Preparation method of Bivalirudin
一种比法卢定、肽树脂的技术，应用在多肽固相合成领域，能够解决操作繁琐、杂质多等问题
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[0046] In an example of the present invention, the preparation method of polypeptide solid-phase synthesis bivalirudin of the present invention comprises the following steps:
[0047] In the first step, Fmoc-leucine (Fmoc-Leu) is bonded to the resin to obtain a resin that is connected to leucine; resins well known in the art can be used, preferably Wang resin, more preferably the substitution ratio of Wang resin 0.6-1.4mmol / g;
[0048] In the second step, the deprotecting agent of the present invention is mixed with the resin connected with leucine to remove the Fmoc group;
[0049] The third step is to condense Fmoc-Tyr(tBu)-OH and Leu on the resin to form a peptide bond to obtain Fmoc-Tyr(tBu)-Leu-resin;
[0050] The fourth step, using the deprotecting agent of the present invention to remove the Fmoc group;
[0051] In the fifth step, repeat the above peptide bond formation steps to make the peptide chain grow from the C-terminus to the N-terminus until Fmoc-Asp(OtBu) is ...
Embodiment 1
[0078] Preparation of Bifaludine 1
[0079] 1. Synthesis of Fmoc-Gly-Gly-Gly-Gly-Gly-OH fragments by liquid phase method
[0080] The reaction formula is:
[0081]
[0082] 1. Synthesis of Z-Gly-Gly-OMe
[0083] Z-Gly-OH (104.55 g) and H-Gly-OMe.HCl (69.05 g) were dissolved in DMF (600 mL), and the solution was cooled to an inner temperature of 0°C. HOBt (74.32g) and EDC.HCl (105.44g) were added to the solution, and NMM was added to adjust the pH value of the reaction solution to 8. After NMM was added, the cooling bath was removed, and the reaction was carried out at room temperature. Monitor the reaction with TLC, after the reaction is complete, the reaction solution is diluted with EtOAc (600ml), washed with 5% H3PO4 (600ml), the aqueous phase is extracted with EtOAc (300ml), and the organic phases are combined, followed by 5% H3PO4, washed with saturated brine Once, washed three times with saturated NaHCO3, and once with saturated brine. It was dried over anhydrous ...
Embodiment 2
[0113] Preparation of Bifaludin 2
[0114] 1. Synthesis of Fmoc-Gly-Gly-Gly-Gly-Gly-OH fragments by liquid phase method
[0115] The reaction formula is:
[0116]
[0117] 1. Synthesis of Z-Gly-Gly-OMe
[0118] Z-Gly-OH (104.55 g) and H-Gly-OMe.HCl (69.05 g) were dissolved in DMF (600 mL), and the solution was cooled to an inner temperature of 0°C. HOBt (74.32g) and EDC.HCl (105.44g) were added to the solution, and NMM was added to adjust the pH value of the reaction solution to 8. After NMM was added, the cooling bath was removed, and the reaction was carried out at room temperature. Monitor the reaction with TLC. After the reaction is complete, the reaction solution is diluted with EtOAc (600ml), washed with 5% H3PO4 (600ml), the aqueous phase is extracted with EA (300ml), and the combined organic phases are washed with 5% H3PO4 and saturated brine successively. Once, washed three times with saturated NaHCO3, and once with saturated brine. It was dried over anhydrous ...
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