Low-cost method for preparing high-purity linaclotide
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A linaclotide and high-purity technology, which is applied in the field of low-cost preparation of high-purity linaclotide, can solve the problems of difficult scale-up production, high cost, complicated process, etc., and achieves low price, improved product yield, and reduced volume. Effect
Inactive Publication Date: 2018-12-21
杭州肽佳生物科技有限公司
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[0008] However, the above-mentioned patents all use special raw materials for synthesis, and use step-by-step oxidation method to oxidize to obtain linaclotide. Not only the process is complicated, the cost is high, but also the scale-up production is not easy.
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Embodiment 1
[0026] Embodiment 1: the synthesis of Fmoc-Tyr (tBu)-CTC resin
[0027] Take 500 g of CTC resin with a substitution degree 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 0.75mol DIPEA, stir for 3 hours, filter the reaction solution, and wash it with DMF for 3 times , and washed 3 times with DCM to obtain Fmoc-Tyr(tBu)-CTC resin. Its substitution value is 0.4 mmol / g.
Embodiment 2
[0028] Embodiment 2: Preparation of linaclotide resin
[0029] Take 0.15 mol of the Fmoc-Tyr(tBu)-CTC resin of Example 1, deprotect it with 20% PIP / DMF solution for 20 minutes, wash and filter to obtain the H-Tyr(tBu)-CTC resin from which Fmoc has been removed.
[0030] Take 0.45mol Fmoc-Cys(Trt)-OH, dissolve it with an appropriate amount of DMF, and add it to the reactor equipped with the above-mentioned H-Tyr(tBu)-CTC resin, and take another 0.45mol HBTU and 0.45mol DIPEA, and add them slowly Into the above-mentioned reactor which is blown with nitrogen. Coupling reaction for 30 to 150 minutes, the end point of the reaction is determined by the ninhydrin method, washed and filtered, then deprotected with 20% PIP / DMF solution for 20 minutes, washed and filtered to obtain H-Cys(Trt)-Tyr(tBu) - CTC resin.
[0031] In the same way as above, the remaining protected amino acids in Table 1 were sequentially inserted to obtain the linaclotide peptide resin:
[0032] H-Cys(Trt)-Cy...
Embodiment 3
[0036] Example 3: Preparation of crude linaclotide linear peptide
[0037] The linaclotide resin obtained in Example 2 was taken, washed after cleavage, and dried under vacuum to constant weight to obtain 201 g of linear linaclotide crude product with a purity of 76%.
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Abstract
The invention discloses a low-cost method for preparing high-purity linaclotide. According to the technical scheme, the low-cost method comprises the following steps: 1) synthesizing linear linaclotide by utilizing resin carriers including CTC resin or Wang resin and the like through a Fmoc method or obtaining the linear linaclotide by utilizing a segment method or a liquid-phase synthesis method;2) obtaining a linaclotide crude product which is accurately matched by adopting a one-step oxidization method; 3) obtaining the high-purity linaclotide through purifying by adopting high performanceliquid chromatography. The method disclosed by the invention is started from the aspects including an oxidization system and the like, and a method for accurately matching a linaclotide disulfide bond is improved; the method is simple and stable in technology and low in cost, and the linaclotide crude product can be obtained through one-step cyclization; the purity of a purified product can be greater than 99 percent and the content of a single impurity can be controlled to be 0.1 percent or lower. Compared with the prior art, the method has better economic benefits and application prospect.
Description
technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a method for preparing high-purity linaclotide at low cost. Background technique [0002] Linaclotide (linaclotide), a new product developed for ironwood, is the first guanylate cyclase agonist (GCCA) drug to date. In August 2012, the US FDA approved linaclotide for the treatment of adults with chronic idiopathic constipation and irritable bowel syndrome with constipation (IBS-C). The concentration of linaclotide in plasma is basically undetectable, but after binding to intestinal GC-C, it can lead to the increase of intracellular and extracellular cyclic guanosine monophosphate (cGMP) concentration. The increase of intracellular cGMP can stimulate the secretion of intestinal juice, accelerate the migration of gastrointestinal tract, thereby increasing the frequency of defecation. This medicine comes in capsule form and is taken by mouth once daily. The compound consist...
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