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A kind of synthetic method of parathyroid hormone analog

A technology for parathyroid hormone and a synthesis method, which is applied in the field of synthesis of parathyroid hormone analogs, can solve the problems such as the inability to reach a high level of yield and purity, many impurities, and difficulty in purification.

Active Publication Date: 2020-06-12
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in the process of preparing Abaloparatide by one-by-one coupling method, the synthesis cycle is long and there are many impurities (impurities such as default peptides are easily produced in the synthesis of long peptides), and most of the impurities are similar to the target polypeptide, making subsequent purification difficult. , the yield and purity cannot reach a higher level

Method used

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  • A kind of synthetic method of parathyroid hormone analog
  • A kind of synthetic method of parathyroid hormone analog
  • A kind of synthetic method of parathyroid hormone analog

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] Example 1: Preparation of Peptide Resin Fragment 1

[0070] 1. Preparation of Fmoc-Thr(tBu)-Rink amide Resin

[0071] Take the Rink amide Resin resin (20g, 12mmol) with a degree of substitution sub=0.6mmol / g, add it to the reaction column, swell it with DMF for more than 30 minutes, drain the DMF, and use DBLK (a DMF solution containing 20% ​​piperidine) Remove Fmoc, each removal reaction is 5 minutes, two times in total, after the removal is completed, wash with DMF 6 times, drain and wait for feeding. Weigh Fmoc-Thr(tBu)-OH (2.4g, 6mmol), HOBt (0.8g, 6mmol) and dissolve it with DMF (30ml) and DCM (30ml) and add DIC (0.9g, 7.2mmol) under ice bath conditions, After activating for 5 minutes, add it to the reaction column. After 60 minutes, the reaction is over. The resin is washed three times with DMF, and the blocking solution (pyridine (20ml) and acetic anhydride (22ml)) is added. After 2 hours of reaction, it is drained and washed with DMF for 6 times. . Then add a...

Embodiment 2

[0074] Embodiment 2: Preparation of peptide fragment 2

[0075] Take by weighing the 2-CTC resin (40g, 20mmol) that substitution degree is 0.5mmol / g, join in the solid-phase reaction column, wash 2 times with DMF, after 30 minutes with DMF swelling resin, take Fmoc-Leu-OH (21.2 g, 60mmol) was dissolved in a mixed solution of DCM (30ml) and DMF (30ml) with a volume ratio of 1:1, DIPEA (15.5g, 120mmol) was added under ice-bath conditions, and the solution was added to the solid-phase reaction column after activation for 5 minutes , reacted at room temperature for 2 hours, and blocked three times with blocking solution (DIPEA:methanol:DCM=1:2:17v:v) after the reaction, 3 minutes each time. The volume of closed liquid is calculated as 4.0ml / gram of resin. Then add an appropriate amount of methanol to wash 3 times, each time for 10 minutes, and wash 6 times with DMF. Fmoc protection was removed with DBLK, followed by 6 washes with DMF.

[0076] Dissolve Fmoc-Glu(OtBu)-OH (25.5g,...

Embodiment 3

[0078] Embodiment 3: the preparation of peptide fragment 3

[0079] Take by weighing the 2-CTC resin (40g, 20mmol) that substitution degree is 0.5mmol / g, join in the solid-phase reaction column, wash 2 times with DMF, after 30 minutes with DMF swelling resin, take Fmoc-Ile-OH (21.2 g, 60mmol) was dissolved in a mixed solution of DCM (30ml) and DMF (30ml) with a volume ratio of 1:1, DIPEA (15.5g, 120mmol) was added under ice-bath conditions, and the solution was added to the solid-phase reaction column after activation for 5 minutes , reacted at room temperature for 2 hours, and blocked three times with blocking solution (DIPEA:methanol:DCM=1:2:17v:v) after the reaction, 3 minutes each time. The volume of closed liquid is calculated as 4.0ml / gram of resin. Then add an appropriate amount of methanol to wash 3 times, each time for 10 minutes, and wash 6 times with DMF. Fmoc protection was removed with DBLK, followed by 6 washes with DMF.

[0080] Dissolve Fmoc-Ser(tBu)-OH (23....

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Abstract

The invention relates to the field of medicine synthesis and discloses a synthesis method of a parathyroid hormone analogue. In the method, according to the amino acid sequence from a C-terminal to an N-terminal of a peptide chain of a parathyroid hormone analogue Abaloparatide, fragments of 1-15, 16-23 and 24-33 are synthesized, and then the three polypeptide fragments are coupled to obtain the Abaloparatide. The syntheses of the fragments are carried out at the same time, so that the method has short synthesis period and an intermediate is easy to purify. The synthesis method has low cost, high finish product purity and total yield, and has advantages on large-scale production of the Abaloparatide.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a method for synthesizing parathyroid hormone analogues. Background technique [0002] Parathyroid hormone is an important calcium-regulating hormone that maintains the balance of calcium and phosphorus metabolism in the body, and is an important bone formation accelerator. Parathyroid hormone can regulate bone metabolism, directly stimulate osteoblasts and osteoclasts, and has dual functions of promoting bone formation and promoting osteoclast activity. Low doses can promote bone remodeling and increase bone strength, but high doses can cause extensive activation of osteoclasts on the one hand, and inhibit the function of osteoblasts on the other hand, which can lead to bone loss [0003] Parathyroid hormone-related peptide is a parathyroid hormone analog, which is a synthetic polypeptide hormone. At present, synthetic teriparatide (FORTEO) is the only effective bone fo...

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 肖庆聂涛陶安进袁建成
Owner HYBIO PHARMA