Preparation method for (2s,3r,4r)-4,5-dihydroxy isoleucine derivative and intermediate

Abstract

The present invention belongs to the technical field of organic synthesis, and provides a preparation method for a (2S,3R,4R)-4,5-dihydroxy isoleucine derivative and an intermediate. The present invention provides a preparation method for a plurality of intermediates of a (2S,3R,4R)-4,5-dihydroxy isoleucine derivative, and a (2S,3R,4R)-4,5-dihydroxy isoleucine derivative can be prepared on this basis. Specifically, in the present invention, a glycine derivative, i.e. benzophenone imine glycine tert-butyl ester (compound 1 having the structural formula as shown in formula 1), is selected as an initial reaction raw material, is convenient to purchase in a commercialized way and has a low price; efficient asymmetric synthesis of a target product is achieved by means of asymmetric allylation, asymmetric dihydroxylation, introduction or removal of a protecting group and other reactions; and the product has a high optical purity and a relatively high yield, the process operation is convenient, and large-scale production is convenient to achieve.

Description

Preparation method of (2S,3R,4R)-4,5-dihydroxyisoleucine derivatives and intermediates

[0001] This application claims priority to a Chinese patent application filed with the Patent Office of China on March 7, 2024, with application number CN202410257052.0 and invention name “Method for preparing (2S,3R,4R)-4,5-dihydroxyisoleucine derivatives and intermediates”, the entire contents of which are incorporated herein by reference. Technical Field

[0002] The present invention relates to the technical field of organic synthesis, and in particular to a preparation method of (2S, 3R, 4R)-4, 5-dihydroxyisoleucine derivatives and intermediates. Background Art

[0003] Amino acids are not only important components of macromolecules in organisms, but also have a wide range of applications in the field of organic synthesis and medicine. However, there are very few naturally occurring amino acids, and a series of unnatural amino acids can be obtained by modifying natural amino acids. Most amino acids are chiral amino acids, and how to obtain unnatural amino acids with high optical purity has always been one of the hot spots and difficulties in organic synthesis research. For example, chiral dihydroxyisoleucine is an unnatural amino acid with three chiral centers and cannot be obtained through commercial channels. Chiral dihydroxyisoleucine has important applications in the synthesis of peptides such as cyclic peptide toxins, but no effective method has been found to obtain dihydroxyisoleucine with low production cost and high optical purity.

[0004] Summary of the Invention

[0005] The object of the present invention is to provide a method for preparing (2S,3R,4R)-4,5-dihydroxyisoleucine derivatives and intermediates. The (2S,3R,4R)-4,5-dihydroxyisoleucine derivatives and intermediates are prepared by the method provided by the present invention. The products have high optical purity and low production cost.

[0006] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0007] The present invention provides a method for preparing a (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A, comprising the following steps:

[0008] Compound 1 is subjected to an asymmetric allylation reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A;

[0009] The structural formulas of the compound 1 and the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A are shown in Formula 1 and Formula 2 respectively:

[0010] The present invention provides a method for preparing a (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A', comprising the following steps:

[0011] According to the preparation method described in the above technical solution, the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A is obtained;

[0012] The (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A is subjected to an imine hydrolysis reaction and a 9-fluorenylmethoxycarbonyl protection reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A';

[0013] The structural formula of the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A' is shown in Formula 2':

[0014] The present invention provides a method for preparing a (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate B, comprising the following steps:

[0015] According to the preparation method described in the above technical solution, the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A is obtained;

[0016] The (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A is subjected to an asymmetric dihydroxylation reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate B;

[0017] The structural formula of the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate B is shown in Formula 3:

[0018] The present invention provides a method for preparing a (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C, comprising the following steps:

[0019] According to the preparation method described in the above technical solution, the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate B is obtained;

[0020] The (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate B is subjected to an imine hydrolysis reaction and a 9-fluorenylmethyloxycarbonyl protection reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C;

[0021] The structural formula of the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C is shown in Formula 4:

[0022] The present invention provides a method for preparing a (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C, comprising the following steps:

[0023] According to the preparation method described in the above technical solution, the (2S, 3R, 4R)-4, 5-dihydroxyisoleucine derivative intermediate A' is obtained;

[0024] The (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A' is subjected to an asymmetric dihydroxylation reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C;

[0025] The structural formula of the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C is shown in Formula 4:

[0026] The present invention provides a method for preparing a (2S,3R,4R)-4,5-dihydroxyisoleucine derivative, comprising the following steps:

[0027] Compound 1 is subjected to an asymmetric allylation reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A;

[0028] The (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A is subjected to an asymmetric dihydroxylation reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate B;

[0029] The (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate B is subjected to an imine hydrolysis reaction and a 9-fluorenylmethyloxycarbonyl protection reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C;

[0030] Acetylation of the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C to obtain a (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate D;

[0031] subjecting the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate D to a tert-butyl ester hydrolysis reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative;

[0032] The structural formulas of the compound 1, (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A, (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate B, (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C, (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate D and (2S,3R,4R)-4,5-dihydroxyisoleucine derivative are shown in Formula 1, Formula 2, Formula 3, Formula 4, Formula 5 and Formula 6 respectively:

[0033] The present invention provides a method for preparing a (2S,3R,4R)-4,5-dihydroxyisoleucine derivative, comprising the following steps:

[0034] Compound 1 is subjected to an asymmetric allylation reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A;

[0035] The (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A is subjected to an imine hydrolysis reaction and a 9-fluorenylmethoxycarbonyl protection reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A';

[0036] The (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A' is subjected to an asymmetric dihydroxylation reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C;

[0037] Acetylation of the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C to obtain a (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate D;

[0038] subjecting the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate D to a tert-butyl ester hydrolysis reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative;

[0039] The structural formulas of the compound 1, (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A, (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A', (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C, (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate D and (2S,3R,4R)-4,5-dihydroxyisoleucine derivative are shown in Formula 1, Formula 2, Formula 2', Formula 4, Formula 5 and Formula 6 respectively:

[0040] Preferably, the raw materials used in the asymmetric allylation reaction include 3-chlorobutene; and the asymmetric allylation reaction is carried out in the presence of a rhodium catalyst, a rhodium catalyst ligand, a copper catalyst, a copper catalyst ligand and an alkaline reagent.

[0041] Preferably, the rhodium catalyst is [Rh(COD)Cl]2, the copper catalyst is Cu(CH3CN)4PF6, and the alkaline reagent is potassium phosphate; the structural formulas of the rhodium catalyst ligand and the copper catalyst ligand are shown below in sequence:

[0042] Preferably, the molar amount of [Rh(COD)Cl]2 is 1 to 20% of the molar amount of compound 1, and the molar amount of the rhodium catalyst ligand is 1 to 10% of the molar amount of compound 1; the molar amount of Cu(CH3CN)4PF6 is 1 to 10% of the molar amount of compound 1, and the molar amount of the copper catalyst ligand is 1 to 20% of the molar amount of compound 1; the molar ratio of the alkaline reagent to compound 1 is 1 to 5:1.

[0043] Preferably, the molar ratio of the compound 1 to 3-chlorobutene is 1:1-4.

[0044] Preferably, the asymmetric allylation reaction is carried out in the presence of an organic solvent, and the ratio of the organic solvent to compound 1 is 2-10 mL:1 mmol.

[0045] Preferably, the temperature of the asymmetric allylation reaction is -10 to 25° C., and the time is 12 to 48 hours.

[0046] Preferably, after the asymmetric allylation reaction, the following steps are further performed: adding water to the obtained product system to quench the reaction, then performing extraction to remove the solvent in the obtained organic phase, and separating the obtained crude product by column chromatography to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A.

[0047] Preferably, the imine hydrolysis reaction is carried out in the presence of hydrochloric acid, the concentration of the hydrochloric acid is 1 to 12 mol / L, and the ratio of the hydrochloric acid to the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A is 1 to 5 L:1 mol;

[0048] The imine hydrolysis reaction is carried out in the presence of an organic solvent, and the ratio of the organic solvent to the (2S, 3R, 4R)-4, 5-dihydroxyisoleucine derivative intermediate A is 1-4 L: 1 mol.

[0049] Preferably, the temperature of the imine hydrolysis reaction is 0-50° C., and the time is 10-40 minutes.

[0050] Preferably, the raw materials used in the 9-Fmoc protection reaction include Fmoc succinimide, and based on the amount of the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A, the molar ratio of the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A to Fmoc succinimide is 1:1-2;

[0051] The 9-fluorenylmethoxycarbonyl protection reaction is carried out in the presence of a sodium carbonate solution, wherein the concentration of the sodium carbonate solution is 5 to 50 wt %, based on the amount of the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A, and the molar ratio of the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A to the sodium carbonate in the sodium carbonate solution is 1:1 to 3;

[0052] The 9-fluorenylmethyloxycarbonyl protection reaction is carried out in the presence of an organic solvent. Based on the amount of the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A, the amount ratio of the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A to the 9-fluorenylmethyloxycarbonyl protection reaction is 1 mol: 1 to 5 L of the organic solvent.

[0053] Preferably, the temperature of the 9-Fmoc protection reaction is 0-50° C., and the time is preferably 1-24 h.

[0054] Preferably, after the 9-fluorenylmethoxycarbonyl protection reaction, the method further comprises: adding hydrochloric acid to the obtained product system to adjust the pH value of the system to 7, then performing extraction, removing the solvent in the obtained organic phase, and separating the obtained crude product by column chromatography to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A'.

[0055] Preferably, the asymmetric dihydroxylation reaction is carried out in the presence of N-methylmorpholine oxide, potassium osmate dihydrate and AD-mix-β, and the molar ratio of the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A, N-methylmorpholine oxide, potassium osmate dihydrate and AD-mix-β is 1:1-5:0.001-0.1:0.001-0.1;

[0056] The asymmetric dihydroxylation reaction is carried out in the presence of water and an organic solvent, and the usage ratio of the water, the organic solvent and the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate A is 1-3L:1-3L:1mol.

[0057] Preferably, the temperature of the asymmetric dihydroxylation reaction is 0 to 50° C., and the time is 1 to 24 hours.

[0058] Preferably, after the asymmetric dihydroxylation reaction, the following steps are further performed: adding a Na2SO3 solution to the obtained product system to quench the reaction, then performing extraction, washing and drying the obtained organic phase in sequence, then removing the solvent, and separating the obtained crude product by column chromatography to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate B.

[0059] Preferably, the raw materials used in the acetylation reaction include acetyl chloride, and the molar ratio of the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C to acetyl chloride is 1:1-10;

[0060] The acetylation reaction is carried out in the presence of pyridine, and the molar ratio of the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C to pyridine is 1:1-10;

[0061] The acetylation reaction is carried out in the presence of an organic solvent, and the usage ratio of the (2S, 3R, 4R)-4, 5-dihydroxyisoleucine derivative intermediate C to the organic solvent is 5-50 mL: 1 mmol.

[0062] Preferably, the acetylation reaction includes sequentially performing a first stage reaction and a second stage reaction; the temperature of the first stage reaction is -10 to 10°C, and the time is 0.5 to 2 hours; the temperature of the second stage reaction is 25 to 50°C, and the time is 0.5 to 2 hours.

[0063] Preferably, after the acetylation reaction, the process further comprises: washing the obtained product system with a saturated NH4Cl solution, collecting the organic phase, removing the solvent, and separating the obtained crude product by column chromatography to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate D.

[0064] Preferably, the tert-butyl ester hydrolysis reaction is carried out in the presence of trifluoroacetic acid, and the usage ratio of the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate D to trifluoroacetic acid is 4 mmol:1-10 mL.

[0065] Preferably, the temperature of the tert-butyl ester hydrolysis reaction is 0-50° C., and the time is 1-4 hours.

[0066] Preferably, after the tert-butyl ester hydrolysis reaction, the process further comprises: removing the solvent in the obtained product system, and separating the obtained crude product by column chromatography to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative.

[0067] The present invention provides an intermediate for synthesizing a (2S,3R,4R)-4,5-dihydroxyisoleucine derivative, which is a compound having a structure shown in Formula 3:

[0068] Beneficial technical effects: The present invention provides a method for preparing a variety of (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediates, on which (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivatives can be prepared, and the product has high optical purity and low production cost. Specifically, the present invention selects the glycine derivative benzophenone imine glycine tert-butyl ester (Compound 1) as the starting reaction raw material, which is easy to purchase through commercial channels and is inexpensive. After asymmetric allylation and asymmetric dihydroxylation reactions and the introduction or removal of protecting groups, efficient asymmetric synthesis of (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivatives is achieved, and the product has high optical purity and high yield. The process operation is convenient, which is easy to achieve large-scale production. DETAILED DESCRIPTION

[0069] The present invention provides a method for preparing a (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A, comprising the following steps:

[0070] Compound 1 is subjected to an asymmetric allylation reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A;

[0071] The structural formulas of the compound 1 and the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A are shown in Formula 1 and Formula 2 respectively:

[0072] In the present invention, unless otherwise specified, the raw materials used are commercially available products well known to those skilled in the art.

[0073] The present invention performs an asymmetric allylation reaction on compound 1 to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A. In the present invention, the raw materials used in the asymmetric allylation reaction preferably include 3-chlorobutene (3-chlorobut-1-ene), and the molar ratio of compound 1 to 3-chlorobutene is preferably 1:1 to 4, more preferably 1:1.2. In the present invention, the asymmetric allylation reaction is preferably carried out in the presence of a rhodium catalyst, a rhodium catalyst ligand, a copper catalyst, a copper catalyst ligand and an alkaline reagent. The alkaline reagent of the present invention is preferably potassium phosphate, and the molar ratio of the alkaline reagent to compound 1 is preferably 1 to 5:1, more preferably 3:1.

[0074] The rhodium catalyst of the present invention is preferably [Rh(COD)Cl]2, and the molar amount of the rhodium catalyst is preferably 1 to 20% of the molar amount of compound 1, more preferably 1%. The rhodium catalyst ligand of the present invention is preferably (R,Sp)-L1, and the molar amount of the rhodium catalyst ligand is preferably 1 to 10% of the molar amount of compound 1, more preferably 2%. The structural formula of (R,Sp)-L1 is as follows:

[0075] The copper catalyst of the present invention is preferably Cu(CH3CN)4PF6, and the molar amount of Cu(CH3CN)4PF6 is preferably 1-10% of the molar amount of compound 1, more preferably 2%. The copper catalyst ligand of the present invention is preferably (4R,2S)-L2, and the molar amount of the copper catalyst ligand is preferably 1-20% of the molar amount of compound 1, more preferably 2%. The structural formula of (4R,2S)-L2 is as follows:

[0076] The asymmetric allylation reaction of the present invention is preferably carried out in the presence of an organic solvent. The organic solvent preferably includes one or more of tetrahydrofuran, dichloromethane, and dioxane, more preferably tetrahydrofuran. The organic solvent is preferably dried and degassed before use. In the present invention, the ratio of the organic solvent to compound 1 is preferably 2-10 mL:1 mmol, more preferably 8 mL:1 mmol.

[0077] The present invention preferably mixes a rhodium catalyst, a rhodium catalyst ligand and part of an organic solvent for complexation to obtain a rhodium catalyst solution; mixes a copper catalyst, a copper catalyst ligand and the remaining organic solvent for complexation to obtain a copper catalyst solution; adds compound 1, an alkaline reagent and 3-chlorobutene to the rhodium catalyst solution, and then adds the copper catalyst solution to carry out the asymmetric allylation reaction. In the present invention, the temperature for the complexation treatment when preparing the rhodium catalyst solution and the copper catalyst solution is independently preferably 0 to 40°C, more preferably 25°C; the time is independently preferably ≤30min, more preferably 15min. In the present invention, the temperature of the asymmetric allylation reaction is preferably -10 to 25°C, more preferably 0°C; the time is preferably 12 to 48h, more preferably 24h; the asymmetric allylation reaction is preferably carried out under closed conditions; the asymmetric allylation reaction is preferably carried out under stirring conditions.

[0078] After the asymmetric allylation reaction, the present invention preferably adds water to the resulting product system to quench the reaction, then extracts the organic phase to remove the solvent. The resulting crude product is separated by column chromatography to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A. In the present invention, the extraction solvent is preferably ethyl acetate. The extraction step preferably includes drying, and the drying agent is preferably anhydrous sodium sulfate. In the present invention, the drying step preferably includes filtration to remove the solvent from the filtrate to obtain the crude product. The solvent removal method is preferably vacuum distillation, and the solvent can be recovered and reused. In the present invention, the silica gel used for separation is preferably 200-300 mesh silica gel. The eluent used for separation is preferably a mixture of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate in the eluent is preferably 99:1.

[0079] The present invention provides a method for preparing a (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A', comprising the following steps:

[0080] According to the preparation method described in the above technical solution, the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A is obtained;

[0081] The (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A is subjected to an imine hydrolysis reaction and a 9-fluorenylmethoxycarbonyl protection reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A';

[0082] The structural formula of the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A' is shown in Formula 2':

[0083] The present invention converts the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A into the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A', which facilitates the use of high-performance liquid chromatography to separate and determine the enantioselectivity. In addition, the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A' can be used to directly prepare the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C, which will be described in detail later.

[0084] The method for preparing the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A in the present invention is preferably consistent with the above technical solution and will not be repeated here.

[0085] After obtaining the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A, the present invention subjects the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A to an imine hydrolysis reaction and a 9-fluorenylmethyloxycarbonyl protection reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A'. This is described in detail below.

[0086] In the present invention, the imine hydrolysis reaction is preferably carried out in the presence of hydrochloric acid, the concentration of which is preferably 1 to 12 mol / L, more preferably 1 mol / L; the ratio of hydrochloric acid to (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A is preferably 1 to 5 L:1 mol, more preferably 1 to 2 L:1 mol. In the present invention, the imine hydrolysis reaction is preferably carried out in the presence of an organic solvent, which preferably includes one or more of tetrahydrofuran, dioxane, and methanol, more preferably tetrahydrofuran; the ratio of the organic solvent to (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A is preferably 1 to 4 L:1 mol, more preferably 2 L:1 mol.

[0087] The present invention preferably dissolves the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A in an organic solvent and adds hydrochloric acid dropwise under stirring to carry out an imine hydrolysis reaction. The temperature of the imine hydrolysis reaction of the present invention is preferably 0 to 50°C, more preferably room temperature. In an embodiment of the present invention, the room temperature is specifically 25°C. The imine hydrolysis reaction time is preferably 10 to 40 minutes, more preferably 20 minutes. The present invention preferably uses TLC to monitor the reaction progress. The imine hydrolysis reaction is preferably carried out under stirring.

[0088] After the imine hydrolysis reaction, the present invention preferably adds a saturated sodium carbonate solution to the resulting product system until the system pH is 7-9 (preferably 8), then extracts and removes the solvent from the resulting organic phase. The resulting crude product is then directly subjected to the subsequent 9-fluorenylmethoxycarbonyl protection reaction. In the present invention, the extraction agent used is preferably ethyl acetate; the extraction is preferably followed by drying, and the drying agent used is preferably anhydrous sodium sulfate. In the present invention, the drying is preferably followed by filtration to remove the solvent from the resulting filtrate to obtain the crude product; the solvent is preferably removed by distillation under reduced pressure, and the solvent can be recovered and reused.

[0089] In the present invention, the raw materials used in the 9-Fmoc protection reaction preferably include Fmoc succinimide. Based on the amount of the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A, the molar ratio of the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A to Fmoc succinimide is preferably 1:1-2, more preferably 1:1.1. In the present invention, the 9-fluorenylmethoxycarbonyl protection reaction is preferably carried out in the presence of a sodium carbonate solution, and the concentration of the sodium carbonate solution is preferably 5 to 50 wt%, more preferably 10 wt%; based on the amount of the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate A, the molar ratio of the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate A to the sodium carbonate in the sodium carbonate solution is preferably 1:1 to 3, more preferably 1:1.5. In the present invention, the 9-fluorenylmethyloxycarbonyl protection reaction is preferably carried out in the presence of an organic solvent, and the organic solvent is preferably one or more of 1,4-dioxane, tetrahydrofuran and methanol, more preferably 1,4-dioxane; based on the amount of the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A, the amount ratio of the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A to the 9-fluorenylmethyloxycarbonyl protection reaction is preferably 1 mol:1-5 L, more preferably 1 mol:2 L.

[0090] In the present invention, the crude product obtained after the imine hydrolysis reaction is preferably dissolved in the organic solvent used for the 9-Fmoc protection reaction, a sodium carbonate solution is added, and then Fmoc succinimide is added dropwise to carry out the 9-Fmoc protection reaction. In the present invention, the 9-Fmoc protection reaction is preferably carried out at a temperature of 0 to 50°C, more preferably at room temperature, for a time of 1 to 24 hours, more preferably 2 hours. The 9-Fmoc protection reaction is preferably carried out under stirring.

[0091] After the 9-Fmoc protection reaction, the present invention preferably adds hydrochloric acid to the resulting product system to adjust the pH to 7, followed by extraction to remove the solvent from the resulting organic phase. The resulting crude product is then separated by column chromatography to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A'. In the present invention, the extraction solvent is preferably ethyl acetate. The extraction step preferably includes drying, and the drying agent is preferably anhydrous sodium sulfate. In the present invention, the drying step preferably includes filtration to remove the solvent from the filtrate to obtain the crude product. The solvent removal step is preferably vacuum distillation, and the solvent can be recovered and reused. In the present invention, the silica gel used for separation is preferably 200-300 mesh silica gel. The eluent used for separation is preferably a mixture of ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether in the eluent is preferably 15:85.

[0092] The present invention provides a method for preparing a (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate B, comprising the following steps:

[0093] According to the preparation method described in the above technical solution, the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A is obtained;

[0094] The (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A is subjected to an asymmetric dihydroxylation reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate B;

[0095] The structural formula of the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate B is shown in Formula 3:

[0096] The method for preparing the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A in the present invention is preferably consistent with the above technical solution and will not be repeated here.

[0097] After obtaining the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A, the present invention performs an asymmetric dihydroxylation reaction on the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate B. In the present invention, the asymmetric dihydroxylation reaction is preferably carried out in the presence of N-methylmorpholine oxide (NMO), potassium osmate dihydrate (K2OsO4·2H2O) and AD-mix-β, and the molar ratio of the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A, N-methylmorpholine oxide (NMO), potassium osmate dihydrate (K2OsO4·2H2O) and AD-mix-β is preferably 1:1~5:0.001~0.1:0.001~0.1, more preferably 1:3:0.01:0.01. The asymmetric dihydroxylation reaction of the present invention is preferably carried out in the presence of water and an organic solvent. The organic solvent preferably includes one or more of acetone, acetonitrile and methanol, more preferably acetone. The amount ratio of the water, organic solvent and (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A is preferably 1-3L:1-3L:1mol, more preferably 1L:2L:1mol.

[0098] The present invention preferably mixes potassium osmate dihydrate and AD-mix-β with a portion of water and a portion of an organic solvent, dissolves the mixture, and then adds N-methylmorpholine oxide, (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A, the remaining water, and the remaining organic solvent to perform an asymmetric bishydroxylation reaction. In the present invention, the temperature of the asymmetric bishydroxylation reaction is preferably 0 to 50°C, more preferably room temperature; the reaction time is preferably 1 to 24 hours, more preferably 12 hours; and the asymmetric bishydroxylation reaction is preferably performed under stirring.

[0099] After the asymmetric bishydroxylation reaction, the present invention preferably adds a Na2SO3 solution to the resulting product system to quench the reaction, followed by extraction. The resulting organic phase is sequentially washed and dried, and the solvent is removed. The resulting crude product is separated by column chromatography to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate B. In the present invention, the extraction solvent is preferably ethyl acetate. In the present invention, the washing agent is preferably a saturated sodium chloride solution; and the drying agent is preferably anhydrous sodium sulfate. In the present invention, the drying step preferably includes filtration to remove the solvent from the filtrate to obtain the crude product. The solvent is preferably removed by distillation under reduced pressure, and the solvent can be recovered and reused. In the present invention, the silica gel used for separation is preferably 200-300 mesh silica gel. The eluent used for separation is preferably a mixture of ethyl acetate and petroleum ether, with the volume ratio of ethyl acetate to petroleum ether in the eluent preferably being 35:65.

[0100] The present invention provides a method for preparing a (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C, comprising the following steps:

[0101] According to the preparation method described in the above technical solution, the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate B is obtained;

[0102] The (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate B is subjected to an imine hydrolysis reaction and a 9-fluorenylmethyloxycarbonyl protection reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C;

[0103] The structural formula of the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C is shown in Formula 4:

[0104] The method for preparing the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A and the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate B of the present invention is preferably consistent with the above technical solution and will not be repeated here.

[0105] After obtaining the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate B, the present invention subjects the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate B to an imine hydrolysis reaction and a 9-fluorenylmethoxycarbonyl protection reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C. In the present invention, the raw materials, reagents, reaction conditions, and post-treatment methods required for the imine hydrolysis reaction and the 9-fluorenylmethoxycarbonyl protection reaction are preferably similar to those of the above-mentioned technical solution and are not further described herein.

[0106] The present invention provides a method for preparing a (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C, comprising the following steps:

[0107] According to the preparation method described in the above technical solution, the (2S, 3R, 4R)-4, 5-dihydroxyisoleucine derivative intermediate A' is obtained;

[0108] The (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A' is subjected to an asymmetric dihydroxylation reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C;

[0109] The structural formula of the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C is shown in Formula 4:

[0110] The method for preparing the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A and the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A' of the present invention is preferably consistent with the above technical solution and will not be repeated here.

[0111] After obtaining the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A', the present invention performs an asymmetric dihydroxylation reaction on the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A' to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C. In the present invention, the raw materials, reagents, reaction conditions, and post-treatment methods required for the asymmetric dihydroxylation reaction are preferably consistent with those of the above technical solution and are not further described herein.

[0112] The present invention provides a method for preparing a (2S,3R,4R)-4,5-dihydroxyisoleucine derivative, comprising the following steps:

[0113] Compound 1 is subjected to an asymmetric allylation reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A;

[0114] The (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A is subjected to an asymmetric dihydroxylation reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate B;

[0115] The (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate B is subjected to an imine hydrolysis reaction and a 9-fluorenylmethyloxycarbonyl protection reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C;

[0116] Acetylation of the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C to obtain a (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate D;

[0117] subjecting the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate D to a tert-butyl ester hydrolysis reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative;

[0118] The structural formulas of the compound 1, (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A, (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate B, (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C, (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate D and (2S,3R,4R)-4,5-dihydroxyisoleucine derivative are shown in Formula 1, Formula 2, Formula 3, Formula 4, Formula 5 and Formula 6 respectively:

[0119] The method for preparing the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A, (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate B and (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C of the present invention is preferably consistent with the above technical solution and will not be repeated here.

[0120] After obtaining the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C, the present invention performs an acetylation reaction on the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate D. In the present invention, the raw materials used in the acetylation reaction preferably include acetyl chloride, and the molar ratio of the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C to acetyl chloride is preferably 1:1-10, more preferably 1:2.2. The acetylation reaction of the present invention is preferably carried out in the presence of pyridine, and the molar ratio of the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C to pyridine is preferably 1:1-10, more preferably 1:1.5. The acetylation reaction of the present invention is preferably carried out in the presence of an organic solvent, and the organic solvent preferably includes one or more of dichloromethane, ethyl acetate and methanol, more preferably dichloromethane; the organic solvent is preferably used after drying; the usage ratio of the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C to the organic solvent is preferably 5-50 mL:1 mmol, more preferably 10 mL:1 mmol.

[0121] The present invention preferably mixes the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C, pyridine, and an organic solvent, and then drops acetyl chloride to carry out an acetylation reaction. In the present invention, the acetylation reaction preferably includes a first-stage reaction and a second-stage reaction carried out sequentially. The temperature of the first-stage reaction of the present invention is preferably -10 to 10°C, more preferably 0°C; the time is preferably 0.5 to 2 hours, more preferably 1 hour, and the time of the first-stage reaction of the present invention is calculated from the completion of the dropwise addition of acetyl chloride. The temperature of the second-stage reaction of the present invention is preferably 0 to 50°C, more preferably room temperature; the time is preferably 0.5 to 2 hours, more preferably 1 hour. The acetylation reaction of the present invention is preferably carried out under stirring conditions.

[0122] After the acetylation reaction, the present invention preferably washes the resulting product system with a saturated NH4Cl solution, collects the organic phase, removes the solvent, and separates the resulting crude product by column chromatography to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate D. In the present invention, after collecting the organic phase, the process preferably includes drying, and the drying agent used is preferably anhydrous sodium sulfate. In the present invention, after drying, the process preferably includes filtering to remove the solvent from the resulting filtrate to obtain the crude product. The solvent is preferably removed by distillation under reduced pressure, and the solvent can be recovered and reused. In the present invention, the silica gel used for separation is preferably 200-300 mesh silica gel. The eluent used for separation is preferably a mixture of ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether in the eluent is preferably 8:92.

[0123] After obtaining the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate D, the present invention performs a tert-butyl ester hydrolysis reaction on the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate D to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative. In the present invention, the tert-butyl ester hydrolysis reaction is preferably carried out in the presence of trifluoroacetic acid, and the ratio of the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate D to trifluoroacetic acid is preferably 4 mmol:1-10 mL, more preferably 4 mmol:5 mL.

[0124] The present invention preferably mixes the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate D with trifluoroacetic acid to perform a tert-butyl ester hydrolysis reaction. The temperature of the tert-butyl ester hydrolysis reaction of the present invention is preferably 0 to 50°C, more preferably room temperature; the time is preferably 1 to 4 hours, more preferably 2 hours. The present invention preferably uses TLC to monitor the reaction progress; the tert-butyl ester hydrolysis reaction is preferably carried out under stirring conditions.

[0125] After the tert-butyl ester hydrolysis reaction, the present invention preferably removes the solvent from the resulting product system and separates the resulting crude product by column chromatography to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative. In the present invention, the solvent is preferably removed by vacuum distillation, and the solvent can be recovered and reused. In the present invention, the silica gel used for separation is preferably 200-300 mesh silica gel; the eluent used for separation is preferably a mixture of methanol and dichloromethane, and the volume ratio of methanol to dichloromethane in the eluent is preferably 5:95.

[0126] The present invention provides a method for preparing a (2S,3R,4R)-4,5-dihydroxyisoleucine derivative, comprising the following steps:

[0127] Compound 1 is subjected to an asymmetric allylation reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A;

[0128] The (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A is subjected to an imine hydrolysis reaction and a 9-fluorenylmethoxycarbonyl protection reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A';

[0129] The (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A' is subjected to an asymmetric dihydroxylation reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C;

[0130] Acetylation of the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C to obtain a (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate D;

[0131] subjecting the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate D to a tert-butyl ester hydrolysis reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative;

[0132] The structural formulas of the compound 1, (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A, (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A', (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C, (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate D and (2S,3R,4R)-4,5-dihydroxyisoleucine derivative are shown in Formula 1, Formula 2, Formula 2', Formula 4, Formula 5 and Formula 6 respectively:

[0133] The method for preparing the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A and the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A' of the present invention is preferably consistent with the above technical solution and will not be repeated here.

[0134] After obtaining the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A', the present invention performs an asymmetric dihydroxylation reaction on the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A' to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C. In the present invention, the raw materials, reagents, reaction conditions, and post-treatment methods required for the asymmetric dihydroxylation reaction are preferably consistent with those of the above technical solution and are not further described herein.

[0135] After obtaining the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C, the method for preparing the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate D and the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative of the present invention is preferably consistent with the above technical solution and will not be repeated here.

[0136] The present invention provides an intermediate for synthesizing the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative described in the above technical solution, which is a compound having a structure shown in Formula 3:

[0137] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions of the present invention. Obviously, the embodiments described are only some of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0138] Example 1 Synthesis of Compound 2

[0139] Under nitrogen protection, [Rh(COD)Cl]2 (50 mg, 1 mol%) and (R,Sp)-L1 (120 mg, 2 mol%) were mixed with dry and degassed tetrahydrofuran (THF, 40 mL), and stirred at 25°C for complexation treatment for 15 min to obtain a rhodium catalyst solution; Cu(CH3CN)4PF6 (70 mg, 2 mol%) and (4R,2S)-L2 (120 mg, 2 mol%) were mixed with dry and degassed tetrahydrofuran (40 mL), and stirred at 25°C for complexation treatment for 15 min to obtain a copper catalyst solution; Compound 1 (3 g, 10 mmol), K3PO4 (3. 6g, 15mmol) and 3-chlorobutene (1.08g, 12mmol), and then the copper catalyst solution was added, and the reaction was stirred at 0°C under sealed conditions for 24h; after the reaction, 100mL of water was added to the obtained product system to quench the reaction, and 300mL of ethyl acetate was used for extraction 3 times, the organic phases were combined, anhydrous sodium sulfate was added to the organic phase for drying, and the phase was filtered. The filtrate was distilled under reduced pressure and the solvent was recovered to obtain a crude product, which was separated and purified by silica gel column chromatography (using 200-300 mesh silica gel and a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 99:1 as an eluent) to obtain 3.35g of a colorless oily liquid, which is compound 2, with a yield of 96%.

[0140] The chemical name of compound 2 is tert-butyl (2S,3S)-2-((diphenylmethylene)amino)-3-methylpent-4-enoate, and the NMR data are as follows:

[0141] 1H NMR (600MHz, CDCl3) δ7.68-7.65(m,2H),7.44-7.41(m,3H),7.38(ddd,J=6.5,3.8,1.2Hz,1H),7.32(dd,J=10.3,4.6Hz,2H),7.16-7.13(m,2H),5. 69(ddd,J=17.6,10.3,7.6Hz,1H),5.06-5.02(m,1H),4.97-4.94(m,1H), 3.86-3.80(m,1H),2.95-2.88(m,1H),1.44(s,9H),1.10(d,J=6.8Hz,3H). 13 C NMR (151MHz, CDCl3) δ170.7,170.3,140.9,139.9,136.9,130.3,128.9,128.6,1 28.5,128.1,128.1,114.8,81.1,70.8,41.8,28.2,15.9.HRMS(ESI+)calcd.for C 23 H 28 NO2(M+H) + :350.2115;found:350.2129.

[0142] Example 2 Synthesis of Compound 2'

[0143] Compound 2 (34 g) was dissolved in tetrahydrofuran (200 mL), and hydrochloric acid (1 mol / L, 100 mL) was added dropwise under stirring. After the addition was complete, the mixture was stirred at room temperature (25°C) for 20 min and monitored by TLC until the reaction of compound 2 was complete. After the reaction was complete, a saturated sodium carbonate solution was added to the resulting product system until the pH value of the system was 8, and then the mixture was extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure to recover the solvent to obtain a crude product.

[0144] The crude product was dissolved in 1,4-dioxane (200 mL), and a 10 wt% aqueous solution of sodium carbonate (21 g, 0.15 mol) was added, followed by dropwise addition of fluorenylmethoxycarbonyl succinimide (Fmoc-Osu, 37 g, 0.11 mol), and the mixture was stirred at room temperature for 2 h. After the reaction, hydrochloric acid (2 mol / L) was added to the resulting product system until the pH value of the system reached 7, and the mixture was extracted three times with 500 mL of ethyl acetate. The organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure to recover the solvent to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (using 200-300 mesh silica gel and a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 15:85 as an eluent) to obtain 3.13 g of a colorless oily liquid compound, compound 2', with a yield of 78%.

[0145] Compound 2' was subjected to high performance liquid chromatography (HPLC) analysis to determine enantioselectivity. The results are shown in Tables 1 and 2, wherein the HPLC analysis conditions included: DAICELCHIRALPAKIC; the mobile phase consisted of n-hexane and isopropanol, with a volume ratio of n-hexane to isopropanol of 95:5; the detection wavelength was 254 nm, and the mobile phase flow rate was 1.0 mL / min; tR1 = 11.353 min (minor), tR2 = 12.350 min (minor), tR3 = 13.032 min (major), and tR4 = 14.610 min (minor); the results showed that the dr value was 12:1 and the ee value was 99%.

[0146] Table 1 HPLC analysis data corresponding to the racemic product of compound 2'

[0147] Table 2 HPLC analysis data corresponding to the chiral product of compound 2'

[0148] The optical rotation data of the compound 2': [α] 25 D =-5.8 (c 0.5, CH2Cl2); NMR data are as follows:

[0149] 1H NMR (600MHz, CDCl3) δ7.77(d,J=7.6Hz,2H),7.61(d,J=7.5Hz,2H),7.40(d,J=7.5Hz,2H) ,7.32(d,J=7.4Hz,2H),5.79(dt,J=17.4,8.7Hz,1H),5.39(d,J=8.7Hz,1H),5.12(d,J=4 .0Hz,1H),5.10(s,1H),4.42(q,J=10.1Hz,1H),4.39-4.34(m,1H),4.33(dd,J=8.8,4.6H z, 1H), 4.24 (t, J = 7.2Hz, 1H), 2.70 (d, J = 6.0Hz, 1H), 1.50 (s, 9H), 1.10 (d, J = 6.9Hz, 3H). 13 C NMR (151MHz, CDCl3) δ170.5,156.0,144.1,143.9,141.4,138.9,127.8,127.14,125.3 ,125.2,120.1,116.1,82.4,67.1,58.2,47.3,41.1,28.2,15.4.HRMS(ESI+)calcd.for C 25 H 29 NNaO4 + (M+Na) + :430.1989;found:430.2008.

[0150] Example 3 Synthesis of Compound 3

[0151] K2OsO4·2H2O (370 mg, 1 mol%), AD-mix-β (780 mg, 1 mol%) and 100 mL of acetone aqueous solution (acetone to water volume ratio of 2:1) were mixed and stirred for 10 min to dissolve. Then, N-methylmorpholine oxide (NMO, 35.1 g, 0.3 mol), compound 2 (35.0 g, 0.1 mol) and 300 mL of acetone aqueous solution (acetone to water volume ratio of 2:1) were added and stirred at room temperature for 12 h. After the reaction was completed, excess The reaction was quenched with a saturated solution of Na2SO3, extracted three times with 500 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was distilled under reduced pressure and the solvent was recovered to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (using 200-300 mesh silica gel and a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 35:65 as eluent) to obtain 3.06 g of a light yellow oily liquid, which was compound 3, with a yield of 80%.

[0152] The chemical name of compound 3 is (2S,3R,4R)-2-((diphenylmethylene)amino)-4,5-dihydroxy-3-methylpentanoate, and the NMR data are as follows:

[0153] 1 H NMR (600MHz, CDCl3) δ7.59(d,J=7.8Hz,2H),7.44(d,J=1.9Hz,3H),7.40(t,J=7.1Hz,1H),7.33(t,J=7.5Hz,2H),7.16(d,J=3.1Hz,2H),4.16(d,J=3.2 Hz,1H),3.79(dd,J=8.0,3.8Hz,1H),3.77-3.69(m,1H),3.54(dd,J=11.2,5 .2Hz,1H),2.20-2.12(m,1H),1.43(d,J=6.4Hz,9H),1.05(d,J=7.0Hz,3H). 13 C NMR (151MHz, CDCl3) δ170.72,170.34,139.01,135.90,130.89,129.04,128.91,128.70, 128.34,127.66,81.64,74.49,69.19,65.05,39.86,28.18,13.95.HRMS(ESI+)calcd.for C 23 H 30 NO4 + (M+H) + :384.2169;found:384.2178.

[0154] Example 3

[0155] Compound 4 was synthesized using compound 3:

[0156] Compound 3 (19.15 g, 50 mmol) was dissolved in 200 mL of tetrahydrofuran, and hydrochloric acid (1 mol / L, 100 mL) was added dropwise with stirring. After the addition was complete, the mixture was stirred at room temperature for 20 min and monitored by TLC until the reaction of compound 3 was complete. After the reaction was complete, a saturated sodium carbonate solution was added to the resulting product system until the pH value of the system was 7, and then the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure to recover the solvent to obtain a crude product.

[0157] The crude product was dissolved in 1,4-dioxane (200 mL), and a 10 wt% aqueous solution of sodium carbonate (7.95 g, 75 mmol) was added, followed by dropwise addition of fluorenylmethoxycarbonyl succinimide (Fmoc-Osu, 18.50 g, 55 mmol), and the mixture was stirred at room temperature for 2 h. After the reaction, hydrochloric acid (2 mol / L) was added to the resulting product system until the pH value of the system reached 7, and the mixture was extracted three times with 500 mL of ethyl acetate. The organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure to recover the solvent to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (using 200-300 mesh silica gel and a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 40:60 as an eluent) to obtain 16.45 g of a colorless oily liquid, which was compound 4, with a yield of 80%.

[0158] Compound 4 was synthesized using compound 2':

[0159] K2OsO4·2H2O (370 mg, 1 mol%), AD-mix-β (780 mg, 1 mol%) and 100 mL of acetone aqueous solution (acetone to water volume ratio of 2:1) were mixed and stirred for 10 min to dissolve. Then, N-methylmorpholine oxide (NMO, 35.1 g, 0.3 mol), compound 2' (40.7 g, 0.1 mol) and 300 mL of acetone aqueous solution (acetone to water volume ratio of 2:1) were added and stirred at room temperature for 12 h. After the reaction was completed, the mixture was added. The reaction was quenched with an amount of saturated Na2SO3 solution, extracted three times with 500mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was distilled under reduced pressure and the solvent was recovered to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (using 200-300 mesh silica gel and a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 35:65 as eluent) to obtain 3.06g of a light yellow oily liquid, which is compound 4, with a yield of 82%.

[0160] The chemical name of compound 4 is (2S,3R,4R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4,5-dihydroxy-3-methylpentanoic acid tert-butyl ester. Compound 4 was subjected to HPLC analysis, and the results are shown in Tables 3 and 4, wherein the conditions of the HPLC analysis include: DAICEL CHIRALPAK IC; the mobile phase is n-hexane and isopropanol, and the volume ratio of n-hexane to isopropanol is 95:5; the detection wavelength is 254 nm, and the mobile phase flow rate is 1.0 mL / min; tR1=13.248 min (major), tR2=34.663 min (minor); the results show that the dr value is 10:1 and the ee value is 99%.

[0161] Table 3 HPLC analysis data corresponding to the racemic product of compound 4

[0162] Table 4 HPLC analysis data corresponding to the chiral product of compound 4

[0163] The NMR data of compound 4 are as follows:

[0164] 1 H NMR (600MHz, CDCl3) δ7.75(dd,J=7.5,3.8Hz,2H),7.58(d,J=7.5Hz,2H),7.42-7.36(m,2H),7.31(t,J =7.4Hz,1H),5.77(d,J=7.9Hz,1H),4.93(s,1H),4.68(d,J=2.2Hz,1H),4.48(dd,J=10.7,7.1Hz,1H), 4.38(dd,J=10.7,6.8Hz,1H),4.20(t,J=6.9Hz,1H),3.75(dd,J=11.2,2.3Hz,1H),3.52(dd,J=11.2,7 .0Hz,1H),3.25(t,J=7.4Hz,1H),2.72(s,1H),2.20-2.11(m,1H),1.47(s,9H),0.72(d,J=6.9Hz,3H). 13 C NMR (151MHz, CDCl3) δ171.1,157.8,143.7,143.5,141.4,141.4,127.8,127.2,127.2,125.1,12 4.9,120.1,120.0,82.8,72.5,67.5,64.3,55.1,47.2,39.4,28.0,10.2.HRMS(ESI+)calcd.for C 25 H 31 NNaO6+ (M+Na) + :464.2044;found:464.2032.

[0165] Example 4 Synthesis of Compound 5

[0166] Compound 4 (22.0 g, 50 mmol) and pyridine (6.0 g, 75 mmol) were added to dry dichloromethane (500 mL), stirred and dissolved at 0°C, and then acetyl chloride (8.6 g, 110 mmol) was added dropwise at a rate of 100 mL / h. After the addition was complete, the mixture was stirred and reacted at 0°C for 1 h, and then the mixture was heated to room temperature and stirred and reacted for 1 h. After the reaction was completed, the resulting product system was washed with saturated NH4Cl solution, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure and the solvent was recovered to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (using 200-300 mesh silica gel and a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 8:92 as eluent) to obtain 22.0 g of a white solid, which was compound 5, with a yield of 84%.

[0167] The chemical name of compound 5 is (2R,3R,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(tert-butoxy)-3-methyl-5-oxopentane-1,2-diacetyl diacetate, and the NMR data are as follows:

[0168] 1 H NMR (600MHz, CDCl3) δ7.76 (d, J=7.5Hz, 2H), 7.61 (dd, J=11.6, 7.6Hz, 2H), 7.39(t,J=7.4Hz,2H),7.31(t,J=7.4Hz,2H),5.24(d,J=9.9Hz,1H),4.84(d, J=9.2Hz,1H),4.65(dd,J=9.8,2.2Hz,1H),4.48(d,J=11.4Hz,1H),4.35(dt,J =17.9,10.5Hz,2H),4.22(t,J=7.1Hz,1H),4.09(dd,J=12.4,4.5Hz,1H),2.5 4-2.45(m,1H),2.11(s,3H),2.08(s,3H),1.50(s,9H),0.91(d,J=7.1Hz,3H). 13C NMR (151MHz, CDCl3) δ170.9,170.8,170.5,156.4,144.1,143.9,141.4,141.4,127.8,127.8,127.2,125.4,1 25.2,120.1,120.0,82.7,71.9,67.4,63.4,54.8,47.3,36.2,28.2,21.2,20.9,11.1.HRMS(ESI+)calcd.for C 29 H 35 NNaO8 + (M+Na) + :548.2255;found:548.2262.

[0169] Example 5 Synthesis of Compound 6

[0170] Compound 5 (21.01 g, 40 mmol) was mixed with trifluoroacetic acid (TFA, 50 mL), stirred at room temperature for 2 h, and monitored by TLC until compound 5 was completely reacted. After the reaction, the resulting product system was distilled under reduced pressure and the solvent was recovered to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (using 200-300 mesh silica gel and a mixed solvent of methanol and dichloromethane with a volume ratio of 5:95 as an eluent) to obtain 16.89 g of a white solid, which is compound 6, with a yield of 90%.

[0171] The inventive name of compound 6 is (2S,3R,4R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4,5-diacetoxy-3-methylpentanoic acid, and the NMR data are as follows:

[0172] 1 H NMR(600MHz,DMSO)δ13.05(s,1H),7.88(d,J=7.2Hz,2H),7.74(dd,J=18.8,7.2Hz,2H), 7.65(d,J=9.4Hz,1H),7.41(t,J=7.0Hz,2H),7.33(d,J=4.6Hz,2H),4.77(d,J=7.5Hz,1H ),4.48-4.44(m,1H),4.38(d,J=11.9Hz,1H),4.28-4.24(m,1H),4.22-4.15(m,2H),4.0 5(dd,J=12.1,4.3Hz,1H),3.43(s,1H),2.00(s,3H),1.96(s,3H),0.93(d,J=6.6Hz,3H). 13C NMR (151MHz, DMSO) δ173.1,170.2,169.7,156.6,144.1,143.7,140.7,140.7,127.7,127.6,127.2,127.1,12 5.6,125.3,120.1,120.1,71.5,66.0,62.8,54.1,46.7,39.5,34.9,20.7,20.6,10.9.HRMS(ESI+)calcd.for C 25 H 27 NNaO8 + (M+Na) + :492.1629;found:492.1635.

[0173] As can be seen from the above examples, the present invention uses benzophenone imine glycine tert-butyl ester as the starting reaction raw material, and realizes the efficient asymmetric synthesis of (2S,3R,4R)-4,5-dihydroxyisoleucine derivatives through asymmetric allylation and asymmetric dihydroxylation reactions and the introduction or removal of protecting groups. At the same time, it can also realize the synthesis of enantiomers and diastereomers of (2S,3R,4R)-4,5-dihydroxyisoleucine derivatives for the first time. The present invention uses a [Rh(COD)Cl]2 catalyst, a Cu(CH3CN)4PF6 catalyst, a josiphos ligand, and a tBu-PHOX ligand to synergistically catalyze the asymmetric allylation reaction of benzophenone imine glycine tert-butyl ester with 3-chlorobutene to produce an allyl-substituted glycine derivative; then, an asymmetric dihydroxylation reaction, an imine hydrolysis reaction, a 9-fluorenylmethyloxycarbonyl protection reaction, and a tert-butyl ester hydrolysis reaction are performed to synthesize N-Fmoc-(2S,3R,4R)-4,5-dihydroxyisoleucine. The raw materials and reagents used in the present invention are readily available, the reaction conditions are mild, the operation process is simple, the stereoselectivity is high, the enantiomeric excess (ee) is as high as 99%, the separation and purification process has good operability, and the total yield is high. The invention has significant application value in the field of amino acid derivative synthesis.

[0174] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A method for preparing a (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate A, comprising the following steps: The compound 1 is subjected to an asymmetric allylation reaction to obtain the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate A; The structural formulas of the compound 1 and the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate A are shown in Formula 1 and Formula 2 respectively:

2. A method for preparing a (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate A', The following steps are involved: According to the preparation method of claim 1, the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate A is obtained; The (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A is subjected to an imine hydrolysis reaction and a 9-fluorenylmethoxycarbonyl protection reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A'; The structural formula of the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate A' is shown in Formula 2':

3. A method for preparing a (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate B, The following steps are involved: According to the preparation method of claim 1, the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate A is obtained; The (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A is subjected to an asymmetric dihydroxylation reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate B; The structural formula of the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate B is shown in Formula 3:

4. A method for preparing a (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate C, The following steps are involved: According to the preparation method of claim 3, the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate B is obtained; The (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate B is subjected to an imine hydrolysis reaction and a 9-fluorenylmethoxycarbonyl protection reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C; The structural formula of the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate C is shown in Formula 4:

5. A method for preparing a (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate C, The following steps are involved: According to the preparation method of claim 2, the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative is obtained. Interbody A'; The (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate A' is subjected to an asymmetric dihydroxylation reaction to obtain the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate C; The structural formula of the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate C is shown in Formula 4:

6. A method for preparing a (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative, comprising the following steps: The compound 1 is subjected to an asymmetric allylation reaction to obtain the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate A; The (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A is subjected to an asymmetric dihydroxylation reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate B; The (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate B is subjected to an imine hydrolysis reaction and a 9-fluorenylmethoxycarbonyl protection reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C; Acetylation reaction is performed on the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate C to obtain a (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate D; The (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate D is subjected to a tert-butyl ester hydrolysis reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative; The structural formulas of the compound 1, (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A, (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate B, (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C, (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate D and (2S,3R,4R)-4,5-dihydroxyisoleucine derivative are shown in Formula 1, Formula 2, Formula 3, Formula 4, Formula 5 and Formula 6 respectively:

7. A method for preparing a (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative, comprising the following steps: The compound 1 is subjected to an asymmetric allylation reaction to obtain the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate A; The (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A is subjected to an imine hydrolysis reaction and a 9-fluorenylmethoxycarbonyl protection reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A'; The (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate A' is subjected to an asymmetric dihydroxylation reaction to obtain the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate C; Acetylation reaction is performed on the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate C to obtain a (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate D; The (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate D is subjected to a tert-butyl ester hydrolysis reaction to obtain the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative; The structural formulas of the compound 1, (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A, (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A', (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate C, (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate D and (2S,3R,4R)-4,5-dihydroxyisoleucine derivative are shown in Formula 1, Formula 2, Formula 2', Formula 4, Formula 5 and Formula 6 respectively:

8. The preparation method according to any one of claims 1 to 7, characterized in that: The raw materials used in the asymmetric allylation reaction include 3-chlorobutene; the asymmetric allylation reaction is carried out in the presence of a rhodium catalyst, a rhodium catalyst ligand, a copper catalyst, a copper catalyst ligand and an alkali reagent.

9. The preparation method according to claim 8, characterized in that: The rhodium catalyst is [Rh(COD)Cl]2, the copper catalyst is Cu(CH3CN)4PF6, and the alkaline reagent is potassium phosphate; the structural formulas of the rhodium catalyst ligand and the copper catalyst ligand are shown below in sequence:

10. The preparation method according to claim 9, characterized in that: The molar amount of [Rh(COD)Cl]2 is 1 to 20% of the molar amount of compound 1, and the molar amount of the rhodium catalyst ligand is 1 to 10% of the molar amount of compound 1; the molar amount of Cu(CH3CN)4PF6 is 1 to 10% of the molar amount of compound 1, and the molar amount of the copper catalyst ligand is 1 to 20% of the molar amount of compound 1; the molar ratio of the alkaline reagent to compound 1 is 1 to 5:

1.

11. The preparation method according to claim 8, characterized in that: The molar ratio of the compound 1 to 3-chlorobutene is 1:1-4.

12. The preparation method according to claim 8, characterized in that: The asymmetric allylation reaction is carried out in the presence of an organic solvent, and the ratio of the organic solvent to compound 1 is 2-10 mL: 1 mmol.

13. The preparation method according to claim 8, characterized in that: The temperature of the asymmetric allylation reaction is -10 to 25° C., and the time is 12 to 48 hours.

14. The preparation method according to claim 13, characterized in that: After the asymmetric allylation reaction, the method further comprises: adding water to the obtained product system to quench the reaction, then extracting, removing the solvent in the obtained organic phase, and separating the obtained crude product by column chromatography to obtain the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate A.

15. The preparation method according to claim 2 or 7, characterized in that: The imine hydrolysis reaction is carried out in the presence of hydrochloric acid, the concentration of the hydrochloric acid is 1-12 mol / L, and the ratio of the hydrochloric acid to the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate A is 1-5L:1mol; The imine hydrolysis reaction is carried out in the presence of an organic solvent, and the usage ratio of the organic solvent to the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate A is 1-4L:1mol.

16. The preparation method according to claim 15, characterized in that: The temperature of the imine hydrolysis reaction is 0-50° C. and the time is 10-40 minutes.

17. The preparation method according to claim 2 or 7, characterized in that: The raw materials used in the 9-fluorenylmethoxycarbonyl protection reaction include fluorenylmethoxycarbonyl succinimide, and the molar ratio of the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A to fluorenylmethoxycarbonyl succinimide is 1:1-2 based on the amount of the (2S,3R,4R)-4,5-dihydroxyisoleucine derivative intermediate A used; The 9-fluorenylmethoxycarbonyl protection reaction is carried out in the presence of a sodium carbonate solution, wherein the concentration of the sodium carbonate solution is 5 to 50 wt %, and based on the amount of the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate A, the molar ratio of the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate A to the sodium carbonate in the sodium carbonate solution is 1:1 to 3; The 9-fluorenylmethoxycarbonyl protection reaction is carried out in the presence of an organic solvent. Based on the amount of the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate A, the amount ratio of the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate A to the 9-fluorenylmethoxycarbonyl protection reaction is 1 mol: 1 to 5 L.

18. The preparation method according to claim 17, characterized in that: The temperature of the 9-fluorenylmethoxycarbonyl protection reaction is 0 to 50° C., and the time is preferably 1 to 24 hours.

19. The preparation method according to claim 18, characterized in that: After the 9-fluorenylmethoxycarbonyl protection reaction, the method further comprises: adding hydrochloric acid to the obtained product system to adjust the pH value of the system to 7, then extracting, removing the solvent in the obtained organic phase, and separating the obtained crude product by column chromatography to obtain the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate A'.

20. The preparation method according to claim 3 or 6, characterized in that: The asymmetric dihydroxylation reaction is carried out in the presence of N-methylmorpholine oxide, potassium osmate dihydrate and AD-mix-β, and the molar ratio of the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate A, N-methylmorpholine oxide, potassium osmate dihydrate and AD-mix-β is 1:1-5:0.001-0.1:0.001-0.1; The asymmetric dihydroxylation reaction is carried out in the presence of water and an organic solvent, and the usage ratio of the water, the organic solvent and the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate A is 1-3L:1-3L:1mol.

21. The preparation method according to claim 20, characterized in that: The temperature of the asymmetric dihydroxylation reaction is 0 to 50° C. and the time is 1 to 24 hours.

22. The preparation method according to claim 21, characterized in that: The asymmetric dihydroxylation reaction further includes: adding a Na2SO3 solution to the obtained product system to quench the reaction, then extracting, washing and drying the obtained organic phase in sequence, then removing the solvent, and separating the obtained crude product by column chromatography to obtain the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate B.

23. The preparation method according to claim 6 or 7, characterized in that: The raw materials used in the acetylation reaction include acetyl chloride, and the molar ratio of the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate C to acetyl chloride is 1:1-10; The acetylation reaction is carried out in the presence of pyridine, and the molar ratio of the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate C to pyridine is 1:1-10; The acetylation reaction is carried out in the presence of an organic solvent, and the dosage ratio of the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate C to the organic solvent is 5-50 mL: 1 mmol.

24. The preparation method according to claim 23, characterized in that: The acetylation reaction includes sequentially performing a first stage reaction and a second stage reaction; the temperature of the first stage reaction is -10 to 10°C and the time is 0.5 to 2 hours; the temperature of the second stage reaction is 25 to 50°C and the time is 0.5 to 2 hours.

25. The preparation method according to claim 24, characterized in that: After the acetylation reaction, the method further comprises: washing the obtained product system with a saturated NH4Cl solution, collecting the organic phase, removing the solvent, and separating the obtained crude product by column chromatography to obtain the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate D.

26. The preparation method according to claim 6 or 7, characterized in that: The tert-butyl ester hydrolysis reaction is carried out in the presence of trifluoroacetic acid, and the dosage ratio of the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative intermediate D to trifluoroacetic acid is 4 mmol: 1-10 mL.

27. The preparation method according to claim 26, characterized in that: The temperature of the tert-butyl ester hydrolysis reaction is 0-50° C. and the time is 1-4 hours.

28. The preparation method according to claim 27, characterized in that: After the tert-butyl ester hydrolysis reaction, the method further comprises: removing the solvent in the obtained product system, and separating the obtained crude product by column chromatography to obtain the (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative.

29. An intermediate for synthesizing a (2S, 3R, 4R)-4,5-dihydroxyisoleucine derivative is a compound having a structure shown in Formula 3:

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