Synthesis method of arginine derivative containing Cbz / Boc protecting group

Abstract

The invention discloses a synthesis method of an arginine derivative containing a Cbz / Boc protecting group. The method comprises the following steps: taking L-Arg as a raw material, firstly carrying out amidation reaction on L-Arg and Fmoc-Osu, and then carrying out acylation reaction on L-Arg and benzyl chloroformate or Boc anhydride to correspondingly prepare Fmoc-L-Arg (Cbz) 2-OH or Fmoc-L-Arg (Boc) 2-OH. The method has the advantages of cheap and easily available raw materials, few preparation steps, simple operation, easy purification, no use of trifluoromethanesulfonic anhydride and other dangerous reagents, and high operation safety.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemical synthesis, and particularly relates to a method for synthesizing an arginine derivative containing a Cbz / Boc protecting group. Background Art

[0002] Arginine is a natural amino acid that reduces cardiac load, improves immunity, and improves liver function. Arginine can be dehydrated and condensed with other amino acids to generate peptides. More than 7,000 peptides have been discovered so far, and peptide synthesis has become a hot research direction in the 21st century. Arginine itself contains guanidine groups, which are highly alkaline and are prone to protonation and side reactions during the preparation of peptides. Therefore, it is necessary to protect the N of arginine and prepare stable arginine derivative intermediates in order to efficiently prepare peptide drugs containing arginine, such as thymopentin, Setmelanotide, Motixafortide and other drugs.

[0003] In order to protect the α-position N of arginine, Shaik Nowshuddin et al. (Synthetic Commun., 2012, 39, 2022-2031) first used dicyclohexylamine and arginine to form a salt, then acylated the salt with Fmoc-Osu, and finally liberated the dicyclohexylamine to prepare N-fluorenylmethoxycarbonyl-L-arginine. This method has cumbersome steps, and the solubility of arginine after salt formation is worse, and the yield is low.

[0004]

[0005] The most commonly used method for preparing arginine derivatives is to use α-position N-protected ornithine and a fluorine-containing sulfonyl reagent to react (J.Org.Chem., 1998, 63, 3804-3805.), and the reaction is carried out in dichloromethane. However, α-position N-protected ornithine has a relatively large polarity and poor solubility in dichloromethane, and the reaction time is long. In addition, α-position N-protected ornithine and fluorine-containing sulfonyl reagents are both relatively expensive and need to be prepared by themselves, and the synthetic route is long.

[0006]

[0007] Calimsiz, Selcuk et al. (J. Org. Chem., 2006, 71, 6351-6356.) prepared Boc-L-Arg(Cbz) 2 , remove the Boc protecting group with trifluoroacetic acid, and then react with Fmoc-Osu to prepare compound Ⅰa), but Boc-L-Arg(Cbz) 2 The price is high, it needs to be prepared by yourself, and the preparation steps are long.

[0008]

[0009] Norbert Schaschke (Bioorg.Med.Chem.Lett.,2004,14,855–857.) used basic copper carbonate to complex with ornithine, used N,N'-di-Boc-1H-pyrazole-1-carboxamidine to react electrophilically with ornithine, then used EDTA to release the copper ion, and finally reacted with Fmoc-Osu under alkaline conditions to generate the compound Fmoc-L-Arg(Boc) 2 -OH (Formula Ib). The N,N'-di-Boc-1H-pyrazole-1-carboxamidine used in this method needs to be prepared by itself, and its reaction activity is not high. The efficiency of dissociating copper ions with EDTA is not high, and multiple dissociations are required. The operation is cumbersome and the synthesis steps are long.

[0010]

[0011] Verdini, Antonio S et al. (Tetrahedron Lett., 1992, 33, 6541-6542.) used Z-Orn and tert-butyloxycarbonyl protected S-methylisothiourea to prepare Cbz-L-Arg, then catalytic hydrogenation to remove the Cbz protecting group, and finally acylation with Fmoc-Osu to obtain compound Ib. This route has a long reaction step, tert-butyloxycarbonyl protected S-methylisothiourea has high requirements for preparation equipment, the raw materials are expensive, and the catalytic hydrogenation reaction involved is relatively dangerous.

[0012] Summary of the invention

[0013] In view of the problems existing in the prior art, the present invention provides a method for synthesizing arginine derivatives containing Cbz / Boc protecting groups. The method has cheap and readily available raw materials, few preparation steps, simple operation and easy purification.

[0014] The specific technical solutions are as follows:

[0015] A method for synthesizing an arginine derivative containing a Cbz / Boc protecting group comprises the following steps: 1) using L-arginine as shown in formula (IV) and Fmoc-Osu as shown in formula (III) as raw materials, adding them into a solvent A, and carrying out an amidation reaction under alkaline conditions, after the reaction is completed, adding hydrochloric acid to the reaction solution to dissolve the solid, separating the liquids, extracting, adjusting the pH value, filtering, washing, and drying to obtain N-fluorenylmethoxycarbonyl-L-arginine as shown in formula (II);

[0016] 2) Adding N-fluorenylmethoxycarbonyl-L-arginine as shown in formula (II), benzyl chloroformate or Boc anhydride and 1-hydroxybenzotriazole to solvent B, an acylation reaction occurs under alkaline conditions. After the reaction is completed, the reaction solution is extracted, concentrated, salted, filtered, freed, separated, concentrated and dried to obtain N-fluorenylmethoxycarbonyl-N,N'-dibenzyloxycarbonyl-L-arginine as shown in formula (Ia) or N-fluorenylmethoxycarbonyl-N',N"-di-tert-butyloxycarbonyl-L-arginine as shown in formula (Ib). The reaction process is as follows:

[0017]

[0018] Furthermore, the solvent A described in step 1) is a mixture of an organic solvent and water, the volume ratio of the organic solvent to water is 1 to 3:1, the organic solvent is ethyl acetate, dichloromethane, acetone, tetrahydrofuran or acetonitrile; the base is sodium carbonate, potassium carbonate or sodium hydroxide; and the reaction temperature is 10 to 50°C.

[0019] Furthermore, in step 1), the molar ratio of the compound represented by formula (IV), the compound represented by formula (III) and the base is 1:0.9-1.5:1-5.

[0020] Furthermore, in the step 1), the pH adjustment range during the pH adjustment process is 5.0 to 8.0.

[0021] Furthermore, in step 2), the solvent B is a mixture of an organic solvent and water, the volume ratio of the organic solvent to water is 1 to 4:1, the organic solvent is tetrahydrofuran or acetonitrile; the base is potassium carbonate, sodium carbonate or sodium hydroxide; and the reaction temperature is 25 to 60°C.

[0022] Furthermore, in step 2), the molar ratio of the compound represented by formula (II), benzyl chloroformate or Boc anhydride, 1-hydroxybenzotriazole and the base is 1:2-4:0.2-1:2-4.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] (1) The synthetic route is short, the process is simple, and the reaction conditions are mild;

[0025] (2) Raw materials are cheap and readily available, so production costs are low;

[0026] (3) Avoid using dangerous reagents such as trifluoromethanesulfonic anhydride, and the operation is highly safe. DETAILED DESCRIPTION

[0027] The specific scheme of the present invention is described by the following specific examples, but the protection scope of the present invention is not limited thereto.

[0028]

[0029] Example 1 Preparation of N-Fmoc-L-arginine (II)

[0030] In a 1000 ml three-necked flask equipped with a magnetic stirring device and a thermometer, L-arginine (IV) (10 g, 57.40 mmol), Fmoc-Osu (III) (51.66 mmol), sodium carbonate (86.11 mmol) were added, and the solvent was a mixed solution of water and ethyl acetate, 350 mL and 420 mL, respectively. The temperature was kept at 30°C, and the reaction was monitored by TLC. 20 mL of hydrochloric acid was added to the reaction solution to dissolve the solid, separate the liquid and take the water layer, extract the water layer with an organic solvent, adjust the pH of the water layer to 6.0, precipitate, filter, wash with clean water, and dry to obtain the compound shown in formula II (20.3 g), with a yield of 89.20% and a purity of 99.91%.

[0031] Example 2 Preparation of N-Fmoc-L-arginine (II)

[0032] In a 1000 ml three-necked flask equipped with a magnetic stirring device and a thermometer, L-arginine (IV) (10 g, 57.40 mmol), Fmoc-Osu (III) (54.53 mmol), sodium carbonate (114.8 mmol) were added, and the solvent was a mixed solution of water and dichloromethane, 250 mL and 600 mL, respectively. The temperature was kept at 40°C, and the reaction was monitored by TLC. 20 mL of hydrochloric acid was added to the reaction solution to dissolve the solid, separate the liquid and take the water layer, extract the water layer with an organic solvent, adjust the pH of the water layer to 7.0, precipitate, filter, wash with clean water, and dry to obtain the compound shown in formula II (18.5 g), with a yield of 81.29% and a purity of 98.48%.

[0033] Example 3 Preparation of N-Fmoc-L-arginine (II)

[0034] In a 1000 ml three-necked flask equipped with a magnetic stirring device and a thermometer, L-arginine (IV) (10 g, 57.40 mmol), Fmoc-Osu (III) (57.40 mmol), sodium hydroxide (68.88 mmol) were added, and the solvent was a mixed solution of water and dichloromethane, 200 mL and 600 mL, respectively. The mixture was kept at 50°C and the reaction was monitored by TLC. 20 mL of hydrochloric acid was added to the reaction solution to dissolve the solid, separate the liquid and take the water layer, extract the water layer with an organic solvent, adjust the pH of the water layer to 8.0, precipitate, filter, wash with clean water, and dry to obtain the compound shown in formula II (16.2 g), with a yield of 71.18% and a purity of 98.94%.

[0035]

[0036] Example 4 Preparation of N-fluorenylmethoxycarbonyl-N,N'-dibenzyloxycarbonyl-L-arginine (Ia)

[0037] In a 100 ml three-necked flask equipped with a magnetic device and a thermometer, N-fluorenylmethoxycarbonyl-L-arginine (II) (1 g, 2.52 mmol), benzyl chloroformate (V) (8.84 mmol), 1-hydroxybenzotriazole (VI) (0.504 mmol), and sodium carbonate (7.57 mmol) were added. The solvent was a mixed solution of tetrahydrofuran and water, 30 mL and 15 mL, respectively. The mixture was kept at 25°C and the reaction was monitored by TLC. The reaction solution was extracted with a citric acid solution, the organic layer was taken, concentrated, and salted with dicyclohexylamine in methyl tert-butyl ether, filtered, and the salted solid was separated with a 10% sulfuric acid solution, and the liquid was extracted with methyl tert-butyl ether, concentrated and dried to obtain 0.42 g of the compound shown in Formula Ia, with a yield of 25.05% and a purity of 98.07%.

[0038] LC-MS (m / z): 665.6 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 )δ9.45(s,1H),7.73(d,J=7.6Hz,2H),7.55(t,J=8.9Hz,2H),7.42–7.18(m,14H),5.92(d,J=8.3Hz,1H),5. 22(s,2H),5.08(s,2H),4.35(d,J=6.9Hz,3H),4.11(t,J=6.9Hz,1H),4.05–3.78(m,2H),2.01–1.50(m,4H).

[0039] Example 5 Preparation of N-fluorenylmethoxycarbonyl-N,N'-dibenzyloxycarbonyl-L-arginine (Ia)

[0040] In a 100 ml three-necked flask equipped with a magnetic device and a thermometer, N-fluorenylmethoxycarbonyl-L-arginine (II) (1 g, 2.52 mmol), benzyl chloroformate (V) (5.04 mmol), 1-hydroxybenzotriazole (VI) (0.504 mmol), potassium carbonate (7.57 mmol) were added, and the solvent was a mixed solution of acetonitrile and water, 30 mL and 10 mL, respectively. The temperature was kept at 45°C, and the reaction was monitored by TLC. The reaction solution was extracted with a citric acid solution, the organic layer was taken, concentrated, and salted with dicyclohexylamine in methyl tert-butyl ether, filtered, and the salt solid was freed with a 10% sulfuric acid solution, and the liquid was extracted with methyl tert-butyl ether, concentrated and dried to obtain 0.51 g of the compound shown in formula Ia, with a yield of 30.42% and a purity of 98.2%.

[0041] Example 6 Preparation of N-fluorenylmethoxycarbonyl-N,N'-dibenzyloxycarbonyl-L-arginine (Ia)

[0042] In a 100 ml three-necked flask equipped with a magnetic device and a thermometer, N-fluorenylmethoxycarbonyl-L-arginine (II) (1 g, 2.52 mmol), benzyl chloroformate (V) (6.31 mmol), 1-hydroxybenzotriazole (VI) (1.26 mmol), and sodium hydroxide (8.83 mmol) were added. The solvent was a mixed solution of tetrahydrofuran and water, 40 mL and 10 mL, respectively. The temperature was kept at 55°C. The reaction was monitored by TLC until the end. The reaction solution was extracted with a citric acid solution, the organic layer was taken, concentrated, and salted with dicyclohexylamine in methyl tert-butyl ether, filtered, and the salt solid was freed with a 10% sulfuric acid solution, and the liquid was extracted with methyl tert-butyl ether, concentrated and dried to obtain 0.53 g of the compound shown in Formula Ia, with a yield of 31.61% and a purity of 98.26%.

[0043] Example 7 Preparation of N-fluorenylmethoxycarbonyl-N,N'-dibenzyloxycarbonyl-L-arginine (Ia)

[0044] In a 100 ml three-necked flask equipped with a magnetic device and a thermometer, N-fluorenylmethoxycarbonyl-L-arginine (II) (1 g, 2.52 mmol), benzyl chloroformate (V) (6.31 mmol), 1-hydroxybenzotriazole (VI) (2.52 mmol), and sodium hydroxide (7.57 mmol) were added. The solvent was a mixed solution of tetrahydrofuran and water, 30 mL and 15 mL, respectively. The mixture was kept at 50°C and the reaction was monitored by TLC. The reaction solution was extracted with a citric acid solution, the organic layer was taken, concentrated, and salted with dicyclohexylamine in methyl tert-butyl ether, filtered, and the salted solid was separated with a 10% sulfuric acid solution, and the separated liquid was extracted with methyl tert-butyl ether, concentrated and dried to obtain 0.64 g of the compound shown in Formula Ia, with a yield of 38.17% and a purity of 99.33%.

[0045] Example 8 Preparation of N-fluorenylmethoxycarbonyl-N,N'-dibenzyloxycarbonyl-L-arginine (Ia)

[0046] In a 100 ml three-necked flask equipped with a magnetic device and a thermometer, N-fluorenylmethoxycarbonyl-L-arginine (II) (1 g, 2.52 mmol), benzyl chloroformate (V) (6.31 mmol), 1-hydroxybenzotriazole (VI) (1.26 mmol), and sodium hydroxide (7.57 mmol) were added. The solvent was a mixed solution of tetrahydrofuran and water, 30 mL and 15 mL, respectively. The temperature was kept at 55°C. The reaction was monitored by TLC until the end. The reaction solution was extracted with a citric acid solution, the organic layer was taken, concentrated, and salted with dicyclohexylamine in methyl tert-butyl ether, filtered, and the salt solid was freed with a 10% sulfuric acid solution, and the liquid was extracted with methyl tert-butyl ether, concentrated and dried to obtain 0.70 g of the compound shown in Formula Ia, with a yield of 41.7% and a purity of 99.27%.

[0047] Example 9 Preparation of N-fluorenylmethoxycarbonyl-N,N'-dibenzyloxycarbonyl-L-arginine (Ia)

[0048] In a 100 ml three-necked flask equipped with a magnetic device and a thermometer, N-fluorenylmethoxycarbonyl-L-arginine (II) (1 g, 2.52 mmol), benzyl chloroformate (V) (6.81 mmol), 1-hydroxybenzotriazole (VI) (2.52 mmol), and sodium hydroxide (7.57 mmol) were added. The solvent was a mixed solution of tetrahydrofuran and water, 25 mL and 15 mL, respectively. The mixture was kept at 45°C and the reaction was monitored by TLC. The reaction solution was extracted with a citric acid solution, the organic layer was concentrated, and salted with dicyclohexylamine in methyl tert-butyl ether, filtered, and the salted solid was freed with a 10% sulfuric acid solution, and the liquid was extracted with methyl tert-butyl ether, concentrated and dried to obtain 0.57 g of the compound shown in Formula Ia, with a yield of 34.00% and a purity of 98.42%.

[0049] Example 10 Preparation of N-fluorenylmethoxycarbonyl-N,N'-dibenzyloxycarbonyl-L-arginine (Ia)

[0050] In a 100 ml three-necked flask equipped with a magnetic device and a thermometer, N-fluorenylmethoxycarbonyl-L-arginine (II) (1 g, 2.52 mmol), benzyl chloroformate (V) (7.57 mmol), 1-hydroxybenzotriazole (VI) (2.52 mmol), and sodium carbonate (10.09 mmol) were added. The solvent was a mixed solution of tetrahydrofuran and water, 30 mL and 15 mL, respectively. The temperature was kept at 55°C. The reaction was monitored by TLC until completion. The reaction solution was extracted with a citric acid solution, the organic layer was taken, concentrated, and salted with dicyclohexylamine in methyl tert-butyl ether, filtered, and the salted solid was freed with a 10% sulfuric acid solution, and the liquid was extracted with methyl tert-butyl ether, concentrated and dried to obtain 0.44 g of the compound shown in Formula Ia, with a yield of 26.24% and a purity of 97.39%.

[0051]

[0052] Example 11 Preparation of N-fluorenylmethoxycarbonyl-N,N'-di-tert-butyloxycarbonyl-L-arginine (Ib)

[0053] In a 100 ml three-necked flask equipped with a magnetic device and a thermometer, N-fluorenylmethoxycarbonyl-L-arginine (II) (1 g, 2.52 mmol), di-tert-butyl dicarbonate (VII) (8.84 mmol), 1-hydroxybenzotriazole (VI) (0.504 mmol), and sodium carbonate (7.57 mmol) were added. The solvent was a mixed solution of tetrahydrofuran and water, 30 mL and 15 mL, respectively. The mixture was kept at 25°C and the reaction was monitored by TLC. The reaction solution was extracted with a citric acid solution, the organic layer was taken, concentrated, and salted with dicyclohexylamine in methyl tert-butyl ether, filtered, and the salted solid was separated with a 10% sulfuric acid solution, and the separated liquid was extracted with methyl tert-butyl ether, concentrated and dried to obtain 0.27 g of the compound shown in Formula Ib, with a yield of 17.94% and a purity of 98.32%.

[0054] LC-MS (m / z): 597.7 [M+H] + ; 1 H NMR (400MHz, CDC l3 )δ8.49(s,1H),7.75(d,J=7.5Hz,2H),7.61(t,J=7.3Hz,2H),7.39(t,J=7.5Hz,2H),7.30(d,J=1.2Hz,2H),5.82(d,J=8.2Hz,1H ),4.88(s,1H),4.40(d,J=7.7Hz,2H),4.22(t,J=6.9Hz,1H),3.41(d,J=23.4Hz,2H),1.96–1.70(m,4H),1.48(d,J=6.7Hz,18H).

[0055] Example 12 Preparation of N-fluorenylmethoxycarbonyl-N,N'-di-tert-butyloxycarbonyl-L-arginine (Ib)

[0056] In a 100 ml three-necked flask equipped with a magnetic device and a thermometer, N-fluorenylmethoxycarbonyl-L-arginine (II) (1 g, 2.52 mmol), di-tert-butyl dicarbonate (VII) (5.55 mmol), 1-hydroxybenzotriazole (VI) (0.504 mmol), and sodium hydroxide (7.57 mmol) were added. The solvent was a mixed solution of tetrahydrofuran and water, 40 mL and 15 mL, respectively. The mixture was kept at 35°C and the reaction was monitored by TLC. The reaction solution was extracted with a citric acid solution, the organic layer was taken, concentrated, and salted with dicyclohexylamine in methyl tert-butyl ether, filtered, and the salted solid was separated with a 10% sulfuric acid solution, and the separated liquid was extracted with methyl tert-butyl ether, concentrated and dried to obtain 0.33 g of the compound shown in Formula Ib, with a yield of 21.94% and a purity of 98.40%.

[0057] Example 13 Preparation of N-fluorenylmethoxycarbonyl-N,N'-di-tert-butyloxycarbonyl-L-arginine (Ib)

[0058] In a 100 ml three-necked flask equipped with a magnetic device and a thermometer, N-fluorenylmethoxycarbonyl-L-arginine (II) (1 g, 2.52 mmol), di-tert-butyl dicarbonate (VII) (6.31 mmol), 1-hydroxybenzotriazole (VI) (1.26 mmol), sodium carbonate (7.57 mmol) were added, and the solvent was a mixed solution of tetrahydrofuran and water, 35 mL and 10 mL, respectively. The mixture was kept at 45°C and the reaction was monitored by TLC. The reaction solution was extracted with a citric acid solution, the organic layer was taken, concentrated, salted with dicyclohexylamine in methyl tert-butyl ether, filtered, freed with a 10% sulfuric acid solution, the salt solid was extracted with methyl tert-butyl ether, concentrated and dried to obtain 0.41 g of the compound shown in Formula Ib, with a yield of 27.24% and a purity of 98.18%.

[0059] Example 14 Preparation of N-Fluorenylmethoxycarbonyl-N,N'-di-tert-butyloxycarbonyl-L-arginine (Ib)

[0060] In a 100 ml three-necked flask equipped with a magnetic device and a thermometer, N-fluorenylmethoxycarbonyl-L-arginine (II) (1 g, 2.52 mmol), di-tert-butyl dicarbonate (VII) (6.31 mmol), 1-hydroxybenzotriazole (VI) (2.52 mmol), and sodium hydroxide (8.83 mmol) were added. The solvent was a mixed solution of tetrahydrofuran and water, 30 mL and 15 mL, respectively. The mixture was kept at 45°C and the reaction was monitored by TLC. The reaction solution was extracted with citric acid solution, the organic layer was taken, concentrated, and salted with dicyclohexylamine in methyl tert-butyl ether, filtered, and the salted solid was separated with 10% sulfuric acid solution, and the separated liquid was extracted with methyl tert-butyl ether, concentrated and dried to obtain 0.4 g of the compound shown in formula Ib, with a yield of 26.58% and a purity of 98.59%.

[0061] Example 15 Preparation of N-fluorenylmethoxycarbonyl-N,N'-di-tert-butyloxycarbonyl-L-arginine (Ib)

[0062] In a 100 ml three-necked flask equipped with a magnetic device and a thermometer, N-fluorenylmethoxycarbonyl-L-arginine (II) (1 g, 2.52 mmol), di-tert-butyl dicarbonate (VII) (7.57 mmol), 1-hydroxybenzotriazole (VI) (1.26 mmol), and sodium carbonate (10.09 mmol) were added. The solvent was a mixed solution of tetrahydrofuran and water, 30 mL and 15 mL, respectively. The mixture was kept at 50°C and the reaction was monitored by TLC. The reaction solution was extracted with a citric acid solution, the organic layer was taken, concentrated, and salted with dicyclohexylamine in methyl tert-butyl ether, filtered, and the salted solid was separated with a 10% sulfuric acid solution, and the separated liquid was extracted with methyl tert-butyl ether, concentrated and dried to obtain 0.49 g of the compound shown in Formula Ib, with a yield of 32.56% and a purity of 99.05%.

[0063] Example 16 Preparation of N-Fluorenylmethoxycarbonyl-N,N'-di-tert-butyloxycarbonyl-L-arginine (Ib)

[0064] In a 100 ml three-necked flask equipped with a magnetic device and a thermometer, N-fluorenylmethoxycarbonyl-L-arginine (II) (1 g, 2.52 mmol), di-tert-butyl dicarbonate (VII) (7.57 mmol), 1-hydroxybenzotriazole (VI) (2.52 mmol), and sodium hydroxide (7.57 mmol) were added. The solution was a mixture of tetrahydrofuran and water, 25 mL and 15 mL, respectively. The mixture was kept at 55°C and the reaction was monitored by TLC. The reaction solution was extracted with a citric acid solution, the organic layer was taken, concentrated, and salted with dicyclohexylamine in methyl tert-butyl ether, filtered, and the salted solid was separated with a 10% sulfuric acid solution, and the liquid was extracted with methyl tert-butyl ether, concentrated and dried to obtain 0.35 g of the compound shown in Formula Ib, with a yield of 23.25% and a purity of 98.70%.

[0065] Finally, it should be noted that the above implementation is only used to illustrate the technical solution of the present invention rather than to limit the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the invention can be modified or replaced by equivalents without departing from the spirit and scope of the technical solution of the present invention, which should all be covered by the scope of the claims of the present invention.

Claims

1. A method for synthesizing an arginine derivative containing a Cbz / Boc protecting group, characterized in that: The steps include: 1) L-arginine as shown in formula (IV) and Fmoc-Osu as shown in formula (III) are used as raw materials, and they are added to solvent A to undergo amidation reaction under alkaline conditions. After the reaction is completed, hydrochloric acid is added to the reaction solution to dissolve the solid, separate the liquids, extract, adjust the pH value, filter, wash, and dry to obtain N-fluorenylmethoxycarbonyl-L-arginine as shown in formula (II); 2) Adding N-fluorenylmethoxycarbonyl-L-arginine, 1-hydroxybenzotriazole, benzyl chloroformate or Boc anhydride as shown in formula (II) to solvent B, and carrying out acylation reaction under alkaline conditions. After the reaction is completed, the reaction solution is extracted, concentrated, salted, filtered, freed, separated, concentrated and dried to obtain N-fluorenylmethoxycarbonyl-N,N'-dibenzyloxycarbonyl-L-arginine as shown in formula (Ia) or N-fluorenylmethoxycarbonyl-N',N"-di-tert-butyloxycarbonyl-L-arginine as shown in formula (Ib). The reaction process is as follows:

2. A method for synthesizing an arginine derivative containing a Cbz / Boc protecting group according to claim 1, characterized in that: The solvent A described in step 1) is a mixture of an organic solvent and water, the volume ratio of the organic solvent to water is 1 to 3:1, the organic solvent is ethyl acetate, dichloromethane, acetone, tetrahydrofuran or acetonitrile; the base is sodium carbonate, potassium carbonate or sodium hydroxide; The reaction temperature is 10-50°C.

3. A method for synthesizing an arginine derivative containing a Cbz / Boc protecting group according to claim 1, characterized in that: In step 1), the molar ratio of the compound represented by formula (IV), the compound represented by formula (III) and the base is 1:0.9-1.5:1-5.

4. A method for synthesizing an arginine derivative containing a Cbz / Boc protecting group according to claim 1, characterized in that: In step 1), the pH adjustment range during the pH separation process is 5.0 to 8.

0.

5. A method for synthesizing an arginine derivative containing a Cbz / Boc protecting group according to claim 1, characterized in that: In step 2), the solvent B is a mixture of an organic solvent and water, the volume ratio of the organic solvent to water is 1 to 4:1, and the organic solvent is tetrahydrofuran or acetonitrile; The base is potassium carbonate, sodium carbonate or sodium hydroxide; the reaction temperature is 25-60°C.

6. A method for synthesizing an arginine derivative containing a Cbz / Boc protecting group according to claim 1, characterized in that: Step 2) The molar ratio of the compound represented by formula (II), benzyl chloroformate or Boc anhydride, 1-hydroxybenzotriazole and base is 1:2-4:0.2-1:2-4.

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