A process for the preparation of an inhibitor of LFA-1

Abstract

This application provides a method for preparing an LFA-1 inhibitor, specifically a compound of formula (IX) or a salt thereof, its uses, and an ophthalmic composition. The compound of formula (IX) or a salt thereof can be used as an LFA-1 inhibitor to treat ophthalmic diseases, such as dry eye syndrome.

Description

Technical Field

[0001] This application relates to the field of organic synthesis technology, and in particular to a compound of formula (IX) or a salt thereof and its uses, and ophthalmic compositions. Background Technology

[0002] Lymphocyte function-associated antigen-1 (LFA-1) (αLβ2, CD11a / CD18), a target receptor, is a member of the integrin superfamily, which currently has 24 known members. It is a receptor involved in inflammation, immune-mediated and infectious diseases, and is overexpressed in certain malignant diseases. These diseases are often serious chronic conditions requiring lifelong treatment, such as dry eye syndrome, which, if not properly diagnosed and treated, can lead to further complications such as infections, ocular surface keratinization, corneal ulcers, and conjunctival squamous metaplasia. From a clinical perspective, there remains a need for effective LFA-1 inhibitors to prevent symptoms or control disease. Summary of the Invention

[0003] The purpose of this application is to provide a compound of formula (IX) or a salt thereof and its uses, and an ophthalmic composition, wherein the compound of formula (IX) or a salt thereof is used as an LFA-1 inhibitor and can treat ophthalmic diseases such as dry eye syndrome.

[0004] The first aspect of this application provides a compound of formula (IX) or a salt thereof:

[0005]

[0006] In some embodiments of this application, the salt is a sodium, calcium, magnesium, or potassium salt of the compound shown in formula (IX), preferably a sodium salt of the compound shown in formula (IX), i.e., the compound shown in formula (I):

[0007]

[0008] A second aspect of this application provides the use of a compound of formula (IX) or a salt thereof as an LFA-1 inhibitor.

[0009] A third aspect of this application provides an ophthalmic composition comprising a compound of formula (IX) and a pharmaceutically acceptable salt. The ophthalmic composition may further comprise an aqueous carrier. The compound of formula (IX) or its salt exhibits high polarity, good water solubility, and LFA-1 inhibitory activity, resulting in an ophthalmic composition with good therapeutic effects on dry eye syndrome. Specifically, the pharmaceutically acceptable salt may be any salt known in the art for use in ophthalmic compositions, and this application does not limit its use. The aqueous carrier may be a sterile aqueous solution or other aqueous carriers known in the art, and this application does not limit its use. It is understood that the above ophthalmic composition may also include other essential components or additives known in the art, and this application does not limit their use.

[0010] A fourth aspect of this application provides a method for preparing the compound shown in formula (IX), comprising the following steps:

[0011] (1) The compound shown in formula (V) and the compound shown in formula (VI) undergo a condensation reaction to obtain the compound shown in formula (VII); or, (1'a) the compound shown in formula (II) and the compound shown in formula (VIII) undergo a coupling reaction to obtain the compound shown in formula (VII'), and (1'b) the compound shown in formula (VII') undergoes a reduction reaction to obtain the compound shown in formula (VII).

[0012] (2) The compound shown in formula (VII) undergoes a deprotection reaction to give the compound shown in formula (IX);

[0013]

[0014] Wherein, PG is a hydroxyl protecting group, which is selected from one of the substituents formed by the following compounds: C2-C8 alkyl, C6-C12 aryl, C1-C8 silane. Exemplarily, the hydroxyl protecting group is selected from one of the substituents formed by the following compounds: methyl, ethyl, isopropyl, tert-butyl, benzyl, phenyl, p-methoxybenzyl, p-nitrobenzoate, tert-butyldimethylsilane, methoxymethyl, benzyloxymethyl, methylthiomethyl, ethoxymethyl, trimethylsilylethyl; R 3 Selected from hydrogen, C1-C8 alkyl, or C6-C18 aryl, exemplarily, R 3 The compounds are selected from hydrogen, methyl, ethyl, tert-butyl, benzyl, phenyl, and p-methoxybenzyl. In the above compounds, -Me represents methyl, and (R) and (S) represent the chiral carbon.

[0015] The fifth aspect of this application provides a method for preparing the compound shown in formula (I), comprising the following steps:

[0016] (1) The compound shown in formula (V) and the compound shown in formula (VI) undergo a condensation reaction to obtain the compound shown in formula (VII); or, (1'a) the compound shown in formula (II) and the compound shown in formula (VIII) undergo a coupling reaction to obtain the compound shown in formula (VII'), and (1'b) the compound shown in formula (VII') undergoes a reduction reaction to obtain the compound shown in formula (VII).

[0017] (2) The compound shown in formula (VII) undergoes a deprotection reaction to give the compound shown in formula (IX);

[0018] (3) The compound shown in formula (IX) undergoes a salt formation reaction to obtain the compound shown in formula (I);

[0019]

[0020] Wherein, PG is a hydroxyl protecting group, which is selected from one of the substituents formed by the following compounds: C2-C8 alkyl, C6-C12 aryl, C1-C8 silane. Exemplarily, the hydroxyl protecting group is selected from one of the substituents formed by the following compounds: methyl, ethyl, isopropyl, tert-butyl, benzyl, phenyl, p-methoxybenzyl, p-nitrobenzoate, tert-butyldimethylsilane, methoxymethyl, benzyloxymethyl, methylthiomethyl, ethoxymethyl, trimethylsilylethyl; R 3 Selected from hydrogen, C1-C8 alkyl, or C6-C18 aryl, exemplarily, R 3 The compounds are selected from hydrogen, methyl, ethyl, tert-butyl, benzyl, phenyl, and p-methoxybenzyl. In the above compounds, -Me represents methyl, and (R) and (S) represent the chiral carbon.

[0021] Preferably, step (1) includes the following steps: mixing the compound shown in formula (V), the first tertiary amine, and the first coupling agent, reacting for 0.5 h-2 h, then adding the compound shown in formula (VI) and reacting for 2 h-3 h, and separating to obtain the compound shown in formula (VII); the first tertiary amine is selected from at least one of N,N-diisopropylethylamine, N-methylpiperidine, N-methylmorpholine, and triethylamine; the first coupling agent is selected from 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(benzotriazole)- At least one of N,N,N',N'-tetramethylurea hexafluorophosphate, benzotriazol-1-yl-oxytripyrrolylphosphine hexafluorophosphate, benzotriazol-1-yl-oxytridimethylaminophosphine hexafluorophosphate, tripyrrolylphosphonium bromide hexafluorophosphate, dicyclohexylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and propylphosphoric anhydride, wherein the molar ratio of the compound shown in formula (V), the first tertiary amine, the first coupling agent, and the compound shown in formula (VI) is 1:(3-10):(0.8-1.5):(0.9-1.2).

[0022] Preferably, step (1'a) may include the following steps: mixing the compound shown in formula (II), the compound shown in formula (VIII), N,N-diisopropylethylamine, and the first catalyst, and reacting at 80°C to 110°C for 10-24 hours under the protection of a protective gas to obtain the compound shown in formula (VII'); the first catalyst is selected from at least one of 1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium, dichloro[bis(triphenylphosphine)]palladium, palladium chloride, palladium acetate, and dibenzylacetone palladium; the molar ratio of the compound shown in formula (II) to the compound shown in formula (VIII) is 1:(1-1.5); and the molar ratio of the compound shown in formula (II), N,N-diisopropylethylamine, and the first catalyst is 1:(1-8):(0.001-1).

[0023] Preferably, step (1'b) includes the following steps: at 20°C to 50°C, in a nitrogen atmosphere, the compound shown in formula (VII'), the third alkali, the second catalyst, and the first reducing agent are mixed and reacted for 10h-25h to obtain the compound shown in formula (VII); the second catalyst is selected from at least one of cuprous iodide, cuprous bromide, cuprous chloride, and cuprous cyanide; the third alkali is selected from at least one of potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate; the first reducing agent is selected from at least one of pinacol ester of borate, boric acid, pinacol borane, and catechol borane; the molar ratio of the compound shown in formula (VII'), the third alkali, the second catalyst, and the first reducing agent is 1:(1-5):(20-40):(1-5).

[0024] Preferably, step (2) may include the following steps: cooling the compound shown in formula (VII) to -70°C to -80°C, adding boron tribromide dropwise, reacting for 4-5 hours, then heating to -30°C to -35°C and reacting for 2-3 hours, then pouring it into a saturated aqueous solution of carbonate, controlling the reaction temperature to 0°C to 10°C, adding hydrochloric acid aqueous solution to adjust the pH to 5-6, and separating to obtain the compound shown in formula (IX); the carbonate is selected from at least one of potassium bicarbonate, potassium carbonate, sodium bicarbonate, and sodium carbonate, and the molar ratio of the compound shown in formula (VII) to boron tribromide is 1:(5-15). Further, in step (2), the aqueous solution of carbonate is added dropwise. This application does not have a particular limitation on the concentration of the aqueous solution of carbonate, as long as it can achieve the purpose of this application. For example, the concentration of the aqueous solution of carbonate can be 0.1 mol / L to 1 mol / L. Even further, the mass ratio of the compound shown in formula (VII) to the saturated aqueous solution of carbonate is 1:(10-100).

[0025] Preferably, step (2) may also include the following steps: adding the compound shown in formula (VII), hydrochloric acid, and a third catalyst under a hydrogen atmosphere, reacting for 10-24 hours, and separating the compound shown in formula (IX); the third catalyst is selected from at least one of palladium on carbon, platinum on carbon, rhodium on carbon, ruthenium on carbon, and Raney nickel, and the molar ratio of the compound shown in formula (VII-1), hydrochloric acid, and the third catalyst is 1:(0.1-10):(0.001-1). The hydrochloric acid is added in the form of an aqueous solution of hydrochloric acid, with a concentration of 0.1 mol / L to 6 mol / L. The molar ratio of the compound shown in formula (VII-1) to hydrochloric acid refers to the molar ratio of the compound shown in formula (VII-1) to the hydrochloric acid in the aqueous solution of hydrochloric acid.

[0026] Preferably, step (3) may include the following steps: controlling the temperature to be less than or equal to 35°C, adding an aqueous sodium hydroxide solution to the compound shown in formula (IX), adjusting the pH to 7.8-8.3, and separating the compound shown in formula (I). Further, the aqueous sodium hydroxide solution is added dropwise. This application does not have a particular limitation on the concentration of the aqueous sodium hydroxide solution, as long as it can achieve the purpose of this application. For example, the concentration of the aqueous sodium hydroxide solution can be from 0.01 mol / L to 10 mol / L. Further, the molar ratio of the compound shown in formula (IX) to sodium hydroxide in the aqueous sodium hydroxide solution is 1:(0.5-2). The above-mentioned control temperature of less than or equal to 35°C can be adjusted to 35°C, 34°C, 33°C, 32°C, 31°C, or 30°C. It is understood that the calcium salt, magnesium salt, and potassium salt of the compound shown in formula (IX) can be prepared by referring to the above preparation method. Specifically, the aqueous sodium hydroxide solution in step (3) can be replaced with an alkaline solution containing calcium, magnesium, and potassium, such as calcium hydroxide, magnesium hydroxide, and potassium hydroxide.

[0027] Preferably, step (3) may also include the following steps: controlling the temperature to be 50°C to 70°C, adding sodium methoxide dropwise to the compound shown in formula (IX), reacting for 2-3 hours, and then reacting at 0°C to 5°C for 1-2 hours to separate the compound shown in formula (I); the molar ratio of the compound shown in formula (IX) to sodium methoxide is 1:(0.8-1.2). It is understood that the calcium, magnesium, and potassium salts of the compound shown in formula (IX) can be prepared by referring to the above preparation method. Specifically, the sodium methoxide in step (3) can be replaced with organic salts containing calcium, magnesium, and potassium, such as calcium methoxide, magnesium ethoxide, and potassium tert-butoxide.

[0028] In some embodiments of this application, the method for preparing the compound shown in formula (IX) or the compound shown in formula (I) further includes the following steps:

[0029] (4) The compound shown in formula (II) and the compound shown in formula (III) are coupled together to obtain the compound shown in formula (IV);

[0030] (5) The compound shown in formula (IV) is subjected to a hydrogenation reduction reaction to obtain the compound shown in formula (IV');

[0031] (6) The compound shown in formula (IV') is hydrolyzed to give the compound shown in formula (V);

[0032]

[0033] Among them, R 1 Substituents selected from halogens or C2-C6 sulfonate compounds, exemplarily, R 1 Selected from Cl, Br, I, and substituents formed from trifluoromethyl sulfonate or methanesulfonate; R 2 Selected from C1-C8 alkyl groups or C6-C18 aryl groups, exemplarily, R 2 Selected from methyl, ethyl, tert-butyl, benzyl, phenyl, and p-methoxybenzyl.

[0034] Preferably, step (4) includes the following steps: under the protection of a protective gas, the compound shown in formula (II), the compound shown in formula (III), the fourth catalyst, and the first base are mixed, heated to 70°C to 75°C, and reacted for 10-24 hours to obtain the compound shown in formula (IV); the fourth catalyst is selected from at least one of dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium, dichloro[bis(triphenylphosphine)]palladium, palladium chloride, palladium acetate, and palladium dibenzylacetone; the first base is selected from at least one of triethylamine, diethylamine, diisopropylethylamine, tetramethylethylenediamine, and N-methylmorpholine; the molar ratio of the compound shown in formula (II), the compound shown in formula (III), the fourth catalyst, and the first base is 1:(0.3-1):(0.001-1):(0.5-1).

[0035] Preferably, step (5) may include the following steps: at 50°C to 55°C, the compound shown in formula (IV), the third alkali agent, and the second reducing agent are mixed and reacted for 1-5 hours to obtain the compound shown in formula (IV'); the second reducing agent is selected from at least one of methanesulfonyl hydrazine, benzenesulfonyl hydrazine, trimethylbenzenesulfonyl hydrazine, pyridinesulfonyl hydrazine, and pinacol diboronate; the third alkali agent is selected from at least one of potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate; and the molar ratio of the compound shown in formula (IV), the second reducing agent, and the third alkali agent is 1:(1-5):(1-10).

[0036] Preferably, step (5) may also include the following steps: at 0°C to 55°C, the compound shown in formula (IV), the acid catalyst, and the third reducing agent are mixed and reacted for 1-5 hours to obtain the compound shown in formula (IV'); the acid catalyst is selected from at least one of boron trifluoride, boron trichloride, aluminum trichloride, tin tetrachloride, hydrochloric acid, trifluoroacetic acid, and trifluoromethanesulfonic acid; the third reducing agent is selected from at least one of triethylsilane and tributyltin hydride; and the molar ratio of the compound shown in formula (IV), the acid catalyst, and the third reducing agent is 1:(0.1-5):(1-5).

[0037] Preferably, step (5) may also include the following steps: at 40°C to 105°C, in a nitrogen atmosphere, the compound shown in formula (IV), the fourth alkali, the fifth catalyst, and the fourth reducing agent are mixed and reacted for 1-5 hours to obtain the compound shown in formula (IV'); the fifth catalyst is selected from at least one of cuprous iodide, cuprous bromide, cuprous chloride, and cuprous cyanide; the fourth alkali is selected from at least one of potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate; and the fourth reducing agent is selected from at least one of pinacol ester of borate, boric acid, pinacol borane, and catechol borane. The molar ratio of the compound shown in formula (IV), the fourth alkali, the fifth catalyst, and the fourth reducing agent is 1:(0.1-5):(0.01-1):(1-5).

[0038] Preferably, step (5) may also include the following steps: at 0°C to 55°C, in a hydrogen atmosphere, the compound shown in formula (IV), the acid, and the sixth catalyst are mixed and reacted for 1-5 hours, and the compound shown in formula (IV') is separated; the acid is selected from at least one of acetic acid and hydrochloric acid, and the sixth catalyst is selected from at least one of palladium on carbon, platinum on carbon, rhodium on carbon, ruthenium on carbon, and Raney nickel, and the molar ratio of the compound shown in formula (IV), the acid, and the sixth catalyst is 1:(0-10):(0.01-1).

[0039] Preferably, step (6) includes the following steps: mixing the compound shown in formula (IV') with an alkaline solution and reacting it at 60°C to 70°C for 6-24 hours to obtain the compound shown in formula (V); the alkali in the alkaline solution is selected from at least one of sodium hydroxide, potassium hydroxide, and barium hydroxide. Further, the molar ratio of the compound shown in formula (IV') to the alkali in the alkaline solution is 1:(1-100).

[0040] In some embodiments of this application, the method for preparing the compound shown in formula (IX) or the compound shown in formula (I) further includes the following steps:

[0041] (7) Under the protection of a protective gas, the temperature is controlled to be less than or equal to 5°C. A halogenating agent is added dropwise to the compound shown in formula (II-3), and the reaction is carried out for 8-20 hours. The compound shown in formula (II-4) is then separated. The halogenating agent is selected from at least one of thionyl chloride, phosphorus pentachloride, oxalyl chloride, and phosphorus tribromooxychloride. The molar ratio of the compound shown in formula (II-3) to the chlorinating agent is 1: (2-5). The above-mentioned temperature control of less than or equal to 5°C can be achieved by adjusting the reaction temperature to -5°C, -4°C, -3°C, -2°C, -1°C, 0°C, 1°C, 2°C, 3°C, 4°C, or 5°C.

[0042] (8) Under a protective atmosphere of a protective gas, Evan's chiral cofactor, Lewis acid, and a second base are mixed, and the temperature is controlled to be less than or equal to 0°C. The compound shown in formula (II-4) is added dropwise, and the reaction is carried out at 10°C to 15°C for 10-24 hours. The compound shown in formula (II-5) is then separated. Evan's chiral cofactor is selected from at least one of (S)-4-isopropyloxazolidin-2-one, (S)-4-phenyloxazolidin-2-one, (S)-4-benzyloxazolidin-2-one, and (S)-4-tert-butyloxazolidin-2-one. The Lewis acid is selected from LiCl. At least one of LiBr, LiI, ZnCl2, and ZnI2; the second base agent is selected from at least one of triethylamine, diisopropylethylamine, and tetramethylethylenediamine; the molar ratio of Evan's chiral cofactor, Lewis acid, second base agent, and the compound shown in formula (II-4) is 1:(1-1.5):(1-2):(1-1.5); the above-mentioned control temperature of less than or equal to 0℃ can be achieved by adjusting the reaction temperature to -5℃, -4℃, -3℃, -2℃, -1℃, or 0℃;

[0043] (9) Under the protection of a protective gas, the temperature is controlled to be less than or equal to -60°C. The compound shown in formula (II-5) is added dropwise to vinyl magnesium bromide, and then acid is added dropwise to carry out the reaction. The temperature is raised to -5°C to 5°C and water is added to quench the reaction. The compound shown in formula (II) is obtained by separation. The acid is selected from at least one of acetic acid, hydrochloric acid, and sulfuric acid. The molar ratio of vinyl magnesium bromide, the compound shown in formula (II-5), and the acid is 1:(0.5-1.5):(1-10). The above-mentioned temperature control of less than or equal to -60°C can be achieved by adjusting the reaction temperature to -85°C, -80°C, -75°C, -70°C, -65°C, or -60°C.

[0044]

[0045] In the above compounds, -Et stands for ethyl.

[0046] In some embodiments of this application, the method for preparing the compound shown in formula (IX) or the compound shown in formula (I) further includes the following steps:

[0047] (7a) At 30°C to 80°C, water was added dropwise to the methyldiethoxyphosphine shown in formula (II-1), and the reaction was carried out for 0.5 h to 2 h to obtain the compound shown in formula (II-2); the molar ratio of the methyldiethoxyphosphine to water shown was 1:(1-1.5);

[0048] (7b) Under a protective atmosphere of a protective gas, the fourth base agent, the reactant, the compound shown in formula (II-2), and the seventh catalyst are mixed and reacted at 80°C to 120°C for 4-5 hours to obtain the compound shown in formula (II-3); the molar ratio of the fourth base agent, the reactant, the compound shown in formula (II-2), and the seventh catalyst is 1:(0.8-1.2):(0.8-1.5):(0.01-1), the fourth base agent is selected from at least one of triethylamine and diisopropylethylamine, the seventh catalyst is selected from at least one of dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium, dichloro[bis(triphenylphosphine)]palladium, palladium chloride, palladium acetate, dibenzylacetone palladium, nickel chloride, and dichloro[bis(triphenylphosphine)]nickel, and the reactant is selected from m-bromoanisole or Wherein, R is an electron-withdrawing group, which is selected from substituents formed by halogens or C1-C9 sulfonate compounds. For example, R is selected from Cl, Br, I, and substituents formed by trifluoromethyl sulfonate or methyl sulfonate.

[0049]

[0050] In some embodiments of this application, the method for preparing the compound shown in formula (IX) or the compound shown in formula (I) further includes the following steps:

[0051] (10) The compound shown in formula (III') and the compound shown in formula (VI) are condensed together to obtain the compound shown in formula (VIII);

[0052]

[0053] Among them, R 1 Substituents selected from halogens or C1-C9 sulfonate compounds, exemplarily, R 1 Substituents selected from Cl, Br, I, and those formed from trifluoromethyl sulfonate or methyl sulfonate.

[0054] Preferably, step (10) includes the following steps: at 20°C to 30°C, the compound shown in formula (III'), the second tertiary amine, and the second coupling agent are mixed and reacted for 1.5 h to 2 h, then the compound shown in formula (VI) is added and reacted for 2 h to 3 h, and the compound shown in formula (VII) is separated; the second tertiary amine is selected from at least one of N,N-diisopropylethylamine and triethylamine, and the second coupling agent is selected from 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(benzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, benzotriazole-1-yl-oxy-tripyrrolidinephosphide hexafluorophosphate, benzotriazole-1-yl- The compound is selected from at least one of the following: trimethylaminophosphine, tripyrrolylphosphonium hexafluorophosphate, dicyclohexylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and propylphosphoric anhydride. The molar ratio of the compound shown in formula (III'), the second tertiary amine, the second coupling agent, and the compound shown in formula (VI) is 1:(3-10):(0.8-1.5):(0.9-1.5). This application does not particularly limit the separation steps in the above steps; separation steps known in the art can be used, as long as they achieve the purpose of this application. For example, the separation steps may include, but are not limited to: quenching the reaction with water or other organic solvents, extraction, washing with water or other solvents, activated carbon treatment, filtration, concentration, recrystallization, etc. The other organic solvents mentioned above may include, but are not limited to, ethyl acetate, isopropyl acetate, diethyl ether, methyl tert-butyl ether, diisopropyl ether, chloroform, dichloromethane, hexane, heptane, benzene, toluene, xylene, etc.

[0055] This application does not impose any particular restrictions on the protective gas used in the above steps. Conventional protective gases known in the art can be used, as long as they can achieve the purpose of this application. For example, the protective gas may include, but is not limited to, nitrogen and / or argon.

[0056] The beneficial effects of this application are:

[0057] The compound shown in formula (IX) or its salt provided in this application can be used as an LFA-1 inhibitor to treat ophthalmic diseases, such as dry eye syndrome. The preparation method provided in this application can synthesize the compound shown in formula (IX) and the compound shown in formula (I). This preparation method is simple to operate, has short reaction steps, high yield, high purity, mild reaction conditions, and is suitable for industrial-scale production.

[0058] Of course, implementing any product or method of this application does not necessarily require achieving all of the advantages described above at the same time. Detailed Implementation

[0059] The technical solutions of this application will be clearly and completely described below with reference to the embodiments. Obviously, the described embodiments are only some embodiments of this application, and not all embodiments. Based on the embodiments of this application, all other embodiments obtained by those of ordinary skill in the art based on this application are within the scope of protection of this application.

[0060] Example 1

[0061] Synthesis of (R)-(3-methoxyphenyl)(methyl)(vinyl)phosphine oxide (compound II-A):

[0062]

[0063] Compound II-2: Ethyl methylphosphinate

[0064] The compound methyldiethoxyphosphine (1493 g, 10.98 mol) shown in formula (II-1) was added to a reaction flask, and the temperature was controlled at 60 °C. H2O (197.4 ml, 10.98 mol) was added dropwise. After the addition was complete, the mixture was stirred for 1 h. The reaction solution was concentrated until no fraction was produced, and 1079 g of colorless and transparent oil (1079 g, yield 91%) was obtained, which was compound II-2.

[0065] 1H NMR (400MHz, DMSO-d6) δ7.09 (dq, J=539.1, 2.1Hz, 1H), 4.01 (ddd, J=10.8, 9.2, 7.0Hz, 1H), 1.48 (dd, J=15.2, 2.1Hz, 3H), 1.26 (t, J=7.0Hz, 3H).

[0066] Compound II-3-A: Ethyl (3-methoxyphenyl)(methyl)phosphinic acid

[0067] Toluene (7.5 L) was added to the reaction vessel, and nitrogen was purged for 35 min. Then, triethylamine (980 g, 9.78 mol), reactant m-bromoanisole (compound II-2a, 1650 g, 8.87 mol), compound II-2 (1048 g, 9.70 mol), and dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium (Pd(dppf)Cl2, 129 g, 0.176 mol) were added. The mixture was purged with nitrogen three times under vacuum. The mixture was heated to 100 °C under nitrogen protection and stirred for 5 h. After cooling to 20 °C, a solid precipitated. The solid was filtered, and the filtrate was concentrated and distilled to obtain a colorless oily product (1.44 kg, yield 75%), which was compound II-3-A.

[0068] LCMSESI(+)m / z: 215.1(M+1).

[0069] Compound II-4-A: (3-methoxyphenyl)(methyl)phosphonochloride

[0070] Under nitrogen protection, dichloromethane (7.2 L) and compound II-3-A (1.44 kg, 6.73 mol) were added, the temperature was controlled at 5 °C, thionyl chloride (1.6 kg, 13.56 mol) was added dropwise, the temperature was raised to room temperature and stirred for 18 h, and the product was concentrated below 35 °C to obtain a pale yellow oily product.

[0071] Compound II-5-A: (S)-4-isopropyl-3-((R)-(3-methoxyphenyl)(methyl)phosphoryl)oxazolidin-2-one

[0072] Under nitrogen protection, dichloromethane (35 L), (S)-4-isopropyloxazolidin-2-one (791.8 g, 6.14 mol), LiCl (286 g, 6.81 mol), and triethylamine (807 g, 7.99 mol) were added to a reaction flask. The temperature was maintained at -3 °C, and a dichloromethane solution (1.6 L) of compound II-5-A (1376 g, 6.74 mol) was added dropwise. The reaction was carried out at 15 °C for 16 h. The mixture was washed with ammonium chloride solution (300 g / L) (4 L × 2), and the organic phase was concentrated until no fraction remained. Ethyl acetate (3.9 L) was added, and the temperature was raised to 60 °C until completely dissolved. The temperature was then lowered to 20 °C over 5 h, and the mixture was stirred at this temperature for 12 h. The mixture was filtered, and the filter cake was washed with ethyl acetate (800 mL) to obtain a white solid (708 g, yield 35%), which was compound II-5-A.

[0073] LCMSESI(+)m / z: 298.1(M+1).

[0074] Compound II-A: (R)-(3-methoxyphenyl)(methyl)(vinyl)phosphine oxide

[0075] Under nitrogen protection, vinyl magnesium bromide (2.25 L, 1 mol / L, tetrahydrofuran (THF)) was added to a reaction flask, and the temperature was lowered to -78 °C. Compound II-5-A (405 g, 1.36 mol) was dissolved in dichloromethane (1336 mL) and THF (1336 mL) to obtain a solution of compound II-5-A. The temperature was controlled at -75 °C, and the solution of compound II-5-A was added dropwise over 4 hours. The temperature was then controlled at -60 °C, and acetic acid (368 g, 6.1 mol) was added dropwise. After the addition was complete, the temperature was naturally raised to 0 °C, and water (2 L) was added. The mixture was separated, and the organic phase was concentrated at 40 °C until no fraction remained, yielding a yellow oily substance, which was compound II-A (150 g crude product), which could be used directly in the next step.

[0076] LCMSESI(+)m / z: 197.1(M+1), chiral purity ee>98%.

[0077] Example 2

[0078] Synthesis of (R)-(3-benzyloxyphenyl)(methyl)(vinyl)phosphine oxide (compound II-B): The synthesis is the same as in Example 1 except that compound II-2a in Example 1 is replaced with compound II-2b in the following synthetic route and the following synthetic route is followed.

[0079]

[0080] In the above compounds, -Bn represents benzyl.

[0081] Example 3

[0082] Synthesis of (R)-2,6-dichloro-4-(2-((3-methoxyphenyl)(methyl)phosphoryl)ethyl)benzoic acid (compound VA):

[0083]

[0084] Compound IV-A: (R,E)-2,6-dichloro-4-(2-((3-methoxyphenyl)(methyl)phosphoryl)vinyl)benzoate methyl benzoate

[0085] Under nitrogen protection, acetonitrile (500 mL), compound II-A (139 g, 709 mmol, crude product), methyl 4-bromo-2,6-dichlorobenzoate (compound III-A, 70.9 g, 238 mmol), Pd(dppf)Cl2 (9.2 g, 12.6 mmol), and triethylamine (50.8 g, 503 mmol) were added to a reaction flask. The mixture was heated to 75 °C and stirred for 16 h. After the reaction was complete, the mixture was cooled to room temperature, and water (250 mL) was added. The mixture was extracted with ethyl acetate (250 mL × 2). The organic phase was washed with water (250 mL) and concentrated until no fraction remained. The product was purified by column chromatography to obtain a pale yellow oily product (92.4 g, yield 81.5%), which was compound IV-A.

[0086] LCMSESI(+)m / z: 399.1(M+1), chiral purity ee>98%.

[0087] Compound IV'-A: (R)-2,6-dichloro-4-(2-((3-methoxyphenyl)(methyl)phosphoryl)ethyl)benzoate methyl ester

[0088] Compound IV-A (1535 g, 3.85 mol) was dissolved in acetonitrile (6100 mL), the temperature was raised to 55 °C, and triethylsilane (1788 g, 15.4 mol) was added. The mixture was stirred for 20 min, and a solution of boron trifluoride (837 g, 7.68 mol) in acetonitrile (3050 mL) was slowly added dropwise. After the addition was complete, the mixture was stirred at 55 °C for 1.5 h, the reaction was stopped, and the temperature was lowered to 8 °C. A saturated potassium carbonate aqueous solution (4.5 L) was added, and the mixture was separated. The aqueous phase was extracted once with dichloromethane (4.5 L), and the organic phases were combined and concentrated at 45 °C until no fraction remained, yielding a crude product, a black oily substance (1580 g), which was compound IV'-A. This crude product was used directly in the next step.

[0089] LCMS ESI(+) m / z: 401.1(M+1), chiral purity ee>98%.

[0090] Compound VA: (R)-2,6-dichloro-4-(2-((3-methoxyphenyl)(methyl)phosphoryl)ethyl)benzoic acid

[0091] Compound IV'-A (1580 g, 3.95 mol) was dissolved in methanol (7900 mL), and sodium hydroxide (787.6 g, 19.69 mol) was dissolved in water (1580 mL). The sodium hydroxide aqueous solution was added dropwise at room temperature. After the addition was complete, the temperature was raised to 60 °C and stirred for 12 h. The mixture was then cooled to room temperature, and water (4500 mL) and dichloromethane (11000 mL) were added. The mixture was separated. The aqueous phase was further extracted with dichloromethane (4500 mL), and the mixture was separated. The pH of the aqueous phase was adjusted to less than or equal to 3 with 2 mol / L hydrochloric acid aqueous solution. Dichloromethane (7500 mL) was added, and the mixture was further extracted. The aqueous phase was then further extracted with dichloromethane (4500 mL), and the mixture was combined. Dicyclohexylamine (780 g, 4.31 mmol) was added to the dichloromethane phase, and the mixture was stirred for 2 h. The pH was adjusted to 3 by adding 2 mol / L hydrochloric acid aqueous solution. The mixture was filtered through diatomaceous earth, and the filter cake was washed once with dichloromethane (DCM, 1500 mL). The organic phase was concentrated at 45 °C until no fraction remained, yielding 1120 g of a black oily substance. Ethylene glycol dimethyl ether (1680 mL) was added to dissolve the oil, and the temperature was raised to 70 °C. During stirring, a large amount of solid precipitated. Heptane (1680 mL) was slowly added dropwise. After the addition was complete, the mixture was kept at this temperature and stirred for 2 h, then slowly cooled to 5 °C over 5 h. The mixture was kept at this temperature and stirred for 2 h, then filtered. The filter cake was washed once with cold ethylene glycol dimethyl ether (896 mL). The solid was dried under vacuum at 45 °C for 24 h, yielding a grayish-white solid (840 g, yield 55%), which was compound VA.

[0092] LCMS ESI(+) m / z: 387.1(M+1), chiral purity ee>98%.

[0093] 1H NMR (400MHz, CDCl3) δ7.47-7.39(m,1H),7.33(d,J=12.6Hz,1H),7.24-7.16(m,1H), 7.17–7.05(m,3H),3.87(s,3H),3.00-2.86(m,1H),2.75-2.65(m,1H),2.50-2.30(m, 1H),2.28-2.15(m,1H),1.85(d,J=12.6Hz,3H).

[0094] Example 4

[0095] Synthesis of (S)-2-(2,6-dichloro-4-(2-((R)-(3-methoxyphenyl)(methyl)phosphoryl)ethyl)benzoylamino)-3-(3-(methylsulfonyl)phenyl)propionate (compound VII-A):

[0096]

[0097] Compound VA (210 g, 544 mmol) was dissolved in N,N-dimethylformamide (2100 mL), and N,N-diisopropylethylamine (DIEA, 352 g, 2.73 mol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 207 g, 545 mmol) were added sequentially. The mixture was stirred at room temperature for 1 h, and then (S)-2-amino-3-(3-(methylsulfonyl)phenyl)propionate benzyl hydrochloride (hydrochloride of compound VI-A, 201 g, 543 mmol) was added. The mixture was stirred at the same temperature for 2.5 h. Ethyl acetate (2100 mL) and water (1050 mL) were added sequentially, and the mixture was stirred to separate the layers. The aqueous phase was further extracted twice with ethyl acetate (630 mL), and the ethyl acetate phases were combined. The ethyl acetate phase was washed once each with saturated sodium bicarbonate aqueous solution (1050 mL) and 1 mol / L hydrochloric acid aqueous solution (1050 mL), resulting in separate layers. The ethyl acetate phase was washed three times with water (630 mL, 3V) and concentrated at 45 °C until no fraction remained, yielding 355 g of a yellow oil. The yellow oil was dissolved in acetonitrile (1065 mL), and the mixture was heated to 60 °C with slow dropwise addition of n-heptane (1775 mL). After the addition was complete, the mixture was slowly cooled to room temperature over 4 h, stirred at 0 °C for 2 h, and filtered. The filter cake was washed with cold acetonitrile (350 mL) and dried under vacuum at 40 °C for 24 h to obtain a white solid (230 g, yield 60%), which was compound VII-A.

[0098] LCMS ESI(+) m / z: 702.0(M+1), chiral purity ee>98%.

[0099] Example 5

[0100] Synthesis of (S)-2-(2,6-dichloro-4-(2-((R)-(3-methoxyphenyl)(methyl)phosphoryl)ethyl)benzoylamino)-3-(3-(methylsulfonyl)phenyl)propionate (compound VII-A):

[0101]

[0102] Compound VIII-A: (S)-2-(4-bromo-2,6-dichlorobenzoamide)-3-(3-(methylsulfonyl)phenyl)propionate benzyl ester

[0103] Under nitrogen protection, N,N-dimethylformamide (DMF, 5.5 L), 4-bromo-2,6-dichlorobenzoic acid (compound III'-A, 550 g, 2.05 mol), HATU (774.8 g, 2.04 mol), and DIEA (1316.9 g, 10.21 mol) were added to a reaction vessel and stirred at 25 °C for 2 h. Then, (S)-2-amino-3-(3-(methylsulfonyl)phenyl)propionate hydrochloride (hydrochloride of compound VI-A, 753.7 g, 2.04 mol) was added to the reaction vessel and stirred for 3 h. Finally, dichloromethane (2.75 L) and water (1.65 L) were added to the reaction vessel and stirred for 20 min. The mixture was allowed to stand for 20 min to separate into layers, and the aqueous phase was continued to be treated with dichloromethane (1.65 L). Extract once, combine the organic phases, wash the organic phase once with 1 mol / L hydrochloric acid (2.2 L), wash the organic phase once with sodium bicarbonate solution (1.65 L), wash the organic phase twice with water (1.65 L), concentrate the organic phase at 45 °C until no fraction remains, add ethyl acetate (2.2 L), heat to 65 °C until dissolved, cool to 5 °C for at least 12 h, stir for at least 2 h, filter, transfer the solid to a vacuum drying oven, dry at 45 °C for at least 16 h to obtain a pale yellow solid (0.9 kg, yield 75%), which is compound VIII-A.

[0104] LCMS ESI(+) m / z: 585.9 (M+1), chiral purity ee > 98%.

[0105] Compound VII'-A: Benzyl(S)-2-(2,6-dichloro-4-((E)-2-((R)-(3-methoxyphenyl)(methyl)phosphoryl)vinyl)benzoamide)-3-(3-(methylsulfonyl))phenyl)propionate

[0106] Add 350 mL of N,N-dimethylformamide, compound II-A (16.8 g, 85.8 mmol), and compound VIII-A (50 g, 85.8 mmol) to the reaction flask, and stir for at least 20 min until dissolved. Then add DIEA (27.6 g, 214 mmol) and 1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride tetrahydrofuran adduct (1.56 g, 1.94 mmol). Purge the reaction vessel three times with nitrogen, raise the temperature to 98 °C, and react for 16 h. Stop the reaction and cool to 25 °C. Add 250 mL of dichloromethane and 400 mL of water to the reaction vessel, stir for at least 20 min, and allow the layers to separate. Temporarily store the organic phase. Extract the aqueous phase once more with 150 mL of dichloromethane, allowing the layers to separate. Combine the organic phases, add 175 mL of 1M hydrochloric acid to the reaction vessel, and stir for at least 20 min until the layers separate. The organic phase was washed twice with 150 mL of water. The organic phase was then passed through an activated carbon filter, which was rinsed once more with 150 mL of dichloromethane. The organic phase was concentrated in a reaction flask to remove the dichloromethane, and evaporated to approximately 120 mL of solution. 3300 mL of methyl tert-butyl ether was added to another reaction flask. The dichloromethane solution was slowly added dropwise to the reaction vessel, and a solid gradually precipitated out. After the addition was complete, the filter cake was transferred to a vacuum drying oven and dried under vacuum to obtain a black solid (47 g, yield 78%), which was compound VII'-A.

[0107] LCMS ESI(+) m / z: 700.0(M+1), chiral purity ee>98%.

[0108] Compound VII-A: (S)-2-(2,6-dichloro-4-(2-((R)-(3-methoxyphenyl)(methyl)phosphoryl)ethyl)benzoylamino)-3-(3-(methylsulfonyl)phenyl)propionate benzyl ester

[0109] Under nitrogen protection, compound VII'-A (1583.4 g, 2.26 mol) and tetrahydrofuran (7.9 L) were added to the reactor and stirred for 20 min until dissolved. Cesium carbonate (1473 g, 4.52 mol), isopropanol (272 g, 4.53 mol), and cuprous iodide (12.9 g, 67.9 mmol) were added to the reactor, and the material adhering to the walls was rinsed off with 1.5 L of tetrahydrofuran. Pinaryl borate (689 g, 2.71 mol) was dissolved in 6.3 L of tetrahydrofuran and added dropwise to the reactor at 30 °C, and the reaction was stirred for 16 h. 10 g of diatomaceous earth was filtered, and the filter cake was washed once with 4.5 L of dichloromethane. 7.5 L of dichloromethane and 7.5 L of water were added to the filtrate and stirred for at least 20 min. The mixture separated into layers, and the aqueous phase was extracted once more with 4.5 L of dichloromethane. The organic phase was washed once with 3.0 L of 1 mol / L hydrochloric acid to separate into layers, and then washed once more with 4.5 L of softened water. The organic phase was then transferred to a reaction vessel through an activated carbon filter, which was rinsed once with 4.5 L of dichloromethane. The organic phase was concentrated to dryness, and acetonitrile (4.5 L) was added. The mixture was heated to 60 °C, and after dissolution and clarification, 7.5 L of n-heptane was added to the reaction solution. The mixture was cooled to 0 °C and stirred at this temperature for at least 4 hours. After filtration, the solution was dried under vacuum to obtain a pale yellow solid (420 g, yield 26%), which was compound VII-A.

[0110] LCMS ESI(+) m / z: 702.0(M+1), chiral purity 98.5%.

[0111] Example 6

[0112] Synthesis of (S)-2-(2,6-dichloro-4-(2-(((R)-(3-benzyloxyphenyl)(methyl)phosphoryl)ethyl)benzoylamino)-3-(3-(methylsulfonyl)phenyl)propionate (compound VII-B): The synthesis was identical to that in Example 5 except that compound II-A in Example 5 was replaced with compound II-B in the following synthetic route and the following synthetic route was followed.

[0113]

[0114] Example 7

[0115] Synthesis of (S)-2-(2,6-dichloro-4-(2-((R)-(3-hydroxyphenyl)(methyl)phosphoryl)ethyl)benzoamide)-3-(3-(methylsulfonyl)phenyl)propionic acid (compound IX-A):

[0116]

[0117] Compound VII-A (213 g, 303 mmol) was dissolved in dichloromethane (773 mL), cooled to -70 °C, and boron tribromide (773 g, 3.09 mol) was slowly added dropwise. After the addition was complete, the mixture was kept at this temperature and stirred for 5 h, then heated to -35 °C and stirred for 3 h. The solution was slowly poured into a saturated potassium bicarbonate aqueous solution (10650 mL), and the temperature was adjusted to 5 °C. 4 mol / L hydrochloric acid aqueous solution was slowly added dropwise to adjust the pH to 5.5, resulting in the continuous precipitation of solids. The solids were filtered. The filter cake was washed with water (600 mL) and dried under vacuum at 40 °C for 24 h to obtain a white solid (136 g, 75% yield) of compound IX-A.

[0118] LCMSESI(+) m / z: 598.0 (M+1), chiral purity 98.5%.

[0119] Example 8

[0120] Synthesis of (S)-2-(2,6-dichloro-4-(2-((R)-(3-hydroxyphenyl)(methyl)phosphoryl)ethyl)benzoamide)-3-(3-(methylsulfonyl)phenyl)propionic acid (compound IX-A):

[0121]

[0122] Compound VII-B (2.0 g, 2.58 mmol) was dissolved in ethyl acetate (20 mL), and chlorobenzene (1.74 g, 15.5 mmol), 1 mol / L hydrochloric acid aqueous solution (5.2 mL), and palladium on carbon (200 mg, 1.88 mmol) were added. The mixture was purged three times with a hydrogen balloon and stirred at room temperature for 16 h. The mixture was filtered through diatomaceous earth, washed once with ethyl acetate (20 mL), and the filtrate was concentrated to dryness to give a white solid (1.5 g, yield 97%, purity 90%), which was compound IX-A.

[0123] LCMSESI(+) m / z: 597.8 (M+1), chiral purity 99%.

[0124] Example 9

[0125] Synthesis of sodium (S)-2-(2,6-dichloro-4-(2-((R)-(3-hydroxyphenyl)(methyl)phosphoryl)ethyl)benzoamide)-3-(3-(methylsulfonyl)phenyl)propionate (compound I):

[0126]

[0127] Dissolve 20.1 g (503 mmol) of sodium hydroxide in deionized water to prepare a 0.5 mol / L sodium hydroxide aqueous solution. Slowly add 300 g (502 mmol) of compound IX-A to the sodium hydroxide aqueous solution, controlling the temperature at 35 °C. Continue adding the sodium hydroxide aqueous solution until the solution becomes clear and the pH is measured to be 8, at which point the addition of sodium hydroxide aqueous solution is stopped. Filter the aqueous solution through a micropore, then add 900 mL of deionized water to the filtrate and freeze-dry the solution to obtain a white solid (310 g, 99% yield) as compound I.

[0128] LCMSES(+)m / z: 620.0(M+1), chiral purity ee>99%.

[0129] 1H NMR (400MHz, DMSO-d6) δ7.82 (s, 1H), 7.78 (d, J = 6.8Hz, 1H), 7.71 (d, J = 7.6Hz, 1H),7.64(d,J=7.6Hz,1H),7.49(t,J=7.6Hz,1H),7.30-7.25(m,3H),7.20(d,J=12.8Hz,1H), 7.10(dd,J=10.8,7.6Hz,1H),6.94(d,J=7.6Hz,1H),4.41(dd,J=12.0,6.8Hz,1H),3.32-3.27 (m,1H),3.19-3.15(m,1H),3.13(s,3H),2.84-2.79(m,1H),2.66-2.51(m,1H),2.29-2.18(m,2H), 1.63(d,J=12.8Hz,3H).

[0130] Example 10

[0131] Synthesis of sodium (S)-2-(2,6-dichloro-4-(2-((R)-(3-hydroxyphenyl)(methyl)phosphoryl)ethyl)benzoamide)-3-(3-(methylsulfonyl)phenyl)propionate (compound I):

[0132]

[0133] Compound IX-A (270 g, 452 mmol) was dissolved in isopropanol (4860 mL) at 60 °C. Sodium methoxide (24.4 g, 452 mmol) was added dropwise, and a solid precipitated immediately. After the addition was complete, the mixture was slowly cooled to room temperature over 3 h, kept at 5 °C with stirring for 2 h, and filtered. The filter cake was dried under vacuum at 40 °C to obtain a white solid (210 g, yield 75%), which was compound I.

[0134] LCMS ES(+)m / z: 620.0(M+1), chiral purity ee>98%.

[0135] The yield calculation for each of the above compounds is as follows: Yield = (moles of actual synthesized product / moles of theoretical synthesized product) × 100%.

[0136] The chiral purity of the above compounds can be tested using methods known in the art, and this application does not limit this.

[0137] The calcium, magnesium, and potassium salts of the compounds shown in formula (IX) can be synthesized by selecting appropriate raw materials according to the synthetic ideas in the above embodiments, or by selecting any other suitable methods and raw materials.

[0138] It should be noted that, in this document, relational terms such as "first" and "second" are used merely to distinguish one entity from another, and do not necessarily require or imply any such actual relationship or order between these entities. Furthermore, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such process, method, article, or apparatus.

[0139] The various embodiments in this specification are described in a related manner. For the same or similar parts between the various embodiments, refer to each other. Each embodiment focuses on describing the differences from other embodiments.

[0140] The above description is only a preferred embodiment of this application and is not intended to limit this application. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this application should be included within the scope of protection of this application.

Claims

1. A method for preparing a compound of formula (IX), comprising the following steps: (1) The compound shown in formula (V) and the compound shown in formula (VI) are condensed together to obtain the compound shown in formula (VII); Alternatively, (1'a) the compound shown in formula (II) and the compound shown in formula (VIII) are coupled to obtain the compound shown in formula (VII'), and (1'b) the compound shown in formula (VII') is reduced to obtain the compound shown in formula (VII); (2) The compound shown in formula (VII) undergoes a deprotection reaction to obtain the compound shown in formula (IX); in, PG is a hydroxyl protecting group, which is selected from one of the substituents formed by the following compounds: C2-C8 alkyl, C6-C12 aryl, and C1-C8 silane; R 3 It is selected from hydrogen, C1-C8 alkyl or C6-C18 aryl.

2. A method for preparing a compound of formula (I), comprising the following steps: (1) The compound shown in formula (V) and the compound shown in formula (VI) are condensed together to obtain the compound shown in formula (VII); Alternatively, (1'a) the compound shown in formula (II) and the compound shown in formula (VIII) are coupled to obtain the compound shown in formula (VII'), and (1'b) the compound shown in formula (VII') is reduced to obtain the compound shown in formula (VII); (2) The compound shown in formula (VII) undergoes a deprotection reaction to obtain the compound shown in formula (IX); (3) The compound shown in formula (IX) undergoes a salt-forming reaction to obtain the compound shown in formula (I); in, PG is a hydroxyl protecting group, which is selected from one of the substituents formed by the following compounds: C2-C8 alkyl, C6-C12 aryl, and C1-C8 silane; R 3 It is selected from hydrogen, C1-C8 alkyl or C6-C18 aryl.

3. The preparation method according to claim 1 or 2, wherein, Step (1) includes the following steps: mixing the compound shown in formula (V), the first tertiary amine, and the first coupling agent, reacting for 0.5 h-2 h, then adding the compound shown in formula (VI) and reacting for 2 h-3 h, and separating to obtain the compound shown in formula (VII); the first tertiary amine is selected from any one of N,N-diisopropylethylamine, N-methylpiperidine, N-methylmorpholine, and triethylamine, and the first coupling agent is selected from 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(benzotriazole)-N,N,N' The compound of formula (V), the first tertiary amine, the first coupling agent and the compound of formula (VI) are in the following molar ratios: N'-tetramethylurea hexafluorophosphate, benzotriazol-1-yl-oxytripyrrolylphosphine hexafluorophosphate, benzotriazol-1-yl-oxytridimethylaminophosphine hexafluorophosphate, tripyrrolylphosphonium bromide hexafluorophosphate, dicyclohexylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and propylphosphoric anhydride.

4. The preparation method according to claim 1 or 2, wherein, Step (1'a) includes the following steps: mixing the compound shown in formula (II), the compound shown in formula (VIII), N,N-diisopropylethylamine, and the first catalyst, and reacting at 80°C to 110°C for 10-24 hours under a protective gas atmosphere, and separating the compound shown in formula (VII'); the first catalyst is selected from any one of 1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, palladium acetate, palladium chloride, dibenzylacetone palladium, dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium, and dichloro[bis(triphenylphosphine)]palladium, the molar ratio of the compound shown in formula (II) to the compound shown in formula (VIII) is 1:(1-1.5), and the molar ratio of the compound shown in formula (II), N,N-diisopropylethylamine, and the first catalyst is 1:(1-8):(0.001-1).

5. The preparation method according to claim 1 or 2, wherein, Step (1'b) includes the following steps: at 20°C to 100°C, in a nitrogen atmosphere, the compound shown in formula (VII'), the third alkali, the second catalyst, and the first reducing agent are mixed and reacted for 10h-25h, and the compound shown in formula (VII) is separated; the second catalyst is selected from at least one of cuprous iodide, cuprous bromide, cuprous chloride, and cuprous cyanide; the third alkali is selected from at least one of potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate; the first reducing agent is selected from at least one of pinacol ester of borate, boric acid, pinacol borane, and catechol borane; the molar ratio of the compound shown in formula (VII'), the third alkali, the second catalyst, and the first reducing agent is 1:(0.1-5):(20-40):(1-5).

6. The preparation method according to claim 1 or 2, wherein, Step (2) includes the following steps: cooling the compound shown in formula (VII) to -70°C to -80°C, adding boron tribromide dropwise, reacting for 4-5 hours, then heating to -30°C to -35°C and reacting for 2-3 hours, then pouring it into a saturated aqueous solution of carbonate, controlling the reaction temperature to 0°C to 10°C, adding hydrochloric acid aqueous solution to adjust the pH to 5-6, and separating to obtain the compound shown in formula (IX); the carbonate is selected from at least one of potassium bicarbonate, potassium carbonate, sodium bicarbonate, and sodium carbonate, and the molar ratio of the compound shown in formula (VII) to the boron tribromide is 1:(5-15); Alternatively, step (2) includes the following steps: adding the compound shown in formula (VII), hydrochloric acid and a third catalyst under a hydrogen atmosphere, reacting for 10 h-24 h, and separating the compound shown in formula (IX); the third catalyst is selected from at least one of palladium on carbon, platinum on carbon, rhodium on carbon, ruthenium on carbon and Raney nickel, and the molar ratio of the compound shown in formula (VII), hydrochloric acid and the third catalyst is 1:(0.1-10):(0.001-1).

7. The preparation method according to claim 2, wherein, Step (3) includes the following steps: controlling the temperature to be less than or equal to 35°C, adding an aqueous sodium hydroxide solution to the compound shown in formula (IX), adjusting the pH to 7.8-8.3, and separating the compound shown in formula (I); Alternatively, step (3) includes the following steps: controlling the temperature to 50°C to 70°C, adding sodium methoxide dropwise to the compound shown in formula (IX), reacting for 2-3 hours, and then reacting for 1-2 hours at 0°C to 5°C to separate the compound shown in formula (I); the molar ratio of the compound shown in formula (IX) to the sodium methoxide is 1:(0.8-1.2).

8. The preparation method according to claim 1 or 2, further comprising the following step: (4) The compound shown in formula (II) and the compound shown in formula (III) undergo a coupling reaction to obtain the compound shown in formula (IV); (5) The compound shown in formula (IV) is hydrogenated to obtain the compound shown in formula (IV'); (6) The compound shown in formula (IV') is hydrolyzed to obtain the compound shown in formula (V); in, R 1 Substituents selected from halogens or C2-C6 sulfonate compounds; R 2 Selected from C1-C8 alkyl groups or C6-C18 aryl groups.

9. The preparation method according to claim 8, wherein, Step (4) includes the following steps: under the protection of a protective gas, the compound shown in formula (II), the compound shown in formula (III), the fourth catalyst, and the first base are mixed, heated to 70°C to 75°C, and reacted for 10-24 hours to obtain the compound shown in formula (IV); the fourth catalyst is selected from at least one of dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium, dichloro[bis(triphenylphosphine)]palladium, palladium chloride, palladium acetate, and dibenzylacetone palladium; the first base is selected from at least one of triethylamine, diethylamine, diisopropylethylamine, tetramethylethylenediamine, and N-methylmorpholine; the molar ratio of the compound shown in formula (II), the compound shown in formula (III), the fourth catalyst, and the first base is 1:(0.3-1):(0.001-1):(0.5-1).

10. The preparation method according to claim 8, wherein... Step (5) includes the following steps: The compound shown in formula (IV), the third alkali agent, and the second reducing agent are mixed at 50°C to 55°C and reacted for 1-5 hours to obtain the compound shown in formula (IV'). The second reducing agent is selected from at least one of methanesulfonyl hydrazine, benzenesulfonyl hydrazine, trimethylbenzenesulfonyl hydrazine, and pyridinesulfonyl hydrazine. The third alkali agent is selected from at least one of potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate. The molar ratio of the compound shown in formula (IV), the second reducing agent, and the third alkali agent is 1:(1-5):(1-10). Alternatively, step (5) includes the following steps: mixing the compound shown in formula (IV), the acidic catalyst, and the third reducing agent at 0°C to 55°C and reacting for 1-5 hours to obtain the compound shown in formula (IV'); the acidic catalyst is selected from at least one of boron trifluoride, boron trichloride, aluminum trichloride, tin tetrachloride, hydrochloric acid, trifluoroacetic acid, and trifluoromethanesulfonic acid; the third reducing agent is selected from at least one of triethylsilane and tributyltin hydride; and the molar ratio of the compound shown in formula (IV), the acidic catalyst, and the third reducing agent is 1:(0.1-5):(1-5). Alternatively, step (5) includes the following steps: at 40°C to 105°C, in a nitrogen atmosphere, the compound shown in formula (IV), the fourth alkali, the fifth catalyst, and the fourth reducing agent are mixed and reacted for 1-5 hours, and the compound shown in formula (IV') is separated; the fifth catalyst is selected from at least one of cuprous iodide, cuprous bromide, cuprous chloride, and cuprous cyanide; the fourth alkali is selected from at least one of potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate; the fourth reducing agent is selected from at least one of pinacol ester of borate, boric acid, pinacol borane, and catechol borane. The molar ratio of the compound shown in formula (IV), the fourth alkali, the fifth catalyst, and the fourth reducing agent is 1:(0.1-5):(0.01-1):(1-5); Alternatively, step (5) includes the following steps: at 0°C to 55°C, in a hydrogen atmosphere, the compound shown in formula (IV), the acid, and the sixth catalyst are mixed and reacted for 1-5 hours, and the compound shown in formula (IV') is separated; the acid is selected from at least one of acetic acid and hydrochloric acid, and the sixth catalyst is selected from at least one of palladium on carbon, platinum on carbon, rhodium on carbon, ruthenium on carbon, and Raney nickel, and the molar ratio of the compound shown in formula (IV), the acid, and the sixth catalyst is 1:(0-10):(0.01-1).

11. The preparation method according to claim 8, wherein, Step (6) includes the following steps: mixing the compound shown in formula (IV') with an alkaline solution and reacting it at 60°C to 70°C for 6-24 hours to obtain the compound shown in formula (V); the alkali in the alkaline solution is selected from at least one of sodium hydroxide, potassium hydroxide, and barium hydroxide.

12. The preparation method according to claim 1 or 2, further comprising the following steps: (7) Under the protection of a protective gas, the temperature is controlled to be less than or equal to 5°C, and a halogenating agent is added dropwise to the compound shown in formula (II-3). The reaction is carried out for 8-20 hours, and the compound shown in formula (II-4) is obtained by separation. The halogenating agent is selected from at least one of thionyl chloride, phosphorus pentachloride, oxalyl chloride, and phosphorus tribromooxychloride. The molar ratio of the compound shown in formula (II-3) to the halogenating agent is 1:(2-5). (8) Under a protective atmosphere of protective gas, Evan's chiral cofactor, Lewis acid, and second base are mixed, and the temperature is controlled to be less than or equal to 0°C. The compound shown in formula (II-4) is added dropwise, and the reaction is carried out at 10°C to 15°C for 10-24 hours. The compound shown in formula (II-5) is then separated. The Evan's chiral cofactor is selected from (S)-4-isopropyloxazolidin-2-one, (S)-4-phenyloxazolidin-2-one, and (S)-4-benzyloxazolidin-2-one. At least one of (S)-4-tert-butyloxazolidin-2-one, wherein the Lewis acid is selected from at least one of LiCl, LiBr, LiI, ZnCl2, and ZnI2, and the second base is selected from at least one of triethylamine, diisopropylethylamine, and tetramethylethylenediamine, wherein the molar ratio of Evan's chiral cofactor, the Lewis acid, the second base, and the compound shown in formula (II-4) is 1:(1-1.5):(1-2):(1-1.5); (9) Under the protection of a protective gas, the temperature is controlled to be less than or equal to -60°C. The compound shown in formula (II-5) is added dropwise to vinyl magnesium bromide and reacted for 0.1-4 h. Then, acid is added dropwise to quench the reaction. The temperature is raised to -5°C to 5°C and the compound shown in formula (II) is extracted and separated. The acid is selected from at least one of acetic acid, hydrochloric acid, and sulfuric acid. The molar ratio of vinyl magnesium bromide, the compound shown in formula (II-5), and the acid is 1:(0.5-1.5):(1-10). 。 13. The preparation method according to claim 1 or 2, further comprising the following steps: (10) The compound shown in formula (III') and the compound shown in formula (VI) are condensed together to obtain the compound shown in formula (VIII); Among them, R 1 Substituents selected from halogens or C1-C9 sulfonate compounds.

14. The preparation method according to claim 13, wherein, Step (10) includes the following steps: at 20°C to 30°C, the compound shown in formula (III'), the second tertiary amine, and the second coupling agent are mixed and reacted for 1.5 h to 2 h, then the compound shown in formula (VI) is added and reacted for 2 h to 3 h, and the compound shown in formula (VII) is separated; the second tertiary amine is selected from at least one of N,N-diisopropylethylamine and triethylamine, and the second coupling agent is selected from 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and 2-(benzotriazole)-N,N,N',N The compound of formula (III'), the second tertiary amine, the second coupling agent and the compound of formula (VI) are in the molar ratio of 1:(3-10):(0.8-1.5):(0.9-1.5).

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