A preparation method of 2-methyl-4-(1-methyl-1H-benzo[d]imidazol-2-yl)aniline

Abstract

The present invention discloses a method for preparing 2-methyl-4-(1-methyl-1H-benzo[d]imidazol-2-yl)aniline. Specifically, the present invention provides a method for preparing compound 31, comprising the steps of: reacting compound 30 with an amino group as shown below in a solvent in the presence of a base to obtain compound 31, wherein the base is an alkali metal carbonate. The raw materials and reagents of the method of the present invention are inexpensive and readily available, and the key intermediate of telmisartan can be obtained in high yield.

Description

Technical Field

[0001] The present invention relates to a preparation method of 2-methyl-4-(1-methyl-1H-benzo[d]imidazol-2-yl)aniline. Background Art

[0002] Telmisartan, developed by Schering-Plough of Germany, is a highly selective angiotensin II receptor antagonist. It was approved by the FDA as an effective antihypertensive drug in 1998 and launched in the United States the following year. It entered the Chinese market in 2001, and several domestic pharmaceutical companies are currently developing and producing telmisartan.

[0003]

[0004] Telmisartan is an FDA-approved antihypertensive drug in the sartan class. It is an angiotensin II receptor antagonist with the advantages of maintaining normal cardiovascular regulation and reducing organ damage caused by hypertension. Compared with other antihypertensive drugs, telmisartan has better efficacy and lower toxicity, and can be used to control blood pressure. The efficient and green synthesis of 2-methyl-4-(1-methyl-1H-benzo[d]imidazol-2-yl)aniline is key to its production.

[0005] The construction of the methyl-substituted benzimidazole ring in 2-methyl-4-(1-methyl-1H-benzo[d]imidazol-2-yl)aniline is a key difficulty, but the methods currently provided in the literature are costly and environmentally polluting. There is a lack of a method to construct the benzimidazole structure from cheap and readily available starting materials and green and environmentally friendly reagents.

[0006] Route 1: Organic Process Research & Development, 2007, 11(1), 81-85

[0007]

[0008] When constructing the propyl-substituted benzimidazole ring (Compound 6), sulfuric acid and fuming nitric acid are used for nitration. The reaction is highly exothermic and poses a major safety hazard. In addition, the strong acid is highly corrosive to the equipment, and the post-processing produces a large amount of waste acid and wastewater, which poses a great threat to the environment.

[0009] When constructing the methyl-substituted benzimidazole ring (compound 9), polyphosphoric acid (2.0 equiv) was used as a solvent and dehydrating agent. However, polyphosphoric acid has poor fluidity and is difficult to feed. The reaction requires a high temperature of 150°C for 4-5 hours, which consumes a lot of energy and is highly corrosive to production equipment. In addition, a large amount of waste acid and wastewater is generated during the post-processing process, which poses a great environmental hazard.

[0010] Route 2 CN113024469 A:

[0011]

[0012] The Duff reaction is used to construct 2-methyl-4-(1-methyl-1H-benzo[d]imidazol-2-yl)aniline. The catalyst trifluoroacetic acid reagent in this reaction is expensive and required in large quantities. During the post-processing process, a large amount of waste acid and wastewater is generated, which poses a great threat to the environment.

[0013] Route 3 CN103755641A:

[0014]

[0015] The expensive and difficult-to-obtain 4-amino-3-methylbenzoic acid (20) was selected as the raw material, and the auxiliary material triethyl orthobutyrate was relatively expensive and costly. Hydrosulfite was used to reduce the nitro group, and the reaction solvent was water. The reaction was highly exothermic and produced toxic and harmful sulfur dioxide and hydrogen sulfide gases. The fourth step used thionyl chloride, which has a strong pungent odor and is highly harmful to the environment and human health.

[0016] The above method has the following disadvantages: expensive raw materials, high temperature reaction conditions are required, the operation is cumbersome, separation and purification by silica gel chromatography is required, and a large amount of waste acid and wastewater is generated, which is not suitable for industrial production.

[0017] In view of the above shortcomings, it is necessary to design a new efficient and practical synthetic route to optimize the synthesis of telmisartan intermediate 2-methyl-4-(1-methyl-1H-benzimidazol-2-yl)amine (1). Summary of the Invention

[0018] The technical problem to be solved by the present invention is to address the shortcomings of the existing methods for preparing 2-methyl-4-(1-methyl-1H-benzo[d]imidazol-2-yl)aniline (Compound 1). The present invention provides a method for preparing 2-methyl-4-(1-methyl-1H-benzo[d]imidazol-2-yl)aniline. The method uses inexpensive and readily available raw materials and reagents, and can produce the key intermediate of telmisartan in high yield. The preparation process does not use hazardous reagents, and is a green and environmentally friendly process with minimal environmental pollution and suitable for large-scale production.

[0019] The present invention solves the above technical problems through the following technical solutions.

[0020] The present invention provides a preparation method 1 of compound 31, comprising the following steps: in a solvent, in the presence of a base, compound 30 undergoes an amino reaction as shown in the following formula to obtain compound 31, wherein the base is an alkali metal carbonate;

[0021]

[0022] The solvent can be any conventional solvent for this type of reaction in the art, preferably a high-boiling-point polar solvent, such as one or more selected from amide solvents, sulfoxide solvents, and alkanone solvents. The amide solvent can be N,N-dimethylformamide (DMF); the sulfoxide solvent can be dimethyl sulfoxide (DMSO); and the alkanone solvent can be N-methylpyrrolidone (NMP). The solvent is preferably DMF, more preferably anhydrous DMF.

[0023] The preparation method 1 of the compound 31 includes a Smiles rearrangement reaction and hydrolysis.

[0024] The amount of the solvent is not limited as long as it does not affect the reaction; for example, the mass ratio of the compound 30 to the solvent can be 1:(1-20), such as 1:3.5.

[0025] The base is preferably potassium carbonate and / or sodium carbonate, more preferably anhydrous potassium carbonate.

[0026] The molar ratio of the compound 30 to the base can be (1-3):1, for example, 1.14:1.

[0027] The preparation method of compound 31 further comprises removing water.

[0028] The dehydration includes physical dehydration and chemical dehydration.

[0029] The physical dehydration is to add toluene to the reaction system to remove water in the reaction system by azeotropy. The azeotropy is preferably a reduced pressure azeotropy.

[0030] The temperature for the physical water removal can be a conventional temperature for this type of method, such as 60-90°C, and for example 80°C.

[0031] The chemical dehydration is to add an ester solvent or a nitrile solvent to the reaction system (the ester solvent or the nitrile solvent consumes a small amount of water in the reaction system by hydrolysis). The ester solvent is preferably methyl formate, ethyl acetate or methyl acetate, more preferably anhydrous methyl formate, anhydrous ethyl acetate or anhydrous methyl acetate. The nitrile solvent is preferably anhydrous acetonitrile.

[0032] The temperature of the chemical dehydration can be a conventional temperature for this type of method, such as 60-90°C, and for example 80°C.

[0033] The temperature of the Smiles rearrangement reaction can be a conventional temperature for such reactions in the art, such as 115°C to 180°C, and in the present invention, preferably 140°C to 160°C, such as 150°C.

[0034] The progress of the Smiles rearrangement reaction can be monitored using conventional monitoring methods in the art (e.g., TLC, HPLC, or NMR), with the disappearance or nonreaction of compound 30 generally being considered the endpoint. The reaction time can be 1-24 hours, e.g., 3-6 hours, or even 4.5 hours.

[0035] The hydrolysis reaction is performed by adding water to the reaction system after the Smiles rearrangement reaction is completed.

[0036] The reaction temperature of the hydrolysis reaction is 115°C to 180°C, preferably 140°C to 160°C, such as 150°C.

[0037] In the hydrolysis reaction, the molar ratio of water to compound 30 is greater than or equal to 1, and preferably the molar ratio of water to compound 30 is 1.67:1.

[0038] The preparation method 1 of the compound 31 may further include post-treatment, and the post-treatment operation may be a conventional post-treatment operation in this type of preparation method in the art, which includes the following steps: after the reaction is completed, cooling, acidification, alkalization, extraction, and concentration.

[0039] The acidification method can be a conventional acidification method in this type of reaction in the art. For example, the acidifying acid is hydrochloric acid, preferably 2M hydrochloric acid, and the molar ratio of the compound 30 to the acidifying acid is 1:1.6.

[0040] The alkalization method can be a conventional alkalization method in the art for this type of reaction. The alkalization base is NaOH, preferably a 15% NaOH aqueous solution. The pH of the alkalization is 8-9. The extraction method can be a conventional extraction method in the art for this type of reaction. The extraction solvent can be ethyl acetate. The concentration method can be a conventional concentration method in the art for this type of reaction, such as concentration under reduced pressure.

[0041] The post-treatment operation may further comprise the following steps: after the reaction is completed, cooling, extraction, washing, and concentration. The extraction may be a conventional extraction method in this type of reaction in the art, for example, extraction with the extraction solvent (e.g., ethyl acetate). The washing may be a conventional washing method in this type of reaction in the art, for example, the washing solvent is NaOH, preferably washing twice with a 10% NaOH aqueous solution. The concentration may be a conventional concentration method in this type of reaction in the art, for example, concentration under reduced pressure.

[0042] In one embodiment, the raw materials and reagents of the preparation method 1 of compound 31 are composed of the following components: the solvent, the base and the compound 30.

[0043] The preparation method 1 of compound 31 also includes a preparation method of compound 30, which comprises the following steps: in a solvent, in the presence of a base and a catalyst, compound 28 and compound 29 undergo an alkylation reaction to obtain compound 30; the catalyst is a halogen metal salt and / or a phase transfer catalyst;

[0044]

[0045] The solvent can be any conventional solvent for this type of reaction in the art, preferably a polar aprotic solvent, such as one or more selected from amide solvents, sulfoxide solvents, nitrile solvents, ketone solvents, and ester solvents. The amide solvent can be N,N-dimethylformamide (DMF); the sulfoxide solvent can be dimethyl sulfoxide (DMSO); the nitrile solvent can be acetonitrile; the ketone solvent can be acetone; and the ester solvent can be ethyl acetate. The solvent is preferably DMF.

[0046] The amount of the solvent is not limited as long as it does not affect the reaction; for example, the mass ratio of the compound 28 to the solvent can be 1:(1-10), such as 1:3.55.

[0047] The base can be a conventional base for this type of reaction in the art, such as an alkali metal carbonate (such as potassium carbonate and / or sodium carbonate), an alkali metal hydroxide (such as sodium hydroxide and / or potassium hydroxide) and an organic base (such as triethylamine (TEA)). The base is further preferably anhydrous potassium carbonate.

[0048] The molar ratio of the compound 28 to the base can be 1:(1-3), for example 1:1.1.

[0049] The halogen metal salt may be an alkali metal salt, preferably potassium iodide and / or potassium bromide, such as potassium iodide.

[0050] The molar ratio of the compound 28 to the halogen metal salt may be 1:(0.05-0.3), for example 1:0.05.

[0051] The phase transfer catalyst may be a conventional phase transfer catalyst for this type of reaction in the art, such as a quaternary ammonium salt (such as tetrabutylammonium bromide (TBAB) and / or tetrabutylammonium fluoride (TBAF)), more preferably tetrabutylammonium bromide.

[0052] The molar ratio of the compound 28 to the phase transfer catalyst may be 1:(0.05-0.3), for example 1:0.1.

[0053] The molar ratio of the compound 28 to the compound 29 may be 1:(1-2.5), for example 1:1.03.

[0054] The temperature of the alkylation reaction can be a conventional temperature for such reactions in the art, such as 70°C to 130°C, and in the present invention, preferably 80°C to 110°C, such as 110°C.

[0055] The progress of the alkylation reaction can be monitored using conventional monitoring methods in the art (e.g., TLC, HPLC, or NMR), and the reaction endpoint is generally determined when compound 28 disappears or ceases to react. The reaction time can be 1-24 hours, for example, 4 hours.

[0056] The preparation method of compound 30 may further comprise the following steps: after the alkylation reaction is completed, cooling, quenching, and separation. The quenching may be a conventional quenching method for this type of reaction in the art, such as water quenching, and further, the mass ratio of water to compound 28 is 5:1. The separation may be a conventional separation method for this type of compound in the art, such as filtration.

[0057] The post-treatment may also be performed by extraction after quenching, and the extraction may be a conventional extraction method for this type of reaction in the art, for example, the extraction solvent is dichloromethane.

[0058] In one embodiment, the raw materials and reagents for the preparation method of compound 30 are composed of the following components: the solvent, the base, the catalyst, the phase transfer catalyst, the compound 28 and the compound 29.

[0059] The present invention also provides a preparation method 2 of compound 31, comprising the following steps: reacting compound 28 with compound 29 in a solvent in the presence of a base and a catalyst to obtain compound 31, wherein the base is an alkali metal carbonate; and the catalyst is a halogen metal salt and / or a phase transfer catalyst;

[0060]

[0061] Specifically, the preparation method 2 of compound 31 comprises the following steps: compound 28 is subjected to step 1 to obtain compound 30, and then subjected to step 2 to obtain compound 31.

[0062]

[0063] The solvent can be any conventional solvent for this type of reaction in the art, preferably a polar aprotic solvent, such as one or more selected from amide solvents, sulfoxide solvents, nitrile solvents, ketone solvents, and ester solvents. The amide solvent can be N,N-dimethylformamide (DMF); the sulfoxide solvent can be dimethyl sulfoxide (DMSO); the nitrile solvent can be acetonitrile; the ketone solvent can be acetone; and the ester solvent can be ethyl acetate. The solvent is preferably DMF.

[0064] The amount of the solvent is not limited as long as it does not affect the reaction; for example, the mass ratio of the compound 28 to the solvent can be 1:(1-10), such as 1:5.

[0065] The base can be a conventional base for this type of reaction in the art, such as an alkali metal carbonate (such as potassium carbonate and / or sodium carbonate), an alkali metal hydroxide (such as sodium hydroxide and / or potassium hydroxide) and an organic base (such as triethylamine (TEA)). The base is further preferably anhydrous potassium carbonate.

[0066] The molar ratio of the compound 28 to the base can be 1:(1-3), for example 1:1.2.

[0067] The halogen metal salt may be an alkali metal salt, preferably potassium iodide and / or potassium bromide, such as potassium iodide.

[0068] The molar ratio of the compound 28 to the catalyst may be 1:(0.05-0.3), for example 1:0.1.

[0069] The molar ratio of the compound 28 to the compound 29 may be 1:(1-2.5), for example 1:1.03.

[0070] The reaction temperature of step 1 can be a conventional temperature for this type of reaction in the art, such as 70°C to 130°C, and in the present invention, preferably 80°C to 110°C, such as 110°C.

[0071] The progress of the reaction in step 1 can be monitored using conventional monitoring methods in the art (e.g., TLC, HPLC, or NMR), and the reaction endpoint is generally determined when compound 28 disappears or no longer reacts. The reaction time can be 1-24 hours, for example, 2 hours.

[0072] Between step 1 and step 2, a water removal operation is further included.

[0073] The dehydration includes physical dehydration and chemical dehydration.

[0074] The physical dehydration is to add toluene to the reaction system to remove water in the reaction system by azeotropic removal. More preferably, the decompression azeotropic removal is performed. The pressure of the decompression azeotropic removal can be -0.08 MPa.

[0075] The temperature for the physical water removal can be a conventional temperature for this type of method, such as 60-90°C, and for example 80°C.

[0076] The chemical dehydration is performed by adding an ester solvent or a nitrile solvent to the reaction system. The ester solvent is preferably methyl formate, ethyl acetate or methyl acetate, more preferably anhydrous methyl formate, anhydrous ethyl acetate or anhydrous methyl acetate. The nitrile solvent is preferably anhydrous acetonitrile.

[0077] The temperature of the chemical dehydration can be a conventional temperature for this type of method, such as 60-90°C, and for example 80°C.

[0078] The reaction temperature of step 2 is 135°C to 180°C, preferably 140°C to 160°C, for example 150°C.

[0079] The progress of the reaction in step 2 can be monitored using conventional monitoring methods in the art (e.g., TLC, HPLC, or NMR). The reaction endpoint is generally determined as the disappearance or non-reaction of compound 30. The reaction time can be 1-24 hours, e.g., 3-6 hours, or even 5 hours.

[0080] Preferably, after step 2, water is further added, and the molar ratio of water to compound 28 is greater than or equal to 1, preferably the molar ratio of water to compound 28 is 2.08:1.

[0081] The preparation method 2 of the compound 31 may further include post-treatment, and the post-treatment operation may be a conventional post-treatment operation in this type of preparation method in the art, which includes the following steps: after the reaction is completed, cooling, acidification, alkalization, and filtering.

[0082] The acidification method can be a conventional acidification method in this type of reaction in the art. For example, the acidification acid is hydrochloric acid, preferably 2M hydrochloric acid, and the molar ratio of the compound 28 to the hydrochloric acid used is 1:2.

[0083] The alkalization can be a conventional alkalization method in this type of reaction in the art, for example, the alkalization base is NaOH, preferably 15% NaOH aqueous solution, and the pH of the alkalization is 8-9. The filtration can be a conventional filtration method in this type of reaction in the art, such as suction filtration.

[0084] In one embodiment, the raw materials and reagents of the preparation method 2 of compound 31 are composed of the following components: the solvent, the base, the catalyst and the compound 28.

[0085] The present invention also provides a method for preparing compound 1, comprising the following steps: reacting compound 31 with N-methyl-o-phenylenediamine or a salt of N-methyl-o-phenylenediamine in a solvent to undergo a ring-closure reaction to obtain compound 1;

[0086]

[0087] The solvent can be a conventional solvent for this type of reaction in the art, for example, one or more selected from amide solvents, sulfoxide solvents, alkanone solvents, alcohol solvents, nitrile solvents, ester solvents, aromatic hydrocarbon solvents, halogenated hydrocarbon solvents, and ether solvents. The amide solvent can be N,N-dimethylformamide (DMF); the sulfoxide solvent can be dimethyl sulfoxide (DMSO); the alkanone solvent can be N-methylpyrrolidone (NMP) and / or acetone; the alcohol solvent can be ethanol; the nitrile solvent can be acetonitrile; the ester solvent can be ethyl acetate; the aromatic hydrocarbon solvent can be toluene; the halogenated hydrocarbon solvent can be 1,2-dichloroethane; and the ether solvent can be tetrahydrofuran. The solvent is preferably DMF.

[0088] The amount of the solvent is not limited as long as it does not affect the reaction; for example, the mass ratio of the compound 31 to the solvent can be 1:(1-10), such as 1:5.

[0089] The N-methyl-o-phenylenediamine salt is further preferably N-methyl-o-phenylenediamine hydrochloride.

[0090] The molar ratio of the compound 31 to the N-methyl-o-phenylenediamine or its salt can be 1:(0.8-1.2), for example 1:1.

[0091] The ring-closure reaction further comprises a base, which can be a conventional base for this type of reaction in the art, such as an organic base (such as triethylamine) and / or an inorganic base; more preferably triethylamine.

[0092] The molar ratio of the N-methyl-o-phenylenediamine or its salt to the base can be 1:(1-3), for example, 1:2.05.

[0093] The ring-closure reaction may be further carried out in the presence of an additive, which may be a conventional additive for this type of reaction in the art (additives increase the reaction efficiency), such as an alkali metal bisulfate (such as sodium bisulfite and / or sodium bisulfite), more preferably sodium bisulfite.

[0094] The molar ratio of the compound 31 to the additive may be 1:(1-2), for example 1:1.2.

[0095] The temperature of the ring-closure reaction can be a conventional temperature for such reactions in the art, such as 60°C to 130°C. In the present invention, it is preferably 70°C to 130°C, such as 70, 80, 90, 110 or 130°C, preferably 130°C.

[0096] The progress of the ring-closure reaction can be monitored using conventional monitoring methods in the art (e.g., TLC, HPLC, or NMR), with the disappearance or non-reaction of compound 31 generally being considered the endpoint. The reaction time can be 1-24 hours, e.g., 3-6 hours, or even 5 hours.

[0097] The preparation method of compound 1 may further include post-treatment, and the post-treatment operation may be a conventional post-treatment operation in this type of preparation method in the art, which includes the following steps: after the ring-closure reaction is completed, cooling, quenching, extraction, concentration, and purification. The quenching may be a conventional quenching method in this type of reaction in the art, such as water quenching. The extraction may be a conventional extraction method in this type of reaction in the art, such as the extraction solvent is dichloromethane. The concentration may be a conventional concentration method in this type of reaction in the art, such as concentration under reduced pressure.

[0098] Purification can be performed by conventional purification methods for compounds of this type in the art, such as recrystallization (V 乙醇 :V 环己烷 =1:5).

[0099] In one embodiment, the raw materials and reagents for the preparation method of compound 1 consist of the following components: a solvent, compound 31 and N-methyl-o-phenylenediamine or a salt thereof.

[0100] The preparation method of compound 1 may further include the following steps:

[0101] Preparation method 1 of compound 31 comprises the following steps: in a solvent, in the presence of a base, compound 30 undergoes an amino reaction as shown in the following formula to obtain compound 31, wherein the base is an alkali metal carbonate;

[0102]

[0103] Alternatively, a preparation method 2 of compound 31 comprises the following steps: reacting compound 28 with compound 29 in a solvent in the presence of a base and a catalyst to obtain compound 31, wherein the base is an alkali metal carbonate; and the catalyst is a halogen metal salt and / or a phase transfer catalyst;

[0104]

[0105] Preferably, the reaction conditions and steps of the preparation method of compound 31 are as described above.

[0106] Preferably, the reaction conditions and steps described in method 2 for preparing compound 31 are as described above.

[0107] The present invention provides a method for preparing compound 30, comprising the following steps: in a solvent, in the presence of a base, a catalyst, and a phase transfer catalyst, alkylating compound 28 with chloroacetamide to obtain compound 30;

[0108]

[0109] The reaction conditions and steps for the preparation of compound 30 are the same as those described in the previous alkylation reaction.

[0110] The present invention also provides a compound 30, the structure of which is shown below:

[0111]

[0112] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0113] The reagents and raw materials used in the present invention are commercially available.

[0114] The positive progress of the present invention is that the route for preparing compound 1 of the present invention has one or more of the following advantages:

[0115] (1) The starting materials are cheap and readily available, and the route preparation cost is low;

[0116] (2) The preparation of compound 1 does not require the use of catalyst PPA and has no side reactions, with a yield of up to 95%. Compared with the ring-closure reaction in other literature, the yield is greatly improved and it is environmentally friendly;

[0117] (3) The route of the present invention can avoid the use of column chromatography to purify the product in each step, which is conducive to industrialization.

[0118] The method for preparing compound 30 from compound 28 improves the yield compared with the similar structure in the prior art.

[0119] The method for preparing compound 31 from compound 30 improves the yield compared with the similar structure in the prior art, and further better avoids the generation of high content of by-products.

[0120] Compound 31 can also be prepared from compound 28 via a one-pot process, which can further save reaction steps and improve the industrial application value of the process.

[0121] The method for preparing compound 1 from compound 31 has the advantages of fewer impurities and complete conversion compared to this type of cyclization method. DETAILED DESCRIPTION

[0122] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0123] A method for preparing telmisartan intermediate 2-methyl-4-(1-methyl-1H-benzimidazol-2-yl)amine (1), the specific route is as follows:

[0124]

[0125] Example 1: Preparation of Compound 27

[0126] Compound 26 (85.52 g, 600 mmol) was dissolved in DMF (56.28 g, 770 mmol). POCl (123.42 g, 805 mmol) was added dropwise at 0°C over 40 min. Stirring was continued for 30 min. The reaction system was heated to 70°C and stirred for 6 h. After completion of the reaction, the temperature was lowered to 25°C, 425 ml of water was slowly added, and the mixture was stirred in an ice bath for 1 h. Extraction with ethyl acetate and concentration under reduced pressure gave a colorless liquid (74.02 g, 82.15%).

[0127] Structural characterization data: 1 HNMR (400MHz, CDCl3) δ2.27(s,3H),3.92(s,3H),6.90(d,1H),7.7(m,2H),9.86(s,1H);

[0128] ESI-MS (m / z): 150.1 [M+H] + .

[0129] Example 2: Preparation of Compound 28

[0130] Compound 27 (75.09 g, 500 mmol) and anhydrous aluminum chloride (120.14 g, 800 mmol) were added to 1,2-dichloromethane (190 g) and reacted at 65°C for 12 h. After completion of the reaction, the mixture was cooled to room temperature and slowly added dropwise to ice-bathed water (200 ml). After stirring for 30 min, dichloromethane (200 g × 3) was added for extraction. The organic phases were combined and washed three times with 10% NaOH (100 g × 3). The organic phases were concentrated under reduced pressure to recover the raw material 27. The aqueous phases were combined and the pH of the aqueous phase was adjusted to 7 with hydrochloric acid. The product precipitated, filtered, and dried in vacuo to obtain 3-methyl-4-hydroxybenzaldehyde 28 (60.05 g, 88.21%) as a purple powder.

[0131] Structural characterization data: 1H NMR (400MHz, CDCl3) δ2.34(s,3H,),6.95(d,J=8.0Hz,1H),7.67(dd,J=1.6,8.0Hz,1H),7.72(s,1H),9.85(s,1H);

[0132] ESI-MS (m / z,%): 137.1 [M+H] + .

[0133] Example 3: Preparation of Compound 30

[0134] 28 (68.07 g, 500 mmol), chloroacetamide (47.92 g, 512.5 mmol), potassium iodide (4.15 g, 25 mmol), and TBAB (16.11 g, 50 mmol) were added to DMF (241.50 g). 76.01 g of anhydrous potassium carbonate (550 mmol) was added, and the mixture was heated to 100°C and reacted for 4 h. After completion of the reaction, the mixture was cooled to room temperature, 340.35 g of water was added, and the mixture was stirred for 5 h. The mixture was filtered, and the filter cake was washed with water and dried to obtain a white powder (92.21 g, 95.46%).

[0135] Structural characterization data: 1 HNMR(400MHz, CDCl3)9.82(1H,s),7.76–7.60(2H,m),7.19(1H,s),6.85(1H,d,J=8.7 Hz),6.39(1H,s),5.73(1H,s),4.53(2H,s),2.29(3H,s).ESI-MS(m / z,%):194.1[M+H] + .

[0136] Example 4: Preparation of Compound 31

[0137] 30 (96.57 g, 500 mmol) and anhydrous potassium carbonate (60.80 g, 440 mmol) were added to DMF (340 g). After the addition of the materials, 1) toluene (20 mL x 3) was added and the mixture was azeotropically distilled at 80°C to remove water (-0.08 MPa). 2) methyl formate (20 mL) was added and the mixture was reacted at 80°C for 2 h to consume the water. After the naturally present water in the system was removed, the temperature was raised to 150°C and the reaction was continued for 4.5 h. 15 g of water was added dropwise and the reaction was continued with stirring for 2 h. After the reaction was completed, 1) the mixture was cooled to room temperature and 2 M hydrochloric acid (400 mL) was added. The mixture was stirred at room temperature for 30 min, filtered, and the pH of the filtrate was adjusted to 8-9 with 15% aqueous NaOH solution. The filtrate was extracted with 150 mL of ethyl acetate and concentrated under reduced pressure to yield a yellow powder (56.92 g, 84.24%). 2) Cool to room temperature, add water (500 g), extract with ethyl acetate (200 mL × 3), combine the organic phases and wash twice with 10% NaOH aqueous solution (50 mL × 2). Concentrate the organic phase under reduced pressure to obtain a yellow powder (58.36 g, 86.38%)

[0138] Structural characterization data: 1 H NMR (400MHz, CDCl3) δ2.24 (s, 3H,), 6.34 (d, J = 10.0Hz, 1H), 7.58 (m, 2H), 9.76 (s, 1H);

[0139] ESI-MS (m / z,%): 137.1 [M+H] + .

[0140] Example 5: Preparation of compound 31 (one-pot method):

[0141] Compound 28 (54.06 g, 400 mmol), chloroacetamide (38.34 g, 410 mmol), anhydrous potassium carbonate (66.34 g, 480 mmol), and potassium iodide (6.64 g, 40 mmol) were added to DMF (270.30 g) and heated to 110°C for 2 h. After completion of the reaction, 1) toluene (20 mL x 2) was added and azeotropic distillation was performed under reduced pressure to remove water. 2) methyl formate (20 mL) was added and the reaction was continued at 80°C for 2 h to consume the water. After removing any water present in the system, the temperature was raised to 150°C and the reaction was continued for 5 h. 15 g of water was added dropwise and the reaction was continued with stirring for 2 h. The mixture was cooled, 400 ml of 2 M hydrochloric acid was added, and the mixture was stirred at room temperature for 30 min. The filtrate was filtered, and the pH was adjusted to 8-9 with 15% aqueous NaOH solution. The mixture was then filtered to obtain a yellow powder (42.83 g, 79.24%).

[0142] Structural characterization data: 1H NMR (400MHz, CDCl3) δ6.72 (d, J = 7.5Hz, 1H), 7.50 (d, J = 6.0Hz, 2H), 2.15 (s, 3H), 6.10 (s, 2H), 9.62 (s, 1H);

[0143] ESI-MS (m / z,%): 136.1 [M+H] + .

[0144] Example 6: Preparation of Compound 1

[0145] 31 (54.06 g, 400 mmol), sodium bisulfite (49.93 g, 480 mmol), and triethylamine (82.97 g, 820 mmol) were added to the solvent (270.3 g) shown in the following table, and N-methyl-o-phenylenediamine hydrochloride (78.03 g, 400 mmol) was slowly added at room temperature. The temperature was raised to 130° C. and the reaction was carried out for 5 h. Water and dichloromethane were added to the system, and the aqueous phase was extracted three times with dichloromethane. The organic phase was concentrated under reduced pressure and recrystallized from a mixed solvent of ethanol and cyclohexane (volume ratio 1:5) to obtain a brown powder. The yields are shown in the following table:

[0146]

[0147]

[0148] Structural characterization data: 1 H NMR(400MHz,DMSO-d6)δ7.59–7.57(m,1H),7.53–7.51(m,1H),7.46(s,1H),7 .41(dd,J=8.4,1.6Hz,1H),7.24-7.15(m,2H),6.73(d,J=8.4Hz,1H),5.36(br s,2H),3.84(s,3H),2.14(s,3H); ESI-MS(m / z,%):238.1[M+H] + .

Claims

1. A method for preparing compound 31, characterized in that: The method comprises the following steps: in a solvent, in the presence of a base, compound 30 undergoes an amino reaction as shown in the following formula to obtain compound 31, wherein the base is an alkali metal carbonate; the solvent is N,N-dimethylformamide; the molar ratio of compound 30 to the base is (1-3):1; the preparation method 1 of compound 31 comprises a Smiles rearrangement reaction and a hydrolysis reaction; the temperature of the Smiles rearrangement reaction is 115°C to 180°C; the reaction temperature of the hydrolysis reaction is 115°C to 180°C; the preparation method 1 of compound 31 further comprises removing water; 。 2. The preparation method 1 of compound 31 according to claim 1, characterized in that: It meets one or more of the following conditions: (1) The solvent is anhydrous DMF; (2) The mass ratio of the compound 30 to the solvent is 1:(1-20); (3) The base is potassium carbonate and / or sodium carbonate; (4) The molar ratio of the compound 30 to the base is 1.14:1; (5) The dehydration includes physical dehydration and chemical dehydration; (6) The preparation method 1 of the compound 31 also includes post-treatment, and the post-treatment operation includes the following steps: cooling, acidification, alkalization, extraction, and concentration after the reaction is completed; (7) The raw materials and reagents of the preparation method 1 of the compound 31 are composed of the following components: the solvent, the base and the compound 30.

3. The preparation method 1 of compound 31 according to claim 2, characterized in that: It meets one or more of the following conditions: (1) The mass ratio of the compound 30 to the solvent is 1:3.5; (2) The base is anhydrous potassium carbonate.

4. The preparation method 1 of compound 31 according to claim 3, characterized in that: It meets one or more of the following conditions: (1) The physical dehydration is to add toluene to the reaction system to remove water in the reaction system by azeotropic method; (2) The temperature of the physical dehydration is 60-90°C; (3) The chemical dehydration is performed by adding an ester solvent or a nitrile solvent to the reaction system; (4) The temperature of the chemical dehydration is 60-90°C; (5) The temperature of the Smiles rearrangement reaction is 140°C to 160°C; (6) The reaction time of the Smiles rearrangement reaction is 1-24 hours; (7) The hydrolysis reaction is performed by adding water to the reaction system after the Smiles rearrangement reaction is completed; (8) The reaction temperature of the hydrolysis reaction is 140°C to 160°C; (9) In the hydrolysis reaction, the molar ratio of water to compound 30 is greater than or equal to 1; (10) The acidifying acid is hydrochloric acid; (11) the molar ratio of the compound 30 to the acidified acid is 1:1.6; (12) The alkalizing base is NaOH; (13) The pH of the alkalinization is 8-9; (14) The extraction solvent is ethyl acetate; and (15) The concentration described is concentration under reduced pressure.

5. The preparation method 1 of compound 31 according to claim 4, characterized in that: It meets one or more of the following conditions: (1) In the physical dehydration, the azeotropic process is a reduced pressure azeotropic process; (2) The temperature of the physical dehydration is 80°C; (3) The ester solvent is methyl formate, ethyl acetate or methyl acetate; (4) The nitrile solvent is anhydrous acetonitrile; (5) The temperature of the chemical dehydration is 80°C; (6) The temperature of the Smiles rearrangement reaction is 150°C; (7) The reaction time of the Smiles rearrangement reaction is 3-6 hours; (8) The reaction temperature of the hydrolysis reaction is 150°C; (9) In the hydrolysis reaction, the molar ratio of water to compound 30 is 1.67:1; (10) The acidified acid is 2M hydrochloric acid; (11) The alkalizing base is a 15% NaOH aqueous solution.

6. The preparation method 1 of compound 31 according to claim 5, characterized in that: It meets one or more of the following conditions: (1) The pressure of the reduced pressure azeotropic mixture is -0.08 MPa; (2) The ester solvent is anhydrous methyl formate, anhydrous ethyl acetate or anhydrous methyl acetate; (3) The reaction time of the Smiles rearrangement reaction is 4.5 hours.

7. The preparation method 1 of compound 31 according to claim 1, characterized in that: The preparation method 1 of compound 31 also includes a preparation method of compound 30, which comprises the following steps: in a solvent, in the presence of a base and a catalyst, compound 28 and compound 29 undergo an alkylation reaction to obtain compound 30; the catalyst is a halogen metal salt and / or a phase transfer catalyst; the solvent is N,N-dimethylformamide; the base is an alkali metal carbonate; the molar ratio of compound 28 to the base is 1:(1-3); 。 8. The preparation method 1 of compound 31 according to claim 7, characterized in that: It meets one or more of the following conditions: (1) The mass ratio of the compound 28 to the solvent is 1:(1-10); (2) The alkali metal carbonate is potassium carbonate and / or sodium carbonate; (3) the molar ratio of the compound 28 to the base is 1:1.1; (4) The halogen metal salt is an alkali metal salt; (5) The molar ratio of the compound 28 to the halogen metal salt is 1:(0.05-0.3); (6) The phase transfer catalyst is a quaternary ammonium salt; (7) The molar ratio of the compound 28 to the phase transfer catalyst is 1:(0.05-0.3); (8) The molar ratio of the compound 28 to the compound 29 is 1:(1-2.5); (9) The temperature of the alkylation reaction is 70°C to 130°C; (10) The reaction time of the alkylation reaction is 1-24 hours; (11) The preparation method of compound 30 may further comprise the following steps: after the alkylation reaction is completed, cooling, quenching, and separation; (12) The raw materials and reagents for the preparation method of the compound 30 are composed of the following components: the solvent, the base, the catalyst, the phase transfer catalyst, the compound 28 and the compound 29.

9. The preparation method 1 of compound 31 according to claim 8, characterized in that: It meets one or more of the following conditions: (1) The mass ratio of the compound 28 to the solvent is 1:3.55; (2) The base is anhydrous potassium carbonate; (3) The halogen metal salt is potassium iodide and / or potassium bromide; (4) The molar ratio of the compound 28 to the halogen metal salt is 1:0.05; (5) The quaternary ammonium salt is tetrabutylammonium bromide and / or tetrabutylammonium fluoride; (6) The molar ratio of the compound 28 to the phase transfer catalyst is 1:0.1; (7) The molar ratio of compound 28 to compound 29 is 1:1.03; (8) The temperature of the alkylation reaction is 80°C to 110°C; (9) The reaction time of the alkylation reaction is 4 hours; (10) The quenching is water quenching; (11) The separation is filtration.

10. The preparation method 1 of compound 31 according to claim 9, characterized in that: It meets one or more of the following conditions: (1) The halogen metal salt is potassium iodide; (2) The quaternary ammonium salt is tetrabutylammonium bromide; (3) The temperature of the alkylation reaction is 110°C; (4) In the water quenching, the mass ratio of the water to the compound 28 is 5:

1.

11. A preparation method 2 of compound 31, characterized in that: The method comprises the following steps: in a solvent, in the presence of a base and a catalyst, reacting compound 28 with compound 29 to obtain compound 31, wherein the base is an alkali metal carbonate; the catalyst is an alkali metal salt; the solvent is N,N-dimethylformamide; the molar ratio of compound 28 to the base is 1:(1-3); the preparation method 2 further comprises a water removal operation; 。 12. The preparation method 2 of compound 31 according to claim 11, characterized in that: It meets one or more of the following conditions: (1) The mass ratio of the compound 28 to the solvent is 1:(1-10); (2) The alkali metal carbonate is potassium carbonate and / or sodium carbonate; (3) The molar ratio of the compound 28 to the base is 1:1.2; (4) The alkali metal salt is potassium iodide and / or potassium bromide; (5) The molar ratio of the compound 28 to the catalyst is 1:(0.05-0.3); (7) The molar ratio of the compound 28 to the compound 29 is 1:(1-2.5); (8) The preparation method 2 of compound 31 comprises the following steps: compound 28 is subjected to step 1 to obtain compound 30, and then subjected to step 2 to obtain compound 31. 。 13. The preparation method 2 of compound 31 according to claim 12, characterized in that: It meets one or more of the following conditions: (1) The mass ratio of the compound 28 to the solvent is 1:5; (2) The base is anhydrous potassium carbonate; (3) The alkali metal salt is potassium iodide; (4) The molar ratio of the compound 28 to the catalyst is 1:0.1; (5) The molar ratio of compound 28 to compound 29 is 1:1.03; (6) The reaction temperature of step 1 is 70°C to 130°C; (7) The reaction time of step 1 is 1-24 hours; (8) The water removal operation is performed between step 1 and step 2; (9) The reaction temperature of step 2 is 135°C to 180°C; (10) The reaction time of step 2 is 1-24 hours; (11) After step 2, water is further added, and the molar ratio of water to compound 28 is greater than or equal to 1; (12) The preparation method 2 of compound 31 may further include post-treatment, wherein the post-treatment steps and operations are as described in any one of claims 2 to 6; (13) The raw materials and reagents of the preparation method 2 of the compound 31 are composed of the following components: the solvent, the base, the catalyst and the compound 28.

14. The preparation method 2 of compound 31 according to claim 13, characterized in that: It meets one or more of the following conditions: (1) The reaction temperature of step 1 is 80°C to 110°C; (2) The reaction time of step 1 is 2 hours; (3) The dehydration operation includes physical dehydration and chemical dehydration; (4) The reaction temperature of step 2 is 140°C to 160°C; (5) The reaction time of step 2 is 3-6 hours; (6) After step 2, water is added, and the molar ratio of water to compound 28 is 2.08:

1.

15. The preparation method 2 of compound 31 according to claim 14, characterized in that: It meets one or more of the following conditions: (1) The reaction temperature of step 1 is 110°C; (2) The reaction temperature of step 2 is 150°C; (3) The reaction time of step 2 is 5 hours.

16. A method for preparing compound 1, characterized in that: The method comprises the following steps: preparing compound 31 according to the preparation method 1 of compound 31 according to any one of claims 1 to 10 or the preparation method 2 of compound 31 according to any one of claims 11 to 15, and subjecting compound 31 to a ring-closure reaction with N-methyl-o-phenylenediamine or a salt of N-methyl-o-phenylenediamine in a solvent to obtain compound 1; the solvent is DMF; 。 17. The method for preparing compound 1 according to claim 16, characterized in that: It meets one or more of the following conditions: (1) The mass ratio of the compound 31 to the solvent is 1:(1-10); (2) The N-methyl-o-phenylenediamine salt is N-methyl-o-phenylenediamine hydrochloride; (3) The molar ratio of the compound 31 to the N-methyl-o-phenylenediamine or its salt is 1:(0.8-1.2); (4) The ring-closure reaction includes a base; (5) The ring-closure reaction includes an additive; (6) The preparation method of compound 1 further includes post-treatment, and the post-treatment operation includes the following steps: after the ring-closure reaction is completed, cooling, quenching, extraction, concentration, and purification; (7) The raw materials and reagents for the preparation method of the compound 1 are composed of the following components: the solvent, the compound 31 and the N-methyl-o-phenylenediamine or its salt.

18. The method for preparing compound 1 according to claim 17, characterized in that: It meets one or more of the following conditions: (1) The mass ratio of the compound 31 to the solvent is 1:5; (2) the molar ratio of the compound 31 to the N-methyl-o-phenylenediamine or its salt is 1:1; (3) The additive is an alkali metal hydrogen sulfate; (4) The base is an organic base and / or an inorganic base; (5) The molar ratio of the N-methyl-o-phenylenediamine or its salt to the base is 1:(1-3); (6) The molar ratio of the compound 31 to the additive is 1:(1-2); (7) The temperature of the ring-closure reaction is 60°C to 130°C; (8) The reaction time of the ring-closure reaction is 1-24 hours.

19. The method for preparing compound 1 according to claim 18, characterized in that: It meets one or more of the following conditions: (1) The alkali metal bisulfate is sodium bisulfite and / or sodium trisulfite; (2) The base is triethylamine; (3) The molar ratio of the N-methyl-o-phenylenediamine or its salt to the base is 1:2.05; (4) The molar ratio of the compound 31 to the additive is 1:1.2; (5) The temperature of the ring-closure reaction is 70°C to 130°C; (6) The reaction time of the ring-closure reaction is 3-6 hours.

20. The method for preparing compound 1 according to claim 19, characterized in that: It meets one or more of the following conditions: (1) The alkali metal bisulfate is sodium bisulfite; (2) The temperature of the ring-closure reaction is 70, 80, 90, 110 or 130°C; (3) The reaction time of the ring-closure reaction is 5 hours.

21. The method for preparing compound 1 according to claim 20, characterized in that: The temperature of the ring-closure reaction is 130°C.

22. A method for preparing compound 30, characterized in that: The method comprises the following steps: in a solvent, in the presence of a base, a catalyst and a phase transfer catalyst, compound 28 undergoes an alkylation reaction with chloroacetamide to obtain compound 30; ； The reaction conditions and steps of the method for preparing compound 30 are as described in any one of claims 7 to 10.

23. A compound 30, whose structure is shown below: 。

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