Preparation method of hepatitis c inhibitor compound and salt thereof

Abstract

The invention belongs to the technical field of medicines, and relates to a preparation method of a hepatitis C inhibitor compound. Specifically, the invention provides the synthetic method of the compound shown in the formula (I), and the method is high in yield and high in process stability. The invention further provides a synthesis method of phosphate of the compound shown in the formula (I), and the obtained phosphate is high in yield, high in purity and suitable for industrial production. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of medicine and relates to a preparation method of a compound for inhibiting hepatitis C and its salt. Background Art

[0002] Hepatitis C virus (HCV) infection is a major health problem leading to chronic liver diseases (such as cirrhosis and hepatocellular carcinoma), and the infected individuals are estimated to account for 2-15% of the world's population. Once infected, about 20% of people can clear the virus, but the rest will carry HCV for the rest of their lives. The viral disease is transmitted parenterally through contaminated blood and blood products, contaminated needles or sexual behavior, and vertically from an infected mother or carrier mother to her offspring. HCV infection can lead to chronic inflammation, necrosis and fibrosis of the liver, and some patients can develop into cirrhosis or even hepatocellular carcinoma. The mortality rate associated with HCV infection will continue to increase, posing a great threat to the health and life of patients.

[0003] Example 5 in Chinese Patent Application CN105968101A discloses a compound shown by the following formula (I). As an anti-drug-resistant full-genotype HCV inhibitor, this compound has a significant effect on the treatment of hepatitis C virus (HCV) infection or hepatitis C disease.

[0004]

[0005] In the process of preparing the compound shown by formula (I) disclosed in Patent Application CN105968101A, column chromatography is used for purification in each step, which is very unfavorable for large-scale production. Subsequent studies found that when using the method of this patent to prepare the compound of formula (I), the purity of the intermediate and the target product obtained by using other purification methods besides column chromatography purification is very low, and the purity of the product obtained by further salifying the compound of formula (I) is also low. Generally speaking, when using this method to prepare the compound of formula (I) and its salt, the overall yield is low and there are many impurities (i.e., the product purity is low), which brings many inconveniences to the subsequent drug development.

[0006] Therefore, there is an urgent need for a preparation method of the compound shown by formula (I) with high yield, high product purity, simple operation and convenient for large-scale production. Summary of the Invention

[0007] The inventors studied the preparation process of the compound shown in formula (I). Referring to the synthetic route in the prior art CN105968101A, they tried to study and optimize the reaction conditions to improve the purity of the compound shown in formula (I). However, after multiple experiments, it was found that the intermediate in this method was not easy to purify, and the salt compound obtained after the final product was salted with phosphoric acid had low purity and many unknown impurities, which was not conducive to impurity removal in the process and subsequent development work. On this basis, the inventors redesigned the synthetic route of the compound shown in formula (I), and through a large number of experiments for screening and verification, a new method for preparing the compound shown in formula (I) and its salt was obtained. This method is simple to operate, low in cost, high in yield, high in purity, and has high process stability, and is suitable for industrial production.

[0008] The present invention provides a method for synthesizing the compound shown in formula (I), which improves the yield and purity of the compound shown in formula (I) and improves the stability of the process. The present invention also provides a method for synthesizing the phosphate of the compound shown in formula (I), which improves the yield and purity of the phosphate of the compound shown in formula (I) and is suitable for industrial production. The phosphate of the compound shown in formula (I) of the present invention has better drug-forming properties.

[0009] On the one hand, the present invention provides a method for synthesizing the compound shown in formula (I), including step (a): subjecting compound 5 and compound 2 to a coupling reaction under the action of a catalyst and a base to obtain compound 6A;

[0010]

[0011] wherein, the compound shown in formula (I) is

[0012] The catalyst is X-Phos Pd G2, Pd(dppf)Cl2·CH2Cl2, Pd(PPh3)2Cl2, Pd(dppf)Cl2 or Pd(PPh3)4;

[0013] The base is K3PO4, NaHCO3, KHCO3, Na2CO3 or K2CO3.

[0014] In some embodiments, in the method for synthesizing the compound shown in formula (I) of the present invention, in step (a), the solvent for the coupling reaction is a mixed solvent of ethylene glycol dimethyl ether and water.

[0015] In some embodiments, in step (a), the volume ratio of ethylene glycol dimethyl ether to water is (2 - 4):1. In some embodiments, the volume ratio of ethylene glycol dimethyl ether to water is 2:1, 3:1 or 4:1.

[0016] In some embodiments, in step (a), the ratio of the volume of the solvent for the coupling reaction to the mass of compound 5 is (7 - 13) mL / g. In some embodiments, the ratio of the volume of the solvent for the reaction to the mass of compound 5 is 7 mL / g, 8 mL / g, 9 mL / g, 10 mL / g, 11 mL / g, 12 mL / g, or 13 mL / g.

[0017] In some embodiments, in step (a), the temperature of the coupling reaction is 75°C to 90°C. In some embodiments, the temperature of the reaction is 75°C, 80°C, 85°C, or 90°C.

[0018] In some embodiments, in step (a), the temperature of the coupling reaction is the reflux temperature of the reaction solvent.

[0019] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, in step (a), the base is KHCO3.

[0020] In some embodiments, the molar ratio of KHCO3 to compound 5 is (1.0 - 2.5):1. In some embodiments, in step (a), the molar ratio of KHCO3 to compound 5 is (1.0 - 1.5):1.

[0021] In some embodiments, in step (a), the molar ratio of KHCO3 to compound 5 is (1.0 - 1.3):1.

[0022] In some embodiments, the molar ratio of KHCO3 to compound 5 is 1.0:1, 1.5:1, 2.0:1, or 2.5:1.

[0023] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, in step (a), the molar ratio of compound 2 to compound 5 is (1.00 - 1.10):1.

[0024] In some embodiments, in step (a), the molar ratio of compound 2 to compound 5 is (1.05 - 1.10):1.

[0025] In some embodiments, in step (a), the molar ratio of compound 2 to compound 5 is 1:1, 1.05:1, or 1.10:1.

[0026] In some embodiments, in step (a), the molar ratio of the catalyst to compound 5 is (0.015 - 0.025):1.

[0027] In some embodiments, in step (a), the molar ratio of the catalyst to compound 5 is (0.015 - 0.020):1.

[0028] In some embodiments, the molar ratio of the catalyst to Compound 5 is 0.015:1, 0.020:1 or 0.025:1.

[0029] In some embodiments, the method for synthesizing the compound represented by formula (I) according to the present invention includes step (b): reacting the compound 6A with oxalic acid to obtain compound 6.

[0030]

[0031] In some embodiments, in step (b), the molar ratio of the oxalic acid to the compound 6A is (1.3 - 1.5):1.

[0032] In some embodiments, in step (b), the molar ratio of the oxalic acid to the compound 6A is 1.3:1, 1.35:1, 1.4:1, 1.45:1 or 1.5:1.

[0033] In some embodiments, in step (b), the reaction solvent is ethyl acetate, dichloromethane, toluene, methyl tert-butyl ether or isopropanol.

[0034] In some embodiments, in step (b), the reaction temperature is 40°C to 60°C.

[0035] In some embodiments, in step (b), the reaction temperature is 40°C, 45°C, 50°C, 55°C or 60°C.

[0036] In some embodiments, after the reaction is completed, the obtained crude product is purified by pulping with ethyl acetate to obtain pure compound 6.

[0037] In some embodiments, the method for synthesizing the compound represented by formula (I) according to the present invention further includes step (c): performing a deprotection reaction on the compound 6 to obtain compound 7.

[0038] Wherein, the deprotection reaction is carried out under the action of trimethylchlorosilane and methanol.

[0039] In some embodiments, in the method for synthesizing the compound represented by formula (I) according to the present invention, in step (c), the molar ratio of trimethylchlorosilane to the compound 6 is ≥7:1.

[0040] In some embodiments, in step (c), the molar ratio of trimethylchlorosilane to the compound 6 is (7 - 15):1.

[0041] In some embodiments, in step (c), the molar ratio of trimethylchlorosilane to the compound 6 is (7 - 11):1.

[0042] In some embodiments, in step (c), the molar ratio of trimethylchlorosilane to Compound 6 is (9 to 11):1.

[0043] In some embodiments, in step (c), the molar ratio of trimethylchlorosilane to Compound 6 is 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, or 15:1.

[0044] In some embodiments, in step (c), the molar ratio of trimethylchlorosilane to methanol is ≤1:1.

[0045] In some embodiments, in step (c), the molar ratio of trimethylchlorosilane to methanol is (7 to 15):(16 to 25).

[0046] In some embodiments, in step (c), the molar ratio of trimethylchlorosilane to methanol is (7 to 15):(16 to 20).

[0047] In some embodiments, in step (c), the molar ratio of trimethylchlorosilane to methanol is 1:1, 7:25, 8:25, 9:25, 10:25, 9.8:24, 11:25, 12:25, 13:25, 14:25, 15:25, 7:20, 8:20, 9:20, 10:20, 11:20, 12:20, 13:20, 14:20, or 15:20.

[0048] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, the reaction solvent in step (c) is dichloromethane, chloroform, or ethyl acetate.

[0049] In some embodiments, in step (c), the volume ratio of the reaction solvent to the mass of Compound 6 is (5 to 15) mL / g.

[0050] In some embodiments, in step (c), the volume ratio of the reaction solvent to the mass of Compound 6 is (9 to 11) mL / g.

[0051] In some embodiments, in step (c), the volume ratio of the reaction solvent to the mass of Compound 6 is 5 mL / g, 6 mL / g, 7 mL / g, 8 mL / g, 9 mL / g, 10 mL / g, 11 mL / g, 12 mL / g, 13 mL / g, 14 mL / g, 15 mL / g.

[0052] In some embodiments, in step (c), the reaction temperature is 15°C to 30°C.

[0053] In some embodiments, in step (c), the reaction temperature is 15°C to 20°C.

[0054] In some embodiments, in step (c), the reaction temperature is 20°C. In some embodiments, in step (c), the reaction temperature is 15°C, 20°C, 25°C or 30°C.

[0055] In some embodiments, after the reaction in step (c) is completed, an aqueous solution of potassium phosphate heptahydrate is added to the reaction solution and stirred; the organic phase is separated by liquid separation, the organic phase is washed with water, cooled with stirring, centrifuged and dried to obtain Compound 7; wherein the molar ratio of potassium phosphate heptahydrate to Compound 6 is (12 - 15):1.

[0056] In some embodiments, after the reaction in step (c) is completed, an aqueous solution of potassium phosphate heptahydrate is added to the reaction solution and stirred; the organic phase is separated by liquid separation, the organic phase is washed with water, cooled with stirring, centrifuged and dried to obtain Compound 7; wherein the molar ratio of potassium phosphate heptahydrate to Compound 6 is 12:1, 13:1, 13:1, 14:1 or 15:1.

[0057] In some embodiments, the method for synthesizing the compound represented by formula (I) according to the present invention further includes step (d): reacting Compound 7 with (S)-2-((methoxycarbonyl)amino)-3-methylbutyric acid under the action of EDCI and ethyl 2-oximinoacetate to obtain the compound represented by formula (I).

[0058] In some embodiments, in step (d) of the method for synthesizing the compound represented by formula (I) according to the present invention, the molar ratio of EDCI to Compound 7 is (1.1 - 1.5):1.

[0059] In some embodiments, in step (d), the molar ratio of EDCI to Compound 7 is (1.2 - 1.4):1.

[0060] In some embodiments, in step (d), the molar ratio of EDCI to Compound 7 is 1.1:1, 1.2:1, 1.3:1 or 1.4:1.

[0061] In some embodiments, in step (d), the molar ratio of (S)-2-((methoxycarbonyl)amino)-3-methylbutyric acid to Compound 7 is (1.05 - 1.3):1.

[0062] In some embodiments, in step (d), the molar ratio of (S)-2-((methoxycarbonyl)amino)-3-methylbutyric acid to Compound 7 is (1.05 - 1.15):1.

[0063] In some embodiments, the molar ratio of (S)-2-((methoxycarbonyl)amino)-3-methylbutyric acid to Compound 7 described in step (d) is 1.05:1, 1.10:1, 1.15:1, 1.20:1, 1.25:1 or 1.30:1. In some embodiments, the molar ratio of ethyl 2-oximinoacetonitrile to Compound 7 described in step (d) is (0.1 - 0.3):1.

[0064] In some embodiments, the molar ratio of ethyl 2-oximinoacetonitrile to Compound 7 described in step (d) is (0.2 - 0.3):1.

[0065] In some embodiments, the molar ratio of ethyl 2-oximinoacetonitrile to Compound 7 described in step (d) is 0.1:1, 0.2:1 or 0.3:1.

[0066] In some embodiments, the solvent for the reaction described in step (d) is an aprotic polar solvent.

[0067] In some embodiments, the solvent for the reaction described in step (d) is dichloromethane, dichloroethane, chloroform, N,N-dimethylformamide, ethyl acetate or tetrahydrofuran, or any combination thereof.

[0068] In some embodiments, the solvent for the reaction described in step (d) is dichloromethane.

[0069] In some embodiments, the volume ratio of the solvent for the reaction described in step (d) to the mass of Compound 7 is (20 - 60) mL / g.

[0070] In some embodiments, the volume ratio of the solvent for the reaction described in step (d) to the mass of Compound 7 is (22 - 44) mL / g.

[0071] In some embodiments, the volume ratio of the solvent for the reaction described in step (d) to the mass of Compound 7 is 20 mL / g, 22 mL / g, 25 mL / g, 30 mL / g, 33 mL / g, 35 mL / g, 40 mL / g, 44 mL / g, 46 mL / g, 50 mL / g, 55 mL / g or 60 mL / g.

[0072] In some embodiments, the reaction temperature for the reaction described in step (d) is 0°C to 30°C.

[0073] In some embodiments, the reaction temperature for the reaction described in step (d) is 5°C to 25°C.

[0074] In some embodiments, the reaction temperature for the reaction described in step (d) is 0°C, 5°C, 10°C, 15°C, 20°C, 25°C or 30°C.

[0075] In some embodiments, the molar ratio of EDCI, ethyl 2-oximinoacetate, (S)-2-((methoxycarbonyl)amino)-3-methylbutanoic acid to compound 7 in step (d) is (1.2 to 1.4):(0.2 to 0.3):(1.05 to 1.15):1.

[0076] In some embodiments, the molar ratio of EDCI, ethyl 2-oximinoacetate, (S)-2-((methoxycarbonyl)amino)-3-methylbutanoic acid to compound 7 in step (d) is 1.3:0.2:1.1:1, 1.2:0.2:1.1:1, 1.4:0.2:1.1:1, 1.3:0.2:1.05:1, 1.3:0.2:1.10:1, 1.3:0.2:1.15:1, 1.3:0.1:1.1:1 or 1.3:0.2:1.1:1.

[0077] In some embodiments, the method for synthesizing the compound represented by formula (I) according to the present invention includes,

[0078] Step (a): Coupling compound 5 with compound 2 under the action of a catalyst and a base to obtain compound 6A;

[0079]

[0080] , wherein step (a) is as defined in the present invention;

[0081] Step (b): Reacting compound 6A with oxalic acid to obtain compound 6;

[0082]

[0083] wherein step (b) is as defined in the present invention;

[0084] Step (c): Performing a deprotection reaction on compound 6 to obtain compound 7;

[0085] wherein step (c) is as defined in the present invention;

[0086] Step (d): Reacting compound 7 with (S)-2-((methoxycarbonyl)amino)-3-methylbutanoic acid to obtain the compound represented by formula (I);

[0087] wherein step (d) is as defined in the present invention;

[0088] The compound represented by formula (I) is

[0089] In some embodiments, the method for synthesizing the compound represented by formula (I) of the present invention further includes a method for preparing compound 5, wherein compound 5 is prepared by condensing compound 3 and compound 4:

[0090]

[0091] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, compound 3 is obtained by reacting the dihydrochloride of compound 3 under the action of a base to obtain compound 3.

[0092] In some embodiments, in the reaction where compound 3 is obtained by reacting the dihydrochloride of compound 3 under the action of a base to obtain compound 3, the base for the reaction is potassium phosphate heptahydrate.

[0093] In some embodiments, in the reaction where compound 3 is obtained by reacting the dihydrochloride of compound 3 under the action of a base to obtain compound 3, the base for the reaction is potassium phosphate heptahydrate, and the molar ratio of the dihydrochloride of compound 3 to potassium phosphate heptahydrate is 1:(2.0 - 2.5).

[0094] In some embodiments, in the reaction where compound 3 is obtained by reacting the dihydrochloride of compound 3 under the action of a base to obtain compound 3, the base for the reaction is potassium phosphate heptahydrate, and the molar ratio of the dihydrochloride of compound 3 to potassium phosphate heptahydrate is 1:2.

[0095] In some embodiments, in the reaction where compound 3 is obtained by reacting the dihydrochloride of compound 3 under the action of a base to obtain compound 3, the base for the reaction is potassium phosphate heptahydrate, and the molar ratio of the dihydrochloride of compound 3 to potassium phosphate heptahydrate is 1:2.0, 1:2.2, or 1:2.5.

[0096] In some embodiments, in the method for preparing compound 5, the solvent for the reaction is a mixed solution of dichloromethane and water.

[0097] In some embodiments, in the method for preparing compound 5, the solvent for the reaction is a mixed solution of dichloromethane and water, and the volume ratio of dichloromethane to water is (2.5 - 4):1.

[0098] In some embodiments, in the method for preparing compound 5, the solvent for the reaction is a mixed solution of dichloromethane and water, and the volume ratio of dichloromethane to water is 2.5:1, 2.8:1, 3.0:1, 3.3:1, 3.5:1, 3.8:1, or 4.0:1.

[0099] On the other hand, the present invention provides a method for synthesizing a compound represented by formula (II), including the method for synthesizing the compound represented by formula (I) of the present invention, wherein the compound represented by formula (II) is:

[0100]

[0101] In some embodiments, the method for synthesizing the compound represented by formula (II) according to the present invention further comprises step (e): reacting the compound represented by formula (I) prepared by the method for synthesizing the compound represented by formula (I) according to the present invention with phosphoric acid to obtain the compound represented by formula (II).

[0102] In some embodiments, in the method for synthesizing the compound represented by formula (II) according to the present invention, in step (e), the molar ratio of phosphoric acid to the compound represented by formula (I) is (2.7 - 3.0):1.

[0103] In some embodiments, in step (e), the molar ratio of phosphoric acid to the compound represented by formula (I) is (2.85 - 2.95):1.

[0104] In some embodiments, in the method for synthesizing the compound represented by formula (II) according to the present invention, in step (e), the reaction solvent is a mixed solvent of acetone and water.

[0105] In some embodiments, in step (e), the reaction solvent is a mixed solvent of acetone and water, and the mass ratio of acetone to water is (8 - 12):1.

[0106] In some embodiments, in step (e), the reaction solvent is a mixed solvent of acetone and water, and the mass ratio of acetone to water is (8.5 - 11):1.

[0107] In some embodiments, in step (e), the reaction temperature is 40°C - 60°C.

[0108] In some embodiments, in step (e), the reaction temperature is 45°C - 55°C.

[0109] In some embodiments, after the reaction in step (e), acetone is added for recrystallization to obtain the compound represented by formula (II).

[0110] The solvents used in the preparation method according to the present invention are not particularly limited, and any solvent that can dissolve the starting materials to a certain extent and does not affect their properties is included in the present invention. In addition, many similar modifications, equivalent substitutions, or solvents equivalent to those described in the present invention, solvent combinations, and different ratios of solvent combinations are considered to be within the scope of the present invention. The present invention provides preferred solvents for each reaction step.

[0111] Definitions and general terms

[0112] Unless otherwise indicated, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and published publications referred to in this invention are incorporated herein by reference in their entirety. Although any methods and materials similar or equivalent to those described in this invention may be used in the practice or testing of the present invention, the preferred methods, devices, and materials are described herein.

[0113] It should be further recognized that certain features of the invention, for clarity, are described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, are described in a single embodiment, but may also be provided separately or in any suitable sub-combination.

[0114] Unless otherwise stated, the following definitions shall apply to the terms used herein. For the purposes of this invention, chemical elements are in accordance with the CAS version of the Periodic Table of the Elements and the Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, general principles of organic chemistry can be referred to the descriptions in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0115] When numerical limits are used in this invention for amounts, temperatures, times, etc., although only a specific value is given, the actual value should include its equivalent techniques, that is, it includes values within 10% of the given value or range, appropriately within 5% of the value, especially within 1% of the value. Alternatively, for those of ordinary skill in the art, these values represent within an acceptable standard error range. Whenever a number with an N value is disclosed, any number with a value within N + / – 1%, N + / – 2%, N + / – 3%, N + / – 5%, N + / – 7%, N + / – 8% or N + / – 10% will be explicitly disclosed, where "+ / –" means plus or minus.

[0116] The term "comprising" or "including" is an open-ended expression, that is, it includes the content specified in this invention, but does not exclude other aspects.

[0117] When "optionally" is placed before a certain condition, it means that both the selection and non-selection of this condition are included.

[0118] Unless otherwise specified, the "equivalent ratio" mentioned in the present invention refers to the molar equivalent ratio of each raw material used in the reaction feedstock.

[0119] Unless otherwise specified, "mL / g" in the present invention represents the volume of the solvent used for the reaction of 1 gram of the raw material, with the unit of milliliter (mL). For example, "the volume ratio of the solvent for the reaction to the mass of compound 5 is (7 - 13) mL / g" means that when the amount of compound 5 used in the reaction is 1 g, the amount of the solvent used for the reaction is (7 - 13) mL.

[0120] The term "solvent" refers to a substance (typically a liquid) that can completely or partially dissolve another substance (typically a solid). Solvents used in the implementation of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, trichloromethane, dimethyl sulfoxide, 1,4 - dioxane, ethanol, ethyl acetate, butanol, tert - butanol, N,N - dimethylacetamide, N,N - dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, N - methylpyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, ethylene glycol dimethyl ether, methyl tert - butyl ether, and their mixtures, etc.

[0121] The term "aprotic polar solvent" refers to a polar organic solvent that does not contain active hydrogen, including but not limited to: ethers (such as diethyl ether, tetrahydrofuran, dioxane, etc.), halogen compounds (such as chloromethane, chloroform, dichloromethane, carbon tetrachloride, etc.), ketones (such as acetone, methyl ethyl ketone, etc.), nitrogen - containing hydrocarbons (such as nitromethane, nitrobenzene, pyridine, acetonitrile, quinoline), sulfoxides (such as dimethyl sulfoxide), etc. Preferred aprotic polar solvents in the present invention are dichloromethane, dichloroethane, trichloromethane, N,N - dimethylformamide, ethyl acetate, or tetrahydrofuran, etc.

[0122] The term "reflux pulping" refers to the process of purifying a solid (including viscous or non - viscous) or oily substance in a certain solvent by vigorously stirring at the solvent reflux temperature.

[0123] In the context of the present invention, when the words "about" or "approximate" are used or whether they are used or not, it means within 10% of the given value or range, preferably within 5%, especially within 1%. Alternatively, for those of ordinary skill in the art, the term "about" or "approximate" means within the acceptable standard error range of the average value. Whenever a number with a value of N is disclosed, any number within the range of N + / - 1%, N + / - 2%, N + / - 3%, N + / - 5%, N + / - 7%, N + / - 8% or N + / - 10% will be explicitly disclosed, where "+ / -" means plus or minus.

[0124] The terms "equivalent", "eq" or "eq." used in the present invention are calculated based on the equivalent relationship of chemical reactions, with the basic raw material used in each step of the reaction as the benchmark (1 equivalent), to calculate the equivalent amount of other materials required. Unless otherwise specified, the equivalent or eq generally described in the present invention is the ratio of the molar amounts between other materials and the basic raw material. For example, based on the molar amount of compound 5, the molar amount of compound 2 can be 1.05 times that of it, i.e., 1.05 eq.

[0125] Detailed description of the present invention

[0126] The present invention provides a method for synthesizing the compound shown in formula (I), which method improves the yield of the compound shown in formula (I) and improves the stability of the process method. The present invention also provides a method for synthesizing the phosphate of the compound shown in formula (I), and the said method also improves the yield and purity of the phosphate of the compound shown in formula (I). The phosphate of the compound shown in formula (I) of the present invention has better druggability.

[0127] Specifically, on the one hand, the present invention provides a method for synthesizing the compound shown in formula (I), including step (a): carrying out a coupling reaction on compound 5 and compound 2 under the action of a catalyst and a base to obtain compound 6A;

[0128] On the one hand, the present invention provides a method for synthesizing the compound shown in formula (I), including step (a): carrying out a coupling reaction on compound 5 and compound 2 under the action of a catalyst and a base to obtain compound 6A;

[0129]

[0130] Wherein, the compound shown in formula (I) is

[0131] The catalyst is X-Phos Pd G2, Pd(dppf)Cl2·CH2Cl2, Pd(PPh3)2Cl2, Pd(dppf)Cl2 or Pd(PPh3)4;

[0132] The base is K3PO4, NaHCO3, KHCO3, Na2CO3 or K2CO3.

[0133] In some embodiments, for the method for synthesizing the compound shown in formula (I) of the present invention, wherein, in step (a), the catalyst is X-Phos Pd G2. The inventors found that when using X-Phos Pd G2 as the catalyst, there is less remaining reaction raw material compound 5 and the highest product purity.

[0134] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, in step (a), the solvent for the reaction is a mixed solvent of ethylene glycol dimethyl ether and water. The inventors have found that when a mixed solvent of ethylene glycol dimethyl ether and water is used as the reaction solvent, the conversion rate of the raw material to the product is high and the product purity is high.

[0135] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, in step (a), the solvent for the coupling reaction is a mixed solvent of ethylene glycol dimethyl ether and water, and the volume ratio of ethylene glycol dimethyl ether to water is (2 - 4):1. In some embodiments, the volume ratio of ethylene glycol dimethyl ether to water is 2:1, 3:1 or 4:1.

[0136] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, in step (a), the volume ratio of the solvent for the coupling reaction to the mass of compound 5 is (7 - 13) mL / g.

[0137] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, in step (a), the volume ratio of the solvent for the coupling reaction to the mass of compound 5 is (8 - 12) mL / g.

[0138] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, in step (a), the volume ratio of the solvent for the coupling reaction to the mass of compound 5 is 7 mL / g, 8 mL / g, 9 mL / g, 10 mL / g, 11 mL / g, 12 mL / g or 13 mL / g.

[0139] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, in step (a), the temperature of the coupling reaction is 75°C - 90°C.

[0140] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, in step (a), the temperature of the coupling reaction is 75°C - 90°C. In some embodiments, the temperature of the reaction is 75°C, 80°C, 85°C or 90°C.

[0141] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, in step (a), the temperature of the coupling reaction is the reflux temperature of the reaction solvent.

[0142] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, in step (a), the base is KHCO3. The inventors have found that when KHCO3 is selected as the base for the reaction, the conversion rate of the raw material to the product is the highest and the impurities generated in the reaction are few.

[0143] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, in step (a), the base is KHCO3, and the molar ratio of KHCO3 to compound 5 is (1.0 - 2.5):1.

[0144] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, in step (a), the base is KHCO3, and the molar ratio of KHCO3 to compound 5 is (1.0 - 1.5):1.

[0145] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, in step (a), the base is KHCO3, and the molar ratio of KHCO3 to compound 5 is (1.0 - 1.3):1.

[0146] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, in step (a), the molar ratio of KHCO3 to compound 5 is 1.0:1, 1.5:1, 2.0:1 or 2.5:1.

[0147] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, in step (a), the molar ratio of compound 2 to compound 5 is (1.00 - 1.10):1.

[0148] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, in step (a), the molar ratio of compound 2 to compound 5 is (1.05 - 1.10):1.

[0149] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, in step (a), the molar ratio of compound 2 to compound 5 is 1:1, 1.05:1 or 1.10:1.

[0150] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, in step (a), the molar ratio of the catalyst to compound 5 is (0.015 - 0.025):1.

[0151] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, in step (a), the molar ratio of the catalyst to compound 5 is (0.015 - 0.020):1.

[0152] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, in step (a), the molar ratio of the catalyst to compound 5 is 0.015:1, 0.020:1 or 0.025:1.

[0153] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, in step (a), the molar ratio of the catalyst X-Phos Pd G2 to compound 5 is (0.015 - 0.025):1.

[0154] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, in step (a), the molar ratio of the catalyst X-Phos Pd G2 to compound 5 is (0.015 - 0.020):1.

[0155] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, in step (a), the molar ratio of the catalyst X-Phos Pd G2 to compound 5 is 0.015:1, 0.020:1 or 0.025:1.

[0156] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, in step (a), the molar ratio of compound 2 to compound 5 is (1.05 - 1.10):1, the molar ratio of the catalyst X-Phos Pd G2 to compound 5 is (0.015 - 0.020):1, the base is KHCO3, the molar ratio of KHCO3 to the compound is (1.0 - 1.3):1, the reaction solvent is a mixed solvent of ethylene glycol dimethyl ether and water, and the volume ratio of ethylene glycol dimethyl ether to water is (2 - 4):1, and the reaction temperature is the reflux temperature of the reaction solvent.

[0157] In some embodiments, the method for synthesizing the compound represented by formula (I) of the present invention further includes step (b): reacting the compound 6A of the present invention with oxalic acid to obtain compound 6;

[0158]

[0159] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, in step (b), the molar ratio of oxalic acid to compound 6A is (1.3 - 1.5):1.

[0160] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, in step (b), the molar ratio of oxalic acid to compound 6A is 1.3:1, 1.35:1, 1.4:1, 1.45:1 or 1.5:1.

[0161] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, in step (b), the reaction solvent is ethyl acetate, dichloromethane, toluene, methyl tert-butyl ether or isopropanol.

[0162] In some embodiments, in the synthesis method of the compound represented by formula (I) of the present invention, in step (b), the reaction temperature is 40°C to 60°C.

[0163] In some embodiments, in the synthesis method of the compound represented by formula (I) of the present invention, in step (b), the reaction temperature is 45°C to 55°C.

[0164] In some embodiments, in the synthesis method of the compound represented by formula (I) of the present invention, in step (b), the reaction temperature is 40°C, 45°C, 50°C, 55°C or 60°C.

[0165] In some embodiments, in the synthesis method of the compound represented by formula (I) of the present invention, in step (b), the reaction solvent is ethyl acetate and the reaction temperature is 40°C to 60°C.

[0166] In some embodiments, in the synthesis method of the compound represented by formula (I) of the present invention, after the reaction in step (b), the obtained crude product is purified by slurrying with ethyl acetate to obtain pure compound 6.

[0167] In some embodiments, the synthesis method of the compound represented by formula (I) of the present invention further includes step (c): subjecting compound 6 of the present invention to a deprotection reaction to obtain compound 7,

[0168] wherein the deprotection reaction is carried out under the action of trimethylchlorosilane and methanol.

[0169] The inventors found that when using trimethylchlorosilane and methanol as the de-Boc protecting reagent, fewer impurities are generated in the reaction and the post-treatment of the reaction is simple.

[0170] In some embodiments, in the synthesis method of the compound represented by formula (I) of the present invention, in step (c), the molar ratio of trimethylchlorosilane to compound 6 is ≥7:1. The inventors found that when the molar ratio of trimethylchlorosilane to compound 6 is less than 7:1, the raw materials do not react completely; when the molar ratio of trimethylchlorosilane to compound 6 is ≥7:1, the raw materials can react completely.

[0171] In some embodiments, in the synthesis method of the compound represented by formula (I) of the present invention, in step (c), the molar ratio of trimethylchlorosilane to compound 6 is (7 to 15):1.

[0172] In some embodiments, in the synthesis method of the compound represented by formula (I) of the present invention, in step (c), the molar ratio of trimethylchlorosilane to compound 6 is (7 to 11):1.

[0173] In some embodiments, in the method for synthesizing the compound represented by formula (I) according to the present invention, in step (c), the molar ratio of trimethylchlorosilane to compound 6 is (9-11):1.

[0174] In some embodiments, in the method for synthesizing the compound represented by formula (I) according to the present invention, in step (c), the molar ratio of trimethylchlorosilane to compound 6 is 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1 or 15:1.

[0175] In some embodiments, in the method for synthesizing the compound represented by formula (I) according to the present invention, in step (c), the molar ratio of trimethylchlorosilane to methanol is ≤1:1.

[0176] In some embodiments, in the method for synthesizing the compound represented by formula (I) according to the present invention, in step (c), the molar ratio of trimethylchlorosilane to methanol is (7-15):(16-25).

[0177] In some embodiments, in the method for synthesizing the compound represented by formula (I) according to the present invention, in step (c), the molar ratio of trimethylchlorosilane to methanol is (7-15):(16-20).

[0178] In some embodiments, in the method for synthesizing the compound represented by formula (I) according to the present invention, in step (c), the molar ratio of trimethylchlorosilane to methanol is 1:1, 7:25, 8:25, 9:25, 10:25, 9.8:24, 11:25, 12:25, 13:25, 14:25, 15:25, 7:20, 8:20, 9:20, 10:20, 11:20, 12:20, 13:20, 14:20 or 15:20.

[0179] In some embodiments, in the method for synthesizing the compound represented by formula (I) according to the present invention, in step (c), the reaction solvent is dichloromethane, chloroform or ethyl acetate.

[0180] In some embodiments, in the method for synthesizing the compound represented by formula (I) according to the present invention, the volume ratio of the reaction solvent in step (c) to the mass of compound 6 is (5-15) mL / g.

[0181] In some embodiments, in the method for synthesizing the compound represented by formula (I) according to the present invention, the volume ratio of the reaction solvent in step (c) to the mass of compound 6 is (9-11) mL / g.

[0182] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, the ratio of the volume of the reaction solvent in step (c) to the mass of compound 6 is 5 mL / g, 6 mL / g, 7 mL / g, 8 mL / g, 9 mL / g, 10 mL / g, 11 mL / g, 12 mL / g, 13 mL / g, 14 mL / g, 15 mL / g.

[0183] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, in step (c), the reaction temperature is 15°C to 30°C.

[0184] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, in step (c), the reaction temperature is 15°C to 20°C.

[0185] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, in step (c), the reaction temperature is 15°C, 20°C, 25°C or 30°C.

[0186] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, in step (c), the reaction temperature is 20°C.

[0187] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, after the reaction in step (c), an aqueous solution of potassium phosphate heptahydrate is added to the reaction solution and stirred; the organic phase is separated by liquid separation, the organic phase is washed with water, cooled and stirred, and centrifuged and dried to obtain compound 7; wherein, the molar ratio of potassium phosphate heptahydrate to compound 6 is (12 to 15):1. In some embodiments, the molar ratio of potassium phosphate heptahydrate to compound 6 is 12:1, 13:1, 13:1, 14:1 or 15:1.

[0188] In some embodiments, the method for synthesizing the compound represented by formula (I) of the present invention further includes step (d): reacting compound 7 with (S)-2-((methoxycarbonyl)amino)-3-methylbutyric acid under the action of EDCI and ethyl 2-oximinoacetate to obtain the compound represented by formula (I).

[0189] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, in step (d), the molar ratio of EDCI to compound 7 is (1.1 to 1.5):1.

[0190] In some embodiments, for the method for synthesizing the compound represented by formula (I) of the present invention, in step (d), the molar ratio of EDCI to compound 7 is (1.2 to 1.4):1.

[0191] In some embodiments, in the synthesis method of the compound represented by formula (I) of the present invention, in step (d), the molar ratio of EDCI to compound 7 is 1.1:1, 1.2:1, 1.3:1 or 1.4:1.

[0192] In some embodiments, in the synthesis method of the compound represented by formula (I) of the present invention, wherein, in step (d), the molar ratio of (S)-2-((methoxycarbonyl)amino)-3-methylbutyric acid to compound 7 is (1.05 - 1.3):1.

[0193] In some embodiments, in the synthesis method of the compound represented by formula (I) of the present invention, wherein, in step (d), the molar ratio of (S)-2-((methoxycarbonyl)amino)-3-methylbutyric acid to compound 7 is (1.05 - 1.15):1.

[0194] In some embodiments, in the synthesis method of the compound represented by formula (I) of the present invention, in step (d), the molar ratio of (S)-2-((methoxycarbonyl)amino)-3-methylbutyric acid to compound 7 is 1.05:1, 1.10:1, 1.15:1, 1.20:1, 1.25:1 or 1.30:1.

[0195] In some embodiments, in the synthesis method of the compound represented by formula (I) of the present invention, wherein, in step (d), the molar ratio of ethyl 2-oximinoacetate to compound 7 is (0.1 - 0.3):1.

[0196] In some embodiments, in the synthesis method of the compound represented by formula (I) of the present invention, wherein, in step (d), the molar ratio of ethyl 2-oximinoacetate to compound 7 is (0.2 - 0.3):1.

[0197] In some embodiments, in the synthesis method of the compound represented by formula (I) of the present invention, in step (d), the molar ratio of ethyl 2-oximinoacetate to compound 7 is 0.1:1, 0.2:1 or 0.3:1.

[0198] In some embodiments, in the synthesis method of the compound represented by formula (I) of the present invention, wherein, in step (d), the molar ratio of EDCI, ethyl 2-oximinoacetate, (S)-2-((methoxycarbonyl)amino)-3-methylbutyric acid to compound 7 is (1.2 - 1.4):(0.2 - 0.3):(1.05 - 1.15):1.

[0199] In some embodiments, in the synthesis method of the compound represented by formula (I) of the present invention, wherein, in step (d), the solvent for the reaction is an aprotic polar solvent.

[0200] In some embodiments, the aprotic polar solvent is dichloromethane, dichloroethane, chloroform, N,N-dimethylformamide, ethyl acetate, or tetrahydrofuran, or any combination thereof.

[0201] In some embodiments, for the method for synthesizing the compound represented by formula (I) according to the present invention, in step (d), the solvent for the reaction is dichloromethane, dichloroethane, chloroform, N,N-dimethylformamide, ethyl acetate, or tetrahydrofuran, or any combination thereof.

[0202] In some embodiments, for the method for synthesizing the compound represented by formula (I) according to the present invention, in step (d), the solvent for the reaction is dichloromethane.

[0203] In some embodiments, for the method for synthesizing the compound represented by formula (I) according to the present invention, in step (d), the ratio of the volume of the solvent for the reaction to the mass of compound 7 is (20 - 60) mL / g.

[0204] In some embodiments, for the method for synthesizing the compound represented by formula (I) according to the present invention, in step (d), the ratio of the volume of the solvent for the reaction to the mass of compound 7 is (22 - 44) mL / g.

[0205] In some embodiments, for the method for synthesizing the compound represented by formula (I) according to the present invention, in step (d), the ratio of the volume of the solvent for the reaction to the mass of compound 7 is 20 mL / g, 22 mL / g, 25 mL / g, 30 mL / g, 33 mL / g, 35 mL / g, 40 mL / g, 44 mL / g, 46 mL / g, 50 mL / g, 55 mL / g, or 60 mL / g.

[0206] In some embodiments, for the method for synthesizing the compound represented by formula (I) according to the present invention, in step (d), the reaction temperature of the reaction is 0°C to 30°C.

[0207] In some embodiments, for the method for synthesizing the compound represented by formula (I) according to the present invention, in step (d), the reaction temperature of the reaction is 5°C to 25°C.

[0208] In some embodiments, for the method for synthesizing the compound represented by formula (I) according to the present invention, in step (d), the reaction temperature of the reaction is 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, or 30°C.

[0209] In some embodiments, in the synthesis method of the compound represented by formula (I) of the present invention, in step (d), the molar ratio of EDCI, ethyl 2-oximinoacetate, (S)-2-((methoxycarbonyl)amino)-3-methylbutyric acid to compound 7 is (1.2 to 1.4):(0.2 to 0.3):(1.05 to 1.15):1.

[0210] In some embodiments, in the synthesis method of the compound represented by formula (I) of the present invention, in step (d), the molar ratio of EDCI, ethyl 2-oximinoacetate, (S)-2-((methoxycarbonyl)amino)-3-methylbutyric acid to compound 7 is 1.3:0.2:1.1:1, 1.2:0.2:1.1:1, 1.4:0.2:1.1:1, 1.3:0.2:1.05:1, 1.3:0.2:1.10:1, 1.3:0.2:1.15:1, 1.3:0.1:1.1:1 or 1.3:0.2:1.1:1.

[0211] In some embodiments, in the synthesis method of the compound represented by formula (I) of the present invention, wherein, in step (d), after the reaction is completed, ammonia water is added to the reaction solution and stirred, and then liquid separation is carried out; a phosphoric acid aqueous solution is added to the organic phase for washing, and the organic phase is concentrated under reduced pressure to obtain the compound represented by formula (I). The inventors found that adding ammonia water can remove large-polarity by-products; adding a phosphoric acid aqueous solution to the subsequent organic phase can remove impurities, achieving the purpose of further purifying the product.

[0212] In some embodiments, the synthesis method of the compound represented by formula (I) of the present invention includes,

[0213] Step (a): Compound 5 and compound 2 are subjected to a coupling reaction under the action of a catalyst and a base to obtain compound 6A;

[0214]

[0215] Wherein, step (a) is as defined in the present invention;

[0216] Step (b): Compound 6A reacts with oxalic acid to obtain compound 6;

[0217]

[0218] Wherein, step (b) is as defined in the present invention;

[0219] Step (c): Compound 6 is subjected to a deprotection reaction to obtain compound 7;

[0220] Wherein, step (c) is as defined in the present invention;

[0221] Step (d): React compound 7 with (S)-2-((methoxycarbonyl)amino)-3-methylbutyric acid to obtain the compound shown by formula (I);

[0222] wherein, step (d) is as defined in the present invention;

[0223] The compound shown by formula (I) is

[0224] In some embodiments, the method for synthesizing the compound shown by formula (I) according to the present invention further includes a method for preparing compound 5, wherein compound 5 is prepared by condensation reaction of compound 3 and compound 4:

[0225]

[0226] In some embodiments, for the method for synthesizing the compound shown by formula (I) according to the present invention, in the method for preparing compound 5, after the reaction of compound 3 and compound 4 is completed, the reaction solution is treated successively with ammonia water and concentrated hydrochloric acid. In other embodiments, after the reaction of compound 3 and compound 4 is completed, ammonia water is added to the reaction solution and stirred; after liquid separation, concentrated hydrochloric acid is added to the organic phase and stirred again. In still other embodiments, after adding concentrated hydrochloric acid and stirring, the mixture is layered, the organic phase is washed with water, concentrated, and the concentrate is slurried with n-heptane for purification to obtain compound 5. The inventors found that adding ammonia water to the reaction solution after the reaction of compound 3 and compound 4 can convert a reaction by-product into a product; the subsequent addition of concentrated hydrochloric acid can remove the by-products of the reaction of raw material compound 3 with DMT-MM. Therefore, treating the reaction solution successively with ammonia water and concentrated hydrochloric acid can improve the reaction yield and product purity and simplify the post-treatment procedure.

[0227] In some embodiments, for the method for synthesizing the compound shown by formula (I) according to the present invention, wherein compound 3 is obtained by reacting the dihydrochloride of compound 3 under the action of a base to obtain compound 3.

[0228] In some embodiments, for the method for synthesizing the compound shown by formula (I) according to the present invention, wherein compound 3 is obtained by reacting the dihydrochloride of compound 3 under the action of a base to obtain compound 3, wherein the base for the reaction is potassium phosphate heptahydrate.

[0229] In some embodiments, for the method for synthesizing the compound shown by formula (I) according to the present invention, wherein compound 3 is obtained by reacting the dihydrochloride of compound 3 under the action of a base to obtain compound 3, wherein the base for the reaction is potassium phosphate heptahydrate, and the molar ratio of the dihydrochloride of compound 3 to potassium phosphate heptahydrate is 1:(2.0 - 2.5).

[0230] In some embodiments, for the synthesis method of the compound represented by formula (I) of the present invention, wherein, compound 3 is obtained by reacting the dihydrochloride of compound 3 under the action of a base, and the base for the reaction is potassium phosphate heptahydrate, and the molar ratio of the dihydrochloride of compound 3 to potassium phosphate heptahydrate is 1:2.

[0231] In some embodiments, for the synthesis method of the compound represented by formula (I) of the present invention, wherein, compound 3 is obtained by reacting the dihydrochloride of compound 3 under the action of a base, and the solvent for the reaction is a mixed solution of dichloromethane and water.

[0232] In some embodiments, for the synthesis method of the compound represented by formula (I) of the present invention, wherein, compound 3 is obtained by reacting the dihydrochloride of compound 3 under the action of a base, and the solvent for the reaction is a mixed solution of dichloromethane and water, and the volume ratio of dichloromethane to water is (2.5 - 4):1.

[0233] On the other hand, the present invention provides a synthesis method of a compound represented by formula (II), including the synthesis method of the compound represented by formula (I) of the present invention, wherein, the compound represented by formula (II) is:

[0234]

[0235] In some embodiments, for the synthesis method of the compound represented by formula (II) of the present invention, it further includes step (e): reacting the compound represented by formula (I) prepared by the synthesis method of the compound represented by formula (I) of the present invention with phosphoric acid to obtain the compound represented by formula (II).

[0236] In some embodiments, for the synthesis method of the compound represented by formula (II) of the present invention, wherein, the molar ratio of phosphoric acid to the compound represented by formula (I) in step (e) is (2.7 - 3.0):1.

[0237] In some embodiments, for the synthesis method of the compound represented by formula (II) of the present invention, wherein, the molar ratio of phosphoric acid to the compound represented by formula (I) in step (e) is (2.85 - 2.95):1.

[0238] In some embodiments, for the synthesis method of the compound represented by formula (II) of the present invention, wherein, the reaction solvent in step (e) is a mixed solvent of acetone and water.

[0239] In some embodiments, for the synthesis method of the compound represented by formula (II) of the present invention, wherein, the reaction solvent in step (e) is a mixed solvent of acetone and water, and the mass ratio of acetone to water is (8 - 12):1.

[0240] In some embodiments, for the method for synthesizing the compound represented by formula (II) according to the present invention, in step (e), the reaction solvent is a mixed solvent of acetone and water, and the mass ratio of acetone to water is (8.5 - 11):1.

[0241] In some embodiments, for the method for synthesizing the compound represented by formula (II) according to the present invention, in step (e), the reaction temperature is 40°C to 60°C.

[0242] In some embodiments, for the method for synthesizing the compound represented by formula (II) according to the present invention, in step (e), the reaction temperature is 45°C to 55°C.

[0243] In some embodiments, for the method for synthesizing the compound represented by formula (II) according to the present invention, after the reaction in step (e) is completed, acetone is added for recrystallization to obtain the pure compound represented by formula (II).

[0244] The preparation methods of the compounds represented by formula (I) or formula (II) according to the present invention are described in detail in the Examples section. Detailed Description of Embodiments

[0245] The present invention will be further illustrated by the following examples, which do not limit the present invention to the scope of the described examples.

[0246] Those skilled in the art will recognize that: the chemical reactions described in the present invention can be used to appropriately prepare the compounds of the present invention, and other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. Such as appropriately protecting interfering groups, by using other known reagents in addition to those described in the present invention, or making some conventional modifications to the reaction conditions.

[0247] The chromatographic column used is a silica gel column. The silica gel (300 - 400 mesh) was purchased from Qingdao Marine Chemical Factory. The nuclear magnetic resonance spectra were recorded in CDC13, DMSO-d6, CD3OD or acetone-d6 as solvents (reported in ppm), using TMS (0 ppm) or chloroform (7.25 ppm) as the reference standard. When multiple peaks appear, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). The coupling constant is expressed in Hertz (Hz).

[0248] The following abbreviations are used throughout the specification

[0249] X-Phos Pd G2 chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0250] Pd(dppf)Cl2·CH2Cl2 dichlorobis(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloromethane complex

[0251] Pd(PPh3)2Cl2 dichlorobis(triphenylphosphine)palladium

[0252] Pd(dppf)Cl2 dichlorobis(1,1'-bis(diphenylphosphino)ferrocene)palladium

[0253] Pd(PPh3)4 tetrakis(triphenylphosphine)palladium

[0254] TMSCl trimethylchlorosilane

[0255] EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

[0256] DMT-MM 4-(4,6-dimethoxytriazin-4-yl)-4-methylmorpholine hydrochloride

[0257] KOAc potassium acetate

[0258] DCM dichloromethane

[0259] DME ethylene glycol dimethyl ether

[0260] EA ethyl acetate

[0261] MeOH methanol

[0262] mL milliliter

[0263] L liter

[0264] g gram

[0265] kg kilogram

[0266] ℃ degree Celsius

[0267] eq. equivalent

[0268] wt% weight percent or mass percent

[0269] v:v volume ratio

[0270] Example

[0271] Synthesis of Intermediate Compound 3A

[0272]

[0273] Compound 3A-1 (141.3 kg, 249.8 mol, 1 eq, prepared according to the method in WO2016141890), toluene (294 L), and ammonium acetate (157.8 kg, 2047 mol, 8.2 eq) were mixed, and stirring was started. The temperature was raised to 102 - 104 °C for reaction, and water was separated by a water separator. The reaction was refluxed for 3 h, and TLC was used to detect the reaction progress by sampling. After the reaction was completed, the temperature was lowered to 20 - 30 °C, and the mixture was allowed to stand for layering. The lower acidic liquid was separated and reserved for extraction. To the upper toluene phase, a saturated sodium chloride solution (231 kg) was added, and an aqueous solution of saturated sodium carbonate (51 kg, sodium carbonate content about 20%) was added under stirring. After sufficient stirring, the lower aqueous phase was separated and combined with the previous acidic liquid. A saturated sodium carbonate aqueous solution (133 kg) was slowly added to adjust the pH to 7. Then, ethyl acetate (83 kg, 92 L) was added to the aqueous phase for stirring extraction. After standing for layering, the lower aqueous phase was discarded, and the ethyl acetate phase was combined with the previous toluene phase. It was concentrated under reduced pressure at 60 - 75 °C to obtain Compound 3A-2, and the yield was counted as 100%.

[0274] The above-mentioned Compound 3A-1 was mixed with ethyl acetate (600 kg, 665 L), stirred and dissolved, and the temperature was lowered to 10 - 20 °C. An EtOH solution of hydrogen chloride (142 kg, mass concentration 32%) was added dropwise, and the internal temperature was controlled at 10 - 20 °C during the addition. After the addition was completed, the temperature was controlled at 25 - 30 °C for reaction for 2 hours. TLC detected that the raw material 3A-1 had completely reacted. It was centrifuged and dried to obtain the crude product. The above crude product was mixed with 185 kg of isopropanol and 16 kg of water, stirred and heated. When the internal temperature rose to about 70 - 75 °C, the material became clear. The temperature was lowered to 20 - 30 °C, and it was kept stirring for 2 - 2.5 h. It was centrifuged, and the filter cake was rinsed with ethyl acetate (45 kg, 50 L). The filter cake was dried in a blast dryer at 50 - 55 °C for about 12 h to obtain Compound 3A (white solid, 70 kg, yield 54%). HRMS-ESI, m / z: 446.1371 [M - 2HCl + H] + ; 11H NMR (400 MHz, DMSO-d6): 10.63 (1H, brs), 10.39 (1H, brs), 7.96 (1H, s), 7.87 (1H, d, J = 8.6 Hz), 7.42 (1H, d, J = 8.6 Hz), 5.16 (1H, s), 3.53 (2H, d, J = 6.6 Hz), 3.47 (1H, m), 3.30 (4H, m), 3.19 (2H, t, J = 7.3 Hz), 3.04 (2H, t, J = 7.3 Hz), 2.73 (1H, m), 2.62 (1H, m), 2.35 (1H, m), 2.16 (2H, m).

[0275] Synthesis of Intermediate Compound 2

[0276]

[0277] Mix ethylene glycol dimethyl ether (104.1 kg, 120 L), Compound 1 (30 kg, 69.7 mol, 1.0 eq), bis(pinacolato)diboron (19.5 kg, 76.7 mol, 1.1 eq), potassium acetate (10.2 kg, 104.1 mol, 1.5 eq) and bis(triphenylphosphine)palladium(II) dichloride (900 g, 1.28 mmol, 0.018 eq), protect with nitrogen, react at 90 ± 5 °C for 4 h and sample for in-process control until Compound 1 ≤ 0.3%, then cool down. Filter, distill the filtrate under reduced pressure at 50 ± 5 °C, add ethyl acetate (324 kg, 360 L) and saturated sodium chloride aqueous solution (120 L) to dissolve and separate layers. Distill the organic phase under reduced pressure at 50 ± 5 °C, add methanol (93 kg, 118 L), heat up to 70 ± 5 °C, reflux and slurry for 4 h, cool down to -10 ± 5 °C, continue to stir for 1 h, centrifuge to obtain a solid, dry in vacuum at 60 ± 5 °C for 8 h to obtain Compound 2 (off-white solid, 27 kg, yield 81%, purity 99.3%). HRMS-ESI, m / z: 478.2877 [M+H] + ; 1 1H NMR (400 MHz, DMSO-d6): δ13.32–12.28 (m, 1H), 8.46–8.32 (m, 2H), 7.82 (t, J = 6.9 Hz, 1H), 7.79–

[0278] 7.65 (m, 2H), 5.04 (brs, 1H), 3.97 (brs, 1H), 2.38–2.04 (m, 3H), 1.73 (brs, 1H), 1.47–0.99 (m, 24H).

[0279] Synthesis of Compound 5

[0280]

[0281] Potassium phosphate heptahydrate (39.3 kg, 116.1 mmol, 2 eq) and water (180 kg, 180 L) were mixed and stirred until completely dissolved to obtain an aqueous potassium phosphate solution for later use.

[0282] Dichloromethane (795 kg, 600 L) and Compound 3A (30 kg, 57.9 mmol, 1 eq) were mixed, and the temperature was controlled at 10 ± 5 °C. The above aqueous potassium phosphate solution was added, and the mixture was stirred for 30 min, allowed to stand, and separated to obtain a first organic phase. The first organic phase was mixed with water (180 kg, 180 L), stirred for 20 min, allowed to stand, and separated to obtain a second organic phase for later use.

[0283] The second organic phase and Compound 4 (14.4 kg, 68.9 mol, 1.2 eq) were mixed and stirred until dissolved. The temperature was controlled at 0 ± 5 °C, and DMT-MM (19.2 kg, 65.1 mmol, 1.13 eq) was added. After holding the temperature for reaction for 12 h, HPLC monitoring was started until the raw material Compound 3 ≤ 0.10%. The temperature was controlled at 0 ± 5 °C, and then ammonia water (25.8 kg, 379.4 mmol, containing 25 wt% NH3) was added, and the mixture was stirred for reaction for 4 h, allowed to stand and separated to obtain a third organic phase. The third organic phase was mixed with water (180 kg, 180 L), stirred for 20 min, allowed to stand and separated to obtain a fourth organic phase. The fourth organic phase was controlled at 0 ± 5 °C, and concentrated hydrochloric acid (127.5 kg, 107 L) was slowly added, and the mixture was stirred while holding the temperature for 4 h, allowed to stand and separated to obtain a fifth organic phase. The fifth organic phase was washed successively with water (180 kg, 180 L), 8 wt% aqueous sodium bicarbonate solution (195 kg, 180 L), and 5 wt% aqueous sodium chloride solution (189 kg, 180 L). The washed fifth organic phase was distilled under reduced pressure at 40 ± 5 °C until there was basically no distillate, and then n-heptane (205.2 kg, 300 L) was added. The mixture was slurried at 25 ± 5 °C for 15 min, filtered by suction, and the wet product was dried in vacuo at 50 ± 5 °C for 8 h to obtain Compound 5 (white solid, 35.0 kg, yield 95%, purity 99.4%). HRMS-ESI, m / z: 637.1956 [M+H] + ; 11H NMR (400 MHz, CDCl3): δ 10.71 (brs, 1H), 7.71 (brs, 1H), 7.40 (m, 5H), 7.13 (s, 1H), 7.08 (d, J = 8.6 Hz, 1H), 6.14 (m, 1H), 5.43 (d, J = 7.1 Hz, 1H), 5.27 (m, 1H), 3.62 (s, 3H), 3.51 (m, 2H), 3.38 (m, 1H), 3.26 (s, 3H), 3.22 (t, J = 8.7 Hz, 1H), 3.11 (t, J = 7.3 Hz, 2H), 3.06 (t, J = 7.5 Hz, 2H), 2.70 (brs, 1H), 2.35 (m, 2H), 2.17 (m, 2H).

[0284] Synthesis of Oxalate of Compound 6A (i.e., Compound 6) in Example 1

[0285]

[0286]

[0287] Step 1: Add potassium bicarbonate (4.70 kg, 47 mol, 1.2 eq), Compound 5 (25 kg, 39.3 mol, 1 eq), X-Phos Pd G2 (0.54 kg, 0.69 mol, 0.018 eq), Compound 2 (19.75 kg, 41.4 mol, 1.05 eq), ethylene glycol dimethyl ether (173.5 kg, 200 L) and water (50 kg, 50 L) into the reaction kettle. Replace and protect with nitrogen, control the temperature at 80 ± 5 °C for reflux reaction. After reacting for 3 h, start HPLC monitoring. When the content of Compound 5 in the middle control is ≤ 0.50%, the reaction ends, and a mixed solution containing Compound 6A is obtained.

[0288] Step 2: Cool the mixed solution containing Compound 6A in Step 1 to 50 °C. Add the reaction solution to water (475 kg) to precipitate a solid, and centrifuge. The solid is dissolved in ethyl acetate (148.5 kg), and the lower aqueous phase is separated. The organic phase is washed with saturated sodium chloride aqueous solution (68 kg) and separated. The organic phase is controlled at 50 ± 5 °C, and a solution of oxalic acid (4.75 kg, 52.8 mol, 1.35 eq) in ethyl acetate (339 kg) is slowly added dropwise. After maintaining the temperature for reaction for 2 h, cool it to 10 ± 5 °C, centrifuge, and dry under vacuum to obtain the oxalate of Compound 6A, i.e., Compound 6 (37.4 kg, the total yield of Steps 1 and 2 is 98%, and the purity is 99.0%). HRMS-ESI, m / z: 838.4287 [M - 1.5HOOCCOOH + H] + ; 11H NMR (600 MHz, DMSO-d6) δ 8.48 (1H, d, J = 8.4 Hz), 8.11 (1H, s), 7.80 (1H, d, J = 7.8 Hz), 7.75 (4H, overlap), 7.57 (1H, s), 7.46 (1H, d, J = 7.9 Hz), 7.40 (4H, m), 7.34 (1H, m), 5.49 (1H, d, J = 7.8 Hz), 5.17 (1H, m), 5.07 (1H, brs), 3.99 (1H, brs), 3.61 (2H, m), 3.55 (3H, s), 3.33 (2H, m), 3.21 (3H, s), 3.11 (4H, m), 2.43 (2H, m), 2.30 (1H, m), 2.25 (1H, m), 2.14 (1H, m), 2.08 (2H, m), 1.93 (1H, m), 1.78 (1H, m), 1.44 (3H, m), 1.43 (4.5H, s), 1.11 (4.5H, s)

[0289] The results of ion chromatography analysis showed that the percentage content of oxalate ions in the sample was 12.6%, which was basically consistent with the theoretical value (13.9%) of the percentage content of oxalate ions in C 49 H 55 N7O6·3 / 2C2H2O4, indicating that the salt formation ratio of the organic base to oxalic acid in the sample structure was consistent with the expected structure, i.e., 1:1.5.

[0290] The reaction conditions for preparing compound 6A from compound 5 as a raw material were investigated.

[0291] 1.1 Investigation of the type of catalyst

[0292] The catalytic effects of different catalysts such as X-Phos Pd G2, Pd(dppf)Cl2·CH2Cl2, Pd(PPh3)4, Pd(dppf)Cl2, and Pd(PPh3)2Cl2 in the reaction for preparing compound 6A were investigated. The reaction conditions were as follows: the catalyst was 0.05 eq, compound 5 was (1.0 g, 1.0 eq), compound 2 was (0.82 g, 1.1 eq), the base was KHCO3 (0.39 g, 2.5 eq), the solvent was a mixed solvent of DME and water (10 mL, v:v = 4:1), the reaction temperature was 85 °C, and the reaction time was 2 h; the experimental operation referred to the steps in paragraph 1 of Example 1. The remaining amount of the raw material and the content of the product in the reaction solution were detected by HPLC, and the results are shown in Table 1.1 below, where the product in the following table refers to compound 6A.

[0293] Table 1.1

[0294]

[0295]

[0296] As can be seen from the above table, under the above reaction conditions, the remaining amount of raw material compound 5 was <0.50% in all cases, and the product content was above 85%. That is, under the action of the said catalyst, compound 5 could basically obtain the target compound 6A with a high yield. Under the action of X-Phos Pd G2, the product content was the highest, that is, the yield was the highest.

[0297] 1.2 Investigation of reaction temperature

[0298] The reaction temperatures such as 65 °C, 75 °C and 85 °C (oil bath temperature) were investigated. The reaction conditions were as follows: under nitrogen protection, the catalyst was X-Phos Pd G2 (65 mg, 0.05 eq), compound 5 (1.0 g, 1 eq), compound 2 (0.82 g, 1.1 eq), the base was KHCO3 (0.39 g, 2.5 eq), and the solvent was a mixed solvent of DME and water (10 mL, v:v = 4:1); the experimental operation referred to the steps in paragraph 1 of Example 1. The remaining amount of raw materials and the product content in the reaction solution were detected by HPLC. The results are shown in Table 1.2 below, where the product in the following table refers to compound 6A.

[0299] Table 1.2

[0300] Temperature Reaction time Residual amount of Compound 5 Product content 65℃ 21h 10.96％ 62.34％ 75℃ 3h 3.60％ 85.10％ 85℃ 2h 0.06％ 93.05％

[0301] Conclusion: During the reaction process, the lower the temperature, the slower the reaction. When the reaction temperature was 75 °C - 90 °C, the product yield was high. Keeping the reaction in a reflux state was beneficial to ensuring the nitrogen atmosphere in the reaction system, reducing the possibility of catalyst oxidation, and having a high product yield.

[0302] 1.3 Investigation of different bases

[0303] The bases in the reaction such as KF·2H2O, K3PO4, NaHCO3, KHCO3, Na2CO3 and Cs2CO3 were investigated. The reaction conditions were as follows: the catalyst was X-Phos Pd G2 (74 mg, 0.03 eq), compound 5 (2 g, 1.0 eq), compound 2 (1.65 g, 1.0 eq), the base 1.0 eq, the solvent was a mixed solvent of DME and water (20 mL, v:v = 4:1), the reaction was heated to reflux, and the reaction time was 2 h; the experimental operation referred to the steps in paragraph 1 of Example 1. The remaining amount of raw materials and the product content in the reaction solution were detected by HPLC. The results are shown in Table 1.3 below, where the product refers to compound 6A.

[0304] Table 1.3

[0305]

[0306]

[0307] Conclusion: The use of K3PO4, NaHCO3, KHCO3, Na2CO3 or Cs2CO3 is beneficial to improving the product yield.

[0308] 1.4 Investigation of the dosage of base

[0309] Taking potassium bicarbonate as an example, the reaction conditions for investigating the dosage of base are as follows: The catalyst is X-Phos Pd G2 (74 mg, 0.03 eq), compound 5 (2 g, 1.0 eq), compound 2 (1.65 g, 1.0 eq), the solvent is a mixed solvent of DME and water (20 mL, v:v = 4:1), and the reaction temperature is the reflux temperature; the experimental operation refers to the steps in paragraph 1 of Example 1. The remaining amount of raw materials and the content of the product in the reaction solution were detected by HPLC, and the results are shown in Table 1.4 below. The product refers to compound 6A:

[0310] Table 1.4

[0311]

[0312] It can be seen from the above table that when the amount of potassium bicarbonate is 0.8 eq and the reaction time is 6 h, the raw material compound 5 cannot completely react. When the amounts of potassium bicarbonate are 1.0 eq, 1.5 eq, 2.0 eq and 2.5 eq, the raw material compound 5 basically completely reacts within 2 h.

[0313] 1.5 Reaction conditions under different solvents

[0314] Different solvent systems such as toluene and water system, acetonitrile and water system, DMF and water system, DME and water system, etc. were investigated. The reaction conditions are as follows: The catalyst is X-Phos Pd G2 (25 mg, 0.02 eq), compound 5 (1.0 g, 1.0 eq), compound 2 (0.79 g, 1.05 eq), potassium bicarbonate (0.19 g, 1.2 eq), solvent (10 mL, the volume ratio of organic solvent to water is 4:1); the experimental operation refers to the steps in paragraph 1 of Example 1. The remaining amount of raw materials and the content of the product in the reaction solution were detected by HPLC, and the results are shown in Table 1.5 below. Among them, the product refers to compound 6A.

[0315] Table 1.5

[0316]

[0317] As can be seen from the above table, under the three conditions of toluene and water, acetonitrile and water, and DMF and water, after reacting for 5 h, there was a large amount of starting compound 5 remaining and the product content was low. Under the condition of DME and water, after reacting for 3 h, the starting materials reacted completely and the product content was high.

[0318] 1.6 Reaction conditions at different solvent ratios

[0319] Taking the mixed solvent of DME and H2O as an example, solvent volume ratios such as 4:1, 2:1, and 1:2 were investigated. The reaction conditions were as follows: the catalyst was X-Phos Pd G2 (74 mg, 0.03 eq), compound 5 (2 g, 1.0 eq), compound 2 (1.65 g, 1.0 eq), potassium bicarbonate (315 mg, 1.0 eq), the mixed solvent was 20 mL, and the reaction temperature was the reflux temperature; the experimental operation referred to the procedure in paragraph 1 of Example 1. The remaining amount of starting materials and the product content in the reaction solution were detected by HPLC. The results are shown in Table 1.6 below, where the product refers to compound 6A.

[0320] Table 1.6

[0321]

[0322] Conclusion: When the volume ratio of DME to H2O is 4:1 to 2:1 (or described as (2 - 4):1), the reaction is more complete.

[0323] 1.7 Investigation of different amounts of solvents

[0324] Taking the mixed solvent of DME and H2O as an example, the amounts of the DME and H2O mixed solvent such as 7 mL / g, 10 mL / g, and 13 mL / g (relative to the amount of compound 5) were investigated. The reaction conditions were as follows: the catalyst was X-Phos Pd G2 (62 mg, 0.05 eq), compound 5 (1.0 g, 1.0 eq), compound 2 (0.79 g, 1.05 eq), potassium bicarbonate (157 mg, 1.0 eq), the solvent was the DME and water mixed solvent (v:v = 4:1), and the reaction temperature was the reflux temperature; the experimental operation referred to the procedure in paragraph 1 of Example 1. The remaining amount of starting materials and the product content in the reaction solution were detected by HPLC. The results are shown in Table 1.7 below, where the product refers to compound 6A.

[0325] Table 1.7

[0326] <![CDATA[DME and H2O mixed solvent amount]]> Reaction time Residual amount of Compound 5 Product content 7 mL / g 4h 0 95.37％ 10 mL / g 4h 0 95.35％ 13 mL / g 4h 0 95.24％

[0327] Conclusion: When the amount of the DME and H2O mixed solvent is (7 - 13) mL / g, the starting materials can all react completely and the product purity is high.

[0328] 1.8 Investigate different dosages of Compound 2

[0329] Investigate different dosages of Compound 2. The reaction conditions are as follows: The catalyst is X-Phos Pd G2 (37 mg, 0.03 eq), Compound 5 (1.0 g, 1.0 eq), Compound 2, potassium bicarbonate (157 mg, 1.0 eq), and the solvent is a mixed solvent of DME and water (10 mL, v:v = 4:1). The reaction temperature is the reflux temperature. The experimental operation refers to the procedure in Paragraph 1 of Example 1. After the reaction is completed, the reaction solution is detected by HPLC. The results are shown in Table 1.8 below, where the product refers to Compound 6A.

[0330] Table 1.8

[0331]

[0332] Conclusion: When the dosage of Compound 2 is 1.0 eq to 1.10 eq, the reaction is relatively complete and the product yield is high. Especially when the dosage of Compound 2 is 1.05 eq to 1.10 eq, less raw materials remain, the reaction is more complete, and the product yield is high.

[0333] 1.9 Investigate different dosages of the catalyst

[0334] Investigate the dosage of the catalyst. The reaction conditions are as follows: The catalyst is X-Phos Pd G2, Compound 5 (1.0 g, 1 eq), Compound 2 (0.79 g, 1.05 eq), the base is KHCO3 (0.19 g, 1.2 eq), the solvent is a mixed solvent of DME and water (10 mL, v:v = 4:1), the reaction temperature is the reflux temperature (about 80 °C), and the reaction time is 3 h. The experimental operation refers to the procedure in Paragraph 1 of Example 1. After the reaction is completed, the reaction solution is detected by HPLC. The results are shown in Table 1.9 below, where the product refers to Compound 6A.

[0335] Table 1.9

[0336] X-Phos G2 Pd equivalent Residual amount of Compound 5 Product content 0.015 eq 0.03％ 93.93％ 0.020 eq 0.03％ 94.46％ 0.025 eq 0.03％ 94.20％

[0337] Conclusion: When the catalyst equivalent is 0.015 eq to 0.025 eq, the reaction is relatively complete and the product yield is high.

[0338] Example 2 Synthesis of Compound 7

[0339]

[0340] Step 1: Add dichloromethane (503.5 kg, 380 L), compound 6 (37.4 kg, 38.4 mol, 1.0 eq), and methanol (30 kg, 37.9 L, 936 mol, 24 eq) into the reaction kettle. After stirring and dissolving, control the temperature at 20 ± 5 °C, and slowly add trimethylchlorosilane (40.7 kg, 375 mol, 9.8 eq). After holding the temperature for reaction for 10 h, start HPLC monitoring. When the content of compound 6 in the in-process control is ≤ 0.10%, the reaction ends.

[0341] Step 2: Control the temperature of the reaction mixture at 15 ± 5 °C, add an aqueous solution of potassium phosphate heptahydrate (169 kg, 499 mol, 13 eq) in water (255 kg). During the dropping process, control the temperature in the kettle not to exceed 25 °C. Hold the temperature and stir for 2 h, then separate the liquid. Cool the organic phase to -5 ± 5 °C and stir for 6 h to precipitate solids. Centrifuge and dry to obtain compound 7 (24.1 kg, the total yield of steps 1 and 2 is 85%, and the purity is 99.0%). HRMS-ESI, m / z: 738.3748 [M+H] + ; 1 1H NMR (600 MHz, DMSO-d6): δ 8.49 (1H, d, J = 8.1 Hz), 8.06 (1H, m), 7.87 (1H, d, J = 7.9 Hz), 7.83 (1H, d, J = 7.9 Hz), 7.72 (2H, overlap), 7.70 (2H, overlap), 7.61 (2H, d, J = 7.0 Hz), 7.41 (2H, overlap), 7.38 (2H, overlap), 7.33 (2H, m), 7.04 (1H, t, J = 7.4 Hz), 5.49 (1H, brs), 5.10 (1H, t, J = 7.0 Hz), 4.45 (1H, t, J = 7.5 Hz), 3.55 (5H, m), 3.29 (3H, m), 3.18 (3H, s), 3.13 (2H, brs), 3.08 (2H, m), 2.34 (2H, brs), 2.23 (1H, m), 2.06 (3H, m), 1.99 (1H, m), 1.95 (1H, m), 1.41 (1H, m), 1.21 (3H, d, J = 6.1 Hz).

[0342] The conditions of the above reaction were investigated, and the details are as follows.

[0343] 2.1 Investigation of different dosages of trimethylchlorosilane

[0344] The amount of trimethylchlorosilane was screened and investigated. The reaction conditions were as follows: Compound 6 (1.0 g, 1.0 eq), dichloromethane (10 mL), methanol (1 mL), and the reaction temperature was 25 ± 5 °C; for the rest of the experimental operations, refer to the first paragraph of Step 1 in Example 2. The reaction solution was detected by HPLC, and the results are shown in Table 2.1 below.

[0345] Table 2.1

[0346]

[0347] Conclusion: Under the condition of 5 eq of trimethylchlorosilane and a reaction time of 24 h, the raw materials could not react completely. When the amount of trimethylchlorosilane was 7 eq - 11 eq, the raw materials reacted completely and the product yield was high; when the amount of trimethylchlorosilane was 9 eq - 11 eq, the raw materials could react completely, the reaction was fast, and the product yield was high.

[0348] 2.2 Investigation of different reaction temperatures

[0349] The effects of different reaction temperatures such as 10 °C, 15 °C, 20 °C, 30 °C, etc. were investigated. The reaction conditions were as follows: Compound 6 (1 g, 1.0 eq), dichloromethane (10 mL), trimethylchlorosilane (1.03 g, 9 eq), methanol (1 mL); for the rest of the experimental operations, refer to the first paragraph of Step 1 in Example 2. The reaction solution was detected by HPLC, and the results are shown in Table 2.2 below.

[0350] Table 2.2

[0351]

[0352]

[0353] Conclusion: When the reaction temperature was in the range of 15 °C - 30 °C, the raw material Compound 6 could react completely and the product yield was high.

[0354] 2.3 Investigation of different amounts of solvents

[0355] The amount of dichloromethane solvent was investigated. The reaction conditions were as follows: Compound 6 (1.0 g, 1 mmol, 1.0 eq), trimethylchlorosilane (1.03 g, 9 eq), methanol (0.791 g, 1 mL, 25 mmol, 25 eq), and the reaction temperature was 20 °C; for the rest of the experimental operations, refer to the first paragraph of Step 1 in Example 2. The reaction solution was detected by HPLC, and the results are shown in Table 2.3 below.

[0356] Table 2.3

[0357] Dosage of dichloromethane Reaction time Residual amount of Compound 6 Product content 5 mL / g 24h Not detected 98.18％ 10 mL / g 24h Not detected 97.41％ 15 mL / g 24h Not detected 96.91％

[0358] Conclusion: When the dosage of dichloromethane is 5 mL / g - 15 mL / g, the raw material compound 6 can react completely, and the product yield is high.

[0359] Synthesis of Compound (II) in Example 3

[0360]

[0361] Step 1: Add dichloromethane (828 kg), compound 7 (24.1 kg, 32.7 mol, 1.0 eq), (S)-2-((methoxycarbonyl)amino)-3-methylbutyric acid (compound 8, 6.3 kg, 36.0, 1.1 eq) into the reaction kettle, control the temperature at 15 ± 5 °C, and slowly add a dichloromethane (207 kg) solution of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.1 kg, 42.3 mol, 1.3 eq) and ethyl 2-oximinoacetate (0.9 kg, 6.3 mol, 0.2 eq). After reacting at 15 ± 5 °C for 10 h, send it for inspection, and control the content of compound 7 ≤ 0.25% in the in-process control. Add ammonia water (45.8 kg, mass fraction 25% - 28%), continue to control the temperature at 15 ± 5 °C, stir for 3 h, then separate the liquid to obtain the organic phase. The organic phase is washed twice with water (250 kg) and three times with 1% phosphoric acid aqueous solution (160 kg), and distilled under reduced pressure until there is no obvious distillate to obtain the free base, that is, the compound of formula (I) of the present invention.

[0362] Step 2: Add the compound of formula (I) in Step 1 and acetone (79.2 kg) into the reaction kettle, control the temperature at 50 ± 5 °C and stir until it is clear, add water (9.2 kg), and then slowly add a acetone (15.1 kg) solution of phosphoric acid (11.05 kg, 95.8 mol, 2.9 eq, calculated based on the equivalent of compound 7 as 1 eq). Stir at 50 ± 5 °C for 10 h, then slowly add acetone (162.6 kg), continue to stir at 55 ± 5 °C for 6 h, cool down to 0 ± 5 °C, continue to stir for 2 h, centrifuge, and dry under vacuum to obtain compound (II) (36 kg, the total yield of Steps 1 and 2 is 95%, and the purity is 99.8%).

[0363] 3.1 Investigation on Different Dosages of EDCI

[0364] The dosage of EDCI was investigated under the reaction conditions: compound 7 (4.0 g, 1.0 eq), compound 8 (1.045 g, 1.1 eq), ethyl 2-oximinoacetate (154 mg, 0.2 eq), dichloromethane (132 mL), and the reaction temperature was 15 ± 5 °C; the remaining experimental operations refer to the first paragraph of Step 1 in Example 3. The reaction solution was detected by HPLC, and the results are shown in Table 3.1 below, where the product refers to the free base of compound (II) before salification, that is, the compound of formula (I).

[0365] Table 3.1

[0366] Dosage of EDCI Reaction time Residual amount of Compound 7 Product content 1.2 eq 4h 0.11％ 93.82％ 1.3 eq 4h 0.09％ 93.19％ 1.4 eq 4h 0.10％ 92.96％

[0367] Conclusion: When the equivalent of EDCI is 1.2eq - 1.4eq, the raw material compound 7 reacts completely and the product yield is high.

[0368] 3.2 Investigation of different dosages of compound 8

[0369] The dosage of compound 8 was investigated under the reaction conditions: compound 7 (1.0 g, 1.0 eq), EDCI (0.34 g, 1.3 eq), ethyl 2 - oximecyanoacetate (39 mg, 0.2 eq), dichloromethane (33 mL), and the reaction temperature was 15 °C; the remaining experimental operations refer to the first paragraph of step 1 in Example 3. The reaction solution was detected by HPLC, and the results are shown in Table 3.2 below. The product refers to the free base of compound (II) before salification, that is, the compound shown in formula (I).

[0370] Table 3.2

[0371] Dosage of Compound 8 Reaction time Residual amount of Compound 7 Product content 1.05 eq 14h 0.11％ 94.55％ 1.10 eq 10h 0.12％ 97.83％ 1.15 eq 10h 0.11％ 98.07％

[0372] Conclusion: When the equivalent of compound 8 is 1.05eq - 1.10eq, the raw material compound 7 reacts completely and the product yield is high.

[0373] 3.3 Investigation of different dosages of ethyl 2 - oximecyanoacetate

[0374] The dosage of ethyl 2 - oximecyanoacetate was investigated under the reaction conditions: compound 7 (1.0 g, 1.0 eq), compound 8 (0.26 g, 1.1 eq), EDCI (0.34 g, 1.3 eq), dichloromethane (33 mL), and the reaction temperature was 15 °C; the remaining experimental operations refer to the first paragraph of step 1 in Example 3. The reaction solution was detected by HPLC, and the results are shown in Table 3.3 below. Among them, the product refers to the free base of compound (II) before salification, that is, the compound shown in formula (I).

[0375] Table 3.3

[0376] Dosage of ethyl 2-oximecyanoacetate Reaction time Residual amount of Compound 7 Product content 0.1 eq 15h 0.09％ 91.58％ 0.2 eq 15h 0.10％ 94.00％ 0.3 eq 15h 0.12％ 96.94％

[0377] Conclusion: When the equivalent of ethyl 2 - oximecyanoacetate is 0.1eq - 0.3eq, the raw material compound 7 reacts completely and the product yield is high.

[0378] 3.4 Investigation of the dosage of the solvent

[0379] Taking dichloromethane as an example, the amount of the solvent was investigated. The reaction conditions were as follows: compound 7 (1.0 g, 1.0 eq), compound 8 (0.26 g, 1.1 eq), EDCI (0.34 g, 1.3 eq), ethyl 2-cyanoiminoacetate (38 mg, 0.2 eq), and the reaction temperature was 15 °C; for the remaining experimental operations, refer to the first paragraph of step 1 in Example 3. The reaction solution was detected by HPLC, and the results are shown in Table 3.4 below. The product refers to the free base of compound (II) before salification, that is, the compound shown in formula (I).

[0380] Table 3.4

[0381] Dosage of dichloromethane Reaction time Residual amount of Compound 7 Product content 22 mL / g 15h 0.11％ 92.75％ 33 mL / g 15h 0.11％ 93.34％ 44 mL / g 15h 0.11％ 94.60％

[0382] Conclusion: When the amount of dichloromethane is 22 mL / g - 44 mL / g, the raw material compound 7 reacts completely and the product yield is high.

[0383] 3.5 Investigation of the reaction temperature

[0384] The effects of different reaction temperatures such as 5 °C, 15 °C, and 25 °C were investigated. The reaction conditions were as follows: compound 7 (1.0 g, 1.0 eq), compound 8 (0.26 g, 1.1 eq), EDCI (0.34 g, 1.3 eq), ethyl 2-cyanoiminoacetate (38 mg, 0.2 eq), dichloromethane (33 mL); for the remaining experimental operations, refer to the first paragraph of step 1 in Example 3. The reaction solution was detected by HPLC, and the results are shown in Table 3.5 below. The product refers to the free base of compound (II) before salification, that is, the compound shown in formula (I).

[0385] Table 3.5

[0386] Reaction temperature Reaction time Residual amount of Compound 7 Product content 5℃ 10h 0.11％ 94.58％ 15℃ 10h 0.11％ 93.94％ 25℃ 10h 0.11％ 94.22％

[0387] Conclusion: At the reaction temperature of 5 °C - 25 °C, the raw material compound 7 reacts completely and the product yield is high.

[0388] The above content is only the basic description under the concept of the present invention, and any equivalent transformation made according to the technical solution of the present invention shall fall within the protection scope of the present invention.

[0389] In the description of this specification, the description referring to terms such as "one embodiment", "some embodiments", "examples", "specific examples", or "some examples", etc. means that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic expressions of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described can be combined in a suitable manner in any one or more embodiments or examples. In addition, without contradiction, those skilled in the art can combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples.

[0390] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention.

Claims

1. A method for synthesizing a compound represented by formula (I), comprising the steps of: (a) coupling compound 5 with compound 2 in the presence of a catalyst and a base to obtain compound 6A, in, The compound represented by formula (I) is The catalyst is X-Phos Pd G2, Pd(dppf)Cl2·CH2Cl2, Pd(PPh3)2Cl2, Pd(dppf)Cl2 or Pd(PPh3)4; The base is K3PO4, NaHCO3, KHCO3, Na2CO3 or K2CO3.

2. The synthesis method according to claim 1, wherein In step (a), the solvent for the coupling reaction is a mixed solvent of ethylene glycol dimethyl ether and water; Optionally, the volume ratio of ethylene glycol dimethyl ether to water is (2-4):1; Optionally, the ratio of the volume of the solvent of the coupling reaction to the mass of compound 5 is (7-13) mL / g; Optionally, the coupling reaction temperature is 75°C to 90°C; Optionally, the coupling reaction temperature is the reflux temperature of the reaction solvent.

3. The synthesis method according to claim 1, wherein In step (a), the base is KHCO3; Optionally, the molar ratio of KHCO3 to compound 5 is (1.0-2.5):1, (1.0-1.5):1 or (1.0-1.3):

1.

4. The synthesis method according to claim 1, wherein In step (a), the molar ratio of compound 2 to compound 5 is (1.00-1.10):1 or (1.05-1.10):1; optionally, the molar ratio of the catalyst to compound 5 is (0.015-0.025):1 or (0.015-0.020):

1.

5. The synthesis method according to any one of claims 1 to 4, further comprising step (b): reacting the compound 6A with oxalic acid to obtain compound 6; in, Optionally, the molar ratio of oxalic acid to compound 6A is (1.3-1.5):1; Optionally, the reaction solvent of step (b) is at least one of ethyl acetate, dichloromethane, toluene, methyl tert-butyl ether or isopropanol; Optionally, the reaction temperature of step (b) is 40°C to 60°C; Optionally, after the reaction of step (b) is completed, the obtained crude product is purified by beating with ethyl acetate to obtain pure compound 6.

6. The synthesis method according to any one of claims 1 to 5, further comprising step (c): subjecting the compound 6 to a deprotection reaction to obtain a compound 7, in, The deprotection reaction is carried out under the action of trimethylsilyl chloride and methanol.

7. The synthesis method according to claim 6, wherein In step (c), the molar ratio of trimethylsilyl chloride to compound 6 is ≥7:1; Optionally, in step (c), the molar ratio of trimethylsilyl chloride to compound 6 is (7-15):1, (7-11):1 or (9-11):1; Optionally, in step (c), the molar ratio of trimethylsilyl chloride to methanol is ≤1:1; Optionally, in step (c), the molar ratio of trimethylsilyl chloride to methanol is (7-15):(16-25) or (7-15):(16-20).

8. The synthesis method according to claim 6 or 7, wherein The reaction solvent of the reaction in step (c) is dichloromethane, chloroform or ethyl acetate; Optionally, the ratio of the volume of the reaction solvent in step (c) to the mass of compound 6 is (5-15) mL / g or (9-11) mL / g; Optionally, the reaction temperature of step (c) is 15°C to 30°C or 15°C to 20°C.

9. The synthesis method according to any one of claims 1 to 8, further comprising step (d): reacting compound 7 with (S)-2-((methoxycarbonyl)amino)-3-methylbutyric acid in the presence of EDCI and ethyl 2-oximecyanoacetate to obtain a compound of formula (I).

10. The synthesis method according to claim 9, wherein The molar ratio of EDCI to compound 7 in step (d) is (1.1-1.5):1 or (1.2-1.4):1; Optionally, the molar ratio of (S)-2-((methoxycarbonyl)amino)-3-methylbutanoic acid to compound 7 in step (d) is (1.05-1.3):1 or (1.05-1.15):1; Optionally, the molar ratio of ethyl 2-oximecyanoacetate to compound 7 in step (d) is (0.1-0.3):1 or (0.2-0.3):1; Optionally, the solvent for the reaction in step (d) is an aprotic polar solvent; Optionally, the solvent for the reaction in step (d) is dichloromethane, dichloroethane, chloroform, N,N-dimethylformamide, ethyl acetate, tetrahydrofuran or any combination thereof; Optionally, the ratio of the volume of the solvent for the reaction in step (d) to the mass of compound 7 is (20-60) mL / g or (22-44) mL / g; Optionally, the reaction temperature of the reaction in step (d) is 0°C to 30°C or 5°C to 25°C.

11. A method for synthesizing a compound represented by formula (II), comprising the method according to any one of claims 1 to 10, wherein: The compound represented by formula (II) is: The method further comprises the step (e): reacting the compound of formula (I) prepared by the synthesis method according to any one of claims 1 to 10 with phosphoric acid to obtain the compound of formula (II).

12. The synthesis method according to claim 11, wherein In step (e), the molar ratio of phosphoric acid to the compound represented by formula (I) is (2.7-3.0):1 or (2.85-2.95):

1.

13. The synthesis method according to claim 11 or 12, wherein the reaction solvent of the reaction in step (e) is a mixed solvent of acetone and water; Optionally, the reaction solvent in step (e) is a mixed solvent of acetone and water, wherein the mass ratio of acetone to water is (8-12):1 or (8.5-11):1; Optionally, the reaction temperature in step (e) is 40°C to 60°C or 45°C to 55°C; Optionally, after the reaction in step (e) is completed, acetone is added for recrystallization to obtain a pure compound of formula (II).

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