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Solid-phase method of Abaloparatide

A synthetic method, the technology of abaloparatide, applied in the field of solid phase synthesis technology to realize the synthesis process of abaloparatide, can solve the problems of many impurities, excessive waste liquid, cumbersome operation steps, etc.

Pending Publication Date: 2020-05-01
NANJING HUAWE MEDICINE TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The technical problem to be solved by the present invention is to provide a kind of Abapa Peptide Synthesis Method

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Example 1: Synthesis of Fragment [1-9] Peptide Resin

[0061]Add Rink-Amide-MBHA Resin (15.00g, 4.25mmol) and 200mL DCM in turn to the solid-phase reaction bottle, and suction filter after swelling. The filter cake was mixed with 300mL of 20% Pip / DMF solution, stirred for 5 minutes, and suction filtered to obtain the filter cake; then 300mL of 20% Pip / DMF solution was added, stirred for 15 minutes, and the filter cake was obtained by suction filtration. Wash with an appropriate amount of DMF, and filter with suction to obtain a filter cake. Add 300mL DMF to Pip / DMF and stir, then add Fmoc-Ala-OH (4.20g), HOBT (1.82g) and DIC (1.70g) sequentially within 30min under ice bath. Stir for about 2 h under nitrogen protection until the reaction is detected by ninhydrin. Wash with an appropriate amount of DMF and drain. Repeat the above deprotection and coupling reaction steps, and connect the amino acids Fmoc-Thr(tBu)-OH, Fmoc-His(Trt)-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Fmoc...

Embodiment 2

[0063] Embodiment two: the synthesis of fragment one

[0064] Add 2-CTC Resin (25.00g) and 400mL DCM to the solid-phase reaction flask in sequence, and suction filter after swelling. Add Fmoc-Glu(OtBu)-OH (8.51g) and 100mL DCM, add DIEA (about 9.53g) dropwise, stir for 2 hours with nitrogen bubbling, then add MeOH (25mL), stir for 30min and filter with suction, filter cake through DMF, DCM was alternately washed and dried in vacuo.

[0065] The above-mentioned materials and 200mL DCM were sequentially added into the solid-phase reaction bottle, and suction filtered after swelling. The filter cake was mixed with 100mL of 20% Pip / DMF solution, stirred for 5 minutes, and suction filtered to obtain the filter cake; then 100mL of 20% Pip / DMF solution was added, stirred for 15 minutes, and suction filtered. The filter cake was washed with an appropriate amount of DMF, and the filter cake was obtained by suction filtration. Pip / DMF. Add 400 mL of DMF, stir, and add Fmoc-Leu-OH (1...

Embodiment 3

[0067] Embodiment three: the synthesis of fragment two

[0068] Add 2-CTC Resin (25.00g) and 400mL DCM into the solid-phase reaction bottle, and suction filter after swelling. Fmoc-Ser(tBu)-OH (6.88g) and 100mL DCM were added, DIEA (about 9.53g) was added dropwise under nitrogen bubbling, stirred for 2h, then MeOH (25mL) was added, stirred for 30min. After filtering, the filter cake was alternately washed three times with MeOH and DCM, and dried under vacuum at room temperature. After testing, the degree of substitution is 0.74mmol / g;

[0069] Add the dry above-mentioned resin and 200mL DCM to the solid-phase reaction bottle, swell, and filter with suction. The filter cake was mixed with 100mL of 20% Pip / DMF solution, stirred for 5 minutes, and suction filtered to obtain the filter cake; then 100mL of 20% Pip / DMF solution was added, stirred for 15 minutes, and suction filtered. The filter cake was washed with an appropriate amount of DMF and drained. Add 400 mL of DMF and ...

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Abstract

The invention provides a solid-phase method of Abaloparatide. The method comprises the steps: synthesizing one-fragment peptide resin and two fragments firstly and separately according to the fact that the peptide sequence of the main chain of Abaloparatide can be divided into one fragment of peptide resin and two fragments which are described in the specification, then coupling the one-fragment peptide resin with the two fragments, cutting the resin so as to obtain the crude product of the final product, finally performing purification, performing salt formation so as to obtain the target product finally, wherein the structures of the fragments and one-fragment resin are described in the specification. The method has simple operation, the purity of the obtained product is high, the process of the method is stable, the purity of the prepared Abaloparatide can reach 99.5% or above, the total yield is high, and the method has easy industrial production.

Description

technical field [0001] The present invention relates to the synthesis technology of polypeptide, especially the synthesis technology of abaloparatide realized by solid phase synthesis technology. Background technique [0002] Parathyroid hormone (PTH) is a polypeptide hormone secreted by parathyroid chief cells that regulates calcium and phosphorus metabolism in the body, and its C-terminal peptide chain binds to the PTH-II receptor to promote bone cell apoptosis, N Binding of telopeptide chains to PTH-I receptors promotes bone remodeling. Abaloparatide, a drug for the treatment of osteoporosis developed by Lilly based on the N-terminal 34 amino acid residues of human parathyroid hormone (hPTH), was approved by the FDA in December 2002. [0003] The structural formula of abaloparatide is as follows: [0004] Ala-Val-Ser-Glu-His-Gln-Leu-Leu-His-Asp-Lys-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg-Arg-Glu-Leu-Leu-Glu- Lys-Leu-Leu-Aib-Lys-Leu-His-Thr-Ala-NH2 [0005] Abaloparatide, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/635C07K1/06C07K1/04
CPCC07K14/635Y02P20/55
Inventor 邹正才张孝清杨凯宋志春包金远
Owner NANJING HUAWE MEDICINE TECH DEV
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