Method for preparing icatibant

A preparation process and coupling technology, applied in the field of preparation of polypeptide drugs, can solve the problems of many impurities, unsuitable for industrial scale production, low synthesis yield, etc., and achieve the effect of low cost

Active Publication Date: 2014-08-20
ADLAI NORTYE BIOPHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] The present inventor prepared icatibant by using the existing synthetic method, and found that the technical problems in the prior art were: low synthesis yiel

Method used

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  • Method for preparing icatibant
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  • Method for preparing icatibant

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0090] Embodiment one: the synthesis of Boc-D-Arg-OSu activated ester

[0091] Weigh 310.67g Boc-D-Arg-OH.HCl (1.0mol), add 138.10g HOSu (1.2mol) into 2000ml DMF, add 247.59g DCC (1.2mol) under ice-water bath, react for 1 hour, heat up to room temperature for reaction After 3 hours, the reaction solution was filtered, the mother liquor was spin-dried, dissolved in DCM, filtered, recrystallized from ice ethanol three times, filtered, and dried by a solid oil pump to obtain 273.90 g of Boc-D-Arg-OSu.HCl activated ester with a yield of 89%.

Embodiment 2

[0092] Example 2: Synthesis of Boc-D-Arg-Arg-OH.2HCl

[0093] Weigh 87.10g H-Arg-OH (0.5mol), 153.88g Boc-D-Arg-OSu.HCl (0.5mol) and 79.50g Na 2 CO 3 (0.75mol) was added to a mixed solution of 500ml water and 500ml THF to dissolve, react overnight at room temperature, 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 obtained white precipitate was recrystallized with ice ethanol, and the obtained solid was stirred and recrystallized in dioxane hydrochloride solution for 2 hours. HPLC spectrum such as figure 2 Shown, HPLC purity is 97.95%, yield 87%; Its mass spectrum is as image 3 Shown, [M+Na] + : 453.255, [M+K] +: 469.605, the theoretical precise molecular weight of the dipeptide fragment Boc-D-Arg-Arg-OH.2HCl is: 430.27, the mass spectrometry result of the sample is consistent with the theoretical molecular weight, and the structure is co...

Embodiment 3

[0094] Embodiment three: the degree of substitution is the synthesis of Fmoc-Arg(Pbf)-king resin of 0.60mmol / g

[0095] Weigh 20 g of Wang resin with a degree of substitution of 1.0 mmol / g, add it to a solid-phase reaction column, wash it once with DMF, and after swelling the resin with DMF for 30 minutes, take 64.88 g of Fmoc-Arg (Pbf)-OH (100 mmol) 13.51g HOBt (100mmol) was dissolved in DMF, after adding 12.62g DIC (100mmol) under ice-water bath to activate, add in the reaction column that above-mentioned resin is housed, add 1.22g DMAP (10mmol) after 5 minutes, after reacting for 2 hours, Washed 3 times with DMF, washed 3 times with DCM, capped overnight with 200ml of acetic anhydride and pyridine with a volume ratio of 1:1, shrunk and dried with methanol to obtain Fmoc-Arg(Pbf)-King resin, the detection degree of substitution was 0.60mmol / g.

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Abstract

The invention relates to a method for preparing icatibant. The method specifically comprises the following steps: A) synthesizing fragment Boc-D-Arg-Arg-OH.2HCl by a liquid phase; B) sequentially coupling amino acids having an N-terminal Fmoc protecting group and a side chain protecting group in accordance with the main chain peptide sequence of icatibant by solid-phase synthesis method, wherein coupling of the last two amino acids is performed by the fragment Boc-D-Arg-Arg-OH.2HCl, and the Wang resin is taken as a starting resin; C) cleaving the peptide from the resin, purifying, desalinating and lyophilizing to obtain icatibant, wherein the content of both of deletion peptide impurities des-D-Arg1-icatibant and des-Arg2-icatibant is less than 0.1%. The invention provides a method for preparing icatibant with the advantages of high purity, low cost and capability of large-scale production; the content of impurities, namely, des-D-Arg1-icatibant and des-Arg2-icatibant can be effectively controlled under the premise of the yield of icatibant is not affected by virtue of the method.

Description

technical field [0001] The present invention relates to a preparation method of polypeptide drugs, which is a preparation method for synthesizing icatibant, a special drug for the treatment of hereditary angioedema, which selectively inhibits the combination of bradykinin and B2 receptor. Background technique [0002] Icatibant, English name: Icatibant, is a decapeptide containing 5 non-protein source amino acids, the structural formula is as follows: [0003] [0004] The peptide sequence is: [0005] H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH [0006] Hereditary angioedema (HAE), also known as C1 inhibitor deficiency, is a rare autosomal dominant genetic disease caused by genetic defects, with an incidence of 1 / 50000~1 / 10000. HAE is characterized by unpredictable episodic edema and swelling of the hands, feet, face, larynx, and abdomen, resulting in disfigurement, disability, or death. Patients usually have a family history of the disease. Patients with HAE may...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/06C07K1/04C07K1/02
CPCY02P20/55
Inventor 何南海叶晓峰林晓峰杨东晖路杨
Owner ADLAI NORTYE BIOPHARMA CO LTD
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