Synthesis method of cyclic pentapeptide

A synthetic method, the technology of cyclic pentapeptide, applied in the field of organic chemical synthesis, can solve the problems of large solvent and time consumption, low yield of cyclization, etc., and achieve the effects of improved purity, low raw material cost, and simple synthesis process

Active Publication Date: 2016-07-20
JINAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because the liquid phase method needs to be purified by column chromatography after each reaction, 5 column chromatography purifications are required in the whole reaction, which consumes a lot of solvent and time, and the cyclization yield of this method is not high, only 50 % or so (XuW.J., LiaoX.J., XuS.H., Organic Letters, 2008, 10(20), 4569-4572.)

Method used

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  • Synthesis method of cyclic pentapeptide
  • Synthesis method of cyclic pentapeptide
  • Synthesis method of cyclic pentapeptide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1 Synthesis of Fmocyl N-methyl-leucine (Fmoc-N-Me-Leu-OH)

[0037] Fmoc-Leu-OH (7.07g, 2mmol) was suspended in 100mL of toluene, paraformaldehyde (9.00g, 3mmol) and p-toluenesulfonic acid (0.200g, catalytic amount) were added, and the mixture was azeotropically refluxed for 30 minutes to remove water. After the solution was cooled, the solution was washed with saturated NaHCO 3 Wash with aqueous solution (25mL×2) and wash with anhydrous Na 2 SO 4 dry. Filter, carry out silica gel column chromatography (eluent V 石油醚 :V 乙酸乙酯 =8:1), to obtain white compound (1), in a 250mL flask, add compound (1) (7.00g, 2mmol), dichloromethane (150mL), anhydrous aluminum trichloride (4.00g, 3mmol), three Ethylsilane (4.8mL, 3mmol) was reacted for several hours, and when the raw material point basically disappeared as monitored by TLC, the reaction was stopped, and the reaction solution was washed twice with 1mol / L hydrochloric acid. Anhydrous Na for washing solution 2 SO ...

Embodiment 2

[0038] Embodiment 2 fluorenyl methaneoxycarbonyl leucine (Fmoc-Leu-OH) is connected to 2-chlorotrityl chloride resin

[0039] Activation of the resin: Add 1.00 g of 2-chlorotrityl chloride resin (loading capacity: 0.985 mmol / g) to the peptide synthesis tube, soak in 15 mL of dichloromethane for 30 min to fully swell and activate the resin, and then drain the liquid.

[0040] Fmoc-Leu-OH is connected to the resin: add Fmoc-Leu-OH (1.06g, 3mmol) in a 50mL Erlenmeyer flask, dissolve it with 20mL DCM (dichloromethane), then add DIEA to it to adjust the pH to about 8, After stirring for 1 minute, the mixed solution was added into the reactor containing the activated resin, nitrogen gas was introduced, and then the reaction was performed on a shaking table for 4 hours. After the reaction was completed, the reaction liquid was drained, and the resin was washed three times with 10 mL of DCM and DMF (dimethylformamide) respectively, and the washing liquid was drained.

Embodiment 3

[0041] The sealing of the residual active site of embodiment 3 resin

[0042] Take 18mL of methanol, dissolve 2mL of DIEA in methanol to make a solution of DIEA / MeOH (1:9), add the resin obtained in Example 2 to which the first amino acid has been connected, and react for 30min. After the blocking reaction, the resin was washed three times with 10 mL DCM and DMF respectively, and the washing solution was drained. The complex Fmoc-Leu-Resin (R-1A) of protected amino acid and resin was obtained.

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Abstract

The invention discloses a synthesis method of cyclic pentapeptide. According to the synthesis method, the 'solid-liquid combined production' strategy is adopted, a proper condensation agent is used for a condensation reaction, linear pentapeptides are prepared respectively through a proper process, the cyclization site is located between N-methyl-leucine and leucine, and the efficiency of linear peptide preparation is effectively improved.The proper condensation agent is used for the condensation reaction, racemization in amido bond formation can be effectively reduced, therefore, the purity of a target product can be effectively improved, reaching 99% or above, the requirements of biological activity tests and clinical application can be fully met, and the synthesis method of cyclic pentapeptide has high medical value. The cyclization agent PyBOP is used for a cyclization reaction, the cyclization yield can be effectively increased and reach up to 84.2%.The synthesis method does not require complex purification by column chromatography, redundant amino acids can be simply washed away, the synthesis process is simple, the cost of raw materials is low, reaction conditions are mild, the purity is high, industrialization is easy, and the synthesis method has broad market prospects.

Description

technical field [0001] The invention belongs to the field of organic chemical synthesis, and in particular relates to a synthesis method of cyclic pentapeptide. Background technique [0002] Marine cyclic peptides are the largest class of compounds among marine bioactive peptides, with more than 10,000 types. They have attracted the attention of biologists, pharmacologists and chemists, and some of their cyclic peptides have entered clinical practice. Most of the naturally occurring cyclic peptides have unique structures (TripathiA, PuddickJ, PrinsepMR.JNatProd, 2010, 73(11), 1810-1814; TanKC, WakimotoT, TakadaK..JNatProd, 2013, 76(7), 1388- 1391.), its bioavailability and biological activity are superior to linear peptides (ZhengLH, WangYJ, ShengJ.MarDrugs, 2011, 9 (10), 1840-1859.) Although cyclic peptides are widely found in animals and plants, low In marine organisms such as microorganisms and bacteria, but the content of cyclic peptides in nature is very small, which b...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/64C07K1/06C07K1/04C07K1/02
CPCC07K7/64
Inventor 徐石海钟生辉白德发陈建维
Owner JINAN UNIVERSITY
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