferably R is methyl or 1-hydroxyethyl; X=CH ２ , or O.

2. The compound 5 is R-lactic acid, and the step 3 is represented by the following formula: 【Chemistry 4】 subjecting Compound 4 or Compound 4 hydrochloride to a ring-closure reaction with R-lactic acid to obtain Compound 6A or Compound 6C, or a hydrate of Compound 6A or Compound 6C; or The compound 5' is acetic acid or acetic anhydride, and the step 3 is represented by the following formula: 【Transformation 5】 and subjecting the compound 4 or compound 4 hydrochloride to a ring-closure reaction with the acetic acid and / or acetic anhydride to obtain compound 6B or compound 6D.

3. The method according to claim 1, wherein step 1 has any one of the following characteristics (i) to (iv): (i) the base is an inorganic base, preferably the inorganic base is sodium carbonate, potassium bicarbonate, or sodium bicarbonate; (ii) the base is an organic base other than N,N-diisopropylethylamine, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); (iii) the base is N,N-diisopropylethylamine, and the solvent is a mixed solvent of ethanol and acetonitrile, preferably with a volume ratio of acetonitrile to ethanol of 1:0.8 to 1:1.2; (iv) the solvent is ethanol and / or acetonitrile, preferably, the solvent is ethanol or a mixed solvent of acetonitrile and ethanol, and the volume ratio of acetonitrile to ethanol is 1:0.8 to 1:1.2; the molar ratio of the compound 1 to the compound 2 is 1:0.8 to 1:1.2; When the compound 2 is in the form of a hydrochloride salt, the molar ratio of the compound 1 to the base is 1:2 to 1:2.5, preferably 1:2.1 to 1:2.3; When the compound 2 is in a salt-free form, the molar ratio of the compound 1 to the base is 1:1 to 1:1.5, preferably 1:1.1 to 1:1.3; the mass-to-volume ratio of compound 1 to the solvent is 1:9 to 1:10; the reaction of step 1 is optionally carried out under the protection of an inert gas; the reaction is carried out at a temperature of 50 to 80°C; After the reaction is completed, the reaction solution is cooled, stirred, filtered, and the filter cake is washed and dried to obtain the compound 3.

4. The reducing agent in step 2 is H ２ / a nitro reducing agent other than Pd, the reaction of step 2 is optionally carried out under the protection of an inert gas; the reaction is carried out at a temperature of 15 to 90°C; Preferably, the reducing agent in step 2 is Fe, B2(OH)4, or SnCl2; Optionally, in step 2, (i) When the reducing agent is Fe, the solvent used in the reduction reaction is acetonitrile, the molar ratio of the compound 3 to Fe is 1:6 to 1:9, the molar ratio of the compound 3 to acetic acid is 1:12 to 1:14, and the mass-to-volume ratio of the compound 3 to the solvent is 1:4 to 1:10, preferably 1:5 to 1:9; After the reaction is completed, the reaction solution is filtered, and the pH is adjusted to about 6 with sodium citrate solution, and then adjusted to 8-9 with diluted K 3 PO 4 solution. After concentration, Celite, water, and ethyl acetate are added to the reaction solution, the solution is filtered and separated into layers. The resulting aqueous phase is extracted with ethyl acetate. The resulting organic phases are combined and washed with sodium citrate aqueous solution and saturated brine respectively. Silica gel and anhydrous sodium sulfate are added. The solution is filtered, washed with ethyl acetate, concentrated, methyl tert-butyl ether is added, and the precipitate is filtered and dried to obtain compound 4; (ii) when the reducing agent is B2(OH)4; the solvent used in the reduction reaction is a mixed solvent of water and methanol, the volume ratio of water to methanol is 1:1 to 9:1, preferably 3:1 to 5:1, more preferably 4:1; the molar ratio of compound 3 to B 2 (OH) 4 is 1:3 to 1:5, preferably 1:3.5; the mass-to-volume ratio of compound 3 to the solvent is 1:4 to 1:10, preferably 1:5 to 1:9; B 2 (OH) 4 is added all at once; 4,4'-bipyridine is optionally added; After the reaction is completed, filter the reaction solution, wash the filter cake with dichloromethane, collect the filtrate, add sodium bicarbonate, stir the resulting system evenly, settle, separate the organic phase, extract the aqueous phase with dichloromethane, then combine the organic phases, dry with anhydrous sodium sulfate, add hydrochloric acid in ethanol solution dropwise, stir the resulting system evenly, add ethyl acetate dropwise, stir the resulting system evenly, filter, then rinse the filter cake with ethyl acetate and dry to obtain compound 4 hydrochloride; (iii) when the reducing agent is stannous chloride SnCl 2 ; the solvent used in the reduction reaction is ethyl acetate, the molar ratio of the compound 3 to stannous chloride is 1:2 to 1:9, preferably 1:3 to 1:6, and the mass-to-volume ratio of the compound 3 to the solvent is 1:4 to 1:20, preferably 1:5 to 1:15; 2. The method of claim 1, wherein after the reaction is completed, sodium bicarbonate is added, the resulting system is stirred, filtered, rinsed with ethyl acetate, and then the filtrate is collected and washed with saturated aqueous sodium bicarbonate solution, the resulting organic phases are combined, then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain compound 4.

5. In step 3, the ring-closure reaction is carried out in a solvent, and the solvent is toluene, dioxane, acetic acid, methylcyclohexane, or acetic anhydride; When the compound 4 is subjected to a ring-closure reaction with R-lactic acid, the molar ratio of the compound 4 to the R-lactic acid is 1:4 to 1:30, preferably 1:4 to 1:20, more preferably 1:4 to 1:10, and the mass-to-volume ratio of the compound 4 to the solvent is 1:1.5 to 1:40, preferably 1:1.5 to 1:30, more preferably 1:1.5 to 1:15; When the compound 4 is subjected to the ring-closure reaction with acetic anhydride or acetic acid, the acetic anhydride or acetic acid acts as a reaction reagent and a solvent at the same time, and the mass-to-volume ratio of the compound 4 to the acetic anhydride or acetic acid is 1:1 to 1:10, preferably 1:2 to 1:5; In the ring-closure reaction between the compound 4 and the compound 5 or the compound 5′, an acid catalyst is optionally added, and the acid catalyst is preferably methanesulfonic acid; The reaction is carried out at a temperature of 80 to 120°C, 3. The method of claim 2, wherein after the reaction is completed, the reaction solution is cooled and extracted, the pH is adjusted to 7-10, and the resulting solid is dried to obtain compound 6 or a hydrate of compound 6.

6. The method of claim 2, having any of the following features (i) to (vi): (i) in the method for synthesizing compound 6A, in step 3, compound 4 is compound 4a; the ring-closure reaction is carried out in a solvent, the solvent being toluene, dioxane, or methylcyclohexane, preferably toluene or methylcyclohexane, more preferably methylcyclohexane; the molar ratio of compound 4a to R-lactic acid is 1:4 to 1:30, preferably 1:4 to 1:20, more preferably 1:4 to 1:10, and most preferably 1:5 to 1:7; the mass-to-volume ratio (g / mL) of compound 4a to the solvent is 1:1.5 to 1:40, preferably 1:1.5 to 1:30, more preferably 1:1.5 to 1:15, and most preferably 1:1.5 to 1:5; After the reaction is completed, methanol is added, the methanol layer is separated, sodium hydroxide solution is added with stirring, then hydrochloric acid is added dropwise to adjust the pH to about 7, the solvent is removed under reduced pressure, water is added with stirring, the solid is filtered, washed with water and dried to obtain compound 6A; (ii) in the method for synthesizing compound 6C, in step 3, compound 4 is compound 4b; the ring-closure reaction is carried out in a solvent, the solvent being toluene, dioxane, or methylcyclohexane, preferably toluene or methylcyclohexane, more preferably methylcyclohexane; the molar ratio of compound 4b to R-lactic acid is 1:4 to 1:30, preferably 1:4 to 1:20, more preferably 1:4 to 1:10, and most preferably 1:5 to 1:7; the mass-to-volume ratio (g / mL) of compound 4B to the solvent is 1:1.5 to 1:40, preferably 1:1.5 to 1:30, more preferably 1:1.5 to 1:15, and most preferably 1:1.5 to 1:5; After the reaction is completed, methanol is added, the methanol layer is separated, sodium hydroxide solution is added with stirring, then hydrochloric acid is added dropwise to adjust the pH to about 7, the solvent is removed under reduced pressure, water is added with stirring, the solid is filtered, washed with water and dried to obtain compound 6C; (iii) in the method for synthesizing compound 6B, in step 3, compound 4 is compound 4a; When the compound 4a is subjected to the ring-closure reaction with acetic anhydride, acetic acid or sodium acetate is optionally added, and the molar ratio of the compound 4a to the acetic acid is 1:0.1 to 1:0.5, preferably 1:0.2 to 1:0.3, and the molar ratio of the compound 4a to the sodium acetate is 1:0.2 to 1:1; When the compound 4a is subjected to the ring-closure reaction with acetic acid, sodium acetate is optionally added, and the molar ratio of the compound 4a to the sodium acetate is 1:1 to 1:3; (iv) in the method for synthesizing compound 6B, in step 3, compound 4 is compound 4a; When the compound 4a is subjected to the ring-closure reaction with acetic anhydride, the mass-to-volume ratio of the compound 4a to the acetic anhydride is 1:2 to 1:5; when the compound 4a is subjected to a ring-closure reaction with acetic acid, the mass-to-volume ratio of the compound 4a to the acetic acid is 1:3 to 1:8; the reaction is carried out at a temperature of 80 to 120°C, preferably 90 to 110°C, After the reaction is completed, add methyl tert-butyl ether, stir the resulting system evenly, and filter. Dissolve the filter cake in a mixed solvent of water and dichloromethane, and add NaOH aqueous solution dropwise to adjust the pH to 7-10. Then, separate the reaction solution into layers, extract the resulting aqueous layer with dichloromethane, combine the resulting organic layers, dry with anhydrous Na 2 SO 4 , filter, concentrate, add ethanol and water with stirring, filter, and then dry the filter cake to obtain compound 6B; (v) in the method for synthesizing compound 6D, in step 3, compound 4 is compound 4b; When the compound 4b is subjected to the ring-closure reaction with acetic anhydride, acetic acid or sodium acetate is optionally added, and the molar ratio of the compound 4b to the acetic acid is 1:0.1 to 1:0.5, preferably 1:0.2 to 1:0.3, and the molar ratio of the compound 4b to the sodium acetate is 1:0.2 to 1:1, preferably 1:0.4 to 1:0.8; When the compound 4b is subjected to the ring-closure reaction with acetic acid, sodium acetate is optionally added, and the molar ratio of the compound 4b to the sodium acetate is 1:1 to 1:3, preferably 1:1.5 to 1:2.5; (vi) in the method for synthesizing compound 6D, in step 3, compound 4 is compound 4b; When the compound 4b is subjected to the ring-closure reaction with acetic anhydride, the mass-to-volume ratio of the compound 4b to the acetic anhydride is 1:2 to 1:5; when the compound 4b is subjected to the ring-closure reaction with acetic acid, the mass-to-volume ratio of the compound 4b to the acetic acid is 1:3 to 1:8; the reaction is carried out at a temperature of from 80°C to 120°C, preferably from 90°C to 110°C; After the reaction is completed, methyl tert-butyl ether is added, the resulting system is stirred evenly and filtered, the filter cake is dissolved in a mixed solvent of water and dichloromethane, and aqueous NaOH solution is added dropwise to adjust the pH to 7-10, the reaction solution is then separated into layers, the resulting aqueous layer is extracted with dichloromethane, the resulting organic phases are combined, dried over anhydrous Na 2 SO 4 , filtered, concentrated, ethanol and water are added with stirring, filtered, and the filter cake is then dried to obtain compound 6D.

7. The compound 1 is Step 1-1: 【Transformation 6】 reacting compound 1-1 with triphenylphosphine to obtain compound 1-2; Step 1-2: 【Transformation 7】 reacting said compound 1-2 with ethyl formate to obtain compound 1-3; Step 1-3: 【Transformation 8】 subjecting said compound 1-3 to a demethylation and acetalization reaction to obtain compound 1-4; Step 1-4: 【Chemistry 9】 subjecting compound 1-4 to a ring-closure reaction under acidic conditions to obtain compound 1-5; Step 1-5: 【Chemistry 10】 subjecting the compound 1-5 to a nitration reaction to obtain a compound 1-6; Step 1-6: 【Chemistry 11】 The method of claim 1, wherein compound 1 is synthesized by subjecting compound 1-6 to a chloro substitution reaction to obtain compound 1.

8. In the method for synthesizing Compound 1, In step 1-1, 【Chemistry 12】 Sodium carbonate is added to a mixture of the compound 1-1, toluene and water, the resulting system is stirred at room temperature and separated into layers, the resulting aqueous phase is extracted with toluene, the resulting organic phase is washed with saturated brine, dried with anhydrous sodium sulfate, filtered, triphenylphosphine is added to the filtrate, and the resulting system is heated at 110-120°C using a Dean-Stark apparatus, and then after the reaction is completed, the reaction solution is cooled to 20-30°C and filtered, and the resulting wet product is dried under reduced pressure to obtain the compound 1-2, In step 1-2, 【Chemistry 13】 Add alkali metal tert-butoxide to the mixture of compound 1-2 and dimethyl sulfoxide, stir the resulting system evenly at room temperature, add ethyl formate dropwise, and stir the reaction solution at 40-50°C. After the reaction is completed, cool the reaction solution to room temperature, add the reaction solution to an organic solvent and water for extraction, wash the resulting organic phase with water, adjust the pH to 5-6 with hydrochloric acid, separate the layers, extract the resulting aqueous phase with an organic solvent, adjust the pH to 8 or more with a base, separate the layer, extract the resulting aqueous phase with an organic solvent, combine the resulting organic phases, wash with water, dry with anhydrous sodium sulfate, filter, and concentrate to obtain compound 1-3. In the steps 1-3, 【Chemistry 14】 Boron tribromide is added dropwise to the mixture of compound 1-3 and dichloromethane. After the dropwise addition, the reaction solution is stirred at 20-30°C. The reaction solution is added dropwise to ethanol, stirred evenly, and concentrated under reduced pressure. After the addition of ethanol, the solution is concentrated under reduced pressure, and the pH is adjusted to 5-6 by dropwise addition of an ethanol solution of sodium ethoxide. Filtering is performed. The filter cake is rinsed with ethanol. The ethanol solution of sodium ethoxide is added dropwise to the filtrate to adjust the pH to 8-9. The solvent is removed under reduced pressure. Methyl tert-butyl ether is added. The resulting system is stirred evenly, filtered, and then the filter cake is rinsed with methyl tert-butyl ether and dried to obtain compound 1-4. In the steps 1-4, 【Chemistry 15】 Add benzoyl chloride dropwise to the dichloromethane solution of compound 1-4, and after the dropwise addition, stir the resulting system evenly. Add the reaction solution dropwise to concentrated sulfuric acid, and stir the resulting system evenly. Then add the reaction solution dropwise to water. Filter the resulting system, adjust the pH of the filtrate to 7-8, and after the dropwise addition, stir the reaction solution evenly, filter, and then rinse the filter cake with water and dry to obtain compound 1-5. In the steps 1-5, 【Chemistry 16】 Nitric acid is added dropwise to the mixed solution of acetic acid and acetic anhydride, and after the dropwise addition, the resulting mixture is stirred evenly; the mixed solution of acetic acid, acetic anhydride and nitric acid is added dropwise to the acetic acid solution of compound 1-5, and after the dropwise addition, the resulting system is stirred evenly; then, after the reaction is completed, methyl tert-butyl ether is added to the reaction solution, and the resulting system is stirred evenly and filtered; then, the filter cake is rinsed with methyl tert-butyl ether and dried to obtain compound 1-6; In the steps 1-6, 【Chemistry 17】 The method of claim 7, wherein phosphorus oxychloride is added dropwise to a mixture of compound 1-6, N,N-dimethylformamide and toluene, the resulting system is stirred at 35 to 75°C, and after the reaction is completed, the reaction solution is cooled to room temperature, toluene is removed, dichloromethane and an aqueous potassium carbonate solution or an aqueous sodium bicarbonate solution are added, the system is separated into layers, and the resulting organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 1.

9. The method of claim 7, wherein the steps have at least one of the following characteristics (i) to (vi): (i) In step 1-1, In the mixture of compound 1-1, toluene, and water, the mass-to-volume ratio of compound 1-1 to toluene and water is 1:5 to 1:6, and the volume ratio of toluene to water is 8:1 to 9:1; the molar ratio of the compound 1-1 to sodium carbonate is 1:1.1 to 1:1.2; the molar ratio of the compound 1-1 to triphenylphosphine is 1:1.1 to 1:1.2; The reaction of step 1-1 is optionally carried out under the protection of an inert gas; (ii) In step 1-2, the alkali metal tert-butoxide is potassium tert-butoxide or sodium tert-butoxide; the base used to adjust the pH is aqueous ammonia or sodium carbonate; the organic solvent used for extraction is methyl tert-butyl ether or ethyl acetate; the mass-to-volume ratio of the compound 1-2 to dimethyl sulfoxide is 1:3 to 1:5; the molar ratio of the compound 1-2 to the alkali metal tert-butoxide is 1:1.05 to 1:1.15, preferably 1:1.1; the molar ratio of the compound 1-2 to ethyl formate is 1:4 to 1:5; The reaction of step 1-2 is optionally carried out under the protection of an inert gas; (iii) In the steps 1-3, the mass-to-volume ratio of the compound 1-3 to dichloromethane is 1:6 to 1:10; the molar ratio of the compound 1-3 to boron tribromide is 1:2.0 to 1:3.5, preferably 1:2.5 to 1:3.2; The reactions of steps 1-3 are optionally carried out under the protection of an inert gas. (iv) In steps 1-4, the mass-to-volume ratio of the compound 1-4 to concentrated sulfuric acid is 1:2 to 1:5; the mass-to-volume ratio of compound 1-4 to dichloromethane is 1:25 to 1:26; The molar ratio of the compound 1-4 to benzoyl chloride is 1:1.5 to 1:2.5, preferably 1:2; (v) In steps 1-5, the mass ratio of the compound 1-5 to the acetic acid in the acetic acid solution of the compound 1-5 is 1:9 to 1:11, preferably 1:10; the mass ratio of the compound 1-5 to the acetic acid in the mixed solution of acetic acid, acetic anhydride, and nitric acid is 1:3 to 1:5; the molar ratio of the compound 1-5 to acetic anhydride is 1:2 to 1:5, preferably 1:2.6 to 1:4.2; the molar ratio of the compound 1-5 to nitric acid is 1:2 to 1:5, preferably 1:2.5 to 1:4.0; The reactions of steps 1-5 are optionally carried out under inert gas protection; and (vi) In steps 1-6, the molar ratio of the compound 1-6 to N,N-dimethylformamide is 1:1 to 1:1.2; the mass-to-volume ratio of the compound 1-6 to toluene is 1:9 to 1:11, preferably 1:10; the molar ratio of the compound 1-6 to phosphorus oxychloride is 1:1.8 to 1:2.2, preferably 1:2; The reactions of steps 1-6 above are optionally carried out under the protection of an inert gas.

10. When the compound 2 is compound 2a, compound 2a hydrochloride is Step 2-1: [Chemistry 18] Compound 2-1 is subjected to a ring-closure reaction under the catalysis of sodium methoxide to obtain compound 2-2, Step 2-2: 【Chemistry 19】 2. The method of claim 1, wherein compound 2-2 is synthesized by reacting compound 2-2 with hydrochloric acid to obtain compound 2a hydrochloride.

11. In the method for synthesizing compound 2a hydrochloride, In step 2-1, 【Chemistry 20】 The methanol solution of sodium methoxide is added dropwise to the mixture of compound 2-1 and tetrahydrofuran, and after the dropwise addition, the resulting system is stirred evenly. After the reaction is completed, ammonium chloride solution is added dropwise to the reaction solution to adjust the pH to 7-8. The mixture is extracted with methyl tert-butyl ether, washed with sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and dried to obtain compound 2-2. In step 2-2, 【Chemistry 21】 The method of claim 10, wherein an ethanol solution of hydrogen chloride is added dropwise to a mixture of compound 2-2 and dichloromethane, the resulting system is stirred evenly after the dropwise addition, and filtered after the reaction is completed, and the filter cake is rinsed with dichloromethane and dried to obtain compound 2a hydrochloride.

12. In step 2-1, the mass-to-volume ratio of the compound 2-1 to tetrahydrofuran is 1:10 to 1:12, preferably 1:10 to 1:11; the molar ratio of the compound 2-1 to sodium methoxide in the methanol solution is 1:0.2 to 1:0.3, preferably 1:0.25; The reaction of step 2-1 is optionally carried out under the protection of an inert gas, and / or In step 2-2, the mass-to-volume ratio of compound 2-2 to dichloromethane is 1:5 to 1:7, preferably 1:6; the molar ratio of the compound 2-2 to hydrogen chloride in the ethanol solution is 1:2 to 1:5, preferably 1:3; The method of claim 10, wherein the reaction of step 2-2 is optionally carried out under the protection of an inert gas.

13. 1. A method for synthesizing a 1H-furo[3,2-b]imidazo[4,5-d]pyridine compound, comprising: Step 1A: 【Chemistry 22】 reacting compound 1 with cis-trans isomer mixture 7 in a solvent in the presence of a base to obtain cis-trans isomer mixture 8; Step 2A: 【Chemistry 23】 subjecting the cis-trans isomer mixture 8 to a reduction reaction to obtain a cis-trans isomer mixture 9 or a cis-trans isomer mixture 9 hydrochloride; Step 3A: 【Chemistry 24】 subjecting the cis-trans isomer mixture 9 or the cis-trans isomer mixture 9 hydrochloride to a ring-closure reaction with compound 5 or compound 5' to obtain mixture 10 or a hydrate of mixture 10, wherein R is methyl or ethyl, and the methyl or ethyl is optionally substituted by hydroxyl, preferably R is methyl or 1-hydroxyethyl; Step 4A: 【Chemistry 25】 and subjecting the mixture 10 or the hydrate of the mixture 10 to an isomerization reaction under basic conditions to obtain compound 6 or a hydrate of compound 6.

14. The method of claim 13, having at least one of the following characteristics (i) to (iii): (i) the reaction conditions of step 1A are as defined in claim 3; (ii) the reaction conditions of step 2A are as defined in claim 4; (iii) The reaction conditions of step 3A are as defined in any one of claims 2, 5 and 6.

15. Step 4A (a) 【Chemistry 26】 subjecting mixture 6Aa or a hydrate of mixture 6Aa to an isomer conversion reaction under basic conditions to obtain a hydrate of compound 6A; or (b) 【Chemistry 27】 subjecting the mixture 6Ba or the mixture 6Ba hydrochloride to an isomer conversion reaction under basic conditions to obtain compound 6B; the base is preferably an alkoxide base, more preferably an alkali metal C 1-6 alkoxide, most preferably potassium tert-butoxide, and optionally In the method for synthesizing the hydrate of compound 6A, in step 4A, the reaction is carried out in a solvent, said solvent being preferably tetrahydrofuran; the molar ratio of the mixture 6Aa to the base is 1:0.05 to 1:0.2, preferably 1:0.1 to 1:0.2; the reaction is carried out at room temperature; After the reaction is complete, dilute hydrochloric acid is added to adjust the pH to 6-7, the solvent is removed by rotary evaporation, water is added with stirring, the mixture is filtered, washed with water, and the filter cake is collected and dried to obtain the hydrate form of compound 6A; and In the method for synthesizing compound 6B, in step 4A, the reaction is carried out in a solvent, said solvent being preferably tetrahydrofuran; the molar ratio of the mixture 6Ba to the base is 1:0.05 to 1:0.2, preferably 1:0.1 to 1:0.2; the reaction is carried out at room temperature; 14. The method of claim 13, wherein after the reaction is complete, dilute hydrochloric acid is added to adjust the pH to 6-7, the solvent is removed by rotary evaporation, water is added with stirring, the mixture is filtered, washed with water, and the filter cake is collected and dried to obtain compound 6B.

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