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A method for synthesizing teriparatide
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A technology of teriparatide and peptide resin, which is applied in the field of synthesizing teriparatide, can solve the problems of low total yield, low total yield, high total yield of only 32.2%, and optimize the synthesis process, The effect of improving the total yield
Active Publication Date: 2018-08-17
CHENGDU SHENGNUO BIOTEC CO LTD
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Chinese patent CN102731643A discloses that 2-chlorotrityl chloride resin (2-CTC resin) is used as solid-phase carrier flavor 5 fragments to couple, although this method can shorten the synthesis cycle, its total yield is the highest only 32.2 %
[0008] Based on the above-mentioned existing synthetic schemes of teriparatide, the total yield is not high, the highest is 42.1%, although CN103467595A claims that its total yield is between 30-50%, but according to its examples Detailed records, the highest is only 42.1%
The lower overall yield is the main factor limiting the production efficiency of teriparatide, and it is necessary to improve the existing synthetic scheme to increase its overall yield
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Embodiment 1
[0047] Example 1: Synthesis of Peptide Resin 1
[0048] Add 200 g of HMP Linker Amide resin with a substitution value of 0.65 mmol / g into the solid phase reaction column, add DMF to swell the resin for 30 minutes and then drain it. Take 100.6g Fmoc-Phe-OH and 35.1g HOBt, dissolve them in DMF, add them to the above resin, stir well, then add 35mL DIC and 3.2g DMAP, stir and react at room temperature for 6 hours, remove the reaction liquid, and wash with DMF for 3 times Finally, DCM was washed 3 times, methanol was washed 3 times, and each washing time was 3 min to obtain Fmoc-Phe-HMP LinkerAmide resin with a substitution value of 0.50 mmol / g.
Embodiment 2
[0049] Example 2: Synthesis of Peptide Resin 1
[0050] Add 200 g of HMP Linker BHA resin with a substitution value of 0.6 mmol / g into the solid phase reaction column, add DMF to swell the resin for 30 minutes and then drain it. Take 92.9g Fmoc-Phe-OH and 32.4g HOBt, dissolve them in DMF, add them to the above resin, stir well, then add 32mL DIC and 2.9g DMAP, stir and react at room temperature for 6 hours, remove the reaction solution, and wash with DMF for 3 times Finally, DCM was washed 3 times, methanol was washed 3 times, each washing time was 3min, and Fmoc-Phe-HMP Linker BHA resin was obtained, and the substitution value was 0.46mmol / g.
Embodiment 3
[0051] Example 3: Synthesis of Peptide Resin 1
[0052] Add 200 g of HMP Linker MBHA resin with a substitution value of 0.6 mmol / g into the solid phase reaction column, add DMF to swell the resin for 30 minutes and then drain it. Take 92.9g Fmoc-Phe-OH and 32.4g HOBt, dissolve them in DMF, add them to the above resin, stir well, then add 32mL DIC and 2.9g DMAP, stir and react at room temperature for 6 hours, remove the reaction solution, and wash with DMF for 3 times Finally, DCM was washed 3 times, methanol was washed 3 times, each washing time was 3min, and Fmoc-Phe-HMP LinkerMBHA resin was obtained, and the substitution value was 0.49mmol / g.
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Abstract
The invention relates to the field of medicine synthesis, and discloses a method for synthesizing teriparatide. The method comprises the following steps: performing esterification reaction between Phe coupled with a protecting group at an N end and HMP Linker resin under the action of a coupling reagent and an activating reagent to obtain peptide resin 1; and performing one-by-one extension coupling on the rest protective amino acids under the reaction of a condensation reagent and an activating reagent according to a sequence from a C end to the N end of a teriparatide amino acid sequence to obtain corresponding peptide resin after each extension coupling and finally obtain teriparatide resin, performing acid hydrolysis to obtain a teriparatide crude product, and purifying the teriparatide crude product into acetate so as to obtain a teriparatide pure product. According to the method disclosed by the invention, a suitable synthesis scheme is selected, the HMP Linker resin is used as carrier resin, the whole synthesis process is optimized, a high-purity product is obtained, the total yield of the teriparatide is improved, and the method is harmless to any environment.
Description
technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a method for synthesizing teriparatide. Background technique [0002] Teriparatide is a synthetic 34-peptide, which is a 1-34 amino acid fragment of human parathyroid hormone PTH. The amino acid sequence is as follows: [0003] H-Ser 1 -Val 2 -Ser 3 -Glu 4 -Ile 5 -Gln 6 -Leu 7 -Met 8 -His 9 -Asn 10 -Leu 11 -Gly 12 -Lys 13 -His 14 -Leu 15 -Asn 16 -Ser 17 -Met 18 -Glu 19 -Arg 20 -Val 21 -Glu 22 -Trp 23 -Leu 24 -Arg 25 -Lys 26 -Lys 27 -Leu 28 -Gln 29 -Asp 30 -Val 31 -His 32 -Asn 33 -Phe 34 -OH [0004] This fragment is the biologically active N-terminal region of endogenous parathyroid hormone PTH containing 84 amino acids. The immunological and biological characteristics of this product are exactly the same as endogenous parathyroid hormone PTH and bovine parathyroid hormone PTH (bPTH). [0005] Teriparatide is the first new drug approved ...
Claims
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