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Liquid phase synthesis method of itkatide

A synthesis method and itkatide technology, applied in the field of peptide synthesis, can solve problems such as cumbersome steps, and achieve the effects of easy availability of raw materials, convenient operation and easy control of purity

Active Publication Date: 2021-01-22
天津凯诺医药科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] The main purpose of the present invention is to provide a liquid-phase synthesis method of itkatide to solve the problem of complicated steps in the prior art

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  • Liquid phase synthesis method of itkatide
  • Liquid phase synthesis method of itkatide
  • Liquid phase synthesis method of itkatide

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preparation example Construction

[0041] As mentioned in the background art, in the existing solid-phase synthesis method, the disulfide bond of itkatide is easily misconnected, and the purity of the crude product is low, while the existing liquid-phase synthesis method has relatively cumbersome steps. In order to improve this situation, in a typical embodiment of the present application, a liquid-phase synthesis method of itkatide is provided, the synthesis method comprising:

[0042] S101, using Cbz as a protecting group to sequentially synthesize the sequence of formula (I) in liquid phase,

[0043] Ac- D -Cys(K)- D -Ala- D -Arg(Pbf)- D -Arg(Pbf)- D -Arg(Pbf)- D -Ala- D -Arg(Pbf)-NH 2 (I);

[0044] S102, removing Ac- in the sequence of formula (I) D -The side chain protecting group K of Cys(K) obtains the sequence of formula (II),

[0045] Ac- D -Cys- D -Ala- D -Arg(Pbf)- D -Arg(Pbf)- D -Arg(Pbf)- D -Ala- D -Arg(Pbf)-NH 2 (II);

[0046] S103, by Boc- L -Cys(S-S-Py)-OtBu in formula (II) s...

Embodiment 1

[0091] Example 1: Cbz- D -Arg(Pbf)-NH 2 Synthesis

[0092] Cbz- D -Arg(Pbf)-OH (56.5g, 0.1mmol) was dissolved in DMAc (1.2L, 20V), Oxymapure (17.2g, 1.2eq); EDCI (23.2g, 1.2eq), DIPEA (19.4g, 1.5 eq), after the reaction solution was stirred for 30 minutes, ammonium acetate (38.5g, 5.0eq) was added, and the reaction was stirred at 26 degrees for 7.5h; HPLC monitored the reaction end point; after the reaction, the reaction solution was added dropwise with water (6.0L, 100 vol. ), stirring and crystallizing at 0-10°C for 2 hours; filtering, drying the filter cake and collecting 52.5g of material, with a purity of 99.5% and a yield of 93%.

[0093] The condensation steps are operated in the same way, and only the amino acid protecting group of the amino acid raw material is changed to Boc or Fmoc protected amino acid; the yield and purity comparison of the obtained products are shown in the following table:

[0094] Table 2:

[0095]

Embodiment 2

[0096] Example 2: Cbz- D -Ala- D -Arg(Pbf)-NH 2 Synthesis

[0097] Under nitrogen protection, Cbz- D -Arg(Pbf)-NH 2 (52.5g, 1.0eq) was dissolved in DMAc (530ml, 10vol.), and Pd / C (5.3g, 0.1eq) was added to the reaction system; the reaction system was replaced by hydrogen six times; the reaction temperature was controlled at 20-30 degrees for 2 hours; The end point of the reaction was monitored by HPLC; after the reaction, the reaction system was replaced with nitrogen six times; filtered, the filter cake was soaked with DMAc (100 ml, 2vol.), and temporarily stored under the protection of nitrogen (the next hydrogenation reaction can still be used); the filtrate was directly for the next reaction.

[0098] Cbz- D -Ala-OH (20.8g, 1.0eq) was dissolved in DMAc (208ml, 10vol.), Oxymapure (13.22g, 1.0eq), EDCI (18.72g, 1.05eq), DIPEA (12.62g, 1.05eq) were added, After the reaction solution was stirred for 30 minutes, NH 2 - D -Arg(Pbf)-NH 2 DMAc solution (1.05eq), the reac...

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Abstract

The invention provides a liquid-phase synthesis method of Etelcalcetide. The synthesis method comprises the following steps: adopting Cbz as a protective group liquid phase sequence to synthesize a sequence as shown in a formula (I), and removing a side chain protective group K of Ac-D-Cys (K) in the sequence as shown in the formula (I) to obtain a sequence as shown in a formula (II); forming a disulfide bond at D-Cys of a sequence shown as a formula (II) through Boc-L-Cys (S-S-Py)-OtBu to obtain a sequence shown as a formula (III), and removing a protecting group in the sequence shown as theformula (III) to obtain the Etelcalcetide; wherein K is Mmt or Trt. The purity of the Cbz protecting group is easy to control, peptide loss is avoided, and simple deprotection can be realized throughPd / C hydrogenation; Boc-L-Cys (S-S-Py)-OtBu is connected with a peptide chain, so that the synthesis of disulfide bonds is conveniently and accurately controlled, and the yield and purity of target polypeptide are improved.

Description

technical field [0001] The invention relates to the field of polypeptide synthesis, in particular to a liquid-phase synthesis method of itkatide. Background technique [0002] Etelcalcetide is a novel calcimimetic agent developed by Kai Pharmaceuticals, Inc., which can inhibit the secretion of parathyroid hormone. Itkatide can bind to and activate the calcium-sensing receptors on the parathyroid gland, thereby reducing the level of parathyroid hormone. [0003] Itkatide has 3 D configuration of arginine, 2 D configuration of alanine, 1 D configuration of arginine amide, 1 L-configuration cysteine ​​and 1 D Configuration cysteine ​​(N segment is blocked by acetyl group), in which D The configuration cysteine ​​and the L configuration cysteine ​​are linked together by a disulfide bond ( N -acetyl- D -cysteinyl- D -alanyl- D -arginyl- D -arginyl- D -ar ginyl- D -alanyl- D -Arg ininamide, disulfid ewith- L -cysteine), shown in its structural formula I: [0004] ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/06C07K1/02C07K1/06
CPCC07K7/06Y02P20/55
Inventor 李九远李常峰荆禄涛巴拉苏布拉马尼安·阿鲁穆加姆
Owner 天津凯诺医药科技发展有限公司
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