Process for the synthesis of L-alpha-methylleucine ester and intermediate (S)-2-amino-2,4-dimethyl-pentenoate

Abstract

This invention discloses L α-methylleucine esters and their intermediates ( S The synthesis method of 2-amino-2,4-dimethyl-4-pentenoate starts from readily available 3-halo-2-methylpropene and alanine ester, and first obtains the intermediate through an asymmetric allylation reaction. S 2-amino-2,4-dimethyl-4-pentenoate is synthesized via a two-step reaction involving hydrogenation reduction and tartaric acid salt formation. L Tartrate of α-methylleucine ester. The synthetic method of this invention is efficient, safe, and economical, enabling high yield and high enantioselectivity of the target product. The raw materials are inexpensive, no toxic reagents are used, the synthetic steps are simplified, and the operation is simple and easy.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology and relates to... L Synthetic methods for α-methylleucine esters and their intermediates. Background Technology

[0002] L -α-Methylleucine, as an important non-natural amino acid, has a dual core role. In basic research, as a metabolic antagonist of leucine, it effectively blocks the mTORC1 signaling pathway through a competitive inhibition mechanism, thereby inhibiting protein synthesis and activating autophagy, making it a key tool for studying cell growth and metabolism. In drug development, especially in peptide drug design, it serves as a crucial structural modification unit. By introducing the steric hindrance effect of the methyl group, it can significantly enhance the metabolic stability of peptides (resistance to protease degradation) and stabilize the bioactive conformation by restricting conformational freedom, ultimately improving the efficacy, selectivity, and stability of peptide drugs. In existing reports, L -α-methylleucine is a key component of the clinical drug molecule Retatrutide (a GLP-1 / GIP / glucagon receptor triple agonist). Therefore, L The chiral synthesis of α-methylleucine has extremely important application and market value.

[0003] Chinese patent (publication number CN119306621A) discloses a method for synthesizing using a phase transfer catalyst. L The method for synthesizing α-methylleucine hydrochloride (synthetic route as follows) uses 2-aminopropionate, i.e., compound 1-1 or its hydrochloride, as the starting material. First, it reacts with an aldehyde or ketone compound (protecting agent) to form an imine, i.e., compound 1-2, thus protecting the amino group. Then, it reacts with 3-halo-2-methylpropene in the presence of a chiral biphenyl quaternary ammonium salt phase-transfer catalyst to obtain compound 1-3. Next, deprotection is performed to obtain compound 1-4. Then, a hydrogenation-reduction reaction is carried out in a hydrogen atmosphere to obtain compound 1-5. Finally, an ester hydrolysis reaction is performed by introducing hydrogen chloride gas or adding hydrochloric acid solution to obtain the final product. L -α-methylleucine hydrochloride is compound 1-6. This method can yield the target product in high yield and with high enantioselectivity, but it adds extra amino protection and deprotection steps, resulting in poor step economy and atom economy. Furthermore, the phase transfer catalyst used has a long synthetic route and is expensive.

[0004]

[0005] Existing technology also reports a method for synthesizing using methyl isobutyl ketone. LThe method for synthesizing -α-methylleucine (synthetic route as follows) uses methyl isobutyl ketone, i.e., compound 2-1, as the starting material. It reacts with sodium cyanide and ammonium chloride to obtain compound 2-2. Then, hydrochloric acid is added to hydrolyze the cyano group to obtain compound 2-3. Finally, chiral resolution yields... L -α-methylleucine is compound of formula 2-4. The raw materials used in this method are inexpensive and do not require a chiral catalyst, but it uses highly toxic sodium cyanide, causing significant pollution, and requires multiple chiral resolution processes, resulting in a low yield (only about 20%).

[0006]

[0007] In summary, the existing L The synthesis of α-methylleucine suffers from problems such as high reagent costs, reliance on highly toxic and risky raw materials, the need for multiple chiral resolutions, cumbersome steps, and low yields. There is an urgent need to develop an efficient, safe, and economical synthesis method. Summary of the Invention

[0008] The purpose of this invention is to develop an efficient, safe, and economical method. L The method for synthesizing α-methylleucine esters and their intermediates can obtain the target products in high yield and with high enantioselectivity. The raw materials are inexpensive, no toxic reagents are used, the synthesis steps are simplified, and the operation is simple and easy.

[0009] Based on research, the present invention provides the following technical solution: 1. Intermediate ( S The synthesis method of 2-amino-2,4-dimethyl-4-pentenoate involves using compounds of Formula I and Formula II as starting materials, and conducting an asymmetric allylation reaction in a solvent under nitrogen protection using a chiral aldehyde catalyst, a palladium catalyst and its ligand, a base, and a Lewis acid, to obtain the compound of Formula III, i.e., the intermediate. S )-2-amino-2,4-dimethyl-4-pentenoate; the chiral aldehyde catalyst is ( S )-2,2′-dihydroxy-[1,1′]-binaphthyl-3-carboxaldehyde, the palladium catalyst is [Pd(C3H5)Cl]2 or Pd(PPh3)4, and the ligand of the palladium catalyst is ( R )-Synphos or ( R Segphos, with NaOH or tetramethylguanidine as the base, ZnCl2 as the Lewis acid, and dichloromethane or toluene as the solvent; the chemical reaction formula is as follows:

[0010] In Formula I above, X is a halogen, and in Formulas II and III, R is methyl, ethyl, or tert-butyl.

[0011] Preferably, the palladium catalyst is Pd(PPh3)4, and the ligand of the palladium catalyst is ( R Segphos, with NaOH as the base and dichloromethane as the solvent.

[0012] Preferably, the molar ratio of the compound shown in Formula I, the compound shown in Formula II, the chiral aldehyde catalyst, the palladium catalyst, the ligand of the palladium catalyst, the base, and the Lewis acid is 100 : 110~150 : 8~10 : 0.2~10 : 0.1~10 : 100~200 : 40~80.

[0013] More preferably, the molar ratio of the compound shown in Formula I, the compound shown in Formula II, the chiral aldehyde catalyst, the palladium catalyst, the ligand of the palladium catalyst, the base, and the Lewis acid is 100 : 110 : 8 : 0.2 : 0.1 : 200 : 40.

[0014] 2. L The method for synthesizing α-methylleucine esters includes the following steps: (1) Using compounds of formula I and formula II as starting materials, an asymmetric allylation reaction is carried out in a solvent under nitrogen protection by the combined action of a chiral aldehyde catalyst, a palladium catalyst and its ligand, a base, and a Lewis acid to obtain the intermediate shown in formula III. S )-2-amino-2,4-dimethyl-4-pentenoate; the chiral aldehyde catalyst is ( S )-2,2′-dihydroxy-[1,1′]-binaphthyl-3-carboxaldehyde, the palladium catalyst is [Pd(C3H5)Cl]2 or Pd(PPh3)4, and the ligand of the palladium catalyst is ( R )-Synphos or ( R Segphos, with NaOH or tetramethylguanidine as the base, ZnCl2 as the Lewis acid, and dichloromethane or toluene as the solvent; the chemical reaction formula is as follows:

[0015] (2) The compound shown in Formula III was subjected to a catalytic hydrogenation reaction with hydrogen to obtain the compound shown in Formula IV; the chemical reaction formula is as follows:

[0016] (3) The compound shown in Formula IV and D - Tartaric acid is converted to a salt to obtain the compound shown in formula V. L Tartrate of α-methylleucine ester; chemical reaction formula is as follows:

[0017] In Formula I above, X is a halogen, and in Formulas II, III, IV and V, R is methyl, ethyl or tert-butyl.

[0018] L Tartrates of α-methylleucine esters can be further prepared using conventional techniques in the art. L -α-methylleucine ester.

[0019] Preferably, in step (1), the palladium catalyst is Pd(PPh3)4, and the ligand of the palladium catalyst is ( R Segphos, with NaOH as the base and dichloromethane as the solvent.

[0020] Preferably, in step (1), the molar ratio of the compound shown in Formula I, the compound shown in Formula II, the chiral aldehyde catalyst, the palladium catalyst, the ligand of the palladium catalyst, the base, and the Lewis acid is 100 : 110~150 : 8~10 : 0.2~10 : 0.1~10 : 100~200 : 40~80.

[0021] More preferably, in step (1), the molar ratio of the compound of formula I, the compound of formula II, the chiral aldehyde catalyst, the palladium catalyst, the ligand of the palladium catalyst, the base, and the Lewis acid is 100 : 110 : 8 : 0.2 : 0.1 : 200 : 40.

[0022] Chiral aldehyde catalysts ( S The structural formula of 2,2′-dihydroxy-[1,1′]-binaphthyl-3-carboxaldehyde is as follows:

[0023] Ligands of palladium catalysts ( R )-Segphos、( R The structural formulas of )-Synphos are as follows:

[0024] The beneficial effects of this invention are as follows: This invention starts from readily available 3-halo-2-methylpropene and alanine ester, and first obtains an intermediate through an asymmetric allylation reaction ( S 2-Amino-2,4-dimethyl-4-pentenoate was synthesized via a two-step reaction involving hydrogenation reduction and tartaric acid salt formation. L Tartrate of α-methylleucine ester. The synthetic method of this invention is efficient, safe, and economical, enabling the target product to be obtained in high yield and with high enantioselectivity. Furthermore, the raw materials are inexpensive, no toxic reagents are used, the synthetic steps are simplified, and the operation is simple and easy. Detailed Implementation

[0025] To make the objectives, technical solutions, and beneficial effects of this invention clearer, the preferred embodiments of this invention are described in detail below. Experimental methods in the preferred embodiments that do not specify specific conditions are generally performed under conventional conditions.

[0026] In this embodiment of the invention, "mol%" represents the percentage of the amount of the substance relative to the amount of the substrate (compound 1), in moles. For example, CA (10 mol%) indicates that the number of moles of CA is 10% of the number of moles of compound 1. "ee" represents enantiomer excess, usually expressed as a percentage, defined as the percentage of the amount of one isomer a exceeding that of another isomer b in an enantiomer mixture, used to indicate the optical purity of a chiral compound. A higher ee value indicates higher optical purity.

[0027] Example 1. Screening of palladium catalysts for asymmetric allylation reaction

[0028] Using compounds 1 and 2 as starting materials, ( S )-2,2′-dihydroxy-[1,1′]-binaphthyl-3-carboxaldehyde is the chiral aldehyde catalyst (CA), Pd* is the palladium catalyst, and the achiral ligand 1,3-bis(diphenylphosphine)propane (dppp) or the chiral ligand ( R Compound 3-1 was prepared by reacting 1.0 mL of toluene (PhCH3) at 50 °C under nitrogen protection with segphos as the ligand for the palladium catalyst, tetramethylguanidine (TMG) as the base, ZnCl2 as the Lewis acid, and 1.0 mL of toluene (PhCH3) as the solvent. The chemical reaction formula is shown above. The experimental conditions and results are shown in Table 1.

[0029] Table 1 shows that when Pd(OAc)2, Pd(dba)3, and PdCl2 were used as palladium catalysts and the achiral ligand dppp was used as the ligand, only trace products were observed (items 1-3); when Pd(PPh3)4 was used as a palladium catalyst and the achiral ligand dppp was used as the ligand, compound 3-1 could be obtained in 30% yield (item 4); replacing the achiral ligand dppp with a chiral ligand ( R )-Segphos, compound 3-1 (entry 7) can be obtained in 66% yield and 75% ee value; when [Pd(C3H5)Cl]2 is used as a palladium catalyst and the achiral ligand dppp is used as a ligand, compound 3-1 can be obtained in 30% yield (entry 5); replacing the achiral ligand dppp with a chiral ligand ( R )-Segphos, compound 3-1 (entry 6) can be obtained in 68% yield and with an ee value of 83%; using chiral ligands ( RUnder the conditions of )-Segphos, the reaction using other palladium catalysts such as Pd(CN)2Cl yields 25% and has an ee value of 84% (item 8). Therefore, the palladium catalyst for this reaction is preferably [Pd(C3H5)Cl]2 or Pd(PPh3)4, with Pd(PPh3)4 being more preferred for economic reasons.

[0030] Table 1 Screening of palladium catalysts

[0031] [a] Unless otherwise specified, the ligand is dppp. [b] This is the separation yield. [c] Determined by chiral HPLC; ND indicates undetermined. [d] The ligand is ( R )-Segphos.

[0032] Example 2. Screening of palladium catalyst ligands for asymmetric allylation reaction

[0033] Using compounds 1 and 2 as starting materials, ( R Compound 3-2 was prepared by reacting 2,2′-dihydroxy-[1,1′]-binaphthyl-3-carboxaldehyde as a chiral aldehyde catalyst (CA), Pd(PPh3)4 as a palladium catalyst, an S-configured bisphosphine ligand or a monophosphine ligand as a ligand for the palladium catalyst, TMG as a base, ZnCl2 as a Lewis acid, and 1.0 mL of toluene as a solvent under nitrogen protection at 50 °C. The chemical reaction formula is shown above. Experimental conditions and results are shown in Table 2.

[0034] Table 2 shows that when ferrocene-type bisphosphine ligands are used as ligands in palladium catalysts, the yield of compound 3-2 (maximum only 34%) and ee value (maximum only -36%) are both low (items 1-3); when monophosphine ligands are used as ligands in palladium catalysts, the reaction only yields trace amounts of product (items 5-6); when biphenyl-type bisphosphine ligands are used as ligands in palladium catalysts, ( S )-Segphos (entry 7) and ( S Synphos (entry 11) showed the best results, yielding compounds 3-2 in 68% yield and -83% ee value, and in 70% yield and -84% ee value, respectively. Therefore, the preferred palladium catalyst ligand for this reaction is ( S )-Segphos and ( S -Synphos. Due to ( S Synphos is more expensive; for better value, it's a better choice. S )-Segphos.

[0035] Compounds 3-1 and 3-2 are enantiomers. Based on the above experimental results, the preferred ligand for the palladium catalyst in the synthesis of compound 3-1 is ( R )-Segphos and ( R )-Synphos, more preferably ( R )-Segphos.

[0036] Table 2 Screening of palladium catalyst ligands

[0037] [a] is the separation yield. [b] is determined by chiral HPLC; ND indicates undetermined.

[0038] Example 3. Screening of chiral aldehyde catalysts for asymmetric allylation reaction Chiral aldehyde catalysts can form imines with compound 2 (amino acid ester) to increase the acidity of α-H, thereby playing an activating role and having a significant impact on the ee value. Therefore, chiral aldehyde catalysts are screened.

[0039]

[0040] Using compounds 1 and 2 as starting materials, with ( S )-2,2′-dihydroxy-[1,1′]-binaphthyl-3-carboxaldehyde-3′-R is a chiral aldehyde catalyst (CA), and Pd(PPh3)4 is a palladium catalyst. R Compound 3-1 was prepared by reacting α-Segphos (a ligand for the palladium catalyst), TMG (a base), ZnCl2 (a Lewis acid), and 1.0 mL of toluene (a solvent) at 50 °C under nitrogen protection. The chemical reaction formula is shown above. Experimental conditions and results are shown in Table 3.

[0041] As shown in Table 3, when the substituent R of 2,2′-dihydroxy-[1,1′]-binaphthyl-3-carboxaldehyde-3′-R is trimethylsilyl (TMS, entry 1), 3,5-diisopropylphenyl (entry 2), 3,5-dimethylphenyl (entry 3), or 3,5-ditrifluoromethylphenyl (entry 4), the yield of compound 3-1 is only 35% at most; when the substituent R is sterically less hindered F (entry 6), Cl (entry 8), or I (entry 5), the yield of compound 3-1 is only trace to micro-yield; when the substituent R is cyano (entry 9) or methoxy (entry 10), although the ee values ​​are 88% and 84% respectively, the reaction yields are only 17% and 18%; when the substituent R is H, the effect is the best (entry 11), with a yield of 68% and an ee value of 83%. Therefore, a chiral aldehyde catalyst is preferred for this reaction. S )-2,2′-dihydroxy-[1,1′]-binaphthyl-3-carboxaldehyde.

[0042] Table 3 Screening of chiral aldehyde catalysts

[0043] [a] is the separation yield. [b] is determined by chiral HPLC; ND indicates undetermined.

[0044] Example 4. Screening of bases for asymmetric allylation reactions Bases promote the deprotonation of imines in asymmetric allylation reactions, so bases are screened.

[0045]

[0046] Using compounds 1 and 2 as starting materials, with ( S )-2,2′-dihydroxy-[1,1′]-binaphthyl-3-carboxaldehyde is a chiral aldehyde catalyst (CA), and Pd(PPh3)4 is a palladium catalyst. R Compound 3-1 was prepared by reacting α-Segphos (ligand for palladium catalyst), Base (base), ZnCl2 (Lewis acid), and 1.0 mL toluene (solvent) at 50 °C under nitrogen protection. The chemical reaction formula is shown above. Experimental conditions and results are shown in Table 4.

[0047] Table 4 shows that among the inorganic bases (items 1-4), NaOH (item 3) is the most effective, yielding compound 3-1 with a 60% yield and an ee value of 84%. Among the organic bases (items 5-11), quinuclidine (item 10) and TMG (item 11) are relatively effective, yielding compound 3-1 with a 42% yield and an ee value of 98%, and a 68% yield and an ee value of 83%, respectively. Therefore, NaOH or TMG is the preferred base for this reaction. However, due to the higher price of TMG, NaOH is preferred for economic reasons.

[0048] Table 4 Screening of bases

[0049] [a] is the separation yield. [b] is determined by chiral HPLC; ND indicates undetermined.

[0050] Example 5. Screening of base dosage for asymmetric allylation reaction Better reaction results can only be obtained when the rate of formation of the nucleophilic carbanion matches the rate of formation of the palladium intermediate. Different amounts of base result in different deprotonation rates of the formed imine; therefore, the amount of base used needs to be carefully selected.

[0051]

[0052] Using compounds 1 and 2 as starting materials, ( S)-2,2′-dihydroxy-[1,1′]-binaphthyl-3-carboxaldehyde is a chiral aldehyde catalyst (CA), and Pd(PPh3)4 is a palladium catalyst. R Segphos is the ligand for the palladium catalyst, NaOH is the base, ZnCl2 is the Lewis acid, and 1.0 mL... Compound 3-1 was prepared by reacting toluene as a solvent at 50°C under nitrogen protection. The chemical reaction formula is shown above. Experimental conditions and results are shown in Table 5.

[0053] As shown in Table 5, when the amount of NaOH increases from 50 mol% to 200 mol%, the reaction yield gradually increases, while the ee value decreases slightly (items 1-6). Further increasing the NaOH amount to 250 mol% significantly reduces the yield, while the ee value remains essentially unchanged (item 7). The reaction is most effective when the NaOH amount is 200 mol% (item 6), with a yield of 65% and an ee value of 85%. Therefore, the preferred NaOH amount for this reaction is 100 mol% to 200 mol%, more preferably 200 mol%.

[0054] Table 5 Screening of NaOH dosage

[0055] [a] is the separation yield. [b] is determined by chiral HPLC.

[0056] Example 6. Solvent Screening for Asymmetric Allylation Reactions Solvent effects can also affect the activity and stereoselectivity of chemical reactions, so solvents were screened.

[0057]

[0058] Using compounds 1 and 2 as starting materials, ( S )-2,2′-dihydroxy-[1,1′]-binaphthyl-3-carboxaldehyde is a chiral aldehyde catalyst (CA), and Pd(PPh3)4 is a palladium catalyst. R Compound 3-1 was prepared by reacting 1.0 mL of solvent with Segphos as the ligand for the palladium catalyst, NaOH as the base, ZnCl2 as the Lewis acid, and nitrogen atmosphere at 50 °C. The chemical reaction formula is shown above. Experimental conditions and results are shown in Table 6.

[0059] As shown in Table 6, the reaction is well performed using dichloromethane (DCM), a non-benzene solvent, with a yield of 70% and an ee value of 87% (Item 1). While the ee values ​​of products using benzene-based solvents such as xylene and mesitylene are as high as 91%, the yields are relatively low (<50%, Items 2-3). Using toluene as the solvent yields 65% with an ee value of 85%, slightly less effective than DCM. Therefore, DCM or toluene is the preferred solvent for this reaction, with DCM being more preferred.

[0060] Table 6 Solvent Screening

[0061] [a] is the separation yield. [b] is determined by chiral HPLC.

[0062] Example 7. Screening of Lewis acid dosage for asymmetric allylation reaction The amount of Lewis acid has a significant impact on the stereoselectivity of the reaction, so it is screened.

[0063]

[0064] Using compounds 1 and 2 as starting materials, ( S )-2,2′-dihydroxy-[1,1′]-binaphthyl-3-carboxaldehyde is a chiral aldehyde catalyst (CA), and Pd(PPh3)4 is a palladium catalyst. R Compound 3-1 was prepared by reacting α-Segphos (a ligand for the palladium catalyst), NaOH (a base), ZnCl2 (a Lewis acid), and 1.0 mL DCM (a solvent) at 50 °C under nitrogen protection. The chemical reaction formula is shown above. Experimental conditions and results are shown in Table 7.

[0065] As shown in Table 7, when ZnCl2 is used as a Lewis acid, the product yield and ee value do not change significantly when its dosage is 40 mol% and 80 mol%, respectively. Therefore, the preferred dosage of ZnCl2 for this reaction is 40 mol% to 80 mol%, more preferably 40 mol%.

[0066] Table 7 Screening of ZnCl2 dosage

[0067] [a] is the separation yield. [b] is determined by chiral HPLC.

[0068] Based on the results of Examples 1-7, and considering the subsequent scale-up of the experiment, the reactants and catalyst amounts for the asymmetric allylation reaction were adjusted. Reducing the amount of palladium catalyst and its ligands had little impact on the reaction yield and ee value; extending the reaction time also yielded similar results. Therefore, the final amount of palladium catalyst was adjusted to 0.1 mol%, and the amount of ligands to 0.2 mol%. Simultaneously, after scale-up, compound 2 was observed to remain; adjusting its amount to 110 mol% also resulted in a well-proportioned reaction.

[0069] Example 8. Substrate screening for asymmetric allylation reactions The ester group of amino acid esters has a significant impact on reactivity and stereoselectivity, so they are screened.

[0070] Table 8. Screening of Substrate 2R

[0071] [a] is the separation yield. [b] is determined by chiral HPLC.

[0072] Example 9. Intermediate 3-1, i.e. ( S Synthesis of ethyl 2-amino-2,4-dimethyl-4-pentenoate

[0073] Starting with 20 mmol of compound 1 and 22 mmol of compound 2, 8 mol% of ( S )-2,2′-dihydroxy-[1,1′]-binaphthyl-3-carboxaldehyde was used as a chiral aldehyde catalyst (CA), 0.1 mol% Pd(PPh3)4 was used as a palladium catalyst, and 0.2 mol% ( R Compound 3-1 was prepared by reacting 200 mol% NaOH as the base, 40 mol% ZnCl2 as the Lewis acid, and 15 mL DCM as the solvent under nitrogen protection at 50 °C.

[0074] Results: The yield of compound 3-1 was 75%, and the ee value was 90%.

[0075] Example 10. Compound 5, i.e. L Synthesis of α-methylleucine ethyl ester tartrate

[0076] (1) Synthesis of compound 3-1 Add ( ) to a 50 mL reaction tube RSegphos (0.024 g, 0.04 mmol), Pd(PPh3)4 (0.023 g, 0.02 mmol), and DCM (5 mL) were stirred at room temperature for 30 min under nitrogen protection. Then, ZnCl2 (1.088 g, 8 mmol), (… S 2,2′-dihydroxy-[1,1′]-binaphthyl-3-carboxaldehyde (CA, 0.502 g, 1.6 mmol), compound 1 (1.820 g, 20 mmol), compound 2 (2.574 g, 22 mmol), NaOH (1.600 g, 40 mmol) and DCM (10 mL) were dissolved in water under nitrogen protection at 50 °C. o The reaction was carried out at C for 15 h. After the reaction was completed, the mixture was filtered, and the filter cake was washed with DCM (200 mL). The filtrate and washings were combined and concentrated to 50 mL. The mixture was extracted three times with 1% formic acid aqueous solution (100 mL). The aqueous phases were combined and back-extracted three times with DCM (50 mL), retaining the organic and aqueous phases respectively. K2CO3 (1.000 g) was added to the aqueous phase and it was extracted three times with DCM (100 mL). The extraction was confirmed by thin-layer chromatography. The organic phase was dried with anhydrous Na2SO4, filtered, and evaporated to dryness to obtain compound 3-1 (3.621 g, yield 91%, ee value 91%).

[0077] (2) Synthesis of compound 4 Compound 3-1 (3.621 g, 18.2 mmol), 10% palladium on carbon (Pd / C, 0.0965 g, 0.91 mmol), and ethyl acetate (EA, 20 mL) were added to a round-bottom flask and reacted at room temperature under a hydrogen atmosphere at atmospheric pressure for 15 h. After the reaction was confirmed by thin-layer chromatography, the mixture was filtered and evaporated to dryness to give compound 4 (3.622 g, 99% yield).

[0078] (3) Synthesis of compound 5 Compound 4 (3.622 g, 18 mmol) was added to a round-bottom flask. D -tartaric acid( D -tartaric acid, 2.295 g, 15.3 mmol), ethanol (EtOH, 36 mL) and H2O (4 mL), 60 o C. Stir until dissolved, slowly cool until cooled, then at 0°C. o After being kept at C for 10 h, the mixture was filtered and dried to give compound 5 (4.675 g, yield 74%, ee value 99.5%).

[0079] The overall yield of the three-step reaction was 67%, and the target product 5 with an optical purity of 99.5% was obtained.

[0080] Finally, it should be noted that the above preferred embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail through the above preferred embodiments, those skilled in the art should understand that various changes can be made to it in form and detail without departing from the scope defined by the claims of the present invention.

Claims

1. A method for synthesizing the intermediate (S)-2-amino-2,4-dimethyl-4-pentenoate, characterized in that: Starting with compounds of Formula I and Formula II, an asymmetric allylation reaction was carried out in a solvent under nitrogen protection using a chiral aldehyde catalyst, a palladium catalyst and its ligand, a base, and a Lewis acid to obtain the intermediate (S)-2-amino-2,4-dimethyl-4-pentenoate, represented by Formula III. The chiral aldehyde catalyst was (S)-2,2′-dihydroxy-[1,1′]-binaphthyl-3-carboxaldehyde, the palladium catalyst was [Pd(C3H5)Cl]2 or Pd(PPh3)4, the ligand for the palladium catalyst was (R)-Synphos or (R)-Segphos, the base was NaOH or tetramethylguanidine, the Lewis acid was ZnCl2, and the solvent was dichloromethane or toluene. The chemical reaction formula is as follows: In Formula I above, X is a halogen, and in Formulas II and III, R is methyl, ethyl, or tert-butyl.

2. The method for synthesizing the intermediate (S)-2-amino-2,4-dimethyl-4-pentenoate as described in claim 1, characterized in that: The palladium catalyst is Pd(PPh3)4, the ligand of the palladium catalyst is (R)-Segphos, the base is NaOH, and the solvent is dichloromethane.

3. The method for synthesizing the intermediate (S)-2-amino-2,4-dimethyl-4-pentenoate as described in claim 1, characterized in that: The molar ratio of the compound shown in Formula I, the compound shown in Formula II, the chiral aldehyde catalyst, the palladium catalyst, the ligand of the palladium catalyst, the base, and the Lewis acid is 100 : 110~150 : 8~10 : 0.2~10 : 0.1~10 : 100~200 : 40~80.

4. The method for synthesizing the intermediate (S)-2-amino-2,4-dimethyl-4-pentenoate as described in claim 3, characterized in that: The molar ratio of the compound shown in Formula I, the compound shown in Formula II, the chiral aldehyde catalyst, the palladium catalyst, the ligand of the palladium catalyst, the base, and the Lewis acid is 100 : 110 : 8 : 0.2 : 0.1 : 200 :

40.

5. A method for synthesizing L-α-methylleucine ester, characterized in that: Includes the following steps: (1) Using the compounds shown in Formula I and Formula II as starting materials, an asymmetric allylation reaction is carried out in a solvent under nitrogen protection using a chiral aldehyde catalyst, a palladium catalyst and its ligand, a base, and a Lewis acid to obtain the compound shown in Formula III, i.e., the intermediate (S)-2-amino-2,4-dimethyl-4-pentenoate; the chiral aldehyde catalyst is (S)-2,2′-dihydroxy-[1,1′]-binaphthyl-3-carboxaldehyde, the palladium catalyst is [Pd(C3H5)Cl]2 or Pd(PPh3)4, the ligand of the palladium catalyst is (R)-Synphos or (R)-Segphos, the base is NaOH or tetramethylguanidine, the Lewis acid is ZnCl2, and the solvent is dichloromethane or toluene; the chemical reaction formula is as follows: (2) The compound shown in Formula III was subjected to a catalytic hydrogenation reaction with hydrogen to obtain the compound shown in Formula IV; the chemical reaction formula is as follows: (3) The compound shown in Formula IV is reacted with D-tartaric acid to form a salt, yielding the tartrate salt of the compound shown in Formula V, namely L-α-methylleucine ester; the chemical reaction formula is as follows: In Formula I above, X is a halogen, and in Formulas II, III, IV and V, R is methyl, ethyl or tert-butyl.

6. The method for synthesizing L-α-methylleucine ester as described in claim 5, characterized in that: In step (1), the palladium catalyst is Pd(PPh3)4, the ligand of the palladium catalyst is (R)-Segphos, the base is NaOH, and the solvent is dichloromethane.

7. The method for synthesizing L-α-methylleucine ester as described in claim 5, characterized in that: In step (1), the molar ratio of the compound shown in Formula I, the compound shown in Formula II, the chiral aldehyde catalyst, the palladium catalyst, the ligand of the palladium catalyst, the base, and the Lewis acid is 100 : 110~150 : 8~10 : 0.2~10 : 0.1~10 : 100~200 : 40~80.

8. The method for synthesizing L-α-methylleucine ester as described in claim 7, characterized in that: In step (1), the molar ratio of the compound shown in Formula I, the compound shown in Formula II, the chiral aldehyde catalyst, the palladium catalyst, the ligand of the palladium catalyst, the base, and the Lewis acid is 100 : 110 : 8 : 0.2 : 0.1 : 200 : 40.

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