Synthesis method of α-methylornithine containing protecting group

Abstract

The present invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing α-methylornithine containing a protecting group. The method for synthesizing α-methylornithine containing a protecting group comprises: synthesizing with reference to the following synthesis route: the raw materials used in the synthesis method are simple, cheap and easy to obtain, and no alkylating agent with high toxicity is used, the number of low-temperature reactions is also significantly reduced, and the operation is convenient, the process is simple, and the total yield is significantly improved, which is more suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing alpha-methylornithine containing a protecting group. Background Art

[0002] Proteins perform a series of significant functions with only 20 natural amino acids. The number of functional groups carried by these 20 natural amino acids is limited, which cannot meet the needs of protein structure and function in chemical and biological science research and applications. At present, although the structural modification of proteins has given natural proteins new functions through chemical modification, gene site-directed mutagenesis and computer-aided protein design, these methods all rely on the 20 natural amino acids themselves; the functional groups used for modification and transformation are limited to a few groups such as thiol, hydroxyl, carboxyl, and amino groups, and the functionalization methods are very limited.

[0003] In contrast, unnatural amino acids (UnnaturalAminoAcids) that can be artificially endowed with diverse functional groups have outstanding performance in protein modification. These unnatural amino acids contain diverse functional groups such as keto, aldehyde, azide, alkynyl, alkenyl, amide, nitro, phosphate, sulfonate, etc., and can undergo a variety of modification reactions, such as click chemistry, photochemistry, glycosylation, fluorescence color development, etc. The modification of proteins by unnatural amino acids has brought new opportunities for the theoretical study and application of their structure and function. Among them, ornithine is one of the most popular ones. However, the synthesis of α-methylornithine in existing literature is complicated, using the more expensive starting material (2R, 3S)-N-benzyloxycarbonyl-2,3-diphenylmorpholine-6-one (CAS: 100516-54-9), using low temperature reactions three times, resulting in high energy consumption and difficult to control process production, using the highly toxic alkylating agent iodomethane, and the total yield is low (<10%) and the cost is high.

[0004] In view of this, the present invention is proposed. Summary of the invention

[0005] The purpose of the present invention is to provide a method for synthesizing α-methylornithine containing a protecting group. The raw materials used in the synthesis method provided in the embodiment of the present invention are simple, cheap and easy to obtain, and no alkylating agent with high toxicity is used, the number of low-temperature reactions is also significantly reduced, and the operation is convenient, the process is simple, and the total yield is significantly improved, which is more suitable for industrial production.

[0006] The present invention is achieved in that:

[0007] In a first aspect, the present invention provides a method for synthesizing α-methylornithine containing a protecting group, comprising: synthesizing according to the following synthetic route:

[0008]

[0009] In an alternative embodiment, R 1 is Boc; preferably, R 2 It is Fmoc.

[0010] In an optional embodiment, the step of forming M1 includes: mixing M0 with benzaldehyde diacetal, a solvent and a catalyst for reaction;

[0011] Preferably, the reaction conditions include: a temperature of -20 to 25°C, a time of 2 to 6 hours; a molar ratio of the M0 to the benzaldehyde diacetal of 1:(1-1.3); a molar ratio of the M0 to the catalyst of 1:(1-2);

[0012] Preferably, the catalyst comprises a zinc salt, more preferably anhydrous zinc chloride.

[0013] In an optional embodiment, the step of forming M2 comprises: mixing M1, M1-1 and a base for reaction; wherein the structural formula of M1-1 is:

[0014]

[0015] Preferably, the reaction conditions include: temperature of -80 to -40°C, time of 1 to 4 h;

[0016] The base is selected from any one of LiHMDS, NaHMDS and LDA;

[0017] The molar ratio of M1, M1-1 and base is: 1:(1-1.5):(1-1.5).

[0018] In an optional embodiment, the step of forming M3 comprises: mixing M2 with a base to perform a ring-opening reaction;

[0019] Preferably, the reaction conditions include: temperature of 25-65°C, time of 2-6 hours;

[0020] Bases include hydroxides; more preferably sodium hydroxide and lithium hydroxide;

[0021] The molar ratio of M2 to base is 1:(2-5).

[0022] In an optional embodiment, the step of forming M3-B includes: mixing M3 with an acid to react;

[0023] Preferably, the reaction conditions include: temperature of 0-50°C, time of 2-6 hours;

[0024] The acid is selected from trifluoroacetic acid or hydrochloric acid;

[0025] The molar ratio of M3 to acid is 1:(3-10).

[0026] In an optional embodiment, the step of forming M3-A includes: M3-B, containing R 1 The compound and the base are mixed to react;

[0027] Preferably, the reaction conditions include: temperature of 0-50°C, time of 10-20 hours;

[0028] M3-B and R 1 The molar ratio of the compound is 1:(1-3);

[0029] The base includes any one of carbonates, amines and bicarbonates;

[0030] Preferably, the base includes any one of sodium carbonate, potassium carbonate, sodium bicarbonate, triethylamine, pyridine and diisopropylethylamine.

[0031] In an optional embodiment, the step of forming M4-A comprises: reacting M3-A with a catalyst;

[0032] Preferably, the catalyst is selected from palladium on carbon;

[0033] Preferably, the reaction conditions include: temperature of 0-50° C. and time of 10-20 hours.

[0034] In an optional embodiment, the step of forming M comprises: M4-A and R 2 The compounds are mixed to react;

[0035] Preferably, the reaction conditions include: temperature of 0-50° C. and time of 3-10 hours.

[0036] In an optional embodiment, the synthesis is carried out with reference to the following synthesis route:

[0037]

[0038] In an optional embodiment, the method comprises: performing post-treatment after each reaction is completed;

[0039] Preferably, the post-treatment includes any one of filtration, washing, drying, concentration and extraction.

[0040] The present invention has the following beneficial effects: in the embodiment of the present invention, cheap benzyloxycarbonyl-L-alanine is used as a starting material to synthesize alpha-methylornithine containing a protective group through ring closure, substitution, hydrolysis, deprotection and protection, thereby reducing production costs; meanwhile, no alkylating agent with high toxicity is used in the synthesis process, the number of low-temperature reactions is reduced to one, the operation is convenient, the process is simple and easy to control, the total yield is high (>30%), the cost is low, and the product is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for use in the embodiments are briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without creative work.

[0042] Figure 1 This is the NMR spectrum of α-methylornithine containing a protecting group provided in Example 1 of the present invention. DETAILED DESCRIPTION

[0043] In order to make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0044] This embodiment provides a method for synthesizing α-methylornithine containing a protecting group, and the specific operation is as follows:

[0045] Specifically, M0 (N-benzyloxycarbonyl-L-alanine) and benzaldehyde diacetal are reacted in an organic solvent, and dichlorothionyl and a catalyst (for example, including but not limited to anhydrous zinc chloride) are added to obtain compound M1.

[0046] Wherein, the organic solvent is tetrahydrofuran, dioxane, DMF, acetonitrile, preferably tetrahydrofuran and dioxane. The molar ratio of N-benzyloxycarbonyl-L-alanine, benzaldehyde diacetal, dichlorothionyl, and anhydrous zinc chloride is 1:(1-1.3):(1-2):(1-2), and the best is 1:1:1.1:1.1. The temperature of the above reaction is -20 to 25°C, and the best is 0°C; the preferred reaction time is 2-6h, and the best is 4h. After the reaction is completed, the reaction product is acidified, extracted, washed, dried, and concentrated to obtain compound M1.

[0047] Specifically, under alkaline conditions, intermediate M1 is reacted with raw material M1-1 in an organic solvent to obtain compound M2.

[0048] Wherein, the organic solvent is tetrahydrofuran, dioxane, preferably tetrahydrofuran; the base used is LiHMDS (lithium bis(trimethylsilyl)amide), NaHMDS (sodium bis(trimethylsilyl)amide), LDA (lithium diisopropylamide), preferably LiHMDS. The molar ratio of M1, M1-1, and LiHMDS is 1:(1-1.5):(1-1.5), and the best is 1:1.15:1.15. The temperature of the above reaction is -80 to -40°C, and the best is -60°C; the preferred reaction time is 1-4h, and the best is 2.5h. After the reaction is completed, the reaction product is acidified, extracted, washed, dried, and concentrated to obtain compound M2.

[0049] Specifically, M2 is reacted with a base (for example, including but not limited to hydrated lithium hydroxide) in an organic solvent to obtain compound M3.

[0050] Wherein, the organic solvent is tetrahydrofuran, dioxane, DMF, acetonitrile, preferably tetrahydrofuran and dioxane. The base used is sodium hydroxide and lithium hydroxide monohydrate, preferably lithium hydroxide monohydrate. The molar ratio of M2 to lithium hydroxide monohydrate is 1: (2-5), and the best is 1: 3.5. The temperature of the above reaction is 25-65 ° C, and the best is 50 ° C; the preferred reaction time is 2-6h, and the best is 4h. After the reaction is completed, the reaction product is extracted, washed, dried, and concentrated to obtain compound M3.

[0051] Specifically, M3 is reacted with an acid in an organic solvent to obtain compound M3-B.

[0052] The organic solvent is tetrahydrofuran, dichloromethane, chloroform, preferably dichloromethane; the acid used is trifluoroacetic acid, hydrochloric acid, preferably trifluoroacetic acid. The molar ratio of M2 to the acid is 1:(3-10), preferably 1:5. The temperature of the above reaction is 0-50°C, preferably 25°C; the preferred reaction time is 2-6h, preferably 4h. The reaction product is directly concentrated to obtain compound M3-B.

[0053] Specifically, under alkaline conditions, M3-B is reacted with a 1 The compound is reacted in an organic solvent to obtain compound M3-A.

[0054] The organic solvent is tetrahydrofuran, dichloromethane, chloroform, preferably tetrahydrofuran; the base used is any one of sodium carbonate, potassium carbonate, sodium bicarbonate, triethylamine, pyridine and diisopropylethylamine, preferably sodium carbonate. 1The molar ratio of the compound is 1:(1-3), and the optimal ratio is 1:1.5. The temperature of the above reaction is 0-50°C, and the optimal ratio is 25°C; the preferred reaction time is 10-20h, and the optimal ratio is 15h. After the above reaction is completed, the reaction product is extracted, washed, dried, and concentrated to obtain compound M3-A.

[0055] Specifically, M3-A is reacted with palladium carbon (eg, Pd / C (5%)) in an organic solvent to obtain compound M4-A.

[0056] Among them, the organic solvent is methanol, ethanol, isopropanol, preferably methanol; the preferred temperature of the substitution reaction is 0-50°C, and the best is 25°C; the preferred reaction time is 10-20h, and the best is 15h; the product is filtered, washed, dried, and concentrated to obtain compound M4-A.

[0057] Among them, M4-A and R 2 The compound is reacted in an organic solvent to obtain compound M.

[0058] The organic solvent is tetrahydrofuran, dioxane, acetonitrile, preferably tetrahydrofuran; the base used is triethylamine, pyridine, diisopropylethylamine, sodium bicarbonate, potassium carbonate, preferably diisopropylethylamine. The temperature of the above reaction is 0-50°C, preferably 25°C; the preferred reaction time is 3-10h, preferably 5h. After the reaction is completed, the reaction product is filtered, washed, dried, and concentrated to obtain compound M.

[0059] It should be noted that the above-mentioned filtration, washing, drying, concentration and extraction are conventional operations in the art and will not be described in detail in the embodiments of the present invention.

[0060] Specifically, the embodiment of the present invention provides a method for 1 Boc; R 2 Taking Fmoc as an example, the synthesis method of α-methylornithine is as follows:

[0061]

[0062] The features and performance of the present invention are further described in detail below in conjunction with the embodiments.

[0063] Example 1

[0064] This embodiment provides a method for synthesizing α-methylornithine containing a protecting group, comprising the following steps:

[0065] S1, synthesis of M1; synthesis was performed according to the following synthesis route;

[0066] Specifically, 500 g M0 and 340.9 g benzaldehyde diacetal were added to 5 L THF, cooled to 0 ° C, 293.2 g thionyl chloride and 335.1 g anhydrous zinc chloride were added, and the reaction was continued for 4 h. 2.5 L saturated sodium bicarbonate solution was added to the reaction solution, and then 6 L ethyl acetate was added, the liquid was separated, and then extracted once with 3 L ethyl acetate, the EA phase was combined, and the combined EA phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 50 ° C to obtain 404 g white solid M1, with a yield of 58%.

[0067] S2, synthesis of M2; synthesis according to the following synthesis route;

[0068] Specifically, 215 g of M1 was added to 6 L of THF, replaced with nitrogen, cooled to -80 ° C, 794 ml of LiHMDS (1 mol / L) was added, reacted for 1 h, and then 305.9 g of M1-1 was added, and reacted at about -60 ° C for 2 h. 1.5 L of saturated ammonium chloride solution was added to the reaction solution, and then 3 L of ethyl acetate was added, the liquid was separated, and then extracted once with 3 L of ethyl acetate, the EA phase was combined, and the combined EA phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 50 ° C, and petroleum ether was crystallized and filtered to obtain 318 g of off-white solid M2, with a yield of 81%.

[0069] S3, synthesis of M3; synthesis according to the following synthesis path;

[0070] Specifically, 198 g of M2, 51.2 g of monohydrate and lithium hydroxide were added to a mixed solution of 2 L THF and 660 ml of water, and the mixture was reacted at 50° C. for 4 h. Most of the THF was concentrated under reduced pressure, extracted twice with 1.3 L of ethyl acetate, and the EA phases were combined. The combined EA phases were washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 50° C. to obtain 167.2 g of oily M3, with a yield of 99.9%.

[0071] S4, synthesis of M3-B; synthesis was performed according to the following synthesis route;

[0072] Specifically, 167.2 g of M3 and 198.3 g of TFA were added to 500 ml of dichloromethane and reacted at room temperature for 3 h. M3-B was obtained by concentration under reduced pressure and directly used in the next step.

[0073] S5. Synthesis of M3-A: Synthesis was performed according to the following synthesis route;

[0074] Specifically, M3-B obtained in step (4) was initially adjusted to alkalinity with saturated sodium carbonate, 1.7 L THF and 91 g (Boc)2O were added, and the mixture was reacted at room temperature for 15 h. Most of the THF was concentrated under reduced pressure, and extracted twice with 1.3 L ethyl acetate, and the EA phases were combined. The combined EA phases were washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 50°C to obtain 132.2 g of an oily substance M3-A, with a yield of 99.9%.

[0075] S6. Synthesis of M4-A: Synthesis was performed according to the following synthesis route;

[0076] Specifically, 132.4 g of M3-A and 66.2 g of Pd / C (5%) were added to 2.5 L of methanol, replaced with hydrogen three times, and reacted at room temperature for 15 h. Filtered, concentrated, crystallized with petroleum ether and ethyl acetate, and filtered to obtain 78.1 g of oily substance M4-A, with a yield of 91%.

[0077] S7, synthesize M; synthesize according to the following synthesis route;

[0078] Specifically, 78.1 g of M4-A and 61.5 g of DIEA were added to a mixed solution of 360 ml of THF and 360 ml of water, and then 101.6 g of Fmoc-osu was added, and the mixture was reacted at room temperature for 4 h. 360 mL of ethyl acetate was used for extraction twice, and the EA phases were combined. The combined EA phases were washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 50 ° C, and crystallized with petroleum ether and filtered to obtain 118.5 g of off-white solid M3, with a yield of 84%.

[0079] The final product, α-methylornithine M, containing a protected group, was characterized. Figure 1 , the characterization data are as follows: 1 HNMR(400MHz,DMSO-d6)δ12.37(br,1H),7.85(d,J=8.0Hz,2H),7.68(d,J=8.0Hz,2H),7.40-7.35(m,3H),7.31-7 .27(m,2H),6.76(d,J=8.0Hz,1H),4.22-4.16(m,3H),2.87-2.82(m,2H),1.75-1.56(m,2H),1.35-1.28(m,14H).

[0080] Example 2

[0081] This embodiment provides a method for synthesizing α-methylornithine containing a protecting group, comprising the following steps:

[0082] S1, synthetic M1;

[0083] 500g M0 and 340.9g benzaldehyde diacetal were added to 5L THF, cooled to -10°C, 293.2g thionyl chloride and 335.1g anhydrous zinc chloride were added, and the reaction was continued for 6h. 2.5L saturated sodium bicarbonate solution was added to the reaction solution, and then 6L ethyl acetate was added, the liquid was separated, and then extracted once with 3L ethyl acetate, the EA phase was combined, the combined EA phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 50°C to obtain 384g white solid M1, with a yield of 55%.

[0084] S2, synthetic M2;

[0085] 215g of M1 was added to 6L of THF, replaced with nitrogen, cooled to -80°C, 794ml of NaHMDS (1mol / L) was added, reacted for 1h, and then 305.9g of M1-1 was added, and reacted at about -50°C for 2h. 1.5L of saturated ammonium chloride solution was added to the reaction solution, and then 3L of ethyl acetate was added, the liquid was separated, and then extracted once with 3L of ethyl acetate, the EA phase was combined, the combined EA phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 50°C, and petroleum ether was crystallized and filtered to obtain 330g of off-white solid M2, with a yield of 84%.

[0086] S3, synthetic M3;

[0087] 198 g of M2 and 34.8 g of sodium hydroxide were added to a mixed solution of 2 L THF and 660 ml of water, and the mixture was reacted at 40° C. for 4 h. Most of the THF was concentrated under reduced pressure, and the mixture was extracted twice with 1.3 L of ethyl acetate. The EA phases were combined, and the combined EA phases were washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 50° C. to obtain 166 g of oily M3, with a yield of 99.5%.

[0088] S4, synthesis of M3-B;

[0089] 167.2 g of M3 and 146 ml of concentrated hydrochloric acid (11.9 mol / L) were added to 500 ml of THF and reacted at room temperature for 4 h. M3-B was obtained by concentration under reduced pressure and used directly in the next step.

[0090] S5, synthesis of M3-A;

[0091] M3-B obtained in step (4) was initially adjusted to alkalinity with saturated potassium bicarbonate, 1.7 L THF and 91 g (Boc)2O were added, and the mixture was reacted at room temperature for 16 h. Most of the THF was concentrated under reduced pressure, and extracted twice with 1.3 L ethyl acetate, and the EA phases were combined. The combined EA phases were washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 50°C to obtain 131.9 g of an oily substance M3-A, with a yield of 99.6%.

[0092] S6, synthesis of M4-A;

[0093] 132.4 g M3-A and 66.2 g Pd / C (5%) were added to 2.5 L ethanol, replaced with hydrogen three times, and reacted at room temperature for 18 h. Filtered, concentrated, crystallized with petroleum ether and ethyl acetate, and filtered to obtain 79.7 g oily substance M4-A, with a yield of 93%.

[0094] S7, synthetic M;

[0095] 78.1g M4-A and 48.2g triethylamine were added to a mixed solution of 360ml THF and 360ml water, and then 101.6g Fmoc-osu was added, and the mixture was reacted at room temperature for 6h. 360mL ethyl acetate was used for extraction twice, and the EA phase was combined. The combined EA phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 50°C, and petroleum ether was crystallized and filtered to obtain 121.4g off-white solid M3, with a yield of 86%.

[0096] Comparative Example 1

[0097] This comparative example provides a synthesis step of M1, comprising: adding 500g M0 and 340.9g benzaldehyde diacetal to 6L THF, cooling to -10°C, adding an ether solution of boron trifluoride, and then naturally warming to room temperature for reaction for 16h. 1.9L triethylamine is added to the reaction solution, and then 6L ethyl acetate is added, the liquid is separated, and then extracted once with 3L ethyl acetate, the EA phase is combined, and the combined EA phase is washed twice with 4.5L 10% saturated ammonium chloride, washed once with 4.5L saturated sodium bicarbonate and once with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 50°C to obtain 226g yellow solid M1, with a yield of 32%.

[0098] Comparative Example 2

[0099] This comparative example provides a synthesis step of M2, including: adding 215g of M1 to 6L of THF, replacing with nitrogen, cooling to -80°C, adding 794ml of LDA (1mol / L), reacting for 1h, and then adding 305.9g of M1-1, reacting at about -50°C for 2h. LCMS monitoring found that no target product M2 was generated.

[0100] Comparative Example 3

[0101] This comparative example provides a synthesis step of M3-A, comprising: adding 167.2g M3 and 119.1g TFA to 3.2L dichloromethane, reacting at room temperature for 3h. Adding saturated sodium bicarbonate solution to the reaction system to adjust the pH to 6-7, concentrating the dichloromethane, then adding 5L of ethyl acetate to extract twice, combining the EA phases, washing once with 0.2N hydrochloric acid, washing twice with clean water and once with saturated ammonium chloride, drying over anhydrous sodium sulfate, and concentrating under reduced pressure at 50°C to obtain 46.2g of oily matter M3-A, with a yield of 34.9%.

[0102] Comparative Example 4

[0103] This comparative example provides a synthesis step of M, comprising: adding 101.6 g of Fmoc-osu to a mixed solution of 78.1 g of M4-A, 360 ml of THF and 360 ml of saturated sodium bicarbonate water, and reacting at room temperature for 10 h. Extracting twice with 360 ml of ethyl acetate, combining the EA phases, washing the combined EA phases once with saturated brine, drying over anhydrous sodium sulfate, concentrating under reduced pressure at 50° C., crystallizing with petroleum ether and filtering, obtaining 76.2 g of off-white solid M3, with a yield of 51%.

[0104] 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.

Claims

1. A method for synthesizing α-methylornithine containing a protecting group, characterized in that: include: The synthesis was carried out according to the following synthesis route:

2. The method for synthesizing α-methylornithine containing a protecting group according to claim 1, characterized in that: The step of forming M1 comprises: mixing M0 with benzaldehyde diacetal, a solvent and a catalyst for reaction.

3. The method for synthesizing α-methylornithine containing a protecting group according to claim 2, characterized in that: The reaction conditions include: a temperature of -20 to 25°C, a time of 2 to 6 hours; a molar ratio of the M0 to the benzaldehyde diacetal of 1:(1-1.3); and a molar ratio of the M0 to the catalyst of 1:(1-2).

4. The method for synthesizing α-methylornithine containing a protecting group according to claim 2, characterized in that: The catalyst is selected from zinc salts.

5. The method for synthesizing α-methylornithine containing a protecting group according to claim 2, characterized in that: The catalyst is anhydrous zinc chloride.

6. The method for synthesizing α-methylornithine containing a protecting group according to claim 1, characterized in that: The step of forming M2 comprises: mixing M1, M1-1 and a base to react; wherein the structural formula of M1-1 is:

7. The method for synthesizing α-methylornithine containing a protecting group according to claim 6, characterized in that: The reaction conditions include: temperature of -80 to -40°C, time of 1 to 4 h; The base is selected from any one of LiHMDS and NaHMDS; The molar ratio of M1, M1-1 and base is: 1:(1-1.5):(1-1.5).

8. The method for synthesizing α-methylornithine containing a protecting group according to claim 1, characterized in that: The step of forming M3 comprises: mixing M2 with a base to perform a ring-opening reaction.

9. The method for synthesizing α-methylornithine containing a protecting group according to claim 8, characterized in that: The reaction conditions include: temperature of 25-65°C and time of 2-6 hours; The base is selected from hydroxides; The molar ratio of M2 to base is 1:(2-5).

10. The method for synthesizing α-methylornithine containing a protecting group according to claim 9, characterized in that: The base is selected from sodium hydroxide and lithium hydroxide.

11. The method for synthesizing α-methylornithine containing a protecting group according to claim 1, characterized in that: The step of forming M3-B comprises: M3 is mixed with an acid for reaction.

12. The method for synthesizing α-methylornithine containing a protecting group according to claim 11, characterized in that: The reaction conditions include: temperature of 0-50°C and time of 2-6 hours; The acid is selected from trifluoroacetic acid or hydrochloric acid; The molar ratio of M3 to acid is 1:(3-10).

13. The method for synthesizing α-methylornithine containing a protecting group according to claim 1, characterized in that: The step of forming M3-A comprises: M3-B, a compound containing R1 and a base are mixed and reacted, and R1 is Boc.

14. The method for synthesizing α-methylornithine containing a protecting group according to claim 13, characterized in that: The reaction conditions include: temperature of 0-50°C and time of 10-20 hours; The molar ratio of M3-B to the compound containing R1 is 1:(1-3); The base is selected from any one of carbonates, amines and bicarbonates.

15. The method for synthesizing α-methylornithine containing a protecting group according to claim 14, characterized in that: The base is selected from any one of sodium carbonate, potassium carbonate, sodium bicarbonate, triethylamine, pyridine and diisopropylethylamine.

16. The method for synthesizing α-methylornithine containing a protecting group according to claim 1, characterized in that: The step of forming M4-A comprises: reacting M3-A with a catalyst; The catalyst is selected from palladium on carbon; The reaction conditions include: temperature of 0-50°C and time of 10-20 hours.

17. The method for synthesizing α-methylornithine containing a protecting group according to claim 1, characterized in that: The step of forming M comprises: M4-A is mixed with a compound containing R2 for reaction; R2 is Fmoc.

18. The method for synthesizing α-methylornithine containing a protecting group according to claim 17, characterized in that: The reaction conditions include: temperature of 0-50°C and time of 3-10 hours.

19. The method for synthesizing α-methylornithine containing a protecting group according to claim 1, characterized in that: include: After each reaction, post-treatment was performed.

20. The method for synthesizing α-methylornithine containing a protecting group according to claim 19, characterized in that: Post-treatment includes any one of filtration, washing, drying, concentration and extraction.

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