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A method of preparing teriparatide

A technology for preparing teriparatide and its preparation process, which is applied in the field of preparation of polypeptide drugs, and can solve problems such as high cost, unsuitability for large-scale production, and high content of teriparatide

Inactive Publication Date: 2016-08-24
ADLAI NORTYE BIOPHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] The present inventor prepared teriparatide by using the existing synthetic method, and found that the technical problems in the prior art are: the synthetic purity is low, the cost is high, especially the impurity Met 8 (O)-Teriparatide content is relatively large, not suitable for large-scale production

Method used

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  • A method of preparing teriparatide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0101] Embodiment one: the synthesis of Fmoc-Phe-Wang resin

[0102] Weigh 5.00 g of Wang resin (4 mmol) with a substitution degree of 0.80 mmol / g, add it to a solid-phase reaction column, wash it once with DMF, swell the resin with DCM for 30 minutes, and drain it for later use. Weigh 7.7g Fmoc-Phe-OH (20mmol), add 2.02g HOBt (15mmol) into the beaker, dissolve with DMF 50mL, add 3.0mL DIC (20mmol) at room temperature, stir and react for 30min, add this reaction solution to the above swelling The reaction is carried out in the resin after. After reacting at room temperature for 24 hours, filter with suction and wash with DMF 6 times, then add DMF to wash 6 times, then add 1.95mL Ac 2 O (20mmol), 3.2mL DIEA (20mmol), react for 1 hour. Drained, washed 6 times with DMF, washed 3 times with DCM, washed 3 times with MeOH, washed 3 times with DCM, washed 3 times with MeOH, and obtained 6.05 g of Fmoc-Phe-Wang resin after drying. The degree of substitution after detection was 0.45...

Embodiment 2

[0103] Embodiment two: the synthesis of Fmoc-Phe-2-CTC resin

[0104] Weigh 5.00 g of 2-CTC resin (4.7 mmol) with a substitution degree of 0.940 mmol / g and add it to a solid-phase reaction column for later use. Another 1.82g Fmoc-Phe-OH (4.7mmol) was weighed, dissolved in 50mL of dried DCM, then 0.62mLDIEA (0.83mmol) was added, stirred for 5min, and then added to the resin for reaction. 1.24 mL DIEA (1.65 mmol) was added to the reaction system, and the reaction was continued for 40 min. Then add 4 mL of anhydrous methanol and react for 10 min. Drained, washed 3 times with DMF, 3 times with DCM, 3 times with MeOH, 3 times with DCM, 3 times with MeOH, and dried to obtain 6.0 g of Fmoc-Phe-2-CTC resin. The degree of substitution is 0.48mmol / g / .

Embodiment 3

[0105] Embodiment three: the preparation of teriparatide Wang resin

[0106] Weigh 2.22 g of Fmoc-Phe-Wang resin (1 mmol) with a substitution degree of 0.45 mmol / g, add it to a solid-phase reaction column, wash it once with DMF, and swell it with DCM for 30 minutes, using a volume ratio of 1:4 The deprotection solution composed of piperidine and DMF was reacted for 5 minutes, washed once with DMF, reacted for 10 minutes with the deprotection solution composed of piperidine and DMF with a volume ratio of 1:4, washed 6 times with DMF, and weighed 1.79 g Fmoc -Asn(Trt)-OH (3 mmol), 0.41 g HOBt (3 mmol) were added to the mixed solution of DCM and DMF with a volume ratio of 1:1, and 0.48 ml DIC (3 mmol) was added under ice-water bath for activation, then added to the above-mentioned In the reaction column with resin, react at room temperature for 2 hours, use the ninhydrin method to detect and judge the reaction end point, if the resin is colorless and transparent, it means that th...

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Abstract

The present invention relates to a method for preparing teriparatide. The specific steps of the present invention are: A) in the presence of an activator system, coupling the resin solid phase carrier and Fmoc-Phe-OH to obtain Fmoc-Phe-resin; B ) Through the solid-phase synthesis method, amino acids with N-terminal Fmoc protection and side chain protection are sequentially coupled according to the peptide sequence of the teriparatide main chain. The amino acid at position 16-17 of the peptide sequence is a pseudo-proline dipeptide Fmoc-Asn ( Trt)-Ser(ψMe,Me Pro)-OH replaces the original two amino acids at 16-17 positions for coupling; C) Peptide resin cleavage uses NH-containing 4 I / Me 2 The lysate of the TFA system of S, the crude product was purified by HPLC and freeze-dried to obtain teriparatide, whose process impurity Met 8 (O)‑Teriparatide content is less than 0.1%. The invention provides a teriparatide preparation process with high purity, low cost and suitable for large-scale production. This process can effectively control Met 8 (O)-Teriparatide content does not affect the overall yield of teriparatide.

Description

technical field [0001] The invention relates to a preparation method of polypeptide medicine, which is a preparation method of teriparatide, a medicine used for osteoporosis treatment, which can regulate calcium and phosphorus metabolism and promote bone formation. Background technique [0002] Teriparatide, British name: Teriparatide, is a straight chain 34 peptide, the structural formula is as follows: [0003] [0004] The peptide sequence is: [0005] 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 [0006] Teriparatide Forteo (Teriparatide) is the first new bone-forming agent drug approved by the US Food and Drug Administration for the treatment of primary osteoporosis, hypogonadal osteoporosis, and postmenopausal osteoporosis . Teriparatide [hPTH(1-34)] is a synthetic polypeptide hormone, which is a 1-34 amino acid fragment of human parathyroid hormone PTH, which is an ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/635C07K1/06C07K1/04
CPCY02P20/55
Inventor 陈晓航路杨杨东晖周亮
Owner ADLAI NORTYE BIOPHARMA CO LTD
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