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A technology of linaclotide and crude peptide, applied in the field of synthesizing linaclotide
Active Publication Date: 2015-08-19
CHENGDU SHENGNUO BIOTEC CO LTD
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[0008] Compared with CN103626849A patent, the other three are lower in total yield, but comprehensively considering the process time and cumbersome degree, the latter three existing technologies are undoubtedly be...
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Embodiment 1
[0051] Example 1: Synthesis of Fmoc-Tyr(tBu)-2-Cl Trt-resin
[0052] Take 500 g of 2-Cl Trt-Cl resin with a substitution value of 0.6 mmol / g, and add DMF to swell the resin. Take 0.6mol Fmoc-Tyr(tBu)-OH, dissolve it with an appropriate amount of DMF, add it to the above resin, stir well, then add 1.2mol DIPEA, stir for 3 hours, remove the reaction solution, wash with DMF for 3 times, then wash with DCM 3 times to obtain Fmoc-Tyr(tBu)-2-Cl Trt-resin with a substitution value of 0.45 mmol / g.
Embodiment 2
[0053] Embodiment 2: the synthesis of Fmoc-Tyr (tBu)-Wang resin
[0054] Take 500 g of Wang resin with a substitution value of 0.5 mmol / g, and add DMF to swell the resin. Take 0.5mol Fmoc-Tyr(tBu)-OH, dissolve it with an appropriate amount of DMF, add it to the above resin, stir well, then add 1.0mol DIC, 0.4molHOBt, 0.04mol 4-N,N-lutidine, and stir to react After 6 hours, the reaction solution was removed, washed three times with DMF and three times with DCM to obtain Fmoc-Tyr(tBu)-Wang resin with a substitution value of 0.39 mmol / g.
Embodiment 3
[0055] Embodiment 3: Preparation of linaclotide resin
[0056] Take 0.1mol of the Fmoc-Tyr(tBu)-2-Cl Trt-resin of Example 1 (substitution value 0.45mmol / g), deprotect it with 20% PIP / DMF solution for 25 minutes, wash and filter to obtain the H- Tyr(tBu)-2-Cl Trt-resin.
[0057] Take 0.3mol Fmoc-Cys(Trt)-OH and 0.3mol HOBt, and dissolve them with an appropriate amount of DMF; take another 0.3mol DIC, add slowly under stirring, continue stirring for 30 minutes, and add to the above H-Tyr(tBu)-2 -Cl Trt-resin, coupling reaction 120 ~ 300 minutes, the reaction end point is determined by the ninhydrin method, wash and filter, then deprotect with 20% PIP / DMF solution for 25 minutes, wash and filter to get H-Cys ( Trt)-Tyr(tBu)-2-Cl Trt-resin.
[0058] In the same way as above, the remaining protected amino acids in Table 3 were sequentially inserted to obtain the linaclotide peptide resin:
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Abstract
The invention relates to the field of medicinal synthesis and discloses a method for synthesizing linaclotide. The method comprises the following steps: synthesizing a linaclotide resin coupled with protecting groups on side chains Thr, Cys, Asn, Tyr and Glu of an amino acid sequence shown as SEQ ID NO:1 and coupled with a resin carrier at the terminal C; performing acid hydrolysis to remove the protecting groups and resin carrier, obtaining a linaclotide linear crude peptide, cyclizing the linear crude peptide by adopting a cysteine/DMSO buffer solution, obtaining a crude linaclotide product, purifying and converting the crude product into acetate, thereby obtaining the finished product. According to the method disclosed by the invention, starting from a cyclizing system, the linaclotide synthesis method is improved, the total yield of linaclotide is improved by a stage by virtue of simple and rapid process steps, and the purity can reach a high level. Meanwhile, the later-stage cyclizing time is greatly shortened, and compared with the prior art, the method has high practical value and application prospects.
Description
technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a method for synthesizing linaclotide. Background technique [0002] Linaclotide (linaclotide), a new product developed by AstraZeneca, is the first guanylate cyclase agonist (GCCA) drug and was approved by the US Food and Drug Administration in August 2012. It binds to guanylate cyclase C located in the intestine, and the concentration of linaclotide in plasma is basically undetectable, but it can increase the concentration of intracellular and extracellular cyclic guanosine monophosphate (cGMP). It is generally believed that the increase of intracellular cGMP concentration can stimulate the secretion of intestinal juice and promote gastrointestinal motility, thereby leading to an increase in the frequency of defecation, and is used for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) and chronic idiopathic constipation (CIC). The structural seq...
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