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Method for synthesizing D-isoglutamine-D-tryptophan

A technology of isoglutamine and tryptophan, applied in the field of peptide synthesis, can solve the problems of difficult purification and inability to meet the needs of large-scale industrial production.

Inactive Publication Date: 2012-07-25
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, purification is difficult, and HPLC purification cannot meet the needs of large-scale industrial production

Method used

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  • Method for synthesizing D-isoglutamine-D-tryptophan
  • Method for synthesizing D-isoglutamine-D-tryptophan
  • Method for synthesizing D-isoglutamine-D-tryptophan

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Synthesis of Fmoc-D-Glu(ONb)-OBzl:

[0062] Fmoc-D-Glu-OBzl (9.18g, 20mmol) and HONb (3.9g, 22mmol) were added into a 100ml two-neck round bottom flask, and stirred with 50mL THF to dissolve. DCC (4.5g, 2.2mmol) was dissolved in 10mL THF and added dropwise in an ice-water bath, and stirred in a water bath for 3h. The reaction solution was filtered, and the filtrate was concentrated to dryness with Et 2 O / DCM (V:V=5:1) dissolves the residual oily matter, and after standing for 1 h, the insoluble matter is removed by filtration. The filtrate is concentrated to dryness by rotary evaporation and then dissolved in 10 mL THF for later use.

[0063] Synthesis of Fmoc-D-Glu(D-Trp-OBzl)-OBzl:

[0064] Add D-Trp-OBzl.HCl (6.6g, 20mmol) and Na in a 250ml two-necked round bottom flask 2 CO 3 (10.6g, 100mmol), dissolved in 40mL deionized water, added 30mL THF and stirred for 10min, slowly added the activated ester THF solution prepared in Example 1, and stirred at room temperatu...

Embodiment 2

[0072] Synthesis of Fmoc-D-Glu(ONb)-OBzl:

[0073] Fmoc-D-Glu-OBzl (9.18g, 20mmol) and HONb (3.9g, 22mmol) were added into a 100ml two-neck round bottom flask, and stirred with 50mL THF to dissolve. DCC (4.5g, 2.2mmol) was dissolved in 10mL THF and added dropwise in an ice-water bath, and stirred in a water bath for 3h. The reaction solution was filtered, and the filtrate was concentrated to dryness with Et 2 O / DCM (V:V=5:1) dissolves the residual oily matter, and after standing for 1 h, the insoluble matter is removed by filtration. The filtrate is concentrated to dryness by rotary evaporation and then dissolved in 10 mL THF for later use.

[0074] Synthesis of Fmoc-D-Glu(D-Trp-OBzl)-OBzl:

[0075] Add D-Trp-OBzl.HCl (6.6g, 20mmol) and Na in a 250ml two-necked round bottom flask 2 CO 3 (10.6g, 100mmol), dissolved in 40mL deionized water, added 30mL THF and stirred for 10min, slowly added the activated ester THF solution prepared in Example 1, and stirred at room temperatu...

Embodiment 3

[0083] Synthesis of Fmoc-D-Glu(ONb)-OMe:

[0084] Add Fmoc-D-Glu-OMe (7.66g, 20mmol) and HONb (3.9g, 22mmol) into a 100ml two-necked round-bottomed flask, and stir to dissolve with 50mL THF. DCC (4.5g, 2.2mmol) was dissolved in 10mL THF and added dropwise in an ice-water bath, and stirred in a water bath for 3h. The reaction solution was filtered, and the filtrate was concentrated to dryness with Et 2 O / DCM (V:V=5:1) dissolves the residual oily matter, and after standing for 1 h, the insoluble matter is removed by filtration. The filtrate is concentrated to dryness by rotary evaporation and then dissolved in 10 mL THF for later use.

[0085] Synthesis of Fmoc-D-Glu(D-Trp-OMe)-OMe:

[0086] Add D-Trp-OMe.HCl (6.6g, 20mmol) and Na in a 250ml two-necked round bottom flask 2 CO 3 (10.6g, 100mmol), dissolved in 40mL deionized water, added 30mL THF and stirred for 10min, slowly added the activated ester THF solution prepared in Example 2, and stirred at room temperature for 4h. ...

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Abstract

The invention relates to the field of synthesis of polypeptides, in particular to a method for synthesizing D-isoglutamine-D-tryptophan. In the method, R1-D-Glu-OR2 and D-Trp-OR2 are taken as initial raw materials; a new protecting strategy is adopted; R1 is Fmoc or Cbz; R2 is benzyl is direct-chain alkane with 1-4 carbon atoms; and the D-isoglutamine-D-tryptophan is obtained by performing activating, condensing, alkaline hydrolysis, hydrogenolysis and purifying. The method has low requirements on a synthesis process, high-purity D-iGlu-D-Trp-OH can be obtained by purifying D-iGlu-D-Trp-OH, and the synthesis route of D-iGlu-D-Trp-OH is expanded.

Description

technical field [0001] The invention relates to the field of polypeptide synthesis, in particular to a method for synthesizing D-isoglutamine-D-tryptophan. Background technique [0002] D-isoglutamine-D-tryptophan, also known as (R)-2-amino-5-((R)-1-carboxy-2-(1H-indol-2-yl)ethylamino)-5 -oxopentanoic acid, Timodepressin, H-D-γ-Glu-D-Trp-OH, H-D-iGlu-D-Trp-OH, iDD or D-iEW, is a synthetic blood regulating dipeptide, molecular weight: 333.34, CAS registration number : 186087-26-3. Has the following chemical structure: [0003] [0004] In the synthetic method described in WO2008064465, the carboxyl protecting group adopts benzyl or an alkyl group with 1-4 C atoms. The synthetic route of this method is as follows: [0005] [0006] US 5736519 uses Boc-D-Glu-OH and D-Trp-OH as raw materials to obtain a mixture of D-Glu-D-Trp-OH and D-iGlu-D-Trp-OH through condensation with DCC and deprotection with formic acid. Finally, D-Glu-D-Trp-OH and D-iGlu-D-Trp-OH were separat...

Claims

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Application Information

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IPC IPC(8): C07D209/20
CPCY02P20/55
Inventor 曾国良陆永章刘建马亚平袁建成
Owner HYBIO PHARMA
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