Synthetic method of alpha-methyl-L-leucine

Abstract

The invention discloses a synthetic method of alpha-methyl-L-leucine. The alpha-methyl-L-leucine is synthesized by the following process route: # imgabs0 #; and the compound III is alpha-methyl-L-leucine with the chiral purity of 100%. According to the invention, resolution of optical isomers is not needed after synthesis.

Description

Technical Field

[0001] The present invention relates to amino acid synthesis, and in particular to a method for synthesizing alpha-methyl-L-leucine. Background Art

[0002] As an important raw material for peptide drugs, alpha-methyl-L-leucine is often introduced into peptide drugs to modify the peptide chain structure. Because of their metabolic stability and rigidity, they may reduce the conformational freedom of peptides containing these amino acids, thereby changing their biological properties. Therefore, the synthesis of alpha-methyl-L-leucine has become a very active research field.

[0003] There are two methods for synthesizing alpha-methyl-L-leucine: chemical synthesis and enzyme catalysis. The chemical synthesis method is synthesized through a series of chemical reaction steps, and the enzyme catalysis method is to synthesize 2-methyl-L-leucine using enzyme catalysis.

[0004] The enzymes used in the enzyme catalysis method need to be produced and extracted and refined through microbial fermentation. The process is relatively complex and costly, so it has not been widely used. The principle of chemical synthesis is relatively simple and inexpensive, but the operation of chemical synthesis is complicated, the reaction conditions are harsh, there are many by-products, the yield is not high, and some methods involve toxic substances; moreover, the existing chemical synthesis method obtains the DL structure of the racemate, and further separation of optical isomers is required to obtain the single configuration L structure.

[0005] The above background technology is for facilitating the 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 technology.

[0007] The technical solution is: a method for synthesizing alpha-methyl-L-leucine, which is synthesized by the following process route:

[0008] ;

[0009] Compound 3 is alpha-methyl-L-leucine with a chiral purity of 100%.

[0010] The technical scheme is: a method for synthesizing alpha-methyl-L-leucine, comprising the following steps:

[0011] S1, using L-leucine cyclodipeptide as a raw material, and protecting the amide group of L-leucine cyclodipeptide to obtain compound 1;

[0012] S2, methylating compound 1 with a methylating agent in the presence of a hydrogen extraction agent to obtain compound 2;

[0013] S3, compound II is hydrolyzed to obtain compound III of a single configuration, and compound III is alpha-methyl-L-leucine with a chiral purity of 100%;

[0014] Compound 1 is:

[0015]

[0016] Compound 2 is:

[0017]

[0018] Compound three is:

[0019]

[0020] The technical scheme is: a method for synthesizing alpha-methyl-L-leucine, comprising the following steps:

[0021] S1, L-leucine cyclodipeptide is dissolved in an organic solvent at 5-10°C, DMAP and amide protecting group are added, and the reaction is carried out at 5-10°C for 6-8h. The reaction is monitored to be complete, and citric acid aqueous solution is added, and the organic solvent is removed by concentration, extraction, and concentration to obtain compound 1;

[0022] S2, dissolving the compound 1 of S1 in an organic solvent at -40 to -50°C, adding a hydrogenation reagent, controlling the temperature at -40 to -50°C, reacting for 1 to 2 hours, adding a methylation reagent dropwise, reacting for 4 to 5 hours, monitoring the reaction to completion, adding the reaction solution into water at 0 to 5°C, adjusting the pH to 2 to 3 with an aqueous citric acid solution, extracting with methyl tert-butyl ether, combining the organic phases, filtering, and concentrating to obtain compound 2;

[0023] S3, reacting the compound of S2 with an acid at 35-40° C. to an end point, adding methyl tert-butyl ether for extraction, and adding an alkali solution to adjust the pH value to 6-7 to obtain compound 3, which is alpha-methyl-L-leucine with a chiral purity of 100%;

[0024] Compound 1 is:

[0025]

[0026] Compound 2 is:

[0027]

[0028] Compound three is:

[0029]

[0030] The molar ratio of L-leucine cyclodipeptide: amide protecting group: DMAP is 1:1-3:0.05-0.1, and the molar ratio of compound 1: strong base reagent: methylating reagent is 1:1-3:1-3.

[0031] Furthermore, in S1, the protecting group of the amide group is one of a Fmoc-group, a Cbz-group, a Boc-group and an Ac-group.

[0032] Furthermore, in S2, the hydrogen extraction reagent is one or more of sodium bis(trifluoromethylsulfonyl)imide, lithium (trifluoromethylsulfonyl)imide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, and sodium hydroxide.

[0033] Furthermore, in S2, the methylating agent is a methyl halide.

[0034] Furthermore, in S2, the methyl halide is methyl iodide.

[0035] Furthermore, in S3, the acid is one or more of hydrochloric acid, sulfuric acid, and acetic acid, and the alkali solution is an aqueous solution of sodium hydroxide.

[0036] Furthermore, the organic solvent is THF.

[0037] Compared with the prior art, the present invention has the following beneficial effects:

[0038] The present invention selects a specific L-leucine cyclodipeptide as a raw material, so that the chirality of the compound does not undergo racemization during the synthesis process, and a compound of a single configuration is obtained after the synthesis. Therefore, there is no need to separate the optical isomers after the synthesis. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 It is a schematic diagram of the synthesis route of the present invention;

[0040] Figure 2 This is the HNMR diagram of the compound of the present invention;

[0041] Figure 3 is a diagram of the three chiral purity of the compounds of Examples 1 to 5 of the present invention;

[0042] Figure 4 This is a diagram of the three chiral purity of the compound in Comparative Example 1 of the present invention;

[0043] Figure 5 It is the three-chiral purity diagram of the compound of Comparative Example 2 of the present invention. DETAILED DESCRIPTION

[0044] As used herein:

[0045] "Prepared from" is synonymous with "comprising." As used herein, the terms "comprising," "including," "having," "containing," or any other variation 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.

[0046] The conjunction "consisting of excludes any unspecified element, step, or component. If used in a claim, this phrase renders the claim closed-ended so that it does not include 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.

[0047] 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 separately. For example, when a range of "1 to 5" is disclosed, the described range should be interpreted as including ranges "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 in this article, unless otherwise stated, the range is intended to include its end values ​​and all integers and fractions within the range.

[0048] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0049] Those skilled in the art will appreciate that the following examples are only used to illustrate the present application and should not be considered as limiting the scope of the present application. If specific conditions are not specified in the examples, they are carried out according to normal conditions or conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0050] In these examples, parts and percentages are by mass unless otherwise indicated.

[0051] "Parts by mass" refers to the basic unit of measurement for expressing the mass ratio of multiple components. 1 part can represent any unit 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, it means the ratio of the mass of component A to the mass of component B is a:b. Alternatively, it means that the mass of component A is aK and the mass of component B is bK (K is an arbitrary number, indicating a multiple factor). It should not be misunderstood that, unlike the mass parts, the sum of the mass of all components is not limited to 100 parts.

[0052] “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).

[0053] Please refer to Figure 1 , Figure 1 This is the synthesis process diagram of the present invention, Figure 1 In the process for synthesizing alpha-methyl-L-leucine, the following steps are included:

[0054] S1, using L-leucine cyclodipeptide as a raw material, and protecting the amide group of the cyclodipeptide to obtain compound 1;

[0055] S2, methylating compound 1 with a methylating agent in the presence of a strong base reagent to obtain compound 2;

[0056] S3, compound II is hydrolyzed to obtain compound III with a single configuration.

[0057] Example 1

[0058] A method for synthesizing alpha-methyl-L-leucine comprises the following steps:

[0059] S1, take 100ml of THF dried over anhydrous sodium hydroxide and add it to a 250ml three-necked flask, weigh 10g of L-leucine cyclodipeptide and add it to the reaction flask, cool to about 5°C, the system is in a clear state, slowly add 0.54g of DMAP and 20.3g of di-tert-butyl dicarbonate, control the temperature at about 5°C, react for 6-8h, monitor the reaction to be complete, add 50ml of 5% citric acid aqueous solution, concentrate tetrahydrofuran, extract with 100ml of ethyl acetate, concentrate, and obtain 18g of compound 1 with a yield of 95%.

[0060] S2, measure 300 ml of THF dried over anhydrous sodium hydroxide and add it to a 500 ml three-necked flask protected by nitrogen, weigh 8.5 g of compound 1 of S1 and add it to the reaction flask, cool to about -40°C, the system is in a clear state, slowly add 6.4 g of sodium bis(trifluoromethylsulfonyl)imide, control the temperature at about -40°C, react for 1 hour, add 6 g of iodomethane dropwise, react for 4-5 hours, monitor the reaction to be complete, add the reaction solution into water at about 5°C, adjust the pH to 2-3 with 20% citric acid, extract with methyl tert-butyl ether 200×3, combine the organic phases, filter, and concentrate to obtain 7.7 g of compound 2, with a yield of 85.0%.

[0061] S3, add 7.7g of compound 2 in S2 into a 250mL reaction bottle, add 100mL of hydrochloric acid (37.5wt%) into the reaction bottle, react at 35-40 degrees to the end point, add 50mL of methyl tert-butyl ether × 3 to extract, add sodium hydroxide solution to adjust the pH value to 6-7, and precipitate compound 3: filter and dry to obtain 3.4g, with a yield of 80%.

[0062] Compound 3 was tested and found to have a purity of 99.7%. Figure 2 , chiral purity such as Figure 3 (Chiral purity 100%).

[0063] Example 2

[0064] A method for synthesizing alpha-methyl-L-leucine comprises the following steps:

[0065] S1, take 100ml of THF dried over anhydrous sodium hydroxide and add it to a 250ml three-necked flask, weigh 10g of L-leucine cyclodipeptide and add it to the reaction flask, cool to about 5°C, the system is in a clear state, slowly add 0.54g of DMAP and 30g of di-tert-butyl dicarbonate, control the temperature at about 5°C, react for 6-8h, monitor the reaction to be complete, add 50ml of 5% citric acid aqueous solution, concentrate tetrahydrofuran, extract with 100ml of ethyl acetate, concentrate, and obtain 17g of compound 1 with a yield of 90%.

[0066] S2, measure 300 ml of THF dried over anhydrous sodium hydroxide and add it to a 500 ml three-necked flask protected by nitrogen, weigh 8.5 g of compound 1 of S1 and add it to the reaction flask, cool to about -40°C, the system is in a clear state, slowly add 6.4 g of sodium bis(trifluoromethylsulfonyl)imide, control the temperature at about -40°C, react for 1 hour, add 8.6 g of iodomethane dropwise, react for 4-5 hours, monitor the reaction to be complete, add the reaction solution into water at about 5°C, adjust the pH to 2-3 with 20% citric acid, extract with methyl tert-butyl ether 200×3, combine the organic phases, filter, and concentrate to obtain 7.0 g of compound 2, with a yield of 77.0%.

[0067] S3, add 7.0g of compound 2 in S2 into a 250mL reaction bottle, add 100mL of hydrochloric acid (37.5wt%) into the reaction bottle, react at 35-40 degrees to the end point, add 50mL of methyl tert-butyl ether × 3 for extraction, add sodium hydroxide solution to adjust the pH value to 6-7, and precipitate compound 3: filter and dry to obtain 3.1g, with a yield of 80%.

[0068] Compound 3 was tested and found to have a purity of 99.6%. Figure 2 , chiral purity such as Figure 3 (Chiral purity 100%).

[0069] Example 3

[0070] A method for synthesizing alpha-methyl-L-leucine comprises the following steps:

[0071] S1, take 100ml of THF dried over anhydrous sodium hydroxide and add it to a 250ml three-necked flask, weigh 10g of L-leucine cyclodipeptide and add it to the reaction flask, cool to about 5°C, the system is in a clear state, slowly add 0.54g of DMAP and 10g of di-tert-butyl dicarbonate, control the temperature at about 5°C, react for 6-8h, monitor the reaction to be complete, add 50ml of 5% citric acid aqueous solution, concentrate tetrahydrofuran, extract with 100ml of ethyl acetate, concentrate, and obtain 9.4g of compound 1 with a yield of 50%.

[0072] S2, measure 300 ml of THF dried over anhydrous sodium hydroxide and add it to a 500 ml three-necked flask protected by nitrogen, weigh 8.5 g of compound 1 of S1 and add it to the reaction flask, cool to about -40°C, the system is in a clear state, slowly add 6.4 g of sodium bis(trifluoromethylsulfonyl)imide, control the temperature at about -40°C, react for 1 hour, add 3 g of iodomethane dropwise, react for 4-5 hours, monitor the reaction to be complete, add the reaction solution into water at about 5°C, adjust the pH to 2-3 with 20% citric acid, extract with methyl tert-butyl ether 200×3, combine the organic phases, filter, and concentrate to obtain 6.3 g of compound 2 with a yield of 70.0%.

[0073] S3, add 6.3g of compound 2 from S2 into a 250mL reaction bottle, add 100mL of hydrochloric acid (37.5wt%) into the reaction bottle, react at 35-40 degrees to the end point, add 50mL of methyl tert-butyl ether × 3 for extraction, add sodium hydroxide solution to adjust the pH value to 6-7, precipitate compound 3: filter and dry to obtain 2.8g, with a yield of 80%,

[0074] Compound 3 was tested and found to have a purity of 99.7%. Figure 2 , chiral purity such as Figure 3 (Chiral purity 100%).

[0075] Example 4

[0076] A method for synthesizing alpha-methyl-L-leucine comprises the following steps:

[0077] S1, take 100ml of THF dried over anhydrous sodium hydroxide and add it to a 250ml three-necked flask, weigh 10g of L-leucine cyclodipeptide and add it to the reaction flask, cool to about 10°C, the system is in a clear state, slowly add 0.54g of DMAP and 20.3g of di-tert-butyl dicarbonate, control the temperature at about 10°C, react for 6-8h, monitor the reaction to be complete, add 50ml of 5% citric acid aqueous solution, concentrate tetrahydrofuran, extract with 100ml of ethyl acetate, concentrate, and obtain 17.5g of compound 1 with a yield of 93%.

[0078] S2, measure 300ml of THF dried over anhydrous sodium hydroxide and add it to a 500ml three-necked flask protected by nitrogen, weigh 8.5g of compound 1 of S1 and add it to the reaction flask, cool to about -45°C, the system is in a clear state, slowly add 6.4g of sodium bis(trifluoromethylsulfonyl)imide, control the temperature at about -40°C, react for 1h, add 6g of iodomethane dropwise, react for 4-5h, monitor the reaction to be complete, add the reaction solution into water at about 5°C, adjust the pH to 2-3 with 20% citric acid, extract with methyl tert-butyl ether 200×3, combine the organic phases, filter, and concentrate to obtain 7.4g of compound 2 with a yield of 82.0%.

[0079] S3, add 7.4g of compound 2 in S2 into a 250mL reaction bottle, add 100mL of hydrochloric acid (37.5wt%) into the reaction bottle, react at 35-40 degrees to the end point, add 50mL of methyl tert-butyl ether × 3 to extract, add sodium hydroxide solution to adjust the pH value to 6-7, and precipitate compound 3: filter and dry to obtain 3.3g, with a yield of 80%.

[0080] Compound 3 was tested and found to have a purity of 99.7%. Figure 2 , chiral purity such as Figure 3 (Chiral purity 100%).

[0081] Example 5

[0082] A method for synthesizing alpha-methyl-L-leucine comprises the following steps:

[0083] S1, take 100ml of THF dried over anhydrous sodium hydroxide and add it to a 250ml three-necked flask, weigh 10g of L-leucine cyclodipeptide and add it to the reaction flask, cool to about 15°C, the system is in a clear state, slowly add 0.54g of DMAP and 20.3g of di-tert-butyl dicarbonate, control the temperature at about 15°C, react for 6-8h, monitor the reaction to be complete, add 50ml of 5% citric acid aqueous solution, concentrate tetrahydrofuran, extract with 100ml of ethyl acetate, concentrate, and obtain 16.3g of compound 1 with a yield of 87%.

[0084] S2, measure 300ml of THF dried over anhydrous sodium hydroxide and add it to a 500ml three-necked flask protected by nitrogen, weigh 8.5g of compound 1 of S1 and add it to the reaction flask, cool to about -50°C, the system is in a clear state, slowly add 6.4g of sodium bis(trifluoromethylsulfonyl)imide, control the temperature at about -40°C, react for 1h, add 6g of iodomethane dropwise, react for 4-5h, monitor the reaction to be complete, add the reaction solution into water at about 5°C, adjust the pH to 2-3 with 20% citric acid, extract with methyl tert-butyl ether 200×3, combine the organic phases, filter, and concentrate to obtain 6.8g of compound 2, with a yield of 75.0%.

[0085] S3, add 6.8g of compound 2 from S2 into a 250mL reaction bottle, add 100mL of hydrochloric acid (37.5wt%) into the reaction bottle, react at 35-40 degrees to the end point, add 50mL of methyl tert-butyl ether × 3 for extraction, add sodium hydroxide solution to adjust the pH value to 6-7, precipitate compound 3: filter and dry to obtain 3.0g, with a yield of 80%,

[0086] Compound 3 was tested and found to have a purity of 99.6%. Figure 2 , chiral purity such as Figure 3 (Chiral purity 100%).

[0087] Comparative Example 1

[0088] A method for synthesizing alpha-methyl-L-leucine comprises the following steps:

[0089] S1, take 100ml of THF dried over anhydrous sodium hydroxide and add it to a 250ml three-necked flask, weigh 10g of L-leucine cyclodipeptide and add it to the reaction flask, cool to about 5°C, the system is in a clear state, slowly add 9.3g of triethylamine and 24.2g of fluorenylmethoxycarbonyl chloride (Fmoc-Cl), control the temperature at about 5°C, react for 6-8h, monitor the reaction to be complete, add 50ml of 5% citric acid aqueous solution, concentrate tetrahydrofuran, extract with 100ml of ethyl acetate, concentrate, and obtain 26.6g of compound 1 with a yield of 90%.

[0090] S2, measure 300ml of THF dried over anhydrous sodium hydroxide and add it to a 500ml three-necked flask protected by nitrogen, weigh 13.3g of compound 1 of S1 and add it to the reaction flask, cool to about -40°C, the system is in a clear state, slowly add 6.4g of sodium bis(trifluoromethylsulfonyl)imide, control the temperature at about -40°C, react for 1h, add 6g of iodomethane dropwise, react for 4-5h, monitor the reaction to be complete, add the reaction solution into water at about 5°C, adjust the pH to 2-3 with 20% citric acid, extract with methyl tert-butyl ether 200×3, combine the organic phases, filter, and concentrate to obtain 11.1g of compound 2 with a yield of 80.0%.

[0091] S3, add 11.8g of compound 2 in S2 into a 250mL reaction bottle, add 100mL of sodium hydroxide solution (35wt%) into the reaction bottle, react at 35-40 degrees to the end point, add 50mL of methyl tert-butyl ether × 3 to extract, add hydrochloric acid solution (10wt%) to adjust the pH value to 6-7, and precipitate compound 3: filter and dry to obtain 3.4g, with a yield of 80%.

[0092] Compound 3 was tested and found to have a purity of 98.5%. Figure 2 , chiral purity such as Figure 4 (Chiral purity 99%).

[0093] Comparative Example 2

[0094] A method for synthesizing alpha-methyl-L-leucine comprises the following steps:

[0095] S1, take 100ml of THF dried over anhydrous sodium hydroxide and add it to a 250ml three-necked flask, weigh 10g of L-leucine cyclodipeptide and add it to the reaction flask, cool to about 5°C, the system is in a clear state, slowly add 9.3g of triethylamine and 15.8g of benzyl chloroformate (CBZ-Cl), control the temperature at about 5°C, react for 6-8h, monitor the reaction to be complete, add 50ml of 5% citric acid aqueous solution, concentrate tetrahydrofuran, extract with 100ml of ethyl acetate, concentrate, and obtain 19g of compound 1 with a yield of 87%.

[0096] S2, measure 300 ml of THF dried over anhydrous sodium hydroxide and add it to a 500 ml three-necked flask protected by nitrogen, weigh 9.9 g of compound 1 of S1 and add it to the reaction flask, cool to about -40°C, the system is in a clear state, slowly add 6.4 g of sodium bis(trifluoromethylsulfonyl)imide, control the temperature at about -40°C, react for 1 hour, add 6 g of iodomethane dropwise, react for 4-5 hours, monitor the completion of the reaction, add the reaction solution into water at about 5°C, adjust the pH to 2-3 with 20% citric acid, extract with methyl tert-butyl ether 200×3, combine the organic phases, filter, and concentrate to obtain 8.4 g of compound 2, with a yield of 81.0%.

[0097] S3, add 8.4g of compound 2 in S2 into a 250mL reaction bottle, add 10g of trifluoroacetic acid into the reaction bottle, react at 35-40 degrees to the end point, add 50ml of purified water, add 50mL of methyl tert-butyl ether × 3 to extract, add sodium hydroxide solution to adjust the pH value to 6-7, and precipitate compound 3: filter and dry to obtain 2.9g, with a yield of 71%.

[0098] Compound 3 was tested and the purity was 99%. Figure 2 , chiral purity such as Figure 5 (Chiral purity 99.4%).

[0099] 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, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

[0100] In addition, those skilled in the art will appreciate that, although some embodiments herein include certain features included in other embodiments but not other features, the combination of features of different embodiments is meant to be within the scope of the present application and form different embodiments. For example, in the above claims, any one of the claimed embodiments may be used in any combination. The information disclosed in this background technology section is intended only to deepen the understanding of the overall background technology of the present application and should not be regarded as an admission or in any form of implication that the information constitutes prior art known to those skilled in the art.

Claims

1. A method for synthesizing alpha-methyl-L-leucine, characterized in that: The synthesis method is synthesized by the following process route: ； Compound 3 is alpha-methyl-L-leucine with a chiral purity of 100%.

2. A method for synthesizing alpha-methyl-L-leucine, characterized in that: The following steps are involved: S1, using L-leucine cyclodipeptide as a raw material, and protecting the amide group of L-leucine cyclodipeptide to obtain compound 1; S2, methylating compound 1 with a methylating agent in the presence of a hydrogen extraction agent to obtain compound 2; S3, compound II is hydrolyzed to obtain compound III of a single configuration, and compound III is alpha-methyl-L-leucine with a chiral purity of 100%; Compound 1 is: Compound 2 is: Compound three is:

3. A method for synthesizing alpha-methyl-L-leucine, characterized in that: The following steps are involved: S1, L-leucine cyclodipeptide is dissolved in an organic solvent at 5-10°C, DMAP and amide protecting group are added, and the reaction is carried out at 5-10°C for 6-8h. The reaction is monitored to be complete, and citric acid aqueous solution is added, and the organic solvent is removed by concentration, extraction, and concentration to obtain compound 1; S2, dissolving the compound 1 of S1 in an organic solvent at -40 to -50°C, adding a hydrogenation reagent, controlling the temperature at -40 to -50°C, reacting for 1 to 2 hours, adding a methylation reagent dropwise, reacting for 4 to 5 hours, monitoring the reaction to completion, adding the reaction solution into water at 0 to 5°C, adjusting the pH to 2 to 3 with an aqueous citric acid solution, extracting with methyl tert-butyl ether, combining the organic phases, filtering, and concentrating to obtain compound 2; S3, reacting the compound of S2 with an acid at 35-40° C. to an end point, adding methyl tert-butyl ether for extraction, and adding an alkali solution to adjust the pH value to 6-7 to obtain compound 3, which is alpha-methyl-L-leucine with a chiral purity of 100%; Compound 1 is: Compound 2 is: Compound three is: The molar ratio of L-leucine cyclodipeptide: amide protecting group: DMAP is 1:1-3:0.05-0.1, and the molar ratio of compound 1: strong base reagent: methylating reagent is 1:1-3:1-3.

4. The method for synthesizing alpha-methyl-L-leucine according to claim 3, characterized in that: In S1, the protecting group of the amide group is one of a Fmoc-group, a Cbz-group and a Boc-group.

5. The method for synthesizing alpha-methyl-L-leucine according to claim 3, characterized in that: In S2, the hydrogen extraction reagent is one or more of sodium bis(trifluoromethylsulfonyl)imide, lithium (trifluoromethylsulfonyl)imide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, and sodium hydroxide.

6. The method for synthesizing alpha-methyl-L-leucine according to claim 3, characterized in that: In S2, the methylating agent is a methyl halide.

7. The method for synthesizing alpha-methyl-L-leucine according to claim 6, characterized in that: In S2, the methyl halide is methyl iodide.

8. The method for synthesizing alpha-methyl-L-leucine according to claim 3, characterized in that: In S3, the acid is one or more of hydrochloric acid, sulfuric acid, and acetic acid, and the alkali solution is an aqueous sodium hydroxide solution.

9. The method for synthesizing alpha-methyl-L-leucine according to claim 3, characterized in that: The organic solvent is THF.

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