Method for synthesizing alpha-methyl-L-lysine and derivatives thereof

Abstract

The invention relates to the technical field of synthesis of Fmoc-alpha-Me-Lys (Boc)-OH, in particular to a method for synthesizing alpha-methyl-L-lysine and a derivative thereof. The preparation method comprises the following steps: S1) carrying out asymmetric catalytic reaction on a compound 1 and a compound 2 to obtain an intermediate 3; s2) carrying out hydrogenation reduction on the intermediate 3 to obtain an intermediate 4; s3) hydrolyzing the intermediate 4 to obtain a compound 5; and S4) the compound 5 is subjected to amino protection to obtain a product 6. According to the method for synthesizing the alpha-methyl-L-lysine and the derivative thereof, provided by the invention, the target product can be obtained from simple and easily available substituted 2, 3-butadiene-1-amine and amino-acid ester in four steps at the total yield of 64% and the optical purity of 94%.

Description

Technical Field

[0001] The invention relates to the technical field of Fmoc-α-Me-Lys(Boc)-OH synthesis, and in particular to a method for synthesizing α-methyl-L-lysine and derivatives thereof. Background Art

[0002] At present, the publicly reported synthetic routes of Fmoc-α-Me-Lys(Boc)-OH are mainly the following:

[0003] In 2009, Satendra's group reported a method for synthesizing (S)-α-methyllysine using William's oxazinone as a chiral auxiliary, such as Figure 1 As shown, the steps are as follows:

[0004] Starting from 1-1, a methylation reaction was performed with iodomethane to obtain the monoalkylated product (5S)-5-methyloxazinone 1-2. 1-2 reacted with 1,4-diiodobutane to obtain 1-3. 1-3 reacted with sodium azide to obtain azide 1-4 by nucleophilic substitution. 1-4 was reduced with trimethylphosphine, and Boc-ON directly reacted with the amine in the azide position to generate Boc-protected secondary amine 1-5. The chiral auxiliary was hydrogenolyzed to obtain L-α-methyl-lysine 1-6 with the amino group at the ε position protected by Boc. Finally, the amino group at the α position was protected with Fmoc-OSU to obtain the target product with a total yield of 26.3%. This method takes 7 steps to obtain the final target product, which has a long process, a low total yield, and an expensive chiral auxiliary. In addition, the third step uses an explosive azide compound, which is not conducive to safe production and is not conducive to large-scale production.

[0005] In 2013, Masterson's group reported a porcine liver esterase (PLE)-catalyzed desymmetrization method for obtaining orthogonally protected (R)- and (S)-α-methyl-α-lysine from optically pure α,α-dialkyl-malonic acid monoesters. Figure 2 As shown, the steps are as follows:

[0006] Diethyl 2-methylmalonate 2-1 and 2-2 are alkylated to obtain the chiral 2-3. 2-3 is hydrolyzed by pig liver esterase (PLE) to obtain the monoester 2-4. 2-4 is subjected to Curtius rearrangement promoted by tetraisopropyl titanate and reacted with Fmoc-OH to obtain the Fmoc group-protected carbamate 2-5. 2-5 is hydrolyzed to obtain the free amino acid 2-6, and 2-6 is reacted with (Boc)2O to obtain Fmoc-α-Me-Lys(Boc)-OH, with a total yield of 42%. In this route, the raw materials are simple and easy to obtain, and the steps are relatively few, but all four steps require column treatment, and the post-treatment is cumbersome and difficult to industrialize.

[0007] In 2022, Liu et al. from Shanghai Yaotan Pharmaceutical Research and Development Co., Ltd. were inspired by the report of Satendra's research group in 2009 and used chiral auxiliary agents to realize the synthesis of Fmoc-α-Me-Lys(Boc)-OH. The steps are as follows:

[0008] 1,4-Diiodobutane reacts with N-Boc benzylamine to produce 3-2 by nucleophilic substitution reaction. 3-2 and chiral auxiliary are chirally constructed under the action of KHMDS to produce 3-3. Hydrogenolysis removes the benzyl protecting group and chiral auxiliary of 3-3 to produce 3-4. Fmoc protecting group is added to 3-4 with Fmoc-OSU to obtain the final product. The total yield is 52.6% and the optical purity is 99%. The disadvantage is that expensive chiral auxiliary is used and the atom economy of the reaction route is poor.

[0009] Based on the above three synthetic routes, the existing method for synthesizing Fmoc-α-Me-Lys(Boc)-OH has the disadvantages of poor atom economy and high cost.

[0010] Therefore, a method for synthesizing α-methyl-L-lysine and its derivatives is designed to provide another technical solution to the above technical problems. Summary of the invention

[0011] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0012] A method for synthesizing α-methyl-L-lysine, comprising the following steps:

[0013] S1) Compound 1 and Compound 2 are subjected to an asymmetric catalytic reaction to obtain an intermediate 3;

[0014] S2) intermediate 3 is reduced by hydrogenation to obtain intermediate 4;

[0015] S3) intermediate 4 is hydrolyzed to obtain compound 5;

[0016] S4) Compound 5 is treated with amino protection to obtain product 6.

[0017] As a preferred embodiment of the method for synthesizing α-methyl-L-lysine provided by the present invention, in the step S1, compound 1 and compound 2 are reacted by asymmetric catalysis to obtain intermediate 3 through the addition of chiral aldehyde, transition metal, ligand, solvent, Lewis acid, base and Bronsted acid.

[0018] As a preferred embodiment of the method for synthesizing α-methyl-L-lysine provided by the present invention, the solvent is at least one of toluene, mesitylene, xylene, and anhydrous CH3CN;

[0019] The base is an organic base or an inorganic base; the organic base is t At least one of BuOK, DBN, EtOK, 2-tert-butyl-1,1,3,3-tetramethylguanidine, DBU, Quinuclidine, TMG; the inorganic base is at least one of Cs2CO3, K2CO3, K3PO4, Na2CO3;

[0020] The Lewis acid is at least one of ZnCl2 or ZnBr2 or Zn(OAc)2 or Zn(OTf)2 or ZnF2 or Zn(CN)2 or Zn(ClO4)2·6H2O or MgCl2 or Mg(OAc)2 or LiBr or LiCl or LiBF4 or LiOTf or NiBr2 or Ni(acac)2 or CuBr2 or FeCl3;

[0021] At least one of Bronsted acids p-nitrobenzoic acid, o-fluorobenzoic acid, o-hydroxybenzoic acid, pentafluorobenzoic acid, 1-naphthoic acid, acetic acid, p-toluenesulfonic acid, benzoic acid, and trifluoroacetic acid;

[0022] The transition metal is at least one of Pd(dppf)Cl2, Pd(PPh3)4, [Pd(C3H5)Cl]2, Pd(dba)3, Pd(OAc)2, Pd(CN)2Cl, Pd(CF3COO)2, PdCl2, [Ru(C2H4)Cl], [RuCl2(p-cymeme)2], [Rh(C2H4)2Cl]2, Ni(COD)2, Ni(OTf)2, and [Ir(COD)Cl]2.

[0023] As a preferred embodiment of the method for synthesizing α-methyl-L-lysine provided by the present invention, in the step S2, intermediate 3 undergoes a hydrogenation reduction reaction with hydrogen under the action of palladium carbon to obtain intermediate 4.

[0024] A method for synthesizing a derivative of alpha-methyl-L-lysine is prepared by using the above product.

[0025] As a preferred embodiment of the method for synthesizing a derivative of α-methyl-L-lysine provided by the present invention, the structural formula of the allylated product 3 is:

[0026] It is a derivative of 2,6-diamino-2-methylhex-4-enoic acid.

[0027] As a preferred embodiment of the method for synthesizing a derivative of α-methyl-L-lysine provided by the present invention, the structural formula of the reduction product 4 is:

[0028] It is a derivative of 2,6-diamino-2-methylhexanoic acid.

[0029] It can be seen without a doubt that the above-mentioned technical solution of the present application can definitely solve the technical problem to be solved by the present application.

[0030] At the same time, through the above technical solutions, the present invention has at least the following beneficial effects:

[0031] The present invention provides a method for synthesizing α-methyl-L-lysine and its derivatives. Compound 1 and compound 2 react under the action of chiral aldehyde, transition metal, ligand, etc. to obtain intermediate 3 with a yield of 75% and an optical purity of 94%. Intermediate 3 is subjected to hydrogenation reduction with hydrogen under the action of Pd / C to obtain intermediate 4 with a yield of 100%. Intermediate 4 is hydrolyzed under alkaline conditions and then acidified with hydrochloric acid to obtain compound 5. Compound 5 is protected with Fmoc-OSu with an Fmoc protecting group under the alkaline condition of sodium bicarbonate to obtain the final target product 6 with a total yield of 85% in two steps. Starting from simple and readily available substituted 2,3-butadiene-1-amine and amino acid ester, the target product is obtained in four steps with a total yield of 64% and an optical purity of 94%.

[0032] By using chiral aldehyde and transition metal as co-catalysts, the allylated product is obtained through an asymmetric α-allylation reaction of substituted 2,3-butadiene-1-amine and alanine ester and its derivatives. At the same time, the allylated product is subjected to hydrogenation reduction, hydrolysis, and a protective group on Fmoc-OSu to obtain Fmoc-α-Me-Lys(Boc)-OH, making the synthetic route more economical and simple. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for use in the description of the embodiments. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0034] Figure 1 Schematic diagram of the preparation of Fmoc-α-Me-Lys(Boc)-OH using chiral auxiliary William's oxazinone in the prior art;

[0035] Figure 2 Schematic diagram of the preparation of Fmoc-α-Me-Lys(Boc)-OH by PLE catalysis in the prior art;

[0036] Figure 3 This is an improved schematic diagram of the preparation of Fmoc-α-Me-Lys(Boc)-OH using chiral auxiliary agents in the prior art;

[0037] Figure 4 It is a synthetic schematic diagram of the present invention;

[0038] Figure 5 It is a schematic diagram of the synthesis process of the present invention;

[0039] Figure 6 It is a schematic diagram of screening in the synthesis of the present invention;

[0040] Figure 7 It is a schematic diagram of ligand screening in the synthesis of the present invention;

[0041] Figure 8 It is a schematic diagram of screening aldehydes in the synthesis of the present invention;

[0042] Fig. 9 In the synthesis of the present invention Schematic diagram of acid screening;

[0043] Fig.10 It is a schematic diagram of the screening of bases in the synthesis of the present invention;

[0044] Fig.11 It is a schematic diagram of the screening of base equivalent in the synthesis of the present invention;

[0045] Fig.12 It is a schematic diagram of solvent screening in the synthesis of the present invention;

[0046] Fig.13 In the synthesis of the present invention Schematic diagram of acid equivalent screening;

[0047] Fig.14 It is a schematic diagram of the amplification experiment and substrate equivalent adjustment of the present invention;

[0048] Fig.15 It is a schematic diagram of the structure of the synthetic product of the present invention;

[0049] Fig.16 It is a production schematic diagram when the present invention is applied. DETAILED DESCRIPTION

[0050] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0051] In order to enable those skilled in the art to better understand the solutions of the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the accompanying drawings.

[0052] It should be noted that, in the absence of conflict, the embodiments of the present invention and the features and technical solutions in the embodiments may be combined with each other.

[0053] It should be noted that similar reference numerals and letters denote similar items in the following drawings, and therefore, once an item is defined in one drawing, further definition and explanation thereof is not required in subsequent drawings.

[0054] Reference Figure 4-Figure 15 , a method for synthesizing α-methyl-L-lysine.

[0055] refer to Figure 4 Starting from substituted 2,3-butadiene-1-amine 1 and alanine ester 2, an asymmetric α-allylation reaction is carried out under nitrogen protection via the combined action of a chiral aldehyde catalyst, a transition metal, a ligand, etc. to obtain intermediate 3. Intermediate 3 reacts with hydrogen under the action of palladium carbon to obtain intermediate 4. Intermediate 4 is hydrolyzed under alkaline conditions to obtain compound 5. Compound 5 reacts with Fmoc-OSu under alkaline conditions to obtain the final target product 6.

[0056] refer to Figure 6 and Table 1, Palladium catalyst screening

[0057] First, the chiral aldehyde of (R)2,2′-dihydroxybinaphthyl-3-carboxaldehyde derived from binaphthol was used as the aldehyde catalyst, tetrakistriphenylphosphine palladium was used as the palladium catalyst, the achiral ligand 1,3-bis(diphenylphosphino)propane dppp was used as the ligand of the metal palladium catalyst, zinc chloride was used as the Lewis acid, tetramethylguanidine TMG was used as the base, benzoic acid was used as the Bronsted acid, and 1.0 mL of toluene was used as the solvent. The reaction was investigated under the initial conditions of 100°C as the reaction temperature under nitrogen protection, and trace amounts of the target product were observed. Then Pd(dba)3 and palladium acetate were used, and only trace amounts of catalytic products were monitored. However, it is gratifying that when Pd(dppf)Cl2 was used, the target product could be obtained with a yield of 30%. In addition, when the ligand used was changed from the achiral dppp to the chiral ligand Segphos, the target product could be obtained with a yield of 68% and an ee value of -83%. In addition, under the conditions of chiral ligand Segpgos, other palladium screening, such as Pd(CN)2Cl, had a 25% yield and -84% ee value, while [Pd(PPh3)]4 as a palladium catalyst had an 18% yield and -59% ee value. Finally, Pd(dppf)Cl2 was selected as the optimal palladium catalyst for the reaction.

[0058] Table 1: Yields of different objects and corresponding values ​​of target products

[0059]

[0060]

[0061] [a] Unless otherwise specified, CA is R-configured chiral aldehyde (R)-I, ligand is S-configured, PhCH3 (1 mL). [b] Separation yield. [c] Determined by chiral HPLC.

[0062] [d] The ligand is Segphos in S configuration.

[0063] refer to Figure 7 and Table 2, Ligand Screening

[0064] After determining the palladium catalyst, a series of bisphosphine ligands and monophosphine ligands were selected for screening. The yield and ee value obtained by using ferrocene-type bisphosphine ligands for the reaction were both low. It can be seen from entries 1-3 that the screened ferrocene-type ligands can obtain the target product with a maximum yield of 34% and an ee value of -36%. The reaction results using monophosphine ligands (entries 5 and 6) were poor, and only trace products could be monitored. Among the biphenyl-type bisphosphine ligands, (S)-Segphos (entry 7) and the benzodioxane-type bisphosphine ligand (S)-Synphos (entry 11) had the best reaction effects, and the target product was obtained with a yield of 68%, an ee value of -83% and a yield of 70%, an ee value of -84%, respectively. However, the cost of using Synphos ligands is relatively high, so Segphos was selected as the best ligand for the reaction.

[0065] Table 2: Correspondence table of ligand screening for different entries

[0066]

[0067]

[0068]

[0069] [a] Unless otherwise specified, CA is R-configured chiral aldehyde (R)-I, ligand is S-configured, PhCH3 (1 mL). [b] Separation yield. [c] Determined by chiral HPLC.

[0070] refer to Figure 8 and Table 3, Screening of aldehydes

[0071] Aldehyde catalysts can form imines with amino acid esters to increase the acidity of α hydrogen, play an activation role, and have a great influence on the ee value. Aldehyde catalysts were screened. Various substituents were introduced at the 3′ position of binaphthol, whether it was TMS group substitution, 3,5-diisopropylphenyl, 3,5-dimethylphenyl, or 3,5-trifluoromethylphenyl substitution, only poor reaction structures could be obtained. Among them, the aldehyde substituted with TMS had the best reaction effect, and the target product could be obtained with a yield of 35% and an ee value of 75%. Only trace amounts of the target product could be detected when using aldehyde catalysts substituted with Cl, F, and I with less steric hindrance. Although the target product could be obtained with methoxy-substituted and cyano-substituted aldehydes with ee values ​​of -84% and -88%, respectively, the yields were low, at 18% and 17%, respectively. The experimental results show that the simplest (R)-2,2′-dihydroxybinaphthalene-3-carboxaldehyde has the best reaction effect (entry 12), and can obtain the target product with a yield of 68% and an ee value of -83%. Therefore, the simplest aldehyde (entry 12) was selected as the aldehyde catalyst.

[0072] Table 3: Aldehyde screening correspondence table for different entries

[0073]

[0074]

[0075] [a] Unless otherwise specified, CA is an S-configuration chiral aldehyde, and the ligand is an R-configuration PhCH3 (1 mL). [b] Separation yield. [c] Determined by chiral HPLC. [d] The ligand used is Segphos with an S configuration, and CA uses an R-configuration chiral aldehyde, PhCH3 (1 mL).

[0076] refer to Fig. 9 and Table 4, Acid screening

[0077] Considering that Bronsted acid provides protons when forming palladium hydrogen species, it has an important influence on the reaction, and Bronsted acid is screened. The screening results show that under the conditions of using o-fluorobenzoic acid and p-nitrobenzoic acid, the target product can be obtained with a yield greater than 50% and an ee value of 98%. Under the conditions of using pentafluorobenzoic acid, although the target product can be obtained with an ee value of 87%, its yield is only 19%. The reaction of o-hydroxybenzoic acid and m-toluic acid can also obtain the target product with an ee value greater than 80%, but the yields are poor, 31% and 21% respectively, and only trace yields can be detected when using m-aminobenzoic acid. The case of using trifluoroacetic acid reaction can obtain the target product with an ee value of -95% and a yield of 8%. Although the reaction using benzoic acid can obtain the target product with a yield of 58% and an ee value of 92%, the reaction using p-nitrobenzoic acid as Bronsted acid is more excellent, and the target product can be obtained with a yield of 53% and an ee value of 98%. Finally, p-nitrobenzoic acid (entry 8) was selected as the optimal Bronsted acid.

[0078] Table 4: Different items Acid screening correspondence table

[0079]

[0080] [a] Unless otherwise specified, CA is chiral aldehyde (S)-I with S configuration, ligand with R configuration, PhCH3 (1 mL). [b] Separation yield. [c] Determined by chiral HPLC. [d] CA is chiral aldehyde (R)-I with R configuration, ligand with S configuration, PhCH3 (1 mL).

[0081] refer to Fig.10 and Table 5, screening of alkali

[0082] Considering that the base has the function of promoting the deprotonation of the imine and plays an important role in the reaction, the base was screened. The reaction yield of the inorganic base was low and the ee value was poor. The screening results showed that the inorganic base with the best reaction result was K3PO4, which could obtain the target product with a yield of 25% and an ee value of -84%. Among the screened organic bases, the target product could be obtained with a yield of 42% and an ee value of -98% using quinuclidine (entry 10), while the target product could only be obtained with a yield of 8% and an ee value of 8% using 2-tert-butyl-1,1,3,3-tetramethylguanidine. Although the target product could be obtained with an ee value of -88% using DBU, its yield was low, only 25%. When TMG was used for the reaction, the target product could be obtained with a yield of 49% and an ee value of -90%. The experimental results show that quinuclidine is the best base, but because of its high price, which is more than 5 times that of TMG, the cost is relatively high, so TMG (entry 11) is still selected as the best base.

[0083] Table 5: Corresponding table of screening values ​​of alkalis in different entries

[0084]

[0085] [a] Unless otherwise specified, CA is R-configured chiral aldehyde (R)-I, ligand is S-configured, PhCH3 (1 mL). [b] Separation yield. [c] Determined by chiral HPLC.

[0086] refer to Fig.11 and Table 6, Alkali Equivalent Screening

[0087] Next, the amount of TMG was optimized, because different amounts of TMG have different deprotonation rates on the formed imine, which will affect the reaction. When the rate of forming the nucleophilic carbon anion matches the rate of forming the allyl palladium intermediate, better results can be achieved. Experiments show that when the amount of TMG is increased from 0.5 equivalents to 1.2 equivalents, the reaction yield changes from 11% to 49%, and the ee value remains at around 90%. When the base equivalent is further increased, the yield gradually decreases from 49% to 22%, and the ee value remains at around 90%. From the experimental results, it can be seen that when 1.2 equivalents of TMG (entry 4) are used, the target product can be obtained with a yield of 49% and an ee value of -90%, which is the best result.

[0088] Table 6: Numerical correspondence table of base equivalent screening in different entries

[0089]

[0090] [a] Unless otherwise specified, CA is R-configured chiral aldehyde (R)-I, ligand is S-configured, PhCH3 (1 mL). [b] Separation yield. [c] Determined by chiral HPLC.

[0091] refer to Fig.12 and Table 7, Solvent Screening

[0092] Solvent effects also affect the activity and stereoselectivity of chemical reactions. Therefore, the solvents were screened. When the non-benzene solvent anhydrous acetonitrile was used as the reaction solvent for the reaction, only trace products could be monitored. Among the benzene solvents, xylene and mesitylene were used as solvents to obtain the target product with a yield of 48% and 24% respectively. Toluene was used as the solvent for the reaction to obtain the target product with a yield of 75%, and the ee values ​​of the three were all -91%. The experimental results showed that toluene still had the best reaction effect as a solvent, and toluene (entry 4) was selected as the optimal solvent for the reaction.

[0093] Table 7: Numerical correspondence table for different solvent screening

[0094]

[0095] [a] Unless otherwise specified, CA is R-configured chiral aldehyde (R)-I, ligand is S-configured, PhCH3 (1 mL). [b] Separation yield. [c] Determined by chiral HPLC.

[0096] refer to Fig.13 and Table 8, Acid equivalent screening

[0097] The amount of Bronsted acid has a great influence on the stereoselectivity of the reaction. After screening, it was found that when the Bronsted acid equivalent was reduced to 70 mol%, the ee value of the target product was reduced to -60%. 80 mol% is still the optimal Bronsted acid equivalent (entry 2), and the target product can be obtained with a yield of 74% and an ee value of -90%.

[0098] Table 8: Different Acid equivalent screening numerical correspondence table

[0099]

[0100] refer to Fig.14 and Table 9, scale-up experiment and substrate equivalent adjustment

[0101] Considering the subsequent scale-up of the experiment and the possibility that allenes may be unstable in the reaction, resulting in incomplete reaction of some amino acid esters when quantified by allene, the reaction scale was scaled up and the equivalent of the substrate was adjusted. When the reaction scale was 0.4 mmol, the reaction was carried out at a reactant equivalent ratio of 1:2, 1:1.2, and 1:1.5, respectively, based on the quantitative allene. When the reactant equivalent ratio was 1:1.5, the target product could be obtained with a yield of 71% and an ee value of 96%. Subsequently, the reaction was expanded to 0.8 mmol, and the reaction was carried out at an equivalent ratio of 1:2, 1:1.1, 1:1.2, and 1:1, respectively. It was observed that as the amino acid ester equivalent decreased, the yield gradually increased from 40% to 60%. Subsequently, the amino acid ester was quantitatively measured, and the amino acid ester and the allene were reacted at an equivalent ratio of 1:1.1, 1:1.2, and 1:1.5, respectively. Finally, the allylated product (entry 11) could be obtained in a reaction of 0.8 mmol amino acid ester and 1.2 mmol allene with a yield of 75% and an ee value of 94%.

[0102] Table 9: Corresponding values ​​of scale-up experiment and substrate equivalent adjustment

[0103]

[0104] [a] Unless otherwise specified, CA is a chiral aldehyde (R)-I with R configuration, and the ligand is a 0.4 mmol quantitative reaction PhCH3 (2 mL), 0.8 mmol quantitative reaction PhCH3 (3 mL) with S configuration. [b] Separation yield. [c] Determined by chiral HPLC. [d] CA is a chiral aldehyde (R)-I with R configuration, and the ligand is a S configuration.

[0105] After the above screening conditions, finally, 1.2mmol N-Boc-2,3-butadiene-1-amine and 0.8mmol alanine ethyl ester were used for reaction. With alanine ethyl ester as quantitative, 10mol% of the simplest aldehyde catalyst (S)-2,2′-dihydroxybinaphthyl-3-carboxaldehyde as aldehyde catalyst, 8mol% of R-configuration Segphos as ligand, 8mol% of Pd(dppf)Cl2 as metal catalyst, 40mol% of ZnCl2 as Lewis acid, 80mol% of p-nitrobenzoic acid as Bronsted acid, 120mol% of TMG as base, 3ml of toluene as solvent, under nitrogen protection at 80°C, the allylation product can be obtained with a yield of 75% and an ee value of 94%.

[0106] Starting from the easily available alanine ethyl ester and N-Boc-2,3-butadiene-1-amine, protected α-methyl-L-lysine (Fmoc-α-Me-Lys(Boc)-OH) and its derivatives were obtained with a total yield of 64% through four steps of asymmetric allylation, hydrogenation reduction, acidolysis, and introduction of protecting groups.

[0107] Embodiment 2

[0108] refer to Fig.16 , providing an implementation method for synthesis:

[0109] (1) Synthesis of Compound 3

[0110] Pd(dppf)Cl2 (0.064mmol), R-configured Segphos (0.064mmol) were added to a Shrek tube, and nitrogen was protected. Toluene (1mL) was added for coordination for 30min. Chiral aldehyde CA (0.08mmol), ZnCl2 (0.32mmol), TMG (0.96mmol), p-nitrobenzoic acid (0.64mmol), compound 1 (1.2mmol) and compound 2 (0.8mmol) were added at once. The reaction was carried out at 80°C, and the reaction progress was monitored by TLC until compound 2 completely disappeared. The reactants were concentrated under reduced pressure and then subjected to column chromatography to obtain compound 3 with yield = 75% and ee = 94%.

[0111] (2) Synthesis of Compound 4

[0112] Compound 3 (1 mmol) and 10% Pd / C (0.05 mmol) were added to the reaction bottle. Under nitrogen protection, ethyl acetate (5 mL) was added and hydrogen was introduced. The reaction was allowed to react at room temperature. The reaction progress was monitored by TLC until compound 3 completely disappeared. The reaction was filtered and rotary evaporated to obtain compound 4 with a yield of 100%.

[0113] (3) Synthesis of Compound 5

[0114] Compound 4 (1 mmol) and NaOH (2 mmol) were added to the reaction flask, and then a mixed solvent (5 mL) of water and ethanol in a ratio of 1:1 was added. The reaction was carried out at 60°C and the reaction progress was monitored by TLC. After the reaction was complete, ethanol was removed by rotary evaporation and 1N hydrochloric acid solution was added dropwise to acidify to a pH of 4-4.5 to obtain a solution of compound 5.

[0115] (4) Synthesis of Compound 6

[0116] Saturated sodium bicarbonate solution was slowly added to the solution of compound 5 to adjust the pH to 8-9, and THF with the same volume of the solution was added. Fmoc-OSu (1.1 mmol) was added and stirred at 25°C until the reaction was complete. The mixture was extracted with ethyl acetate and subjected to column chromatography to obtain compound 6 with a yield of 85%.

[0117] In this embodiment, the Lewis acid is at least one of ZnCl2, ZnBr2, Zn(OAc)2, Zn(OTf)2, ZnF2, Zn(CN)2, Zn(ClO4)2·6H2O, MgCl2, Mg(OAc)2, LiBr, LiCl, LiBF4, LiOTf, NiBr2, Ni(acac)2, CuBr2, and FeCl3, preferably ZnCl2;

[0118] In this embodiment, the Bronsted acid is at least one of p-nitrobenzoic acid, o-fluorobenzoic acid, o-hydroxybenzoic acid, pentafluorobenzoic acid, 1-naphthoic acid, acetic acid, p-toluenesulfonic acid, benzoic acid, and trifluoroacetic acid, preferably p-nitrobenzoic acid;

[0119] In this embodiment, the transition metal is at least one of Pd(dppf)Cl2, Pd(PPh3)4, [Pd(C3H5)Cl]2, Pd(dba)3, Pd(OAc)2, Pd(CN)2Cl, Pd(CF3COO)2, PdCl2, [Ru(C2H4)Cl], [RuCl2(p-cymeme)2], [Rh(C2H4)2Cl]2, Ni(COD)2, Ni(OTf)2, and [Ir(COD)Cl]2, preferably Pd(dppf)Cl2;

[0120] In this embodiment, the allene is at least one of 1-(Boc-amino)-2,3-butadiene, 1-(Fmoc-amino)-2,3-butadiene, 1-(Cbz-amino)-2,3-butadiene, and 1-(Bz-amino)-2,3-butadiene.

[0121] In this embodiment, the amino acid ester is preferably alanine ethyl ester. In other embodiments, the amino acid ester may also be at least one of alanine methyl ester, alanine tert-butyl ester, alanine benzyl ester, alanine isopropyl ester, and the like.

[0122] Embodiment 3

[0123] Based on the above-mentioned Example 2, a method for synthesizing a derivative of α-methyl-L-lysine is disclosed.

[0124] When compound 3 is prepared from compound 1 and compound 2, the corresponding derivatives are obtained.

[0125] Compound 3 is subjected to hydrogen reduction reaction with hydrogen under the action of palladium carbon to obtain compound 4, and compound 4 is hydrolyzed under alkaline conditions to obtain compound 5. Compound 5 is reacted with Fmoc-OSu under alkaline conditions to obtain the final target product 6. At the same time, this method can also be used to obtain a derivative with a similar skeleton to product 6.

[0126] The preferred embodiments of the present invention disclosed above are only used to help explain the present invention. The preferred embodiments do not describe all the details in detail, nor do they limit the present invention to the specific implementation methods described. Obviously, many modifications and changes can be made according to the content of this specification. This specification selects and specifically describes these embodiments in order to better explain the principles and practical applications of the present invention, so that those skilled in the art can understand and use the present invention well. The present invention is limited only by the claims and their full scope and equivalents.

Claims

1. A method for synthesizing α-methyl-L-lysine, characterized in that: Here are the steps: S1) Compound 1 and Compound 2 are subjected to an asymmetric catalytic reaction to obtain an intermediate 3; S2) intermediate 3 is reduced by hydrogenation to obtain intermediate 4; S3) intermediate 4 is hydrolyzed to obtain compound 5; S4) Compound 5 is treated with amino protection to obtain product 6.

2. A method for synthesizing α-methyl-L-lysine according to claim 1, characterized in that: In the step S1, compound 1 and compound 2 are reacted by asymmetric catalysis to obtain intermediate 3 by adding chiral aldehyde, transition metal, ligand, solvent, Lewis acid, base and Bronsted acid.

3. A method for synthesizing α-methyl-L-lysine according to claim 2, characterized in that: The solvent is at least one of toluene, mesitylene, xylene, and anhydrous CH3CN; The base is an organic base or an inorganic base; the organic base is t At least one of BuOK, DBN, EtOK, 2-tert-butyl-1,1,3,3-tetramethylguanidine, DBU, Quinuclidine, TMG; the inorganic base is at least one of Cs2CO3, K2CO3, K3PO4, Na2CO3; The Lewis acid is at least one of ZnCl2 or ZnBr2 or Zn(OAc)2 or Zn(OTf)2 or ZnF2 or Zn(CN)2 or Zn(ClO4)2·6H2O or MgCl2 or Mg(OAc)2 or LiBr or LiCl or LiBF4 or LiOTf or NiBr2 or Ni(acac)2 or CuBr2 or FeCl3; The Bronsted acid is at least one of p-nitrobenzoic acid, o-fluorobenzoic acid, o-hydroxybenzoic acid, pentafluorobenzoic acid, 1-naphthoic acid, acetic acid, p-toluenesulfonic acid, benzoic acid and trifluoroacetic acid; The transition metal is at least one of Pd(dppf)Cl2, Pd(PPh3)4, [Pd(C3H5)Cl]2, Pd(dba)3, Pd(OAc)2, Pd(CN)2Cl, Pd(CF3COO)2, PdCl2, [Ru(C2H4)Cl], [RuCl2(p-cymeme)2], [Rh(C2H4)2Cl]2, Ni(COD)2, Ni(OTf)2, and [Ir(COD)Cl]2.

4. A method for synthesizing α-methyl-L-lysine according to claim 1, characterized in that: In the step S2, intermediate 3 is subjected to a hydrogenation reduction reaction with hydrogen under the action of palladium carbon to obtain intermediate 4.

5. A method for synthesizing a derivative of α-methyl-L-lysine, which is prepared by the product of claims 1-5.

6. A method for synthesizing a derivative of α-methyl-L-lysine according to claim 5, characterized in that: The structural formula of allylated intermediate 3 is: It is a derivative of 2,6-diamino-2-methylhex-4-enoic acid.

7. A method for synthesizing a derivative of α-methyl-L-lysine according to claim 5, characterized in that: The structural formula of intermediate 4 is: It is a derivative of 2,6-diamino-2-methylhexanoic acid.

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