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A method for synthesizing palmitoyl hexapeptide using a microchannel modular reaction device

A microchannel module and palmitoyl hexapeptide technology, which is applied in the field of synthesizing peptides by applying a microchannel modular reaction device, can solve problems such as rare peptide synthesis, and achieve the effects of shortening the coupling reaction time, high repetition rate and reducing cost.

Active Publication Date: 2020-11-17
SUZHOU NOVARTIS PHARMA TECHONOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, continuous flow microchannel reactors have been widely used in the synthesis of small organic molecules, but the cases of applying them to the synthesis of peptides are still rare.

Method used

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  • A method for synthesizing palmitoyl hexapeptide using a microchannel modular reaction device
  • A method for synthesizing palmitoyl hexapeptide using a microchannel modular reaction device
  • A method for synthesizing palmitoyl hexapeptide using a microchannel modular reaction device

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0086] a. Preparation process of Boc-Pro-Gly-OBzl

[0087] Preparation material 1: Boc-Pro-OH (5g, 23.22mmol), EDC.HCl (5.34g, 27.87mmol) and HOBt (3.765g, 27.87mmol) were dissolved in 250ml of dichloromethane, Boc-Pro-OH The concentration is 0.09289mmol / ml;

[0088] Preparation material 2: H-Gly-OBzl.HCl (4.075g, 19.35mmol) and DIEA (1.000g, 38.7mmol) were dissolved in 250ml of dichloromethane, and the concentration of H-Gly-OBzl was 0.0774mmol / ml. The feed flow rate of material 1 and material 2 is adjusted by a metering pump, and the flow rate is equal to 2ml / min. The condensation reaction was carried out in the first microstructure reactor with a reaction time of 10 min and a temperature of 30° C. to obtain the dipeptide Boc-Pro-Gly-OBzl.

[0089] b.Boc-Pro-Gly-OBzl washing process

[0090] Material 3: 10wt% Na 2 CO 3 aqueous solution.

[0091] The feed flow rate of material 3 is 5ml / min, adjusted by a metering pump, washed in the second microstructure reactor, washed...

Embodiment 2

[0107] a. Preparation process of Boc-Gly-OTMES

[0108] Boc-Gly-OH (8 g, 45.66 mmol), TMES-OH (6.479 g, 54.79 mmol), EDC.HCl (10.50 g, 54.79 mmol) and DMAP (1.114 g, 9.132 mmol) were dissolved in 1 L of dichloromethane in 30°C for 3 hours, poured into a 3L separatory funnel after the reaction, washed 3 times with 5% potassium carbonate solution, dried, concentrated, and then purified by column chromatography. The TLC development condition was PE:EA= 1:4, spin-dried to obtain 10.12g of solid, yield 80.45%.

[0109] b. The process of de-Boc protection of Boc-Gly-OTMES

[0110] Add 8g of Boc-Gly-OTMES into the prepared 500ml of 20% TFA / dichloromethane, and react at 30°C for 2h. After the reaction, TFA was neutralized with 10% sodium carbonate aqueous solution until no bubbles were released, the aqueous phase was alkaline, and the organic layer was collected, dried and spin-dried to obtain 4.63g, with a yield of 91.14%.

[0111] c. Preparation process of Boc-Pro-Gly-OTMES

[0...

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Abstract

The invention discloses a method for synthesizing palmitoyl hexapeptide by using a microchannel modular reaction device. The method includes the specific steps of introducing the activated Boc-Pro-OHand H-Gly-OPg respectively into a first microstructure reactor by using a metering pump and conducting washing, extraction and impurity removal through a second microstructure reactor to collect the organic phase to obtain Boc-Pro-Gly-OPg; introducing the Boc-Pro-Gly-OPg and TFA respectively into a third microstructure reactor with the metering pump for reaction to obtain dipeptide H-Pro-Gly-OPg;repeating the above operation, introducing the remaining amino acids and palmitoyl according to the peptide sequence respectively to obtain Polmitoyl-Val-Gly-Val-Ala-Pro-Gly-OPg; finally, removing a C-terminal protecting group and conducting liquid chromatography purification to obtain the palmitoyl hexapeptide. According to the method, the consumption of amino acid raw materials, coupling reagents and organic solvents, is greatly reduced, the cost is greatly reduced, the emission of three wastes is less, the process is environmentally friendly, the yield is high, and the method is suitable for large-scale production.

Description

technical field [0001] The invention relates to the field of polypeptide synthesis, in particular to a method for synthesizing polypeptides using a microchannel modular reaction device. Background technique [0002] In the early development stage of peptide chemistry, peptide synthesis reactions were generally carried out in the liquid phase. Unfortunately, solution-phase synthesis of peptides is laborious and requires knowledge of strategies and strategies in choosing protecting groups and condensation methods, as well as addressing solubility issues. Since the solid-phase peptide synthesis method was proposed by Merrifield in 1963, it has become the preferred method for peptide synthesis due to its convenient and rapid synthesis. The advantage of solid-phase synthesis is that the initial reactants and products are connected to the solid-phase carrier, so all reactions can be carried out in one reaction vessel, which is convenient for automatic operation, and high-yield pr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/06C07K1/02C07K1/06
CPCY02P20/55
Inventor 苏贤斌杨洋卞亚楠崔营营
Owner SUZHOU NOVARTIS PHARMA TECHONOLOGY CO LTD