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A technology for solid-phase synthesis of teriparatide, applied in the field of solid-phase synthesis of teriparatide
Inactive Publication Date: 2015-04-22
哈尔滨吉象隆生物技术有限公司
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[0010]
The existing synthesis method of teriparatide has the disadvantages of cumbersome operation, a lot of waste liquid, which is not conducive to environmental protection, and requires a large amount of acetonitrile and cutting reagents, resulting in high cost and disadvantages for large-scale production
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Embodiment 1
[0250] Preparation of Fmoc-Phe-Wang Resin with Substitution Degree of 0.167mmol / g
[0251] Weigh 50g of Wang resin with a degree of substitution of 1.08mmol / g, add it to a solid phase reaction column, and after swelling the resin with DMF for 30 minutes, weigh 8.36g of Fmoc-Phe-OH, 2.9g of HOBT and 0.23g of DMAP in a beaker, and dissolve them in DMF , add 4.0mL DIC to activate for 5min, add to the above reaction column with resin, react for 2h, wash with DMF twice, shrink and dry with methanol to obtain Fmoc-Phe-Wang resin, the substitution degree of Wang-F amino acid resin is 0.167 mmol / g.
Embodiment 2
[0253] Synthesis of Fmoc-Phe-Wang resin with a substitution degree of 0.323mmol / g.
[0254] Weigh 10g of Wang resin with a substitution degree of 0.56mmol / g and add it to a solid-phase reaction column. After swelling the resin with DMF for 30 minutes, dissolve 13.56g of Fmoc-Phe-OH and 4.72g of HOBT with DMF, add 5.42mL of DIC for activation, and add the above In the reaction column equipped with resin, react for 4 hours, wash with DMF twice, shrink and dry with methanol to obtain Fmoc-Phe-Wang resin, and the detection substitution degree is 0.323mmol / g.
Embodiment 3
[0256] Synthesis of Fmoc-Phe-Wang resin with a substitution degree of 0.372mmol / g.
[0257] Weigh 10g of Wang resin with a substitution degree of 1.08mmol / g, add it to the solid-phase reaction column, swell the resin with DMF for 30 minutes, weigh 2.926gFmoc-Phe-OH, 1.015gHOBT and 0.080gDMAP in the beaker, dissolve in DMF, add 1.4 mLDIC was activated for 5 minutes, added to the above-mentioned reaction column equipped with resin, reacted for 3 hours, washed twice with DMF, and dried with methanol shrinkage to obtain Fmoc-Phe-Wang resin. The detected substitution degree was 0.372 mmol / g. Example 4
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Abstract
The invention provides a solid-phase synthesis method of teriparatide. The method comprises the following steps that Wang resin is used as a resin solid-phase carrier and is coupled with phenylalanine (Fmoc-Phe-OH) protected by N-end Fmoc to obtain Fmoc-Phe-resin; HOBT / DIC or HBTU / DIEA or TBTU / DIEA serves as a condensating agent, and through the solid-phase synthesis method, amino acid which has the N-end Fmoc protection and side chain protection is sequentially coupled according to a main chain peptide sequence of the teriparatide to obtain teriparatide resin; the teriparatide resin is split, a protecting group and the resin are removed, absolute ether is added into resin for precipitation, and crude teriparatide is obtained; c cartridges are adopted for separation and purification, lyophilization is carried out, and the teriparatide is obtained.
Description
Technical field [0001] The present invention relates to polypeptide synthesis and cleavage methods, and in particular to a solid-phase synthesis method of teriparatide. Background technique: [0002] Teriparatide, the English name is Teriparatide, and its peptide sequence is: [0003] H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-Ser-Met-Glu-Arg-Val-Glu-Trp-Leu- Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe-OH, trade name Forteo, was developed by Eli Lilly and Company and was first launched in the United States in December 2002. The existing technology has high production costs and is not conducive to the large-scale production of teriparatide. The relevant documents are as follows: [0004] Method 1: CN102731643A reports the fragment connection method and corresponding cleavage method of teriparatide. Each peptide resin fragment is gradually coupled to teriparatide resin on 0.8 mmol / g Wang resin, and then cleaved to obtain crude teriparatide. , purified to ...
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