Method for synthesizing high-purity pseudo proline dipeptide heterocycle

Abstract

The invention discloses a method for synthesizing a high-purity pseudo proline dipeptide heterocyclic ring. The method comprises the following steps: (1) preparing L-serine or L-threonine into corresponding methyl ester hydrochloride; (2) condensing the methyl ester hydrochloride obtained in the step (1) with a condensation reagent to form a corresponding pseudo proline ring; and (3) condensing the pseudo-proline ring formed in the step (2) and related amino acid protected by Fmoc to obtain the corresponding pseudo-proline dipeptide heterocyclic ring. The total yield of the target product synthesized by the reaction can reach more than 80%. The method solves the problems of long reaction time, low yield, high safety risk and the like in the reported route, and has the advantages of cheap and easily available raw materials, lower production cost, simplicity in operation, environmental friendliness, high yield, short reaction time, simplicity in post-treatment and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of peptide synthesis, and particularly relates to a method for synthesizing high-purity pseudoproline dipeptide heterocycle. Background Art

[0002] Pseudoproline dipeptide heterocycles are important fragments in drugs such as telpotide and semaglutide, such as pseudoproline dipeptide heterocycles with CAS numbers of 1425938-63-1, 252554-778-2, 168216-05-5, 1147996-34-6, etc., and their demand has increased year by year. The synthesis of pseudoproline dipeptide heterocycles reported at present mainly includes the following: Among them, patents CN101472939A and CN 102159587A describe the method for preparing pseudoproline dipeptide according to "Reaction Formula 1". Its preparation process requires repeated salting and purification of intermediates, and the method is complicated to operate and has a low overall yield. The catalyst used is p-toluenesulfonic acid or pyridine p-toluenesulfonate catalysis, but the reaction time is long, separation and purification are difficult, the reaction is incomplete, and the product yield is low.

[0003]

[0004] Patent CN 107176970A describes a new method, as shown in reaction formula 2, using Dowex 50 resin as a catalyst for condensation reaction, but this method requires the carboxyl group of serine, threonine or cysteine ​​to be protected with benzyl first and then reacted with α-amino acid to form a ring, and then treated with methanol, formic acid, and Pd-C to remove the benzyl group and then post-processed to obtain the target product. A complete process takes more than 24 hours. In addition, the palladium carbon used is expensive, flammable and has great harm to the environment, which does not meet the requirements of green chemistry.

[0005]

[0006] The traditional method for preparing pseudoproline dipeptide has the following disadvantages: each time a pseudoproline dipeptide ring is prepared, the corresponding dipeptide needs to be synthesized first, but the yield of the synthesized dipeptide is low and there are obvious by-products. When the dipeptide is ring-closed, molecular sieves are required, and the ring-closure reaction has poor selectivity, post-treatment is relatively difficult, purification is not easy, and the production cycle is long.

[0007] Compared with the reported reactions, the novel method for preparing high-purity pseudoproline dipeptide developed by the present invention first prepares common intermediates Ser[Psi(Me,Me)Pro]-OMe 3 and Thr[Psi(Me,Me)Pro]-OMe 10, and then directly condenses with the required Fmoc-amino acid and hydrolyzes to obtain the target product, so that when preparing pseudoproline dipeptide, it is not necessary to first prepare dipeptide and then perform ring closure, which greatly improves the reaction efficiency and reduces the generation of three wastes.

[0008]

[0009] The structures of the intermediates Ser[Psi(Me,Me)Pro]-OMe 3 and Thr[Psi(Me,Me)Pro]-OMe 10 of the present invention.

[0010] The invention solves the problems of long reaction time, low yield, high safety risk and the like of the reported route reaction, and has the advantages of cheap and readily available raw materials, low production cost, simple operation, environmental friendliness, high yield, short reaction time, simple post-processing and the like.

[0011] In view of the above technical problems existing in the prior art, the object of the present invention is to provide a new method for synthesizing high-purity pseudoproline dipeptide heterocycle. The method of the present invention has the advantages of short reaction time, high product yield, low impurity content, low safety risk and low cost.

[0012] In order to achieve the above object, the technical solution adopted by the present invention is as follows:

[0013] A novel method for synthesizing a high-purity pseudoproline dipeptide heterocycle, the general synthesis formula is as follows:

[0014]

[0015] Wherein the substituent R1 is H or methyl, and the substituent R1 is the α-amino side chain of the corresponding amino acid.

[0016] It includes the following steps:

[0017] 1) L-serine or L-threonine reacts with thionyl chloride in a solvent to generate methyl ester hydrochloride of L-serine or L-threonine;

[0018] 2) Under organic base or acidic catalytic conditions, the methyl ester hydrochloride of L-serine or L-threonine reacts with a cyclization reagent to generate an intermediate 1, the structural formula of which is as follows:

[0019]

[0020] Wherein the substituent R1 is H or methyl;

[0021] 3) In the presence of an inorganic base, the amino acid with a carboxyl end is recorded as X-OH, and X-OH reacts with Fmoc-OSu in a solvent to generate the corresponding Fmoc-X-OH. The reaction formula is as follows:

[0022]

[0023] wherein the substituent R2 is an α-amino side chain substituent of the amino acid X-OH;

[0024] 4) The intermediate 1 of step 2) and the Fmoc-X-OH group of step 3) are condensed with a condensing agent in the presence of a base to obtain intermediate 2, whose structural formula is as follows:

[0025]

[0026] 5) The intermediate 2 in step 4) is hydrolyzed in an alkaline solution environment to obtain a crude product of the target product, and finally the target product is obtained by pulping and recrystallization with an organic solvent, and its structural formula is as follows:

[0027]

[0028] Furthermore, in step 1), the solvent is methanol, and the molar ratio of L-serine or L-threonine to thionyl chloride is 1:1.2-2, preferably 1:1.5-2.0.

[0029] Furthermore, step 1) is to stir the reaction at room temperature for 5-8 hours, and after the reaction is completed, the solvent is removed by distillation under reduced pressure to obtain the methyl ester hydrochloride of L-serine or L-threonine.

[0030] Further, in step 2), the cyclization reagent is one of 2,2-dimethoxypropane, acetone, and 2-methoxypropylene, preferably acetone or 2,2-dimethoxypropane;

[0031] When the cyclization reagent is acetone or 2-methoxypropylene, the cyclization reaction is carried out under the catalysis of an organic base, and the organic base is one of triethylamine, N,N-diisopropylethylamine, pyridine, 4-methylpyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and isopropylamine, preferably triethylamine or N,N-diisopropylethylamine; the molar ratio of the methyl ester hydrochloride of L-serine or L-threonine to the organic base is 1.0:1.0-5.0, preferably 1.0:1.5-4.0;

[0032] When the cyclization reagent is 2,2-dimethoxypropane, the cyclization reaction is carried out under the catalysis of an acidic substance, the acidic substance is at least one of formic acid, concentrated sulfuric acid, p-toluenesulfonic acid, and camphorsulfonic acid, preferably camphorsulfonic acid, and the molar ratio of the methyl ester hydrochloride of L-serine or L-threonine to the acidic substance is 1.0:0.05-0.2;

[0033] When the cyclization reagent is acetone, acetone itself serves as both a reactant and a reaction solvent. When the cyclization reagent is 2,2-dimethoxypropane or 2-methoxypropylene, a reaction solvent is also added to the cyclization reaction. The reaction solvent is DCM or THF. The concentration of L-serine or L-threonine methyl ester hydrochloride dispersed in the solvent is 0.5-2 mmol / mL.

[0034] Furthermore, in step 2), when the cyclization reagent is acetone or 2-methoxypropylene, the reaction is stirred at room temperature for 5-8 hours, filtered after the reaction, and the filtrate is distilled under reduced pressure to remove the solvent to obtain intermediate 1; when the cyclization reagent is 2,2-dimethoxypropane, the reaction is stirred at 65-75°C for 5-8 hours, and the solvent is distilled under reduced pressure to obtain intermediate 1.

[0035] Furthermore, in step 3), the solvent is EA, the inorganic base is Na2CO3, the molar amount of the inorganic base is 1-2 times the molar amount of the amino acid X-OH, preferably 1.2-1.5 times; the molar amount of Fmoc-OSu is 0.8-1.2 times the molar amount of the amino acid X-OH, preferably 0.9-1.0 times.

[0036] Further, step 3) is to stir the reaction at room temperature for 5-8h, and after the reaction is completed, the following post-treatment steps are included: the reaction solution is adjusted to a pH of 1-2 with an acid, the liquid is separated, the organic phase is washed with a 3-8% mass fraction saline solution, dried over anhydrous sodium sulfate, and the solvent is removed by reduced pressure distillation to obtain Fmoc-X-OH.

[0037] Furthermore, in step 4), the condensing agent is one of DCC / NHS, EDCI / HOBT, and HATU / DIPEA, preferably DCC / NHS; and in step 4), the base is DIPEA.

[0038] Furthermore, in step 5), the alkaline solution environment is an aqueous solution of at least one of NaOH, KOH, Na2CO3, and K2CO3, and the molar amount of the alkali is 1.5-2 times the molar amount of the intermediate 2. After the hydrolysis reaction is completed, EA is added to the system, and the pH of the system is adjusted to 1-2 with HCl solution. The liquids are separated, and the organic phase is dried over anhydrous Na2SO4 and then distilled under reduced pressure to remove the solvent to obtain a crude product.

[0039] Furthermore, the solvent used for recrystallization in step 5) is at least one of petroleum ether, n-heptane, dioxane, methyl tert-butyl ether, cyclohexane, and n-hexane, preferably n-heptane, n-hexane, or methyl tert-butyl ether.

[0040] Furthermore, in step 3), the amino acid X-OH is O-tert-butyl-L-tyrosine, L-alanine or L-phenylalanine.

[0041] The method used in the present invention is to prepare a pseudoproline dipeptide heterocycle, which has the advantages of high reaction efficiency, short reaction time and less reaction impurities. The obtained pseudoproline dipeptide heterocycle does not need to undergo complicated post-treatment, and a pure product can be obtained by n-heptane recrystallization. The yield of the pseudoproline dipeptide heterocycle reaches more than 70%, and the purity exceeds 99%.

[0042] Compared with the prior art, the present invention has the following beneficial effects:

[0043] 1. The synthetic route of the present invention is simple and efficient, and various raw materials are low in cost and easily available.

[0044] 2. Compared with the existing synthesis methods, the synthesis route of the present invention is time-saving, efficient, high yield, less reaction impurities, and high product purity.

[0045] 3. The synthetic route of the present invention adopts the method of first preparing a universal intermediate and then condensing it with the required Fmoc-amino acid to obtain a pseudoproline dipeptide, thereby avoiding the shortcomings of incomplete reaction when preparing dipeptides and poor selectivity when the dipeptide ring is closed, and harsh reaction conditions.

[0046] 4. The present invention studies post-treatment and uses n-heptane recrystallization after the reaction to obtain a product with extremely high purity, which is simple and efficient; the solvent is recycled and reused to reduce costs, meeting the requirements of green chemistry.

[0047] In summary, the present invention is based on the concept of green synthesis process, adopts a new route, solvent treatment and recycling, and provides a green, safe and environmentally friendly preparation method of pseudoproline dipeptide heterocycle, which has good application prospects. DETAILED DESCRIPTION

[0048] The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto.

[0049] The purity of the product was confirmed by high performance liquid chromatography (HPLC).

[0050] HPLC assay conditions:

[0051] Chromatographic column: Thermo liquid chromatography column C18 (4.6mm×250mm, 5μL), mobile phase: 0.1% phosphoric acid aqueous solution: 0.1% phosphoric acid acetonitrile solution = 80:20. Flow rate: 1mL / min; detection wavelength: 200nm; injection volume: 10μL; column temperature: 25℃.

[0052] The structure of the obtained product was confirmed by NMR spectroscopy ( 1 HNMR) to confirm the structure of the compound.

[0053] The method of the present invention has a wide range of applications and has good adaptability to almost all pseudoproline dipeptide cyclization reactions. The generated pseudoproline dipeptide structure (I) has the following characteristics: R1 is H or CH3, R2 is an α-amino side chain, and R3 is an amino acid protecting group.

[0054]

[0055] Compound I specifically includes but is not limited to the following pseudoproline dipeptide:

[0056]

[0057]

[0058] The method of this patent is specifically described by taking the synthesis of (4S)-3-[(2S)-3-[4-(tert-butoxy)phenyl]-2-[[fluorenylmethoxycarbonyl]amino]-1-oxopropyl]-2,2-dimethyl-4-oxazolidinecarboxylic acid, (4S,5R)-3-(N-fluorenylmethoxycarbonylalanyl)-2,2,5-trimethyloxazolidine-4-carboxylic acid and (4S,5R)-3-[(2S)-2-[[fluorenylmethoxycarbonyl]amino]-1-oxo-3-phenylpropyl]-2,2,5-trimethyl-4-oxazolidinecarboxylic acid as examples.

[0059] Example 1

[0060] Using L-serine 1 and O-tert-butyl-L-tyrosine 4 as starting materials, (4S)-3-[(2S)-3-[4-(tert-butyloxy)phenyl]-2-[[fluorenylmethoxycarbonyl]amino]-1-oxopropyl]-2,2-dimethyl-4-oxazolidinecarboxylic acid 7 was prepared according to the following synthetic route:

[0061]

[0062] (1) L-serine 1 (47.6 mmol, 1.0 eq.) was dissolved in 30 mL of anhydrous methanol and stirred at 25°C. Sulfonyl chloride (71.4 mmol, 1.5 eq.) was slowly added dropwise to the reaction system. The reaction was stirred at 25°C for 6 h. The solvent was removed by distillation under reduced pressure to obtain L-serine methyl ester hydrochloride 2 (46.3 mmol, purity 99.1%) as a white solid.

[0063] (2) L-serine methyl ester hydrochloride 2 (46.3 mmol, 1.0 eq.) was added to 50 mL of acetone, and triethylamine (69.4 mmol, 1.5 eq.) was added. The mixture was stirred at 25°C for 6 h, filtered, and the filtrate was distilled under reduced pressure to remove the solvent to obtain intermediate 3 (44.6 mmol, purity 98.9%).

[0064] (3) O-tert-butyl-L-tyrosine 4 (63.2 mmol, 1.0 eq.) and Fmoc-OSu (60.0 mmol, 0.95 eq.) were dissolved in 100 mL EA, 94.8 mmol (1.5 eq.) Na2CO3 was dissolved in 100 mL water to form a Na2CO3 solution which was added dropwise to the above system, and the reaction was stirred at 25°C for 8 h. After the reaction, the pH of the system was adjusted to 1-2 with 1 M HCl. The organic phase was allowed to stand for stratification, and washed with 50 mL × 3 of 5% NaCl solution, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain Fmoc-Tyr(tBu)-OH 5 (54.0 mmol, purity 99.4%).

[0065] (4) Fmoc-Tyr(tBu)-OH 5 (45.2 mmol, 1.0 eq.) and NHS (52.0 mmol, 1.15 eq.) were dissolved in 100 mL THF, and DCC (67.9 mmol, 1.5 eq.) was added dropwise. The reaction was stirred at 25°C for 3 h. Intermediate 3 (44.6 mmol, 1.0 eq.) and DIPEA (67.9 mmol, 1.5 eq.) were added dropwise to the reaction system. The reaction was stirred at 25°C for 8 h. After the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain a white solid 6 (40.5 mmol, purity 99.2%).

[0066] (5) The white solid 6 (40.5 mmol) was dissolved in 300 mL of a solution containing NaOH (80 mmol, 2.0 eq.), and the mixture was stirred at 25°C for 12 h. After the reaction, 150 mL of EA was added to the system, and the pH of the system was adjusted to 1-2 with 2 M HCl. The organic phase was separated, and the solvent was removed by distillation under reduced pressure to obtain a crude product 7 (39.0 mmol, purity 97.4%).

[0067] (6) The crude product 7 (39.0 mmol) was recrystallized using 60 mL of n-heptane to obtain a white solid (4S)-3-[(2S)-3-[4-(tert-butyloxy)phenyl]-2-[[fluorenylmethoxycarbonyl]amino]-1-oxopropyl]-2,2-dimethyl-4-oxazolidinecarboxylic acid (36.0 mmol). The purity was 99.5% by HPLC. 1H NMR(400MHz,DMSO)δ13.15(s,1H),7.89(d,2H),7.74(t,2H),7.63–7.24(m,5H),7.24–7.10(m,2H),7.00–6.76(m,2H),4 .37–4.29(m,1H),4.18–3.99(m,3H),3.87(dd,1H),2.93(dd,2H),2.87(dd,2H),1.61(d,3H),1.41(s,3H),1.15(s,9H).

[0068] Example 2

[0069] Using L-threonine 8 and L-alanine 11 as starting materials, (4S,5R)-3-(N-fluorenylmethoxycarbonylalanyl)-2,2,5-trimethyloxazolidine-4-carboxylic acid 14 was prepared according to the following synthetic route:

[0070]

[0071] (1) L-threonine 8 (42.0 mmol, 1.0 eq.) was dissolved in 30 mL of anhydrous methanol and stirred at 25°C. Sulfonyl chloride (84 mmol, 2.0 eq.) was slowly added dropwise to the reaction system. The reaction was stirred at 25°C for 6 h. The solvent was removed by distillation under reduced pressure to obtain a white solid L-threonine methyl ester hydrochloride 9 (41.3 mmol, purity 99.4%).

[0072] (2) L-threonine methyl ester hydrochloride 9 (41.3 mmol, 1.0 eq.) was added to 50 mL of acetone, and N,N-diisopropylethylamine (82.5 mmol, 2.0 eq.) was added dropwise. The reaction was stirred at 25° C. for 6 h. After filtration, the solvent was removed by distillation under reduced pressure to obtain intermediate 10 (39.8 mmol, purity 99.1%).

[0073] (3) L-alanine 11 (56.1 mmol, 1.0 eq.) and Fmoc-OSu (53.3 mmol, 0.95 eq.) were dissolved in 50 mL EA, 84.2 mmol (1.5 eq.) Na2CO3 was dissolved in 50 mL water to form a Na2CO3 solution which was added dropwise to the reaction system and reacted at 25°C for 6 h. After the reaction, the pH of the system was adjusted to 1-2 with 1 M HCl. The organic phase was washed with 50 mL × 3 of 5% NaCl solution, dried over anhydrous Na2SO4, and the solvent was removed by distillation under reduced pressure to obtain Fmoc-L-Ala-OH 12 (47.9 mmol, purity 99.4%).

[0074] (4) Fmoc-L-Ala-OH 12 (39.8 mmol, 1.0 eq.) and NHS (45.8 mmol, 1.15 eq.) were dissolved in 50 mL THF, and DCC (59.7 mmol, 1.5 eq.) was added dropwise, and the reaction was stirred at 25°C for 2 h. Intermediate 10 (39.8 mmol, 1.0 eq.) and DIPEA (79.7 mmol, 2.0 eq.) were added dropwise to the reaction system, and the reaction was stirred at 25°C for 6 h. After the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain a white solid 13 (35.2 mmol, purity 98.2%).

[0075] (5) The white solid 13 (35.2 mmol, 1.0 eq.) was dissolved in 300 mL of a solution containing KOH (70.3 mmol, 2.0 eq.) and stirred at 25°C for 12 h. After the reaction, 150 mL of EA was added to the system and the pH of the system was adjusted to 1-2 with 2 M HCl. The organic phase was separated, and the solvent was removed by distillation under reduced pressure to obtain a crude product 14 (34.0 mmol, purity 97.1%).

[0076] (6) The crude product 14 (34.0 mmol) was recrystallized using 50 mL of methyl tert-butyl ether to obtain a white solid (4S,5R)-3-(N-fluorenylmethoxycarbonylalanyl)-2,2,5-trimethyloxazolidine-4-carboxylic acid (31.8 mmol). The purity of the product was 99.3% by HPLC. 1 HNMR(400MHz,DMSO)δ13.44(s,1H),7.91(d,2H),7.75(dt,2H),7.48–7.27 (m,5H),4.37–4.06(m,4H),3.36(s,1H),3.12(m,1H),1.63–1.22(m,12H).

[0077] Example 3

[0078] Using L-threonine 8 and L-phenylalanine 15 as starting materials, (4S,5R)-3-[(2S)-2-[[Fluorenylmethoxycarbonyl]amino]-1-oxo-3-phenylpropyl]-2,2,5-trimethyl-4-oxazolidinecarboxylic acid 18 was prepared according to the following synthetic route:

[0079]

[0080] (1) L-threonine 8 (42.0 mmol, 1.0 eq.) was dissolved in 30 mL of anhydrous methanol and stirred at 25°C. Sulfonyl chloride (84 mmol, 2.0 eq.) was slowly added dropwise to the reaction system. The reaction was stirred at 25°C for 6 h. The solvent was removed by distillation under reduced pressure to obtain a white solid L-threonine methyl ester hydrochloride 9 (41.5 mmol, purity 99.6%).

[0081] (2) L-threonine methyl ester hydrochloride 9 (41.3 mmol, 1.0 eq.) and camphorsulfonic acid (4.1 mmol, 0.1 eq.) were added to 50 mL of THF, and 2,2-dimethoxypropane (330 mmol, 8.0 eq.) was added dropwise. The mixture was stirred and refluxed at 70° C. for 6 h. After the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain intermediate 10 (40.0 mmol, purity 99.0%).

[0082] (3) L-phenylalanine 15 (60.5 mmol, 1.0 eq.) and Fmoc-OSu (57.5 mmol, 0.95 eq.) were dissolved in 100 mL EA, 90.8 mmol (1.5 eq.) Na2CO3 was dissolved in 100 mL water to form a Na2CO3 solution which was added dropwise to the reaction system and reacted at 25°C for 6 h. After the reaction, the pH of the system was adjusted to 1-2 with 1 M HCl. The organic phase was washed with 100 mL × 3 of 5% NaCl solution, dried over anhydrous Na2SO4, and the solvent was removed by distillation under reduced pressure to obtain Fmoc-L-Phe-OH 16 (54.7 mmol, purity 99.7%).

[0083] (4) Fmoc-L-Phe-OH 16 (51.6 mmol, 1.0 eq.) and NHS (59.4 mmol, 1.15 eq.) were dissolved in 100 mL THF, and DCC (77.4 mmol, 1.5 eq.) was added dropwise. The reaction was stirred at 25°C for 2 h for activation. Intermediate 10 (40.0 mmol, 1.0 eq.) and DIPEA (80.3 mmol, 2.0 eq.) were added dropwise to the reaction system. The reaction was stirred at 25°C for 6 h. After the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain a white solid 17 (37.2 mmol, purity 98.7%).

[0084] (5) The white solid 17 (37.2 mmol, 1.0 eq.) was dissolved in 300 mL of a solution containing NaOH (74.4 mmol, 2.0 eq.) and stirred at 25°C for 12 h. After the reaction, 150 mL of EA was added to the system and the pH of the system was adjusted to 1-2 with 2 M HCl. The organic phase was separated, and the solvent was removed by distillation under reduced pressure to obtain a crude product 18 (36.1 mmol, purity 97.6%).

[0085] (6) The crude product 18 (36.1 mmol) was recrystallized using 100 mL of methyl tert-butyl ether to obtain a white solid (4S,5R)-3-[(2S)-2-[[fluorenylmethoxycarbonyl]amino]-1-oxo-3-phenylpropyl]-2,2,5-trimethyl-4-oxazolidinecarboxylic acid (35.8 mmol). The purity of the product was 99.4% by HPLC. 1 H NMR(400MHz,DMSO)δ14.4-12.3(s,1H),8.04–7.83(m,2H),7.81–7.65(m,2H),7.58–7.06(m,10H) ,4.59–3.96(m,4H),3.72(d,1H),3.07-2.76(m,2H),2.51(m,1H),1.75–1.29(m,6H),1.14(d,3H).

[0086] The contents described in this specification are merely an enumeration of implementation forms of the inventive concept, and the protection scope of the present invention should not be regarded as being limited to the specific forms described in the embodiments.

Claims

1. A method for synthesizing a high-purity pseudoproline dipeptide heterocycle, characterized in that: The following steps are involved: 1) L-serine or L-threonine reacts with thionyl chloride in a solvent to generate methyl ester hydrochloride of L-serine or L-threonine; 2) Under organic base or acidic catalytic conditions, the methyl ester hydrochloride of L-serine or L-threonine reacts with a cyclization reagent to generate an intermediate 1, the structural formula of which is as follows: Wherein the substituent R1 is H or methyl; 3) In the presence of an inorganic base, the amino acid with a carboxyl end is recorded as X-OH, and X-OH reacts with Fmoc-OSu in a solvent to generate the corresponding Fmoc-X-OH. The reaction formula is as follows: wherein the substituent R2 is an α-amino side chain substituent of the amino acid X-OH; 4) The intermediate 1 of step 2) and the Fmoc-X-OH group of step 3) are condensed with a condensing agent in the presence of a base to obtain intermediate 2, whose structural formula is as follows: 5) The intermediate 2 in step 4) is hydrolyzed in an alkaline solution environment to obtain a crude product of the target product, and finally the target product is obtained by pulping and recrystallization with an organic solvent, and its structural formula is as follows:

2. A method for synthesizing a high-purity pseudoproline dipeptide heterocycle as claimed in claim 1, characterized in that: In step 1), the solvent is methanol, and the molar ratio of L-serine or L-threonine to thionyl chloride is 1:1.2-2, preferably 1:1.5-2.0; step 1) is stirred at room temperature for 5-8 hours, and after the reaction is completed, the solvent is removed by reduced pressure distillation to obtain the methyl ester hydrochloride of L-serine or L-threonine.

3. A method for synthesizing a high-purity pseudoproline dipeptide heterocycle as claimed in claim 1, characterized in that: In step 2), the cyclization reagent is one of 2,2-dimethoxypropane, acetone, and 2-methoxypropylene, preferably acetone or 2,2-dimethoxypropane; When the cyclization reagent is acetone or 2-methoxypropylene, the cyclization reaction is carried out under the catalysis of an organic base, and the organic base is one of triethylamine, N,N-diisopropylethylamine, pyridine, 4-methylpyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and isopropylamine, preferably triethylamine or N,N-diisopropylethylamine; the molar ratio of the methyl ester hydrochloride of L-serine or L-threonine to the organic base is 1.0:1.0-5.0, preferably 1.0:1.5-4.0; When the cyclization reagent is 2,2-dimethoxypropane, the cyclization reaction is carried out under the catalysis of an acidic substance, the acidic substance is at least one of formic acid, concentrated sulfuric acid, p-toluenesulfonic acid, and camphorsulfonic acid, preferably camphorsulfonic acid, and the molar ratio of the methyl ester hydrochloride of L-serine or L-threonine to the acidic substance is 1.0:0.05-0.2; When the cyclization reagent is acetone, acetone itself serves as both a reactant and a reaction solvent. When the cyclization reagent is 2,2-dimethoxypropane or 2-methoxypropylene, a reaction solvent is also added to the cyclization reaction, and the reaction solvent is DCM or THF. The concentration of L-serine or L-threonine methyl ester hydrochloride dispersed in the solvent is 0.5-2 mmol / mL.

4. A method for synthesizing a high-purity pseudoproline dipeptide heterocycle as claimed in claim 3, characterized in that: In step 2), when the cyclization reagent is acetone or 2-methoxypropylene, the reaction is stirred at room temperature for 5-8 hours, and after the reaction is completed, the reaction is filtered, and the filtrate is distilled under reduced pressure to remove the solvent to obtain intermediate 1; when the cyclization reagent is 2,2-dimethoxypropane, the reaction is stirred at 65-75°C for 5-8 hours, and after the reaction is completed, the solvent is distilled under reduced pressure to obtain intermediate 1.

5. A method for synthesizing a high-purity pseudoproline dipeptide heterocycle as claimed in claim 1, characterized in that: In step 3), the solvent is EA, the inorganic base is Na2CO3, the molar amount of the inorganic base is 1-2 times the molar amount of the amino acid X-OH, preferably 1.2-1.5 times; the molar amount of Fmoc-OSu is 0.8-1.2 times the molar amount of the amino acid X-OH, preferably 0.9-1.0 times.

6. A method for synthesizing a high-purity pseudoproline dipeptide heterocycle as claimed in claim 1, characterized in that: Step 3) is to stir the reaction at room temperature for 5-8 hours. After the reaction is completed, the following post-treatment steps are included: the reaction solution is adjusted to a pH of 1-2 with an acid, the organic phase is washed with a 3-8% mass fraction saline solution, dried over anhydrous sodium sulfate, and the solvent is removed by reduced pressure distillation to obtain Fmoc-X-OH.

7. A method for synthesizing a high-purity pseudoproline dipeptide heterocycle as claimed in claim 1, characterized in that: In step 4), the condensing agent is one of DCC / NHS, EDCI / HOBT, and HATU / DIPEA, preferably DCC / NHS; and in step 4), the base is DIPEA.

8. A method for synthesizing a high-purity pseudoproline dipeptide heterocycle as claimed in claim 1, characterized in that: In step 5), the alkaline solution environment is an aqueous solution of at least one of NaOH, KOH, Na2CO3, and K2CO3, and the molar amount of the alkali is 1.5-2 times the molar amount of the intermediate 2. After the hydrolysis reaction is completed, EA is added to the system, and the pH of the system is adjusted to 1-2 with HCl solution. The liquids are separated, and the organic phase is dried over anhydrous Na2SO4 and then distilled under reduced pressure to remove the solvent to obtain a crude product.

9. A method for synthesizing a high-purity pseudoproline dipeptide heterocycle as claimed in claim 1, characterized in that: The solvent used for recrystallization in step 5) is at least one of petroleum ether, n-heptane, dioxane, methyl tert-butyl ether, cyclohexane, and n-hexane, preferably n-heptane, n-hexane, or methyl tert-butyl ether.

10. A method for synthesizing a high-purity pseudoproline dipeptide heterocycle according to claim 1, characterized in that: In step 3), the amino acid X-OH is O-tert-butyl-L-tyrosine, L-alanine or L-phenylalanine.

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