Cyclo-pentapeptide and synthesizing method

A synthetic method and technology of cyclic pentapeptide, which is applied in the field of cyclic pentapeptide and its synthesis, can solve the problems of difficult synthesis and decreased yield, and achieve the effects of high product purity, low cost of raw materials, and mild reaction conditions

Inactive Publication Date: 2008-09-24
JINAN UNIVERSITY
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  • Description
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  • Application Information

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Problems solved by technology

[0005] The chemical synthesis of cyclic peptides can be divided into two categories: liquid phase synthesis and solid phase synthesis. In the synthesis of cyclic peptides, it is generally believed that the synthesis of

Method used

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  • Cyclo-pentapeptide and synthesizing method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1 Synthesis of protective dipeptide (Boc-Leu-N-Me-Leu-OBzl)

[0028] Take N-Me-Leu-OBzl hydrochloride (6mmol, 1.63g) and dissolve it in 15mL of dichloromethane. Under ice bath, use N,N-diisopropylethylamine (DIEA) to adjust PH=7~8, HOBt (6.6 mmol, 0.89 g) and tert-butyloxycarbonyl leucine (6.6 mmol, 1.52 g) were sequentially added, and after stirring for 15 minutes under an ice bath, DCC (6.6 mmol, 1.36 g) was added. The temperature was naturally raised to room temperature, and the reaction was carried out for 18 hours, and then filtered. The filtrate was washed with 10% citric acid, saturated sodium bicarbonate and saturated sodium chloride solution successively, the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After passing through a silica gel column, 2.34 g of a crystalline solid (Boc-Leu-N-Me-Leu-Obzl) was obtained with a yield of 87%.

Embodiment 2

[0029] Example 2 Synthesis of protective tripeptide (Boc-Leu-Leu-N-Me-Leu-OBzl)

[0030] Take (Boc-Leu-N-Me-Leu-Obzl) (4mmol, 1.8g) obtained in Example 1 and add 30mL of dichloromethane and 0.86mL of anisole. Fluoroacetic acid, react under ice bath for 3 hours, followed by TLC. After the reaction is complete, concentrate under reduced pressure, add dichloromethane, concentrate under reduced pressure, repeat three times, and then drain with an oil pump to obtain H--Leu-N-Me-Leu -OBzl. Used directly in the next reaction. Add 10 mL of dichloromethane to the above product, adjust pH to 7-8 with DIEA under ice bath, add HOBt (4.4mmol, 0.59g), tert-butyloxycarbonyl leucine (4.4mol, 1.01g) in sequence, After stirring for 15 minutes under ice bath, DCC (4.4 mmol, 0.91 g) was added. Spontaneously warm to room temperature, after 18 hours of reaction, followed by TLC, after the reaction is complete, filter, the filtrate is washed with 10% citric acid, saturated sodium carbonate and saturated...

Embodiment 3

[0031] Example 3 Preparation of protected pentapeptide (Boc-Leu-N-Me-Leu-Leu-Leu-N-Me-Leu-OBzl)

[0032] (1) Synthesis of H-Leu-Leu-N-Me-Leu-OBzl

[0033] Take the (Boc-Leu-Leu-N-Me-Leu-OBzl) (2mmol, 1.12g) obtained in Example 2, add 30mL of dichloromethane and 0.43mL of anisole, and add 4mL of 20% while stirring under an ice bath. The trifluoroacetic acid was reacted under ice bath for 3 hours, followed by TLC. After the reaction was complete, concentrated under reduced pressure, then added dichloromethane, concentrated under reduced pressure, repeated three times, and then drained with an oil pump to obtain the product (H-Leu-Leu- N-Me-Leu-Obzl) to be used.

[0034] (2) Synthesis of Boc-Leu-N-Me-Leu-OH

[0035] Take the (Boc-Leu-N-Me-Leu-Obzl) (2mmol, 0.90g) obtained in Example 1 and put it into a two-neck round bottom flask, add 20mL of ethyl acetate / methanol (volume ratio=1:1), After being protected by nitrogen gas, 0.3 g of 10% palladium / carbon was added, hydrogen gas was int...

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Abstract

The present invention discloses a cyclic pentapeptide and a synthesization method, and the cyclic pentapeptide, the molecular formula of which is C32H59N5O5 and the constitutional formula of which is shown as the formula (I), is cyclic (leucyl-N-methylleucyl-leucyl-leucyl-N-methylleucyl). In the synthesization method of the present invention, butoxycarbonyl leucine and N-methylleucine benzyl ester hydrochloride are used as materials, which are condensed to produce protected dipeptide, the protected dipeptide is linked with a leucine to produce protected tripeptide, protected linear pentapeptide is produced by a ''2 plus 3'' synthesization strategy, products are respectively removed of the protecting groups of both ends, and a target product is produced after ring closure carried out by cyclizing reagent. In the synthesization method, ring closure is at the adjacent positions of two N-Mes, and ring closure yield reaches 62.7 percent. The synthesization process of the present invention has the advantages of simplicity, low material cost, bland reaction conditions and high purity, can be easily industrialized and can sufficiently satisfy the requirements of medical experiments and clinic applications.

Description

Technical field [0001] The invention relates to the field of organic synthesis, in particular to a cyclic pentapeptide and a synthesis method thereof. Background technique [0002] Cyclic peptides have shown great development potential in anti-tumor, anti-viral, anti-bacterial and enzyme inhibitor activities, and are a hot spot in the 21st century. Cyclic peptide molecules have a clear fixed conformation (Fairlie, DP, Abbenante, G., March, DR, Curr. Med. Chem., 1995, 2, 654-686), which can fit well with the receptor, plus the molecule The absence of free amino and carboxyl ends makes the sensitivity to aminopeptidase and carboxypeptidase greatly reduced (Bruce J, Aungst and Hirosi Saitoh, Pharmaceutical Research, 1996, 13(1), 114-119; Dae-Yeon Suh, Yong Chul Kim, Young-Hwa Kang J. Nat. Prod. 1997, 60, 265-269; Bogdanowich-Knipp, SJ, Jois D. SS, Siahaan T. JJPept. Res. 1999, 53, 523-529). Generally speaking, the metabolic stability and bioavailability of cyclic peptides are much h...

Claims

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Application Information

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IPC IPC(8): C07K7/64C07K1/06
CPCY02P20/55
Inventor 徐石海许文杰
Owner JINAN UNIVERSITY
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