Preparation method for LFA-1 inhibitor

Abstract

The present application provides a preparation method for an LFA-1 inhibitor. The LFA-1 inhibitor is a compound represented by formula (IX) or a salt thereof, and can be used for treating ophthalmic diseases, such as dry eye syndrome.

Description

A preparation method of LFA-1 inhibitor Technical Field

[0001] The present application relates to the technical field of organic synthesis, and in particular to a method for preparing an LFA-1 inhibitor. Background Art

[0002] The target receptor, lymphocyte function-associated antigen-1 (LFA-1) (αLβ2, CD11a / CD18), is a member of the integrin superfamily with 24 known members to date. It is a receptor involved in inflammatory, immune-mediated, and infectious diseases and is overexpressed in certain malignant diseases. These diseases are often serious, chronic conditions that often require lifelong treatment, such as dry eye syndrome. If not properly diagnosed and treated, further complications such as infection, ocular surface keratinization, corneal ulcers, and conjunctival squamous changes may occur. From a clinical perspective, there is still a need for effective LFA-1 inhibitors to prevent symptoms or control the disease.

[0003] Summary of the Invention

[0004] The purpose of the embodiments of the present application is to provide a compound represented by formula (IX) or a salt thereof, its use, and an ophthalmic composition. The compound represented by formula (IX) or a salt thereof is used as an LFA-1 inhibitor and can treat ophthalmic diseases, such as dry eye syndrome.

[0005] The first aspect of the present application provides a method for preparing a compound represented by formula (IX), comprising the following steps:

[0006] (1) a compound represented by formula (II) and a compound represented by formula (VIII) are subjected to a coupling reaction to obtain a compound represented by formula (VII'), and then (2) the compound represented by formula (VII') is subjected to a reduction reaction to obtain a compound represented by formula (VII); or (3) a compound represented by formula (V) and a compound represented by formula (VI) are subjected to a condensation reaction to obtain a compound represented by formula (VII);

[0007] (4) The compound represented by formula (VII) is subjected to a deprotection reaction to obtain the compound represented by formula (IX);

[0008] or,

[0009] (3') The compound represented by formula (V') and the compound represented by formula (VI') are subjected to coupling reaction to obtain the compound represented by formula (IX);

[0010] Wherein, PG is a hydroxyl protecting group, which is selected from one of the following substituents: methyl, ethyl, isopropyl, tert-butyl, benzyl, phenyl, p-methoxybenzyl, p-nitrobenzoate, tert-butyldimethylsilyl, methoxymethyl, benzyloxymethyl, methylthiomethyl, ethoxymethyl, trimethylsilylethyl; R 1 A substituent selected from halogen or C2-C6 sulfonate compounds; illustratively, R 1 R is selected from Cl, Br, I, and a substituent formed by trifluoromethylsulfonate or methylsulfonate (i.e., trifluoromethylsulfonate or methylsulfonate); 3 is selected from hydrogen, methyl, ethyl, tert-butyl, benzyl, phenyl, and p-methoxybenzyl. -Me in the above compounds is methyl, and (R) and (S) in the above compounds are labels for chiral carbons.

[0011] In some embodiments of the present application, step (1) includes the following steps: mixing the compound represented by formula (II), the compound represented by formula (VIII), N,N-diisopropylethylamine, and a first catalyst, heating the mixture to 80°C to 110°C in a protective environment of protective gas, reacting for 10h-24h, and separating to obtain the compound represented by formula (VII'); the first catalyst is selected from at least one of 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium, dichloro[bis(triphenylphosphine)]palladium, palladium chloride, palladium acetate, and dibenzylideneacetonepalladium, the molar ratio of the compound represented by formula (II) to the compound represented by formula (VIII) is 1:(1-1.5), and the molar ratio of the compound represented by formula (II), N,N-diisopropylethylamine, and the first catalyst is 1:(1-8):(0.001-1).

[0012] In some embodiments of the present application, step (2) includes the following steps: at 20°C to 50°C, in a nitrogen atmosphere, mixing the compound represented by formula (VII'), a third alkaline agent, a second catalyst, and a first reducing agent, reacting for 10h-25h, and separating to obtain the compound represented by formula (VII); the second catalyst is selected from at least one of cuprous iodide, cuprous bromide, cuprous chloride, and cuprous cyanide, the third alkaline agent 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 biboric acid bis(pyridoyl)boron, biboric acid, bis(pyridoyl)borane, and catechol borane, and the molar ratio of the compound represented by formula (VII'), the third alkaline agent, the second catalyst, and the first reducing agent is 1:(0.1-5):(20-40):(1-5).

[0013] In some embodiments of the present application, step (3) includes the following steps: mixing the compound represented by formula (V), the first tertiary amine, and the first coupling agent, reacting for 0.5h-2h, then adding the compound represented by formula (VI) and reacting for 2h-3h, and separating to obtain the compound represented by formula (VII); the first tertiary amine is selected from at least 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'-tetramethyluronium hexafluorophosphate, 2-(benzotriazole)-N , at least one of N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazole-1-yl-oxytripyrrolidinophosphine hexafluorophosphate, benzotriazole-1-yl-oxytrisdimethylaminophosphine hexafluorophosphate, tripyrrolidinophosphine bromide hexafluorophosphate, dicyclohexylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and propyl phosphoric anhydride, the molar ratio of the compound represented by formula (V), the first tertiary amine, the first coupling agent and the compound represented by formula (VI) is 1:(3-10):(0.8-1.5):(0.9-1.2).

[0014] In some embodiments of the present application, step (4) may include the following steps: cooling the compound represented by formula (VII) to -70°C to -80°C, adding boron tribromide dropwise, reacting for 4h-5h, heating to -30°C to -35°C and reacting for 2h-3h, pouring into a saturated carbonate aqueous solution, controlling the reaction temperature to 0°C to 10°C, adding hydrochloric acid aqueous solution to adjust the pH to 5-6, and isolating to obtain the compound represented by 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 represented by formula (VII) to boron tribromide is 1:(5-15). Furthermore, in step (4), the carbonate aqueous solution is added dropwise. The present application has no particular limitation on the concentration of the carbonate aqueous solution, as long as the purpose of the present application can be achieved. For example, the concentration of the carbonate aqueous solution can be 0.1mol / L to 1mol / L. Furthermore, the mass ratio of the compound represented by formula (VII) to the saturated carbonate aqueous solution is 1:(10-100).

[0015] In some embodiments of the present application, step (4) may also include the following steps: adding a compound represented by formula (VII), hydrochloric acid, and a third catalyst under a hydrogen atmosphere, reacting for 10 h to 24 h, and separating to obtain a compound represented by formula (IX); the third catalyst is selected from at least one of palladium carbon, platinum carbon, rhodium carbon, ruthenium carbon, and Raney nickel, and the molar ratio of the compound represented by formula (VII), hydrochloric acid, and the third catalyst is 1: (0.1-10): (0.001-1). Wherein, the hydrochloric acid is added in the form of an aqueous hydrochloric acid solution, the concentration of the aqueous hydrochloric acid solution is 0.1 mol / L to 6 mol / L, and the molar ratio of the compound represented by formula (VII) to the hydrochloric acid refers to the molar ratio of the compound represented by formula (VII) to the hydrochloric acid in the aqueous hydrochloric acid solution.

[0016] In some embodiments of the present application, step (3') includes the following steps: mixing a compound represented by formula (V'), a first tertiary amine, and a first coupling agent, reacting for 0.5h-20h, adding a compound represented by formula (VI'), reacting for 2h-3h, and separating to obtain a compound represented by formula (IX); the first tertiary amine is selected from at least 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'-tetramethyluronium hexafluorophosphate, 2-(benzotriazole)- At least one of N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yl-oxytripyrrolidinylphosphine hexafluorophosphate, benzotriazol-1-yl-oxytrisdimethylaminophosphine hexafluorophosphate, tripyrrolidinylphosphonium bromide hexafluorophosphate, dicyclohexylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and propylphosphonic anhydride, the molar ratio of the compound represented by formula (V'), the first tertiary amine, the first coupling agent, and the compound represented by formula (VI') is 1:(3-10):(0.8-1.5):(0.9-1.2).

[0017] The present application provides a method for preparing a compound represented by formula (I), comprising the steps of:

[0018] The temperature is regulated to be less than or equal to 35°C, and an aqueous sodium hydroxide solution is added to the compound represented by formula (IX), and the pH is adjusted to 7.8-8.3, and the compound represented by formula (I) is separated. Furthermore, the aqueous sodium hydroxide solution is added dropwise, and the present application has no particular limitation on the concentration of the aqueous sodium hydroxide solution, as long as the purpose of the present application can be achieved. For example, the concentration of the aqueous sodium hydroxide solution can be 0.01 mol / L to 10 mol / L. Furthermore, the molar ratio of the compound represented by formula (IX) to the sodium hydroxide in the aqueous sodium hydroxide solution is 1: (0.5-2). The above-mentioned regulating temperature is less than or equal to 35°C, which can be adjusting the reaction temperature 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 represented by formula (IX) can be prepared with reference to the above-mentioned preparation method. Specifically, the aqueous sodium hydroxide solution in the step can be replaced with an alkaline solution containing calcium, magnesium and potassium, such as calcium hydroxide, magnesium hydroxide and potassium hydroxide.

[0019] In some embodiments of the present application, the preparation method of the compound represented by formula (I) may further include the steps of: regulating the temperature to 50°C to 70°C, adding sodium methoxide dropwise to the compound represented by formula (IX), reacting for 2h-3h, and then reacting at 0°C to 5°C for 1h-2h to separate the compound represented by formula (I); the molar ratio of the compound represented by formula (IX) to sodium methoxide is 1:(0.8-1.2). It is understood that the calcium salt, magnesium salt, and potassium salt of the compound represented by formula (IX) can be prepared with reference to the above preparation method. Specifically, the sodium methoxide in the step can be replaced with an organic salt containing calcium, magnesium, and potassium, such as calcium methoxide, magnesium ethoxide, and potassium tert-butoxide.

[0020] The second aspect of the present application provides a method for preparing a compound represented by formula (V), comprising the following steps:

[0021] (1') The compound represented by formula (II) and the compound represented by formula (III) undergo coupling reaction to obtain the compound represented by formula (IV);

[0022] (2') The compound represented by formula (IV) is subjected to hydrogenation reduction reaction to obtain the compound represented by formula (IV');

[0023] (5) The compound represented by formula (IV') is subjected to a hydrolysis reaction to obtain the compound represented by formula (V);

[0024] or,

[0025] (1") The compound represented by formula (II) and the compound represented by formula (III') are subjected to coupling reaction to obtain the compound represented by formula (IV");

[0026] (2") The compound represented by formula (IV") is subjected to hydrogenation reduction reaction to obtain the compound represented by formula (V);

[0027] or,

[0028] (1″′) The compound represented by formula (II) and the compound represented by formula (III′) are subjected to coupling reaction to obtain the compound represented by formula (V);

[0029] Wherein, PG is a hydroxyl protecting group, which is selected from one of the following substituents: methyl, ethyl, isopropyl, tert-butyl, benzyl, phenyl, p-methoxybenzyl, p-nitrobenzoate, tert-butyldimethylsilyl, methoxymethyl, benzyloxymethyl, methylthiomethyl, ethoxymethyl, trimethylsilylethyl; R 1 A substituent selected from halogen or C2-C6 sulfonate compounds, illustratively, R 1 A substituent selected from Cl, Br, I, and trifluoromethylsulfonate or methylsulfonate; R 2 Selected from methyl, ethyl, tert-butyl, benzyl, phenyl, p-methoxybenzyl.

[0030] In some embodiments of the present application, step (1') includes the following steps: under a protective environment of protective gas, mixing the compound represented by formula (II), the compound represented by formula (III), a fourth catalyst, and a first alkaline agent, heating to 70°C to 75°C, reacting for 10h-24h, and separating to obtain the compound represented by formula (IV); the fourth catalyst is selected from at least one of dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium, dichloro[bis(triphenylphosphine)]palladium, palladium chloride, palladium acetate, and dibenzylideneacetonepalladium, and the first alkaline agent is selected from at least one of triethylamine, diethylamine, diisopropylethylamine, tetramethylethylenediamine, and N-methylmorpholine, and the molar ratio of the compound represented by formula (II), the compound represented by formula (III), the fourth catalyst, and the first alkaline agent is 1:(0.3-1):(0.001-1):(0.5-1).

[0031] In some embodiments of the present application, step (2') may include the following steps: mixing the compound represented by formula (IV), a third alkaline agent, and a second reducing agent at 50°C to 55°C, reacting for 1h-5h, and separating to obtain the compound represented by formula (IV'); the second reducing agent is selected from at least one of methylsulfonylhydrazine, benzenesulfonylhydrazine, trimethylbenzenesulfonylhydrazine, pyridinesulfonylhydrazine, and diboronic acid pyranol ester, and the third alkaline 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 represented by formula (IV), the second reducing agent, and the third alkaline agent is 1:(1-5):(1-10).

[0032] In some embodiments of the present application, step (2') may also include the following steps: mixing the compound represented by formula (IV), an acidic catalyst, and a third reducing agent at 0°C to 55°C, reacting for 1h-5h, and separating to obtain the compound represented by 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, and the third reducing agent is selected from at least one of triethylsilyl hydride and tributyltin hydride, and the molar ratio of the compound represented by formula (IV), the acidic catalyst, and the third reducing agent is 1:(0.1-5):(1-5).

[0033] In some embodiments of the present application, step (2') may also include the following steps: at 40°C to 105°C, in a nitrogen atmosphere, mixing the compound represented by formula (IV), a fourth alkaline agent, a fifth catalyst, and a fourth reducing agent, reacting for 1h-5h, and separating to obtain the compound represented by formula (IV'); the fifth catalyst is selected from at least one of cuprous iodide, cuprous bromide, cuprous chloride, and cuprous cyanide, the fourth alkaline agent 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 biboric acid bis(pyridoyl)boron, biboric acid, bis(pyridoyl)borane, and catechol borane; the molar ratio of the compound represented by formula (IV), the fourth alkaline agent, the fifth catalyst, and the fourth reducing agent is 1:(0.1-5):(0.01-1):(1-5).

[0034] In some embodiments of the present application, step (2') may also include the following steps: at 0°C to 55°C, in a hydrogen atmosphere, mixing the compound represented by formula (IV), an acid, and a sixth catalyst, reacting for 1h-5h, and separating to obtain the compound represented by formula (IV'); 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 carbon, platinum carbon, rhodium carbon, ruthenium carbon, and Raney nickel. The molar ratio of the compound represented by formula (IV), the acid, and the sixth catalyst is 1: (0-10): (0.01-1).

[0035] In some embodiments of the present application, step (5) includes the following steps: mixing the compound represented by formula (IV') with an alkaline solution, reacting the mixture at 60°C to 70°C for 6-24 hours, and isolating the compound represented by formula (V); the alkali in the alkaline solution is selected from at least one of sodium hydroxide, potassium hydroxide, and barium hydroxide. Furthermore, the molar ratio of the compound represented by formula (IV') to the alkali in the alkaline solution is 1:(1-100).

[0036] In some embodiments of the present application, step (5) may also include the following steps: mixing the compound represented by formula (IV') with a second Lewis acid, reacting at 80°C to 120°C for 1-24 hours, and isolating to obtain the compound represented by formula (V); the second Lewis acid is selected from at least one of lithium iodide, lithium bromide, lithium chloride, and pyridine hydrochloride. Furthermore, the molar ratio of the compound represented by formula (IV') to the second Lewis acid is 1:(1-100).

[0037] In some embodiments of the present application, step (1") includes the following steps: under a protective environment of protective gas, mixing the compound represented by formula (II), the compound represented by formula (III'), a fourth catalyst, and a first alkaline agent, heating to 70°C to 100°C, reacting for 10h-24h, and separating to obtain the compound represented by formula (IV"); the fourth catalyst is selected from at least one of dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium, dichloro[bis(triphenylphosphine)]palladium, palladium chloride, palladium acetate, and dibenzylideneacetonepalladium, and the first alkaline agent is selected from at least one of triethylamine, diethylamine, diisopropylethylamine, tetramethylethylenediamine, and N-methylmorpholine, and the molar ratio of the compound represented by formula (II), the compound represented by formula (III'), the fourth catalyst, and the first alkaline agent is 1:(0.3-1):(0.001-1):(0.5-1).

[0038] In some embodiments of the present application, step (2") includes the following steps: at 0°C to 55°C, in a hydrogen atmosphere, mixing the compound represented by formula (IV") and the sixth catalyst and reacting them for 1h-20h, and separating to obtain the compound represented by formula (V); the sixth catalyst is selected from at least one of palladium carbon, platinum carbon, rhodium carbon, ruthenium carbon, and Raney nickel, and the molar ratio of the compound represented by formula (IV") and the sixth catalyst is 1:(0.01-1).

[0039] In some embodiments of the present application, step (1') includes the following steps: under a protective environment of protective gas, mixing the compound represented by formula (II), the compound represented by formula (III'), the seventh catalyst, the first ligand, and the third Lewis acid, heating the mixture to 70°C to 85°C, reacting for 10h-24h, and separating to obtain the compound represented by formula (V); the seventh catalyst is selected from at least one of cobalt chloride, cobalt bromide, cobalt iodide, rhodium acetate, and rhodium chloride; the first ligand is selected from at least one of 1,1'-bis(diphenylphosphino)ferrocene, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, triphenylphosphine, and cyclooctadiene; the third Lewis acid is selected from at least one of zinc chloride, zinc fluoride, ferric chloride, tin chloride, stannous chloride, and aluminum chloride; and the molar ratio of the compound represented by formula (II), the compound represented by formula (III'), the seventh catalyst, and the third Lewis acid is 1:(0.5-5):(0.001-1):(0.5-2).

[0040] The third aspect of the present application provides a method for preparing the compound represented by (V'), which comprises the following steps:

[0041] (4') The compound represented by formula (V) is subjected to a deprotection reaction to obtain a compound represented by formula (V'); wherein the compound represented by formula (V) is prepared by the method described in this application;

[0042] Wherein, PG is a hydroxyl protecting group, and the hydroxyl protecting group is selected from one of the following substituents: methyl, ethyl, isopropyl, tert-butyl, benzyl, phenyl, p-methoxybenzyl, p-nitrobenzoate, tert-butyldimethylsilyl, methoxymethyl, benzyloxymethyl, methylthiomethyl, ethoxymethyl, and trimethylsilylethyl.

[0043] In some embodiments of the present application, step (4') may include the following steps: cooling the compound represented by formula (V) to -70°C to -80°C, adding boron tribromide dropwise, reacting for 4h-5h, heating to -30°C to 0°C and reacting for 2h-3h, adding a saturated carbonate aqueous solution, controlling the reaction temperature to 0°C to 10°C, adding a hydrochloric acid aqueous solution to adjust the pH to 1-2, and isolating to obtain the compound represented by formula (V'); 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 represented by formula (V) to boron tribromide is 1:(5-15). Furthermore, in step (4'), the carbonate aqueous solution is added dropwise. The present application does not particularly limit the concentration of the carbonate aqueous solution, as long as the purpose of the present application can be achieved. For example, the concentration of the carbonate aqueous solution can be 0.1mol / L to 1mol / L. Furthermore, the mass ratio of the compound represented by formula (V) to the saturated carbonate aqueous solution is 1:(10-100).

[0044] The fourth aspect of the present application provides a method for preparing a compound represented by formula (II), comprising the following steps:

[0045] (6) Formula (II-2) reacts with the Evans prosthetic group to produce the compound shown in (II-1);

[0046] (7) reacting the compound represented by formula (II-1) with a vinyl Grignard reagent to produce the compound represented by formula (II);

[0047] Wherein, PG is a hydroxyl protecting group, which is selected from one of the following substituents: methyl, ethyl, isopropyl, tert-butyl, benzyl, phenyl, p-methoxybenzyl, p-nitrobenzoate, tert-butyldimethylsilyl, methoxymethyl, benzyloxymethyl, methylthiomethyl, ethoxymethyl, trimethylsilylethyl; R4 Selected from phenyl, tert-butyl, benzyl, isopropyl, p-methoxybenzyl.

[0048] In some embodiments of the present application, step (6) may include the following steps: in a protective environment of protective gas, mixing an Evan's chiral auxiliary group, a Lewis acid, and a second alkaline agent, regulating the temperature to -5°C-0°C, adding dropwise a compound represented by formula (II-2), reacting at -10°C to 15°C for 10h-24h, and separating to obtain a compound represented by formula (II-1); the Evan's chiral auxiliary group is selected from (S)-4-isopropyloxazolidin-2-one, (S)-4-phenyloxazolidin-2-one, (S)-4-benzyloxazolidin-2-one, (S)-4 - at least one of tert-butyloxazolidin-2-one, the Lewis acid is selected from at least one of LiCl, LiBr, LiI, ZnCl2, and ZnI2, the second base is selected from at least one of triethylamine, diisopropylethylamine, and tetramethylethylenediamine, and the molar ratio of Evan's chiral auxiliary group, Lewis acid, second base and compound represented by formula (II-2) is 1: (1-1.5): (1-2): (1-1.5); the above-mentioned temperature control of -5°C-0°C can be to adjust the reaction temperature to -5°C, -4°C, -3°C, -2°C, -1°C or 0°C.

[0049] In some embodiments of the present application, step (7) may include the following steps: in a protective environment of protective gas, regulating the temperature to -85°C to -60°C, mixing the compound represented by formula (II-1), Lewis acid and Grignard reagent, reacting for 0.5h-8h, quenching with water and then heating to -5°C to 25°C, and separating to obtain the compound represented by formula (II); the Lewis acid is selected from at least one of lithium chloride, lithium bromide, and lithium iodide, the Grignard reagent is vinylmagnesium bromide or vinylmagnesium chloride, and the molar ratio of the Grignard reagent, the compound represented by formula (II-1) and the Lewis acid is 1: (0.5-1.5): (1-10); the above-mentioned regulating the temperature to -85°C to -60°C may be adjusting the reaction temperature to -85°C, -80°C, -75°C, -70°C, -65°C or -60°C.

[0050] The fifth aspect of the present application provides a method for preparing a compound represented by formula (II-2), comprising the following steps:

[0051] (8) Diethyl methylphosphite represented by formula (II-5) is hydrolyzed to monoethyl methylphosphite represented by formula (II-4);

[0052] (9) Monoethyl methylphosphite represented by formula (II-4) is subjected to a coupling reaction to produce a compound represented by formula (II-3);

[0053] (10) The compound represented by formula (II-3) is subjected to chlorination reaction to generate the compound represented by formula (II-2);

[0054] or (11) triethyl phosphite represented by formula (II-7) undergoes coupling reaction to produce a compound represented by formula (II-6");

[0055] (12) The compound represented by formula (II-6") is hydrolyzed to form a phosphate monoester represented by formula (II-6');

[0056] (10') The phosphoric acid monoester represented by formula (II-6') is chlorinated to the phosphorus oxychloride represented by formula (II-6);

[0057] (13) Phosphorus oxychloride represented by formula (II-6) reacts with a methyl Grignard reagent to produce a compound represented by formula (II-3);

[0058] (10) Chlorination of the compound represented by formula (II-3) to produce the compound represented by formula (II-2);

[0059] or (14) trimethyl methylphosphite represented by formula (II-7') is rearranged to dimethyl methylphosphite represented by formula (II-8");

[0060] (10") The dimethyl methyl phosphate represented by formula (II-8") is chlorinated to form the methyl phosphorus dichloride represented by formula (II-8');

[0061] (15) Methylphosphoryl dichloride represented by formula (II-8') reacts with isopropyl alcohol to produce methylphosphonic acid isopropyl ester monochloride represented by formula (II-8);

[0062] (13') Methylphosphonic acid isopropyl chloride represented by formula (II-8) reacts with a Grignard reagent to produce a compound represented by formula (II-3');

[0063] (10″′) The compound represented by formula (II-3′) is subjected to chlorination reaction to generate the compound represented by formula (II-2);

[0064] Wherein, PG is a hydroxyl protecting group, and the hydroxyl protecting group is selected from one of the following substituents: methyl, ethyl, isopropyl, tert-butyl, benzyl, phenyl, p-methoxybenzyl, p-nitrobenzoate, tert-butyldimethylsilyl, methoxymethyl, benzyloxymethyl, methylthiomethyl, ethoxymethyl, trimethylsilylethyl; Me is methyl, Et is ethyl, and iPr is isopropyl.

[0065] In some embodiments of the present application, step (8) includes the following steps: adding water dropwise to the methyldiethoxyphosphine represented by formula (II-5) at 30°C to 80°C, reacting for 0.5h-2h, and separating to obtain the compound represented by formula (II-4); the molar ratio of methyldiethoxyphosphine to water is 1:(1-1.5).

[0066] In some embodiments of the present application, step (9) includes the following steps: under the protection of protective gas, mixing the fifth alkali agent, the reactant, the compound represented by formula (II-4), and the eighth catalyst, reacting at 80°C to 120°C for 4h-5h, and separating to obtain the compound represented by formula (II-3); the molar ratio of the fifth alkali agent, the reactant, the compound represented by formula (II-4) and the eighth catalyst is 1: (0.8-1.2): (0.8-1.5): (0.01-1), the fifth alkali agent is selected from at least one of triethylamine and diisopropylethylamine, the eighth catalyst is selected from at least one of dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium, dichloro[bis(triphenylphosphine)]palladium, palladium chloride, palladium acetate, dibenzylideneacetonepalladium, nickel chloride, dichloro[bis(triphenylphosphine)]nickel, the reactant is selected from at least one of m-bromoanisole or Wherein, R is an electron-withdrawing group, and the electron-withdrawing group is selected from a substituent formed by a halogen or a C1-C9 sulfonate compound. Exemplarily, R is selected from Cl, Br, I, and a substituent formed by trifluoromethylsulfonate or methylsulfonate.

[0067] In some embodiments of the present application, step (10) includes the following steps: in a protective environment of protective gas, regulating the temperature to -5°C-5°C, adding a halogenating agent dropwise to the compound represented by formula (II-3), reacting for 8h-20h, and separating to obtain the compound represented by formula (II-2); the halogenating agent is selected from at least one of thionyl chloride, phosphorus pentachloride, oxalyl chloride, and phosphorus oxychloride, and the molar ratio of the compound represented by formula (II-3) to the halogenating agent is 1:(2-5); the above-mentioned regulating temperature of -5°C-5°C can be 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;

[0068] In some embodiments of the present application, step (11) includes the following steps: mixing the reactant, triethyl phosphite represented by formula (II-7), and the eighth catalyst, reacting at 100°C to 200°C for 4h-6h, and separating to obtain the compound represented by formula (II-6"); the molar ratio of the reactant, triethyl phosphite represented by formula (II-7) and the eighth catalyst is 1: (0.8-1.5): (0.01-1), the eighth catalyst is selected from at least one of dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium, dichloro[bis(triphenylphosphine)]palladium, palladium chloride, palladium acetate, dibenzylideneacetonepalladium, nickel chloride, and dichloro[bis(triphenylphosphine)]nickel, and the reactant is selected from m-bromoanisole or Wherein, R is an electron-withdrawing group, and the electron-withdrawing group is selected from a substituent formed by a halogen or a C1-C9 sulfonate compound. Exemplarily, R is selected from Cl, Br, I, and a substituent formed by trifluoromethylsulfonate or methylsulfonate.

[0069] In some embodiments of the present application, step (12) includes the following steps: mixing the compound represented by formula (II-6") with an alkali solution, reacting at 50°C to 100°C for 1h-20h, and separating to obtain a phosphate monoester represented by formula (II-6'); the alkali in the alkali solution is selected from at least one of sodium hydroxide, potassium hydroxide, and barium hydroxide. Furthermore, the molar ratio of the compound represented by formula (II-6") to the alkali in the alkali solution is 1:(0.5-1.5).

[0070] In some embodiments of the present application, step (10') includes the following steps: under the protection of protective gas, adding a halogenating agent to the phosphoric acid monoester represented by formula (II-6'), reacting for 1h-20h, and separating to obtain the compound represented by formula (II-6); the halogenating agent is selected from at least one of thionyl chloride, phosphorus pentachloride, oxalyl chloride, and phosphorus oxychloride, and the molar ratio of the phosphoric acid monoester represented by formula (II-6') to the halogenating agent is 1:(1-5).

[0071] In some embodiments of the present application, step (13) includes the following steps: in a protective environment of protective gas, regulating the temperature to -50°C to -20°C, adding a methyl Grignard reagent to the compound represented by formula (II-6), reacting for 1h-8h, and separating to obtain the compound represented by formula (II-3); the molar ratio of the compound represented by formula (II-6) to the methyl Grignard reagent is 1: (1.0-2.5); the above-mentioned regulating the temperature to -50°C to -20°C can be adjusting the reaction temperature to -50°C, -40°C, -30°C, or -20°C.

[0072] In some embodiments of the present application, step (10) includes the following steps: in a protective environment of protective gas, the temperature is adjusted to -5°C-5°C, a halogenating reagent is added dropwise to the compound represented by formula (II-3), the reaction is carried out for 8h-20h, and the compound represented by formula (II-2) is separated; the halogenating reagent is selected from at least one of thionyl chloride, phosphorus pentachloride, oxalyl chloride, and phosphorus oxychloride, and the molar ratio of the compound represented by formula (II-3) to the halogenating reagent is 1:(2-5).

[0073] In some embodiments of the present application, step (14) includes the following steps: in a protective environment of protective gas, reacting trimethyl methyl phosphite represented by formula (II-7') with a Lewis acid at 50°C-100°C for 8h-20h; the Lewis acid is selected from at least one of TMSCl, TMSBr, TMSI, LiCl, LiBr, LiI, ZnCl2, and ZnI2; the molar ratio of trimethyl methyl phosphite represented by formula (II-7') to the Lewis acid is 1:(0.01-1.0).

[0074] In some embodiments of the present application, step (10") includes the following steps: adding a halogenating agent dropwise to dimethyl methyl phosphate represented by formula (II-8"), reacting for 8h-20h, and separating to obtain methyl phosphorus dichloride represented by formula (II-8'); the halogenating agent is selected from at least one of thionyl chloride, phosphorus pentachloride, oxalyl chloride, and phosphorus oxychloride, and the molar ratio of dimethyl methyl phosphate represented by formula (II-8") to the halogenating agent is 1:(2-5).

[0075] In some embodiments of the present application, step (15) includes the following steps: adding isopropyl alcohol and a first alkaline agent dropwise to the methylphosphonic acid dichloride shown in formula (II-8'), reacting for 8h-20h, and separating to obtain methylphosphonic acid isopropyl ester monochloride shown in formula (II-8); the first alkaline agent is selected from at least one of triethylamine, diethylamine, diisopropylethylamine, tetramethylethylenediamine, and N-methylmorpholine; the molar ratio of methylphosphonic acid dichloride shown in formula (II-8'), isopropyl alcohol and the first alkaline agent is 1: (1-5): (2-5); the above-mentioned temperature control of -5℃-5℃ can be adjusting the reaction temperature to -5℃, -4℃, -3℃, -2℃, -1℃, 0℃, 1℃, 2℃, 3℃, 4℃, or 5℃.

[0076] In some embodiments of the present application, step (13') includes the following steps: in a protective environment of protective gas, regulating the temperature to -5℃-5℃, adding phenyl Grignard reagent to methyl isopropyl phosphate monochloride shown in formula (II-8), reacting for 1h-18h, and separating to obtain the compound shown in formula (II-3'); the molar ratio of methyl isopropyl phosphate monochloride shown in formula (II-8) to phenyl Grignard reagent is 1: (0.5-2.5); the above-mentioned regulating temperature of -5℃-5℃ can be adjusting the reaction temperature to -5℃, -4℃, -3℃, -2℃, -1℃, 0℃, 1℃, 2℃, 3℃, 4℃, 5℃.

[0077] In some embodiments of the present application, step (10') includes the following steps: regulating the temperature to 20°C-100°C, adding a halogenating agent dropwise to the compound represented by formula (II-3'), reacting for 8h-20h, and separating to obtain the compound represented by formula (II-2); the halogenating agent is selected from at least one of thionyl chloride, phosphorus pentachloride, oxalyl chloride, and phosphorus oxychloride, and the molar ratio of the compound represented by formula (II-3') to the halogenating agent is 1:(2-5); the above-mentioned regulating temperature of 20°C-100°C can be adjusting the reaction temperature to 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, or 100°C.

[0078] The sixth aspect of the present application provides a method for preparing a compound represented by formula (VIII), comprising the following steps:

[0079] (16) The compound represented by formula (III') and the compound represented by formula (VI) are subjected to condensation reaction to obtain the compound represented by formula (VIII);

[0080] Among them, R 1 A substituent selected from halogen or C1-C9 sulfonate compounds, illustratively, R 1 R is selected from Cl, Br, I, and a substituent formed by trifluoromethylsulfonate or methylsulfonate (ie, a trifluoromethylsulfonate group or a methylsulfonate group). 3 is selected from hydrogen, methyl, ethyl, tert-butyl, benzyl, phenyl, and p-methoxybenzyl. -Me in the above compounds is methyl, and (R) and (S) in the above compounds are labels for chiral carbons.

[0081] In some embodiments of the present application, step (16) includes the following steps: mixing the compound represented by formula (III'), the second tertiary amine, and the second coupling agent at 20°C to 30°C, reacting for 1.5h-2h, then adding the compound represented by formula (VI) and reacting for 2h-3h, and separating to obtain the compound represented by formula (VIII); 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'-tetramethyluronium hexafluorophosphate, 2-(benzotriazole)-N, At least one of N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yl-oxytripyrrolidinylphosphine hexafluorophosphate, benzotriazol-1-yl-oxytrisdimethylaminophosphine hexafluorophosphate, tripyrrolidinylphosphonium bromide hexafluorophosphate, dicyclohexylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and propylphosphonic anhydride, the molar ratio of the compound represented by formula (III'), the second tertiary amine, the second coupling agent, and the compound represented by formula (VI) is 1:(3-10):(0.8-1.5):(0.9-1.5).

[0082] The present application does not particularly limit the separation steps in the above steps, and separation steps known in the art can be used as long as the purpose of the present application can be achieved. 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, treating with activated carbon, filtering, concentrating, recrystallizing, etc. The above-mentioned other organic solvents 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.

[0083] The present application has no particular limitation on the protective gas in the above steps. Conventional protective gases known in the art can be used as long as the purpose of the present application can be achieved. For example, the protective gas can include but is not limited to nitrogen and / or argon.

[0084] The seventh aspect of the present application provides a compound represented by formula (IX) or a salt thereof:

[0085] In some embodiments of the present application, the salt is a sodium salt, calcium salt, magnesium salt or potassium salt of the compound represented by formula (IX), preferably a sodium salt of the compound represented by formula (IX), that is, a compound represented by formula (I):

[0086] The eighth aspect of the present application provides an ophthalmic composition, which includes a compound represented by formula (IX) or a salt thereof, and a pharmaceutically acceptable carrier. The ophthalmic composition may also include an aqueous carrier. The compound represented by formula (IX) or a salt thereof has a large polarity, good water solubility and LFA-1 inhibitory activity, and the obtained ophthalmic composition has a good therapeutic effect on dry eye syndrome. Specifically, the pharmaceutically acceptable carrier may be a carrier for ophthalmic compositions known in the art, which is not limited in this application. The aqueous carrier may be a sterile aqueous solution or other aqueous carrier known in the art, which is not limited in this application. It is understandable that the above-mentioned ophthalmic composition may also include other essential components or additives known in the art, which are not limited in this application.

[0087] The ninth aspect of the present application provides a use of a compound represented by formula (IX) or a salt thereof, or an ophthalmic composition in the preparation of a medicament for treating or preventing an ophthalmic disease; preferably, the ophthalmic disease includes dry eye syndrome mediated by LFA-1.

[0088] The tenth aspect of the present application provides a method for treating or preventing an ophthalmic disease, comprising administering a therapeutically effective amount of a compound represented by formula (IX) or a salt thereof or an ophthalmic composition to a subject in need thereof; preferably, the ophthalmic disease includes dry eye syndrome mediated by LFA-1.

[0089] As used herein, a therapeutically effective amount refers to an amount of a drug sufficient to affect the treatment of a disease, or at least one clinical symptom of a disease or condition, when used to treat a subject. A therapeutically effective amount can vary depending on the drug, the symptoms of the disease or condition, the severity of the symptoms of the disease or condition, and the like. Wherever possible, an appropriate dosage will be readily apparent to one skilled in the art or can be determined by routine experimentation.

[0090] Beneficial effects of this application:

[0091] The compound of formula (IX) or a salt thereof provided herein can be used as an LFA-1 inhibitor to treat ophthalmic diseases, such as dry eye syndrome. The preparation method provided herein can synthesize the compound of formula (IX) and various intermediates. This preparation method is simple to operate, requires only a few reaction steps, has high yield and purity, operates under mild reaction conditions, and is suitable for industrial-scale production.

[0092] Of course, it is not necessary to achieve all the advantages described above at the same time when implementing any product or method of the present application. DETAILED DESCRIPTION

[0093] The following will be combined with the embodiments of the present application to clearly and completely describe the technical solutions in the embodiments of the present application. Obviously, the embodiments described are only part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field based on the present application are within the scope of protection of this application.

[0094] Example 1

[0095] Synthesis of (R)-(3-methoxyphenyl)(methyl)(vinyl)phosphine oxide (Compound II-A):

[0096] Compound II-4: Ethyl methylphosphinate

[0097] Add methyldiethoxyphosphine (1493 g, 10.98 mol), a compound represented by formula (II-5), into the reaction flask, control the temperature at 60°C, add H2O (197.4 ml, 10.98 mol) dropwise, stir for 1 hour after the addition is complete, and concentrate the reaction solution until no fraction is produced to obtain 1079 g of colorless transparent oil (1079 g, yield 91%) as compound II-4.

[0098] 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).

[0099] Compound II-3-A: Ethyl (3-methoxyphenyl)(methyl)phosphinate

[0100] Toluene (7.5 L) was added to the reactor, and nitrogen was blown for 35 minutes. Then triethylamine (980 g, 9.78 mol), reactant m-bromoanisole (compound II-2a, 1650 g, 8.87 mol), compound II-4 (1048 g, 9.70 mol), and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (Pd(dppf)Cl2, 129 g, 0.176 mol) were added respectively. The nitrogen was replaced by vacuum three times. The temperature was raised to 100 ° C under nitrogen protection and the reaction was stirred for 5 hours. The mixture was cooled to 20 ° C, the solid was precipitated, filtered, and the filtrate was concentrated and distilled to obtain a colorless oily product (1.44 kg, yield 75%) as compound II-3-A.

[0101] LCMS ESI (+) m / z: 215.1 (M+1).

[0102] Compound II-2-A: (3-methoxyphenyl)(methyl)phosphonyl chloride

[0103] Under nitrogen protection, dichloromethane (7.2 L) and compound II-3-A (1.44 kg, 6.73 mol) were added, the temperature was controlled to 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 concentrated below 35°C to obtain a light yellow oily product.

[0104] Compound II-1-A: (S)-4-isopropyl-3-((R)-(3-methoxyphenyl)(methyl)phosphoryl)oxazolidin-2-one

[0105] Under nitrogen, a reaction flask was charged with 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). The temperature was maintained at -3°C, and a dichloromethane solution (1.6 L) of compound II-2-A (1376 g, 6.74 mol) was added dropwise. The mixture was reacted at 15°C for 16 h. The mixture was washed with ammonium chloride solution (300 g / L) (4 L x 2), and the organic phase was separated and concentrated until no fraction remained. Ethyl acetate (3.9 L) was added, the temperature was raised to 60°C, and the mixture was completely dissolved. The temperature was then lowered to 20°C over 5 h, stirred at this temperature for 12 h, and filtered. The filter cake was rinsed with ethyl acetate (800 mL) to obtain compound II-1-A as a white solid (708 g, 35% yield).

[0106] LCMS ESI (+) m / z: 298.1 (M+1).

[0107] Compound II-A: (R)-(3-methoxyphenyl)(methyl)(vinyl)phosphine oxide

[0108] Under nitrogen protection, vinylmagnesium bromide (2.25L, 1mol / L, solvent is tetrahydrofuran (THF)) was added to the reaction flask, and the temperature was lowered to -78°C. Compound II-5-A (405g, 1.36mol) was dissolved in dichloromethane (1336mL) and THF (1336mL) to obtain a solution of compound II-1-A. The temperature was controlled at -75°C, and the solution of compound II-1-A was added dropwise over 4 hours. The temperature was controlled at -60°C, and acetic acid (368g, 6.1mol) was added dropwise. After the addition was completed, the temperature was naturally raised to 0°C, water (2L) was added, the liquids were separated, and the organic phase was concentrated at 40°C until there was no fraction. The yellow oil was compound II-A (150g crude product), which could be used directly in the next step.

[0109] LCMSESI (+) m / z: 197.1 (M+1), chiral purity ee>98%.

[0110] Example 2

[0111] 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 by Compound II-2b in the following synthetic route and the following synthetic route is used as a reference.

[0112] -Bn in the above compounds is benzyl.

[0113] Example 3

[0114] Synthesis of (R)-2,6-dichloro-4-(2-((3-methoxyphenyl)(methyl)phosphoryl)ethyl)benzoic acid (Compound VA):

[0115] Compound IV-A: Methyl (R,E)-2,6-dichloro-4-(2-((3-methoxyphenyl)(methyl)phosphoryl)vinyl)benzoate

[0116] Under nitrogen, 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 temperature was raised to 75°C and stirred for 16 h. After the reaction, the temperature was lowered to room temperature, water (250 mL) was added, and extraction with ethyl acetate (250 mL x 2) was performed. 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 light yellow oily product (92.4 g, 81.5% yield), which was compound IV-A.

[0117] LCMSESI (+) m / z: 399.1 (M+1), chiral purity ee>98%.

[0118] Compound IV'-A: (R)-methyl 2,6-dichloro-4-(2-((3-methoxyphenyl)(methyl)phosphoryl)ethyl)benzoate

[0119] Compound IV-A (1535 g, 3.85 mol) was dissolved in acetonitrile (6100 mL), heated to 55°C, and triethylsilyl hydrochloride (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 completion of the addition, the mixture was stirred at 55°C for 1.5 h. The reaction was stopped, the temperature was lowered to 8°C, and a saturated aqueous potassium carbonate solution (4.5 L) was added. The layers were separated, and the aqueous phase was extracted once with dichloromethane (4.5 L). The layers were separated, and the organic phases were combined and concentrated at 45°C until no fractions remained. This afforded a crude black oil (1580 g) as compound IV'-A. This crude product was used directly in the next step.

[0120] LCMS ESI (+) m / z: 401.1 (M+1), chiral purity ee>98%.

[0121] Compound VA: (R)-2,6-dichloro-4-(2-((3-methoxyphenyl)(methyl)phosphoryl)ethyl)benzoic acid

[0122] 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). Aqueous sodium hydroxide solution was added dropwise at room temperature. The mixture was heated to 60°C and stirred for 12 h. The mixture was cooled to room temperature, and water (4500 mL) and dichloromethane (11000 mL) were added and the layers separated. The aqueous phase was further extracted with dichloromethane (4500 mL), and the layers separated. The pH of the aqueous phase was adjusted to ≤3 with 2 mol / L aqueous hydrochloric acid. Dichloromethane (7500 mL) was added to separate the layers, and the aqueous phase was further extracted with dichloromethane (4500 mL). The dichloromethane phases were combined. Dicyclohexylamine (780 g, 4.31 mmol) was added to the dichloromethane phase and stirred for 2 h. 2 mol / L aqueous hydrochloric acid solution was added dropwise to adjust the pH to 3, filtered through diatomaceous earth, and the filter cake was rinsed once with dichloromethane (DCM, 1500 mL). The organic phase was concentrated at 45°C until there was no fraction to obtain 1120 g of a black oil. Ethylene glycol dimethyl ether (1680 mL) was added to dissolve the mixture, and a large amount of solid precipitated during the stirring process of heating to 70°C. N-heptane (1680 mL) was slowly added dropwise. The mixture was stirred for 2 h and then slowly cooled to 5°C within 5 h. The mixture was stirred for 2 h and filtered. The filter cake was rinsed once with cold ethylene glycol dimethyl ether (896 mL). The solid was dried in vacuo at 45°C for 24 h to obtain an off-white solid (840 g, 55% yield) as compound VA.

[0123] LCMS ESI (+) m / z: 387.1 (M+1), chiral purity ee>98%.

[0124] 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).

[0125] Example 4

[0126] Synthesis of benzyl (S)-2-(2,6-dichloro-4-(2-((R)-(3-methoxyphenyl)(methyl)phosphoryl)ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoate (Compound VII-A):

[0127] 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'-tetramethyluronium hexafluorophosphate (HATU, 207 g, 545 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour. (S)-2-amino-3-(3-(methylsulfonyl)phenyl)propionic acid benzyl ester hydrochloride (the hydrochloride salt of compound VI-A, 201 g, 543 mmol) was added and stirred at the same temperature for 2.5 hours. Ethyl acetate (2100 mL) and water (1050 mL) were added sequentially, and the layers were stirred to separate. The aqueous phase was extracted twice with ethyl acetate (630 mL), and the ethyl acetate phases were combined. The ethyl acetate phase was washed once with a saturated aqueous sodium bicarbonate solution (1050 mL) and once with a 1 mol / L aqueous hydrochloric acid solution (1050 mL), and the layers were separated. 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), heated to 60°C, and n-heptane (1775 mL) was slowly added dropwise. The temperature was slowly lowered to room temperature over 4 hours, and the mixture was stirred at 0°C for 2 hours and filtered. The filter cake was rinsed with cold acetonitrile (350 mL) and dried under vacuum at 40°C for 24 hours to yield a white solid (230 g, 60% yield) as compound VII-A.

[0128] LCMS ESI (+) m / z: 702.0 (M+1), chiral purity ee>98%.

[0129] Example 5

[0130] Synthesis of benzyl (S)-2-(2,6-dichloro-4-(2-((R)-(3-methoxyphenyl)(methyl)phosphoryl)ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoate (Compound VII-A):

[0131] Compound VIII-A: (S)-benzyl 2-(4-bromo-2,6-dichlorobenzamido)-3-(3-(methylsulfonyl)phenyl)propionate

[0132] 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 the reactor respectively, and the mixture was stirred at 25°C for 2 h. (S)-2-amino-3-(3-(methylsulfonyl)phenyl)propionic acid benzyl ester hydrochloride (hydrochloride of Compound VI-A, 753.7 g, 2.04 mol) was added to the reactor, and the mixture was stirred for 3 h. Dichloromethane (2.75 L) and water (1. 65L) and stirred for 20min, allowed to stand for 20min to separate the layers, the aqueous phase was continuously extracted once with dichloromethane (1.65L), the organic phases were separated and combined, the organic phase was washed once with 1mol / L hydrochloric acid (2.2L), the organic phase was continuously washed once with sodium bicarbonate (1.65L) solution, the separated organic phase was continuously washed twice with water (1.65L), the separated organic phase was concentrated at 45°C until there was no fraction, ethyl acetate (2.2L) was added, the temperature was raised to 65°C until the solution was clear, the temperature was lowered to 5°C for at least 12h, the temperature was maintained at this temperature and stirred for at least 2h, filtered, and the solid was transferred to a vacuum drying oven and dried at 45°C for at least 16h to obtain a light yellow solid (0.9kg, yield 75%) as compound VIII-A.

[0133] LCMS ESI (+) m / z: 585.9 (M+1), chiral purity ee>98%.

[0134] Compound VII'-A: Benzyl (S)-2-(2,6-dichloro-4-((E)-2-((R)-(3-methoxyphenyl)(methyl)phosphoryl)vinyl)benzamido)-3-(3-(methylsulfonyl))phenyl)propanoate

[0135] To a reaction flask, 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). Stir for at least 20 minutes until dissolved. Then add DIEA (27.6 g, 214 mmol) and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) tetrahydrofuran adduct (1.56 g, 1.94 mmol). Purge the reactor with nitrogen three times, raise the temperature to 98°C, and react for 16 hours. Stop the reaction and cool to 25°C. Add 250 mL of dichloromethane and 400 mL of water to the reactor, stir for at least 20 minutes, separate the layers, and store the organic phase. Extract the aqueous phase once more with 150 mL of dichloromethane, separate the layers, and combine the organic phases. Add 175 mL of 1M hydrochloric acid to the reactor, stir for at least 20 minutes, and store the layers. The organic phase was washed twice with 150 mL of water. The organic phase was passed through an activated carbon filter cartridge, and the filter cartridge was rinsed once with 150 mL of dichloromethane. The organic phase was concentrated in a reaction flask to remove dichloromethane and evaporated to about 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 reactor, and solids gradually precipitated. After the addition was complete, the filter cake was transferred to a vacuum drying oven and vacuum dried to obtain a black solid (47 g, 78% yield) as compound VII'-A.

[0136] LCMS ESI (+) m / z: 700.0 (M+1), chiral purity ee>98%.

[0137] Compound VII-A: (S)-benzyl 2-(2,6-dichloro-4-(2-((R)-(3-methoxyphenyl)(methyl)phosphoryl)ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoate

[0138] Under nitrogen, compound VII'-A (1583.4 g, 2.26 mol) and tetrahydrofuran (7.9 L) were added to a reactor and stirred for 20 min until dissolved. Cesium carbonate (1473 g, 4.52 mol), isopropyl alcohol (272 g, 4.53 mol), and cuprous iodide (12.9 g, 67.9 mmol) were added to the reactor, and any material adhering to the walls was washed down with 1.5 L of tetrahydrofuran. Bis(pinacol)diboronate (689 g, 2.71 mol) was dissolved in 6.3 L of tetrahydrofuran and added dropwise to the reactor at 30°C. The reaction was stirred for 16 h. 10 g of the mixture was filtered through celite, and the filter cake was rinsed 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 layers were separated, 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 the layers. The organic phase was then washed once with 4.5 L of demineralized water. The organic phase was pumped through an activated carbon filter into the reactor, and the activated carbon filter was rinsed once with 4.5 L of dichloromethane. The organic phase was concentrated to dryness, acetonitrile (4.5 L) was added, and the temperature was raised to 60°C. After dissolution and clarification, 7.5 L of n-heptane was added to the reaction solution, which was cooled to 0°C and stirred at this temperature for at least 4 h. The mixture was filtered and dried under vacuum to obtain a pale yellow solid (420 g, 26% yield) as compound VII-A.

[0139] LCMS ESI (+) m / z: 702.0 (M+1), chiral purity 98.5%.

[0140] Example 6

[0141] Synthesis of benzyl (S)-2-(2,6-dichloro-4-(2-((R)-(3-benzyloxyphenyl)(methyl)phosphoryl)ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoate (Compound VII-B): The same as in Example 5, except that Compound II-A in Example 5 was replaced by Compound II-B in the following synthetic route and the following synthetic route was used as reference.

[0142] Example 7

[0143] Synthesis of (S)-2-(2,6-dichloro-4-(2-((R)-(3-hydroxyphenyl)(methyl)phosphoryl)ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (Compound IX):

[0144] Compound VII-A (213 g, 303 mmol) was dissolved in dichloromethane (773 mL) and cooled to -70°C. Boron tribromide (773 g, 3.09 mol) was slowly added dropwise. After complete addition, the mixture was stirred for 5 h and then heated to -35°C, where it was stirred for 3 h. The solution was slowly poured into saturated aqueous potassium bicarbonate (10650 mL) and the temperature was adjusted to 5°C. 4 mol / L aqueous hydrochloric acid was slowly added dropwise to adjust the pH to 5.5. Solids precipitated continuously and were filtered. The filter cake was rinsed with water (600 mL) and dried under vacuum at 40°C for 24 h to obtain compound IX-A as a white solid (136 g, 75% yield).

[0145] LCMSESI (+) m / z: 598.0 (M+1), chiral purity 98.5%.

[0146] Example 8

[0147] Synthesis of (S)-2-(2,6-dichloro-4-(2-((R)-(3-hydroxyphenyl)(methyl)phosphoryl)ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (Compound IX):

[0148] Compound VII-B (2.0 g, 2.58 mmol) was dissolved in ethyl acetate (20 mL). Chlorobenzene (1.74 g, 15.5 mmol), 1 mol / L aqueous hydrochloric acid (5.2 mL), and palladium on carbon (200 mg, 1.88 mmol) were added. The mixture was purged with a hydrogen balloon three times and stirred at room temperature for 16 h. Filtered through celite, rinsed once with ethyl acetate (20 mL), and the filtrate was concentrated to dryness to obtain a white solid (1.5 g, 97% yield, 90% purity) as Compound IX.

[0149] LCMSESI (+) m / z: 597.8 (M+1), chiral purity 99%.

[0150] Example 9

[0151] Synthesis of sodium (S)-2-(2,6-dichloro-4-(2-((R)-(3-hydroxyphenyl)(methyl)phosphoryl)ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propionate (Compound I):

[0152] Sodium hydroxide (20.1 g, 503 mmol) was dissolved in deionized water to prepare a 0.5 mol / L aqueous sodium hydroxide solution. Compound IX (300 g, 502 mmol) was slowly added dropwise to the aqueous sodium hydroxide solution at 35°C. The addition of the aqueous sodium hydroxide solution was stopped until the solution became clear and the pH value reached 8. The aqueous solution was microporously filtered, and 900 mL of deionized water was added to the filtrate. The solution was lyophilized in a freeze dryer to obtain a white solid (310 g, 99% yield) as Compound I.

[0153] LCMS ES (+) m / z: 620.0 (M+1), chiral purity ee>99%.

[0154] 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=10.8,7.6 Hz,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).

[0155] Example 10

[0156] Synthesis of sodium (S)-2-(2,6-dichloro-4-(2-((R)-(3-hydroxyphenyl)(methyl)phosphoryl)ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propionate (Compound I):

[0157] Compound IX (270 g, 452 mmol) was dissolved in isopropanol (4860 mL) at 60°C, and sodium methoxide (24.4 g, 452 mmol) was added dropwise. A solid precipitated immediately. After the addition was completed, the temperature was slowly cooled to room temperature over 3 h. The mixture was stirred at 5°C for 2 h and filtered. The filter cake was dried in vacuo at 40°C to obtain a white solid (210 g, yield 75%) as compound I.

[0158] LCMS ES (+) m / z: 620.0 (M+1), chiral purity ee>98%.

[0159] Example 11

[0160] Synthesis of ethyl (3-methoxyphenyl)methylphosphonate (Compound II-3):

[0161] 3-Methoxybromobenzene (800 g, 4.3 mol) and nickel chloride (55.4 g, 0.43 mol) were heated to 165°C, and triethyl phosphite (1070 g, 6.5 mol) was added dropwise. The resulting solution was heated at 165°C for 6 hours, and the product II-6 (800 g, 76% yield) was distilled off under reduced pressure at 125°C and 0.5 mmHg.

[0162] Intermediate II-6" (300 g, 1.2 mol) was dissolved in 1.5 L of ethanol, and aqueous sodium hydroxide solution (590 g / 1.5 L) was added dropwise over 0.5 hours. The mixture was reacted at 80°C for 3 hours and then concentrated under reduced pressure. 0.5 L of water was added and the mixture was extracted with 1.5 L of ethyl acetate. The aqueous phase was adjusted to pH 3 with 1 N hydrochloric acid and extracted twice with 1 L of ethyl acetate. The organic phases were combined and dried over sodium sulfate. After filtration and concentration, the product II-6' was obtained and used directly in the next step.

[0163] Dissolve 250 g of crude product II-6' in 2.5 L of dichloromethane, add DMF (2 g) and oxalyl chloride (440 g, 3.6 mol) under nitrogen protection, react at 20°C for 3 hours, and concentrate under reduced pressure to obtain product II-6, which is used directly in the next step.

[0164] The crude product II-6 was dissolved in 2.5 L of tetrahydrofuran and a 3 M solution of methylmagnesium chloride in tetrahydrofuran (540 mL) was added at -40 ° C. After stirring for 2 hours, 1 L of saturated aqueous ammonium chloride was added to quench the mixture. The mixture was extracted twice with 0.75 L of ethyl acetate, and the combined organic phases were washed with 0.25 L of saturated brine, dried over sodium sulfate, and concentrated to obtain the crude product. The product II-3 (380 g, 50% yield in three steps) was obtained by distillation under reduced pressure (110 ° C, 0.5 mmHg).

[0165] 1 H NMR (400MHz, CDCl3): δ7.37-7.27(m,3H),7.04-7.01(m,1H),3.81(s,3H),3.95-3.71(m,2H),1.62(d,J=16Hz,3H),1.19(t,J=8Hz,3H).

[0166] 31 P NMR (400MHz, CDCl3): δ41.02.

[0167] Example 12

[0168] Synthesis of (3-methoxyphenyl)methylphosphonyl chloride (Compound II-2):

[0169] Add trimethylsilyl iodide (6 g, 30 mmol, 5% eq) to trimethyl phosphite (75 g, 604 mmol, 1 eq). Heat to 70°C under N2 and react for 1 hour (condensation required). Continue heating to 90°C and react for 16 hours. Cool to room temperature after post-treatment to obtain 82 g of crude product. Use directly in the next step.

[0170] To the crude dimethyl methyl phosphate (82 g) in the previous step, add thionyl chloride (215 g, 1806 mmol, 3 eq) and DMF (2 g), heat to 90 ° C, react for 1 hour, then add DMF (2 g × 2), react for 16 hours, cool to room temperature, concentrate the system to 85 g-90 g, and use it directly in the next step.

[0171] To the crude methylphosphonyl dichloride (21 g, 157 mmol, 1 eq) was added dry dichloromethane (220 mL), cooled to 0°C, and a solution of triethylamine (19.2 g, 190 mmol, 1.2 eq) in dichloromethane (50 mL) was added dropwise. Then, a solution of isopropyl alcohol (10.4 g, 174 mmol, 1.1 eq) in dichloromethane (50 mL) was added dropwise over 0.5 hours. The mixture was allowed to warm to room temperature and allowed to react for 16 hours. The reaction solution was concentrated to approximately 100 mL, 100 mL of n-hexane was added, filtered, concentrated, and distilled under reduced pressure (52°C, 2 mmHg) to give compound II-8 (18 g, 73% yield, phosphine spectrum purity >93%).

[0172] Compound II-8 (11.5 g, 73 mmol, 1 eq) was dissolved in dry tetrahydrofuran (80 mL) under nitrogen, cooled to 0°C, and a solution of m-methoxyphenylmagnesium bromide in tetrahydrofuran (1 mol / L) (75 ml, 75 mmol, 1 eq) was added dropwise. The mixture was naturally warmed to room temperature and allowed to react for 16 h. The reaction solution was concentrated to about 60 mL, cooled with ice water, and saturated NH4Cl solution (30 wt% aqueous solution, 80 mL) and dichloromethane (150 mL) were added and stirred for 15 min. The layers were separated, and the aqueous phase was extracted with dichloromethane (50 mL). The organic phases were combined, dried, filtered, and concentrated to 60 mL. The crude product was dissolved in toluene (60 mL) and concentrated again to 60 mL. This was repeated once to obtain a toluene solution of crude product II-3'.

[0173] To the toluene solution of II-3' was added thionyl chloride (8.7 g, 73 mmol, 1 eq), heated to 80 ° C, stirred for 16 h, cooled to room temperature, allowed to stand, the upper layer was poured out and concentrated, and distilled under reduced pressure (130 ° C, 2 mmHg) to obtain compound II-2 (10 g, two-step yield = 67%).

[0174] 1H NMR (400MHz, CDCl3): δ7.44-7.35(m,3H),7.13-7.11(m,1H),3.84(s,3H),2.11(d,J=14Hz,3H).

[0175] 31 P NMR (400MHz, CDCl3): δ51.68.

[0176] Example 13

[0177] Synthesis of (S)-2-(2,6-dichloro-4-(2-((R)-(3-hydroxyphenyl)(methyl)phosphoryl)ethyl)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (Compound IX):

[0178] Under nitrogen, 16g of II-2 was dissolved in 2-methyltetrahydrofuran (24mL). Lithium chloride (6.0g, 1.9eq) and triethylamine (28g, 3.6eq) were added sequentially to the solution. The temperature was lowered to 0°C, and then (S)-4-tert-butyloxazolin-2-one (10g, 0.92eq) was added portionwise. The reaction was allowed to proceed at -10-0°C for 20h. The mixture was quenched with 64mL of water. After separation, the organic phase was washed with 64mL of water and concentrated. The concentrate was dissolved in 2-methyltetrahydrofuran (28mL), heated to 40°C, and heptane (57mL, 4.0V) was added. The temperature was lowered to 15°C over 6 hours, filtered, and the filter cake was washed with heptane. The resulting solid was dried at 40-50°C to yield 16g of dry product II-1 with an HPLC purity of 99.94% and a yield of 69%.

[0179] Under nitrogen, vinyl magnesium chloride (305.5 g, 2 M THF, 5.0 eq) was added to a solution of lithium chloride (20.2 g, 4.0 eq) in dichloromethane (196 g, 4 V) and stirred at room temperature for 50 min. Dichloromethane (397 g, 8 V) was then added dropwise over 2 hours. The mixture was cooled to -70 to -65°C and stirred at -70 to -65°C for 6 hours. 500 mL of a 5% aqueous citric acid solution was slowly added dropwise while maintaining the temperature below -25°C. The mixture was heated to 20°C and stirred for 30 min. After standing for stratification, the lower organic phase was separated. The mixture was washed with 150 mL of a sodium chloride aqueous solution and concentrated to obtain the crude product, Compound II.

[0180] Dissolve the crude compound II in toluene (300 mL, 12.0 V), add 4-bromo-2,6-dichlorobenzoic acid (27.6 g, 1.0 eq, compound III'), DIPEA (diisopropylethylamine, 53.0 g, 4.0 eq), and Pd(dppf)Cl2 (3.8 g, 0.05 eq), and heat to 100°C under nitrogen and stir for 20 hours. Cool to 40°C, add 30 g of diatomaceous earth, and then add 2N sodium hydroxide solution (160 mL). Stir for 30 minutes, filter through diatomaceous earth, and wash the filter cake with 50 mL of water. Combine the washings and filtrate, and allow the layers to separate. Extract the aqueous phase with 2-methyltetrahydrofuran (50 mL x 2). Add 6N HCl to adjust the pH to 1-2, and then extract with 2-methyltetrahydrofuran (70 mL x 3). The combined organic phases were decolorized with activated carbon for 3 hours, filtered, concentrated to 100 mL, and crystallized by adding isopropyl acetate (60 mL) at 60°C. After filtration and drying, 25.6 g of compound IV"-A was obtained with a yield of 65%.

[0181] 13 g of compound IV"-A was dissolved in dioxane (150 mL) and platinum carbon (1.92 g, 15%) was added. After replacing the hydrogen, the hydrogen pressure was filled to 1.6 MPa. Stir at 20°C for 20 hours. The reaction solution was filtered through diatomaceous earth and concentrated. After dissolving in ethylene glycol dimethyl ether (26 mL), the temperature was lowered to 0°C for crystallization. After filtration and drying, 10.9 g of compound VA was obtained with an isolation yield of 84.4%.

[0182] Dissolve 11g of compound VA in dichloromethane (100mL) and cool to -70°C under nitrogen. Add boron tribromide (37g) portionwise over 1 hour. Raise the temperature to 0°C. After separation, adjust the pH of the aqueous phase to 1-2 with 6N hydrochloric acid. Filter to obtain crude product V'. Dissolve in tetrahydrofuran (60mL) and decolorize with activated charcoal. After filtration, add 2-methyltetrahydrofuran (150mL) at 40°C and cool to crystallize. Filter and dry to obtain 9g of compound V' in an 84% yield.

[0183] Dissolve 6.4 g of HATU (1.1 eq) and 2.45 g of 2,6-dimethylpyridine (1.5 eq) in 200 mL of acetonitrile, cool to 10°C, add V' (5.6 g, 1.0 eq), raise the temperature to 30°C, stir for 20 hours, and filter the precipitated solid. Dissolve compound VI' (5.2 g, 1.22 eq) and DIPEA (6.4 g, 3 eq) in 15 mL of water, add 50 mL of acetonitrile, and add the filtered solid portionwise. Stir at room temperature for 3 hours after addition, then concentrate to remove the acetonitrile. Add 16 mL of 50 wt% aqueous sodium hydroxide solution, stir for 2 hours, filter, add 50 mL of water and 50 mL of isopropyl acetate, stir, and separate the layers. Separate the aqueous phase and adjust the pH to 2-3 with 6N hydrochloric acid at 0°C. Filter the precipitated crude compound IX. After drying, the product was crystallized with 80 mL of isopropyl acetate:tetrahydrofuran (volume ratio 10:1) to obtain 5.2 g of the product with a yield of 51%.

[0184] 1 HNMR(400MHz,DMSO)δ7.47-7.39(m,1H),7.78(d,J=7Hz,1H),7.71(d,J=8Hz, 1H),7.64(d,J=8Hz,1H),7.49(t,J=8Hz,1H),7.30-7.25(m,3H),7.20(d,J=1 3Hz,1H),7.10(dd,J=13Hz,8Hz,1H),4.41(m,1H),3.28(m,1H),3.17(m,1H), 3.12(s,3H),2.82(m,1H),2.63(m,1H),2.26(m,2H),1.63(d,J=12.8Hz,3H).

[0185] 31 P NMR (400 MHz, DMSO) δ 36.04.

[0186] Example 14

[0187] Synthesis of (S)-2-(2,6-dichloro-4-(2-((R)-(3-hydroxyphenyl)(methyl)phosphoryl)ethyl)benzoic acid (Compound VA):

[0188] Dissolve 10 g of compound II and 3,5-dichloro-4-carboxyphenylboronic acid (23.4 g, 2 eq) in acetonitrile / tetrahydrofuran (30 mL / 10 mL) under nitrogen. Add cobalt chloride (1.3 g, 0.2 eq), 1,2-bis(diphenylphosphino)ethane (4 g, 0.2 eq), and zinc chloride (6.8 g, 1 eq). Heat to 80°C and stir for 20 hours. Cool to 40°C, add 30 g of celite, and then add 2N sodium hydroxide solution (160 mL). Stir for 30 minutes, filter through celite, and wash the filter cake with 50 mL of water. Combine the washings and filtrate, and allow the layers to separate. Extract the aqueous phase with 2-methyltetrahydrofuran (50 mL x 2). Add 6N HCl to adjust the pH to 1-2, and then extract with 2-methyltetrahydrofuran (70 mL x 3). The organic phases were combined and concentrated, and the crude product was dissolved in ethylene glycol dimethyl ether (26 mL) and then cooled to 0° C. for crystallization. After filtration and drying, 10.8 g of compound VA was obtained with an isolated yield of 55%.

[0189] 1 H NMR (400MHz, CDCl3) δ7.82 (s, 1H), 7.47-7.39 (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).

[0190] The yield of each compound was calculated as follows: yield = actual number of moles of synthesized product / theoretical number of moles of synthesized product × 100%.

[0191] The chiral purity of the above compounds can be tested using testing methods known in the art, which are not limited in this application.

[0192] The calcium salt, magnesium salt and potassium salt of the compound represented by formula (IX) described in the present application can be synthesized by selecting appropriate raw materials according to the synthesis ideas of the above embodiments, or by selecting any other suitable method and raw materials for synthesis.

[0193] It should be noted that, in this document, relational terms such as first and second, etc., are used only to distinguish one entity from another, and do not necessarily require or imply any actual relationship or order between these entities. Moreover, the terms "comprises," "comprising," or any other variations thereof are intended to encompass non-exclusive inclusion, such that a process, method, article, or apparatus that includes a list of elements includes not only those elements but also other elements not explicitly listed, or elements inherent to such process, method, article, or apparatus.

[0194] The various embodiments in this specification are described in a related manner. The same or similar parts between the various embodiments can be referenced to each other. Each embodiment focuses on the differences from other embodiments.

[0195] The above description is only a preferred embodiment of the present application and is not intended to limit the present application. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present application shall be included in the scope of protection of the present application.

Claims

1. A method for preparing a compound represented by formula (IX), comprising the following steps: (1) a compound represented by formula (II) and a compound represented by formula (VIII) are subjected to a coupling reaction to obtain a compound represented by formula (VII'), and then (2) the compound represented by formula (VII') is subjected to a reduction reaction to obtain a compound represented by formula (VII); or (3) a compound represented by formula (V) and a compound represented by formula (VI) are subjected to a condensation reaction to obtain a compound represented by formula (VII); (4) The compound represented by formula (VII) is subjected to a deprotection reaction to obtain a compound represented by formula (IX); or, (3') The compound represented by formula (V') and the compound represented by formula (VI') are subjected to coupling reaction to obtain the compound represented by formula (IX); in, PG is a hydroxyl protecting group selected from methyl, ethyl, isopropyl, tert-butyl, benzyl, phenyl, p-methoxybenzyl, p-nitrobenzoate, tert-butyldimethylsilyl, methoxymethyl, benzyloxymethyl, methylthiomethyl, ethoxymethyl or trimethylsilylethyl; R 1 is selected from Cl, Br, I, trifluoromethylsulfonate or methylsulfonate; R 3 is selected from hydrogen, methyl, ethyl, tert-butyl, benzyl, phenyl or p-methoxybenzyl.

2. The preparation method according to claim 1, wherein Step (1) comprises the following steps: mixing the compound represented by formula (II), the compound represented by formula (VIII), N,N-diisopropylethylamine, and a first catalyst, heating the mixture to 80° C. to 110° C. under a protective gas environment, reacting for 10 h to 24 h, and separating to obtain the compound represented by formula (VII'); the first catalyst is selected from at least one of 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, palladium acetate, palladium chloride, dibenzylideneacetone palladium, dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium, and dichloro[bis(triphenylphosphine)]palladium; the molar ratio of the compound represented by formula (II) to the compound represented by formula (VIII) is 1:(1-1.5), and the molar ratio of the compound represented by formula (II), the N,N-diisopropylethylamine, and the first catalyst is 1:(1-8):(0.001-1); Preferably, step (2) comprises the following steps: mixing the compound represented by formula (VII'), a third alkaline agent, a second catalyst, and a first reducing agent at 20°C to 50°C in a nitrogen atmosphere and reacting for 10h-25h to obtain the compound represented by formula (VII); the second catalyst is selected from cuprous iodide, At least one of cuprous bromide, cuprous chloride, and cuprous cyanide; the third alkaline agent 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 biboric acid pyralidol ester, biboric acid, pyralidol borane, and catechol borane; and the molar ratio of the compound represented by formula (VII'), the third alkaline agent, the second catalyst, and the first reducing agent is 1:(0.1-5):(20-40):(1-5).

3. The preparation method according to claim 1, wherein Step (3) comprises the following steps: mixing the compound represented by formula (V), a first tertiary amine, and a first coupling agent, reacting for 0.5h-2h, adding the compound represented by formula (VI), reacting for 2h-3h, and separating to obtain the compound represented by formula (VII); the first tertiary amine is selected from at least 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'-tetramethyluronium hexafluorophosphate, 2-(benzotriazole)-N,N,N' , at least one of N'-tetramethyluronium hexafluorophosphate, benzotriazole-1-yl-oxytripyrrolidinophosphine hexafluorophosphate, benzotriazole-1-yl-oxytrisdimethylaminophosphine hexafluorophosphate, tripyrrolidinophosphine bromide hexafluorophosphate, dicyclohexylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and propyl phosphoric anhydride, the molar ratio of the compound represented by formula (V), the first tertiary amine, the first coupling agent, and the compound represented by formula (VI) is 1:(3-10):(0.8-1.5):(0.9-1.2).

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

5. The preparation method according to claim 1, wherein Step (3') comprises the following steps: mixing the compound represented by formula (V'), a first tertiary amine, and a first coupling agent, reacting for 0.5h-20h, adding the compound represented by formula (VI'), and continuing to react for 2h-3h, and separating to obtain the compound represented by formula (IX); the first tertiary amine is selected from at least 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'-tetramethyluronium hexafluorophosphate, 2-(benzotriazole)-N,N,N', at least one of N'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yl-oxytripyrrolidinophosphine hexafluorophosphate, benzotriazol-1-yl-oxytrisdimethylaminophosphine hexafluorophosphate, tripyrrolidinophosphine bromide hexafluorophosphate, dicyclohexylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and propylphosphonic anhydride; the molar ratio of the compound represented by formula (V'), the first tertiary amine, the first coupling agent, and the compound represented by formula (VI') is 1:(3-10):(0.8-1.5):(0.9-1.2).

6. A method for preparing a compound represented by formula (V), comprising the following steps: (1') The compound represented by formula (II) and the compound represented by formula (III) undergo coupling reaction to obtain the compound represented by formula (IV); (2') the compound represented by formula (IV) is subjected to a hydrogenation reaction to obtain a compound represented by formula (IV'); (5) The compound represented by the formula (IV') is subjected to a hydrolysis reaction to obtain the compound represented by the formula (V); or, (1") The compound represented by formula (II) and the compound represented by formula (III') are subjected to coupling reaction to obtain the compound represented by formula (IV"); (2") The compound represented by formula (IV") is subjected to hydrogenation reduction reaction to obtain the compound represented by formula (V); or, (1″′) The compound represented by formula (II) and the compound represented by formula (III′) are subjected to coupling reaction to obtain the compound represented by formula (V); in, PG is a hydroxyl protecting group selected from methyl, ethyl, isopropyl, tert-butyl, benzyl, phenyl, p-methoxybenzyl, p-nitrobenzoate, tert-butyldimethylsilyl, methoxymethyl, benzyloxymethyl, methylthiomethyl, ethoxymethyl or trimethylsilylethyl; R 1 is selected from Cl, Br, I, trifluoromethylsulfonate or methylsulfonate; R 2 is selected from methyl, ethyl, tert-butyl, benzyl, phenyl or p-methoxybenzyl.

7. The preparation method according to claim 6, wherein Step (1') comprises the following steps: under a protective gas environment, mixing the compound represented by formula (II), the compound represented by formula (III), a fourth catalyst, and a first alkaline agent, heating to 70° C. to 75° C., reacting for 10 h to 24 h, and separating to obtain the compound represented by formula (IV); the fourth catalyst is selected from at least one of dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium, dichloro[bis(triphenylphosphine)]palladium, palladium chloride, palladium acetate, and dibenzylideneacetone palladium; the first alkaline agent is selected from at least one of triethylamine, diethylamine, diisopropylethylamine, tetramethylethylenediamine, and N-methylmorpholine; and the molar ratio of the compound represented by formula (II), the compound represented by formula (III), the fourth catalyst, and the first alkaline agent is 1:(0.3-1):(0.001-1):(0.5-1); Preferably, step (2') comprises the following steps: mixing the compound represented by formula (IV), a third alkaline agent, and a second reducing agent at 50° C. to 55° C. and reacting for 1 h to 5 h to separate the compound represented by formula (IV'); the second reducing agent is selected from at least one of methylsulfonylhydrazine, benzenesulfonylhydrazine, trimethylbenzenesulfonylhydrazine, and pyridinesulfonylhydrazine; the third alkaline 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 represented by formula (IV), the second reducing agent, and the third alkaline agent is 1:(1-5):(1-10); Alternatively, step (2') comprises the following steps: mixing the compound represented by formula (IV), an acidic catalyst, and a third reducing agent and reacting them for 1 hour to 5 hours at 0°C to 55°C to obtain the compound represented by 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 triethylsilyl hydride and tributyltin hydride; and the molar ratio of the compound represented by formula (IV), the acidic catalyst, and the third reducing agent is 1:(0.1-5):(1-5); Alternatively, step (2') comprises the following steps: at 40°C to 105°C, in a nitrogen atmosphere, mixing the compound represented by formula (IV), a fourth alkaline agent, a fifth catalyst, and a fourth reducing agent, reacting them for 1h-5h, and separating to obtain the compound represented by formula (IV'); the fifth catalyst is selected from at least one of cuprous iodide, cuprous bromide, cuprous chloride, and cuprous cyanide; the fourth alkaline agent 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 biboric acid pyrinatoyl ester, biboric acid, pyrinatoyl borane, and catechol borane; the molar ratio of the compound represented by formula (IV), the fourth alkaline agent, the fifth catalyst, and the fourth reducing agent is 1:(0.1-5):(0.01-1):(1-5); Alternatively, step (2') comprises the following steps: mixing the compound represented by formula (IV), an acid, and a sixth catalyst, reacting them for 1 h to 5 h in a hydrogen atmosphere at 0° C. to 55° C., and separating to obtain the compound represented by formula (IV'); the acid is selected from at least one of acetic acid and hydrochloric acid, the sixth catalyst is selected from at least one of palladium carbon, platinum carbon, rhodium carbon, ruthenium carbon, and Raney nickel, and the molar ratio of the compound represented by formula (IV), the acid, and the sixth catalyst is 1:(0-10):(0.01-1); Preferably, step (5) comprises the following steps: mixing the compound represented by formula (IV') with an alkali solution, reacting at 60°C to 70°C for 6h-24h, and separating to obtain the compound represented by formula (V); the alkali in the alkali solution is selected from at least one of sodium hydroxide, potassium hydroxide, and barium hydroxide; Alternatively, step (5) comprises the following steps: mixing the compound represented by formula (IV') with a second Lewis acid, reacting at 80°C to 120°C for 1h-24h, and separating to obtain the compound represented by formula (V); the second Lewis acid is selected from at least one of lithium iodide, lithium bromide, lithium chloride, and pyridine hydrochloride; preferably, the molar ratio of the compound represented by formula (IV') to the second Lewis acid is 1:(1-100).

8. The preparation method according to claim 6, wherein Step (1") comprises the following steps: in a protective environment of protective gas, mixing the compound represented by formula (II), the compound represented by formula (III'), a fourth catalyst, and a first alkaline agent, heating to 70°C to 100°C, reacting for 10h-24h, and separating to obtain the compound represented by formula (IV"); the fourth catalyst is selected from at least one of dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium, dichloro[bis(triphenylphosphine)]palladium, palladium chloride, palladium acetate, and dibenzylideneacetone palladium; the first alkaline agent is selected from at least one of triethylamine, diethylamine, diisopropylethylamine, tetramethylethylenediamine, and N-methylmorpholine; and the molar ratio of the compound represented by formula (II), the compound represented by formula (III'), the fourth catalyst, and the first alkaline agent is 1:(0.3-1):(0.001-1):(0.5-1); Preferably, step (2") includes the following steps: at 0°C to 55°C, in a hydrogen atmosphere, mixing the compound represented by formula (IV") and the sixth catalyst and reacting them for 1h-20h, and separating to obtain the compound represented by formula (V); the sixth catalyst is selected from at least one of palladium carbon, platinum carbon, rhodium carbon, ruthenium carbon, and Raney nickel, and the molar ratio of the compound represented by formula (IV") and the sixth catalyst is 1: (0.01-1).

9. The preparation method according to claim 6, wherein Step (1') comprises the following steps: in a protective environment of protective gas, mixing the compound represented by formula (II), the compound represented by formula (III'), a seventh catalyst, a first ligand, and a third Lewis acid, heating the mixture to 70° C. to 85° C., reacting the mixture for 10 h to 24 h, and separating the compound represented by formula (V); the seventh catalyst is selected from at least one of cobalt chloride, cobalt bromide, cobalt iodide, rhodium acetate, and rhodium chloride; the first ligand is selected from at least one of 1,1'-bis(diphenylphosphino)ferrocene, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, triphenylphosphine, and cyclooctadiene; the third Lewis acid is selected from at least one of zinc chloride, zinc fluoride, ferric chloride, tin chloride, stannous chloride, and aluminum chloride; and the molar ratio of the compound represented by formula (II), the compound represented by formula (III'), the seventh catalyst, and the third Lewis acid is 1:(0.5-5):(0.001-1):(0.5-2).

10. A method for preparing a compound represented by formula (V'), comprising the following steps: (4') The compound represented by formula (V) is subjected to a deprotection reaction to obtain a compound represented by formula (V'); wherein the compound represented by formula (V) is prepared by the method according to any one of claims 6 to 9; wherein PG is a hydroxyl protecting group selected from methyl, ethyl, isopropyl, tert-butyl, benzyl, phenyl, p-methoxybenzyl, p-nitrobenzoate, tert-butyldimethylsilyl, methoxymethyl, benzyloxymethyl, methylthiomethyl, ethoxymethyl or trimethylsilylethyl; Preferably, step (4') comprises the following steps: cooling the compound represented by formula (V) to -70°C to -80°C, adding boron tribromide dropwise, reacting for 4h-5h, heating to -30°C to 0°C and reacting for 2h-3h, adding a saturated carbonate aqueous solution, controlling the reaction temperature to 0°C to 10°C, adding a hydrochloric acid aqueous solution to adjust the pH to 1-2, and isolating to obtain the compound represented by formula (V'); the carbonate is selected from at least one of potassium bicarbonate, potassium carbonate, sodium bicarbonate, and sodium carbonate, the molar ratio of the compound represented by formula (V) to the boron tribromide is 1:(5-15), and the mass ratio of the compound represented by formula (V) to the saturated carbonate aqueous solution is 1:(10-100).

11. A method for preparing a compound represented by formula (II), comprising the following steps: (6) Formula (II-2) reacts with the Evans prosthetic group to produce the compound shown in (II-1); (7) reacting the compound represented by formula (II-1) with a vinyl Grignard reagent to produce the compound represented by formula (II); in, PG is a hydroxyl protecting group selected from methyl, ethyl, isopropyl, tert-butyl, benzyl, phenyl, p-methoxybenzyl, p-nitrobenzoate, tert-butyldimethylsilyl, methoxymethyl, benzyloxymethyl, methylthiomethyl, ethoxymethyl or trimethylsilylethyl; R 4 is selected from phenyl, tert-butyl, benzyl, isopropyl or p-methoxybenzyl.

12. The preparation method according to claim 11, wherein Step (6) comprises the following steps: in a protective environment of protective gas, mixing Evan's chiral auxiliary group, Lewis acid, and a second alkaline agent, controlling the temperature to be -5°C-0°C, dropwise adding the compound represented by the formula (II-2), reacting at -10°C to 15°C for 10h-24h, and separating to obtain the compound represented by the formula (II-1); the Evan's chiral auxiliary group is selected from (S)-4-isopropyloxazolidin-2-one, (S)-4-phenyloxazolidin-2-one, (S)-4-benzyl At least one of oxazolidin-2-one and (S)-4-tert-butyloxazolidin-2-one, the Lewis acid is selected from at least one of LiCl, LiBr, LiI, ZnCl2, and ZnI2, the second alkaline agent is selected from at least one of triethylamine, diisopropylethylamine, and tetramethylethylenediamine, and the molar ratio of the Evan's chiral auxiliary group, the Lewis acid, the second alkaline agent, and the compound represented by formula (II-2) is 1:(1-1.5):(1-2):(1-1.5); Preferably, step (7) comprises the following steps: in a protective environment of protective gas, controlling the temperature to -85°C to -60°C, mixing the compound represented by formula (II-1), a Lewis acid and a Grignard reagent, reacting for 0.5h-8h, adding water to quench, and then heating to -5°C to 25°C, and separating to obtain the compound represented by formula (II); the Lewis acid is selected from at least one of lithium chloride, lithium bromide, and lithium iodide, the Grignard reagent is vinylmagnesium bromide or vinylmagnesium chloride, and the molar ratio of the Grignard reagent, the compound represented by formula (II-1) and the Lewis acid is 1:(0.5-1.5):(1-10).

13. A method for preparing a compound represented by formula (II-2), comprising the following steps: (8) Diethyl methylphosphite represented by formula (II-5) is hydrolyzed to monoethyl methylphosphite represented by formula (II-4); (9) Monoethyl methylphosphite represented by formula (II-4) is subjected to a coupling reaction to produce a compound represented by formula (II-3); (10) The compound represented by formula (II-3) is subjected to chlorination reaction to generate the compound represented by formula (II-2); or (11) triethyl phosphite represented by formula (II-7) undergoes coupling reaction to produce a compound represented by formula (II-6"); (12) The compound represented by formula (II-6") is hydrolyzed to form a phosphate monoester represented by formula (II-6'); (10') The phosphoric acid monoester represented by formula (II-6') is chlorinated to the phosphorus oxychloride represented by formula (II-6); (13) Phosphorus oxychloride represented by formula (II-6) reacts with a methyl Grignard reagent to produce a compound represented by formula (II-3); (10) Chlorination of the compound represented by formula (II-3) to produce the compound represented by formula (II-2); or (14) trimethyl methylphosphite represented by formula (II-7') is rearranged to dimethyl methylphosphite represented by formula (II-8"); (10") The dimethyl methyl phosphate represented by formula (II-8") is chlorinated to form the methyl phosphorus dichloride represented by formula (II-8'); (15) Methylphosphoryl dichloride represented by formula (II-8') reacts with isopropyl alcohol to produce methylphosphonic acid isopropyl ester monochloride represented by formula (II-8); (13') Methylphosphonic acid isopropyl chloride represented by formula (II-8) reacts with a Grignard reagent to produce a compound represented by formula (II-3'); (10″′) The compound represented by formula (II-3′) is subjected to chlorination reaction to generate the compound represented by formula (II-2); Wherein, PG is a hydroxyl protecting group selected from methyl, ethyl, isopropyl, tert-butyl, benzyl, phenyl, p-methoxybenzyl, p-nitrobenzoate, tert-butyldimethylsilyl, methoxymethyl, benzyloxymethyl, methylthiomethyl, ethoxymethyl or trimethylsilylethyl.

14. The preparation method according to claim 13, wherein Step (8) comprises the following steps: adding water dropwise to the methyldiethoxyphosphine represented by the formula (II-5) at 30° C. to 80° C., reacting for 0.5 h to 2 h, and separating to obtain the compound represented by the formula (II-4); the molar ratio of the methyldiethoxyphosphine to water is 1:(1-1.5); Preferably, step (9) comprises the following steps: under a protective environment of protective gas, mixing a fifth alkali agent, a reactant, a compound represented by formula (II-4), and an eighth catalyst, reacting at 80° C. to 120° C. for 4 h-5 h, and separating to obtain a compound represented by formula (II-3); the molar ratio of the fifth alkali agent, the reactant, the compound represented by formula (II-4), and the eighth catalyst is 1: (0.8-1.2): (0.8-1.5): (0.01-1), the fifth alkali agent is selected from at least one of triethylamine and diisopropylethylamine, the eighth catalyst is selected from at least one of dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium, dichloro[bis(triphenylphosphine)]palladium, palladium chloride, palladium acetate, dibenzylideneacetonepalladium, nickel chloride, and dichloro[bis(triphenylphosphine)]nickel, and the reactant is selected from at least one of m-bromoanisole or Wherein, R is an electron-withdrawing group, and the electron-withdrawing group is selected from a substituent formed by a halogen or a C1-C9 sulfonate compound; Preferably, step (10) includes the following steps: in a protective environment of protective gas, regulating the temperature to -5°C-5°C, adding a halogenating agent dropwise to the compound represented by formula (II-3), reacting for 8h-20h, and separating to obtain the compound represented by formula (II-2); the halogenating agent is selected from at least one of thionyl chloride, phosphorus pentachloride, oxalyl chloride, and phosphorus oxychloride, and the molar ratio of the compound represented by formula (II-3) to the halogenating agent is 1:(2-5).

15. The preparation method according to claim 13, wherein Step (11) comprises the following steps: mixing the reactant, the triethyl phosphite represented by the formula (II-7), and the eighth catalyst, reacting at 100° C. to 200° C. for 4 h to 6 h, and separating to obtain the compound represented by the formula (II-6”); the molar ratio of the reactant, the triethyl phosphite represented by the formula (II-7), and the eighth catalyst is 1: (0.8-1.5): (0.01-1), the eighth catalyst is selected from at least one of dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium, dichloro[bis(triphenylphosphine)]palladium, palladium chloride, palladium acetate, dibenzylideneacetone palladium, nickel chloride, and dichloro[bis(triphenylphosphine)]nickel, and the reactant is selected from m-bromoanisole or Wherein, R is an electron-withdrawing group, and the electron-withdrawing group is selected from a substituent formed by a halogen or a C1-C9 sulfonate compound; Preferably, step (12) comprises the following steps: mixing the compound represented by formula (II-6") with an alkali solution, reacting at 50°C to 100°C for 1h-20h, and separating to obtain the phosphate monoester represented by formula (II-6'); the alkali in the alkali solution is selected from at least one of sodium hydroxide, potassium hydroxide, and barium hydroxide; the molar ratio of the compound represented by formula (II-6") to the alkali in the alkali solution is 1:(0.5-1.5); Preferably, step (10') comprises the following steps: adding halogenated reagent, react for 1h-20h, and separate to obtain the phosphorus oxychloride represented by the formula (II-6); the halogenating agent is selected from at least one of thionyl chloride, phosphorus pentachloride, oxalyl chloride, and phosphorus oxychloride, and the molar ratio of the phosphoric acid monoester represented by the formula (II-6') to the halogenating agent is 1:(1-5); Preferably, step (13) comprises the following steps: in a protective environment of protective gas, controlling the temperature to -50°C to -20°C, adding a methyl Grignard reagent to the phosphorus oxychloride represented by the formula (II-6), reacting for 1h-8h, and separating to obtain a compound represented by the formula (II-3); the molar ratio of the phosphorus oxychloride represented by the formula (II-6) to the methyl Grignard reagent is 1:(1.0-2.5); Preferably, step (10) includes the following steps: in a protective environment of protective gas, regulating the temperature to -5°C-5°C, adding the halogenating reagent dropwise to the compound represented by formula (II-3), reacting for 8h-20h, and separating to obtain the compound represented by formula (II-2); the halogenating reagent is selected from at least one of thionyl chloride, phosphorus pentachloride, oxalyl chloride, and phosphorus oxychloride, and the molar ratio of the compound represented by formula (II-3) to the halogenating reagent is 1:(2-5).

16. The preparation method according to claim 13, wherein Step (14) comprises the following steps: reacting the trimethyl methylphosphite represented by the formula (II-7') with a Lewis acid at 50° C.-100° C. for 8 h-20 h under a protective gas environment; the Lewis acid is selected from at least one of TMSCl, TMSBr, TMSI, LiCl, LiBr, LiI, ZnCl2, and ZnI2; and the molar ratio of the trimethyl methylphosphite represented by the formula (II-7') to the Lewis acid is 1:(0.01-1.0); Preferably, step (10") comprises the following steps: dropwise adding a halogenating agent to the dimethyl methyl phosphate represented by the formula (II-8"), reacting for 8-20 hours, and separating to obtain the methyl phosphorus dichloride represented by the formula (II-8'); the halogenating agent is selected from at least one of thionyl chloride, phosphorus pentachloride, oxalyl chloride, and phosphorus oxychloride, and the molar ratio of the dimethyl methyl phosphate represented by the formula (II-8") to the halogenating agent is 1:(2-5); Preferably, step (15) comprises the following steps: adding isopropyl alcohol and a first alkaline agent dropwise to the methylphosphonic acid dichloride represented by the formula (II-8'), reacting for 8-20 hours, and separating to obtain the methylphosphonic acid isopropyl ester monochloride represented by the formula (II-8); the first alkaline agent is selected from at least one of triethylamine, diethylamine, diisopropylethylamine, tetramethylethylenediamine, and N-methylmorpholine, and the molar ratio of the methylphosphonic acid dichloride represented by the formula (II-8'), isopropyl alcohol, and the first alkaline agent is 1:(1-5):(2-5); Preferably, step (13') comprises the following steps: in a protective environment of protective gas, controlling the temperature to be between -5°C and 5°C, adding a phenyl Grignard reagent to the methylphosphonic acid isopropyl chloride represented by the formula (II-8), reacting for 1h-18h, and separating to obtain the compound represented by the formula (II-3'); the molar ratio of the methylphosphonic acid isopropyl chloride represented by the formula (II-8) to the phenyl Grignard reagent is 1:(0.5-2.5); Preferably, step (10') includes the following steps: controlling the temperature to 20°C-100°C, adding a halogenating agent dropwise to the compound represented by formula (II-3'), reacting for 8h-20h, and separating to obtain the compound represented by formula (II-2); the halogenating agent is selected from at least one of thionyl chloride, phosphorus pentachloride, oxalyl chloride, and phosphorus oxychloride, and the molar ratio of the compound represented by formula (II-3') to the halogenating agent is 1:(2-5).

17. A method for preparing a compound represented by formula (VIII), comprising the following steps: (16) The compound represented by formula (III') and the compound represented by formula (VI) are subjected to condensation reaction to obtain the compound represented by formula (VIII); Among them, R 1 is selected from Cl, Br, I, trifluoromethylsulfonate or methylsulfonate; R 3 is selected from hydrogen, methyl, ethyl, tert-butyl, benzyl, phenyl or p-methoxybenzyl.

18. The preparation method according to claim 17, wherein Step (16) comprises the following steps: At 20° C. to 30° C., the compound represented by formula (III'), a second tertiary amine, and a second coupling agent are mixed and reacted for 1.5 h to 2 h, and then the compound represented by formula (VI) is added and reacted for 2 h to 3 h, and the compound represented by 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'-tetramethyluronium hexafluorophosphate, 2-(benzotriazole)-N,N,N',N'-tetramethyluronium at least one of hexafluorophosphate, benzotriazole-1-yl-oxytripyrrolidinophosphine hexafluorophosphate, benzotriazole-1-yl-oxytrisdimethylaminophosphine hexafluorophosphate, tripyrrolidinophosphine bromide hexafluorophosphate, dicyclohexylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and propylphosphonic anhydride; the molar ratio of the compound represented by formula (III'), the second tertiary amine, the second coupling agent, and the compound represented by formula (VI) is 1:(3-10):(0.8-1.5):(0.9-1.5).

19. A compound represented by formula (IX) or a salt thereof:

20. The compound or salt thereof according to claim 19, wherein The salt is a sodium salt, calcium salt, magnesium salt or potassium salt of the compound represented by formula (IX).

21. An ophthalmic composition comprising the compound represented by formula (IX) or a salt thereof according to claim 19 or 20, and a pharmaceutically acceptable carrier.

22. Use of the compound of formula (IX) or a salt thereof according to claim 19 or 20, or the ophthalmic composition according to claim 21, in the preparation of a medicament for treating or preventing an ophthalmic disease; preferably, the ophthalmic disease includes dry eye syndrome mediated by LFA-1.

23. A method for treating or preventing an ophthalmic disease, wherein: The method comprises administering a therapeutically effective amount of a compound of formula (IX) or a salt thereof according to claim 19 or 20 or an ophthalmic composition according to claim 21 to a subject in need thereof; preferably, the ophthalmic disease comprises dry eye syndrome mediated by LFA-1.

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