Synthetic method of fenerenone intermediate

Abstract

The invention belongs to the field of medicinal chemistry, and relates to a synthetic method of a fenerenone intermediate. According to the synthetic method, only one solvent is involved in the whole preparation process, so that the cost of solvent residue detection and three-waste treatment is greatly reduced, the production efficiency is improved, and the synthetic method has the advantages of mild conditions, few impurities, high yield and the like.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical chemistry, and in particular to a method for synthesizing a finerenone intermediate. Background Art

[0002] Finerenone (BAY 94-8862) is a nonsteroidal selective mineralocorticoid receptor antagonist used primarily to treat chronic kidney disease associated with type 2 diabetes.

[0003] Patent application CN201580053456.7 discloses the following synthetic process route of finerenone (i.e. compound 10 in the following route):

[0004]

[0005] The research found that the preparation of the phenelenone intermediate (i.e. compound 7) in the synthesis process has the following technical problems:

[0006] (1) The detection work is cumbersome and the cost of waste liquid treatment is high: A variety of solvents are used in the synthesis process of compound 7 (step 1, reaction system - dichloromethane or isopropanol, crystallization system - methanol or unpurified; step 2, reaction system - 2-butanol or isopropanol; step 3, reaction system - NMP; step 4, reaction system - tetrahydrofuran, post-treatment system - ethyl acetate, methyl tert-butyl ether), which increases the cumbersome quality research work of detecting solvent residues in API and also increases the cost of three waste treatment.

[0007] (2) Long production cycle: Each step of the reaction requires post-processing and drying, which makes the production process time-consuming.

[0008] (3) Harsh production conditions: The reaction in step 2 needs to be carried out under pressure, and the environmental requirements for scaled-up production are relatively stringent.

[0009] (4) Difficulty in impurity control: The isopropanol used in step 2 is not easy to remove, and it is easy to react with compound 5 to form impurity 1 in step 3 of the synthesis process. The impurity 1 has a similar chemical structure to compound 6 and is not easy to remove. In addition, the impurity will be converted into impurity 2 in the subsequent steps ( Produced in step 4 of the synthesis process) and impurity 3 ( produced in the phenerenone finishing step of the synthesis process).

[0010] Therefore, there is still a need for a method for synthesizing a phenerenone intermediate with less solvent residue, less three wastes, simple operation, low production condition requirements, and simple impurity control. Summary of the invention

[0011] In order to solve the above technical problems, the present invention provides the following technical solutions.

[0012] In a first aspect, the present invention provides a method for synthesizing compound 3.

[0013] A method for synthesizing compound 3, comprising:

[0014]

[0015] Compound 1 and compound 2 react in a solvent in the presence of a catalyst to obtain compound 3, wherein the solvent is at least one of DMAC, DMF and NMP.

[0016] In some embodiments, the catalyst is acetic acid and at least one selected from morpholine and piperidine. In some preferred embodiments, the catalyst is acetic acid and morpholine.

[0017] In some preferred embodiments, the solvent is DMAC.

[0018] In some embodiments, the molar ratio of compound 2 to compound 1 is 1.0:1.0-1.25:1.0. In some embodiments, the molar ratio of compound 2 to compound 1 is 1.0:1.0, 1.1:1.0, 1.2:1.0 or 1.25:1.0.

[0019] In some embodiments, the molar ratio of the catalyst to compound 1 is 0.05:1.0-0.2:1.0. In some embodiments, the molar ratio of the catalyst to compound 1 is 0.05:1.0-0.1:1.0.

[0020] In some embodiments, the reaction temperature of the reaction in the synthesis method of compound 3 is 25° C.-35° C. In some embodiments, the reaction temperature of the reaction in the synthesis method of compound 3 is 25° C., 30° C. or 35° C.

[0021] In some embodiments, the synthesis method of compound 3 further includes a post-treatment step, and the post-treatment step includes: adding methyl tert-butyl ether, cooling to 0±5°C, and keeping warm for crystallization.

[0022] In a second aspect, the present invention provides a method for synthesizing compound 5.

[0023] A method for synthesizing compound 5, comprising:

[0024]

[0025] Compound 3 and compound 4 react in a solvent to obtain compound 5, wherein the solvent is at least one of DMAC, DMF and NMP.

[0026] In some embodiments, the molar ratio of compound 4 to compound 3 is 0.8:1.0 to 1.2:1.0. In some embodiments, the molar ratio of compound 4 to compound 3 is 0.8:1.0, 0.9:1.0, 1.0:1.0, 1.1:1.0 or 1.2:1.0.

[0027] In some preferred embodiments, the solvent is DMAC.

[0028] In some embodiments, the reaction temperature of the reaction of the synthesis method of compound 5 is 70° C.-120° C. In some embodiments, the reaction temperature of the reaction of the synthesis method of compound 5 is 70° C., 75° C., 80° C., 85° C., 90° C., 95° C., 100° C., 105° C., 110° C., 115° C. or 120° C.

[0029] In some embodiments, the synthesis method of compound 5 also includes the preparation step of compound 3: preparing compound 3 according to the synthesis method described in the first aspect.

[0030] In a third aspect, the present invention provides a method for synthesizing compound 6.

[0031] A method for synthesizing compound 6, comprising:

[0032]

[0033] Compound 5 is prepared according to the synthesis method of the second aspect; the obtained compound 5 reacts with triethyl orthoacetate in a solvent in the presence of a catalyst to obtain compound 6; the solvent is at least one of DMAC, DMF and NMP.

[0034] In some embodiments, the catalyst comprises at least one of sulfuric acid, p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, and methanesulfonic acid. In some preferred embodiments, the catalyst is sulfuric acid.

[0035] In some embodiments, the molar ratio of the catalyst to compound 5 is 0.1:1.0-0.5:1.0. In some embodiments, the molar ratio of the catalyst to compound 5 is 0.1:1.0, 0.15:1.0, 0.2:1.0, 0.3:1.0, 0.4:1.0 or 0.5:1.0. In some preferred embodiments, the molar ratio of the catalyst to compound 5 is 0.1:1.0-0.2:1.0.

[0036] In some embodiments, the molar ratio of triethyl orthoacetate to compound 5 is 2.5:1.0 to 6.0:1.0. In some embodiments, the molar ratio of triethyl orthoacetate to compound 5 is 2.5:1.0, 3.0:1.0, 3.5:1.0, 4.0:1.0, 4.5:1.0, 5.0:1.0, 5.5:1.0 or 6.0:1.0. In some preferred embodiments, the molar ratio of triethyl orthoacetate to compound 5 is 3.0:1.0.

[0037] In some embodiments, the reaction temperature of the reaction of the synthesis method of compound 6 is 80°C-130°C. In some embodiments, the reaction temperature of the reaction of the synthesis method of compound 6 is 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, 120°C, 125°C or 130°C. In some preferred embodiments, the reaction temperature of the reaction of the synthesis method of compound 6 is 105°C-115°C.

[0038] In a fourth aspect, the present invention provides a method for synthesizing compound 7.

[0039] A method for synthesizing compound 7, comprising:

[0040]

[0041] Compound 6 is prepared according to the synthesis method of the third aspect, and the obtained compound 6 reacts with a base in a solvent to obtain compound 7; the solvent is at least one of DMAC, DMF and NMP.

[0042] In some embodiments, the base comprises at least one of LiOH, NaOH, and KOH. In some preferred embodiments, the base is NaOH.

[0043] In some embodiments, the molar ratio of the base to compound 6 is 1.3:1.0 to 5.0:1.0. In some embodiments, the molar ratio of the base to compound 6 is 1.3:1.0, 1.5:1.0, 2.0:1.0, 2.5:1.0, 3.0:1.0, 3.5:1.0, 4.0:1.0, 4.5:1.0 or 5.0:1.0. In some embodiments, the molar ratio of the base to compound 6 is 1.5:1.0 to 2.0:1.0.

[0044] In some embodiments, the reaction temperature of the reaction of the synthesis method of compound 7 is -5°C to 5°C. In some embodiments, the reaction temperature of the reaction of the synthesis method of compound 7 is -5°C, -4°C, -3°C, -2°C, -1°C, 0°C, 1°C, 2°C, 3°C, 4°C or 5°C.

[0045] In some embodiments, the synthesis method of compound 7 also includes post-treatment, which includes: adding isopropyl acetate, extracting, separating the liquids to obtain an aqueous phase, adjusting the pH of the obtained aqueous phase to 6-7 with an acid at -5°C to 5°C, then adding a saturated aqueous ammonium chloride solution, crystallizing, filtering, washing the filter cake, and drying the washed filter cake.

[0046] In a fifth aspect, the present invention provides a method for synthesizing compound 7.

[0047] A method for synthesizing compound 7, comprising the following steps:

[0048] Step 1: Preparation of compound 3:

[0049]

[0050] Compound 1 and Compound 2 react in a solvent in the presence of a catalyst to obtain a reaction solution A containing Compound 3, wherein the solvent is at least one of DMAC, DMF and NMP;

[0051] Step 2: Preparation of compound 5:

[0052]

[0053] The reaction solution A containing compound 3 obtained in step 1 is mixed with compound 4, and reacted to obtain a reaction solution B containing compound 5;

[0054] Step 3: Preparation of compound 6:

[0055]

[0056] The reaction solution B obtained in step 2 is mixed with triethyl orthoacetate and a catalyst to react to obtain a reaction solution C containing compound 6;

[0057] Step 4: Preparation of compound 7:

[0058]

[0059] The reaction solution C obtained in step 3 is mixed with a base to react to obtain compound 7.

[0060] In some embodiments, the catalyst in step 1 is acetic acid and at least one selected from morpholine and piperidine.

[0061] In some embodiments, the catalyst in step 1 is acetic acid and morpholine.

[0062] In some embodiments, the solvent in step 1 is DMAC.

[0063] In some embodiments, the molar ratio of compound 2 to compound 1 in step 1 is 1.0:1.0-1.25:1.0. In some embodiments, the molar ratio of compound 2 to compound 1 in step 1 is 1.0:1.0, 1.1:1.0, 1.15:1.0, 1.2:1.0 or 1.25:1.0.

[0064] In some embodiments, the molar ratio of the catalyst to compound 1 in step 1 is 0.05:1.0-0.2:1.0. In some embodiments, the molar ratio of the catalyst to compound 1 in step 1 is 0.05:1.0, 0.1:1.0, 0.15:1.0 or 0.2:1.0.

[0065] In some embodiments, the reaction temperature of the reaction in the synthesis method of compound 3 in step 1 is 25° C.-35° C. In some embodiments, the reaction temperature of the reaction in the synthesis method of compound 3 in step 1 is 25° C., 30° C. or 35° C.

[0066] In some embodiments, the molar ratio of the compound 4 in step 2 to the compound 1 in step 1 is 0.8:1.0 to 1.2:1.0. In some embodiments, the molar ratio of the compound 4 in step 2 to the compound 1 in step 1 is 0.8:1.0, 0.9:1.0, 1.0:1.0, 1.1:1.0 or 1.2:1.0.

[0067] In some embodiments, the reaction temperature of the reaction of step 2 is 70° C.-120° C. In some embodiments, the reaction temperature of the reaction of step 2 is 70° C., 75° C., 80° C., 85° C., 90° C., 95° C., 100° C., 105° C., 110° C., 115° C., or 120° C.

[0068] In some embodiments, the catalyst of step 3 comprises at least one of sulfuric acid, p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, and methanesulfonic acid. In some preferred embodiments, the catalyst of step 3 is sulfuric acid.

[0069] In some embodiments, the molar ratio of the triethyl orthoacetate in step 3 to the compound 1 in step 1 is 2.5:1.0 to 6.0:1.0. In some embodiments, the molar ratio of the triethyl orthoacetate in step 3 to the compound 1 in step 1 is 2.5:1.0, 3.0:1.0, 3.5:1.0, 4.0:1.0, 4.5:1.0, 5.0:1.0, 5.5:1.0 or 6.0:1.0. In some preferred embodiments, the molar ratio of the triethyl orthoacetate in step 3 to the compound 1 in step 1 is 3.0:1.0.

[0070] In some embodiments, the molar ratio of the catalyst in step 3 to compound 1 is 0.1:1.0-0.5:1.0. In some embodiments, the molar ratio of the catalyst in step 3 to compound 1 is 0.1:1.0, 0.2:1.0, 0.3:1.0, 0.4:1.0 or 0.5:1.0. In some preferred embodiments, the molar ratio of the catalyst in step 3 to compound 1 is 0.1:1.0-0.2:1.0.

[0071] In some embodiments, the reaction temperature of the reaction in step 3 is 80° C.-130° C. In some embodiments, the reaction temperature of the reaction in step 3 is 80° C., 85° C., 90° C., 95° C., 100° C., 105° C., 110° C., 115° C., 120° C., 125° C., or 130° C. In some embodiments, the reaction temperature of the reaction in step 3 is 105° C.-115° C.

[0072] In some embodiments, the base in step 4 comprises at least one of LiOH, NaOH, and KOH. In some preferred embodiments, the base in step 4 is NaOH.

[0073] In some embodiments, the molar ratio of the base in step 4 to the compound 1 in step 1 is 1.05:1.0 to 5.0:1.0. In some embodiments, the molar ratio of the base in step 4 to the compound 1 in step 1 is 1.05:1.0, 1.1:1.0, 1.2:1.0, 1.5:1.0, 2.0:1.0, 2.5:1.0, 3.0:1.0, 3.5:1.0, 4.0:1.0, 4.5:1.0 or 5.0:1.0. In some preferred embodiments, the molar ratio of the base in step 4 to the compound 1 in step 1 is 1.1:1.0 to 2.0:1.0.

[0074] In some embodiments, the reaction temperature of the reaction in step 4 is -5°C to 5°C. In some embodiments, the reaction temperature of the reaction in step 4 is -5°C, 0°C or 5°C.

[0075] In some embodiments, step 4 also includes post-treatment, which includes: adding isopropyl acetate, extracting, separating the liquids to obtain an aqueous phase, adjusting the pH of the obtained aqueous phase to 6-7 with an acid at -5°C to 5°C, then adding a saturated aqueous ammonium chloride solution, crystallizing, filtering, washing the filter cake, and drying the washed filter cake.

[0076] Beneficial Effects

[0077] Compared with the prior art, the present invention has the following beneficial effects:

[0078] (1) The same solvent can be used in each step of the present invention, which can minimize the types of solvents, reduce the time and detection amount required for developing analytical methods for detecting multiple solvent residues in the finished product, and also minimize the cost of treating the three wastes generated by the four-step process.

[0079] (2) The present invention reduces preparation time and improves production efficiency.

[0080] (3) The reaction conditions of the present invention are simple and mild, and can be carried out under normal pressure without sealing and pressurizing, which improves the safety of production and is conducive to scale-up production.

[0081] (4) The use of the solvent provided by the present invention can avoid the generation of impurities 1, 2 and 3 (the structures of which are described in the previous background technology), which is beneficial to impurity control.

[0082] (5) Using the solvent provided by the present invention, preferably DMAC, is more conducive to improving the yield of the product in each step, and has unexpected technical effects.

[0083] (6) The present invention preferably uses morpholine and acetic acid as catalysts for preparing compound 3, which is more conducive to improving the yield and purity of the obtained compound 3 and has unexpected technical effects.

[0084] (7) The synthesis method provided by the present invention has high yield and high purity.

[0085] Definition of terms

[0086] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0087] The term "room temperature" refers to a temperature between about 20°C and 35°C, or between about 23°C and 28°C, or about 25°C.

[0088] The reaction involved in the present invention can be monitored by high performance liquid chromatography (HPLC) to monitor the reaction endpoint. When the detection shows that the reaction raw material compound is less than 1.0%, the reaction is considered to be completed. The reaction time is usually within 24 hours.

[0089] The method of the present invention can use high performance liquid chromatography (HPLC) to monitor the purity of the reactants.

[0090] The wavy line in compound 3 of the present invention indicates the existence of cis isomers and / or trans isomers, that is, compound 3 includes DETAILED DESCRIPTION

[0091] In order to enable those skilled in the art to better understand the technical solution of the present invention, some non-limiting embodiments are further disclosed below to further describe the present invention in detail.

[0092] The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention.

[0093] In the present invention, mL means milliliter, h means hour, g means gram, mg means milligram, °C means degree Celsius, and HPLC means high performance liquid chromatography. DMAC means N-dimethylacetamide; DMF means N,N-dimethylformamide; NMP means N-methylpyrrolidone. eq means molar equivalent.

[0094] Impurity 1:

[0095] Example 1: Preparation of Compound 3

[0096]

[0097] Compound 1 (10 g, 1 eq), DMAC (50 mL), morpholine (0.05 eq) and acetic acid (0.05 eq) were mixed and stirred. The system was temperature controlled to 30±5°C, and compound 2 (1.2 eq) was added. After the addition was completed, the reaction was kept at this temperature for 4 hours. After the reaction was completed, the reaction system was temperature controlled to room temperature to obtain a DMAC solution of compound 3 (reaction solution A-1) for standby use.

[0098] Example 2: Preparation of Compound 3

[0099] Compound 1 (10 g, 1 eq), DMF (50 mL), morpholine (0.1 eq) and acetic acid (0.1 eq) were mixed and stirred. The stirring was turned on and the temperature of the system was controlled to 25±5°C. Compound 2 (1.1 eq) was added. After the addition was completed, the reaction was kept at this temperature for 5 hours. After the reaction was completed, the reaction system was returned to room temperature to obtain a DMF solution of compound 3 (reaction solution A-2) for standby use.

[0100] Example 3: Preparation of Compound 3

[0101] Compound 1 (10 g, 1 eq), NMP (40 mL), piperidine (0.1 eq) and acetic acid (0.1 eq) were mixed and stirred. Stirring was started and the system temperature was controlled to 30±5°C. Compound 2 (1.2 eq) was then added. After the addition was completed, the reaction was kept at this temperature for 5 h. After the reaction was completed, the reaction system was returned to room temperature to obtain a NMP solution of compound 3 (reaction solution A-3) for standby use.

[0102] Example 4: Preparation of Compound 5

[0103]

[0104] The DMAC solution of compound 3 (reaction solution A-1 obtained in Example 1) was mixed with compound 4 (0.9 eq). After the addition was completed, the system temperature was controlled to 95±5°C and stirred for reaction at this temperature for 6 hours. After the reaction was completed, the reaction system was slowly cooled to room temperature to obtain a DMAC solution of compound 5 (reaction solution B-1) for standby use.

[0105] Example 5: Preparation of Compound 5

[0106] The DMF solution of the above-mentioned compound 3 (reaction liquid A-2 obtained in Example 2) was mixed with compound 4 (1.0 eq). After the addition was completed, the system temperature was controlled to 100±5°C and stirred for reaction at this temperature for 6 hours. After the reaction was completed, the reaction system was slowly cooled to room temperature to obtain a DMF solution of compound 5 (reaction liquid B-2) for standby use.

[0107] Example 6: Preparation of Compound 5

[0108] The NMP solution of the above-mentioned compound 3 (reaction liquid A-3 obtained in Example 3) was mixed with compound 4 (0.95eq). After the addition was completed, the system temperature was controlled to 90±5°C and stirred for reaction at this temperature for 8 hours. After the reaction was completed, the reaction system was slowly cooled to room temperature to obtain an NMP solution of compound 5 (reaction liquid B-3) for standby use.

[0109] Example 7: Preparation of Compound 6

[0110]

[0111] The DMAC solution of the above compound 5 (reaction solution B-1 obtained in Example 4) was mixed with triethyl orthoacetate (3.0 eq), and then sulfuric acid (0.1 eq) was slowly added. The system temperature was controlled to 110±5°C and reacted at this temperature for 5 hours. After the reaction was completed, the system was slowly cooled to room temperature to obtain a DMAC solution of compound 6 (reaction solution C-1) for standby use.

[0112] Example 8: Preparation of Compound 6

[0113] The DMF solution of the above compound 5 (reaction liquid B-2 obtained in Example 5) was mixed with triethyl orthoacetate (2.5 eq), and then sulfuric acid (0.15 eq) was slowly added. The system temperature was controlled to 100±5°C and the reaction was carried out at this temperature for 8 hours. After the reaction was completed, the system was slowly cooled to room temperature to obtain a DMF solution of compound 6 (reaction liquid C-2) for standby use.

[0114] Example 9: Preparation of Compound 6

[0115] The NMP solution of the above-mentioned compound 5 (reaction liquid B-3 obtained in Example 6) was mixed with triethyl orthoacetate (4.0 eq), and then sulfuric acid (0.2 eq) was slowly added. The system temperature was controlled to 90±5°C and reacted at this temperature for 5 hours. After the reaction was completed, the system was slowly cooled to room temperature to obtain an NMP solution of compound 6 (reaction liquid C-3) for standby use.

[0116] Example 10: Preparation of Compound 7

[0117]

[0118] The DMAC solution of the above compound 6 (reaction solution C-1 obtained in Example 7) was cooled to 0±5°C, and an aqueous solution of NaOH (1.1 eq) was slowly added dropwise to the system. After the addition was completed, the reaction was carried out at 0±5°C for 2 h. After the reaction was completed, the system was temperature-controlled to 20±5°C, and dichloromethane was used to extract the liquid (50 mL×2). The obtained aqueous phase was temperature-controlled to 0±5°C. Hydrochloric acid was added dropwise at this temperature to adjust the pH of the system to 6-7, and then 20 mL of a saturated aqueous solution of ammonium chloride was added. The system was heated to 20±5°C and kept warm for crystallization for 1 h. The filter cake was filtered, rinsed with water, and then dried under vacuum at 60°C to constant weight to obtain 17.78 g of compound 7. The total yield of 4 steps was 83.7%, and the HPLC purity was ≥98.0%. Impurity 2 was not detected.

[0119] Example 11: Preparation of Compound 7

[0120] At room temperature, the reaction flask containing the DMF solution of compound 6 (reaction solution C-2 obtained in Example 8) was cooled to 0±5°C, and an aqueous solution of NaOH (1.2 eq) was slowly added dropwise to the system. After the addition was completed, the reaction was kept at 0±5°C for 1 h. After the reaction was completed, the system was temperature-controlled to 20±5°C, and ethyl acetate was used for extraction and separation (50 mL×2). The obtained aqueous phase was temperature-controlled to 0±5°C. Hydrochloric acid was added dropwise at this temperature to adjust the pH of the system to 6-7, and then 25 mL of saturated aqueous ammonium chloride solution was added. The system was heated to 20±5°C and kept for crystallization for 2 h. The filter cake was filtered, rinsed with water, and then dried under vacuum at 60°C to constant weight to obtain 17.05 g of compound 7, with a total yield of 64.4% for 4 steps and a purity of ≥98.0% by HPLC, wherein impurity 2 was not detected.

[0121] Example 12. Preparation of Compound 7

[0122] At room temperature, the reaction flask containing the NMP solution of compound 6 (reaction solution C-3 obtained in Example 9) was cooled to 0±5°C, and an aqueous solution of NaOH (1.1 eq) was slowly added dropwise to the system. After the addition was completed, the reaction was kept at 0±5°C for 2 h. After the reaction was completed, the system was temperature controlled to 20±5°C, and isopropyl acetate was used to extract the liquid (50 mL×2). The resulting aqueous phase was temperature controlled to 0±5°C, and hydrochloric acid was added dropwise at this temperature to adjust the pH of the system to 6-7. Then 25 mL of saturated aqueous ammonium chloride solution was added, and the system was heated to 20±5°C and kept for crystallization for 3 h. The filter cake was filtered, rinsed with water, and then dried under vacuum at 60°C to constant weight to obtain 16.75 g of compound 7, with a total yield of 60.6% for 4 steps and a purity of ≥98.0% by HPLC, wherein impurity 2 was not detected.

[0123] Example 13: Preparation of Compound 3

[0124]

[0125] Compound 1 (10 g, 1 eq), DMAC (50 mL), morpholine (0.05 eq) and acetic acid (0.05 eq) were mixed and stirred. The system was temperature-controlled to 30±5°C, and compound 2 (1.2 eq) was added. After the addition was completed, the reaction was kept at this temperature for 4 hours. After the reaction was completed, the reaction system was temperature-controlled to room temperature, methyl tert-butyl ether (150 mL) was added, the temperature was lowered to 0±5°C, and the temperature was kept for crystallization for 2 hours to obtain compound 3 with a yield of 95.37% and a HPLC purity of 99.38%.

[0126] Comparative Example 1-Comparative Example 3: Investigation of reaction solvents for preparing compound 3

[0127] Compound 3 was prepared by the method of Reference Example 13, and the same volume of the reaction solvent described in Table 1 was replaced by DMAC to carry out the reaction to obtain Compound 3 using different reaction solvents. The yield and purity of Compound 3 were calculated. The results are shown in Table 1.

[0128] Table 1: Investigation of reaction solvents for preparing compound 3

[0129] test Reaction solvent Yield of compound 3 Purity of compound 3 Comparative Example 1 Ethyl acetate 75.33％ 92.47％ Comparative Example 2 Isopropyl alcohol 84.26％ 95.42％ Comparative Example 3 Tetrahydrofuran 86.43％ 98.14％

[0130] Conclusion: In the reaction of preparing compound 3, compared with using other reaction solvents, using the reaction solvent provided by the present invention is more conducive to improving the yield and purity of compound 3, and has unexpected technical effects.

[0131] The method of the present invention has been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein within the content, spirit and scope of the present invention to implement and apply the technology of the present invention. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters. It is particularly important to point out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.

Claims

1. A method for synthesizing compound 3, characterized in that: include: Compound 1 and compound 2 react in a solvent in the presence of a catalyst to obtain compound 3, wherein the solvent is at least one of DMAC, DMF and NMP.

2. The synthesis method according to claim 1, wherein the catalyst is acetic acid and at least one selected from morpholine and piperidine; and / or Preferably, the catalyst is acetic acid and morpholine; and / or Preferably, the solvent is DMAC; and / or Optionally, the molar ratio of compound 2 to compound 1 is 1.0:1.0-1.25:1.0; and / or Optionally, the molar ratio of the catalyst to compound 1 is 0.05:1.0-0.2:1.0; and / or Optionally, the reaction temperature in the synthesis method of compound 3 is 25°C-35°C.

3. A method for synthesizing compound 5, characterized in that: include: Compound 3 and compound 4 react in a solvent to obtain compound 5, wherein the solvent is at least one of DMAC, DMF and NMP.

4. The synthesis method according to claim 3, wherein the molar ratio of compound 4 to compound 3 is 0.8:1.0 to 1.2:1.0; and / or Preferably, the solvent is DMAC; and / or Optionally, the reaction temperature of the synthesis method of compound 5 is 70°C-120°C; and / or Optionally, the synthesis method of compound 5 further comprises the step of preparing compound 3: preparing compound 3 according to the synthesis method according to any one of claims 1-2.

5. A method for synthesizing compound 6, characterized in that: include: Compound 5 is prepared according to the synthesis method according to any one of claims 3 to 4; the obtained compound 5 reacts with triethyl orthoacetate in a solvent in the presence of a catalyst to obtain compound 6; the solvent is at least one of DMAC, DMF and NMP.

6. The synthesis method according to claim 5, wherein the catalyst comprises at least one of sulfuric acid, p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, and methanesulfonic acid; preferably sulfuric acid; and / or Optionally, the molar ratio of the catalyst to compound 5 is 0.1:1.0-0.5:1.0, preferably 0.1:1.0-0.2:1.0; and / or Optionally, the molar ratio of triethyl orthoacetate to compound 5 is 2.5:1.0 to 6.0:1.0, preferably 3.0:1.0; and / or Optionally, the reaction temperature of the synthesis method of compound 6 is 80°C-130°C, preferably 105°C-115°C.

7. A method for synthesizing compound 7, characterized in that: include: Compound 6 is prepared according to the synthesis method according to any one of claims 5-6, and the obtained compound 6 reacts with a base in a solvent to obtain compound 7; the solvent is at least one of DMAC, DMF and NMP.

8. The synthesis method according to claim 7, wherein the base comprises at least one of LiOH, NaOH, and KOH, preferably NaOH; and / or Optionally, the molar ratio of the base to compound 6 is 1.3:1.0 to 5.0:1.0, preferably 1.5:1.0 to 2.0:1.0; and / or Optionally, the reaction temperature of the synthesis method of compound 7 is -5°C to 5°C; and / or Optionally, the synthesis method of compound 7 further comprises post-treatment, wherein the post-treatment comprises: Add isopropyl acetate, extract, separate the liquids to obtain an aqueous phase, adjust the pH of the aqueous phase to 6-7 with acid at -5°C to 5°C, then add saturated ammonium chloride aqueous solution, crystallize, filter, wash the filter cake, and dry the washed filter cake.

9. A method for synthesizing compound 7, characterized in that: The following steps are involved: Step 1: Preparation of compound 3: Compound 1 and Compound 2 react in a solvent in the presence of a catalyst to obtain a reaction solution A containing Compound 3, wherein the solvent is at least one of DMAC, DMF and NMP; Step 2: Preparation of compound 5: The reaction solution A containing compound 3 obtained in step 1 is mixed with compound 4, and reacted to obtain a reaction solution B containing compound 5; Step 3: Preparation of compound 6: The reaction solution B obtained in step 2 is mixed with triethyl orthoacetate and a catalyst to react to obtain a reaction solution C containing compound 6; Step 4: Preparation of compound 7: The reaction solution C obtained in step 3 is mixed with a base to react to obtain compound 7.

10. The synthesis method according to claim 9, wherein the catalyst in step 1 is acetic acid and at least one selected from morpholine and piperidine; and / or Preferably, the catalyst in step 1 is acetic acid and morpholine; and / or Preferably, the solvent in step 1 is DMAC; and / or Optionally, the molar ratio of compound 2 to compound 1 in step 1 is 1.0:1.0-1.25:1.0; and / or Optionally, the molar ratio of the catalyst to compound 1 in step 1 is 0.05:1.0-0.2:1.0; and / or Optionally, the reaction temperature in the synthesis method of compound 3 in step 1 is 25°C-35°C; and / or Optionally, the molar ratio of the compound 4 in step 2 to the compound 1 in step 1 is 0.8:1.0 to 1.2:1.0; and / or Optionally, the reaction temperature of step 2 is 70°C-120°C; and / or Optionally, the catalyst in step 3 comprises at least one of sulfuric acid, p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, and methanesulfonic acid; preferably sulfuric acid; and / or Optionally, the molar ratio of the triethyl orthoacetate in step 3 to the compound 1 in step 1 is 2.5:1.0 to 6.0:1.0, preferably 3.0:1.0; and / or Optionally, the molar ratio of the catalyst to compound 1 in step 3 is 0.1:1.0-0.5:1.0, preferably 0.1:1.0-0.2:1.0; and / or Optionally, the reaction temperature of step 3 is 80°C-130°C, preferably 105°C-115°C; and / or Optionally, the base in step 4 comprises at least one of LiOH, NaOH, KOH, preferably NaOH; and / or Optionally, the molar ratio of the base in step 4 to the compound 1 in step 1 is 1.05:1.0 to 5.0:1.0, preferably 1.1:1.0 to 2.0:1.0; and / or Optionally, the reaction temperature of step 4 is -5°C to 5°C; and / or Optionally, the step 4 further comprises post-processing, wherein the post-processing comprises: Add isopropyl acetate, extract, separate the liquids to obtain an aqueous phase, adjust the pH of the aqueous phase to 6-7 with acid at -5°C to 5°C, then add saturated ammonium chloride aqueous solution, crystallize, filter, wash the filter cake, and dry the washed filter cake.

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