Preparation method for DOTA residue-containing compound

Abstract

The present disclosure relates to a preparation method for a DOTA residue-containing compound, particularly a preparation method for a DOTA residue-containing compound suitable for industrial production. The preparation method has the advantages of high product purity, high yield, and low cost, being suitable for industrial production, etc.

Description

Preparation method of compounds containing DOTA residues This application is based on and claims priority to Chinese patent application No. 202510117858.4, filed on January 24, 2025, the disclosure of which is incorporated herein by reference in its entirety. Technical Field This disclosure pertains to the field of medicinal chemistry, specifically relating to a method for preparing a high-purity compound containing DOTA residues, and particularly to a method for preparing a compound containing DOTA residues suitable for industrial production. Background Technology Compound 1, as shown below, is a precursor compound that, upon radio-chelation, can generate a radiolabel for the treatment of bone metastases from advanced solid tumors: Chinese patent application CN114230610A discloses a method for preparing compound 1. In this method, compound 1 is prepared only at the milligram scale. The entire route involves two steps of preparation and purification, resulting in extremely low yield, high reaction cost, and low purity of the product. This method cannot meet the purity requirements of the precursor compound for radio-chelation reactions and is difficult to scale up for industrial production. In addition, this route uses commercially available compound 2 (structure shown below) as raw material. Due to the technical difficulties in the preparation process, compound 2 is expensive and has low purity, which is very detrimental to the quality control of subsequent intermediates and compound 1, as well as to reducing the cost of the route. Currently, the preparation methods of compound 2 reported in the literature mainly include the following two: One approach is disclosed in patent publication WO2023059583A1, which follows this route: using 4-(N-tert-butoxycarbonylamino)-1-butanol as a raw material, introducing bromine atoms via a carbon tetrabromide / triphenylphosphine reaction, and then reacting it with methylamine to obtain compound 2. In this approach, the purity of compound 2 is only 60%, and the purification process is not disclosed. Another approach, as disclosed in patent publication CN117924117A, involves the following route: N-tert-butoxycarbonyl-1,4-butanediamine undergoes a condensation reaction with an aldehyde compound to form an imine, which is then reacted with a methylating agent to introduce a methyl group, followed by hydrolysis to obtain the target compound 2. This method is lengthy and only yields a crude product of compound 2, lacking intermediate purification steps and making product quality control impossible. Furthermore, the methylating agent used in this method is highly toxic and / or highly sensitizing, posing significant risks to worker safety. In summary, the reported synthetic yields of Compound 1 are currently low, with an overall yield of only 0.2%. Two steps require Prep-HPLC purification, resulting in high production costs. Furthermore, key testing items such as related substances for Compound 1 are not controlled, making it suitable only for preparing small-scale samples and unable to meet the needs of clinical and large-scale production. There is an urgent need in this field to develop a method for preparing Compound 1 and its starting material Compound 2 that utilizes readily available raw materials, operates under mild reaction conditions, is easy to operate, and achieves high purity and high overall yield, suitable for large-scale industrial production. Summary of the Invention The purpose of this disclosure is to provide a simple, high-yield, and easily industrialized preparation method that can synthesize high-purity compound 1 at a low cost, thereby providing a reliable raw material for the next step of radioactive chelation. On one hand, this disclosure provides a method for preparing compound 5, comprising reacting compound 4 with phosphorus tribromide and phosphorous acid, and then hydrolyzing it to generate compound 5. In some embodiments, the reaction is carried out in a solvent selected from sulfolane, toluene, or 1,4-dioxane. In some embodiments, the reaction is carried out in sulfolane. In some embodiments, the reaction is carried out in toluene. In some embodiments, the molar ratio of phosphorous acid to compound 4 is (4–40):1, for example (6–40):1, (6–32):1, (8–32):1 or (10–32):1, and even more for example 4:1, 5:1, 6:1, 8:1, 10:1, 12:1, 14:1, 16:1, 20:1, 24:1, 28:1 or 32:1. In some embodiments, the molar ratio of phosphorus tribromide to compound 4 is (2-24):1, for example (4-24):1 or (4-20):1, and even more for example 2:1, 3:1, 4:1, 5:1, 6:1, 8:1, 10:1, 12:1, 13:1, 14:1, 16:1 or 20:1. In some embodiments, the molar ratio of phosphorous acid, phosphorus tribromide and compound 4 is (4-40):(2-24):1, for example (6-40):(4-20):1, (6-32):(4-20):1, (8-32):(4-20):1 or (10-32):(4-20):1, and further for example 8:4:1, 8:10:1, 10:4:1, 12:4:1, 14:4:1, 16:4:1, 16:6:1, 16:10:1, 16:20:1, 24:10:1, 28:10:1 or 32:10:1. In some embodiments, phosphorous acid and / or phosphorus tribromide are added in batches or all at once. In some embodiments, phosphorous acid and phosphorus tribromide are added all at once. In some embodiments, the reaction is carried out at 40–120°C. In some preferred embodiments, the reaction is carried out at 50–100°C, for example, 45–55°C, 55–65°C, 65–70°C, 65–75°C, 70–80°C, 75–85°C, 85–95°C, or 90–100°C, and even more specifically, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, or 120°C. In some implementations, the reaction is carried out for 0.5-24 hours, for example 1-12 hours, and even more specifically 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours. In some embodiments, hydrolysis is carried out in the presence of pure water. In some embodiments, the volume of pure water added is 1 to 10 times the volume of the reaction liquid before hydrolysis, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times. In some implementations, hydrolysis is carried out under reflux conditions. In some implementations, hydrolysis lasts for 1–24 hours, for example, 1–12 hours, or even for 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours. In some embodiments, the method further includes a step of treating the pre-hydrolysis reaction solution to remove phosphorus tribromide and solvent. In some specific embodiments, one or more of dichloromethane, trichloromethane, toluene, and dimethyltetrahydrofuran are mixed into the pre-hydrolysis reaction solution, followed by separation and collection of the product phase. In one specific embodiment, dichloromethane is mixed into the pre-hydrolysis reaction solution, followed by separation and collection of the lower liquid layer. After hydrolysis, a large amount of water-soluble phosphorous acid and phosphate remain in the reaction solution, which cannot be separated from the product. Therefore, in some embodiments, the method also includes a post-processing step. In some embodiments, the post-processing step includes purifying the resulting crude compound 5. In some embodiments, the purification step includes one or more of extraction, desalting, and crystallization operations. In some embodiments, the extraction operation may remove a portion of the reaction solvent. In some embodiments, the extraction operation includes extraction using an organic solvent. In some embodiments, the organic solvent is selected from 2-methyltetrahydrofuran, toluene, ethyl acetate, or dichloromethane. In some embodiments, the organic solvent is dichloromethane. In some embodiments, the extraction operation includes adjusting the pH of the reaction solution to pH 0.5–4.0, and then extracting with an organic solvent. In some embodiments, the pH is adjusted to pH 0.5–1.0, pH 1.0–1.5, pH 1.5–2.0, pH 2.0–2.5, pH 2.5–3.0, pH 3.0–3.5, or pH 3.5–4.0, for example, pH 0.5, pH 1.0, pH 1.5, pH 2.0, pH 2.5, pH 3.0, pH 3.5, or pH 4.0. In some embodiments, the desalination operation includes filtration. In some embodiments, the desalination operation includes the removal of phosphorous acid and / or bromides. In some embodiments, the filtration includes nanofiltration using a nanofiltration membrane. In some embodiments, the nanofiltration membrane has a molecular weight cutoff of 200 Daltons or higher. In some embodiments, the nanofiltration membrane has a molecular weight cutoff of 200–300 Daltons. In some embodiments, the nanofiltration membrane has a molecular weight cutoff of 300–400 Daltons. In some implementations, the pH of the desalination reaction solution is adjusted to be acidic, for example, pH 0.5–4.0, or adjusted to pH 0.5–1.0, pH 1.0–1.5, pH 1.5–2.0, pH 2.0–2.5, pH 2.5–3.0, pH 3.0–3.5, or pH 3.5–4.0, or even pH 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, or 4.0. In some embodiments, the filtration continues until the nanofiltration solution pH > 4 and the permeate conductivity < 2000 μS / cm. In some embodiments, the crystallization operation includes carrying out the crystallization under suitable pH conditions in a suitable solvent. In some embodiments, the suitable solvent is a combination of solvent A, in which compound 5 is soluble, and solvent B, in which compound 5 is sparingly or slightly soluble. In some embodiments, solvent A is water. In some embodiments, solvent B is methanol. In some embodiments, the pH conditions are neutral to weakly alkaline. In some embodiments, the pH is 6.0–10.0. In some embodiments, the pH is 6.0–6.5, 6.5–7.0, 7.0–7.5, 7.5–8.0, 8.0–8.5, 8.5–9.0, 9.0–9.5, 9.5–10.0, 6.2–9.5, or 7.2–9.5. In some embodiments, the pH is, for example, 6.0, 6.2, 6.5, 7.0, 7.2, 7.5, 8.0, 8.5, 9.0, 9.5, or 10.0. In some embodiments, the volume ratio of solvent A to solvent B is 1:(2.2–8), for example 1:(2.4–8), 1:3–1:8, 1:4–1:8, 1:4–1:7, or 1:4–1:6, and further for example 1:4, 1:5, or 1:6. In some embodiments, the crystallization operation includes dissolving crude compound 5 in solvent A, adding solvent B, heating and stirring (e.g., heating to 35–75°C, 35–65°C, or 45–55°C), then cooling to crystallize (e.g., cooling to -10–30°C, 0–10°C, 0–20°C, 0–30°C, or 10–30°C), and filtering to obtain compound 5. In some embodiments, the crystallization operation further includes introducing a seed crystal of compound 5. On the other hand, this disclosure provides a method for purifying compound 5, the method comprising a crystallization purification operation. In some embodiments, the crystallization purification operation is performed on a crude product of compound 5 produced by the aforementioned method. In some embodiments, the crystallization purification operation is the crystallization operation described in the aforementioned method. In some embodiments, the method includes performing a crystallization purification operation on the crude product of compound 5. In some embodiments, the crude product of compound 5 is produced by the aforementioned method and optionally subjected to the aforementioned extraction operation and / or desalting operation. On the other hand, this disclosure provides a method for preparing compound 1, comprising reacting compound 5 and compound 6 under alkaline aqueous conditions to generate compound 1. In some implementations, the solvent in alkaline aqueous conditions is purified water. In some embodiments, the base is sodium hydroxide, potassium carbonate, sodium bicarbonate, DIPEA, or TEA. In some embodiments, the base is potassium carbonate or sodium bicarbonate, for example, sodium bicarbonate. In some implementations, when sodium bicarbonate is used as the base, the pH is controlled within the range of 6 to 8, for example, within the range of 7 to 8. In some implementations, the reaction temperature is -10 to 50°C, for example 0 to 30°C, or even 0 to 5°C, 10 to 30°C, or 20 to 30°C. In some implementations, the reaction time is 1 min to 2 h, for example 1 min to 1 h or 5 to 30 min. In some implementations, the method also includes a post-processing step. In some embodiments, the post-processing includes a step of purifying the crude compound 1. In some implementations, the purification step includes one or more of the following: desalting, preparative chromatographic purification operations. In some embodiments, the desalination step includes filtration. In some embodiments, the filtration operation can remove byproducts such as NHS and inorganic salts. In some embodiments, the filtration operation includes nanofiltration using a nanofiltration membrane. In some embodiments, the nanofiltration membrane has a molecular weight cutoff of 200–300 Daltons or 300–400 Da. In some embodiments, the nanofiltration continues until the NHS content in the nanofiltrate is ≤15%. In some embodiments, the preparative chromatographic purification operation removes the byproduct DOTA, as well as optionally excess alkali, the byproduct NHS, etc. In some embodiments, the preparative chromatography uses 5-bromophenyl-bonded silica gel or HILIC high-purity silica gel as packing material. The inventors unexpectedly discovered that the pH of the sample to be purified by preparative chromatography has a significant impact on the yield and purity of the preparation. Therefore, in some embodiments, the pH of the sample to be purified by preparative chromatography is controlled to be 0.5–4.0, for example, pH 0.5–1.0, pH 1.0–1.5, pH 1.5–2.0, pH 2.0–2.5, pH 2.5–3.0, pH 3.0–3.5, pH 3.5–4.0, pH 1.0–3.0, pH 1.0–2.5, or pH 1.5–2.5, and further for example, pH 0.5, pH 1.0, pH 1.5, pH 2.0, pH 2.5, pH 3.0, pH 3.5, or pH 4.0. In some embodiments, the elution process for preparative chromatographic purification is isocratic elution. In some embodiments, the eluent used is eluent A alone. In some embodiments, the eluent used is a mixture of eluent A and eluent B. In some embodiments, eluent A is an aqueous solution containing an acid, preferably trifluoroacetic acid, formic acid, acetic acid, or phosphoric acid. In some embodiments, eluent B is an organic solvent, preferably one or more selected from acetonitrile, methanol, and tetrahydrofuran. In some embodiments, the eluent is an aqueous formic acid solution. In some embodiments, the eluent is an aqueous trifluoroacetic acid solution. In some embodiments, the eluent is a combination of an aqueous formic acid solution and acetonitrile. In some embodiments, the eluent is a combination of an aqueous trifluoroacetic acid solution and acetonitrile. In some embodiments, when the eluent is a mixture of eluent A and eluent B, the volume ratio of eluent A to eluent B is about (0.5 to 3):1, for example, about (1 to 2):1, for example, about 1:1, about 1.5:1, or about 2:1, etc. In some embodiments, eluent A is an aqueous solution of trifluoroacetic acid, preferably at a concentration of 0.01 to 0.5% (v / v), more preferably 0.02 to 0.2% (v / v), for example, 0.03% to 0.1% (v / v), for example, 0.03% (v / v), 0.05% (v / v), 0.07% (v / v), or 0.1% (v / v). In some embodiments, the eluent A is an aqueous formic acid solution, preferably at a concentration of 0.01 to 0.5% (v / v), more preferably 0.02 to 0.2% (v / v), for example 0.03% to 0.1% (v / v), such as 0.03% (v / v), 0.05% (v / v), 0.07% (v / v), 0.1% (v / v), or 0.2% (v / v). In some embodiments, the purification step is followed by a step of removing the eluent. In some embodiments, the eluent removal step includes a step of concentrating the prepared solution. In some embodiments, the concentration step is azeotropic distillation. In some embodiments, the entrained solvent introduced in the azeotropic distillation is water. In some embodiments, the azeotropic distillation step is repeated multiple times, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times. On the other hand, this disclosure provides a method for preparing compound 4, comprising: reacting compound 2 with tert-butyl acrylate to obtain compound 3; and / or, deprotecting compound 3 to obtain compound 4. In some embodiments, compound 2 is reacted with tert-butyl acrylate at 20–100°C, for example at 25–70°C or 60–70°C. In some implementations, the stirring reaction time is 1 to 24 hours, for example, 2 to 24 hours. In some implementations, a step of concentrating the reaction solution is also included after the reaction is complete. Since the main impurity in the reaction solution after the formation of compound 3 is excess tert-butyl acrylate, which will participate in the next reaction step, the post-treatment method disclosed in CN114230610A is direct distillation concentration. However, compound 3 is an oily substance, and tert-butyl acrylate has a high boiling point, making direct distillation difficult and time-consuming. Prolonged heating may also lead to product decomposition. Therefore, in some embodiments, the reaction solution is concentrated by azeotropic distillation. In some embodiments, an entrainer solvent is added during the distillation concentration process. In some embodiments, the entrainer solvent is selected from toluene, methanol, and tert-butanol. In some embodiments, the deprotection reaction is carried out in the presence of hydrochloric acid. In some embodiments, the deprotection reaction is carried out in a hydrochloric acid / water or hydrochloric acid / acetone system. In some embodiments, the method further includes post-processing of the crude compound 4. In some embodiments, the post-processing includes one or more of extraction, concentration, and solvent treatment of the reaction solution containing compound 4. In some embodiments, the solvent treatment is a pulping operation. In some embodiments, an organic solvent is added to perform the extraction operation. In some preferred embodiments, the organic solvent is toluene, dichloromethane, ethyl acetate, or 2-methyltetrahydrofuran, for example, toluene. In some embodiments, the concentration operation is used to remove water from the system. In some embodiments, the concentration operation is distillation concentration. In some embodiments, the distillation concentration is azeotropic distillation concentration with the addition of an entrained solvent. In some embodiments, the entrained solvent is 1,4-dioxane, toluene, isopropanol, tert-butanol, cyclohexane, or acetone, for example, 1,4-dioxane. In some embodiments, the solvent treatment operation (e.g., pulping) is used to further remove water from the system, thereby improving product purity. In some embodiments, the solvent used in the solvent treatment operation is acetone. In some embodiments, the solvent treatment includes dispersing crude compound 4 in acetone, heating to reflux, then cooling and filtering. This solvent treatment reduces the water content of the product and further improves its purity. In some embodiments, this solvent treatment transforms compound 4 into a new crystal form. In another aspect, this disclosure provides a method for purifying compound 2, comprising the steps of converting crude compound 2 into a salt and then freeing it into compound 2. In some embodiments, the salt-forming operation includes reacting the crude compound 2 with an acid in a solvent. In some embodiments, the acid is fumaric acid. In some embodiments, the solvent is selected from dichloromethane (DCM), isopropyl acetate, acetone, methyl tert-butyl ether (MTBE), methyl isobutyl ketone (MIBK), and 2-methyltetrahydrofuran. In some embodiments, the solvent is acetone or 2-methyltetrahydrofuran. In some embodiments, the salt-forming temperature is -25 to 25°C, for example -25 to 15°C, -10 to 10°C, or 0 to 10°C. In some embodiments, the salt-forming time is 6 to 18 hours, for example 8 to 14 hours or 10 to 12 hours. In some embodiments, the salt formation process includes dissolving crude compound 2 in a solvent, adding fumaric acid, cooling and stirring, and filtering to obtain fumarate of compound 2. In some embodiments, the preparation of crude compound 2 includes: reacting compound 7 with methaneyl chloride or methanesulfonic anhydride in a solvent to generate compound 8; and / or reacting compound 8 with methylamine to generate compound 2. In some embodiments, the molar ratio of methylamine to compound 8 is greater than 3. In some embodiments, the molar ratio of methylamine to compound 8 is (4–50):1, for example (5–50):1, (5–40):1, (8–40):1, such as 4:1, 5:1, 8:1, 10:1, 15:1, 20:1, 25:1, 30:1, 35:1 or 40:1. In some embodiments, the methylamine is provided as an alcohol solution, such as a methylamine methanol solution or a methylamine ethanol solution. Alternatively, in some embodiments, compound 8 reacts with methylamine in an alcohol solvent, such as methanol or ethanol. In some embodiments, the reaction time of compound 8 with methylamine is 1-12 hours, for example 2-8 hours, 3-5 hours, 3-4 hours, etc., or even 1, 2, 3, 4, 5, 6, 7, 9, 10, 11 or 12 hours. In some embodiments, the reaction temperature of compound 8 with methylamine is about 20 to 80°C, for example 40 to 60°C. All technical features of this disclosure, or steps in all methods or processes disclosed, may be combined in any way, except for mutually exclusive technical features and / or steps. Beneficial effects Compared with the prior art, the preparation method disclosed herein has the following advantages: 1. The obtained product, compound 1, has high purity, up to 98.5%; 2. It can meet the needs of industrial-scale production, and the overall yield of the route for preparing compound 1 is increased from 0.2% to 41.3%. 3. The route cost is significantly reduced and the preparation cycle is shortened. Detailed Implementation Terminology Definition Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention. The terms “including,” “comprising,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps. As used in this article, "DOTA" refers to the following structure: "DOTA residues" refer to the following structures: Unless otherwise specified, the reagent “hydrochloric acid” in this article refers to hydrochloric acid with a mass fraction of 36-38%. Unless otherwise specified, all numerical values ​​in this application are modified by the term "about". The term "about" means within ±20%, preferably ±10%, more preferably ±5%, and more preferably ±2% of the stated numerical value. Example The present disclosure will be further described in detail below with reference to embodiments. However, these embodiments are only for illustrating the present disclosure and are not intended to limit the scope of the present disclosure. The abbreviations used in this article have the following meanings: Example 1: Preparation of Compound 3 Example 1.1 Compound 2 (1.2 kg) was added to the reactor, and stirring was started. Then, 1.0 kg of tert-butyl acrylate was added to the reactor, and the reaction was carried out at 60–70 °C for 24 h. After the reaction was completed, 8.0 kg of toluene was added to the reactor, and the mixture was distilled under reduced pressure to obtain 2.081 kg of a colorless oil. The crude product was used directly for the next reaction without purification, and the GC content was 98.4%. 1HNMR (400MHz, CDCl3): δ: 5.13 (brs, 1H), 3.15~3.08 (m, 2H), 2.66 (t, J = 7.6Hz, 2H), 2.40 ( t,J=7.6Hz,2H),2.38~2.33(m,2H),2.21(s,3H),1.53~1.48(m,4H),1.46~1.43(m,18H). 13 CNMR (101MHz, CDCl3): δ: 172.0, 156.1, 80.3, 78.8, 57.1, 52.9, 41.8, 40.5, 33.6, 28.5, 28.1, 27.8, 24.8. LCMS (ESI): C 17 H 34 N₂O₄[M+H] + Calculated value: 331.3; Measured value: 331.3. Example 1.2 Similar reactions and post-treatments were performed using procedures similar to those in Example 1.1, with similar results obtained when toluene was replaced with methanol or tert-butanol. Comparative Example 1.1 The reaction was carried out using a similar procedure to that in Example 1.1. After the reaction was complete, distillation was not performed. Instead, three times the volume of solvent 1 (adding solvent 1 according to the theoretical yield ratio of 1g compound 3: 3mL solvent 1) and three times the volume of solvent 2 were added for extraction, as shown in Table 1 below. The results showed that the extraction operation shown in Table 1 below could not achieve effective separation of compound 3 from tert-butyl acrylate. Table 1 Screening of extraction methods for compound 3 Comparative Example 1.2 The reaction was carried out using a similar procedure to that in Example 1.1. After the reaction was complete, the reaction product was dissolved in acetone, and different acids were added for crystallization. If no solid precipitated, the antisolvent ethyl acetate was added and the phenomenon was observed, as detailed in Table 2. The results showed that no solid precipitated or only a small amount of solid precipitated with any of the acids. Therefore, the salt formation and crystallization method shown in Table 2 below could not effectively purify compound 3. Table 2 Screening of Compound 3 for Salt Formation and Crystallization Comparative Example 1.3 The reaction was carried out using a similar procedure to that in Example 1.1. After the reaction was completed, 300g of crude product containing compound 3 was directly distilled and concentrated. It took 3 days to achieve a purity similar to that in Example 1.1, while the same amount of crude product only took 6 hours when azeotropic distilled using the procedure in Example 1.1. Example 2: Preparation of Compound 4 Example 2.1 2.05 kg of crude compound 3 was dissolved in 2.05 kg of purified water, and 4.87 kg of hydrochloric acid was added dropwise while maintaining the temperature at 20–30 °C. After the addition was complete, the mixture was stirred at 20–30 °C for 16 h. After the reaction was complete, 1.80 kg of toluene was added to the reaction vessel, and the aqueous phase was collected and concentrated until almost no fraction was distilled off. Then, 6.36 kg of 1,4-dioxane was added and concentrated until almost no fraction was distilled off. The resulting solid was ground and sieved to obtain crude compound 4 (hydrochloride). The crude compound 4 was added to 11.90 kg of acetone, and the mixture was refluxed for 16 h. After cooling to room temperature, it was filtered, and the filter cake was washed with 2.36 kg of acetone. Drying at 55 °C yielded 1.28 kg of compound 4 (hydrochloride), with a yield of 83.0% (Examples 1.1 and 2). Example 2.1 Two steps (based on free alkali), content 67.0% (based on free alkali), GC 97.7%, moisture 1.8%. 1 HNMR (400MHz, D2O): δ: 3.59~3.52(m,1H), 3.37~3.14(m,3H), 3.03(t,J=7.6Hz,2H), 2.91~2.84(m,5H), 1.88~1.80(m,2H), 1.77~1.67(m,2H). 13 CNMR(101MHz,D2O):δ:174.0,66.6,55.8,51.4,40.2,38.8,28.6,23.9,20.9.LCMS(ESI):C8H 18 N₂O₂[M+H] + Calculated value: 175.2; Measured value: 175.2. Comparative Example 2.1 Using CN114230610A, the first

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[0054] Compound 4 was prepared using the same method and conditions. However, a large amount of sticky solid was observed to precipitate during the reaction, which contained impurities 9, and the product had poor properties, making further purification difficult. Example 2.2 The reaction was carried out using a similar procedure to that in Example 2.1, with the differences shown in Table 3 below. As shown in Table 3, the hydrochloric acid / water and hydrochloric acid / acetone systems showed fast reaction rates, no intermediate impurities were generated, and no significant impurities were generated even with extended reaction time. The reaction system was clear, and impurity encapsulation was avoided. Table 3 Screening of reaction conditions for compound 4 Note: In Table 3, “solvent / 1V” means that the volume of solvent used is 1 times the mass of crude compound 3 (i.e., 1g crude compound 3: 1mL solvent); “reagent / 3V” means that the volume of reagent used is 3 times the mass of crude compound 3 (i.e., 1g crude compound 3: 3mL reagent). Comparative Example 2.2 The same operation as in Example 2.1 was used, except that acetone was replaced with ethyl acetate in the post-processing, but the purity of the product was not improved. Comparative Example 2.3 The operation was similar to that in Example 2.1, except that acetone was replaced with toluene in the post-processing, but the purity of the product was not improved. Example 3: Preparation of Compound 5 Example 3.1 Compound 4 (85.0 g, hydrochloride, 63.2% purity) was added to 736.1 g of toluene, followed by the addition of 202.2 g of phosphorous acid. The temperature was raised to 90–100 °C and maintained at 90–100 °C. 834.4 g of phosphorus tribromide was added dropwise to the reaction flask. After the addition was complete, the mixture was stirred at this temperature for 1 hour. After the reaction was complete, the supernatant was decanted, and the residue was added to 382.5 g of water. The mixture was then refluxed for 3 hours. After the reaction was complete, the pH was adjusted to 6.0–10.0 with 30% sodium hydroxide solution. The mixture was filtered, and the filter cake was washed with 42.5 g of purified water. The filtrates were combined, and 5.60 kg of methanol was added under stirring at 10–30 °C. After stirring for 48 h, the mixture was filtered to obtain 121.7 g of crude product. 150.0 g of purified water was added to the crude product, and the temperature was raised to 45–55 °C. 118.7 g of methanol was added along with the seed crystals, and the mixture was stirred for 1–2 h. Another 118.7 g of methanol was added, and the temperature was lowered to 10–30 °C. The mixture was stirred to induce crystallization, and the crystals were filtered and dried to obtain 46.55 g of compound 5 (sodium salt). MicroED analysis of the obtained crystals showed that compound 5 had a Z' value of 1, and the asymmetric unit consisted of one C8H group. 21 N₂O₇P₂ - Ions, one Na + It consists of ions and 6 water molecules. Compound 5: phosphorous acid:phosphoric acid 1:0.01:0.2 (molar ratio), yield 42.3%. 1 HNMR (400MHz, D2O): δ: 3.36~3.26(m,2H), 3.11~3.03(m,2H), 2.97(t,J=7.6Hz,2H), 2.74(s,3H), 2.29~2.17(m,2H), 1.79~1.64(m,4H). 13 CNMR(101MHz,D2O):72.3(t,J=126.9Hz),55.1,53.3(t,J=6.1Hz),39.3,38.7,28.2,23.9,20.8.31 PNMR(162MHz,D2O):δ:17.47.LCMS(ESI):C8H 22 N₂O₇P₂[MH] - Calculated value: 319.2; Measured value: 319.1. Example 3.2 Compound 4, 298.5 g (67.0% purity), was added to 1.26 kg of sulfolane, followed by 1.51 kg of phosphorous acid. The mixture was then heated to 65–75 °C and stirred until the solid dissolved. Maintaining the temperature at 65–75 °C, 1.87 kg of phosphorus tribromide was added dropwise to the reaction flask. After the addition was complete, the mixture was kept at this temperature and stirred for 6 hours. After the reaction was complete, the reaction system was cooled to 10–30 °C, and 2.12 kg of dichloromethane was added. The mixture was allowed to stand and separated. The lower layer was separated, and the temperature was maintained at ≤50 °C. 0.40 kg of purified water was added dropwise. After the addition was complete, the mixture was heated to reflux and stirred for 2–3 hours. Cool to 10–20°C, maintain temperature at 10–30°C, and add 33% sodium hydroxide solution dropwise to adjust pH to 0.5–4.0. Wash with dichloromethane (1.33 kg * 3), filter with an aqueous layer, and transfer the filtrate to a laboratory membrane separation system. Nanofilter using a 200–300 D nanofiltration membrane until the nanofiltrate pH > 4 and the permeate conductivity < 2000 μS / cm. Discharge the nanofiltrate and concentrate until 0.75–0.77 kg of liquid remains. Adjust pH to 6.0–10.0 with 33% sodium hydroxide solution, add 0.13 kg of purified water, raise temperature to 45–55°C, maintain temperature at 45–55°C, and add 0.43 kg of methanol dropwise. Add 1.27 g of seed crystals, maintain temperature and stir for 1–2 h, maintain temperature at 45–55°C, and add 1.30 kg of methanol dropwise. After the addition is complete, cool to 0–10°C and stir for 1.5–2.5 h. After filtration until no obvious drops fell, the filter cake was washed with 0.22 kg of pre-frozen methanol-water (2.4:1 v / v) and filtered to dryness. The filter cake was dried at 30–40 °C to give 345.6 g of compound 5, yield 67.0%, phosphorous acid:ND; phosphoric acid:ND; HPLC: 99.5%. Example 3.3 Reagent Screening for Compound 5 The reaction was carried out using a similar procedure to that in Example 3.1, with the differences shown in the table below. As shown in Table 4, when phosphorous acid / phosphorus tribromide was used as the reaction reagent, a clear product was observed and few reaction byproducts were produced. Table 4. Screening of reagents for compound 5 Example 3.4 Solvent Screening for Compound 5 The reaction was carried out using a similar procedure to that in Example 3.1, with the differences shown in the table below. As shown in Table 5, the product was generated when the reaction solvent was sulfolane or 1,4-dioxane, and the reaction was carried out under a dispersible stirring state. Table 5. Solvent screening for compound 5 Example 3.5 Screening of reagent ratios for compound 5 The reaction was carried out using a similar procedure to that in Example 3.1, with the differences shown in the table below. As shown in Table 6, when the phosphorous acid equivalent relative to compound 4 is less than 2, compound 5 is not produced well. Table 6 Screening of phosphorous acid / phosphorus tribromide ratio *Phosphorous acid and PBr3 are added in batches during the reaction. Example 3.6 Screening of crystallization and purification conditions for compound 5 The reaction and post-treatment operations were performed similarly to those in Example 3.1, with the differences shown in Tables 7-9 below. The methanol used in the post-treatment operation of Example 3.1 was replaced with the antisolvents shown in Tables 7-9. As shown in Table 7, when the water-antisolvent volume ratio was 1:2, good crystallization could not be obtained under any pH conditions; as shown in Table 8, when the water-antisolvent volume ratio was 1:4, only methanol precipitated as a solid; as shown in Table 9, when the water-methanol volume ratio was 1:6, a solid also precipitated. Table 7 Screening of Compound 5 under different pH conditions with a water:antisolvent ratio of 1:2. Note: Oil separation: a small amount of viscous oily substance; Oil droplets: a free-flowing oily substance. Table 8 Screening of crystallization of compound 5 at different pH values ​​using a water:antisolvent ratio of 1:4 Note: Oil separation: a small amount of viscous oily substance; Oil droplets: a free-flowing oily substance. Table 9 Screening of Compound 5 under different pH conditions: water:antisolvent 1:6 crystallization. Note: Oil separation: a small amount of viscous oily substance; Oil droplets: a free-flowing oily substance. Example 4: Preparation of Compound 1 Example 4.1 Add 1.85 kg of purified water and 185 g of compound 5 to the reaction vessel, stir at 10–30 °C until the solid dissolves completely, then add 1.87 kg of sodium bicarbonate. Add compound 6 to the reaction vessel in batches, and after the addition is complete, maintain the temperature and stir for about 15 min. After the reaction is complete, filter, and rinse the filter cake with 0.37 kg of purified water. Control the temperature at 0–15 °C, slowly add sulfuric acid solution to adjust the pH of the filtrate to 1.5–2.5, and stir for 1–2 h. Filter again, and rinse the filter cake with 0.37 kg of purified water. Transfer the filtrate to a laboratory membrane separation system and perform nanofiltration using a 200–300 D nanofiltration membrane. During nanofiltration, continuously add purified water until the NHS content of the nanofiltrate sample is controlled to be ≤15%. The nanofiltration solution was eluted isocratically using a HILIC preparative column packed with 0.1% formic acid aqueous solution:acetonitrile = 60:40 (v / v) as the eluent. The main peak preparation solution was collected, and the reversed-phase preparation solution was added in batches to a rotary evaporator to remove most of the solvent by rotary evaporation. Ultrapure water was added to the rotary evaporation flask, and most of the solvent was removed by rotary evaporation. Ultrapure water was added to the remaining liquid after rotary evaporation, and the mixture was lyophilized to constant weight to obtain 150.3 g of product, with a yield of 74.2%, HPLC purity of 98.5%, content (based on anhydrous matter) of 99.2%, and total elemental impurities of 26.76 ppm. 1 HNMR (600MHz, D2O, 353K): δ: 4.23 (s, 4H), 4.13 (s, 2H), 4.10 (s, 2H), 4.02~3.98 (m, 1H), 3.81~3.77 (m, 9H), 3 .69~3.63(m,11H),3.54~3.49(m,1H),3.29(s,3H),2.86~2.76(m,2H),2.23~2.14(m,2H),2.05~2.00(m,2H). 13 CNMR(151MHz,D2O,353K):173.2,171.2,170.1,72.8(J=134.6Hz),55.5,55.2,5 5.9,54.9,53.5(J=6.6Hz),51.2,50.8,50.2,49.8,40.4,39.3,28.5,26.0,21.7. 31 PNMR(243MHz,D2O,363K):δ:17.57.HRMS(ESI):C 24 H 48 N6O 14 P2[M+H] + Calculated value: 707.3; Measured value: 707.3. Example 4.2 The reaction was carried out using a similar procedure to that in Example 4.1, with the differences shown in Table 10 below. As shown in Table 10, when NaOH is used as the alkali, a large amount of impurities are generated. Table 10 Screening of reaction conditions for compound 1 Example 4.3 The reaction and post-processing operations were performed similarly to those in Example 4.1, except that the pH value of the sample to be purified was adjusted according to Table 11. As shown in Table 11, the yield of the purified sample was significantly reduced when the pH was 4.55. Table 11 pH of Compound 1 sample to be prepared and purified Example 5: Preparation of Compound 8 Compound 7 (1.67 kg) was dissolved in 22.13 kg of dichloromethane. 2.68 kg of triethylamine was added, and the mixture was cooled to 0–10 °C and stirred. The temperature was maintained at 0–15 °C. 2.31 kg of methanesulfonic anhydride was added, and the mixture was stirred at 10–30 °C for 3–4 h after the addition was complete. After the reaction was complete, the mixture was washed with saturated sodium bicarbonate solution (18.20 kg*1) and purified water (10.02 kg*1). The organic phase was separated and rotary evaporated to dryness to obtain 2.30 kg of a pale yellow oil. Compound 8 (crude product) was directly used in the next reaction without purification. Example 6: Preparation of Compound 2 Example 6.1 2.30 kg of crude compound 8 was added to 12.35 kg of 30% methylamine methanol solution, and the mixture was heated to reflux for 3–4 h. After the reaction was complete, the mixture was concentrated to dryness, and 16.31 kg of purified water was added to dissolve the concentrate. The pH was adjusted to 5–6 with 2 mol / L hydrochloric acid, and the aqueous phase was separated. The aqueous phase was washed with dichloromethane (14.05 kg * 2); the pH of the aqueous phase was then adjusted to 12–13 with 2 mol / L sodium hydroxide solution, and extracted with dichloromethane (14.05 kg * 2). The organic layers were combined and evaporated to dryness to obtain crude compound 2. The crude compound 2 was dissolved in 12.33 kg of acetone, cooled to 0–10 °C, and 0.89 kg of fumaric acid was added. The mixture was kept warm and stirred for 10–12 h. The mixture was then filtered, and the filter cake was washed with 1.12 kg of acetone and dried to obtain 2.00 kg of compound 2 fumarate. Add 10.60 kg of purified water to the reaction flask, add compound 2 fumarate at 10-30 °C and stir until the solid dissolves. Adjust the pH to 12-13 by adding sodium hydroxide solid at 10-30 °C. Extract the aqueous phase with dichloromethane (14.05 kg * 2). Combine the organic phases and concentrate to dryness to obtain 1.25 kg of compound 2 with a purity of 92.7% (the impurity is dichloromethane, and no dimer impurities were detected). The GC purity is 99.1%, and the yield is 70.2% (two steps). 1HNMR (400MHz, CDCl3): δ3.68~3.65(m,2H), 3.17~3.14(m,2H), 1.62~1.54(m,4H), 1.44(s,9H). Example 6.2 Screening of reagent dosage for compound 2 The amount of methylamine used in the preparation of crude compound 2 in Example 6.1 was screened. A similar procedure to that used in the preparation of crude compound 2 in Example 6.1 was employed, with differences shown in Table 12 below. The content of dimer impurities in the crude compound 2 was also measured. As shown in Table 12, when the methylamine equivalent relative to compound 8 was below 3, the amount of reaction product was low, the amount of dimer impurities generated was high, and the reaction of the starting materials was incomplete. Table 12 Screening of reagent dosage for Compound 2 Example 6.3 Salt formation purification and screening of compound 2 The reaction and post-treatment operations were performed similarly to those in Example 6.1, except that the acids and solvents used in the post-treatment operations are shown in the table below. As shown in Table 13, when using acids other than fumaric acid, compound 2 could not be precipitated as a solid salt; even when using fumaric acid, compound 2 could not be precipitated as a solid salt in solvents such as ethanol and tetrahydrofuran. Table 13 Screening for salt formation and purification of compound 2 Although embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. All content disclosed in the specification, including the abstract, and all disclosed methods and steps, can be combined arbitrarily unless these features and / or steps are mutually exclusive combinations. Those skilled in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention.

Claims

1. A process for preparing compound 5 comprising reacting compound 4 with phosphorus tribromide and phosphorous acid, followed by hydrolysis to produce compound 5, ###000001### 4 5 2. The method of claim 1, wherein it has one or more of the following features: (1) The reaction is carried out in a reaction solvent selected from sulfolane, toluene or 1,4-dioxane, for example in sulfolane; (2) The molar ratio of phosphorous acid to compound 4 is (4-40):1, for example (6-40):1, (6-32):1, (8-32):1 or (10-32):1, and for example 4:1, 5:1, 6:1, 8:1, 10:1, 12:1, 14:1, 16:1, 20:1, 24:1, 28:1 or 32:1; (3) The molar ratio of phosphorus tribromide to compound 4 is (2-24):1, for example (4-24):1 or (4-20):1, and for example 2:1, 3:1, 4:1, 5:1, 6:1, 8:1, 10:1, 12:1, 13:1, 14:1, 16:1 or 20:1; (4) The reaction temperature is 40-120℃, preferably 50-100℃, for example 45-55℃, 55-65℃, 65-70℃, 65-75℃, 70-80℃, 75-85℃, 85-95℃ or 90-100℃, and for example 40℃, 45℃, 50℃, 55℃, 60℃, 65℃, 70℃, 75℃, 80℃, 85℃, 90℃, 95℃, 100℃, 105℃, 110℃, 115℃ or 120℃; (5) The reaction time is 0.5-24h, for example, 1-12h, and for example, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, 21h, 22h, 23h, 24h; (6) The hydrolysis is carried out in the presence of pure water; preferably, the volume of pure water added is 1 to 10 times the volume of the reaction liquid before hydrolysis, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 times; preferably, the hydrolysis is carried out under reflux conditions, for example, hydrolysis for 1-24 hours, for example, 1-12h, and even more preferably 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, 21h, 22h, 23h or 24h; (7) Before hydrolysis, the reaction solution is further treated. Preferably, one or more of dichloromethane, trichloromethane, toluene and dimethyltetrahydrofuran are mixed into the reaction solution before hydrolysis, the liquid is separated, and the phase containing the product is collected.

3. The method of claim 1 or 2, further comprising a step of purifying the crude compound 5, for example including one or more of extraction, desalting and crystallization operations.

4. The method of claim 3, wherein the extraction operation includes extraction using an organic solvent; Preferably, the extraction has one or more of the following characteristics: (1) The organic solvent is selected from 2-methyltetrahydrofuran, toluene, ethyl acetate or dichloromethane, preferably dichloromethane; (2) Adjust the pH of the reaction solution to pH 0.5 to 4.0 during the extraction process, for example, pH 0.5 to 1.0, pH 1.0 to 1.5, pH 1.5 to 2.0, pH 2.0 to 2.5, pH 2.5 to 3.0, pH 3.0 to 3.5 or pH 3.5 to 4.0, or even pH 0.5, pH 1.0, pH 1.5, pH 2.0, pH 2.5, pH 3.0, pH 3.5 or pH 4.

0.

5. The method of claim 3 or 4, wherein the desalination operation includes filtration desalination. Preferably, the filtration includes nanofiltration using a nanofiltration membrane, and preferably, the nanofiltration membrane has a molecular weight cutoff of 200 Daltons or higher. Preferably, the pH of the desalination reaction solution is adjusted to be acidic, for example, pH 0.5–4.0, such as pH 0.5–1.0, pH 1.0–1.5, pH 1.5–2.0, pH 2.0–2.5, pH 2.5–3.0, pH 3.0–3.5 or pH 3.5–4.0, or even pH 0.5, pH 1.0, pH 1.5, pH 2.0, pH 2.5, pH 3.0, pH 3.5 or pH 4.

0.

6. The method of any one of claims 3 to 5, wherein the crystallization operation is carried out in a suitable solvent under neutral to weakly alkaline pH conditions; Preferably, the crystallization operation has one or more of the following characteristics: (1) The suitable solvent is a combination of solvent A, in which compound 5 is soluble, and solvent B, in which compound 5 is sparingly or slightly soluble; preferably, solvent A is water and solvent B is methanol; more preferably, the volume ratio of solvent A to solvent B is 1:(2.2-8), for example 1:(2.4-8), 1:3-1:8, 1:4-1:8, 1:4-1:7 or 1:4-1:6, and even more for example 1:4, 1:5 or 1:6; (2) The pH is 6.0 to 10.0, for example, 6.0 to 6.5, 6.5 to 7.0, 7.0 to 7.5, 7.5 to 8.0, 8.0 to 8.5, 8.5 to 9.0, 9.0 to 9.5, 9.5 to 10.0, 6.2 to 9.5 or 7.2 to 9.5, and even more for example, 6.0, 6.2, 6.5, 7.0, 7.2, 7.5, 8.0, 8.5, 9.0, 9.5 or 10.0; (3) The crystallization operation includes the introduction of seed crystals of compound 5.

7. The method of any one of claims 1-6, further comprising: reacting compound 2 with tert-butyl acrylate to produce compound 3; and / or, deprotecting compound 3 to produce compound 4, 8. The method of claim 7, wherein it has one or more of the following features: (1) The reaction solution for preparing compound 3 is concentrated by distillation, for example by adding an entrained solvent and concentrating by azeotropic distillation. Preferably, the entrained solvent is selected from toluene, methanol or tert-butanol, for example toluene. (2) The deprotection reaction is carried out in the presence of hydrochloric acid, preferably in a hydrochloric acid / water or hydrochloric acid / acetone system.

9. The method of claim 7 or 8, further comprising a post-processing operation on the crude compound 4, preferably, the post-processing operation comprising one or more of extraction, concentration and solvent treatment operations, more preferably, the post-processing operation having one or more of the following characteristics: (1) The extraction operation is carried out by adding an organic solvent. Preferably, the organic solvent is toluene, dichloromethane, ethyl acetate or 2-methyltetrahydrofuran, for example, toluene. (2) The concentration operation is azeotropic distillation concentration by adding an entrained solvent, wherein the entrained solvent is 1,4-dioxane, toluene, isopropanol, tert-butanol, cyclohexane or acetone, for example 1,4-dioxane; (3) The solvent used in the solvent treatment operation is acetone.

10. A method of preparing compound 1 comprising reacting compound 5 with compound 6 under basic aqueous conditions to form compound 1, 11. The method of claim 10, wherein it has one or more of the following features: (1) The solvent in alkaline aqueous conditions is purified water; (2) The base is sodium hydroxide, sodium carbonate, sodium bicarbonate, DIPEA or TEA, for example, sodium bicarbonate; (3) The reaction temperature is -10 to 50°C, for example, 0 to 30°C, or even 0 to 5°C, 10 to 30°C or 20 to 30°C; (4) The reaction time is 1 min to 2 h, for example, 1 min to 1 h or 5 to 30 min.

12. The method of claim 10 or 11, further comprising a step of purifying the crude compound 1, for example including one or more of desalting, preparative chromatographic purification operations.

13. The method of claim 12, wherein the desalination operation includes filtration desalination, preferably, the filtration includes nanofiltration using a nanofiltration membrane.

14. The method of claim 13, wherein the preparative chromatographic purification operation has one or more of the following characteristics: (1) The chromatographic column packing material used in the preparative chromatography is 5-bromophenyl bonded silica gel or HILIC; (2) Control the pH of the sample to be purified by chromatography to 0.5–4.0, for example, pH 0.5–1.0, pH 1.0–1.5, pH 1.5–2.0, pH 2.0–2.5, pH 2.5–3.0, pH 3.0–3.5, pH 3.5–4.0, pH 1.0–3.0, pH 1.0–2.5 or pH 1.5–2.5, or for example, pH 0.5, pH 1.0, pH 1.5, pH 2.0, pH 2.5, pH 3.0, pH 3.5 or pH 4.0; (3) The elution process for the preparation of chromatographic purification is isocratic elution; (4) the eluent is either eluent A alone or a mixture of eluent A and eluent B, wherein, The eluent A is an aqueous solution containing an acid, preferably trifluoroacetic acid, formic acid, acetic acid, or phosphoric acid; the eluent B is an organic solvent, preferably one or more selected from acetonitrile, methanol, and tetrahydrofuran. Preferably, the eluent is an aqueous formic acid solution, an aqueous trifluoroacetic acid solution, a combination of an aqueous formic acid solution and acetonitrile, or a combination of an aqueous trifluoroacetic acid solution and acetonitrile; More preferably, the volume ratio of eluent A to eluent B in the mixture of eluent A and eluent B is about 0.5 to 3:1, for example about 1 to 2:1, for example about 1:1, about 1.5:1, or about 2:1; More preferably, the eluent A is an aqueous solution of trifluoroacetic acid, with a concentration preferably of 0.01–0.5% (v / v), more preferably of 0.02–0.2% (v / v), for example 0.03%–0.1% (v / v), such as 0.03% (v / v), 0.05% (v / v), 0.07% (v / v), or 0.1% (v / v); or the eluent A is an aqueous solution of formic acid, with a concentration preferably of 0.01–0.5% (v / v), more preferably of 0.02–0.2% (v / v), for example 0.03%–0.1% (v / v), such as 0.03% (v / v), 0.05% (v / v), 0.07% (v / v), 0.1% (v / v), or 0.2% (v / v).

15. The method of any one of claims 10-14, further comprising the method of any one of claims 1-9.

16. A method for purifying compound 2, comprising the steps of salting crude compound 2 and then freeing it into compound 2, preferably comprising the step of reacting crude compound 2 with an acid in a solvent.

17. The method of claim 16, wherein it has one or more of the following features: (1) The acid mentioned is fumaric acid; (2) The solvent is selected from dichloromethane (DCM), isopropyl acetate, acetone, methyl tert-butyl ether (MTBE), methyl isobutyl ketone (MIBK) and 2-methyltetrahydrofuran, for example acetone or 2-methyltetrahydrofuran; (3) The salt formation temperature is -25 to 25°C, for example -25 to 15°C, -10 to 10°C or 0 to 10°C.

18. The process of claim 16 or 17, comprising the step of preparing crude compound 2 by reacting compound 7 with formyl chloride or formic anhydride in a solvent to form compound 8; and / or, reacting compound 8 with methylamine to form compound 2, Preferably, the molar ratio of methylamine to compound 8 is 4 to 50:1, for example 5 to 50:1, 5 to 40:1, 8 to 40:1, for example 4:1, 5:1, 8:1, 10:1, 15:1, 20:1, 25:1, 30:1, 35:1 or 40:

1.

19. A method for purifying compound 5, comprising crystallizing the crude product of compound 5, preferably comprising crystallizing in a suitable solvent under neutral to weakly alkaline pH conditions, more preferably satisfying one or more of the following: (1) The suitable solvent is a combination of solvent A, in which compound 5 is soluble, and solvent B, in which compound 5 is sparingly or slightly soluble; preferably, solvent A is water and solvent B is methanol; more preferably, the volume ratio of solvent A to solvent B is 1:2.2 to 8, for example 1:2.4 to 8, 1:3 to 1:8, 1:4 to 1:8, 1:4 to 1:7 or 1:4 to 1:6, and even more for example 1:4, 1:5 or 1:6; (2) The pH is 6.0 to 10.0, for example, 6.0 to 6.5, 6.5 to 7.0, 7.0 to 7.5, 7.5 to 8.0, 8.0 to 8.5, 8.5 to 9.0, 9.0 to 9.5, 9.5 to 10.0, 6.2 to 9.5 or 7.2 to 9.5, and even more for example, 6.0, 6.2, 6.5, 7.0, 7.2, 7.5, 8.0, 8.5, 9.0, 9.5 or 10.0; (3) The crystallization operation includes introducing seed crystals of compound 5; (4) The crude compound 5 is a crude product prepared by the method of claim 1 or 2, optionally further subjected to the extraction operation as described in claim 4 and / or the desalting operation as described in claim 5.

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