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Preparation method for pro-his cyclic dipeptide

A technology of cyclic dipeptide and protease group, which is applied in the field of preparation of peptide drugs, can solve the problems of low yield and few synthesis methods of proteocyclic dipeptide, and achieve simple post-processing, considerable economic use value and low pollution Effect

Inactive Publication Date: 2007-04-25
HAINAN ZHONGHE PHARM CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] At present, there are few synthetic methods about proline group cyclic dipeptides, and the reported yields of L-L type proline group cyclic dipeptides, D-L type proline group cyclic dipeptides, L-D type proline group cyclic dipeptides and D-D type proline group cyclic dipeptides Very low, only 8% to 30% (reported in the literature: Kukla, M.J.; Breslin, H.J.; Bowden, C.R. Synthesis, characterization, andanorectic testing of the four stereoisomers of cyclo(histidylproline). J. Med. Chem. 1985, 28 (11), 1745-1747)

Method used

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  • Preparation method for pro-his cyclic dipeptide
  • Preparation method for pro-his cyclic dipeptide
  • Preparation method for pro-his cyclic dipeptide

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Experimental program
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Effect test

Embodiment 1

[0028] Embodiment 1, L-L type proline group cyclic dipeptide

[0029] 1. Add 450 mg of L-form proline methyl ester (Pro-OMe) and 744 mg of Boc-protected L-form histidine (Boc-His-OH) dropwise to 10 ml containing 1150 mg of dicyclohexyl carbon di The imine (DCC) in DCM was stirred at room temperature for 20 hours. After filtration, the reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography to obtain 210 mg of protected promethazine dipeptide methyl ester (Boc-His-Pro-OMe), with a yield of 20.5%. electrospray mass spectrometry (ESI-MS) and nuclear magnetic resonance ( 1 H NMR 13 C NMR) measurement, proves that the obtained product is correct.

[0030] 2. Dissolve 150 mg of the obtained protected dipeptide methyl ester in 5 ml of ethyl acetate, add 2 ml of trifluoroacetic acid, and stir for 1 hour. The reaction solution was concentrated under reduced pressure to obtain 119 mg of trifluoroacetic acid salt of dipeptide methyl...

Embodiment 2

[0032] Embodiment 2, L-L type proline group cyclic dipeptide

[0033] 1. 450 mg of L-type proline methyl ester (Pro-OMe) and 744 mg of Boc-protected L-type histidine (Boc-His-OH), 320 mg of 4-dimethylaminopyridine (DMAP) Add to 15 ml of dichloromethane (DCM) and stir to dissolve at room temperature, then add dropwise 10 ml of DCM solution containing 1150 mg of dicyclohexylcarbodiimide (DCC), and stir at room temperature for 18 hours. After filtration, the reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography to obtain 270 mg of protected promethazine dipeptide methyl ester (Boc-His-Pro-OMe) with a yield of 26.3%. electrospray mass spectrometry (ESI-MS) and nuclear magnetic resonance ( 1 H NMR 13 C NMR) measurement, proves that the obtained product is correct.

[0034] 2. Dissolve 150 mg of the obtained protected dipeptide methyl ester in 5 ml of ethyl acetate, add 2 ml of trifluoroacetic acid, and stir for 1 hour. The r...

Embodiment 3

[0036] Embodiment 3, L-L type proline group cyclic dipeptide

[0037] 1. 450 mg of L-type proline methyl ester (Pro-OMe) and 744 mg of Boc-protected L-type histidine (Boc-His-OH), 440 mg of 1-hydroxybenzotriazole (HOBt ) was added to 20 ml of dichloromethane (DCM) and stirred at room temperature to dissolve, then 10 ml of DCM solution containing 1150 mg of dicyclohexylcarbodiimide (DCC) was added dropwise, and stirred at room temperature for 4 hours. After filtration, the reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography to obtain 550 mg of protected promethazine dipeptide methyl ester (Boc-His-Pro-OMe), with a yield of 52.3%. electrospray mass spectrometry (ESI-MS) and nuclear magnetic resonance ( 1 H NMR 13 C NMR) measurement, proves that the obtained product is correct.

[0038]2. Dissolve 150 mg of the obtained protected dipeptide methyl ester in 5 ml of ethyl acetate, add 2 ml of trifluoroacetic acid, and stir f...

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Abstract

The invention discloses a new preparing method of pro-his cyclodipeptide, which comprises the following steps: 1) reacting proline methyl ester and N-tertiary-butyl carbonyl-Nim-tritylhistidine to obtain protected pro-his peptide methyl ester; 2) removing protection to generate pro-his cyclodipeptide directly with total receiving rate at 86%.

Description

technical field [0001] The invention relates to a preparation method of peptide drugs, in particular to a new method for preparing prosynthetic cyclic dipeptides. Background technique [0002] Procyclic dipeptide is an active dipeptide in the human body, widely present in body fluids and interstitial fluids. The cyclic dipeptide can resist the effect of some central inhibitory drugs, can affect certain behaviors of the human body, and has a regulating effect on body temperature, prolactin level, blood sugar, and animal feeding and drinking, and is expected to be put into the market as a drug. [0003] At present, there are few synthetic methods about proline group cyclic dipeptides, and the reported yields of L-L type proline group cyclic dipeptides, D-L type proline group cyclic dipeptides, L-D type proline group cyclic dipeptides and D-D type proline group cyclic dipeptides Very low, only 8% to 30% (reported in the literature: Kukla, M.J.; Breslin, H.J.; Bowden, C.R. Synt...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/12
Inventor 马亚平白威钟飞崔学云
Owner HAINAN ZHONGHE PHARM CO LTD
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