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A kind of method for preparing alendidil

A synthesis method and technology of peptide fragments, applied in the field of polypeptide drug preparation, can solve problems such as low synthesis efficiency, unsuitability for large-scale production, and high cost of histidine racemization

Active Publication Date: 2017-11-07
ADLAI NORTYE BIOPHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In summary, the disadvantages of the current preparation of alendidil are: low synthesis efficiency, high cost of reducing histidine racemization, and not suitable for large-scale production

Method used

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  • A kind of method for preparing alendidil
  • A kind of method for preparing alendidil
  • A kind of method for preparing alendidil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0086] Synthesis of Fmoc-Leu-OSu Activated Ester

[0087] Weigh 353.41g Fmoc-Leu-OH (1.0mol), add 138.10g HOSu (1.2mol) into 2000ml THF, add 247.56g DCC (1.2mol) under ice-water bath, react for 1 hour, warm up to room temperature for 3 hours, and react liquid filtration, mother liquor was spin-dried, dissolved in DCM, filtered, washed 3 times with saturated sodium bicarbonate, 2 times with pure water, back-extracted 2 times, combined organic phase, dried with anhydrous sodium carbonate, spin-dried, and recrystallized 3 times with ice ethanol , filtered, and the solid oil pump was dried to obtain 400.95g Fmoc-Leu-OSu activated ester, yield 89%.

Embodiment 2

[0089] Synthesis of Fmoc-Leu-Asn-OH

[0090] Weigh 66.06g H-Asn-OH (0.5mol) and 79.50g Na 2 CO 3 (0.75mol) was added to the mixed solution of 500ml water and 500ml THF to dissolve, weighed 225.25g Fmoc-Leu-OSu (0.5mol) was added to 500ml THF, dissolved and added dropwise to the above mixed solution, reacted overnight at room temperature, with Adjust the pH to 7 with 10% dilute hydrochloric acid, remove THF by rotary evaporation, and then adjust the pH to 3. A large white precipitate was obtained which was filtered. The resulting white precipitate was recrystallized from ice ethanol. The solid oil pump was dried to obtain 203.38g Fmoc-Leu-Asn-OH, the yield was 87%. Its HPLC spectrum is as figure 2 Shown, HPLC purity 95.46%, yield 89%. Its mass spectrum is as image 3 Shown, [M+Na] + : 490.2075, [M+K] + : 506.2078, the theoretical exact molecular weight of the compound dipeptide fragment Fmoc-Leu-Asn-OH is: 467.2056, the mass spectrometry result of the sample is consis...

Embodiment 3

[0092] Synthesis of Altideil-Rink Amide MBHA Resin

[0093] Weigh 100 g of Rink Amide MBHA resin with a degree of substitution of 0.10 mmol / g, add it to a solid-phase reaction column, wash it once with DMF, and swell the resin with DCM for 30 minutes, then use piperidine and The deprotection solution composed of DMF removes the Fmoc protecting group on the amino resin, washes it 6 times with DMF, takes 14.03g Fmoc-Leu-Asn-OH (30mmol), 4.05g HOBt (30mmol) and dissolves it in DMF, and adds 3.88 After g DIC (30mmol) is activated, add in the reaction column that above-mentioned resin is housed, after reacting at room temperature for 2 hours, detect and judge the end of the reaction with the ninhydrin method, if the resin is colorless and transparent, it means that the reaction is complete; the resin develops color, It means that the reaction is not complete and needs to be reacted for another 1 hour. This judgment standard is applicable to the ninhydrin method detection and judgme...

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Abstract

The invention relates to the technical field of polypeptide synthesis, and in particular relates to a method for preparing aviptadil. The method specifically comprises the following steps: (A) synthesizing a dipeptide fragment Fmoc-Leu-Asn-OH by virtue of a liquid phase method; (B) sequentially coupling amino acids with N end Fmoc protection and side chain protection according to an aviptadil main chain peptide sequence by adopting a solid phase synthesis method and taking Rink Amide MBHA amino resin as initial resin, wherein the amino acid coupling of 23, 24, 27 and 28 positions is realized by adopting the dipeptide fragment Fmoc-Leu-Asn-OH coupling, and the histidine coupling of a first position is realized by adopting Boc-His(Trt)-OH; and (C) performing peptide resin pyrolysis, purification and freeze-drying to obtain aviptadil. The invention provides D-His1-aviptadil which is high in synthetic efficiency and low in cost and can avoid racemization impurities, so that the method is suitable for a synthetic process of aviptadil in scale production.

Description

technical field [0001] The invention belongs to the technical field of preparation methods of polypeptide drugs, and in particular relates to a method for preparing alendidel. Background technique [0002] Aviptadil, British name: Aviptadil. [0003] The peptide sequence of the alendidil is as follows: [0004] H-His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn- Ser-Ile-Leu-Asn-NH 2 [0005] Altideil, developed for Mondobiotech AG and Biogen Idec, is a linear peptide of 28 amino acids. It is mainly used for the treatment of acute respiratory distress syndrome and idiopathic pulmonary fibrosis. It has better effect and less side effects, and is a promising peptide drug. [0006] At present, the conventional synthesis method of alendidil is a one-by-one coupling method, and the synthesis efficiency is low, and the coupled histidine is easy to racemize; in addition, CN201310100852.3 reports the use of Boc-His(3-Bum)-Ser(Psi(Me...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/00C07K1/06C07K1/04C07K1/02
CPCC07K14/00
Inventor 杨东晖路杨周亮
Owner ADLAI NORTYE BIOPHARMA CO LTD
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