Preparation method of oxygen-containing heterocyclic compound

Abstract

The invention discloses a preparation method of an oxygen-containing heterocyclic compound. The method comprises a preparation method of a compound 15, and the preparation method comprises the following step: in an organic solvent, in the presence of alkali, carrying out amidation reaction as shown in the specification on a compound 13 and a compound 14 to obtain the compound 15. The product obtained by adopting the preparation method is high in yield, mild in reaction condition, simple and convenient to operate and suitable for industrial production. # imgabs0 #

Description

Technical Field

[0001] The invention relates to a method for preparing oxygen-containing heterocyclic compounds. Background Art

[0002] GalNAc (N-acetylgalactosamine) is a high-affinity targeting ligand of asialoglycoprotein receptor (ASGPR). ASGPR is highly expressed on the surface of hepatocytes. After binding to GalNAc, ASGPR enters the cell through endocytosis to form endosomes, thereby bringing a sufficient number of nucleic acid drugs into the cell and achieving liver-targeted delivery of nucleic acid drugs.

[0003] ASGPR receptor-mediated liver-targeted oligonucleotides are a hot topic in the field of nucleic acid drug research. CN110846320B discloses a series of GalNAc-SiRNA drugs, which are composed of three parts, namely, interfering nucleotides, transfer points, and terminal modified chains. Through the terminal modified chains, two or three N-acetylgalactosamines can be introduced into the 3' end of the antisense chain of the SiRNA, and two or one N-acetylgalactosamines can be introduced into the 5' end of the sense chain accordingly. For the terminal modified chain, such as compound 17, the synthetic route is relatively long, and the current preparation method is limited.

[0004] Summary of the invention

[0005] The technical problem to be solved by the present invention is to provide a method for preparing an oxygen-containing heterocyclic compound in order to overcome the limited defects of the preparation method of compound 17. The product yield obtained by the preparation method is high. The preparation method of compound 17 has mild reaction conditions, simple operation, and is suitable for industrial production. The present application provides a new method for synthesizing terminal modified chains in nucleic acid drugs.

[0006] The present invention provides a method for preparing compound 15, comprising the following steps: in an organic solvent, in the presence of a base, subjecting compound 13 and compound 14 to an amidation reaction as shown below, to obtain compound 15;

[0007]

[0008] In the amidation reaction, the organic solvent may be a conventional organic solvent in the art, preferably a halogenated alkane solvent or an ether solvent. The halogenated alkane solvent is preferably dichloromethane or chloroform. The ether solvent is preferably tetrahydrofuran or 1,4-dioxane.

[0009] In the amidation reaction, the mass volume ratio of the compound 13 to the organic solvent may be a conventional mass volume ratio in the art, preferably 0.05-0.15 g / mL, more preferably 0.07-0.12 g / mL, such as 0.09 g / mL.

[0010] In the amidation reaction, the base is preferably an organic base, more preferably triethylamine or N,N-diisopropylethylamine.

[0011] In the amidation reaction, the molar ratio of the base to the compound 13 is preferably (1-3):1, more preferably (1-1.5):1, for example 1:1.

[0012] In the amidation reaction, the molar ratio of the compound 14 to the compound 13 is preferably (1-2):1, more preferably (1-1.5):1, for example 1.1:1.

[0013] In the preparation method of the compound 15, the reaction temperature of the amidation reaction can be a conventional temperature in the art, preferably 10-50° C., more preferably room temperature.

[0014] In the preparation method of the compound 15, the reaction time of the amidation reaction can be monitored by conventional means in the art (such as TLC, HPLC or LC-MS), and the reaction time of the amidation reaction is preferably 2-6 h, more preferably 4 h.

[0015] In the preparation method of the compound 15, preferably, after the amidation reaction is completed, it can further include a post-treatment operation, and the post-treatment operation includes the following steps: washing the reaction solution (the washing solvent is preferably saturated sodium chloride saline), drying, filtering, and spin drying.

[0016] In a certain embodiment of the present invention, in the amidation reaction, the organic solvent is dichloromethane; the mass volume ratio of the compound 13 to the organic solvent is 0.09 g / mL; the base is N,N-diisopropylethylamine; the molar ratio of the base to the compound 13 is 1:1; the molar ratio of the compound 14 to the compound 13 is 1.1:1; and the reaction temperature of the amidation reaction is room temperature.

[0017] In the preparation method of the compound 15, the preparation method of the compound 13 may include the following steps: in an organic solvent, in the presence of a metal catalyst, subjecting the compound 12 to a deprotection reaction with hydrogen as shown below, to obtain the compound 13;

[0018]

[0019] In the deprotection reaction, the organic solvent may be a conventional organic solvent in the art, preferably an alcohol solvent or an ether solvent. The alcohol solvent is preferably methanol, ethanol or isopropanol. The ether solvent is preferably tetrahydrofuran or 1,4-dioxane.

[0020] In the deprotection reaction, the mass volume ratio of the compound 12 to the organic solvent may be a conventional mass volume ratio in the art, preferably 0.05-0.15 g / mL, more preferably 0.08-0.12 g / mL, such as 0.1 g / mL.

[0021] In the deprotection reaction, the metal catalyst may be a conventional metal catalyst in the art, preferably Pd / C, Pd(OH)2, Raney nickel, Pt / C or PtO2, more preferably Pd / C.

[0022] In the deprotection reaction, the mass ratio of the metal catalyst to the compound 12 is preferably (0.1-0.5):1, more preferably (0.1-0.3):1, for example 0.2:1.

[0023] In the method for preparing compound 13, the temperature of the deprotection reaction can be a conventional temperature in the art, preferably 10-50° C., more preferably room temperature.

[0024] In the preparation method of the compound 13, the reaction time of the deprotection reaction can be monitored by conventional means in the art (such as TLC, HPLC or LC-MS), and the reaction time of the deprotection reaction is preferably 8-24 hours, more preferably overnight.

[0025] In the preparation method of the compound 13, preferably, after the deprotection reaction is completed, it may further include a post-treatment operation, and the post-treatment operation includes the following steps: filtering the reaction solution (preferably diatomaceous earth filtration), and spinning the filtrate to dryness.

[0026] In the preparation method of the compound 13, the preparation method of the compound 12 may include the following steps: in an organic solvent, in the presence of a condensing agent and a base, subjecting the compound 11 and the compound 5 to a condensation reaction as shown below, to obtain the compound 12;

[0027]

[0028] In the condensation reaction, the organic solvent may be a conventional organic solvent in the art, preferably a halogenated alkane solvent, a nitrile solvent, an amide solvent or an ether solvent, preferably a halogenated alkane solvent. The halogenated alkane solvent is preferably dichloromethane or chloroform. The nitrile solvent is preferably acetonitrile. The amide solvent is preferably N,N-dimethylformamide or N,N-dimethylacetamide. The ether solvent is preferably tetrahydrofuran or 1,4-dioxane.

[0029] In the condensation reaction, the mass volume ratio of the compound 5 to the organic solvent may be a conventional mass volume ratio in the art, preferably 0.01-0.05 g / mL, more preferably 0.03 g / mL.

[0030] In the condensation reaction, the condensation agent can be a conventional condensation agent in the art, preferably N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl) uron hexafluorophosphate (HATU), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), or 1-hydroxybenzotriazole (HOBT) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI·HCl), more preferably 1-hydroxybenzotriazole (HOBT) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI·HCl).

[0031] In the condensation reaction, the molar ratio of the condensing agent to the compound 5 is preferably (1-10):1, more preferably 6.2:1.

[0032] In the condensation reaction, when the condensing agent is HOBT and EDCI·HCl, the molar ratio of HOBT to the compound 5 is preferably (1-3):1, more preferably 2.2:1. The molar ratio of EDCI·HCl to the compound 5 is preferably (2-6):1, more preferably 4:1.

[0033] In the condensation reaction, the base can be a conventional base in the art, such as an organic base. The organic base is preferably triethylamine or N,N-diisopropylethylamine.

[0034] In the condensation reaction, the molar ratio of the base to the compound 5 is preferably (1-5):1, more preferably (2-4):1, for example 3.1:1.

[0035] In the condensation reaction, the molar ratio of the compound 11 to the compound 5 is preferably (2-3):1, more preferably 2.2:1.

[0036] In the method for preparing compound 12, the reaction temperature of the condensation reaction can be a conventional temperature in the art, preferably 10-50° C., more preferably room temperature.

[0037] In the method for preparing compound 12, the reaction time of the condensation reaction can be monitored by conventional means in the art (such as TLC, HPLC or LC-MS), and the reaction time of the condensation reaction is preferably 8-24 h, more preferably overnight.

[0038] In the preparation method of compound 12, preferably, after the condensation reaction is completed, it further includes a post-treatment operation, and the post-treatment operation includes the following steps: after the reaction solution is vortexed to remove a large amount of the organic solvent, ethyl acetate is added, and then saturated sodium bicarbonate is added for washing, and then saturated brine is used for washing, drying, filtering, vortexing, and column chromatography.

[0039] In the preparation method of the compound 12, the preparation method of the compound 11 may include the following steps: in an organic solvent, in the presence of a metal catalyst, subjecting the compound 10 to a deprotection reaction with hydrogen as shown below, to obtain the compound 11;

[0040]

[0041] In the deprotection reaction, the organic solvent may be a conventional organic solvent in the art, preferably an alcohol solvent or an ether solvent. The alcohol solvent is preferably methanol, ethanol or isopropanol. The ether solvent is preferably tetrahydrofuran or 1,4-dioxane.

[0042] In the deprotection reaction, the mass volume ratio of the compound 10 to the organic solvent may be a conventional mass volume ratio in the art, preferably 0.05-0.15 g / mL, more preferably 0.08-0.12 g / mL, such as 0.1 g / mL.

[0043] In the deprotection reaction, the metal catalyst may be a conventional metal catalyst in the art, preferably Pd / C, Pd(OH)2, Raney nickel, Pt / C or PtO2, more preferably Pd / C.

[0044] In the deprotection reaction, the mass ratio of the metal catalyst to the compound 10 is preferably (0.1-0.5):1, more preferably (0.1-0.3):1, for example 0.1:1.

[0045] In the deprotection reaction, the reaction temperature of the deprotection reaction can be a conventional temperature in the art, preferably 10-50° C., more preferably room temperature.

[0046] In the preparation method of the compound 11, the reaction time of the deprotection reaction can be monitored by conventional means in the art (such as TLC, HPLC or LC-MS), and the reaction time of the deprotection reaction is preferably 1-3 h, more preferably 2 h.

[0047] In the preparation method of the compound 11, preferably, after the deprotection reaction is completed, it may further include a post-treatment operation, and the post-treatment operation includes the following steps: filtering the reaction solution (preferably diatomaceous earth filtration), and spinning the filtrate to dryness.

[0048] In the preparation method of the compound 11, the preparation method of the compound 10 may include the following steps: in an organic solvent, in the presence of p-toluenesulfonic acid, subjecting the compound 8 and the compound 9 to an etherification reaction as shown below, to obtain the compound 10;

[0049]

[0050] In the etherification reaction, the organic solvent may be a conventional organic solvent in the art, preferably a halogenated alkane solvent, a nitrile solvent or an ether solvent, preferably a halogenated alkane solvent. The halogenated alkane solvent is preferably dichloromethane or chloroform. The nitrile solvent is preferably acetonitrile. The ether solvent is preferably tetrahydrofuran or 1,4-dioxane.

[0051] In the etherification reaction, the mass volume ratio of the compound 8 to the organic solvent may be a conventional mass volume ratio in the art, preferably 0.05-0.15 g / mL, more preferably 0.08-0.12 g / mL, such as 0.1 g / mL.

[0052] In the etherification reaction, the molar ratio of the p-toluenesulfonic acid to the compound 8 is preferably (0.1-0.5):1, more preferably (0.1-0.3):1, for example 0.2:1.

[0053] In the etherification reaction, the molar ratio of the compound 9 to the compound 8 is preferably (1-2):1, more preferably (1-1.2):1, for example 1.05:1.

[0054] In the etherification reaction, the reaction temperature of the etherification reaction can be a conventional temperature for such reactions in the art, preferably 25-65°C, more preferably 45°C.

[0055] In the preparation method of the compound 10, the reaction time of the etherification reaction can be monitored by conventional means in the art (such as TLC, HPLC or LC-MS), and the reaction time of the etherification reaction is preferably 8-24 hours, more preferably overnight.

[0056] In the preparation method of the compound 10, preferably, after the etherification reaction is completed, it can further include a post-treatment operation, and the post-treatment operation includes the following steps: cooling the reaction solution to room temperature, adding a saturated sodium bicarbonate aqueous solution to quench, adjusting the pH to neutral (for example, pH 7), separating the liquids, washing the organic phase with saturated brine, drying, filtering, and spin-drying, slurrying the crude product with a mixed solution (the mixed solution is preferably 2-methyltetrahydrofuran and n-heptane, and the slurrying temperature is preferably 50°C), cooling, and filtering.

[0057] In the preparation method of the compound 10, the preparation method of the compound 8 is conventional in the art, and the present invention is preferably prepared by referring to the method in the literature (Org. Biomol. Chem., 2018, 16, 8115-8129).

[0058] The present invention provides a method for preparing compound 17, which comprises the following steps: in an organic solvent, in the presence of a condensing agent, subjecting compound 15 and compound 16 to an esterification reaction as shown below, to obtain compound 17; the method for preparing compound 15 is as described in any of the previous schemes;

[0059]

[0060] In the esterification reaction, the organic solvent may be a conventional organic solvent in the art, preferably a halogenated alkane solvent, a nitrile solvent or an ether solvent, more preferably a halogenated alkane solvent. The halogenated alkane solvent is preferably dichloromethane or chloroform. The nitrile solvent is preferably acetonitrile. The ether solvent is preferably tetrahydrofuran or 1,4-dioxane.

[0061] In the esterification reaction, the mass volume ratio of the compound 15 to the organic solvent can be a conventional mass volume ratio in the art, preferably 0.05-0.15 g / mL, more preferably 0.08-0.12 g / mL, such as 0.1 g / mL.

[0062] In the esterification reaction, the condensing agent may be a conventional condensing agent in the art, preferably N,N′-dicyclohexylcarbodiimide or N,N′-diisopropylcarbodiimide.

[0063] In the esterification reaction, the molar ratio of the condensing agent to the compound 15 is preferably (1-2):1, more preferably 1.5:1.

[0064] In the esterification reaction, the molar ratio of the compound 16 to the compound 15 is preferably (1-2):1, more preferably 1.5:1.

[0065] In the preparation method of the compound 17, the reaction temperature of the esterification reaction can be a conventional temperature in the art, preferably 10-50° C., more preferably room temperature.

[0066] In the preparation method of the compound 17, the reaction time of the esterification reaction can be monitored by conventional means in the art (such as TLC, HPLC or LC-MS), and the reaction time of the esterification reaction is preferably 10-15 h, more preferably 13 h.

[0067] In the preparation method of the compound 17, preferably, after the esterification reaction is completed, it can further include a post-treatment operation, and the post-treatment operation includes the following steps: adding water to the reaction solution, drying the organic phase, filtering and spin-drying, and passing the crude product through a column.

[0068] The present invention provides a method for preparing compound 17, comprising the following steps: in an organic solvent, in the presence of a condensing agent, subjecting compound 15 and compound 16 to an esterification reaction as shown below, to obtain compound 17;

[0069]

[0070] The conditions and operation of the esterification reaction are the same as those of the aforementioned esterification reaction.

[0071] The present invention provides a method for preparing compound 5, which comprises the following steps: in an organic solvent, in the presence of a base, subjecting compound 4 or a salt of compound 4 to an amidation reaction with benzyl chloroformate as shown below, to obtain compound 5;

[0072]

[0073] In the amidation reaction, the organic solvent may be a conventional organic solvent in the art, preferably a halogenated alkane solvent, a nitrile solvent or an ether solvent, more preferably an ether solvent. The halogenated alkane solvent is preferably dichloromethane or chloroform. The nitrile solvent is preferably acetonitrile. The ether solvent is preferably tetrahydrofuran or 1,4-dioxane.

[0074] In the amidation reaction, the mass volume ratio of the compound 4 or the salt of the compound 4 to the organic solvent may be a conventional mass volume ratio in the art, preferably 0.01-0.1 g / mL, more preferably 0.03-0.05 g / mL.

[0075] In the amidation reaction, the base is preferably an alkali metal hydroxide, more preferably lithium hydroxide, potassium hydroxide or sodium hydroxide, such as a 2.5 M sodium hydroxide aqueous solution.

[0076] In the amidation reaction, the molar ratio of the base to the compound 4 or the salt of the compound 4 is preferably (1-3):1, more preferably (1-1.5):1, for example 1.2:1.

[0077] In the amidation reaction, the molar ratio of the benzyl chloroformate to the compound 4 or the salt of the compound 4 is preferably (1-1.5):1, for example 1.1:1.

[0078] In the preparation method of the compound 5, the reaction temperature of the amidation reaction can be a conventional temperature in the art, preferably 0-40° C., more preferably room temperature.

[0079] In the preparation method of the compound 5, the reaction time of the amidation reaction can be monitored by conventional means in the art (such as TLC, HPLC or LC-MS), and the reaction time of the amidation reaction is preferably 8-24 h, more preferably overnight.

[0080] In the preparation method of the compound 5, the salt of the compound 4 can be a salt formed by the compound 4 and an acid. The acid can be an inorganic acid or an organic acid conventional in the art. The inorganic acid can be hydrochloric acid, sulfuric acid or phosphoric acid, preferably hydrochloric acid. The organic acid can be trifluoroacetic acid.

[0081] In the preparation method of the compound 5, preferably, after the amidation reaction is completed, it can further include a post-treatment operation, and the post-treatment operation includes the following steps: spinning off a large amount of solvent, extracting with an organic solvent (preferably methyl tert-butyl ether), discarding the organic phase, adjusting the pH of the aqueous phase to acidic (for example, pH 2-3) with concentrated hydrochloric acid, extracting with an organic solvent (preferably methyl tert-butyl ether), combining the organic phases, washing with saturated brine, drying, filtering, and spinning dry.

[0082] In a certain embodiment of the present invention, the organic solvent is tetrahydrofuran; the mass volume ratio of the compound 4 to the organic solvent is 0.03-0.05 g / mL; the base is a 2.5 M sodium hydroxide aqueous solution; the molar ratio of the base to the compound 4 is 1.2:1; the molar ratio of the benzyl chloroformate to the compound 4 is 1.1:1; the reaction temperature of the amidation reaction is room temperature; the salt of the compound 4 is a salt formed by the compound 4 and trifluoroacetic acid.

[0083] In the preparation method of the compound 5, when the salt of the compound 4 is used for the amidation reaction, the salt of the compound 4 can be freed to the compound 4 by a conventional method in the art and then participate in the reaction. The freeing of the salt of the compound 4 may include the following steps: freeing the salt of the compound 4 in an organic solvent in the presence of a base to obtain the compound 4;

[0084]

[0085] In the free salt of the compound 4, the base can be a conventional base for such reactions in the art, for example, an alkali metal carbonate, an alkali metal bicarbonate or an alkali metal hydroxide, such as sodium carbonate, sodium bicarbonate or sodium hydroxide, and another example is a 2.5M sodium hydroxide aqueous solution. The amount of the base is generally such that the pH value in the reaction solution is adjusted to neutral.

[0086] In the free salt of the compound 4, the organic solvent may be a conventional solvent for such reactions in the art, preferably a halogenated alkane solvent, a nitrile solvent or an ether solvent, preferably an ether solvent. The halogenated alkane solvent is preferably dichloromethane or chloroform. The nitrile solvent is preferably acetonitrile. The ether solvent is preferably tetrahydrofuran or 1,4-dioxane.

[0087] In the release of the salt of compound 4, the mass volume ratio of the salt of compound 4 to the organic solvent can be a conventional mass volume ratio in the art, preferably 0.01-0.1 g / mL, more preferably 0.03-0.05 g / mL.

[0088] The preparation method of the compound 5 may further include a purification operation, wherein the purification operation includes the following steps: (1) using methanol as a solvent, in the presence of thionyl chloride, subjecting the compound 5 to an esterification reaction as shown below to obtain a compound 6;

[0089]

[0090] (2) In an organic solvent, in the presence of a base, subjecting the compound 6 to a hydrolysis reaction as shown below to obtain a compound 5;

[0091]

[0092] The operation and conditions of step (1) and step (2) may be conventional operations and conditions of esterification reaction and hydrolysis reaction in the art. The present invention is preferably as follows:

[0093] In the esterification reaction, the mass volume ratio of the compound 5 to the methanol is preferably 0.05-0.15 g / mL, more preferably 0.08-0.12 g / mL, such as 0.1 g / mL.

[0094] In the esterification reaction, the molar ratio of the thionyl chloride to the compound 5 is preferably (1-5):1, more preferably (1-3):1, for example 2.25:1.

[0095] In the esterification reaction, the reaction temperature of the esterification reaction is preferably 0-40° C., more preferably room temperature.

[0096] In the esterification reaction, the reaction time of the esterification reaction can be monitored by conventional means in the art (such as TLC, HPLC or LC-MS), and the reaction time of the esterification reaction is preferably 0.5-2 h, more preferably 1 h.

[0097] In the hydrolysis reaction, the organic solvent is preferably an alcohol solvent or an ether solvent. The alcohol solvent is preferably methanol, ethanol or isopropanol. The ether solvent is preferably tetrahydrofuran or 1,4-dioxane.

[0098] In the hydrolysis reaction, the mass volume ratio of the compound 6 to the organic solvent is preferably 0.05-0.25 g / mL, more preferably 0.1-0.25 g / mL, such as 0.2 g / mL.

[0099] In the hydrolysis reaction, the base is preferably an alkali metal hydroxide, such as lithium hydroxide, potassium hydroxide or sodium hydroxide, and for example a 2M sodium hydroxide aqueous solution.

[0100] In the hydrolysis reaction, the molar ratio of the base to the compound 6 is preferably (1-5):1, more preferably (2-4):1, for example 3:1.

[0101] In the hydrolysis reaction, the reaction temperature of the hydrolysis reaction is preferably 0-40° C., more preferably room temperature.

[0102] In the hydrolysis reaction, the reaction time of the hydrolysis reaction can be monitored by conventional means in the art (such as TLC, HPLC or LC-MS), and the reaction time of the hydrolysis reaction is preferably 8-24 hours, more preferably overnight.

[0103] In the preparation method of the compound 5, the preparation method of the salt of the compound 4 may include the following steps: in an organic solvent, in the presence of an acid, subjecting the compound 3 to a de-Boc reaction as shown below, to obtain the salt of the compound 4;

[0104]

[0105] Wherein, the salt of compound 4 is as described above.

[0106] In the method for preparing the salt of compound 4, the operation and conditions of the de-Boc reaction can be conventional operations and conditions of the de-Boc reaction in the art. The present invention is preferably as follows:

[0107] In the de-Boc reaction, the organic solvent may be a conventional solvent for such reactions in the art, preferably a halogenated alkane solvent, an ester solvent or an ether solvent, more preferably a halogenated alkane solvent. The halogenated alkane solvent is preferably dichloromethane or chloroform. The ester solvent is preferably ethyl acetate. The ether solvent is preferably tetrahydrofuran or 1,4-dioxane.

[0108] In the de-Boc reaction, the mass volume ratio of the compound 3 to the organic solvent is preferably 0.05-0.25 g / mL, more preferably 0.1-0.25 g / mL, such as 0.2 g / mL.

[0109] In the de-Boc reaction, the acid may be an inorganic acid or an organic acid. The inorganic acid is preferably hydrochloric acid, sulfuric acid or phosphoric acid, preferably hydrochloric acid. The organic acid is preferably trifluoroacetic acid.

[0110] In the de-Boc reaction, when the acid is trifluoroacetic acid, the volume ratio of the trifluoroacetic acid to the organic solvent is preferably (1-5):1, more preferably (1-3):1, for example 1:1.

[0111] In the method for preparing the salt of compound 4, the reaction temperature of the de-Boc reaction is preferably 0-40° C., more preferably room temperature.

[0112] In the method for preparing the salt of compound 4, the reaction time of the de-Boc reaction can be monitored by conventional means in the art (such as TLC, HPLC or LC-MS), and the reaction time of the de-Boc reaction is preferably 8-24 h, more preferably overnight.

[0113] In the method for preparing the salt of the compound 4, the method for preparing the compound 3 may include the following steps: in an organic solvent, in the presence of a base, subjecting the compound 2 and tert-butyl acrylate to an addition reaction as shown below, to obtain the compound 3;

[0114]

[0115] In the addition reaction, the organic solvent may be a conventional solvent for such reactions in the art, preferably a sulfoxide solvent, a nitrile solvent or an ether solvent, more preferably a sulfoxide solvent. The sulfoxide solvent is preferably dimethyl sulfoxide. The nitrile solvent is preferably acetonitrile. The ether solvent is preferably tetrahydrofuran or 1,4-dioxane.

[0116] In the addition reaction, the mass volume of the compound 2 and the organic solvent is preferably 0.05-0.25 g / mL, more preferably 0.1-0.25 g / mL, such as 0.2 g / mL.

[0117] In the addition reaction, the base is preferably an alkali metal hydroxide, such as lithium hydroxide, potassium hydroxide or sodium hydroxide, and another example is a 2.5 M sodium hydroxide aqueous solution.

[0118] In the addition reaction, the molar ratio of the base to the compound 2 is preferably (1-5):1, more preferably (2-3):1.

[0119] In the addition reaction, the molar ratio of the tert-butyl acrylate to the compound 2 is preferably (2-3):1, more preferably 2.2:1.

[0120] In the method for preparing compound 3, the reaction temperature of the addition reaction is preferably 0-40° C., more preferably room temperature.

[0121] In the preparation method of the compound 3, the reaction time of the addition reaction can be monitored by conventional means in the art (such as TLC, HPLC or LC-MS), and the reaction time of the addition reaction is preferably 8-24 hours, more preferably overnight.

[0122] In the method for preparing the salt of the compound 3, the method for preparing the compound 2 may include the following steps: in an organic solvent, subjecting the compound 1 and di-tert-butyl dicarbonate to an amidation reaction as shown below, to obtain the compound 2;

[0123]

[0124] In the preparation method of the compound 2, the operation and conditions of the amidation reaction can be conventional operations and conditions of amidation reactions in the art. The present invention is preferably as follows:

[0125] In the amidation reaction, the organic solvent is preferably an alcohol solvent or an ether solvent. The alcohol solvent is preferably methanol, ethanol or isopropanol. The ether solvent is preferably tetrahydrofuran or 1,4-dioxane.

[0126] In the amidation reaction, the mass volume ratio of the compound 1 to the organic solvent is preferably 0.05-0.25 g / mL, more preferably 0.1-0.25 g / mL, such as 0.23 g / mL.

[0127] In the amidation reaction, the molar ratio of the di-tert-butyl dicarbonate to the compound 1 is preferably (1-3):1, more preferably 1:1.

[0128] In the preparation method of the compound 2, the reaction temperature of the amidation reaction is preferably 0-40° C., more preferably room temperature.

[0129] In the preparation method of the compound 2, the reaction time of the amidation reaction can be monitored by conventional means in the art (such as TLC, HPLC or LC-MS), and the reaction time of the amidation reaction is preferably 1-3 h, more preferably 2 h.

[0130] The present invention also provides a method for purifying compound 5, which comprises the following steps: (1) using methanol as a solvent, in the presence of thionyl chloride, subjecting the crude compound 5 to an esterification reaction as shown below to obtain compound 6;

[0131]

[0132] (2) In an organic solvent, in the presence of a base, subjecting the compound 6 to a hydrolysis reaction as shown below to obtain a compound 5;

[0133]

[0134] The conditions and operations of the esterification reaction and the hydrolysis reaction are the same as those of the aforementioned esterification reaction and the hydrolysis reaction.

[0135] In some embodiments, the crude compound 5 can be prepared by the aforementioned method for preparing compound 5. The purity of the crude compound 5 can be 70-90%, preferably 83%.

[0136] In the present invention, the synthetic route of compound 17 is as follows:

[0137]

[0138]

[0139] The conditions and operations of any reaction in the synthetic route are the same as those of the aforementioned reaction.

[0140] In the present invention, the synthetic route of compound 5 is as follows:

[0141]

[0142] The conditions and operations of any reaction in the synthetic route are the same as those of the aforementioned reaction.

[0143] The present invention also provides the following compounds:

[0144] In the present invention, the room temperature refers to 20-30°C.

[0145] In the present invention, overnight refers to 10-12 hours.

[0146] On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0147] The reagents and raw materials used in the present invention are commercially available.

[0148] The positive and progressive effects of the present invention are: providing a synthetic route of compound 17 with a high yield. The preparation method of compound 17 has mild reaction conditions, is easy to operate, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0149] Figure 1 is the hydrogen spectrum of compound 2.

[0150] Figure 2 is the hydrogen spectrum of compound 3.

[0151] Figure 3 is the hydrogen spectrum of compound 5.

[0152] Figure 4 is the hydrogen spectrum of compound 6.

[0153] Figure 5 is the hydrogen spectrum of compound 5 after purification.

[0154] Figure 6 is the hydrogen spectrum of compound 8.

[0155] Figure 7 is the hydrogen spectrum of compound 10.

[0156] Figure 8 is the hydrogen spectrum of compound 11.

[0157] Fig. 9 is the hydrogen spectrum of compound 12.

[0158] Fig.10 is the hydrogen spectrum of compound 13.

[0159] Fig.11 is the hydrogen spectrum of compound 15.

[0160] Fig.12 is the hydrogen spectrum of compound 17. DETAILED DESCRIPTION

[0161] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0162] Example 1. Synthesis of Compound 5

[0163]

[0164] Compound 1 (100.0 g, 1.098 mol) was dissolved in methanol (220 mL), cooled in an ice bath, and a solution of di-tert-butyl dicarbonate (241.94 g, 1.109 mol) in methanol (220 mL) was slowly added dropwise. The temperature was controlled below 20°C during the addition. After the addition was completed, the mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC to be complete. The methanol was dried to obtain a white solid, which was recrystallized by adding ethyl acetate (400 mL). The filter cake was obtained by filtration. The mother liquor was dried and then recrystallized by using ethyl acetate (260 mL). The filter cakes were combined and dried to obtain 176.33 g of a white solid. The yield of compound 2 was 84.01%. The hydrogen spectrum of compound 2 is shown in Figure 1 shown.

[0165] 2. Synthesis of Compound 3

[0166]

[0167] Compound 2 (30 g, 0.1569 mol) was dissolved in DMSO (150 mL), and NaOH aqueous solution (2.5 M, 125.5 mL, 0.3137 mol) was added. Tert-butyl acrylate (44.24 g, 0.3451 mol) was added under ice bath, and stirred for 3 h and then stirred at room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride solution to make pH = 8-9. Ethyl acetate (200 mL) was added and the liquids were separated by oscillation. The aqueous phase was extracted with ethyl acetate (100 mL × 2), the organic phases were combined, washed once with saturated brine, dried with sodium sulfate, filtered, and spin-dried. 19.35 g of colorless oily liquid was obtained by column chromatography with PE-PE: EA = 8:1 (V / V), and the yield of compound 3 was 27.56%. The hydrogen spectrum of compound 3 is as follows Figure 2 shown.

[0168] 3. Synthesis of Compound 5

[0169]

[0170] Compound 3 (85.77 g, 0.1916 mol) was dissolved in dichloromethane (429 mL), trifluoroacetic acid (429 mL) was added, and the mixture was stirred at room temperature overnight. The reaction was monitored by HPLC, and the mixture was dried by spin drying. Dichloromethane (200 mL) was added and the mixture was dried by spin drying. The reaction was repeated three times to remove a large amount of trifluoroacetic acid, and the trifluoroacetate salt of compound 4 was obtained, which was used for the next step without purification.

[0171] The above product was dissolved in tetrahydrofuran (958mL), and the pH was adjusted to neutral with NaOH aqueous solution (2.5M), and then NaOH aqueous solution (2.5M, 91.98mL, 0.2300mol) was added, and benzyl chloroformate (35.96g, 0.2108mol) was added, and stirred at room temperature overnight. The reaction solution was adjusted to pH=5 with 5wt% acetic acid aqueous solution and then subjected to HPLC. The reaction was complete. After removing a large amount of solvent, it was extracted with methyl tert-butyl ether (277mL×3), and the organic phase was discarded. The aqueous phase was adjusted to pH 2-3 with concentrated hydrochloric acid, and extracted with methyl tert-butyl ether (277mL×3). The organic phases were combined and washed once with saturated brine (300mL). Drying with anhydrous sodium sulfate, filtering, and spin-drying to obtain 59.86g of colorless oily liquid, the two-step yield was 84.56%, and the purity of compound 5 was 83.14%. The hydrogen spectrum of compound 5 is as follows Figure 3 shown.

[0172] 4. Purification of Compound 5

[0173]

[0174] Compound 5 (59.86 g, 0.16 mol) was dissolved in methanol (600 mL), and thionyl chloride (42.4 g, 0.36 mol) was added dropwise under an ice bath so that the temperature did not exceed 20°C. After the addition was complete, the mixture was returned to room temperature and stirred for 1 hour. The reaction was monitored by HPLC to be complete. The reaction solution was neutralized to neutrality with a saturated aqueous solution of sodium bicarbonate and solid sodium bicarbonate. It was extracted with ethyl acetate (500 mL × 3), the organic phases were combined, washed once with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered and dried, and passed through a column with PE:EA=5:2 (V / V) to obtain 46.9 g of a colorless oil. The yield of compound 6 was 72.8%, and the purity was 95.32%. The hydrogen spectrum of compound 6 is as follows Figure 4 shown.

[0175]

[0176] Compound 6 (46.8 g, 0.118 mol) was dissolved in methanol (235 mL) and NaOH aqueous solution (2 M, 176.8 mL, 0.354 mol) was added under ice bath. The mixture was stirred at room temperature overnight. The reaction was monitored by HPLC to be complete. The methanol was dried by spin-drying, water (250 mL) was added, and the mixture was extracted with methyl tert-butyl ether (250 mL×3). The organic phase was discarded, the pH of the aqueous phase was adjusted to 1-2 with concentrated hydrochloric acid, and the mixture was extracted with methyl tert-butyl ether (300 mL×3). The organic phase was synthesized and washed once with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered and dried, and 43.85 g of a colorless oily liquid was obtained by drying. The yield of compound 5 was 100.8%, and the purity was 97.4%. The hydrogen spectrum of compound 5 after purification was as follows: Figure 5 shown.

[0177] Example 2: Synthesis of Compound 17

[0178]

[0179]

[0180] 1. Synthesis of Compound 8

[0181]

[0182] Dissolve compound 7 (250g, 1.16mol) in pyridine (1.1kg, 13.92mol), and add acetic anhydride (1.073kg, 10.44mol) dropwise in an ice bath. Stir at 0-5°C for 2h after the addition is complete, then stir at room temperature overnight. HPLC monitors the reaction to be complete. Slowly pour the reaction solution into 2.5kg of ice to quench, and control the temperature not to exceed 2°C. After quenching, stir in an ice bath for 1h. Filter, wash the filter cake with water 5 times, and then dry to obtain 288.27g of white solid. The yield of compound 8 is 63.9%, and the purity is 97.17%. The hydrogen spectrum of compound 8 is as follows Figure 6 shown.

[0183] 2. Synthesis of Compound 10

[0184]

[0185] Compound 8 (100.0 g, 0.2568 mol) and compound 9 (67.78 g, 0.2697 mol) were dissolved in dichloromethane (1 L), p-toluenesulfonic acid (8.89 g, 0.0516 mol) was added, and the mixture was heated at 45°C overnight. The reaction was monitored by HPLC to be complete. The mixture was cooled to room temperature and quenched by adding saturated aqueous sodium bicarbonate solution (340 mL), pH = 7. The organic phase was separated, and the organic phase was washed once with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered and spin-dried to obtain 170.7 g of a white solid. A mixed solution of 2-methyltetrahydrofuran (200 mL) and n-heptane (300 mL) was slurried at 50°C overnight. The mixture was cooled and filtered to obtain 107.2 g of a white solid. The yield of compound 10 was 71.9% and the purity was 96.59%. The hydrogen spectrum of compound 10 is as follows: Figure 7 shown.

[0186] 3. Synthesis of Compound 11

[0187]

[0188] Compound 10 (180.6 g, 0.3110 mol) was dissolved in methanol (1.8 L), palladium carbon (10 wt%, 18.0 g) was added to replace the hydrogen atmosphere, and stirred at room temperature for 2 h. The reaction was complete under TLC monitoring, filtered through diatomaceous earth, and the filtrate was dried to obtain 137.35 g of white solid. The yield of compound 11 was 98.9% and the purity was 95.1%. The hydrogen spectrum of compound 11 is as follows Figure 8 shown.

[0189] 3. Synthesis of Compound 12

[0190]

[0191] Compound 5 (43.77 g, 0.1185 mol) and compound 11 (116.40 g, 0.2607 mol) were dissolved in dichloromethane (1.4 L) and stirred in an ice bath. HOBT (35.23 g, 0.2607 mol), EDCI·HCl (90.87 g, 0.4740 mol), and DIPEA (47.48 g, 0.3677 mol) were added in sequence and stirred overnight at room temperature. HPLC monitored the reaction to be complete. After removing a large amount of solvent, ethyl acetate (1 L) was added to the solvent and then saturated sodium bicarbonate was added to wash twice, 500 mL each time, and then washed once with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered and dried. DCM:MeOH = 100:1-25:1-15:1 was used to pass through the column to obtain 111.6 g of white solid. The yield of compound 12 was 76.8% and the purity was 97.233%. The hydrogen spectrum of compound 12 is as follows Fig. 9 shown.

[0192] 4. Synthesis of Compound 13

[0193]

[0194] Compound 12 (57.15 g, 0.0466 mol) was dissolved in methanol (571 mL), palladium carbon (10 wt%, 11.43 g) was added to replace the hydrogen atmosphere, and stirred at room temperature overnight. The reaction was complete under TLC monitoring, and the filtrate was filtered through diatomaceous earth and dried to obtain 49.83 g of white solid. The yield of compound 13 was 97.9% and the purity was 96.524%. The hydrogen spectrum of compound 13 is as follows Fig.10 shown.

[0195] 5. Synthesis of Compound 15

[0196]

[0197] Compound 13 (18.35 g, 16.8 mmol) and compound 14 (2.11 g, 18.48 mmol) were dissolved in DCM (200 mL), and DIPEA (2.17 g, 16.8 mmol) was added. The mixture was stirred at room temperature for 4 h. The reaction was completed after TLC monitoring. The mixture was washed with saturated brine (100 mL×3), dried over anhydrous sodium sulfate, filtered and dried to obtain 20.47 g of a white solid. The yield of compound 15 was 100.98% and the purity was 97.34%. The hydrogen spectrum of compound 15 is shown in FIG. Fig.11 shown.

[0198] 6. Synthesis of Compound 17

[0199]

[0200] Compound 15 (14.85 g, 12.31 mmol) and compound 16 (3.40 g, 18.47 mmol) were dissolved in DCM (148.5 mL), N, N′-dicyclohexylcarbodiimide (3.81 g, 18.47 mmol) was added, and the mixture was stirred at room temperature for 13 h. The reaction was basically completed by HPLC monitoring, and the mixture was washed once with water (200 mL), dried over anhydrous sodium sulfate, filtered and dried, and 100-200 mesh silica gel was used as the stationary phase, and dichloromethane:acetone = 5:3-1:4-1:6 was used as the mobile phase to pass through the column to obtain 11.69 g of a white solid. The yield of compound 17 was 69.2%, and the purity was 95.65%. The hydrogen spectrum data of compound 17 are shown as follows: Fig.12 The hydrogen spectrum data are as follows: 1 H NMR (400MHz, DMSO) δ7.80(dd,J=15.5,8.7Hz,5H),5.22(d,J=3.3Hz,2H),4.97(dd,J=11.2,3.3Hz,2H),4.49(d,J=8 .5Hz,2H),4.10–3.93(m,7H),3.87(dd,J=19.9,8.9Hz,2H),3.70(dt,J=9.8,6.1Hz,2H),3.58(t,J=6.4Hz,4H),3.4 5-3.35(m,3H),3.02(dd,J=12.8,6.5Hz,4H),2.80(t,J=7.4Hz,2H),2.29(t,J=6.4Hz,4H),2.22(t,J=7.3Hz,2H),2 .11(s,6H),2.00(s,6H),1.95–1.82(m,8H),1.77(s,6H),1.50–1.32(m,9H),1.25(d,J=3.8Hz,10H).LCMSm / z[M+H] + :1373.50.

Claims

1. A method for preparing compound 15, characterized in that: The method comprises the following steps: in an organic solvent, in the presence of a base, subjecting compound 13 and compound 14 to an amidation reaction as shown below, to obtain compound 15; 2. The method for preparing compound 15 according to claim 1, characterized in that: The amidation reaction satisfies one or more of the following conditions: (1) The organic solvent is a halogenated alkane solvent or an ether solvent; the halogenated alkane solvent is preferably dichloromethane or chloroform; the ether solvent is preferably tetrahydrofuran or 1,4-dioxane; (2) The mass volume ratio of the compound 13 to the organic solvent is 0.05-0.15 g / mL, preferably 0.07-0.12 g / mL, for example 0.09 g / mL; (3) The base is an organic base, preferably triethylamine or N,N-diisopropylethylamine; (4) The molar ratio of the base to the compound 13 is (1-3):1, preferably (1-1.5):1, for example 1:1; (5) The molar ratio of the compound 14 to the compound 13 is (1-2):1, preferably (1-1.5):1, for example 1.1:1; (6) The reaction temperature of the amidation reaction is 10-50°C, preferably room temperature.

3. The method for preparing compound 15 according to claim 1, characterized in that: The preparation method of the compound 13 comprises the following steps: in an organic solvent, in the presence of a metal catalyst, subjecting the compound 12 to a deprotection reaction with hydrogen as shown below, to obtain the compound 13; 4. The method for preparing compound 15 according to claim 3, characterized in that: In the preparation method of the compound 13, the deprotection reaction satisfies one or more of the following conditions: (1) The organic solvent is an alcohol solvent or an ether solvent; the alcohol solvent is preferably methanol, ethanol or isopropanol; the ether solvent is preferably tetrahydrofuran or 1,4-dioxane; (2) The mass volume ratio of the compound 12 to the organic solvent is 0.05-0.15 g / mL, preferably 0.08-0.12 g / mL, for example 0.1 g / mL; (3) The metal catalyst is Pd / C, Pd(OH)2, Raney nickel, Pt / C or PtO2; (4) The mass ratio of the metal catalyst to the compound 12 is (0.1-0.5):1, preferably (0.1-0.3):1, for example 0.2:1; (5) The reaction temperature of the deprotection reaction is 10-50°C, preferably room temperature.

5. The method for preparing compound 15 according to claim 3, characterized in that: The preparation method of the compound 12 comprises the following steps: in an organic solvent, in the presence of a condensing agent and a base, subjecting the compound 11 and the compound 5 to a condensation reaction as shown below, to obtain the compound 12; 6. The method for preparing compound 15 according to claim 5, characterized in that: In the preparation method of the compound 12, the condensation reaction satisfies one or more of the following conditions: (1) The organic solvent is a halogenated alkane solvent, a nitrile solvent, an amide solvent or an ether solvent; the halogenated alkane solvent is preferably dichloromethane or chloroform; the nitrile solvent is preferably acetonitrile; the amide solvent is preferably N,N-dimethylformamide or N,N-dimethylacetamide; the ether solvent is preferably tetrahydrofuran or 1,4-dioxane; (2) The mass volume ratio of the compound 5 to the organic solvent is 0.01-0.05 g / mL, preferably 0.03 g / mL; (3) The condensing agent is HATU, HBTU, or HOBT and EDCI·HCl; (4) The molar ratio of the condensing agent to the compound 5 is (1-10):1, preferably 6.2:1; when the condensing agent is HOBT and EDCI·HCl, the molar ratio of HOBT to the compound 5 is preferably (1-3):1, for example 2.2:1; when the condensing agent is HOBT and EDCI·HCl, the molar ratio of EDCI·HCl to the compound 5 is preferably (2-6):1, for example 4:1; (5) The base is an organic base, preferably triethylamine or N,N-diisopropylethylamine; (6) The molar ratio of the base to the compound 5 is (1-5):1, preferably (2-4):1, for example 3.1:1; (7) The molar ratio of the compound 11 to the compound 5 is (2-3):1, preferably 2.2:1; (8) The reaction temperature of the condensation reaction is 10-50°C, preferably room temperature.

7. The method for preparing compound 15 according to claim 5, characterized in that: The preparation method of the compound 11 comprises the following steps: in an organic solvent, in the presence of a metal catalyst, subjecting the compound 10 to a deprotection reaction with hydrogen as shown below, to obtain the compound 11; Alternatively, the preparation method of the compound 5 comprises the following steps: in an organic solvent, in the presence of a base, subjecting the compound 4 or a salt of the compound 4 to an amidation reaction with benzyl chloroformate as shown below, to obtain the compound 5; 8. The method for preparing compound 15 according to claim 7, characterized in that: In the preparation method of the compound 11, the deprotection reaction satisfies one or more of the following conditions: (1) The organic solvent is an alcohol solvent or an ether solvent; the alcohol solvent is preferably methanol, ethanol or isopropanol; the ether solvent is preferably tetrahydrofuran or 1,4-dioxane; (2) The mass volume ratio of the compound 10 to the organic solvent is 0.05-0.15 g / mL, preferably 0.08-0.12 g / mL, for example 0.1 g / mL; (3) The metal catalyst is Pd / C, Pd(OH)2, Raney nickel, Pt / C or PtO2; (4) The mass ratio of the metal catalyst to the compound 10 is (0.1-0.5):1, preferably (0.1-0.3):1, for example 0.1:1; (5) The reaction temperature of the deprotection reaction is 10-50° C., preferably room temperature; or, In the preparation method of the compound 5, the amidation reaction satisfies one or more of the following conditions: (1) The organic solvent is a halogenated alkane solvent, a nitrile solvent or an ether solvent; the halogenated alkane solvent is preferably dichloromethane or chloroform; the nitrile solvent is preferably acetonitrile; the ether solvent is preferably tetrahydrofuran or 1,4-dioxane; (2) The mass volume ratio of the compound 4 or the salt of the compound 4 to the organic solvent is 0.01-0.1 g / mL, preferably 0.03-0.05 g / mL; (3) The base is an alkali metal hydroxide, preferably lithium hydroxide, potassium hydroxide or sodium hydroxide, such as a 2.5 M sodium hydroxide aqueous solution; (4) The molar ratio of the base to the compound 4 or the salt of the compound 4 is (1-3):1, preferably (1-1.5):1, for example 1.2:1; (5) The molar ratio of the benzyl chloroformate to the compound 4 or the salt of the compound 4 is (1-1.5):1, for example 1.1:1; (6) The reaction temperature of the amidation reaction is 0-40°C, preferably room temperature; (7) The salt of compound 4 is a salt formed by compound 4 and an acid; the acid is preferably an inorganic acid or an organic acid; the inorganic acid is preferably hydrochloric acid, sulfuric acid or phosphoric acid; the organic acid is preferably trifluoroacetic acid; Preferably, when the salt of the compound 4 is used to carry out the amidation reaction, the free salt of the compound 4 is then used to participate in the reaction; The release of the salt of compound 4 preferably comprises the following steps: in an organic solvent, in the presence of a base, releasing the salt of compound 4 to obtain compound 4; Further preferably, the free salt of compound 4 satisfies one or more of the following conditions: (1) The base is an alkali metal carbonate, an alkali metal bicarbonate or an alkali metal hydroxide, such as sodium carbonate, sodium bicarbonate or sodium hydroxide, and another example is a 2.5 M sodium hydroxide aqueous solution; (2) The organic solvent is a halogenated alkane solvent, a nitrile solvent or an ether solvent; the halogenated alkane solvent is preferably dichloromethane or chloroform; the nitrile solvent is preferably acetonitrile; the ether solvent is preferably tetrahydrofuran or 1,4-dioxane; (3) The mass volume ratio of the salt of compound 4 to the organic solvent is 0.01-0.1 g / mL, preferably 0.03-0.05 g / mL; Still more preferably, the preparation method of compound 5 further comprises a purification operation, and the purification operation comprises the following steps: (1) using methanol as solvent and in the presence of thionyl chloride, subjecting the compound 5 to an esterification reaction as shown below to obtain compound 6; (2) In an organic solvent, in the presence of a base, subjecting the compound 6 to a hydrolysis reaction as shown below to obtain a compound 5; Still more preferably, the purification operation satisfies one or more of the following conditions: (1) In the esterification reaction, the mass volume ratio of the compound 5 to the methanol is 0.05-0.15 g / mL, preferably 0.08-0.12 g / mL, for example 0.1 g / mL; (2) In the esterification reaction, the molar ratio of the thionyl chloride to the compound 5 is (1-5):1, preferably (1-3):1, for example 2.25:1; (3) The reaction temperature of the esterification reaction is 0-40°C, preferably room temperature; (4) In the hydrolysis reaction, the organic solvent is an alcohol solvent or an ether solvent; the alcohol solvent is preferably methanol, ethanol or isopropanol; the ether solvent is preferably tetrahydrofuran or 1,4-dioxane; (5) In the hydrolysis reaction, the mass volume ratio of the compound 6 to the organic solvent is 0.05-0.25 g / mL, preferably 0.1-0.25 g / mL, for example 0.2 g / mL; (6) In the hydrolysis reaction, the base is an alkali metal hydroxide, such as lithium hydroxide, potassium hydroxide or sodium hydroxide, and another example is a 2M sodium hydroxide aqueous solution; (7) In the hydrolysis reaction, the molar ratio of the base to the compound 6 is (1-5):1, preferably (2-4):1, for example 3:1; (8) In the hydrolysis reaction, the reaction temperature of the hydrolysis reaction is 0-40°C, preferably room temperature.

9. The method for preparing compound 15 according to claim 7, characterized in that: The preparation method of the compound 10 comprises the following steps: in an organic solvent, in the presence of p-toluenesulfonic acid, subjecting the compound 8 and the compound 9 to an etherification reaction as shown below, to obtain the compound 10; Alternatively, the method for preparing the salt of the compound 4 comprises the following steps: in an organic solvent, in the presence of an acid, subjecting the compound 3 to a de-Boc reaction as shown below, to obtain the salt of the compound 4; 10. The method for preparing compound 15 according to claim 9, characterized in that: In the preparation method of the compound 10, the etherification reaction satisfies one or more of the following conditions: (1) The organic solvent is a halogenated alkane solvent, a nitrile solvent or an ether solvent; the halogenated alkane solvent is preferably dichloromethane or chloroform; the nitrile solvent is preferably acetonitrile; the ether solvent is preferably tetrahydrofuran or 1,4-dioxane; (2) The mass volume ratio of the compound 8 to the organic solvent is 0.05-0.15 g / mL, preferably 0.08-0.12 g / mL, for example 0.1 g / mL; (3) The molar ratio of p-toluenesulfonic acid to compound 8 is (0.1-0.5):1, preferably (0.1-0.3):1, for example 0.2:1; (4) The molar ratio of the compound 9 to the compound 8 is (1-2):1, preferably (1-1.2):1, for example 1.05:1; (5) The reaction temperature of the etherification reaction is 25-65° C., preferably 45° C.; or, In the method for preparing the salt of compound 4, the de-Boc reaction satisfies one or more of the following conditions: (1) The organic solvent is a halogenated alkane solvent, an ester solvent or an ether solvent; the halogenated alkane solvent is preferably dichloromethane or chloroform; the ester solvent is preferably ethyl acetate; the ether solvent is preferably tetrahydrofuran or 1,4-dioxane; (2) The mass volume ratio of the compound 3 to the organic solvent is 0.05-0.25 g / mL, preferably 0.1-0.25 g / mL, for example 0.2 g / mL; (3) The acid is an inorganic acid or an organic acid; the inorganic acid is preferably hydrochloric acid, sulfuric acid or phosphoric acid; the organic acid is preferably trifluoroacetic acid; (4) When the acid is trifluoroacetic acid, the volume ratio of the trifluoroacetic acid to the organic solvent is (1-5):1, preferably (1-3):1, for example 1:1; (5) The reaction temperature of the de-Boc reaction is 0-40°C; preferably room temperature; Preferably, the preparation method of the salt of the compound 3 comprises the following steps: in an organic solvent, in the presence of a base, subjecting the compound 2 and tert-butyl acrylate to an addition reaction as shown below, to obtain the compound 3; Further preferably, in the method for preparing the salt of compound 3, the addition reaction satisfies one or more of the following conditions: (1) The organic solvent is a sulfoxide solvent, a nitrile solvent or an ether solvent; the sulfoxide solvent is preferably dimethyl sulfoxide; the nitrile solvent is preferably acetonitrile; the ether solvent is preferably tetrahydrofuran or 1,4-dioxane; (2) The mass volume of the compound 2 and the organic solvent is 0.05-0.25 g / mL, preferably 0.1-0.25 g / mL, for example 0.2 g / mL; (3) The base is an alkali metal hydroxide, such as lithium hydroxide, potassium hydroxide or sodium hydroxide, and another example is a 2.5 M sodium hydroxide aqueous solution; (4) The molar ratio of the base to the compound 2 is (1-5):1, preferably (2-3):1; (5) The molar ratio of the tert-butyl acrylate to the compound 2 is (2-3):1, preferably 2.2:1; (6) The reaction temperature of the addition reaction is 0-40°C, preferably room temperature; Still further preferably, the method for preparing the salt of the compound 2 comprises the following steps: in an organic solvent, subjecting the compound 1 and di-tert-butyl dicarbonate to an amidation reaction as shown below, to obtain the compound 2; Still further preferably, in the method for preparing the salt of compound 2, the amidation reaction satisfies one or more of the following conditions: (1) The organic solvent is an alcohol solvent or an ether solvent; the alcohol solvent is preferably methanol, ethanol or isopropanol; the ether solvent is preferably tetrahydrofuran or 1,4-dioxane; (2) The mass volume ratio of the compound 1 to the organic solvent is 0.05-0.25 g / mL, preferably 0.1-0.25 g / mL, for example 0.23 g / mL; (3) The molar ratio of di-tert-butyl dicarbonate to compound 1 is (1-3):1, preferably 1:1; (4) The reaction temperature of the amidation reaction is 0-40°C, preferably room temperature.

11. A method for preparing compound 17, characterized in that: The method comprises the following steps: in an organic solvent, in the presence of a condensing agent, subjecting compound 15 and compound 16 to an esterification reaction as shown below, to obtain compound 17; Wherein, the preparation method of compound 15 is as described in any one of claims 1-10.

12. The method for preparing compound 17 according to claim 11, characterized in that: The esterification reaction satisfies one or more of the following conditions: (1) The organic solvent is a halogenated alkane solvent, a nitrile solvent or an ether solvent; the halogenated alkane solvent is preferably dichloromethane or chloroform; the nitrile solvent is preferably acetonitrile; the ether solvent is preferably tetrahydrofuran or 1,4-dioxane; (2) The mass volume ratio of the compound 15 to the organic solvent is 0.05-0.15 g / mL, preferably 0.08-0.12 g / mL, for example 0.1 g / mL; (3) The condensing agent is N,N′-dicyclohexylcarbodiimide or N,N′-diisopropylcarbodiimide; (4) The molar ratio of the condensing agent to the compound 15 is (1-2):1, preferably 1.5:1; (5) The molar ratio of the compound 16 to the compound 15 is (1-2):1, preferably 1.5:1; (6) The reaction temperature of the esterification reaction is 10-50°C, preferably room temperature.

13. A method for preparing compound 5, characterized in that: The method comprises the following steps: in an organic solvent, in the presence of a base, subjecting compound 4 or a salt of compound 4 to an amidation reaction with benzyl chloroformate as shown below, to obtain compound 5; The conditions of the preparation method of compound 5 are the same as those described in any one of claims 7-10.

14. A method for purifying compound 5, characterized in that: The method comprises the following steps: (1) using methanol as a solvent, in the presence of thionyl chloride, subjecting the crude compound 5 to an esterification reaction as shown below to obtain a compound 6; (2) In an organic solvent, in the presence of a base, subjecting the compound 6 to a hydrolysis reaction as shown below to obtain a compound 5; The conditions and operations of the esterification reaction and the hydrolysis reaction are as described in claim 8.

15. A compound as shown below:

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