Synthetic method of medical intermediate 7-hydroxyfuro [3, 2-b] pyridine and intermediate compound thereof

Abstract

The invention belongs to the technical field of medicine synthesis, and provides a synthesis method of a medical intermediate 7-hydroxyfuro [3, 2-b] pyridine and an intermediate compound thereof. The preparation method comprises the following steps: taking maltol as a raw material, carrying out hydroxyl protection to obtain a compound shown in a formula II, reacting with N, N-dimethylformamide dimethyl acetal to obtain a compound shown in a formula III, reacting with alcohol under an acidic condition to obtain a compound shown in a formula IV, reacting with ammonia water to obtain a compound shown in a formula V, and carrying out dehydroxylation protection to obtain a compound shown in a formula VI. And performing dealcoholization and cyclization under an acidic condition to obtain the target compound 7-hydroxyfuro [3, 2-b] pyridine. The method has the advantages of simple synthesis steps, convenient process, simple and easily available raw materials, low cost, convenient operation method and high overall yield, and is suitable for industrial large-scale production. The intermediate compounds shown in the formula IV and the formula V and tautomers of the intermediate compounds can be used for preparing 7-chloro-6-nitrofuro [3, 2-b] pyridine as a key starting material of a JAK1 / TYK2 dual inhibitor.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a method for synthesizing the pharmaceutical intermediate 7-hydroxyfurano[3,2-b]pyridine and its intermediate compound. Background Technology

[0002] Compound 7-hydroxyfurano[3,2-b]pyridine, as a pharmaceutical intermediate, can be used in the synthesis of highly selective JAK1 inhibitors and JAK1 / TYK2 dual inhibitors. It has been used in patents WO2018067422 and WO2023125102, as shown in the reaction routes below, for the synthesis of 1H-furano[3,2-b]imidazole[4,5-d]pyridine derivatives, such as compound 6B (formula VIII, CAS No. 2222137-86-0), which can be used to synthesize its key starting material, 7-chloro-6-nitrofurano[3,2-b]pyridine (formula IX, CAS No. 2222137-89-3).

[0003]

[0004] The prior art for the synthesis of compound 7-hydroxyfurano[3,2-b]pyridine is as follows:

[0005] (1) The synthetic route disclosed in patent WO200551304 is as follows:

[0006]

[0007] (2) The synthetic route disclosed in patent CN114213424B is as follows:

[0008]

[0009] (3) The synthetic route disclosed in patent CN118324772A is as follows:

[0010]

[0011] The aforementioned existing technologies all have various shortcomings. For example, WO200551304 uses 2-bromo-3-hydroxypyridine as a raw material and trimethylsilyne to undergo a Sonogashira coupling reaction under palladium metal catalysis. It also requires the use of palladium metal catalyst Pd(PPh3)2Cl2, resulting in high synthesis costs. Furthermore, the yield of each step is relatively low, around 60%, and several steps require column purification, making it unsuitable for industrial production.

[0012] CN114213424B uses 2-chloromethyl-3,4-dimethoxypyridine hydrochloride as a raw material. This raw material itself is prepared from methyl maltol through a 6-step reaction. The price of the raw material is relatively high. The demethylation process in the reaction requires a large amount of boron tribromide, which is also expensive. In addition, a large amount of hydrogen bromide fumes are generated, which is unsafe, uneconomical and environmentally unfriendly.

[0013] CN118324772A also uses 2-chloromethyl-3,4-dimethoxypyridine hydrochloride as raw material, which involves complicated steps and the use of precious metal reagent silver carbonate, resulting in poor selectivity and high cost.

[0014] Although the literature (Org. Process Res.Dev.2023,27,1015-1026) discloses Equations II and III (R 1 =Bn,R 2 The preparation method of =Me) is described, but formulas IV and V or V' have not been reported. Summary of the Invention

[0015] To address the aforementioned technical problems, this invention provides a method for synthesizing the pharmaceutical intermediate 7-hydroxyfurano[3,2-b]pyridine and its intermediate compound, aiming to overcome the shortcomings of existing methods for synthesizing 7-hydroxyfurano[3,2-b]pyridine compounds, such as high cost, complex operation, and unsuitability for industrial production.

[0016] To achieve this objective, the present invention adopts the following technical solution:

[0017] In a first aspect, the present invention provides a method for synthesizing the pharmaceutical intermediate 7-hydroxyfurano[3,2-b]pyridine, comprising the following steps:

[0018] Step S1: Compound I is protected by a protecting group on its hydroxyl group under alkaline conditions to generate compound II;

[0019] In step S2, compound II reacts with N,N-dimethylformamide dimethyl acetal (DMF-DMA) in a solvent to generate compound III;

[0020] Step S3: Compound III reacts in an alcohol under acidic conditions to generate compound IV;

[0021] Step S4: Compound IV reacts with an amination agent in a solvent to generate compound V or V'.

[0022] Step S5: Compound V or V' undergoes dehydroxylation protection in a solvent to generate compound VI or VI'.

[0023] Step S6, under acidic conditions, compound VI or VI' is cyclized to form compound VII or VII', namely 7-hydroxyfurano[3,2-b]pyridine;

[0024] The specific synthetic route of this method is as follows:

[0025]

[0026] Among them, R 1 It is any one of methyl, benzyl, or 4-methoxybenzyl; N(R 2 )2 is dimethylamino, tetrahydropyrrole, or morpholino; R 3 It is a C1-C4 alkyl group. In this invention, R 1 For protection of the base. Also, when R... 1 Methyl, N(R) 2 When )2 is a dimethylamino group, compound III can be prepared directly from compound I.

[0027] Preferably, in step S1, a benzyl compound is added as a reactant to carry out the reaction, R 1 The solvent is benzyl, and the reaction solvent is acetonitrile or N,N-dimethylformamide, preferably acetonitrile; the base is potassium carbonate, sodium carbonate or potassium hydroxide, preferably potassium carbonate; the reaction is preferably carried out by heating to reflux.

[0028] More preferably, in step S1, the benzyl compound is a halobenzyl (R 1 -X), where benzyl halide is benzyl chloride or benzyl bromide. The molar ratio of benzyl halide to compound I is 1-1.5:1, preferably 1:1; the volume ratio of reaction solvent to compound I is 5-15:1, preferably 8:1; the molar ratio of base to compound I is 0.8-1.8:1, preferably 1.2:1.

[0029] Preferably, in step S2, the solvent is any one of N,N-dimethylformamide, toluene, or xylene, with N,N-dimethylformamide being preferred; when N(R 2 When )2 is tetrahydropyrrole or morpholino, tetrahydropyrrole or morpholino is added as an additional reactant, and the molar ratio of tetrahydropyrrole or morpholino to compound II is 1:1.

[0030] Preferably, in step S2, the volume ratio of the solvent to the compound of formula II is 2-5:1, more preferably 2.5:1; the molar ratio of N,N-dimethylformamide dimethyl acetal (DMF-DMA) to the compound of formula II is 1-5:1, more preferably 1.5:1; and the reaction temperature is 110℃-140℃, more preferably 120℃-130℃.

[0031] Preferably, in step S3, the alcohol is one of C1-C4 alkyl alcohols, preferably ethanol; the acid is one or more of sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid or trifluoromethanesulfonic acid, preferably p-toluenesulfonic acid; and the reaction is preferably carried out by heating to reflux.

[0032] Preferably, in step S3, the volume ratio of alcohol to compound of formula III is 5-20:1, more preferably 10:1; the molar ratio of acid to compound of formula III is 1.5-3:1, more preferably 2:1.

[0033] Preferably, in step S3, after the reaction is complete, potassium carbonate, sodium carbonate, sodium hydroxide, or potassium hydroxide is added to the system to adjust the pH value.

[0034] Preferably, in step S4, the solvent is any one or more of methanol, ethanol, dioxane, or tetrahydrofuran, with ethanol being preferred; the ammonia-forming agent is any one or more of ammonia, ammonium acetate, or ammonium carbonate, with concentrated ammonia having a concentration of 25%-28% being preferred; the reaction is preferably carried out at a temperature of 35°C-100°C, and more preferably at a reaction temperature of 60°C-70°C.

[0035] Preferably, in step S4, the volume ratio of the solvent to the compound of formula IV is 3-10:1, more preferably 5:1; the ammoniaizing agent is ammonia water, and the volume ratio of ammonia water to the compound of formula IV is 3-10:1, more preferably 5:1.

[0036] Preferably, in step S5, the solvent is any one or more of ethanol, methanol, tetrahydrofuran, dichloromethane or ethyl acetate, with ethanol being preferred; the volume ratio of the solvent to the compound of formula V is 5-15:1, with a preferred volume ratio of 10:1.

[0037] Preferably, in step S5, when R 1 When the protecting group is benzyl, the dehydroxylation protection is performed by palladium-carbon hydrogenation with 10% palladium on carbon, and the weight ratio of 10% palladium on carbon to compound of formula V is 0.1:1. In step S5, the pyridine-3-O- protecting group is selectively removed, and the protecting group is benzyl or 4-methoxybenzyl selectively hydrogenated with palladium on carbon; when the protecting group is methyl, methods such as boron tribromide, hydrogen bromide, or a pyridine-magnesium bromide composition can be selected.

[0038] Preferably, in step S6, the acid is concentrated sulfuric acid.

[0039] Preferably, in step S6, the volume ratio of concentrated sulfuric acid to compound of formula VI is 2-5:1, and more preferably 4:1.

[0040] Secondly, the present invention provides an intermediate compound that can be used in the synthesis of the pharmaceutical intermediate 7-hydroxyfurano[3,2-b]pyridine, the structure of which is shown in Formula IV:

[0041] Among them, R 1 It is any one of methyl, benzyl, or 4-methoxybenzyl; R 3 It is a C1-C4 alkyl group.

[0042] Preferred, R 1It is benzyl; R 3 It is methyl or ethyl, more preferably ethyl.

[0043] Thirdly, the present invention provides an intermediate compound that can be used in the synthesis of the pharmaceutical intermediate 7-hydroxyfurano[3,2-b]pyridine, the structure of which is shown in formula V or V':

[0044] Wherein, equations V and V' are tautomers; R 1 It is any one of methyl, benzyl, or 4-methoxybenzyl; R 3 It is a C1-C4 alkyl group.

[0045] Preferred, R 1 It is benzyl; R 3 It is methyl or ethyl, more preferably ethyl.

[0046] This invention uses inexpensive chemical maltol (compound I) as a raw material. After hydroxyl protection, compound II is obtained. This compound reacts with N,N-dimethylformamide dimethyl acetal to obtain compound III. Under acidic conditions, it reacts with an alcohol to obtain compound IV. It reacts with ammonia to obtain compound V. Dehydroxylation protection yields compound VI. Under acidic conditions, de-alcoholization and cyclization give the target compound 7-hydroxyfurano[3,2-b]pyridine (compound VII). Compared with the prior art, this invention has at least the following beneficial effects:

[0047] 1. The synthesis steps of this invention are simple, the process is simple, the raw materials are simple and readily available, the cost is low, and the operation method is convenient, making it suitable for industrial-scale production.

[0048] 2. Low raw material cost and large output, high yield per step, high overall yield, economical, safe and environmentally friendly.

[0049] 3. Intermediate compounds of formulas IV and V and their tautomers can be used as key starting materials for the preparation of JAK1 / TYK2 dual inhibitors, namely 7-chloro-6-nitrofurano[3,2-b]pyridine. Attached Figure Description

[0050] Figure 1 The NMR spectrum of compound II-a;

[0051] Figure 2 The NMR spectrum of compound III-a in Example 1;

[0052] Figure 3 The NMR spectrum of compound IV-a in Example 1;

[0053] Figure 4 The NMR spectrum of compound V-a in Example 1;

[0054] Figure 5The NMR spectrum of compound VI-a in Example 1;

[0055] Figure 6 The NMR spectrum of compound VII in Example 1;

[0056] Figure 7 The HPLC chromatogram of compound VII in Example 1;

[0057] Figure 8 The NMR spectrum of compound III-b in Example 2;

[0058] Figure 9 The NMR spectrum of compound IV-b in Example 2;

[0059] Figure 10 The NMR spectrum of compound V-b in Example 2;

[0060] Figure 11 The NMR spectrum of compound VI-b in Example 2;

[0061] Figure 12 The NMR spectrum of compound VII in Example 2;

[0062] Figure 13 The NMR spectrum of compound VIII in the application example;

[0063] Figure 14 The NMR spectrum of compound IX in the application example. Detailed Implementation

[0064] The technical solution of the present invention will be further described below with reference to the accompanying drawings and specific embodiments. However, the following examples are merely simplified examples of the present invention and do not represent or limit the scope of protection of the present invention. The scope of protection of the present invention is determined by the claims.

[0065] Unless otherwise specified, the raw materials and materials used in the embodiments of the present invention were purchased through general commercial channels.

[0066] The source information of the relevant raw materials and instruments involved in the following embodiments is as follows:

[0067] Raw material information:

[0068] Name Manufacturer

[0069] Maltol (Formula I), Leyan;

[0070] Benzyl chloride, Amex;

[0071] Benzyl bromide, Energi;

[0072] Potassium carbonate, Shanghai Chutai Pharmaceutical & Chemical Technology Co., Ltd.

[0073] Acetonitrile, Shanghai Chutai Pharmaceutical & Chemical Technology Co., Ltd.;

[0074] N,N-Dimethylformamide, Anage;

[0075] Tetrahydropyrrole, Amex;

[0076] Ethyl acetate (Shanghai Chutai Pharmaceutical Chemical Technology Co., Ltd.)

[0077] Methyl tert-ethyl ether (Shanghai Chutai Pharmaceutical Chemical Technology Co., Ltd.)

[0078] Amex p-Toluenesulfonic acid;

[0079] Ethanol, Shanghai Chutai Pharmaceutical Chemical Technology Co., Ltd.;

[0080] Sodium carbonate, Shanghai Chutai Pharmaceutical Chemical Technology Co., Ltd.

[0081] Ammonia water from Shanghai Chutai Pharmaceutical Chemical Technology Co., Ltd.

[0082] 10% Palladium on Carbon (Antec);

[0083] Yonghua sulfuric acid;

[0084] Instrument Information:

[0085] Name Model

[0086] Magnetic stirrer, 98-2;

[0087] Thermostatic magnetic stirrer, HQ98-3;

[0088] Circulating water type multi-purpose vacuum pump, SHZ-DⅢ;

[0089] Rotary evaporator, RE206B;

[0090] High performance liquid chromatograph, Agilent 1260;

[0091] Chromatographic column: YMC-AQ 150mm*4.6mm, 5µm;

[0092] Liquid chromatography-mass spectrometry (LC-MS) system, Shimadzu LCMS-2020;

[0093] Outsourced testing: MRI H 1 -NMR, Ausnutria (Shanghai) Testing Technology Co., Ltd.

[0094] <Example 1>

[0095] This embodiment prepares 7-hydroxyfurano[3,2-b]pyridine, including the following steps:

[0096] Step S1: Synthesize compound II-a from compound I according to the following synthetic route.

[0097]

[0098] The specific steps are as follows:

[0099] 800 mL of acetonitrile was added to a 2 L three-necked flask, followed by stirring and the addition of 100 g of maltol (compound of formula I), 131.4 g of potassium carbonate, and 100.3 g of benzyl chloride. The mixture was heated under reflux for 5 h. After the reaction was complete, the mixture was cooled to room temperature, filtered, and evaporated to dryness to obtain 171.5 g of an oily substance, which is compound of formula II. The molar yield was 100% (based on compound of formula I). ​​NMR data are available. Figure 1 . 1 ¹H NMR (400MHz, Chloroform-d) δ 7.58 (dd, J = 5.6, 1.5Hz, 1H), 7.43–7.22 (m, 5H), 6.35 (dd, J = 5.5, 2.0Hz, 1H), 5.14 (d, J = 1.9Hz, 2H), 2.07 (d, J = 1.8Hz, 3H). Mass analysis of compound II was performed using LC-MS (M+H). + =217.02.

[0100] Step S2: Synthesize compound III-a from compound II-a according to the following synthetic route.

[0101]

[0102] The specific steps are as follows:

[0103] 170g of compound II-a was added to a 2L three-necked flask, along with 425mL of N,N-dimethylformamide, 55.9g of tetrahydropyrrole, and 40.5g of N,N-dimethylformamide dimethyl acetal. The mixture was heated to 120℃-130℃ and reacted for 2 hours until complete. The mixture was then cooled, and 1300mL of water was added. The mixture was extracted three times with 600mL of ethyl acetate, washed twice with 500mL of saturated brine, and evaporated to dryness. The residue was then slurried with 1700mL of methyl ether and filtered to obtain 197.2g of a pale yellow solid, which is compound III-a (N(R...). 2 (2 is tetrahydropyrrole), molar yield 84.3% (based on compound II-a), NMR data are shown below. Figure 2 . 1¹H NMR (400 MHz, Chloroform-d) δ 7.45 (d, J = 6.6 Hz, 2H), 7.39 (d, J = 5.6 Hz, 1H), 7.35–7.19 (m, 4H), 6.20 (d, J = 5.5 Hz, 1H), 5.09 (s, 2H), 4.97 (d, J = 13.3 Hz, 1H), 3.20 (s, 4H), 1.91 (q, J = 4.5, 3.0 Hz, 4H). Mass analysis of compound III-a was performed using LC-MS (M+H). + =298.14.

[0104] Step S3: Synthesize compound IV-a from compound III-a according to the following synthetic route.

[0105]

[0106] The specific steps are as follows:

[0107] 190 g of compound III-a was added to a 3 L three-necked flask, followed by 1900 mL of ethanol and 220 g of p-toluenesulfonic acid. The mixture was heated to reflux and reacted for 4 h until complete. The mixture was then cooled to room temperature, and sodium carbonate was slowly added to adjust the pH to alkalinity. The mixture was stirred for 1 h, filtered, and evaporated to dryness to obtain 173.6 g of an oily substance, which is compound IV-a, with a molar yield of 85.3% (based on compound III-a). NMR data are shown below. Figure 3 . 1 ¹H NMR (400MHz, Chloroform-d) δ 7.64 (dd, J = 5.6, 1.0 Hz, 1H), 7.44–7.28 (m, 5H), 6.38 (dd, J = 5.7, 1.0 Hz, 1H), 5.18 (s, 2H), 4.68 (t, J = 5.9 Hz, 1H), 3.60 (dq, J = 8.8, 7.0 Hz, 2H), 3.42 (dq, J = 9.1, 7.0 Hz, 2H), 2.84 (d, J = 5.9 Hz, 2H), 1.13 (t, J = 7.1 Hz, 6H). Mass analysis of compound IV-a was performed using LC-MS / MS. MS: [M+H] + =319.12.

[0108] Step S4: Synthesize compound V-a from compound IV-a according to the following synthetic route.

[0109]

[0110] The specific steps are as follows:

[0111] 170 g of compound IV-a was added to a 3 L three-necked flask, followed by 850 ml of ethanol and 850 ml of 28% concentrated ammonia. The mixture was heated to 60-70 °C and reacted for 10 h until complete. The mixture was then cooled to room temperature, and the ethanol was removed by rotary evaporation. The extract was obtained twice with 600 ml of ethyl acetate and washed twice with 500 ml of saturated brine. The extract was then evaporated to dryness to obtain 124.4 g of an oily substance, which is compound V-a, with a molar yield of 73.1% (based on compound IV-a). NMR data are shown below. Figure 4 . 1 ¹H NMR (400MHz, Chloroform-d) δ 7.37 (d, J = 6.0 Hz, 2H), 7.35–7.27 (m, 5H), 6.45 (d, J = 6.4 Hz, 1H), 5.22 (s, 2H), 4.39 (d, J = 5.1 Hz, 1H), 3.58 (dt, J = 14.5, 7.2 Hz, 2H), 3.37 (dt, J = 9.3, 6.8 Hz, 2H), 2.78 (d, J = 5.0 Hz, 2H), 1.13 (t, J = 7.0 Hz, 6H). Mass analysis of compound V-a was performed using LC-MS. MS: [M+H] + =318.12.

[0112] Step S5: Synthesize compound VI-a from compound V-a according to the following synthetic route.

[0113]

[0114] The specific steps are as follows:

[0115] 120 g of compound V-a was added to a 2 L three-necked flask, followed by 1200 mL of ethanol and 12 g of 10% palladium on carbon. Hydrogen gas was bubbled through the mixture, and the reaction was allowed to proceed for 18 h until complete. The palladium on carbon was filtered off, and the mixture was evaporated to dryness to obtain 81.3 g of solid, which is compound VI-a. The molar yield was 95.3% (based on compound V-a). NMR data are shown below. Figure 5 . 1 ¹H NMR (400 MHz, Chloroform-d) δ 9.76 (s, 1H), 7.32 (d, J = 7.0 Hz, 1H), 6.42 (d, J = 6.7 Hz, 1H), 4.77 (q, J = 6.7, 4.8 Hz, 1H), 3.74 (td, J = 12.9, 10.9, 6.2 Hz, 2H), 3.56 (dt, J = 14.1, 7.1 Hz, 2H), 3.07 (d, J = 4.7 Hz, 2H), 1.22 (t, J = 7.0 Hz, 6H). The mass fraction of compound VI-a was analyzed using LC-MS (M+H). + =228.14.

[0116] Step S6: Synthesize compound VII from compound VI-a according to the following synthetic route.

[0117]

[0118] The specific steps are as follows:

[0119] 320 ml of concentrated sulfuric acid was added to a 2 L three-necked flask, and 80 g of compound VI-a was slowly added. The reaction temperature was controlled at room temperature, and the mixture was stirred for 2 hours until the reaction was complete. The temperature was then lowered to 0-5 °C, and 640 ml of water was slowly added to dilute the sulfuric acid. The pH was adjusted to above 8 with 28% concentrated ammonia. The solid was filtered off and dried to obtain 33.9 g of compound VII, with a molar yield of 71.2% (based on compound VI-a). NMR results are shown in [reference needed]. Figure 6 . 1 ¹H NMR (400MHz, DMSO-d⁶) δ 8.01 (d, J = 2.1Hz, 1H), 7.71 (d, J = 7.3Hz, 1H), 16.81 (d, J = 2.1Hz, 1H), 6.11 (d, J = 7.3Hz, 1H). Mass analysis of compound VII was performed using LC-MS / MS: [M+H]. + =137.07. Compound VII was analyzed using HPLC; the HPLC chromatogram is shown below. Figure 7 The purity, calculated by area normalization, was 98.51%. The HPLC chromatographic conditions were as follows: High-performance liquid chromatograph: Agilent 1260; Column: YMC-AQ 150mm*4.6mm, 5µm; Mobile phase A: phosphoric acid / water (1:1000v / v), Mobile phase B: acetonitrile; Flow rate: 1ml / min; Detection wavelength: 210nm; Column temperature: 35℃; Gradient elution.

[0120] <Example 2>

[0121] This embodiment prepares 7-hydroxyfurano[3,2-b]pyridine, including the following steps:

[0122] Step S1: Synthesize compound II-a from compound I according to the following synthetic route.

[0123]

[0124] The specific steps are as follows:

[0125] Add 300 mL of acetonitrile to a 1 L three-necked flask, stir, and add 30 g of maltol (compound of formula I), 42.7 g of potassium carbonate, and 40.7 g of benzyl bromide. Heat under reflux for 3 h. After the reaction is complete, cool to room temperature, filter, and evaporate to dryness to obtain 51.4 g of an oily substance, which is compound of formula II-a, with a molar yield of 100% (based on compound of formula I). ​​NMR results are shown below. Figure 1 . 1¹H NMR (400MHz, Chloroform-d) δ 7.58 (dd, J = 5.6, 1.5Hz, 1H), 7.43–7.22 (m, 5H), 6.35 (dd, J = 5.5, 2.0Hz, 1H), 5.14 (d, J = 1.9Hz, 2H), 2.07 (d, J = 1.8Hz, 3H); Mass analysis of compound II-a was performed using LC-MS (M+H). + =217.02.

[0126] Step S2: Synthesize compound III-b from compound II-a according to the following synthetic route.

[0127]

[0128] The specific steps are as follows:

[0129] Add 30g of formula II-a to a 250ml three-necked flask, add 75ml of N,N-dimethylformamide and 113.4g of N,N-dimethylformamide dimethyl acetal, heat to 120℃-130℃, react for 22h until the reaction is complete, cool, add 500ml of water, extract three times with 200ml of ethyl acetate, wash twice with 200ml of saturated brine, evaporate to dryness to obtain an oily substance, slurry with 300ml of methyl tert-methyl ether, filter to obtain 23.5g of a pale yellow solid, which is compound III-b (N(R 2 (2 is dimethylamino), molar yield 82.5% (based on compound II-a), NMR data are shown below. Figure 8 , 1 ¹H NMR (400 MHz, Chloroform-d) δ 7.49–7.39 (m, 3H), 7.33 (s, 1H), 7.26 (s, 1H), 7.03 (d, J = 13.3 Hz, 1H), 6.22 (d, J = 5.6 Hz, 1H), 5.10 (s, 2H), 5.00 (d, J = 13.4 Hz, 1H), 2.83 (s, 6H). Mass analysis of compound III-b was performed using LC-MS / MS. + =272.23.

[0130] Step S3: Synthesize compound IV-b from compound III-b according to the following synthetic route.

[0131]

[0132] The specific steps are as follows:

[0133] 10 g of compound III-b was added to a 250 ml three-necked flask, followed by 100 ml of methanol and 15.8 g of p-toluenesulfonic acid. The mixture was heated to reflux and reacted for 4 hours until complete. The mixture was then cooled to room temperature, and sodium carbonate was slowly added to adjust the pH to alkalinity. The mixture was stirred for 1 hour, filtered, and evaporated to dryness to obtain 8.1 g of an oily substance, which is compound IV-b (R). 1 =Bn,R 3 =Me), molar yield 76.2% (based on compound III-b), NMR data are shown below. Figure 9 . 1 ¹H NMR (400MHz, Chloroform-d) δ 7.64 (dd, J = 5.7, 1.1Hz, 1H), 7.44–7.30 (m, 5H), 6.38 (dd, J = 5.6, 1.1Hz, 1H), 5.18 (s, 2H), 4.52 (t, J = 5.9Hz, 1H), 3.26 (s, 6H), 2.79 (d, J = 5.9Hz, 2H). Mass analysis of compound IV-b was performed using LC-MS / MS: [M+H]. + =291.11.

[0134] Step S4: Synthesize compound V-b from compound IV-b according to the following synthetic route.

[0135]

[0136] The specific steps are as follows:

[0137] Add 5g of compound IV-b to a 250ml three-necked flask, add 50ml of methanol and 50ml of 28% concentrated ammonia, heat to 50℃-55℃, and react for 10h until the reaction is complete. Cool to room temperature, remove methanol by rotary evaporation, extract twice with 50ml of ethyl acetate, wash twice with 50ml of saturated brine, and evaporate to dryness to obtain 2.3g of oily substance, which is compound V-b (R). 1 =Bn,R 3 =Me), molar yield 56.1% (based on compound IV-b), NMR data are available. Figure 10 . 1 ¹H NMR (400MHz, Chloroform-d) δ 7.76–6.81 (m, 7H), 6.42 (d, J = 6.7 Hz, 1H), 5.16 (s, 2H), 4.41 (d, J = 5.6 Hz, 1H), 3.22 (s, 6H), 2.82 (d, J = 5.4 Hz, 2H). Mass analysis of compound V-b was performed using LC-MS / MS: [M+H]. + =290.11.

[0138] Step S5: Synthesize compound VI-b from compound V-b according to the following synthetic route.

[0139]

[0140] The specific steps are as follows:

[0141] 2 g of compound V-b was added to a 100 ml three-necked flask, followed by 100 ml of methanol and 0.2 g of 10% palladium on carbon. Hydrogen gas was bubbled through the flask, and the reaction was allowed to proceed for 5 hours until complete. The palladium on carbon was filtered off, and the mixture was evaporated to dryness to obtain 1.2 g of solid, which is compound VI-b. The molar yield was 87.5% (based on compound V-b). NMR data are shown below. Figure 11 . 1 ¹H NMR (400 MHz, Chloroform-d) δ 7.33 (d, J = 7.0 Hz, 1H), 6.57–6.23 (m, 1H), 4.64 (t, J = 4.7 Hz, 1H), 3.44 (d, J = 1.1 Hz, 6H), 3.14–2.97 (m, 2H). Mass analysis of compound VI-b was performed using LC-MS / MS: [M+H]. + =200.01.

[0142] Step S6: Synthesize compound VII from compound VI-b according to the following synthetic route.

[0143]

[0144] The specific steps are as follows:

[0145] Add 5 ml of concentrated sulfuric acid to a 100 ml three-necked flask, slowly add 1 g of compound VI-b, maintain room temperature, stir for 2 hours until the reaction is complete, cool to 0-5 °C, slowly add 10 ml of water to dilute the sulfuric acid, adjust the pH to above 8 with 25%-28% concentrated ammonia, filter out the solid, dry to obtain 0.5 g, which is compound VII, with a molar yield of 73.5% (based on compound VI-b); NMR results are available. Figure 12 , 1 ¹H NMR (400MHz, DMSO-d⁶) δ 8.01 (d, J = 2.1Hz, 1H), 7.71 (d, J = 7.3Hz, 1H), 16.81 (d, J = 2.1Hz, 1H), 6.11 (d, J = 7.3Hz, 1H); Mass analysis of compound VI-b was performed using LC-MS / MS: [M+H]. + =137.07. This indicates that the product is the same as the product from step S6 of Example 1, both being the target product compound of formula VII.

[0146] <Refer to the embodiment>

[0147] The preparation of intermediates of formula II-b, II-c and formula III-c of 7-hydroxyfurano[3,2-b]pyridine according to this reference example includes the following steps:

[0148] (1) Referring to the corresponding preparation in patent US3022 / 274982, compound II-b was synthesized from compound I according to the following synthetic route.

[0149]

[0150] 10 g of maltol (compound of formula I), 50 ml of water, and 4.9 g of potassium hydroxide were added to a 250 ml three-necked flask. 10 g of dimethyl sulfate was added dropwise. The mixture was heated to 70 °C and stirred for 5 h. After the reaction was complete, the mixture was extracted three times with 50 ml of dichloromethane, washed with 50 ml of 5% potassium hydroxide solution, and dried by rotary evaporation to obtain 8.5 g of an oily substance, which is compound II-b. MS: [M+H] + =141.0.

[0151] (2) Synthesize compound II-c from compound I according to the following synthetic route.

[0152]

[0153] The specific steps are as follows:

[0154] 300 mL of acetonitrile was added to a 1 L three-necked flask, followed by stirring and the addition of 30 g of maltol (compound of formula I), 42.7 g of potassium carbonate, and 41.7 g of 4-methoxybenzyl chloride. The mixture was heated under reflux for 3 h. After the reaction was complete, the mixture was cooled to room temperature, filtered, and evaporated to dryness to obtain 56.4 g of an oily substance, which is compound of formula II-c. The molar yield was 96.3% (based on compound I). The mass of compound II-c was analyzed using liquid chromatography-mass spectrometry (LC-MS): [M+H]. + =247.02.

[0155] (3) Synthesize compound III-c from compound I according to the following synthetic route.

[0156]

[0157] Add 5g of compound I to a 100ml three-necked flask, add 15ml of N,N-dimethylformamide and 23.6g of N,N-dimethylformamide dimethyl acetal, heat to 120℃-130℃, react for 24h until the reaction is complete, cool, add 50ml of water, extract three times with 40ml of ethyl acetate, wash twice with 40ml of saturated brine, evaporate to dryness to obtain an oily substance, beat with 20ml of methyl tert-methyl ether, filter to obtain 3.2g of a pale yellow solid, which is compound III-c (N(R 2 (2 is dimethylamino), molar yield 41.4% (as compound of formula I), MS: [M+H) + 196.31.

[0158] <Application Example>

[0159] This application example uses the compound of formula VII prepared in Example 1 to prepare compounds of formula VIII and formula IX.

[0160] (1) Synthesis method of compound VIII:

[0161]

[0162] Add 15 ml of acetic acid to a 100 ml three-necked flask, stir, add 10 g of acetic anhydride, and add 5.8 g of fuming nitric acid dropwise. Stir for 1 h. Add 5 g of compound VII to a 250 ml three-necked flask, add 50 ml of acetic acid, heat to 110 °C, and add the mixed solution dropwise while maintaining stability. After the addition is complete, maintain the temperature and stir for 1 h. Cool down, add 50 ml of methyl tert-ethyl ether, and filter out the solid to obtain 5 g of compound VIII. The molar yield is 75.0% (based on compound VII). NMR results are shown below. Figure 13 , 1 H NMR(400MHz,DMSO-d6)δ9.00(s,1H),8.20(s,1H),6.94(s,1H);[M+H] + =181.02.

[0163] (2) Synthesis method of compound IX:

[0164]

[0165] Add 15 ml of DMF to a 100 ml three-necked flask, stir, add 4 g of compound VII and 4 g of phosphorus oxychloride, heat to 40 °C, stir for 1 h, cool, and add the reaction mixture dropwise to 40 ml of water. Filter to obtain the solid, add the solid to 40 ml of dichloromethane, add 20 ml of sodium bicarbonate solution, add 0.5 g of activated carbon, stir for 30 min, filter, reverse the filtrate, extract twice with 20 ml of dichloromethane, combine the organic phases, dry to anhydrous sodium sulfate, and evaporate to dryness to obtain 3.8 g of solid compound IX, molar yield 86.0% (based on compound VII). NMR results are shown below. Figure 14 , 1 HNMR (400MHz, Chloroform-d) δ9.22 (s, 1H), 8.17 (d, J = 2.3, 1.1Hz, 1H), 7.17 (s, 1H); MS: [M+H] + =198.92 / 200.92(3:1).

[0166] The applicant declares that the above are merely specific embodiments of the present invention, but the scope of protection of the present invention is not limited thereto. Those skilled in the art should understand that any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention fall within the scope of protection and disclosure of the present invention.

Claims

1. A method for synthesizing the pharmaceutical intermediate 7-hydroxyfurano[3,2-b]pyridine, characterized in that, Includes the following steps: Step S1: Compound I is protected by a protecting group on its hydroxyl group under alkaline conditions to generate compound II; Step S2, the compound of formula II reacts with N,N-dimethylformamide dimethyl acetal in a solvent to generate compound of formula III; Step S3, the compound of formula III reacts in an alcohol under acidic conditions to generate compound of formula IV; Step S4, the compound of formula IV reacts with an amination agent in a solvent to generate a compound of formula V or V'; Step S5, the compound of formula V or V' is dehydroxylated in a solvent to generate compound of formula VI or VI'; Step S6, the compound of formula VI or VI' is cyclized under acidic conditions to generate compound of formula VII or VII', namely 7-hydroxyfurano[3,2-b]pyridine; The specific synthetic route of this method is as follows: Among them, R 1 It is any one of methyl, benzyl, or 4-methoxybenzyl; N(R 2 )2 is dimethylamino, tetrahydropyrrole, or morpholino; R 3 It is a C1-C4 alkyl group.

2. The method for synthesizing the pharmaceutical intermediate 7-hydroxyfurano[3,2-b]pyridine as described in claim 1, characterized in that, In step S1, a benzyl compound is added to carry out the reaction, R 1 The radical is benzyl, the reaction solvent is acetonitrile or N,N-dimethylformamide, the base is potassium carbonate or sodium carbonate, and the reaction is carried out by heating to reflux.

3. The method for synthesizing the pharmaceutical intermediate 7-hydroxyfurano[3,2-b]pyridine as described in claim 2, characterized in that, In step S1, the benzyl compound is a halobenzyl, the molar ratio of the halobenzyl to the compound of formula I is 1-1.5:1, the volume ratio of the reaction solvent to the compound of formula I is 5-15:1, and the molar ratio of the base to the compound of formula I is 0.8-1.8:

1.

4. The method for synthesizing the pharmaceutical intermediate 7-hydroxyfurano[3,2-b]pyridine as described in claim 3, characterized in that, In step S1, the halobenzyl is benzyl chloride or benzyl bromide, the reaction solvent is acetonitrile, and the base is potassium carbonate.

5. The method for synthesizing the pharmaceutical intermediate 7-hydroxyfurano[3,2-b]pyridine as described in claim 1, characterized in that, In step S2, the solvent is any one of N,N-dimethylformamide, toluene, or xylene; when N(R 2 When )2 is tetrahydropyrrole or morpholino, tetrahydropyrrole or morpholino is added as an additional reactant.

6. The method for synthesizing the pharmaceutical intermediate 7-hydroxyfurano[3,2-b]pyridine as described in claim 5, characterized in that, In step S2, the volume ratio of the solvent to the compound of formula II is 2-5:1, the molar ratio of N,N-dimethylformamide dimethyl acetal to the compound of formula II is 1-5:1, the molar ratio of tetrahydropyrrole or morpholine to the compound of formula II is 1:1, and the reaction temperature is 110℃-140℃.

7. The method for synthesizing the pharmaceutical intermediate 7-hydroxyfurano[3,2-b]pyridine as described in claim 1, characterized in that, In step S3, the alcohol is one of C1-C4 alkyl alcohols, and the acid is one or more of sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, or trifluoromethanesulfonic acid. The reaction is carried out by heating to reflux.

8. The method for synthesizing the pharmaceutical intermediate 7-hydroxyfurano[3,2-b]pyridine as described in claim 7, characterized in that, In step S3, the volume ratio of the alcohol to the compound of formula III is 5-20:1, and the molar ratio of the acid to the compound of formula III is 1.5-3:

1.

9. The method for synthesizing the pharmaceutical intermediate 7-hydroxyfurano[3,2-b]pyridine as described in claim 1, characterized in that, In step S3, after the reaction is complete, an alkali is added to adjust the pH value. The alkali is any one of potassium carbonate, sodium carbonate, sodium hydroxide, or potassium hydroxide.

10. The method for synthesizing the pharmaceutical intermediate 7-hydroxyfurano[3,2-b]pyridine as described in claim 1, characterized in that, In step S4, the solvent is any one or more of methanol, ethanol, dioxane, or tetrahydrofuran, and the amination agent is any one or more of ammonia, ammonium acetate, or ammonium carbonate. The reaction is carried out at 35°C-100°C.

11. The method for synthesizing the pharmaceutical intermediate 7-hydroxyfurano[3,2-b]pyridine as described in claim 10, characterized in that, In step S4, the volume ratio of the solvent to the compound of formula IV is 3-10:1, the ammonia agent is ammonia water, and the volume ratio of the ammonia water to the compound of formula IV is 3-10:

1.

12. The method for synthesizing the pharmaceutical intermediate 7-hydroxyfurano[3,2-b]pyridine as described in claim 1, characterized in that, In step S5, the solvent is any one or more of ethanol, methanol, tetrahydrofuran, dichloromethane or ethyl acetate, and the volume ratio of the solvent to the compound of formula V is 5-15:

1.

13. The method for synthesizing the pharmaceutical intermediate 7-hydroxyfurano[3,2-b]pyridine as described in claim 1, characterized in that, In step S5, R 1 The benzyl group is dehydroxylated using palladium carbon hydrogenation with 10% palladium on carbon, wherein the weight ratio of the 10% palladium on carbon to the compound of formula V is 0.1:

1.

14. The method for synthesizing the pharmaceutical intermediate 7-hydroxyfurano[3,2-b]pyridine as described in claim 1, characterized in that, In step S6, the acid is concentrated sulfuric acid.

15. The method for synthesizing the pharmaceutical intermediate 7-hydroxyfurano[3,2-b]pyridine as described in claim 14, characterized in that, In step S6, the volume ratio of the concentrated sulfuric acid to the compound of formula VI is 2-5:

1.

16. An intermediate compound that can be used in the synthetic method according to any one of claims 1-15, having the structure shown in Formula IV: in, R 1 It is any one of methyl, benzyl, or 4-methoxybenzyl; R 3 It is a C1-C4 alkyl group.

17. The intermediate compound as claimed in claim 16, characterized in that, R 1 It is benzyl, R 3 It can be methyl or ethyl.

18. An intermediate compound that can be used in the synthetic method according to any one of claims 1-15, having a structure as shown in formula V or V': in, Formulas V and V' are tautomers; R 1 It is any one of methyl, benzyl, or 4-methoxybenzyl; R 3 It is a C1-C4 alkyl group.

19. The intermediate compound as claimed in claim 18, characterized in that, R 1 It is benzyl, R 3 It can be methyl or ethyl.

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