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Whole liquid phase synthetic method for sinapultide

A cinaputide and liquid phase technology, which is applied in the field of total liquid phase synthesis of cinaputide, can solve problems such as difficulty in scaling up, high cost, and low purity of crude peptides

Active Publication Date: 2020-03-31
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method is easy to shrink during the synthesis of peptide resin, and the purity of crude peptide is low, resulting in low overall yield.
[0011] Disadvantages of solid-phase synthesis: it is necessary to use a solid carrier and ensure complete reaction through excessive feeding, and the cost is high; the peptide resin will shrink significantly during the synthesis process, resulting in poor coupling effect; the synthesis scale of the solid-phase synthesis method is limited by the equipment The impact is large and difficult to amplify

Method used

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  • Whole liquid phase synthetic method for sinapultide
  • Whole liquid phase synthetic method for sinapultide
  • Whole liquid phase synthetic method for sinapultide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Embodiment 1, the synthesis of fully protected peptide 1

[0066] Preparation of Fmoc-Leu-ONb: Weigh 3534g (10mol) of Fmoc-Leu-OH and 1969g (11mol) of HONb and dissolve in 15L tetrahydrofuran, and stir in an ice-water bath. Weigh 2476g (12.0mol) of DCC, dissolve in 10L tetrahydrofuran, slowly add dropwise to the above solution, stir the reaction, and monitor the reaction with TLC. Suction filtration was performed after the reaction was completed, the reaction solution was concentrated to 8 L, and then 50 L of tertiary methyl ether was added to the concentrated solution, a large amount of white solid was precipitated, and the solution was left standing at -20°C for 4 hours. Suction filtration, the solid was dissolved in 5L of ethyl acetate, 50L of tertiary methyl ether was added for crystallization, suction filtration, and the solid was dried in vacuum to obtain 4837g of Fmoc-Leu-ONb with a purity greater than 99% and a yield of 94.0%.

[0067] Preparation of Fmoc-Leu-L...

Embodiment 2

[0073] Embodiment 2, the synthesis of fully protected peptide 2

[0074] Preparation of H-Leu-Leu-Leu-Leu-Lys(Boc)-OH: Weigh Fmoc-Leu-Leu-Leu-Leu-Lys(Boc)-OH1470g (1.6mmol), stir and dissolve with 8L dichloromethane , and then weighed 427g AlCl 3 (3.2mmol) and 242g N-methylmorpholine (2.4mol), were added to the reaction solution and stirred for 3 hours, and the reaction was monitored by TLC. The reaction solution was rotary evaporated to 1.6L, added to 16L of tertiary methyl ether to precipitate, and the solid precipitate was collected by centrifugation, and after vacuum drying, 1029g of H-Leu-Leu-Leu-Leu-Lys(Boc)-OH was obtained, with a purity greater than 98.5%. Yield 92%.

Embodiment 3

[0075] Embodiment 3, the synthesis of fully protected peptide 3

[0076]Preparation of Fmoc-Leu-Leu-Leu-Leu-Lys(Boc)-ONb: Weigh Fmoc-Leu-Leu-Leu-Leu-Lys(Boc)-OH1470g (1.6mmol) and HONb 322g (1.8mol) in 4L tetrahydrofuran, stirring in an ice-water bath. Weigh 396g (1.9mol) of DCC, dissolve it in 4L tetrahydrofuran, slowly add it dropwise to the above solution, stir the reaction, and monitor the reaction by TLC. Suction filtration was performed after the reaction was completed, the reaction solution was concentrated to 3 L, 20 L of tertiary methyl ether was added to the concentrated solution, a large amount of white solid was precipitated, and the solution was left standing at -20°C for 4 hours. After standing still, filter with suction, dissolve the solid with 3L of ethyl acetate, add 25L of tertiary methyl ether, crystallize, filter with suction, and dry the filter cake in vacuum to obtain 1538g of Fmoc-Leu-Leu-Leu-Leu-Lys(Boc)-ONb , the purity is greater than 98.5%, and the...

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Abstract

The invention relates to a whole liquid phase synthetic method of sinapultide. The whole liquid phase synthetic method comprises the following steps: firstly synthesizing Fmoc-Leu-Leu-Leu-Leu-Lys(Boc)-OH, synthesizing a fully protected fragment Fmoc-Leu-Leu-Leu-Leu-Lys(Boc)-Leu-Leu-Leu-Leu-Lys(Boc)-Leu-Leu-Leu-Leu-Lys(Boc)-Leu-Leu-Leu-Leu-Lys(Boc)-OH based on the fragment in two times, and performing liquid phase coupling on Boc-Lys(Boc)-OH to obtain fully protected sinapultide; and performing pyrolysis under liquid phase conditions to remove protective group Boc. The preparation method is simple, the yield and purity are higher, the solvent is saved to achieve the purpose of environmental protection, and the method is suitable for large-scale production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a method for synthesizing cinaputide in full liquid phase. Background technique [0002] Neonatal respiratory distress syndrome (NRDS) refers to the short-term (minutes to hours) natural breathing of newborns after birth, followed by progressive dyspnea, cyanosis, moaning and other acute respiratory distress symptoms and respiratory failure. Hyaline membrane disease of newborns is also called hyaline membrane disease of newborns because the main lesion is the formation of hyaline membrane in the lungs of children. [0003] On March 6, 2012, the US FDA approved lucinactant (Surfaxin) for respiratory distress syndrome (RDS) in premature infants. Surfaxin (Lucinactant, Lucinactant) is a product designed on the basis of the 21-amino acid peptide KL4 (sinapultide, Sinapultide) according to the characteristics of natural human lung surfactant, and is used to simulate hum...

Claims

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Application Information

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IPC IPC(8): C07K14/00C07K1/02C07K1/06C07K1/08
CPCC07K14/001C07K1/02C07K1/04C07K1/06C07K1/08C07K7/08C07K14/00Y02P20/55
Inventor 陈永汉汪伟宓鹏程陶安进袁建成
Owner HYBIO PHARMA
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