Method for synthesizing 1H-furo[3,2-b]imidazo[4,5-d]pyridine compound

Abstract

The present invention provides a method for synthesizing a 1H-furo[3,2-b]imidazo[4,5-d]pyridine compound, the method comprising the following steps: reacting a compound 1 with a compound 2 in a solvent in the presence of a base to obtain a compound 3, reducing the compound 3 in a reduction reaction to obtain a compound 4, reacting the compound 4 with a compound 5 or compound 5' in a ring-closing reaction to obtain a compound 6 or a hydrate thereof, wherein R is methyl or ethyl, and the methyl or ethyl is optionally substituted with hydroxy, X=O or CH2. The method for synthesizing the 1H-furo[3,2-b]imidazo[4,5-d]pyridine compound of the present invention has a high yield and few impurities, and is easy to control, low cost, simple and convenient to operate, and suitable for industrial scale.

Description

Synthesis method of 1H-furo[3,2-b]imidazo[4,5-d]pyridine compound Technical Field

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

[0002] 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 relative to other related kinases. Therefore, they are expected to be useful in treating diseases mediated by the selectively inhibited one or more kinases while avoiding the adverse side effects associated with the inhibition of other kinases. For example, they can be used to treat disorders related to JAK1 / TYK2 activity, such as autoimmune diseases or disorders, or inflammatory diseases or disorders, as well as cancer or tumor diseases or disorders.

[0003] Existing synthesis methods for such compounds are costly and complex, making them unsuitable for industrial scale production (WO 2018 / 067422 A1, WO 2020 / 244348 A1, WO 2020 / 244349 A1). Consequently, there is a need to develop a method for synthesizing 1H-furo[3,2-b]imidazo[4,5-d]pyridine compounds that is both high in yield and low in impurities, easily controllable, cost-effective, and simple to operate, making it suitable for industrial scale production.

[0004] Summary of the Invention

[0005] 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 is cost-effective, simple to operate and suitable for industrial scale.

[0006] In order to achieve the above object, the present invention adopts the following technical solutions:

[0007] A method for synthesizing a 1H-furo[3,2-b]imidazo[4,5-d]pyridine compound (hereinafter referred to as "Synthesis Route 1") comprises the following steps:

[0008] Step 1:

[0009]

[0010] Compound 1 reacts with compound 2 or its hydrochloride in the presence of a base in a solvent to obtain compound 3;

[0011] Step 2:

[0012]

[0013] Compound 3 is subjected to reduction reaction to obtain compound 4 or its hydrochloride;

[0014] Step 3:

[0015]

[0016] Compound 4 or its hydrochloride is reacted with compound 5 or compound 5' through a ring-closure reaction to obtain compound 6 or a hydrate of compound 6, wherein R is a methyl or ethyl group, wherein the methyl or ethyl group is optionally substituted with a hydroxy group, preferably, R is a methyl group or a 1-hydroxyethyl group; X = CH2, or O; the hydrate of compound 6 is preferably a monohydrate.

[0017] According to an embodiment of the present invention, in step 1,

[0018] The base is an organic base other than N,N-diisopropylethylamine, wherein the organic base is preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); alternatively, the base is an inorganic base, wherein the inorganic base is preferably sodium carbonate (Na2CO3), potassium bicarbonate (KHCO3) or sodium bicarbonate (NaHCO3), more preferably sodium bicarbonate (NaHCO3); or the base is N,N-diisopropylethylamine.

[0019] The solvent is ethanol and / or acetonitrile, preferably, the solvent is ethanol, or a mixed solvent of acetonitrile and ethanol, wherein the volume ratio of acetonitrile to ethanol (mL / mL, or L / L) is 1:0.8 to 1:1.2, preferably 1:1;

[0020] The molar 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, 1:1.2;

[0021] When compound 2 is a hydrochloride salt, the molar ratio of compound 1 to the 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;

[0022] When compound 2 is in a salt-free form, the molar ratio of compound 1 to the base is 1:1 to 1:1.5, preferably 1:1.1 to 1:1.3;

[0023] The mass volume ratio (g / mL) of compound 1 to solvent was 1:9 to 1:10;

[0024] The reaction in step 1 is optionally carried out under the protection of an inert gas (e.g., nitrogen);

[0025] The reaction temperature is 50-80°C and the reaction time is 16-22h;

[0026] After the reaction is completed, the reaction solution is cooled, stirred, filtered, and the filter cake is washed and dried to obtain the product (for example, after the reaction is completed, the reaction solution is cooled to 20-30°C, water is added, and the mixture is stirred at this temperature for 0.5-2h, cooled to 0-15°C, stirred at this temperature for 2-4h, filtered, and the filter cake is washed and dried to obtain the product).

[0027] According to an embodiment of the present invention, in step 2,

[0028] The reducing agent used in the reduction reaction is a nitro reducing agent other than H2 / Pd;

[0029] The reducing agent used in the reduction reaction is Fe / acetic acid, or B2(OH)4, or SnCl2;

[0030] When the reducing agent is Fe / acetic acid, the solvent used in the reduction reaction is acetonitrile; the molar ratio of compound 3 to Fe is 1:6 to 1:9, and the molar ratio of compound 3 to acetic acid is 1:12 to 1:14; the mass volume ratio (g / mL) of compound 3 to solvent is 1:4 to 1:10, preferably 1:5 to 1:9;

[0031] When the reducing agent is B2(OH)4, the solvent used for the reduction reaction is a mixed solvent of water and methanol, wherein the volume ratio of water to methanol (mL / mL, or L / L) is 1:1 to 9:1, preferably 3:1 to 5:1, and more preferably 4:1; the molar ratio of compound 3 to B2(OH)4 is 1:3 to 1:5; preferably 1:3.5; the mass volume ratio of compound 3 to solvent (g / mL) is 1:4 to 1:10, preferably 1:5 to 1:9; and B2(OH)4 is fed in batches;

[0032] When the reducing agent is SnCl2, the solvent used in the reduction reaction is ethyl acetate, wherein the molar ratio of compound 3 to SnCl2 is 1:2 to 1:9, preferably 1:3 to 1:6; the mass volume ratio (g / mL) of compound 3 to the solvent is 1:4 to 1:20, preferably 1:5 to 1:15;

[0033] In the case where the reducing agent is B2(OH)4, 4,4'-bipyridine is optionally added;

[0034] The reaction in step 2 is optionally carried out under the protection of an inert gas (e.g., nitrogen);

[0035] The reaction temperature is 15-90°C and the reaction time is 1-18h;

[0036] When the reducing agent is Fe / acetic acid, after the reaction is completed, the mixture is filtered while hot, rinsed with hot acetonitrile, and the pH is adjusted to about 6 (e.g., pH to 6) with sodium citrate solution, and the pH is adjusted to 8-9 with K3PO4 solution (e.g., 30% K3PO4 solution). After concentration, diatomaceous earth, water, and ethyl acetate are added, filtered, and the layers are separated. The aqueous phase is extracted with ethyl acetate, and the organic phases are combined and washed with sodium citrate aqueous solution and brine, respectively. Silica gel and anhydrous sodium sulfate are added and filtered, and the filter residue is rinsed with ethyl acetate and concentrated. Methyl tert-butyl ether is added to precipitate a solid, which is filtered and dried to obtain compound 4.

[0037] When the reducing agent is B2(OH)4, after the reaction is completed, the temperature is lowered to 35-45°C, part of the solvent is concentrated under reduced pressure, the temperature is lowered to 0-10°C and stirred, filtered, the filter cake is rinsed with dichloromethane, the filtrate is collected and sodium bicarbonate is added in batches at 20-30°C, and the mixture is stirred at this temperature. The mixture is allowed to stand, the organic phase is separated, the aqueous phase is extracted with dichloromethane, the organic phases are combined, the organic phases are dried over anhydrous sodium sulfate, and an ethanol solution of hydrochloric acid is added dropwise at 15-25°C, the mixture is stirred at this temperature, ethyl acetate is added dropwise at 15-25°C and stirred at this temperature, filtered, the filter cake is rinsed with ethyl acetate, and dried to obtain the hydrochloride salt of compound 4;

[0038] When the reducing agent is SnCl2, after the reaction is completed, the temperature is cooled to room temperature, sodium bicarbonate is added in an ice bath, stirred, and filtered. The filter cake is rinsed with ethyl acetate, and the filtrate is collected and washed three times with a saturated sodium bicarbonate aqueous solution. The organic phases are combined, and then washed three times with saturated brine. The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain compound 4.

[0039] According to an embodiment of the present invention, in step 3,

[0040] Compound 5 is R-lactic acid Compound 5' is acetic acid or acetic anhydride;

[0041] The ring-closure reaction is carried out in a solvent, wherein the solvent is toluene, dioxane, acetic acid, methylcyclohexane or acetic anhydride;

[0042] In the case of a ring-closing reaction between compound 4 and 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; the mass 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;

[0043] In the case of a ring-closing reaction of compound 4 with acetic anhydride or acetic acid, acetic anhydride or acetic acid acts as both a reagent and a solvent, and the mass 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;

[0044] An acid catalyst is optionally added to the ring-closure reaction of compound 4 with compound 5 or compound 5', wherein the acid catalyst is preferably methanesulfonic acid;

[0045] In the ring-closure reaction of compound 4 and compound 5', acetic acid (AcOH) or sodium acetate (NaOAc) is optionally added when the reaction reagent / solvent is acetic anhydride;

[0046] In the ring-closure reaction of compound 4 and compound 5', sodium acetate (NaOAc) is optionally added when the reaction reagent / solvent is acetic acid;

[0047] The reaction temperature is 80-120°C, and the reaction time is 5-24h, preferably 16-18h;

[0048] After the reaction is completed, the mixture is cooled, extracted, the pH is adjusted to 7-10, and the obtained solid is dried to obtain the product.

[0049] 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 (using "Synthetic Route 1" for synthesizing compounds 6A, 6C, or hydrates thereof, preferably monohydrates), comprising the following steps:

[0050] Step 1:

[0051]

[0052] Compound 1 reacts with compound 2 or its hydrochloride in the presence of a base in a solvent to obtain compound 3;

[0053] Step 2:

[0054]

[0055] Compound 3 is subjected to reduction reaction to obtain compound 4 or its hydrochloride;

[0056] Step 3:

[0057]

[0058] Compound 4 or its hydrochloride is reacted with R-lactic acid through a ring-closure reaction to obtain compounds 6A, 6C, or their hydrates.

[0059] According to an embodiment of the present invention, in the synthesis method of compound 6A, 6C or a hydrate thereof, steps 1 and 2 are as described above, and in step 3,

[0060] The ring-closure reaction is carried out in a solvent, wherein the solvent is toluene, dioxane, or methylcyclohexane, preferably toluene or methylcyclohexane, more preferably methylcyclohexane;

[0061] 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;

[0062] The mass 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;

[0063] Reflux and separate water at 87-110℃ for 5-24h;

[0064] After the reaction is completed, methanol is added, the liquid is separated to obtain a methanol layer, sodium hydroxide solution is added and stirred, hydrochloric acid is added dropwise until the pH is about 7, the solvent is removed under reduced pressure, water is added and stirred, 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 mixture is cooled to 20-30°C, methanol (for example, 3 times the volume) is added and stirred, the liquid is separated to obtain a methanol layer, the mixture is cooled to -10-0°C, sodium hydroxide solution is added and stirred, hydrochloric acid is added dropwise until the pH is about 7, the solvent is removed under reduced pressure, water is added and stirred, the solid is filtered, washed with water, and dried to obtain compound 6A).

[0065] 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 (using "Synthetic Route 1" for synthesizing compound 6B or 6D), comprising the following steps:

[0066] Step 1:

[0067]

[0068] Compound 1 reacts with compound 2 or its hydrochloride in the presence of a base in a solvent to obtain compound 3;

[0069] Step 2:

[0070]

[0071] Compound 3 is subjected to reduction reaction to obtain compound 4 or its hydrochloride;

[0072] Step 3:

[0073]

[0074] Compound 4 or its hydrochloride is reacted with acetic anhydride and / or acetic acid through a ring-closure reaction to obtain compound 6B or 6D.

[0075] According to an embodiment of the present invention, in the synthesis method of compound 6B or 6D, steps 1 and 2 are as described above, and in step 3,

[0076] When compound 4 is subjected to the ring-closure reaction with acetic anhydride, acetic acid or sodium acetate is optionally added, wherein 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;

[0077] In the case of the ring-closure reaction of compound 4 with acetic acid, sodium acetate is optionally added, wherein 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;

[0078] In the case of the ring-closure reaction of compound 4 and acetic anhydride, the mass volume ratio of compound 4 to acetic anhydride is 1:2 to 1:5, preferably 1:3;

[0079] In the case of the ring-closure reaction of compound 4 with acetic acid, the mass volume ratio of compound 4 to acetic acid is 1:3 to 1:8, preferably 1:5;

[0080] The reaction temperature is 80-120°C, preferably 90-110°C, and the reaction time is 12-24h, preferably 12-18h;

[0081] After the reaction is completed, methyl tert-butyl ether is added, stirred evenly, filtered, and the filter cake is dissolved in a mixed solvent of water and dichloromethane, and a NaOH aqueous solution is added dropwise to pH = 7-10, the layers are separated, the aqueous layer is extracted with dichloromethane, the organic phases are combined, dried over anhydrous Na2SO4, filtered, concentrated, and ethanol is added, water is added and stirred, filtered, and the filter cake is dried to obtain compound 6B or 6D (for example, in the reaction for synthesizing compound 6B, methyl tert-butyl ether is added after the reaction is completed, stirred evenly at 0-10°C, filtered, the filter cake is dissolved in a mixed solvent of water and dichloromethane, a 10% NaOH aqueous solution is added dropwise to pH = 7-10, the layers are separated, the aqueous layer is extracted with dichloromethane, the organic phases are combined, dried over anhydrous Na2SO4, filtered, concentrated, and ethanol is added, the solution is dissolved at 45-55°C, the temperature is lowered to 0-10°C to precipitate, water is added and stirred, filtered, and the filter cake is dried to obtain compound 6B).

[0082] According to an embodiment of the present invention, the present invention further provides a method for synthesizing compound 1, comprising the following steps:

[0083] Step 1-1:

[0084]

[0085] Compound 1-1 reacts with triphenylphosphine to obtain compound 1-2;

[0086] Step 1-2:

[0087]

[0088] Compound 1-2 reacts with ethyl formate to obtain compound 1-3;

[0089] Steps 1-3:

[0090]

[0091] Compound 1-3 is subjected to demethylation reaction and acetalization reaction to obtain compound 1-4;

[0092] Steps 1-4:

[0093]

[0094] Compound 1-4 is cyclized under acidic conditions to give compound 1-5;

[0095] Steps 1-5:

[0096]

[0097] Compound 1-5 is subjected to nitration reaction to obtain compound 1-6;

[0098] Steps 1-6:

[0099]

[0100] Compound 1-6 is substituted with chlorine to obtain compound 1.

[0101] According to an embodiment of the present invention, in the synthesis method of compound 1, preferably,

[0102] In step 1-1:

[0103]

[0104] Sodium carbonate was added in batches to a mixture of compound 1-1, toluene and water, stirred at room temperature, separated, the aqueous phase was extracted with toluene, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and triphenylphosphine was added to the filtrate. The temperature was raised to 110-120°C (preferably 108-115°C), a water separator was added, and the reaction solution was refluxed for 14-20h (preferably 16-18h). After the reaction was completed, the reaction solution was cooled to 20-30°C, filtered, rinsed with toluene, and the wet product was evaporated under reduced pressure to obtain compound 1-2;

[0105] In steps 1-2:

[0106]

[0107] The mixture of compound 1-2 and dimethyl sulfoxide was cooled to 18-25°C, tert-butoxide metal salt was added in batches while controlling the temperature at 20-35°C, and stirred at room temperature for 1-2 hours after the addition was complete. Ethyl formate was added dropwise, and the reaction solution was heated to 40-50°C and stirred at this temperature for 8-12 hours. After the reaction was completed, the reaction solution was cooled to room temperature and extracted with an organic solvent and water. The layers were separated, and the organic phase was washed with water. The pH was adjusted to 5-6 with hydrochloric acid. The layers were separated, and the aqueous phase was extracted with an organic solvent. The pH was adjusted to ≥8 with a base. The layers were separated, and the aqueous phase was extracted with an organic solvent. The organic phases were combined, washed with water, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and the solvent was removed to obtain compound 1-3.

[0108] In steps 1-3:

[0109]

[0110] The mixture of compound 1-3 and dichloromethane was cooled to 10-20°C, and boron tribromide was added dropwise, and the temperature was controlled at 20-30°C during the addition. After the addition was completed, the reaction solution was kept stirred at 20-30°C for 1-1.5h, and the reaction solution was slowly added dropwise to ethanol, and the quenching temperature was controlled at 10-35°C. After the addition was completed, the mixture was stirred for 0.5-2.5h. The solvent was removed under reduced pressure, ethanol was added, and the solvent was removed under reduced pressure. The mixture was cooled to 15-20°C, and sodium ethanol ethanol solution was added dropwise, and the temperature was controlled at 15-30°C until the pH of the material reached 5-6, and the addition was stopped. The mixture was filtered and the filter cake was rinsed with ethanol. The sodium ethanol ethanol solution was added dropwise to the filtrate, and the temperature was controlled at 15-30°C until the pH of the material reached 8-9, and the addition was stopped. The solvent was removed under reduced pressure, and methyl tert-butyl ether was added. The mixture was cooled to 5-15°C, stirred for 0.5-1h, filtered, and the filter cake was rinsed with methyl tert-butyl ether and dried to obtain compound 1-4.

[0111] In steps 1-4:

[0112]

[0113] Benzoyl chloride was added dropwise to a dichloromethane solution of compound 1-4, with the temperature controlled at 0-10°C during the addition. After the addition was completed, the mixture was stirred at 0-10°C for 1-1.5 hours. The reaction solution was added dropwise to concentrated sulfuric acid, with the temperature controlled at 15-25°C during the addition. The mixture was stirred at 15-25°C for 0.5-1.5 hours. The reaction solution was added dropwise to water, with the temperature controlled at no more than 25°C during the addition. The mixture was filtered, and the filtrate was added dropwise to ammonia water (adjusted to pH 7-8). After the addition was completed, the mixture was stirred for 0.5-1 hour, filtered, and the filter cake was rinsed with water and dried to obtain compound 1-5.

[0114] In steps 1-5:

[0115]

[0116] Nitric acid was added dropwise to a mixture of acetic acid and acetic anhydride, with the temperature controlled at 15-30°C during the addition. After the addition was completed, the mixture was stirred at 20-30°C for uniformity. The mixture of acetic acid, acetic anhydride, and nitric acid was added dropwise to the acetic acid solution of compound 1-5, with the temperature controlled at 110-120°C during the addition. After the addition was completed, the mixture was stirred for 1-1.5 hours. After the reaction was completed, the temperature was lowered to 20-30°C. Methyl tert-butyl ether was added to the reaction solution, stirred for uniformity, and filtered. The filter cake was rinsed with methyl tert-butyl ether and dried to obtain compound 1-6.

[0117] In steps 1-6:

[0118]

[0119] Phosphorus oxychloride was added dropwise to a mixture of compound 1-6, N,N-dimethylformamide, and toluene. After the addition was complete, the temperature was raised to 35-75°C and stirred for 1-2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, the toluene was removed, and dichloromethane and a 10% aqueous potassium carbonate solution or a 5% aqueous sodium bicarbonate solution were added. The layers were separated, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed to obtain compound 1.

[0120] According to an embodiment of the present invention, further, in step 1-1,

[0121] In the mixture of compound 1-1, toluene and water, the mass 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;

[0122] The molar ratio of compound 1-1 to sodium carbonate is 1:1.1 to 1:1.2;

[0123] The molar ratio of compound 1-1 to triphenylphosphine is 1:1.1 to 1:1.2;

[0124] The reaction of step 1-1 is optionally carried out under the protection of an inert gas (eg, nitrogen).

[0125] According to an embodiment of the present invention, further, in step 1-2,

[0126] The metal salt of tert-butoxide is potassium tert-butoxide or sodium tert-butoxide;

[0127] The base used for pH adjustment is ammonia or sodium carbonate;

[0128] The organic solvent used for extraction is methyl tert-butyl ether or ethyl acetate;

[0129] The mass volume ratio of compound 1-2 to dimethyl sulfoxide is 1:3 to 1:5;

[0130] The molar ratio of compound 1-2 to the metal salt of tert-butoxide is 1:1.05 to 1:1.15, preferably 1:1.1;

[0131] The molar ratio of compound 1-2 to ethyl formate is 1:4 to 1:5;

[0132] The reaction of step 1-2 is optionally carried out under the protection of an inert gas (eg, nitrogen).

[0133] According to an embodiment of the present invention, further, in steps 1-3,

[0134] The mass volume ratio (g / mL) of compound 1-3 to dichloromethane is 1:6 to 1:10;

[0135] 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;

[0136] The reaction of steps 1-3 is optionally carried out under the protection of an inert gas (eg, nitrogen).

[0137] According to an embodiment of the present invention, further, in steps 1-4,

[0138] The mass volume ratio (g / mL) of compound 1-4 to concentrated sulfuric acid is 1:2 to 1:5;

[0139] The mass volume ratio (g / mL) of compound 1-4 to dichloromethane is 1:25 to 1:26;

[0140] The molar ratio of compound 1-4 to benzoyl chloride is 1:1.5 to 1:2.5, preferably 1:2.

[0141] According to an embodiment of the present invention, further, in steps 1-5,

[0142] The mass ratio of compound 1-5 to acetic acid in the acetic acid solution of compound 1-5 is 1:9 to 1:11, preferably 1:10;

[0143] The mass ratio of compound 1-5 to acetic acid in the mixture of acetic acid, acetic anhydride and nitric acid is 1:3 to 1:5;

[0144] The molar ratio of compound 1-5 to acetic anhydride is 1:2 to 1:5, preferably 1:2.6 to 1:4.2;

[0145] The molar ratio of compound 1-5 to nitric acid is 1:2 to 1:5, preferably 1:2.5 to 1:4.0;

[0146] The reaction of steps 1-5 is optionally carried out under the protection of an inert gas (eg, nitrogen).

[0147] According to an embodiment of the present invention, further, in steps 1-6,

[0148] The molar ratio of compound 1-6 to N,N-dimethylformamide is 1:1 to 1:1.2;

[0149] The mass volume ratio of compound 1-6 to toluene is 1:9 to 1:11, preferably 1:10;

[0150] The molar ratio of compound 1-6 to phosphorus oxychloride is 1:1.8 to 1:2.2, preferably 1:2;

[0151] The reaction of steps 1-6 is optionally carried out under the protection of an inert gas (eg, nitrogen).

[0152] According to an embodiment of the present invention, when compound 2 is compound 2a, the present invention further provides a method for synthesizing the hydrochloride salt of compound 2a, comprising the following steps:

[0153] Step 2-1:

[0154]

[0155] Compound 2-1 undergoes a ring-closure reaction catalyzed by sodium methoxide to obtain compound 2-2;

[0156] Step 2-2:

[0157]

[0158] Compound 2-2 reacts with hydrochloric acid to obtain the hydrochloride of compound 2a.

[0159] According to an embodiment of the present invention, in the synthesis method of the hydrochloride salt of compound 2a, preferably,

[0160] In step 2-1:

[0161]

[0162] To a mixture of compound 2-1 and tetrahydrofuran, sodium methoxide methanol solution was added dropwise, and the temperature was controlled at 0-10°C during the addition process. After the addition was completed, the temperature was raised to 20-30°C and the reaction was kept warm for 3-8 hours. After the reaction was completed, ammonium chloride solution was added dropwise to the reaction solution until the pH of the system was 7-8. The temperature was controlled at 15-25°C, extracted with methyl tert-butyl ether, washed with sodium chloride solution, dried over anhydrous sodium sulfate, cooled to 0-10°C, filtered, and the filter cake was dried to obtain compound 2-2;

[0163] In step 2-2:

[0164]

[0165] To the mixture of compound 2-2 and dichloromethane, add hydrogen chloride ethanol solution dropwise. After the addition is complete, the system is heated to 20-25°C and kept warm for 4-8 hours. After the reaction is completed, the system is cooled to 0-5°C and filtered. The filter cake is rinsed with dichloromethane and dried to obtain the hydrochloride salt of compound 2a.

[0166] According to an embodiment of the present invention, further, in step 2-1,

[0167] The mass volume ratio (g / mL) of compound 2-1 to tetrahydrofuran is 1:10 to 1:12, preferably 1:10 to 1:11;

[0168] The molar ratio of compound 2-1 to sodium methoxide methanol solution is 1:0.2 to 1:0.3, preferably 1:0.25;

[0169] The reaction in step 2-1 is optionally carried out under the protection of an inert gas (eg, nitrogen).

[0170] According to an embodiment of the present invention, further, in step 2-2,

[0171] The mass volume ratio of compound 2-2 to dichloromethane is 1:5 to 1:7, preferably 1:6;

[0172] The molar ratio of compound 2-2 to hydrogen chloride ethanol solution is 1:2 to 1:5, preferably 1:3;

[0173] The reaction in step 2-2 is optionally carried out under the protection of an inert gas (eg, nitrogen).

[0174] According to an embodiment of the present invention, the present invention provides another method for synthesizing a 1H-furo[3,2-b]imidazo[4,5-d]pyridine compound (hereinafter referred to as "Synthetic Route 2", used for synthesizing compounds 6A and 6B), comprising the following steps:

[0175] Step 1A:

[0176]

[0177] Compound 1 reacts with a cis-trans isomer mixture 7 in the presence of a base in a solvent to obtain a cis-trans isomer mixture 8;

[0178] Step 2A:

[0179]

[0180] The cis-trans isomer mixture 8 is subjected to a reduction reaction to obtain the cis-trans isomer mixture 9 or its hydrochloride;

[0181] Step 3A:

[0182]

[0183] A cis-trans isomer mixture 9 or its hydrochloride is reacted with compound 5 or compound 5' through a ring-closure reaction to obtain a mixture 10 or a hydrate of the mixture 10, wherein R is a methyl group or an ethyl group, wherein the methyl group or the ethyl group is optionally substituted with a hydroxyl group, preferably, R is a methyl group or a 1-hydroxyethyl group, and the hydrate of the mixture 10 is preferably a monohydrate of the mixture 10;

[0184] Step 4A:

[0185]

[0186] The mixture 10 or the hydrate of the mixture 10 undergoes an isomer conversion reaction under alkaline conditions to obtain compound 6 or the hydrate of compound 6. The hydrate of compound 6 is preferably the monohydrate of compound 6.

[0187] According to an embodiment of the present invention, in Synthesis Route 2, Step 1A, Step 2A and Step 3A are in accordance with Step 1, Step 2 and Step 3 of Synthesis Route 1. In Step 4A, the reaction is carried out under alkaline conditions, wherein the base is an alkoxide base, preferably an alkali metal C 1-6 Alkoxide, more preferably, potassium tert-butoxide.

[0188] According to an embodiment of the present invention, the present invention provides another synthesis method of compound 6A, comprising step 1A, step 2A, step 3A and step 4A, wherein step 1A, step 2A and step 3A are according to the method of step 1, step 2 and step 3 for preparing compound 6A (synthetic route 1) above, wherein:

[0189] Step 1A:

[0190]

[0191] Compound 1 reacts with a cis-trans isomer mixture 7 in the presence of a base in a solvent to obtain a cis-trans isomer mixture 8;

[0192] Step 2A:

[0193]

[0194] The cis-trans isomer mixture 8 is subjected to a reduction reaction to obtain the cis-trans isomer mixture 9 or its hydrochloride;

[0195] Step 3A:

[0196]

[0197] The cis-trans isomer mixture 9 or its hydrochloride is reacted with R-lactic acid through a ring-closure reaction to obtain the mixture 6Aa or a hydrate of the mixture 6Aa;

[0198] Step 4A:

[0199]

[0200] The mixture 6Aa or the hydrate of the mixture 6Aa undergoes an isomer conversion reaction under alkaline conditions to obtain the hydrate of compound 6A. The base is an alkoxide base, preferably an alkali metal C 1-6 The alkoxide is preferably potassium tert-butoxide; the hydrate of compound 6A is preferably the monohydrate of compound 6A.

[0201] According to an embodiment of the present invention, in the synthesis method of compound 6A through steps 1A-4A, in step 4A,

[0202] The reaction is carried out in a solvent, wherein the solvent is preferably tetrahydrofuran;

[0203] 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;

[0204] The reaction was carried out at room temperature;

[0205] After the reaction, dilute hydrochloric acid was added to adjust the pH to 6-7, the solvent was removed by vortexing, water was added and stirred, the mixture was filtered, washed with water, and the filter cake was collected and dried at 50°C to obtain compound 6A.

[0206] According to an embodiment of the present invention, the present invention provides another synthesis method of compound 6B, comprising step 1A, step 2A, step 3A and step 4A, wherein step 1A, step 2A and step 3A are according to the method described in step 1, step 2 and step 3 of preparing compound 6B (Synthetic Route 1) above, wherein:

[0207] Step 1A:

[0208]

[0209] Compound 1 reacts with a cis-trans isomer mixture 7 in the presence of a base in a solvent to obtain a cis-trans isomer mixture 8;

[0210] Step 2A:

[0211]

[0212] The cis-trans isomer mixture 8 is subjected to a reduction reaction to obtain the cis-trans isomer mixture 9 or its hydrochloride;

[0213] Step 3A:

[0214]

[0215] The cis-trans isomer mixture 9 or its hydrochloride is reacted with acetic anhydride and / or acetic acid to obtain a mixture 6Ba;

[0216] Step 4A:

[0217]

[0218] The mixture 6Ba undergoes isomer conversion reaction under alkaline conditions to obtain compound 6B. The base is an alcohol salt base, preferably an alkali metal C 1-6 Alkoxide, more preferably, potassium tert-butoxide.

[0219] According to an embodiment of the present invention, in the synthesis method of compound 6B through steps 1A-4A, in step 4A,

[0220] The reaction is carried out in a solvent, wherein the solvent is preferably tetrahydrofuran;

[0221] 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;

[0222] The reaction was carried out at room temperature;

[0223] After the reaction, dilute hydrochloric acid was added to adjust the pH to 6-7, the solvent was removed by vortexing, water was added and stirred, the mixture was filtered, washed with water, and the filter cake was collected and dried at 50°C to obtain compound 6B.

[0224] The present application also provides a mixture of formula 8 (cis-trans isomer mixture 8):

[0225]

[0226] or a salt thereof, wherein the mixture of Formula 8 comprises a compound of Formula 3a and a compound of Formula 8A:

[0227]

[0228] The present application also provides a mixture of formula 9 (cis-trans isomer mixture 9):

[0229]

[0230] or a salt thereof, wherein the mixture of Formula 9 comprises a compound of Formula 4a and a compound of Formula 9A:

[0231]

[0232] The present application also provides a mixture of formula 6Aa (mixture 6Aa):

[0233]

[0234] or a hydrate of a mixture of formula 6Aa, or a salt of a mixture of formula 6Aa, wherein the mixture of formula 6Aa comprises a compound of formula 6A and a compound of formula 6Ab:

[0235]

[0236] The present application also provides a mixture of formula 6Ba (mixture 6Ba):

[0237]

[0238] or a salt of a mixture of formula 6Ba, wherein the mixture of formula 6Ba comprises a compound of formula 6B and a compound of formula 6Bb:

[0239] Beneficial effects

[0240] The synthesis method of the 1H-furo[3,2-b]imidazo[4,5-d]pyridine compound of the present invention has high yield, few impurities, is easy to control, saves costs, is simple to operate, and is suitable for industrial scale. BRIEF DESCRIPTION OF THE DRAWINGS

[0241] Figure 1 is a diagram of compound 1 obtained in Example 6 of the present invention. 1 H NMR spectrum.

[0242] FIG2 is the LCMS spectrum of compound 1 prepared in Example 6 of the present invention.

[0243] Figure 3 is a diagram of compound 2a obtained in Example 8 of the present invention. 1 H NMR spectrum.

[0244] FIG4 is a TsCl-derivative HPLC spectrum of compound 2a prepared in Example 8 of the present invention.

[0245] FIG5 is a HPLC spectrum of Nα-(2,4-dinitro-5-fluorophenyl)-L-valinamide derivatization of compound 2a prepared in Example 8 of the present invention.

[0246] Figure 6 is a graph showing the structure of compound 6A obtained by method A in Example 13 of the present invention. 1 H NMR spectrum.

[0247] FIG7 is a HPLC spectrum of compound 6A prepared by method A in Example 13 of the present invention.

[0248] FIG8 is an HPLC spectrum of the isomer of compound 6A prepared by method A in Example 13 of the present invention.

[0249] Figure 9 is a graph showing the structure of compound 6B obtained by method A in Example 15 of the present invention. 1 H NMR spectrum.

[0250] FIG10 is a HPLC spectrum of compound 6B prepared by method A in Example 15 of the present invention.

[0251] Figure 11 is a tartrate of compound 6B obtained in Example 16 of the present invention. 1 H NMR spectrum.

[0252] FIG12 is an HPLC spectrum of the tartrate salt of compound 6B prepared in Example 16 of the present invention.

[0253] FIG13 is a HPLC spectrum of compound 1 prepared in Example 6 of the present invention.

[0254] Figure 14 is a graph showing the structure of compound 6C obtained in Example 14 of the present invention. 1 H NMR spectrum.

[0255] FIG15 is a TGA spectrum of compound 6A prepared in Example 13 of the present invention. Specific implementation plan

[0256] The sources of the main materials in the following examples are shown in the following table:

[0257] Material Name Source Compound 1-1 Ruifuxin Jiangsu Pharmaceutical Compound 2-1 Hangzhou Aosino Toluene Lotte Chemical Sodium Carbonate Hangzhou Longshan Chemical Sodium Chloride Jiangxi Jinghao Salt Anhydrous Sodium Sulfate Huai'an Nanfeng Salt Triphenylphosphine Shaoxing Huawei Chemical Dimethyl Sulfoxide Hubei Xingfa Chemical Sodium tert-Butol Changzhou Jisi Pharmaceutical Ethyl Formate Linmu County Huasheng Chemical Ethyl Acetate Jin Yimeng Group Hydrochloric Acid Lanxi Xuri Chemical n-Heptane Yueyang Jiaxing Chemical Dichloromethane Zhejiang Juhua Boron Tribromide Shandong Yanfeng New Materials Technology Anhydrous Ethanol Jiangsu Huating Biotechnology 18% Sodium Ethanol / Ethanol Linyi Zhenfeng Chemical Methyl Tert-Butyl Ether Sinopec Benzoyl Chloride Jiangsu Wanlong Chemical Sulfuric Acid Zhejiang Jiangxi Copper Fuye Heding Copper Industry 25-28% Ammonia Water Hangzhou Aosino Acetic Acid (Glacial Acetic Acid) Shanghai Wujing Chemicals: Acetic Anhydride, Ningbo Wanglong Technology, 98% Nitric Acid, Lanxi Xuri Chemical, Methyl Tert-Butyl Ether, Sinopec Qilu Branch, Sodium Bicarbonate, Hangzhou Longshan Chemical, Diatomaceous Earth, Yixing Junlian Diatomaceous Earth, n-Heptane, Yueyang Taixin Chemical, Tetrahydrofuran, Jiangsu Changchun Chemical, Sodium Methanol Methanol Solution, Anhui Jinbang Pharmaceutical Chemical, Ammonium Chloride, Zhejiang Dayang Biotechnology, Activated Carbon, Liyang Jiangyang Activated Carbon Factory, DIPEA, Hangzhou Xinde Environmental Protection Technology, Acetonitrile, Shanghai Saike Petrochemical, Reduced Iron Powder, Jiangsu Feixing Powder Metallurgy, Acetic Acid, Yankuang Lunan Chemical, Sodium Citrate, Weifang Yingxuan Industrial, Potassium Phosphate, Jiangsu Kelunduo Food Ingredients, Silica Gel, Rushan Shangbang New Materials, Isopropyl Alcohol, Zhejiang Xinhua Chemical, R-Lactic Acid, Musashino Chemical, Methylcyclohexane, Jiangsu Yangnong Chemical, 2-(trans-4-aminocyclohexyl)acetonitrile, Bid Pharmaceuticals

[0258] Testing and inspection methods for compound 1

[0259] Test Method 1

[0260] instrument:

[0261] Agilent 1200 high performance liquid chromatograph or similar liquid chromatograph

[0262] Chromatographic column: Poroshell 120 EC-C18 (4.6 × 50 mm × 2.7 μm)

[0263] method:

[0264] The area normalization method was used for determination.

[0265] Chromatographic analysis conditions are:

[0266] Flow rate: 1.0ml / min

[0267] Column temperature: 30°C

[0268] Detector: UV (210nm)

[0269] Post-run: 1 minute

[0270]

[0271] Test Method 2

[0272] Karl Fischer test for moisture:

[0273] According to the operating procedures of the moisture determination method, weigh about 0.2-0.5 g of the test sample of compound 1, with the result accurate to 0.1 mg, add it to the titration cup of the titrator for determination, record the results, and measure twice in parallel using the same method. The average of the two results is the moisture content of the test sample, and the result is rounded to one decimal place.

[0274] Test Method 3

[0275] Gas chromatograph, such as Shimadzu GC-2014C or similar

[0276] Gas phase column: HP-5 30m×320μm×0.25μm column

[0277] Column temperature: 40°C, hold for 3 minutes, 10°C / min, increase to 260°C, hold for 2 minutes.

[0278] Injector temperature: 230°C.

[0279] Detector temperature: 260°C.

[0280] Air flow rate: 400mL / min

[0281] Hydrogen flow rate: 40mL / min

[0282] Tail nitrogen: 25ml / min

[0283] Column flow rate (nitrogen): 1 mL / min

[0284] Test Method 4

[0285] Loss on drying:

[0286] Take the mixed sample of Compound 1 to be tested (if the sample is relatively large crystals, quickly crush it into particles approximately 2 mm in diameter). Accurately weigh 1-2 grams and place it in a flat, stoppered weighing bottle that has been dried under the same conditions as the sample. Tare the bottle first. After adding the sample, cap the bottle and weigh the total weight. Gently shake the bottle horizontally to spread the sample as evenly as possible, with a thickness of no more than 5 mm. Place the weighing bottle containing the sample in a constant temperature, reduced pressure drying oven (with the bottle cap removed and placed in a desiccator) and dry at 50°C and -0.09 to -0.1 MPa for 4 hours. Immediately cap the oven-dried sample after drying, transfer it to a desiccator and cool it to room temperature before weighing.

[0287] Loss on drying calculation formula

[0288] Loss on drying = (W1-W2) / W1*100%.

[0289] W1 is the weight of the sample before drying, and W2 is the weight of the sample after drying.

[0290] Compound 1 finished product detection method

[0291] 1. Appearance

[0292] Take this product and inspect it visually under natural light.

[0293] 2. Identification

[0294] Using nuclear magnetic resonance

[0295] The solvent is CDCl3, and the external unit is based on USP <761> Conduct testing.

[0296] 3. Purity and related substances

[0297] Instruments and Equipment

[0298] Name Specifications Model HPLC DAD or VWD system, Agilent 1260 or equivalent analytical balance METTLER TOLEDO XPR205 or equivalent, d = 0.01 mg or above Chromatographic column Agilent Zorbax SB C18 4.6 mm × 250 mm, 5 μm or similar model Water purifier Milli-Q IQ7000 or equivalent

[0299] Reagents

[0300] Name Grade / Purity Acetonitrile (ACN) HPLC grade or equivalent Pure water Milli-Q grade or equivalent Trifluoroacetic acid (TFA) HPLC grade or equivalent

[0301] Sample Information

[0302] Sample compound 1 test product

[0303] Chromatographic conditions

[0304]

[0305] Detection method of compound 2a

[0306] GC chromatography detection method of compound 2a

[0307]

[0308]

[0309] HPLC purity and de value detection method of finished compound 2a

[0310]

[0311] EE value detection method for finished compound 2a

[0312]

[0313]

[0314] Detection methods for compounds 3a, 4a, and 6A

[0315] Test Method 1

[0316]

[0317] Detection method 2

[0318]

[0319]

[0320] Detection method 3

[0321]

[0322] Detection method 4

[0323]

[0324]

[0325] Detection method of compound 6B and 6B tartrate

[0326] Chromatograph: Agilent 1260 high performance liquid chromatograph

[0327] Column model: Waters Xbridge C18 250mm×4.6mm×5μm

[0328] Mobile phase A: 20 mM potassium hydrogen phosphate in water

[0329] Mobile phase B: methanol

[0330] gradient:

[0331] Time (min)Mobile phase A (%, V / V)Mobile phase B (%, V / V)0802020505030307040307040.018020508020

[0332] Column temperature: 40°C

[0333] Sample chamber temperature: room temperature

[0334] Flow rate: 1 mL / min

[0335] Injection volume: 5 μL

[0336] Run time: 50 minutes

[0337] Test sample concentration: approximately 1 mg / mL

[0338] Detection wavelength: UV230nm

[0339] The following examples further illustrate the present invention; however, they are not intended to limit or define the scope of the invention.

[0340] Example 1 Preparation of Compound 1-2

[0341] Reactor 1 was nitrogen-protected. 2-chloromethyl-3,4-dimethoxypyridine hydrochloride (250 kg, 1.0 eq) was added, along with toluene (1050 kg) and drinking water (150 kg). Stirring was initiated and the temperature was lowered to 20-25°C. Sodium carbonate (68.8 kg, 0.58 eq) was added in portions, and the temperature in the reactor was maintained at ≤30°C. Stirring was continued for 0.5 h. Stirring was stopped, and the reactor was allowed to stand for 20 minutes. The upper organic phase was retained. The lower aqueous phase was transferred to Reactor 2 and extracted with toluene (435 kg). The organic phases were then combined with Reactor 1. The aqueous phase was further extracted with toluene (225 kg). The lower aqueous phase was discarded, and the organic phases were combined with Reactor 1. The organic phase was washed with saturated brine (204 kg) and dried over anhydrous sodium sulfate (150 kg). The filtrate was filtered and transferred to Reactor 3, where the solids were rinsed with toluene (50 kg). Add triphenylphosphine (350 kg, 1.2 eq) to reactor 3, stir, and raise the internal temperature to 108-115°C. Reflux for 18 hours, and remove water using a water separator. After the reaction is complete, cool the contents of reactor 3 to 20-30°C. Centrifuge, and rinse the solid with toluene (100 kg). Dry the wet product using a double-cone oven with the jacket hot water at 50-60°C and a vacuum below -0.090 MPa until the moisture content is ≤0.2%. Collect the material, package it in double-layer PE bags, and place it into cardboard drums (yield 489.8 kg, yield 97.4%, HPLC purity 99.8%).

[0342] Example 2 Preparation of Compound 1-3

[0343] Compound 1-2 (489.8 kg, 1.0 eq) and dimethyl sulfoxide (1614.2 kg, 3 V) were added to reactor 1, stirred, and cooled to 20-25°C. Sodium tert-butoxide (114.9 kg, 1.1 eq) was added portionwise. After addition, the temperature was raised to 25-32°C and stirred for 1.5 hours. Ethyl formate (397.8 kg, 5.0 eq) was added dropwise to reactor 1, and the temperature was raised to 40-50°C. The temperature was stirred for 8 hours. After the reaction, the temperature of reactor 1 was lowered to ≤25°C. The mixture was extracted with ethyl acetate (1320.7 kg, 3 V) and drinking water (1467.4 kg, 3 V). The organic layer was separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were 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 a pH of 5-6. The organic phase was separated and washed once with water (250.0 kg), and the aqueous phases were combined and extracted twice with ethyl acetate (1320.2 kg). Ethyl acetate (1320.7 kg, 3 V) was added to the aqueous phase and sodium carbonate (54.0 kg) was added in batches to adjust to pH ≥ 8. The organic phase was separated, the aqueous phase was extracted with ethyl acetate (880.4 kg, 2 V), the organic phase was washed with saturated sodium chloride aqueous solution (341.3 kg), dried over anhydrous sodium sulfate (217.4 kg), and filtered. The solid was rinsed with ethyl acetate (81.5 kg). The filtrate was collected and the solvent was removed. N-heptane (337.0 kg) was added and centrifuged, and the solid was rinsed with n-heptane (76.0 kg). After drying, compound 1-3 was obtained (yield 202.0 kg, yield 88.8%, HPLC purity 97.3%).

[0344] Example 3 Preparation of Compound 1-4

[0345] Reactor 1 was protected by nitrogen. Compound 1-3 (200.0 kg, 1.0 eq) and dichloromethane (1431.0 kg, 6 V) were added, and the temperature within the reactor was maintained at 15-20°C. Boron tribromide (600.0 kg, 2.5 eq) was added, and the temperature within the reactor was maintained at 20-30°C. After addition, the mixture was stirred at 20-30°C for 1 hour. Under nitrogen protection, the mixed solution in reactor 1 was slowly added dropwise to reactor 2 containing anhydrous ethanol (1422.0 kg, 10 V) at 15-30°C. The reaction system was stirred at 30-35°C for 2 hours. The solvent was removed under reduced pressure to 1600 L, and the volume was stripped twice with anhydrous ethanol (570.0 kg, 4 V) to 1600 L. An 18% sodium ethoxide solution in ethanol (1367.0 kg) was added, while the temperature was maintained at 15-30°C, until the pH reached 5-6. The solid was separated and rinsed with anhydrous ethanol (143.0 kg, 1 V). 18% sodium ethoxide in ethanol (1378.4 kg) was added to the mother liquor until the pH was 8-9, and the solvent was removed under reduced pressure. Methyl tert-butyl ether (540.0 kg, 4 V) was added to the system, and the solid was separated and rinsed with methyl tert-butyl ether (135.0 kg, 1 V), and dried to obtain compound 1-4 (yield 170 kg, yield 78.3%, HPLC purity 97.9%).

[0346] Example 4 Preparation of Compound 1-5

[0347] Benzoyl chloride (214.6 kg, 2.0 eq) was slowly added dropwise to a dichloromethane (3271.0 kg, 25.5 V) solution containing compound 1-4 (170.0 kg, 1.0 eq) at 0-10 ° C. The reaction was stirred at 0-10 ° C for 1 hour. The reaction solution was slowly added dropwise to a reactor containing sulfuric acid (1518.0 kg, 4.85 V) at 15-25 ° C and stirred at this temperature for 1 hour. The reaction 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 ammonia (1841.3 kg) was added dropwise to pH = 7-8. The material was stirred at 53-57 ° C for 0.5 h and then cooled to 20-25 ° C. The solid was separated and rinsed with water (170.0 kg, 1 V). After drying, compound 1-5 was obtained (yield 92.7 kg, yield 91.7%, HPLC purity 98.3%).

[0348] Example 5 Preparation of Compound 1-6

[0349] Nitric acid (52.5 kg) was added dropwise to a reactor (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 mixed solution was slowly added dropwise to a solution of compound 1-5 (45.0 kg, 1.0 eq) in acetic acid (450.0 kg, 10 W) at 113-116°C under nitrogen over a period of 2 h. The temperature was maintained at 112-117°C during the addition. After the addition was complete, the mixture was stirred for 1 h. After the temperature dropped to 20-30°C, methyl tert-butyl ether (337.5 kg, 10 V) was added and stirred for 0.5 h. The solid was separated and rinsed with methyl tert-butyl ether (100.8 kg, 3 V). After drying, compound 1-6 was obtained (yield 44.4 kg, yield 74.0%, HPLC purity 94.7%).

[0350] Example 6 Preparation of Compound 1

[0351] Phosphorus oxychloride (72.8 kg, 1.2 eq) was added dropwise to a solution of N,N-dimethylformamide (214.2 kg, 3.0 W) containing compound 1-6 (71.8 kg) under nitrogen protection at 15-25 ° C. The system was stirred at 38-43 ° C for 1 hour and then cooled to 15-20 ° C. The reaction solution was added dropwise to water (714.0 kg, 10 W) to quench the reaction, and the mixture was stirred at 20-30 ° C for 1 hour. The solid was separated and rinsed with water (214.2 kg, 3 W). The solid was stirred in dichloromethane (1224.0 kg, 13 V) for 15 minutes, and a 5% aqueous sodium bicarbonate solution (357.0 kg) and diatomaceous earth (35.7 kg) were added and stirred for 0.5 hours. The solid was separated and rinsed with dichloromethane (195.3kg, 2V), the filtrate was collected and the dichloromethane layer was separated, and extracted with dichloromethane (474.3kg, 5V), the dichloromethane layers were combined and washed with saturated brine (485.5kg), anhydrous sodium sulfate (107.0kg, 1.5W) was dried for 1 hour, filtered, the solid was rinsed with dichloromethane (188.7kg, 2V), the filtrate was collected and activated carbon (7.0kg, 0.1W) was added, and after stirring at 20-30°C for 1 hour, the solid was filtered and rinsed with dichloromethane (93.8kg, 1V). After removing the solvent, n-heptane (242.8kg, 5V) was added to make a pulp and separate the solid, which was rinsed with n-heptane (47.9kg, 1V). Drying gave compound 1 (output 62.2kg, yield 78.5%, HPLC purity 99.96%). 1 The H NMR spectrum is shown in Figure 1 , the LCMS spectrum is shown in Figure 2 , and the HPLC spectrum is shown in Figure 13 .

[0352] Example 7 Preparation of Compound 2-2

[0353] Sodium methoxide methanol solution (19.18 kg, 0.25 eq) and tetrahydrofuran (91.1 kg, 1.0 V) were added to a solution of compound 2-1 (102.4 kg, 1.0 eq) in tetrahydrofuran (911.4 kg, 10 V) at 0-5°C. The reaction was allowed to proceed at 20-25°C for 4-8 hours. Samples were taken for GC and HPLC analysis. When the starting material concentration was ≤1.0%, the temperature was lowered to 15-20°C. An aqueous solution of ammonium chloride (5.69 kg, 0.25 eq) (13.3 kg, 0.13 V) was added to the reaction mixture at 15-25°C until the pH reached 7-8. To the mixed solution were added 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). The organic phase was separated, and the aqueous phase was extracted with methyl tert-butyl ether (75.8 kg, 1 V). The organic phases were combined. The organic phase was washed with 30% sodium chloride aqueous solution (43.0 kg, 0.42 W sodium chloride solid, 100.4 kg, 0.98 W drinking water). The organic phase was separated, and 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 carbon (10.24 kg, 0.1 W) were added. The solids were filtered and rinsed with methyl tert-butyl ether (41.0 kg, 0.4 W). The filtrate was collected and concentrated, and methyl tert-butyl ether (227.3 kg, 3.0 V) was added. The temperature was raised to 50-55 ° C and refluxed for 2 h. The temperature was slowly lowered to 0-10 ° C. The solid was collected by filtration and dried to obtain compound 2-2 (yield 43.2 kg, yield: 42.2%).

[0354] Compound 2-2 Quality Standard: Appearance: Off-white solid Purity (GC): 96.0% Maximum unknown single impurity: 1.6% Water: 0.0%

[0355] Example 8 Preparation of Compound 2a Hydrochloride

[0356] Compound 2-2 (43.21 kg, 1.0 eq) and dichloromethane (192 kg, 6 V) were added to reactor R01 and cooled to 0-5°C. A 35% ethanolic hydrogen chloride solution (19.3 kg hydrogen chloride, 35.9 kg anhydrous ethanol) was added dropwise. After completion, the system was heated to 20-25°C and incubated for 4-8 hours. TLC and GC analysis were performed. When the content of the starting compound 2-2 was ≤1.0%, the system was cooled to 0-5°C. The wet product of compound 2a hydrochloride was obtained by centrifugation. The wet product was rinsed with dichloromethane (32.0 kg, 1 V) and centrifuged to dryness. The product was then dried under a double-tapered jacket at 55-65°C under a vacuum of ≤-0.095 MPa for 12 hours to obtain compound 2a hydrochloride (yield 28.96 kg, yield 91.2%). 1The H NMR spectrum is shown in Figure 3 , the TsCl-derivative HPLC spectrum is shown in Figure 4 , and the Nα-(2,4-dinitro-5-fluorophenyl)-L-valinamide-derivative HPLC spectrum is shown in Figure 5 .

[0357] Compound 2a hydrochloride quality standard: Appearance: white solid, purity (TsCl derivatization HPLC): 99.8%, de value (TsCl derivatization HPLC): 99.8%, ee value (Nα-(2,4-dinitro-5-fluorophenyl)-L-valinamide derivatization HPLC): 99.9%, maximum single impurity: 0.2%, water: 0.1%

[0358] Example 9 Preparation of Compound 3a

[0359] Method A

[0360] Into a 1000L reactor (R01), pump in (110.6kg, 5V) anhydrous ethanol, (109.2kg, 5V) acetonitrile, (27.97kg, 1.0eq) of compound 1, and (25.07kg, 1.0eq) of compound 2a hydrochloride. Finally, pump in (40.0kg, 2.2eq) of N,N-diisopropylethylamine under nitrogen. The reaction mixture was reacted at 50-60°C for 16 hours. Samples were taken and HPLC analysis was performed to determine the concentration of compound 1, which was no greater than 1.0%. The reaction mixture was cooled to 20-30°C and water (560kg, 20V) was added dropwise, maintaining the temperature at 20-30°C. After the addition was complete, stirring was continued at 20-30°C for 1.0 hour. Stirring was continued at 0-5°C for 2 hours, the mixture was discharged and centrifuged. The filter cake was rinsed once with a mixture of acetonitrile and water (25kg acetonitrile + 56kg water) at 0-10°C. The filter cake was dried in a vacuum drying oven at 45-55° C. to obtain compound 3a (yield: 37.51 kg, moisture: 0.03%, yield: 88.1%).

[0361] Method B

[0362] Under nitrogen, ethanol (1.9 L), compound 1 (200 g, 1.0 eq), compound 2a hydrochloride (179.7 g, 1.01 eq), and sodium bicarbonate (188 g, 2.23 eq) were added to a reaction flask and incubated at 70-80°C for 16 h. The reaction mixture was cooled to 20-30°C, and water (2.9 L) was slowly added and stirred for 2 h. The mixture was cooled to 5-15°C and stirred for 4 h. The mixture was filtered, and the filter cake was rinsed with water and ethanol (600 mL, water / ethanol = 1:2). After drying, compound 3a was obtained as a yellow solid (yield 286.9 g, yield 94%).

[0363] Method C

[0364] Compound 3a was prepared by the same preparation method as method B, except that the added base was different from that of method B, wherein the added base was sodium carbonate (2.2 eq), and the content was 72% by HPLC.

[0365] Method D

[0366] Compound 3a was prepared by the same preparation method as method B, except that the added base was different from that of method B, wherein the added base was potassium bicarbonate (2.2 eq). The content of the compound 3a was 83% according to HPLC.

[0367] Method E

[0368] In a 40 mL reaction flask, anhydrous ethanol (1 mL), acetonitrile (1 mL), compound 1 (200 mg, 1.0 eq), compound 2a hydrochloride (179 mg, 1.0 eq), and 1,8-diazabicyclo[5.4.0]undec-7-ene (339 mg, 2.2 eq) were added and reacted at 55 ° C for 16 hours. The temperature was cooled to room temperature, concentrated, and separated by column chromatography to obtain compound 3a (yield 198 mg, yield 65.1%).

[0369] Example 10 Preparation of Compound 3b

[0370] Under nitrogen, ethanol (27 mL), compound 1 (2.84 g, 1.0 eq), compound 2b (2-(trans-4-aminocyclohexyl)acetonitrile, 2 g, 1.01 eq), and sodium bicarbonate (1.44 g, 1.2 eq) were added to a reaction flask and reacted at 75°C for 16 h. The reaction mixture was cooled to 20-30°C, and water (30 mL) was slowly added and stirred for 2 h. The mixture was filtered, and the filter cake was rinsed with water and ethanol (6 mL, water / ethanol = 1:2). After drying, compound 3b was obtained as a yellow solid (yield 3.694 g, 86%).

[0371] Example 11 Preparation of Compound 4a / Compound 4a Hydrochloride

[0372] Method A

[0373] Under nitrogen, a 1000L glass-lined reactor was charged with (264kg, 9V) acetonitrile, (90kg, 12eq) acetic acid, and compound 3a (37.43kg, 1.0eq). Iron powder (41.17kg, 6.0eq) was added portionwise at 60-70°C and stirred for 1 hour. Additional iron powder (14kg, 2.02eq) and acetic acid (10kg, 1.34eq) were added until the reaction was complete. The reaction mixture was cooled to 30-40°C, filtered, and rinsed with hot acetonitrile (50-60°C, 176kg, 6V). A 30% aqueous sodium citrate solution (164.56kg, 5.15eq, 380kg of water) was added to the filtrate at 10-25°C until pH = 6. Subsequently, a 30% aqueous potassium phosphate solution (224.46kg, 8.5eq, 522kg of water) was added until pH = 8. After vacuum distillation, ethyl acetate (167.8 kg, 5 V) and water (112 kg, 3 V) were added, the organic phase separated, and the aqueous phase extracted with ethyl acetate (101 kg, 3 V). The organic phases were combined. The organic phase was washed sequentially with a 20% aqueous sodium citrate solution (60 kg of water, 15 kg of sodium citrate, 0.47 eq) and a 15% aqueous sodium chloride solution (61.3 kg of water, 10.8 kg of sodium chloride). Anhydrous sodium sulfate (41.5 kg) and silica gel (5.23 kg) were added and stirred for 30 minutes. The mixture was filtered and rinsed with ethyl acetate (67 kg). Vacuum distillation was performed, and 30 kg of isopropyl alcohol was added to the system and evaporated to dryness under reduced pressure. An additional 30 kg of isopropyl alcohol was added and evaporated to dryness under reduced pressure. 101.15 kg of isopropyl alcohol was added, and the mixture was stirred and heated to 80°C to dissolve the clear solution. After dissolving, the temperature was slowly lowered to 0-10°C and stirred for 2 hours. The solid was separated, and the filter cake was rinsed with 18.72 kg of isopropanol and dried to obtain compound 4a (21.15 kg, yield: 55%). Isopropanol content: 12.65%.

[0374] Method B

[0375] Compound 3a (210 g, 1.0 eq), water (840 mL) and methanol (210 mL) were added to the reaction flask, stirred and heated to 65-75 ° C, and diboric acid (218 g, 3.5 eq, added in 7 times) was added in batches. The reaction temperature was controlled at 65-75 ° C and reacted overnight. Sampling was tested (diboric acid was added until the reaction was completed). After the reaction was completed, the temperature was cooled to 35-45 ° C, and part of the solvent was concentrated under reduced pressure. The temperature was cooled to 0-10 ° C and stirred for 1-2 h, filtered, and the filter cake was rinsed with 1000 mL of dichloromethane. The filtrate was collected and sodium bicarbonate (105 g) was added in batches at 20-30 ° C, and the mixture was stirred for 1 h. After standing for 0.5 h, the organic phase was separated, and the water was added. The phase was extracted with dichloromethane (660 mL×3), the organic phases were combined, and the organic phase was dried over anhydrous sodium sulfate (210 g). An ethanolic solution of hydrochloric acid (230 mL, 30%) was added dropwise at 15-25° C. and stirred at this temperature for 8 h. Ethyl acetate (1050 mL) was added dropwise at 15-25° C. and stirred at this temperature for 1 h. The mixture was filtered, and the filter cake was rinsed with ethyl acetate (420 mL) and dried in a vacuum drying oven at 30-40° C. to obtain the hydrochloride salt of compound 4a, 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%).

[0376] Method C

[0377] In a 50 mL multi-necked flask equipped with a magnetic rod, compound 3a (1.00 g, 3.31 mmol), 4,4'-bipyridine (2.58 mg, 0.0165 mmol), and 20 mL of DMF were added at room temperature. The mixture was stirred and the atmosphere was replaced with nitrogen three times. B2(OH)4 (0.89 g, 9.92 mmol) was added and allowed to react at 15-25°C for 5 h. The reaction was monitored by HPLC. After the reaction of compound 3a was complete, the reaction was stopped. 200 mL of water was added and the mixture was extracted five times with ethyl acetate (50 mL each time). The mixture was washed with 100 mL of saturated brine and dried over anhydrous sodium sulfate. The ethyl acetate was removed by rotary evaporation to obtain the crude product. Further separation was performed by column chromatography using a 30:1 (v / v) ratio of dichloromethane to methanol to afford compound 4a in a 44.4% yield.

[0378] Method D

[0379] Ethyl acetate (2 mL), compound 3a (198 mg, 1.0 eq), and stannous chloride (373 mg, 3.0 eq) were added to a reaction flask and reacted at 85°C for 3 h. The mixture was cooled to room temperature and sodium bicarbonate was added under ice bath, stirred, and filtered. The filter cake was rinsed with 2 mL of ethyl acetate. The filtrate was collected and washed three times with saturated sodium bicarbonate solution. The organic phases were combined and then washed three times with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 4a (yield 123 mg, yield 69%).

[0380] Example 12 Preparation of Compound 4b

[0381] Compound 3b (3.69 g, 1.0 eq), water (14.8 mL) and methanol (3.7 mL) were added to a reaction flask, stirred and heated to 65-75°C, and diboric acid (4.51 g, 4.1 eq, added in 4 portions) was added in batches. The reaction temperature was controlled at 65-75°C and the reaction was allowed to react overnight. After completion of the reaction, the temperature was lowered to 20-30°C, sodium bicarbonate (1.85 g) was added in batches, and the mixture was stirred for 0.5 h. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with water (10 mL × 3), then washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate (3.7 g), filtered, and concentrated to obtain compound 4b (yield 3.02 g, yield 90.9%).

[0382] Example 13 Preparation of Compound 6A

[0383] Method A

[0384] To a 300L reactor R01, add R-lactic acid (30.5kg, 5.0eq, isomer content 0.25%), compound 4a (21.14kg, 1.0eq), and methylcyclohexane (37.0kg). Stir and heat to reflux at 87.2-101°C for 5 hours, removing water and taking samples for control. After the reaction is complete, turn off the steam heating and slowly add methanol (43.8kg, 3V) dropwise to reactor R01. Cool to 20-30°C. Allow to stand and separate. Remove the lower layer and add methanol (29.6kg, 2V). Add sodium hydroxide solution (25.3kg water, 10.9kg sodium hydroxide) dropwise at -10-0°C and incubate until the reaction passes HPLC analysis. Aqueous hydrochloric acid (4.81 kg concentrated hydrochloric acid + 45.03 kg water) was added dropwise to adjust the pH to 7. After removing the solvent, water (277.5 kg, 15 V) was added. After stirring for 1 hour, the mixture was centrifuged and the filter cake was rinsed with water (55.5 kg, 3 V). The wet product was added to 185 kg of water, stirred at approximately 30°C for 2 hours, centrifuged, washed with 30 kg of water, and dried to obtain crude compound 6A. The HPLC purity of compound 6A was 97.24%; the HPLC content of compound 6A isomers was 1.95%; and the moisture content was 5.2%.

[0385] Refined compound 6A:

[0386] 20.49 kg of crude compound 6A was stirred with 116 kg of isopropanol and 50 kg of water, heated to reflux, and then cooled to -5-5°C. The mixture was stirred for 3 hours, discharged, and centrifuged. The filter cake was rinsed once with 12 kg of isopropanol and 5 kg of water at 0-10°C to obtain the primary recrystallized compound 6A. The HPLC purity of compound 6A was 99.03%, and the HPLC content of compound 6A isomers was 1.03%. A second recrystallization (107.16 kg of isopropanol and 45.36 kg of water) yielded the secondary recrystallized compound 6A. The HPLC purity of compound 6A was 99.66%, and the HPLC content of compound 6A isomers was 0.43%. 17.1 kg of wet compound 6A was added to 87.7 kg of methanol and 1.2 kg of activated carbon, and the mixture was stirred at reflux for 1 hour. The mixture was filtered (through a carbon rod and filter cartridge) and rinsed with 13.5 kg of methanol. The solvent was removed under reduced pressure, and 13.5 kg of isopropanol was added and the solvent was removed under reduced pressure again. Recrystallization was performed using the above recrystallization method, and after drying, compound 6A was obtained (compound 6A was characterized as compound 6A monohydrate. The thermogravimetric analysis (TGA) spectrum is shown in Figure 15. The TGA spectrum shows a 5.353% step loss from 25°C to 133°C, corresponding to the loss of one water molecule). The yield was 14.76 kg, with 5.2% water content and 0.0405% residual isopropanol. The HPLC purity of compound 6A was 99.94%; the HPLC content of compound 6A isomers was 0.21%, and the yield was 66.2%. 1The H NMR spectrum is shown in Figure 6 , the HPLC spectrum of compound 6A is shown in Figure 7 , and the HPLC spectrum of the isomer of compound 6A is shown in Figure 8 .

[0387] Method B

[0388] Compound 6A was prepared by the same preparation method as Method A except for the following differences from Method A, wherein the amount of compound 4a charged was 1 g, the reaction solvent was 1,4-dioxane (6 mL), R-lactic acid (20 eq), and methanesulfonic acid (2 g) was added. The HPLC content was 91.1%, and the HPLC content after hydrolysis with sodium hydroxide was 98.2%.

[0389] Method C

[0390] Compound 6A was prepared by the same preparation method as method A except for the following differences from method A, wherein the amount of compound 4a charged was 1 g, the reaction solvent was 1,4-dioxane (10 mL), R-lactic acid (30.2 eq), and the mixture was heated at 95-105°C for 16 hours. The HPLC content was 70%, the HPLC content after hydrolysis with sodium hydroxide was 99.6%, and the chiral purity was 99.0%.

[0391] Method D

[0392] Compound 6A was prepared by the same preparation method as Method A except for the following differences: Compound 4a was added in an amount of 10 g, the reaction solvent was toluene (75 mL), and the mixture was heated at 108-113°C for 10 hours. The HPLC assay showed a content of 97% and a chiral purity of 96%.

[0393] Example 14 Preparation of Compound 6C

[0394] Add R-lactic acid (1.66g, 5.0eq), compound 4b (1g, 1.0eq) and methylcyclohexane (5.25g) to the reaction flask, stir and heat to reflux 110℃, react for 24h, cool to 20-30℃, and add methanol. Let stand and separate, remove the upper organic phase, collect the lower layer and add sodium hydroxide solution (1.2g water, 0.52g sodium hydroxide) dropwise in an ice bath and stir for 0.5h. Add hydrochloric acid aqueous solution (0.23g concentrated hydrochloric acid + 2.15g water) dropwise to adjust to pH=7, concentrate under reduced pressure, add water and stir for 0.5h, then filter and dry the filter cake to obtain compound 6C (yield 0.984g, yield 82%). 1 The H NMR spectrum is shown in Figure 14.

[0395] Example 15 Preparation of Compound 6B

[0396] Method A

[0397] The hydrochloride of compound 4a (200 g) and acetic anhydride (600 mL) were added to the reaction vessel, stirred and heated to 90°C and kept for 12 h, cooled to 0-10°C, methyl tert-butyl ether (2 L) was added, and stirred at 0-10°C for 1 h, filtered, and the filter cake was rinsed with methyl tert-butyl ether (400 mL). The filter cake was placed in water (600 mL) and stirred, and dichloromethane (1 L) was added. The temperature was maintained at 15-25°C, and sodium hydroxide (10% aqueous solution) was added in batches to pH = 7-9. After standing for half an hour, the organic phase was separated, and the aqueous phase was extracted three times with dichloromethane (600 mL). The organic phases were combined and anhydrous sodium sulfate (200 g) was added and stirred to dryness. The filtrate was concentrated at 30-40°C to 5% ethanol. 400 mL, ethanol (400 mL) was added, and the mixture was concentrated under reduced pressure to 400 mL. Ethanol (400 mL) was added again, and the mixture was concentrated under reduced pressure to 600 mL. The temperature was raised to 45-55 ° C and stirred until the compound was dissolved. The temperature was lowered to 0-10 ° C, and water (2 L) was slowly added dropwise over about 1 hour, and the mixture was stirred for 1 hour at this temperature. The mixture was filtered, and the filter cake was rinsed with an ethanol aqueous solution (400 mL, ethanol: water = 1: 5). The filter cake was dried in a vacuum drying oven at 35-45 ° C to obtain synthetic 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, 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=5.2Hz,2H),2.30–2.06(m,2H),1.93–1.78(m,1H). 1 The H NMR spectrum is shown in Figure 9, and the HPLC spectrum is shown in Figure 10.

[0398] Method B

[0399] Compound 6B was prepared by the same preparation method as Method A except for the following differences from Method A: the hydrochloride salt of compound 4a (0.5 g) was used, the reaction reagent / solvent was acetic acid (2.5 mL), the temperature was controlled at 100-110°C, and the HPLC content was 26% after 23 hours.

[0400] Method C

[0401] Compound 6B was prepared using the same preparation method as Method A except for the following differences from Method A: the hydrochloride salt of compound 4a (0.5 g) was used, acetic acid (2.5 mL) was used as the reaction reagent / solvent, and sodium acetate (0.24 g, 2 eq) was added. The HPLC content was 93% after 23 hours.

[0402] Method D

[0403] Compound 6B was prepared by the same preparation method as Method A except for the following difference from Method A, wherein acetic acid (0.2 eq) was added to the system, and the HPLC content was 99% after 18 hours.

[0404] Method E

[0405] Compound 6B was prepared by the same preparation method as Method A except for the following differences from Method A, wherein sodium acetate (0.5 eq) was added to the system, and the HPLC content was 99% after 18 hours.

[0406] Example 16 Preparation of Compound 6B Tartrate

[0407] Compound 6B (100 g) and acetone (500 mL) were added to the reaction vessel, the temperature was raised to 40-50 ° C and stirred for 1 h until dissolved, a solution of L-tartaric acid (30 g) in acetone (1 L) was added and stirred at 40-50 ° C for 4 h, the temperature was lowered to 15-25 ° C and stirred for 1 h, the temperature was further lowered to 0-10 ° C and stirred for 1 h, and the filter cake was filtered. The filter cake was rinsed with acetone (500 mL) and dried in a vacuum drying oven at 45-55 ° C for 24 h to obtain compound 6B tartrate (yield 122.3 g, yield 81%). 1 H 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,2 H),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 H NMR spectrum is shown in Figure 11, and the HPLC spectrum is shown in Figure 12.

[0408] Example 17 Preparation of cis-trans isomer mixture 8

[0409] To a reaction flask, add cis-trans isomer mixture 7 (25.1 g, cis:trans = 1:1.7, 1.01 eq), compound 1 (28 g, 1.0 eq), anhydrous ethanol (210 g, 9.5 V), and sodium bicarbonate (54.9 g, 4.5 eq). Heat to 70-80°C and react for 6-10 hours. After cooling to room temperature (20-30°C), add 20 V water dropwise and stir at this temperature for 0.5-1.0 hour. Cool the system further to 0-10°C and stir at this temperature for 0.5-1.0 hour. Filter under reduced pressure and rinse the filter cake with 4 V water (20-25°C). After rinsing, slurry the filter cake with 5 V water for 0.5-1.0 hour at 20-25°C, filter, rinse with 4 V water (20-25°C), and filter. The wet product was dried at 50° C. to obtain a mixture of cis and trans isomers 8 (41.9 g, 98% yield, 97.9% purity, 0.26% moisture, wherein the ratio of compound 8A to compound 3a was 1:1.7).

[0410] Example 18 Preparation of cis-trans isomer mixture 9

[0411] Combine the cis- and trans-isomer mixture 8 (19 g, 1.0 eq), water (76 g, 4 V), and methanol (15.0 g, 1 V) and raise the temperature to 60-70°C. Add 20 g of diboric acid (1.0 eq + 1.0 eq + 1.0 eq + 0.5 eq) in small portions to the mixture. After addition, raise the temperature to 70-80°C and continue the reaction for 1-3 hours. Stop the reaction when the mixture 8 is ≤ 1%. Cool the reaction mixture to 45°C and concentrate under reduced pressure to 4-5 V (primarily to remove some methanol). Continue cooling to 0-10°C and stirring for 1.0 hour. Filter under reduced pressure, rinse the filter cake with 6 V DCM, and then add sodium bicarbonate (35.43 g, 0.5 W) to the filtrate while stirring. Stir for 0.5-1.0 hour before separating the two layers. The aqueous phase was extracted four times with 3V DCM, and the combined organic phases were dried over 1W anhydrous sodium sulfate and filtered. The filtrate was concentrated to 2V DCM, and 10V TBME was slowly added dropwise with the temperature controlled at ≤30°C. After mechanical stirring for 1-2 hours, the temperature was lowered to 1-10°C and kept warm for 1-2 hours. The mixture was filtered under reduced pressure and dried at 50°C to obtain a mixture of cis and trans isomers 9 (12.77 g, 74.64% yield, 98.9% purity, 0.79% moisture, compound 9A: compound 4a = 1:1.4).

[0412] Example 19 Preparation of mixture 6Aa

[0413] R-lactic acid (13.2 g, 5 eq) was added to the cis-trans isomer mixture 9 (8 g, 1 eq), followed by methylcyclohexane (20 g). The mixture was refluxed and dehydrated until the IPC:isomer intermediate amide was less than 3%. 24 mL of methanol was added dropwise, the mixture was cooled to room temperature, and the methanol layer was separated. 15 mL of methanol was added. The mixture was cooled to below 0°C, and 4.72 g of sodium hydroxide in 11 g of water was added dropwise. The reaction was stirred until the reaction was complete. Dilute hydrochloric acid was added dropwise to adjust the pH to 7-8. After removing the solvent, 120 mL of water was added and the mixture was filtered. The wet product was added to 120 mL of water, stirred for 2 hours, filtered, and dried at 50°C to yield 5 g. The combined filtrates were extracted with 100 mL of dichloromethane (3 times), yielding the dichloromethane layer, which was then dried by spin drying to yield 3.5 g. The combined solids yielded mixture 6Aa (8.5 g, 88.6% yield, compound 6Ab:compound 6A = 1:2).

[0414] Example 20 Preparation of Compound 6A

[0415] Take the mixture 6Aa (6.5g), add potassium tert-butoxide (0.39g, 10.5mL tetrahydrofuran) solution, stir until the isomer 6Ab is 2.85%, add dilute hydrochloric acid to adjust the pH to 6-7, spin off the solvent, add 98mL water, stir for 2 hours, filter, wash with 20ml*2 water, collect the filter cake, and dry at 50℃ to obtain compound 6A (5.35g). Take 5 grams, add 28.3g isopropanol, 12g water, heat to reflux and dissolve, cool to below 5 degrees and keep warm for 3 hours, wash with 4mL mixed solvent to obtain 4.35g wet product. Add 28.3g isopropanol, 12g water, heat to reflux and dissolve, cool to below 5 degrees and keep warm for 3 hours, filter to obtain compound 6A (3.5g, purity 99.62%, isomer 0.49%, yield 54%), the obtained compound 6A 1 The H NMR spectrum is consistent with that in Figure 6.

Claims

1. A method for synthesizing a 1H-furo[3,2-b]imidazo[4,5-d]pyridine compound, comprising the following steps: Step 1: Compound 1 reacts with compound 2 or its hydrochloride salt in the presence of a base in a solvent to obtain compound 3; Step 2: Compound 3 undergoes a reduction reaction to obtain compound 4 or its hydrochloride salt; Step 3: Compound 4 or its hydrochloride salt reacts with compound 5 or compound 5' through a ring-closing reaction to obtain compound 6 or the hydrate of compound 6, where R is methyl or ethyl, and the methyl or ethyl is optionally substituted by a hydroxyl group. Preferably, R is methyl or 1-hydroxyethyl; X = CH 2 , or O.

2. According to the method described in claim 1, wherein, Compound 5 is R-lactic acid, and step 3 is: Compound 4 or its hydrochloride salt reacts with R-lactic acid through a ring-closing reaction to obtain compound 6A or compound 6C, or the hydrate of compound 6A or compound 6C.

3. According to the method described in claim 1, wherein, Compound 5' is acetic acid or acetic anhydride, and step 3 is: Compound 4 or its hydrochloride salt reacts with acetic acid and / or acetic anhydride through a ring-closing reaction to obtain compound 6B or compound 6D.

4. According to the method described in claim 1, wherein, In step 1, the base is an inorganic base.

5. According to the method described in claim 4, wherein, In step 1, the inorganic base is sodium carbonate, potassium bicarbonate or sodium bicarbonate.

6. According to the method described in claim 1, wherein, In step 1, the base is an organic base other than N,N-diisopropylethylamine.

7. According to the method described in claim 6, wherein, In step 1, the organic base is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

8. According to the method described in claim 1, wherein, In step 1, the base is N,N-diisopropylethylamine, and the solvent is a mixed solvent of ethanol and acetonitrile. Preferably, the volume ratio of acetonitrile to ethanol is 1:0.8 to 1:1.

2.

9. According to the method described in claim 1, wherein, In step 1, the solvent is ethanol and / or acetonitrile. Preferably, the solvent is ethanol, or a mixed solvent of acetonitrile and ethanol, where the volume ratio of acetonitrile to ethanol is 1:0.8 to 1:1.2; The molar ratio of compound 1 to compound 2 is 1:0.8 to 1:1.2; When compound 2 is a hydrochloride salt, the molar ratio of compound 1 to the base is 1:2 to 1:2.5, preferably 1:2.1 to 1:2.3; When compound 2 is in a salt-free form, the molar ratio of compound 1 to the base is 1:1 to 1:1.5, preferably 1:1.1 to 1:1.3; The mass-volume ratio of compound 1 to the solvent is 1:9 to 1:10; The reaction in step 1 is optionally carried out under the protection of an inert gas; The reaction temperature is 50 - 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 product.

10. According to the method described in any one of claims 1-9, wherein, In step 2, the reducing agent is a nitro reducing agent other than H 2 / Pd; The reaction in step 2 is optionally carried out under the protection of an inert gas; The reaction temperature is 15 - 90 °C.

11. According to the method described in claim 10, wherein, In step 2, the reducing agent used in the reduction reaction is Fe, B 2 (OH) 4 , or SnCl 2 .

12. According to the method described in claim 11, Among them, in Step 2, when the reducing agent is Fe, the solvent used for the reduction reaction is acetonitrile; the molar ratio of Compound 3 to Fe is 1:6 to 1:9, and the molar ratio of Compound 3 to acetic acid is 1:12 to 1:14; the mass-volume ratio of Compound 3 to the solvent is 1:4 to 1:10, preferably 1:5 to 1:9; After the reaction is completed, filter, and adjust the pH to about 6 with a sodium citrate solution, K 3 PO 4 Adjust the pH of the dilute solution to 8 - 9. After concentration, add diatomaceous earth, water, and ethyl acetate. After filtration, separate the layers. Extract the aqueous phase with ethyl acetate. After combining the organic phases, wash them with an aqueous sodium citrate solution and brine respectively. Add silica gel and anhydrous sodium sulfate, filter, rinse the filter residue with ethyl acetate, concentrate, add methyl tert-butyl ether, precipitate solids, filter, and dry to obtain the product.

13. According to the method described in Claim 11, wherein, In step 2, when the reducing agent is B 2 (OH) 4 in the case of The solvent used in the reduction reaction is a mixed solvent of water and methanol, where the volume ratio of water to methanol is from 1:1 to 9:1, preferably from 3:1 to 5:1, more preferably 4:1; Compound 3 and B 2 (OH) 4 are in a molar ratio of from 1:3 to 1:5; preferably 1:3.5; the mass-to-volume ratio of Compound 3 to the solvent is from 1:4 to 1:10, preferably from 1:5 to 1:9; B 2 (OH) 4 is fed in batches; optionally add 4,4'-bipyridine; After the reaction is completed, filter, wash the filter cake with dichloromethane, collect the filtrate and add sodium bicarbonate, stir evenly, let stand, separate the organic phase, extract the aqueous phase with dichloromethane, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, add dropwise an ethanol solution of hydrochloric acid, stir evenly, add dropwise ethyl acetate and stir evenly, filter, wash the filter cake with ethyl acetate, and dry to obtain the product.

14. According to the method described in Claim 11, wherein, In step 2, when the reducing agent is stannous chloride SnCl 2 under the condition that the solvent used for the reduction reaction is ethyl acetate; the molar ratio of Compound 3 to stannous chloride is 1:2 to 1:9, preferably 1:3 to 1:6; the mass-volume ratio of Compound 3 to the solvent is 1:4 to 1:20, preferably 1:5 to 1:15; After the reaction is completed, add sodium bicarbonate, stir and filter, wash with ethyl acetate, collect the filtrate, wash with a saturated aqueous solution of sodium bicarbonate, combine the organic phases, then wash with saturated brine, combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the product.

15. According to the method described in Claim 2 or 3, wherein, in Step 3, the ring-closing reaction is carried out in a solvent, and the solvent is toluene, dioxane, acetic acid, methylcyclohexane or acetic anhydride; when Compound 4 undergoes 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; the mass-volume ratio 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 undergoes a ring-closing reaction with acetic anhydride or acetic acid, acetic anhydride or acetic acid serves as both a reaction reagent and a solvent, and the mass-volume ratio 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 to the ring-closing reaction of Compound 4 with Compound 5 or Compound 5', and the acid catalyst is preferably methanesulfonic acid; the reaction temperature is 80 - 120 °C; After the reaction is completed, cool, extract, adjust the pH to 7 - 10, and dry the obtained solid to obtain the product.

16. According to the method described in Claim 2, wherein, in the synthesis method of Compound 6A, in Step 3, Compound 4 is Compound 4a, the ring-closing reaction is carried out in a solvent, and the solvent is 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-volume ratio (g / mL) of compound 4a to the solvent is from 1:1.5 to 1:40, preferably from 1:1.5 to 1:30, more preferably from 1:1.5 to 1:15, and most preferably from 1:1.5 to 1:5; After the reaction is completed, methanol is added, and the methanol layer is obtained by liquid separation. Sodium hydroxide solution is added and stirred, hydrochloric acid is added dropwise until the pH is about 7, the solvent is removed under reduced pressure and water is added and stirred, the solid is filtered, washed with water, and dried to obtain compound 6A.

17. According to the method described in claim 2, wherein, In the synthesis method of compound 6C, in step 3, compound 4 is compound 4b, The ring-closing reaction is carried out in a solvent, wherein the solvent is toluene, dioxane, or methylcyclohexane, preferably toluene or methylcyclohexane, and more preferably methylcyclohexane; The molar ratio of compound 4b to R-lactic acid is from 1:4 to 1:30, preferably from 1:4 to 1:20, more preferably from 1:4 to 1:10, and most preferably from 1:5 to 1:7; The mass-volume ratio (g / mL) of compound 4b to the solvent is from 1:1.5 to 1:40, preferably from 1:1.5 to 1:30, more preferably from 1:1.5 to 1:15, and most preferably from 1:1.5 to 1:5; After the reaction is completed, methanol is added, and the methanol layer is obtained by liquid separation. Sodium hydroxide solution is added and stirred, hydrochloric acid is added dropwise until the pH is about 7, the solvent is removed under reduced pressure and water is added and stirred, the solid is filtered, washed with water, and dried to obtain compound 6C.

18. According to the method described in claim 3, wherein in the synthesis method of compound 6B, in step 3, compound 4 is compound 4a, Acetic acid or sodium acetate is optionally added in the ring-closing reaction of compound 4a with acetic anhydride, wherein the molar ratio of compound 4a to acetic acid is from 1:0.1 to 1:0.5, preferably from 1:0.2 to 1:0.3, and the molar ratio of compound 4a to sodium acetate is from 1:0.2 to 1:1; Sodium acetate is optionally added in the ring-closing reaction of compound 4a with acetic acid, wherein the molar ratio of compound 4a to sodium acetate is from 1:1 to 1:

3.

19. According to the method described in claim 3, wherein in the synthesis method of compound 6B, in step 3, compound 4 is compound 4a, In the case of the ring-closing reaction of compound 4a with acetic anhydride, the mass-volume ratio of compound 4a to acetic anhydride is from 1:2 to 1:5; In the case of the ring-closing reaction of compound 4a with acetic acid, the mass-volume ratio of compound 4a to acetic acid is from 1:3 to 1:8; The reaction temperature is 80 - 120 °C, preferably 90 - 110 °C; After the reaction was completed, methyl tert-butyl ether was added, and the mixture was stirred evenly, filtered, and the filter cake was dissolved in a mixed solvent of water and dichloromethane. An aqueous NaOH solution was added dropwise until the pH = 7-10. The layers were separated, and the aqueous layer was extracted with dichloromethane. The organic phases were combined and dried over anhydrous Na 2 SO 4 dried, filtered, concentrated, ethanol was added, water was added and stirred, filtered, and the filter cake was dried to obtain Compound 6B.

20. According to the method described in claim 3, wherein, In the synthesis method of compound 6D, in step 3, compound 4 is compound 4b, Acetic acid or sodium acetate is optionally added in the ring-closing reaction of compound 4b with acetic anhydride, wherein the molar ratio of compound 4b to acetic acid is from 1:0.1 to 1:0.5, preferably from 1:0.2 to 1:0.3, and the molar ratio of compound 4b to sodium acetate is from 1:0.2 to 1:1, preferably from 1:0.4 to 1:0.8; In the case of the cyclization reaction of compound 4b with acetic acid, sodium acetate is optionally added, where the molar ratio of compound 4b to sodium acetate is 1:1 to 1:3, preferably 1:1.5 to 1:2.

5.

21. The method according to claim 3, wherein in the synthesis method of compound 6D, in step 3, compound 4 is compound 4b, In the case of the cyclization reaction of compound 4b with acetic anhydride, the mass-to-volume ratio of compound 4b to acetic anhydride is 1:2 to 1:5; In the case of the cyclization reaction of compound 4b with acetic acid, the mass-to-volume ratio of compound 4b to acetic acid is 1:3 to 1:8; The reaction temperature is 80 - 120 °C, preferably 90 - 110 °C; After the reaction was completed, methyl tert-butyl ether was added, and the mixture was stirred evenly, filtered, and the filter cake was dissolved in a mixed solvent of water and dichloromethane. An aqueous NaOH solution was added dropwise until the pH was 7-10. Liquid separation was carried out, and the aqueous layer was extracted with dichloromethane. The organic phases were combined and dried over anhydrous Na 2 SO 4 dried, filtered, concentrated, ethanol was added, water was added and stirred, filtered, and the filter cake was dried to obtain Compound 6D.

22. The method according to claim 1, wherein compound 1 is synthesized through the following steps: Step 1-1: Compound 1-1 reacts with triphenylphosphine to obtain compound 1-2; Step 1-2: Compound 1-2 reacts with ethyl formate to obtain compound 1-3; Step 1-3: Compound 1-3 undergoes demethylation reaction and acetal reaction to obtain compound 1-4; Step 1-4: Compound 1-4 cyclizes under acidic conditions to obtain compound 1-5; Step 1-5: Compound 1-5 undergoes nitration reaction to obtain compound 1-6; Step 1-6: Compound 1-6 undergoes chlorine substitution to obtain compound 1.

23. The method according to claim 22, wherein, in the synthesis method of compound 1, in step 1-1: Sodium carbonate is added to the mixture of compound 1-1, toluene and water, stirred at room temperature, layered, the aqueous phase is extracted with toluene, the organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, triphenylphosphine is added to the filtrate, heated to 110 - 120 °C for reflux reaction, after the reaction is completed, the reaction solution is cooled to 20 - 30 °C, filtered, the wet product is rotary evaporated under reduced pressure to obtain compound 1-2; in step 1-2: A metal tert-butoxide is added to the mixture of compound 1-2 and dimethyl sulfoxide, after addition, stirred evenly at room temperature, ethyl formate is added dropwise, the reaction solution is heated to 40 - 50 °C, kept stirring, after the reaction is completed, the reaction solution is cooled to room temperature, added to an organic solvent and water for extraction, layered, the organic phase is washed with water, the pH is adjusted to 5 - 6 with hydrochloric acid, layered, the aqueous phase is extracted with an organic solvent, the pH is adjusted to ≥8 with a base, layered, the aqueous phase is extracted with an organic solvent, the organic phases are combined, washed with water, anhydrous sodium sulfate is added to the organic phase for drying, filtered, the solvent is removed to obtain compound 1-3; in step 1-3: Boron tribromide is added dropwise to the mixture of compound 1-3 and dichloromethane, after the addition is completed, the reaction solution is kept stirring evenly at 20 - 30 °C, the reaction solution is added dropwise to ethanol, after the addition is completed, stirred evenly, the solvent is removed under reduced pressure, ethanol is added, the solvent is removed under reduced pressure, an ethanol solution of sodium ethoxide is added dropwise until the pH of the material is 5 - 6 and the addition is stopped, filtered, the filter cake is rinsed with ethanol, an ethanol solution of sodium ethoxide is added dropwise to the filtrate until the pH of the material is 8 - 9 and the addition is stopped, the solvent is removed under reduced pressure, methyl tert-butyl ether is added, stirred evenly, filtered, the filter cake is rinsed with methyl tert-butyl ether, dried to obtain compound 1-4; in step 1-4: Add benzoyl chloride dropwise to the dichloromethane solution of Compound 1-4. After the addition is complete, stir evenly. Then add the reaction solution dropwise to concentrated sulfuric acid, stir evenly, add the reaction solution dropwise to water, filter, adjust the pH of the filtrate to 7-8, stir evenly after the addition is complete, filter, wash the filter cake with water, and dry to obtain Compound 1-5; In Step 1-5: Add nitric acid dropwise to the mixed solution of acetic acid and acetic anhydride. After the addition is complete, stir evenly. Then add the mixed solution of acetic acid, acetic anhydride and nitric acid dropwise to the acetic acid solution of Compound 1-5. After the addition is complete, stir evenly. After the reaction is complete, add methyl tert-butyl ether to the reaction solution, stir evenly and then filter. Wash the filter cake with methyl tert-butyl ether and dry to obtain Compound 1-6; In Step 1-6: Add phosphorus oxychloride dropwise to the mixture of Compound 1-6, N,N-dimethylformamide and toluene. After the addition is complete, heat to 35-75 °C, stir evenly. After the reaction is complete, cool the reaction solution to room temperature, distill off toluene, add dichloromethane and an aqueous solution of potassium carbonate or sodium bicarbonate, separate the layers, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, filter, and distill off the solvent to obtain Compound 1.

24. According to the method described in Claim 22, wherein, in Step 1-1, in the mixture of Compound 1-1, toluene and water, the mass-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 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 in Step 1-1 is optionally carried out under the protection of an inert gas.

25. According to the method described in Claim 22, wherein, in Step 1-2, the metal tert-butoxide is potassium tert-butoxide or sodium tert-butoxide; the base used to adjust the pH is ammonia water or sodium carbonate; the organic solvent used for extraction is methyl tert-butyl ether or ethyl acetate; the mass-volume ratio of Compound 1-2 to dimethyl sulfoxide is 1:3 to 1:5; the molar ratio of Compound 1-2 to the 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 in Step 1-2 is optionally carried out under the protection of an inert gas.

26. According to the method described in Claim 22, wherein, in Step 1-3, the mass-volume ratio 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 reaction in Step 1-3 is optionally carried out under the protection of an inert gas.

27. According to the method described in Claim 22, wherein, in Step 1-4, the mass-volume ratio of Compound 1-4 to concentrated sulfuric acid is 1:2 to 1:5; the mass-volume ratio 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.

28. According to the method described in Claim 22, wherein, in Step 1-5, In the acetic acid solution of Compounds 1-5, the mass ratio of Compounds 1-5 to acetic acid is from 1:9 to 1:11, preferably 1:10; In the mixture of Compounds 1-5, acetic acid, acetic anhydride and nitric acid, the mass ratio of Compounds 1-5 to acetic acid is from 1:3 to 1:5; The molar ratio of Compounds 1-5 to acetic anhydride is from 1:2 to 1:5, preferably from 1:2.6 to 1:4.2; The molar ratio of Compounds 1-5 to nitric acid is from 1:2 to 1:5, preferably from 1:2.5 to 1:4.0; The reaction of Step 1-5 is optionally carried out under the protection of an inert gas.

29. According to the method described in Claim 22, wherein, In Step 1-6, The molar ratio of Compounds 1-6 to N,N-dimethylformamide is from 1:1 to 1:1.2; The mass-to-volume ratio of Compounds 1-6 to toluene is from 1:9 to 1:11, preferably 1:10; The molar ratio of Compounds 1-6 to phosphorus oxychloride is from 1:1.8 to 1:2.2, preferably 1:2; The reaction of Step 1-6 is optionally carried out under the protection of an inert gas.

30. According to the method described in Claim 1, wherein, When Compound 2 is Compound 2a, the hydrochloride of Compound 2a is synthesized by the following steps: Step 2-1: Compound 2-1 undergoes a ring-closing reaction under the catalysis of sodium methoxide to obtain Compound 2-2; Step 2-2: Compound 2-2 reacts with hydrochloric acid to obtain the hydrochloride of Compound 2a.

31. According to the method described in Claim 30, wherein, In the synthesis method of the hydrochloride of Compound 2a, In Step 2-1: A sodium methoxide methanol solution is added dropwise to the mixture of Compound 2-1 and tetrahydrofuran. After the addition is complete, the mixture is stirred evenly. After the reaction is completed, an ammonium chloride solution is added dropwise to the reaction solution until the pH of the system is 7-8. Then, extraction is carried out with methyl tert-butyl ether, washing is carried out with a sodium chloride solution, drying is carried out with anhydrous sodium sulfate, filtration is carried out by suction, and the filter cake is dried to obtain Compound 2-2; In Step 2-2: A hydrogen chloride ethanol solution is added dropwise to the mixture of Compound 2-2 and dichloromethane. After the addition is complete, the mixture is stirred evenly. After the reaction is completed, filtration is carried out, and the filter cake is rinsed with dichloromethane and dried to obtain the hydrochloride of Compound 2a.

32. According to the method described in Claim 30, wherein, In Step 2-1, The mass-to-volume ratio of Compound 2-1 to tetrahydrofuran is from 1:10 to 1:12, preferably from 1:10 to 1:11; The molar ratio of Compound 2-1 to the sodium methoxide methanol solution is from 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.

33. According to the method described in Claim 30, wherein, In Step 2-2, The mass-to-volume ratio of Compound 2-2 to dichloromethane is from 1:5 to 1:7, preferably 1:6; The molar ratio of Compound 2-2 to the hydrogen chloride ethanol solution is from 1:2 to 1:5, preferably 1:3; The reaction of Step 2-2 is optionally carried out under the protection of an inert gas.

34. A method for synthesizing a 1H-furo[3,2-b]imidazo[4,5-d]pyridine compound, comprising the following steps: Step 1A: Compound 1 reacts with a cis-trans isomer mixture 7 in the presence of a base in a solvent to obtain a cis-trans isomer mixture 8; Step 2A: The cis-trans isomer mixture 8 is subjected to a reduction reaction to obtain a cis-trans isomer mixture 9 or its hydrochloride salt; Step 3A: The cis-trans isomer mixture 9 or its hydrochloride salt reacts with compound 5 or compound 5' through a ring-closing reaction to obtain a mixture 10 or a hydrate of mixture 10, where R is methyl or ethyl, and the methyl or ethyl is optionally substituted by a hydroxyl group. Preferably, R is methyl or 1-hydroxyethyl; Step 4A: The mixture 10 or the hydrate of mixture 10 undergoes an isomerization reaction under alkaline conditions to obtain compound 6 or a hydrate of compound 6.

35. The method according to claim 34, wherein, the reaction conditions of Step 1A are defined as in any one of claims 4-9.

36. The method according to claim 34, wherein, the reaction conditions of Step 2A are defined as in any one of claims 10-14.

37. The method according to claim 34, wherein, the reaction conditions of Step 3A are defined as in any one of claims 2, 3, 15-21.

38. The method according to claim 34, wherein, Step 4A is: The mixture 6Aa or the hydrate of mixture 6Aa undergoes an isomer conversion reaction under alkaline conditions to obtain a hydrate of compound 6A.

39. The method according to claim 38, wherein, The base is an alcoholate base, preferably an alkali metal C 1-6 alcoholate, more preferably, potassium tert-butoxide.

40. The method according to claims 38-39, wherein, in the synthesis method of the hydrate of compound 6A, in Step 4A, the reaction is carried out in a solvent, and the solvent is 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 completed, dilute hydrochloric acid is added to adjust the pH to 6-7, the solvent is removed by rotary evaporation, water is added and stirred, filtered, washed with water, the filter cake is collected, and dried to obtain the hydrate of compound 6A.

41. The method according to claim 34, wherein, Step 4A is: The mixture 6Ba or the hydrochloride salt of mixture 6Ba undergoes an isomer conversion reaction under alkaline conditions to obtain compound 6B.

42. The method according to claim 41, wherein, the base is an alcohol salt of an alkali metal, preferably an alkali metal C1-6 alcohol salt, more preferably potassium tert-butoxide.

43. The method according to claims 41-42, wherein, in the synthesis method of compound 6B, in Step 4A, the reaction is carried out in a solvent, and the solvent is 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 completed, dilute hydrochloric acid is added to adjust the pH to 6-7, the solvent is removed by rotary evaporation, water is added and stirred, filtered, washed with water, the filter cake is collected, and dried to obtain compound 6B.