Dipeptide for synthesizing relin drugs

A drug, Relin's technology, applied in the field of peptide synthesis, can solve problems that affect product quality, drug safety, difficulty in complete removal, and product yield that cannot be effectively improved.

Active Publication Date: 2019-02-01
QILU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since the [1-2] peptide fragment in the ralin drug molecule is Pyr-His, the process of sequentially inserting Fmoc-His(R) and Pyr in the solid-phase chemical method, due to the molecular characteristics of the two amino acids His and Pyr , resulting in [D-His 2 ]-Raylin impurity, the impurity is very similar to the polarity of the raylin drug itself, it is difficult to completely remove it during the purification process, and the product yield cannot be effectively improved, resulting in a decrease in product purity, affecting product quality and drug use Safety

Method used

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  • Dipeptide for synthesizing relin drugs
  • Dipeptide for synthesizing relin drugs
  • Dipeptide for synthesizing relin drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] The preparation of embodiment 1, H-Pyr-His (Fmoc)-OH

[0054] Add anhydrous methanol (1.35L) to a 5L two-neck flask equipped with electromagnetic stirring, and add SOCl dropwise under ice-cooling 2 (78.1ml, 1100.0mmol), control the reaction temperature below -10°C, maintain the low temperature reaction for 1h, then add histidine (His) (77.5g, 500.0mmol) at one time, and heat to reflux for 1h. After the reaction, concentrate under reduced pressure to remove methanol and SOCl 2 , to obtain white solid H-His-OMe·2HCl (110.9 g, yield 91.61%). Ms=169.99(M+H + ).

[0055] Pyroglutamic acid (12.9g, 100.0mmol) and 200ml DMF were added to a 1.5L flask, HBTU (37.9g, 100.0mol) was added under ice cooling, the pH was adjusted to about 8 with NMM, and stirred for 30min under ice cooling. Add H-His-OMe·2HCl (24.2g, 100.0mol) and 600ml DMF to another single-necked bottle, adjust the pH to about 8 with NMM, and pre-cool. Add the latter after the activation of the carboxyl componen...

Embodiment 2

[0058] The preparation of embodiment 2, H-Pyr-His (Boc)-OH

[0059] Add anhydrous methanol (1.35L) to a 5L two-neck flask equipped with electromagnetic stirring, and add SOCl dropwise under ice-cooling 2 (78.1ml, 1100.0mmol), control the reaction temperature below -10°C, maintain the low temperature reaction for 1h, then add histidine (His) (77.5g, 500.0mmol) at one time, and heat to reflux for 1h. After the reaction, concentrate under reduced pressure to remove methanol and SOCl 2 , to obtain white solid H-His-OMe·2HCl (110.9 g, yield 91.61%).

[0060] Pyroglutamic acid (12.9g, 100.0mmol) and 200ml DMF were added to a 1.5L flask, HBTU (37.9g, 100.0mol) was added under ice cooling, the pH was adjusted to about 8 with NMM, and stirred for 30min under ice cooling. Add H-His-OMe·2HCl (24.2g, 100.0mol) and 600ml DMF to another single-necked bottle, adjust the pH to about 8 with NMM, and pre-cool. Add the latter after the activation of the carboxyl component is completed, adjust...

Embodiment 3

[0063] The preparation of embodiment 3, H-Pyr-His(Trt)-OH

[0064] Add anhydrous methanol (1.35L) to a 5L two-neck flask equipped with electromagnetic stirring, and add SOCl dropwise under ice-cooling 2 (78.1ml, 1100.0mmol), control the reaction temperature below -10°C, maintain the low temperature reaction for 1h, then add H-His(Trt)-OH (198.7g, 500.0mmol) in one go, and heat to reflux for 1h. After the reaction, concentrate under reduced pressure to remove methanol and SOCl 2 , to obtain white solid H-His(Trt)-OMe·2HCl (206.6 g, yield 85.2%).

[0065] Pyroglutamic acid (5.3g, 41.1mmol) and 70ml DMF were added to a 500ml flask, HBTU (15.6g, 41.1.0mol) was added under ice cooling, the pH was adjusted to about 8 with NMM, and stirred for 30min under ice cooling. Add H-His(Trt)-OMe·2HCl (19.9g, 41.1mol) and 200ml DMF to another single-necked bottle, adjust the pH to about 8 with NMM, and pre-cool. Add the latter after the activation of the carboxyl component is completed, adj...

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Abstract

The invention provides a dipeptide having the structure of formula I and a preparation method thereof. Pyroglutamic acid (Pyr) and histidine (His) can be introduced into relin peptide-like drugs by solid-phase synthesis in one step by using dipeptide segments, which greatly reduces the production of [D-His<2>] relin drug impurity, improves the yield and purity of the product, and the reaction efficiency is high, which is conducive to the realization of large-scale solid-state synthesis process.

Description

technical field [0001] The invention belongs to the field of polypeptide synthesis, and in particular relates to a dipeptide used for synthesizing ralin drugs and its preparation method and application. Background technique [0002] Relin drugs refer to a class of polypeptide drugs based on the structure of gonadotropin-releasing hormone. Gonadotropin-releasing hormone is also known as luteinizing hormone-releasing hormone, and its molecular structure is: Pyr 1 -His 2 -Trp 3 -Ser 4 -Tyr 5 -Gly 6 -Leu 7 -Arg 8 -Pro 9 -Gly 10 -NH 2 , which is a polypeptide hormone secreted by the hypothalamus, which is secreted in pulses and released every 90 to 120 minutes to promote the secretion of pituitary follicle-stimulating hormone and luteinizing hormone. [0003] When exogenous gonadotropin-releasing hormone or its analogues are administered in a short-term and small dose at a physiological pulse frequency, they can promote the pituitary gonad system, and can be used to tr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/078C07K7/23C07K1/06C07K1/04
CPCC07K5/06173C07K7/23Y02P20/55
Inventor 田振平韩荣刚薛琛琛彭海涛匡德琦
Owner QILU PHARMA CO LTD
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