Synthesis method of (4S, 5R)-3-[2-[[fluorenylmethoxycarbonyl] amino] acetyl]-2, 2, 5-trimethyl-4-oxazolidine carboxylic acid

Abstract

The invention discloses a synthesis method of (4S, 5R)-3-[2-[[fluorenylmethoxycarbonyl] amino] acetyl]-2, 2, 5-trimethyl-4-oxazolidine carboxylic acid, which comprises the following steps: S1, carrying out amino protection reaction on L-threonine methyl ester hydrochloride to form a compound I; s2, reacting the compound I with Lewis acid and a cyclization reactant to generate a compound II; s3, performing ammonolysis on the compound II to obtain a compound III; s4, carrying out hydrolysis reaction on the compound III and an alkali reagent to obtain a compound IV; and S5, reacting the compound IV with an fmoc protection reagent to obtain a final product (4S, 5R)-3-[2-[[fluorenylmethoxycarbonyl] amino] acetyl]-2, 2, 5-trimethyl-4-oxazolidine carboxylic acid. The method is high in yield and purity and low in cost.

Description

Technical Field

[0001] The present invention relates to amino acid synthesis, and in particular to a method for synthesizing (4S,5R)-3-[2-[[fluorenylmethyloxycarbonyl]amino]acetyl]-2,2,5-trimethyl-4-oxazolidinecarboxylic acid. Background Art

[0002] Fmoc-gly-thr(psi(me,me)pro)-OH, Chinese name is (4S,5R)-3-[2-[[fluorenylmethoxycarbonyl]amino]acetyl]-2,2,5-trimethyl-4-oxazolidinecarboxylic acid, molecular formula is C 24 H 26 N2O6, the structural formula is:

[0003]

[0004] The current synthesis route for (4S,5R)-3-[2-[[fluorenylmethoxycarbonyl]amino]acetyl]-2,2,5-trimethyl-4-oxazolidinecarboxylic acid is to first synthesize the corresponding dipeptide using CBZ-glycine or FMOC-glycine as a raw material, and then undergo a ring-closure reaction to obtain Fmoc-gly-thr(psi(me,me)pro)-OH. However, the yield of the synthesized dipeptide is low, and significant by-products are produced. Molecular sieves are required for the ring-closure of the dipeptide, and the ring-closure reaction has poor selectivity, making post-processing relatively difficult, purification difficult, and the production cycle long.

[0005] The above background technology is for facilitating understanding of the present invention and is not a known technology disclosed to the general public before the application of the present invention. Summary of the Invention

[0006] In view of the above-mentioned defects, the present invention provides a method for improving at least one of the problems mentioned in the background art.

[0007] The technical solution is: a method for synthesizing (4S,5R)-3-[2-[[fluorenylmethyloxycarbonyl]amino]acetyl]-2,2,5-trimethyl-4-oxazolidinecarboxylic acid, comprising the following steps:

[0008] S1, L-threonine methyl ester hydrochloride is subjected to amino protection reaction to form compound 1;

[0009] S2, compound 1 reacts with Lewis acid and cyclization reagent to form compound 2;

[0010] S3, compound diammonialysis to obtain compound 3;

[0011] S4, compound 3 is hydrolyzed with an alkaline reagent to obtain compound 4;

[0012] S5, compound 4 reacts with an fmoc protecting reagent to obtain the final product (4S,5R)-3-[2-[[fluorenylmethyloxycarbonyl]amino]acetyl]-2,2,5-trimethyl-4-oxazolidinecarboxylic acid;

[0013] Among them, the structural formula of compound 1 is:

[0014]

[0015] The structural formula of compound II is:

[0016]

[0017] The structural formula of compound three is:

[0018] The structural formula of compound 4 is:

[0019] Furthermore, in S1, the amino protecting group of the amino protection is a chloroacetyl group or a bromoacetyl group; in S2, the Lewis acid is trifluoroacetic acid, boron trifluoride etherate or triphenylboron, and the cyclization reagent is 2,2-dimethoxypropane, 2,2-diethoxypropane or 2,2-diisopropoxypropane; in S3, the aminolysis reagent is ammonia water or ammonia methanol; in S4, the alkaline reagent is sodium hydroxide, potassium hydroxide or lithium hydroxide; in S5, the Fmoc protecting reagent is Fmoc-osu or Fmoc-Cl.

[0020] Furthermore, in S1, the molar ratio of L-threonine methyl ester to amino protecting group is 1:1~1.5; in S2, the molar ratio of compound 1: Lewis acid: cyclization reagent is 1:0.01~0.1:5~10; in S3, the molar ratio of compound 2: aminolysis reagent is 1:5-15; in S4, the molar ratio of compound 3: alkaline reagent is 1:2.0~2.5; in S5, the molar ratio of compound 4: FMOC protecting reagent is 1:1.0~1.2.

[0021] Furthermore, the molar ratio of the L-threonine methyl ester to the amino protecting group is 1:1.1, the molar ratio of the compound one: Lewis acid: cyclization reagent is 1:0.05:5, the molar ratio of the compound two: aminolysis reagent is 1:10; the molar ratio of the compound two: aminolysis reagent is 1:2.0; and the molar ratio of the compound four: Fmoc protecting reagent is 1:1.0.

[0022] Furthermore, in S1, the amino protection reaction is carried out in THF and triethylamine; and in S4 and S5, the reaction is carried out in tetrahydrofuran.

[0023] Furthermore, in S1, the reaction temperature is 5-10°C, and the reaction time is 6-8h; in S2, the reaction temperature is 50-60°C, and the reaction time is 4-6h; in S3, the reaction temperature is 35-40°C; in S4, the reaction temperature is 15-25°C, and the reaction time is 4-6h; in S5, the reaction temperature is 15-25°C, the pH is 7-8, and the reaction time is 4-6h.

[0024] Furthermore, in S1, after the reaction, citric acid water is added, extracted with 100 ml of ethyl acetate, and concentrated; in S2, after the reaction, the reaction solution is added to water, the pH is adjusted to 6-7 with sodium bicarbonate, extracted with methyl tert-butyl ether, the organic phases are combined, filtered, and concentrated; in S3, after the reaction, methyl tert-butyl ether is added for extraction, the organic phases are combined, filtered, concentrated, and dried; in S4, after the reaction, the reaction solution is adjusted to a pH of 5-6 with citric acid, extracted with n-butanol, the organic phases are combined, filtered, and concentrated; in S5, after the reaction, the reaction solution is adjusted to a pH of 3-4 with citric acid, extracted with methyl tert-butyl ether, the organic phases are combined, filtered, concentrated, crystallized with n-heptane, and dried.

[0025] Compared with the prior art, the present invention has the following beneficial effects:

[0026] The invention uses L-threonine methyl ester hydrochloride as a raw material, obtains a pseudo-proline dipeptide of glycylthreonine by protecting the amino group, then cyclizing and then aminolyzing, and then protecting the amino group by FMOC to obtain a product, with high yield and purity and low cost.

[0027] The invention uses chloroacetyl to protect the amino group of threonine, then performs cyclization to form pseudo-proline, performs aminolysis to obtain a glycylthreonine pseudo-proline dipeptide, and then uses Fmoc-osu to protect the amino group to obtain a product. The invention solves the problems of long reaction time, low yield, and high safety risk of the reported reaction route, and has the advantages of cheap and readily available raw materials, low production cost, simple operation, environmental friendliness, high yield, short reaction time, simple post-processing, and the like. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 Schematic diagram of the synthesis route of the present invention;

[0029] Figure 2 This is the four HNMR diagram of the compound of the present invention;

[0030] Figure 3 It is the purity diagram of the compound of the present invention;

[0031] Figure 4 This is the HNMR diagram of the final product of the present invention;

[0032] Figure 5 It is the purity diagram of the final product of the present invention. DETAILED DESCRIPTION

[0033] As used herein:

[0034] "Prepared from" is synonymous with "comprising." As used herein, the terms "comprising," "including," "having," "containing," or any other variations thereof, are intended to cover a non-exclusive inclusion. For example, a composition, process, method, article, or apparatus that comprises the listed elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, process, method, article, or apparatus.

[0035] The conjunction "consisting of" excludes any unspecified element, step, or component. If used in a claim, this phrase renders the claim closed, excluding materials other than those described, except for conventional impurities associated therewith. When the phrase "consisting of" appears in a clause of the body of a claim, rather than immediately following the subject matter, it limits only the elements described in that clause; other elements are not excluded from the claim as a whole.

[0036] When an amount, concentration, or other value or parameter is expressed as a range, a preferred range, or a range defined by a series of upper preferred values ​​and lower preferred values, this should be understood as specifically disclosing all ranges formed by any pairing of any range upper limit or preferred value with any range lower limit or preferred value, regardless of whether the range is disclosed alone. For example, when a range of "1 to 5" is disclosed, the described range should be interpreted as including the range "1 to 4", "1 to 3", "1 to 2", "1 to 2 and 4 to 5", "1 to 3 and 5", etc. When a numerical range is described herein, unless otherwise stated, the range is intended to include its end values ​​and all integers and fractions within the range.

[0037] The following will clearly and completely describe the technical solutions of the present invention in conjunction with the embodiments. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. 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.

[0038] Those skilled in the art will appreciate that the following examples are intended to illustrate the present invention only and should not be construed as limiting the scope of the present invention. In the examples, where specific conditions are not specified, conventional conditions or manufacturer-recommended conditions were used. Reagents or instruments used where the manufacturer is not specified are conventional products that can be purchased commercially.

[0039] In these examples, parts and percentages are by mass unless otherwise indicated.

[0040] "Parts by mass" refers to the basic unit of measurement used to express the mass ratio of multiple components. One part can represent any unit of mass, such as 1g or 2.689g. If we say that the mass of component A is a parts and the mass of component B is b parts, this means the ratio of the mass of component A to the mass of component B is a:b. Alternatively, we could say that the mass of component A is aK and the mass of component B is bK (K is an arbitrary number representing a multiplication factor). It's important to note that, unlike parts by mass, the sum of the mass of all components is not limited to 100 parts.

[0041] "And / or" is used to indicate that one or both of the stated situations may occur, for example, A and / or B includes (A and B) and (A or B).

[0042] Please refer to Figure 1 , Figure 1 This is the synthesis process diagram of the present invention, Figure 1 The synthesis process of (4S,5R)-3-[2-[[Fluorenylmethyloxycarbonyl]amino]acetyl]-2,2,5-trimethyl-4-oxazolidinecarboxylic acid comprises the following steps:

[0043] S1, L-threonine methyl ester hydrochloride amino group protection to form compound 1, wherein the protecting group can be chloroacetyl or bromoacetyl, preferably chloroacetyl, and the molar ratio of L-threonine methyl ester to the protecting group is: 1:1-1.5, preferably 1:1.1;

[0044] S2, compound 1 reacts with a Lewis acid and 2,2-dioxypropane to form compound 2, wherein the Lewis acid is trifluoroacetic acid, boron trifluoride ethyl ether or triphenylboron, preferably triphenylboron; 2,2-dioxypropane is 2,2-dimethoxypropane, 2,2-diethoxypropane or 2,2-diisopropoxypropane, preferably 2,2-diisopropoxypropane; the mol ratio of compound 1: Lewis acid: 2,2-diisopropoxypropane is 1:0.01~0.1:5~10, preferably 1:0.05:5.

[0045] S3, compound 2 is subjected to ammonolysis to obtain compound 3, wherein the ammonolysis reagent can be aqueous ammonia or ammonia methanol, preferably aqueous ammonia; the molar ratio of compound 2 to ammonolysis reagent is 1:5-15, preferably 1:10;

[0046] S4, compound 3 reacts with an alkaline reagent to obtain compound 4, wherein the alkaline reagent is sodium hydroxide, potassium hydroxide or lithium hydroxide, preferably sodium hydroxide, and the molar ratio of compound 3 to the alkaline reagent is 1:2.0 to 2.5, preferably 1:2.0;

[0047] S5. Compound 4 is reacted with an Fmoc protecting agent to obtain the final product, (4S,5R)-3-[2-[[Fmoc-amino]acetyl]-2,2,5-trimethyl-4-oxazolidinecarboxylic acid. The Fmoc protecting agent is Fmoc-Osu or Fmoc-Cl, preferably Fmoc-Osu. The molar ratio of Compound 4 to Fmoc protecting agent is 1:1.0 to 1.2, preferably 1:1.0.

[0048] Among them, the structural formula of compound 1 is:

[0049]

[0050] The structural formula of compound II is:

[0051]

[0052] The structural formula of compound three is:

[0053]

[0054] The structural formula of compound 4 is:

[0055]

[0056] Example 1

[0057] A method for synthesizing (4S,5R)-3-[2-[[fluorenylmethyloxycarbonyl]amino]acetyl]-2,2,5-trimethyl-4-oxazolidinecarboxylic acid comprises the following steps:

[0058] S1. Measure 100 ml of THF and add it to a three-necked flask. Weigh 10 g (1.0 eq) of L-threonine methyl ester hydrochloride and add it to the three-necked flask. Cool the mixture to 5-10°C until the solution is clear. Slowly add 7.3 g (1.1 eq) of chloroacetyl chloride and 11.9 g (2.0 eq) of triethylamine. Control the temperature at 5-10°C. React for 6-8 h. Monitor the reaction until complete. Add 50 ml of 5 wt% citric acid water, extract with 100 ml of ethyl acetate, and concentrate to obtain 10.5 g of compound 1 with a yield of 85.1%.

[0059] S2, measured 100 ml of acetone and added it to a three-necked flask protected by nitrogen, added compound 1 of S1 and 40 g (5.0 eq) of 2,2-diisopropoxypropane and 0.6 g (0.05 eq) of triphenylboron to the three-necked flask, heated to 50-60°C until the system was in a clear state, reacted for 4-6 hours, and when the reaction reached the end point, added the reaction solution to water at 0-5°C, adjusted the pH to 6-7 with 0.42 g (0.1 eq) of sodium bicarbonate, extracted with 200 ml of methyl tert-butyl ether × 3, combined the organic phases, filtered, and concentrated to obtain 9.98 g of compound 2 with a yield of 80.3%.

[0060] S3, add compound 2 of S2 into a three-necked flask, then add 87.5 g of 20 wt% ammonia water, react at 35-40°C, add 50 mL of methyl tert-butyl ether × 3 times for extraction after reaching the end point, combine the organic phases, filter, concentrate, and dry to obtain 8.28 g of compound 3 with a yield of 89.9%.

[0061] S4, weigh 50ml of tetrahydrofuran and add it to a three-necked flask, weigh 8.28g (1.0eq) of compound three and add it to the three-necked flask, weigh 2.88g (2.0eq) of sodium hydroxide and prepare a 20wt% solution and add it to the three-necked flask, control the temperature at 15-25℃, react for 4-6h, and when the reaction reaches the end point, control the temperature of the reaction solution at 0-5℃ and use 20wt% citric acid to adjust the pH of the system to 5-6, extract with 100ml of n-butanol × 3, combine the organic phases, filter, and concentrate to obtain 6.99g of compound four, with a yield of 90%. HNMR of compound four is as follows Figure 2 , purity as Figure 3 .

[0062] S5, weigh 50ml of tetrahydrofuran and add it to a three-necked flask, weigh 6.99g (1.0eq) of compound 4 and add it to the three-necked flask, weigh 6.52g (2.0eq) of triethylamine and 10.9g (1.0eq) of Fmoc-osu and add it to the three-necked flask, control the temperature at 15-25°C, control the pH at 7-8, and react for 4-6h. When the reaction reaches the end point, control the temperature of the reaction solution at 0-5°C and adjust the pH to 3-4 with 20% citric acid, extract with 100ml of methyl tert-butyl ether × 3 times, combine the organic phases, filter, concentrate, crystallize with 100ml of n-heptane, and dry to obtain 12.05g of the final product with a yield of 85.2%. The HNMR of the final product is as follows Figure 4 , purity as Figure 5 .

[0063] Example 2

[0064] A method for synthesizing (4S,5R)-3-[2-[[fluorenylmethyloxycarbonyl]amino]acetyl]-2,2,5-trimethyl-4-oxazolidinecarboxylic acid comprises the following steps:

[0065] S1. Measure 100 ml of THF and add it to a three-necked flask. Weigh 10 g (1.0 eq) of L-threonine methyl ester hydrochloride and add it to the flask. Cool the mixture to 5-10°C until the solution is clear. Slowly add 7.3 g (1.1 eq) of chloroacetyl chloride and 11.9 g (2.0 eq) of triethylamine. Control the temperature at 5-10°C. React for 6-8 h. Monitor the reaction until complete. Add 50 ml of 5 wt% citric acid water, extract with 100 ml of ethyl acetate, and concentrate to obtain 10.5 g of compound 1 with a yield of 85.2%.

[0066] S2, measured 100 ml of acetone and added it to a three-necked flask protected by nitrogen, added compound 1 of S1 and 40 g (5.0 eq) of 2,2-diisopropoxypropane and 0.35 g (0.05 eq) of boron trifluoride ether into the three-necked flask, heated to 50-60°C until the system was in a clear state, reacted for 4-6 hours, and when the reaction reached the end point, the reaction solution was added to water at 0-5°C, adjusted to pH 6-7 with 0.42 g (0.1 eq) of sodium bicarbonate, extracted with 200 ml × 3 of methyl tert-butyl ether, combined the organic phases, filtered, and concentrated to obtain 9.4 g of compound 2 with a yield of 75.1%.

[0067] S3, add compound 2 of S2 into a three-necked flask, then add 65.8 g of 20 wt% ammonia water, react at 35-40°C, add 50 mL of methyl tert-butyl ether × 3 times for extraction after reaching the end point, combine the organic phases, filter, concentrate, and dry to obtain 7.8 g of compound 3 with a yield of 90.3%.

[0068] S4, measure 50 ml of tetrahydrofuran and add it to a three-necked flask, weigh 7.8 g (1.0 eq) of compound three and add it to the three-necked flask, weigh 2.7 g (2.0 eq) of sodium hydroxide and prepare it into a 20 wt% solution and add it to the three-necked flask, control the temperature at 15-25 ° C, react for 4-6 hours, and when the reaction reaches the end point, control the temperature of the reaction solution to 0-5 ° C, use 20 wt% citric acid to adjust the pH of the system to 5-6, extract with 100 ml of n-butanol × 3, combine the organic phases, filter, and concentrate to obtain 6.6 g of compound four with a yield of 89.4%.

[0069] S5, measured 50 ml of tetrahydrofuran and added to a three-necked flask, weighed 6.6 g (1.0 eq) of compound 4 and added to the three-necked flask, weighed 6.1 g (2.0 eq) of triethylamine, and 10.3 g (1.0 eq) of Fmoc-osu were added to the three-necked flask, the temperature was controlled at 15-25 ° C, the pH was controlled at 7-8, the reaction was carried out for 4-6 hours, and the reaction reached the end point. The temperature of the reaction solution was controlled at 0-5 ° C, and the pH of the system was adjusted to 3-4 using 20% ​​citric acid. The reaction was extracted with 100 ml of methyl tert-butyl ether × 3, the organic phases were combined, filtered, concentrated, crystallized using 100 ml of n-heptane, and dried to obtain 11.37 g of the final product with a yield of 85.0%.

[0070] The difference between this embodiment and embodiment 1 is that in step S2, boron trifluoride etherate is selected as the catalyst, and the yield in step S2 is reduced by about 5% compared with triphenylboron.

[0071] Example 3

[0072] S1. Measure 100 ml of THF and add it to a three-necked flask. Weigh 10 g (1.0 eq) of L-threonine methyl ester hydrochloride and add it to the flask. Cool the mixture to 5-10°C until the solution is clear. Slowly add 7.3 g (1.1 eq) of chloroacetyl chloride and 11.9 g (2.0 eq) of triethylamine. Control the temperature at 5-10°C. React for 6-8 h. Monitor the reaction until complete. Add 50 ml of 5 wt% citric acid water, extract with 100 ml of ethyl acetate, and concentrate to obtain 10.5 g of compound 1 with a yield of 85.4%.

[0073] S2, measured 100 ml of acetone and added it to a three-necked flask protected by nitrogen, added compound 1 of S1, 26 g (5.0 eq) of 2,2-dimethoxypropane and 0.6 g (0.05 eq) of triphenylboron to the three-necked flask, heated to 50-60°C until the system was in a clear state, reacted for 4-6 hours, and when the reaction reached the end point, added the reaction solution to water at 0-5°C, adjusted the pH to 6-7 with 0.42 g (0.1 eq) of sodium bicarbonate, extracted with 200 ml of methyl tert-butyl ether × 3, combined the organic phases, filtered, and concentrated to obtain 8.75 g of compound 2 with a yield of 70.2%.

[0074] S3, add compound 2 of S2 into a three-necked flask, then add 61.3 g of 20 wt% ammonia water, react at 35-40°C, add 50 mL of methyl tert-butyl ether × 3 times for extraction after reaching the end point, combine the organic phases, filter, concentrate, and dry to obtain 7.26 g of compound 3 with a yield of 90.1%.

[0075] S4, measure 50 ml of tetrahydrofuran and add it to a three-necked flask, weigh 7.26 g (1.0 eq) of compound three and add it to the three-necked flask, weigh 2.52 g (2.0 eq) of sodium hydroxide and prepare it into a 20 wt% solution and add it to the three-necked flask, control the temperature at 15-25 ° C, react for 4-6 hours, and when the reaction reaches the end point, control the temperature of the reaction solution to 0-5 ° C, use 20 wt% citric acid to adjust the pH of the system to 5-6, extract with 100 ml of n-butanol × 3, combine the organic phases, filter, and concentrate to obtain 6.13 g of compound four, with a yield of 91.0%.

[0076] S5, measured 50 ml of tetrahydrofuran and added to a three-necked flask, weighed 6.13 g (1.0 eq) of compound 4 and added to the three-necked flask, weighed 5.72 g (2.0 eq) of triethylamine, and 9.58 g (1.0 eq) of Fmoc-osu and added to the three-necked flask, controlled the temperature at 15-25° C., controlled the pH at 7-8, reacted for 4-6 h, and when the reaction reached the endpoint, controlled the temperature of the reaction solution at 0-5° C., used 20% citric acid to adjust the pH of the system to 3-4, extracted with methyl tert-butyl ether (100 ml×3), combined the organic phases, filtered, concentrated, crystallized using 100 ml of n-heptane, and dried to obtain 10.56 g of the final product with a yield of 84.8%.

[0077] Compared with Example 1, this embodiment differs in that: in step S2, 2,2-dimethoxypropane is used as the cyclization reagent, and the yield of step S2 is reduced by about 9%-10% compared with 2,2-diisopropoxypropane.

[0078] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the scope of protection of the present invention.

[0079] Furthermore, those skilled in the art will appreciate that although some embodiments herein include certain features included in other embodiments but not others, combinations of features from different embodiments are intended to be within the scope of this application and to form distinct embodiments. For example, in the claims above, any of the claimed embodiments may be used in any combination. The information disclosed in this background section is intended solely to enhance understanding of the overall background of this application and should not be construed as an admission or any implication that such information constitutes prior art known to those skilled in the art.

Claims

1. A method for synthesizing (4S,5R)-3-[2-[[Fluorenylmethyloxycarbonyl]amino]acetyl]-2,2,5-trimethyl-4-oxazolidinecarboxylic acid, characterized in that: The following steps are involved: S1, L-threonine methyl ester hydrochloride is subjected to amino protection reaction to form compound 1; S2, compound 1 reacts with Lewis acid and cyclization reagent to form compound 2; S3, compound diammonialysis to obtain compound 3; S4, compound 3 is hydrolyzed with an alkaline reagent to obtain compound 4; S5, compound 4 reacts with an fmoc protecting reagent to obtain the final product (4S,5R)-3-[2-[[fluorenylmethyloxycarbonyl]amino]acetyl]-2,2,5-trimethyl-4-oxazolidinecarboxylic acid; Among them, the structural formula of compound 1 is: The structural formula of compound II is: The structural formula of compound three is: The structural formula of compound 4 is:

2. The method for synthesizing (4S,5R)-3-[2-[[Fluorenylmethyloxycarbonyl]amino]acetyl]-2,2,5-trimethyl-4-oxazolidinecarboxylic acid according to claim 1, characterized in that: In S1, the amino protecting group of the amino protection is a chloroacetyl group or a bromoacetyl group; in S2, the Lewis acid is trifluoroacetic acid, boron trifluoride ethyl ether or triphenylboron, and the cyclization reagent is 2,2-dimethoxypropane, 2,2-diethoxypropane or 2,2-diisopropoxypropane; in S3, the aminolysis reagent is ammonia water or ammonia methanol; in S4, the alkaline reagent is sodium hydroxide, potassium hydroxide or lithium hydroxide; in S5, the Fmoc protecting reagent is Fmoc-osu or Fmoc-Cl.

3. The method for synthesizing (4S,5R)-3-[2-[[Fluorenylmethyloxycarbonyl]amino]acetyl]-2,2,5-trimethyl-4-oxazolidinecarboxylic acid according to claim 2, characterized in that: In S1, the molar ratio of L-threonine methyl ester to amino protecting group is 1:1~1.5; in S2, the molar ratio of compound 1: Lewis acid: cyclization reagent is 1:0.01~0.1:5~10; in S3, the molar ratio of compound 2: aminolysis reagent is 1:5-15; in S4, the molar ratio of compound 3: alkaline reagent is 1:2.0~2.5; in S5, the molar ratio of compound 4: FMOC protecting reagent is 1:1.0~1.

2.

4. The method for synthesizing (4S,5R)-3-[2-[[Fluorenylmethyloxycarbonyl]amino]acetyl]-2,2,5-trimethyl-4-oxazolidinecarboxylic acid according to claim 3, characterized in that: The mol ratio of the L-threonine methyl ester to the amino protecting group is 1: 1.1, the molar ratio of the compound 1: Lewis acid: cyclization reagent is 1:0.05:5, the molar ratio of the compound 2: aminolysis reagent is 1:10; the molar ratio of the compound 2: aminolysis reagent is 1:2.0; the molar ratio of the compound 4: Fmoc protection reagent is 1:1.

0.

5. The method for synthesizing (4S,5R)-3-[2-[[Fluorenylmethyloxycarbonyl]amino]acetyl]-2,2,5-trimethyl-4-oxazolidinecarboxylic acid according to any one of claims 1 to 4, characterized in that: In S1, the amino protection reaction is carried out in THF and triethylamine; in S4 and S5, the reaction is carried out in tetrahydrofuran.

6. The method for synthesizing (4S,5R)-3-[2-[[Fluorenylmethyloxycarbonyl]amino]acetyl]-2,2,5-trimethyl-4-oxazolidinecarboxylic acid according to any one of claims 1 to 5, characterized in that: In S1, the reaction temperature is 5-10°C, and the reaction time is 6-8h; in S2, the reaction temperature is 50-60°C, and the reaction time is 4-6h; in S3, the reaction temperature is 35-40°C; in S4, the reaction temperature is 15-25°C, and the reaction time is 4-6h; in S5, the reaction temperature is 15-25°C, the pH is 7-8, and the reaction time is 4-6h.

7. The method for synthesizing (4S,5R)-3-[2-[[Fluorenylmethyloxycarbonyl]amino]acetyl]-2,2,5-trimethyl-4-oxazolidinecarboxylic acid according to any one of claims 1 to 6, characterized in that: In S1, after the reaction, citric acid water was added, extracted with 100 ml of ethyl acetate, and concentrated; in S2, after the reaction, the reaction solution was added to water, the pH was adjusted to 6-7 with sodium bicarbonate, extracted with methyl tert-butyl ether, the organic phases were combined, filtered, and concentrated; in S3, after the reaction, methyl tert-butyl ether was added for extraction, the organic phases were combined, filtered, concentrated, and dried; In S4, after the reaction, the reaction solution is adjusted to a pH of 5 to 6 with citric acid, extracted with n-butanol, and the organic phases are combined, filtered, and concentrated; In S5, after the reaction, the reaction solution is adjusted to a pH of 3-4 using citric acid, extracted with methyl tert-butyl ether, and the organic phases are combined, filtered, concentrated, crystallized with n-heptane, and dried.

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