A method for synthesizing goserelin by fragment method
A synthesis method and technology of goserelin, applied in the field of fragment method synthesis of goserelin, can solve problems such as affecting the separation of final products
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Embodiment 1
[0037] Example 1: Synthesis of H-Arg(pbf)-Pro-Azagly-Resin.
[0038] Add 741g of MBHA Resin with a substitution degree of 0.54 mmol / g into the solid-phase reactor, add DCM to swell the resin for 2 hours, remove the DCM, and wash once with DMF. Add 2.5 times the volume of the resin layer of 5% TEA / DMF (v:v) mixed solution to neutralize the resin for 5 minutes, remove the reaction solution, wash twice with DMF, twice with methanol, twice with DMF, ninhydrin method Tested positive.
[0039] Dissolve 648g Rink Amide Linker and 432g HBTU in DMF under ice-bath conditions, add to the resin and react for 5 minutes, add 264mL NMM, and react at room temperature for 2.5 hours. The reaction end point is determined by the ninhydrin method. After the reaction, wash twice with DMF, once with methanol, and twice with DMF.
[0040] Add 2.5 times the volume of the resin layer of DBLK to remove the Fmoc protection, react at room temperature for 30 minutes, wash twice with DMF, wash twice with ...
Embodiment 2
[0045] Example 2: H-Arg-Pro-Azagly-NH 2 preparation.
[0046] Prepare 10L of lysis reagent, including 9.5L of TFA, 0.25L of water, and 0.25L of triisopropylsilane, and pre-cool in a -20°C refrigerator for more than 30 minutes. Weigh 1000 g of the peptide resin obtained by the method described in Example 1, slowly add the resin to 10 L of cleavage reagent under stirring condition, and react at room temperature for 3 hours. Filter the resin, collect the filtrate, slowly add the filtrate to 100L cold ether for precipitation, centrifuge, wash with cold ether for 3 times, and dry under reduced pressure to obtain the crude peptide H-Arg-Pro-Azagly-NH 2 178g.
Embodiment 3
[0047] Example 3: H-Arg-Pro-Azagly-NH 2 preparation.
[0048] 12.6 g Fmoc-Pro-OH was dissolved in 100 mL DMF solvent, and 8.6 g EDC·HCl, 6.0 g HOBt, and 12.46 mL NMM were added under ice-water bath conditions. After the weight is completely dissolved, slowly add 5.0 g H-Azagly-NH 2 · HCl, the reaction mixture continued to react at 25°C. The progress of the reaction was monitored by TLC on a thin-layer chromatography plate. After the reaction was complete, it was neutralized with 600 mL of 5% phosphoric acid aqueous solution. The aqueous phase was extracted with 400 mL of DCM, and the DCM organic phase was then washed with 200 mL of water and 200 mL of saturated brine, and dried over anhydrous sodium sulfate after washing. Filtration, decompression rotary evaporation to remove DCM to obtain a solid, the resulting solid was vacuum-dried, weighing 20.0g Fmoc-Pro-Azagly-NH 2 Crude product, purity 66%.
[0049] To 20.0g Fmoc-Pro-Azagly-NH 2 Add 150 mL of 20% PiP / DMF to the cr...
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