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A kind of preparation method of pramlintide acetate

A technology of pramlintide acetate and crude peptides, which is applied in the preparation method of peptides, chemical instruments and methods, peptides, etc., can solve the problem that the purification process of pramlintide acetate is not mentioned in detail, the iodine oxidation method is not simple and practical, and the process is complicated and other problems, to achieve the effect of improving production efficiency and quality, convenient operation and simple process

Active Publication Date: 2018-07-20
YANGTZE RIVER PHARM GRP SICHUAN HAIRONG PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

U.S. Patent No. 5,424,394 discloses the synthesis of pramlintide acetate by sequentially coupling amino acid segments. Another U.S. Patent No. 2009055867 also discloses that four amino acid segments are first synthesized, and then these amino acid segments are sequentially coupled to synthesize pramlintide acetate. For the method of pramlintide acetate, the above methods all adopt the Fmoc solid-phase synthesis method with mild conditions, but the iodine oxidation method used to construct disulfide bonds is not simple and practical, and the purification process of pramlintide acetate is not mentioned in detail; The purification method of pramlintide acetate is disclosed in the existing Chinese patent CN101525382. This method requires two high-efficiency liquid phase purifications and one anion exchange and salt conversion to obtain a refined product with a purity greater than 98%. The process is complicated and the purification yield Only 40.3%

Method used

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  • A kind of preparation method of pramlintide acetate
  • A kind of preparation method of pramlintide acetate

Examples

Experimental program
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Effect test

Embodiment 1

[0063] Embodiment 1: the preparation of Fmoc-Tyr (tBu)-Rink MBHA Resin amino resin

[0064] Add 40g (10mmol) of Rink Amide-MBHA Resin amino resin with a substitution degree of 0.25mmol / g to the glass reaction column, add 200mL DMF to it for swelling for 30min, and then add 200mL to the glass reaction column to configure a volume concentration of 20 % piperidine in DMF, and stirred for 30min, then the reaction solution was removed, and then DMF was added to the glass reaction column for washing, washing 6 times, each consumption 200mL; simultaneously weighed 50mmol of Fmoc-Tyr ( tBu)-OH and 50mmol of HOBT, these two substances were dissolved with 200mL of DMF, after the dissolution was complete, 50mmol of DIC was added to it to form a mixed solution, and after stirring again, the mixed solution was added to the glass reaction column, and stirred for 2 Hour. Thereafter, the liquid was extracted and washed with DMF for 6 times, each time with a dosage of 200 mL; namely, about 42...

Embodiment 2

[0065] Embodiment 2: the synthesis of whole peptide resin

[0066] To the Fmoc-Tyr(tBu)-Rink MBHA Resin amino resin generated in step 1), add 200mL of the DMF solution of piperidine with a volume concentration of 20% configured, stir and allow it to react for 30min, then remove the liquid and wash with DMF The product was used 10 times, each dosage was 200mL, the washing solution DMF was drained, and then 50mmol of Fmoc-Thr(tBu)-OH and 50mmol of HOBT were weighed, and these two substances were dissolved in 200mL of DMF. Add 50mmol of DIC to form a mixed solution, stir again, add the mixed solution into the glass reaction column, stir and react for 2 hours, then remove the liquid, wash the product 6 times with DMF, each time 200mL, and drain it. Obtain Fmoc-Thr(tBu)-Tyr(tBu)-Rink MBHA Resin amino resin, then add a deprotection reagent to sequentially couple and deprotect the remaining amino acids, and operate until the last amino acid is coupled to obtain a full peptide resin ...

Embodiment 3

[0067] Embodiment 3: the cleavage of whole peptide resin

[0068] Preparation of lysate:

[0069] Take a 2000mL round bottom flask, add 850mL of TFA, 100mL of EDT, 50mL of H 2 0, and stirred to obtain a lysate.

[0070] Cracking:

[0071] Add 100 g of peptide resin to the lysate, stir and react for 3 hours, then filter with a sand core funnel, wash the filtered resin with 400 mL of TFA, repeat the filtration and washing twice, combine the filtrate, and concentrate under reduced pressure to the volume of the filtrate. It is about 1 / 10 of the original volume, and then it is added to the pre-cooled ethyl acetate solvent whose volume is 10 times that of the concentrated solution, and a white solid is precipitated, and the white solid is filtered, and the filtered white solid is washed with ethyl acetate The ester was washed 4 times, each time with 400 mL of ethyl acetate, filtered to obtain a solid powder, dried in vacuum for 12 hours, taken out and weighed to obtain 23.5 g of ...

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Abstract

The invention discloses a preparation method of pramlintide acetate. The preparation method comprises synthesis and purification steps and belongs to the field of drug preparation. The preparation method comprises the steps of (1) preparing Fmoc-Tyr(tBu)-Rink Amide-MBHA Resin; (2) synthesizing total peptide resin; (3) cutting the total peptide resin; (4) cyclizing an intermediate peptide; (5) carrying out primary purification; and (6) refining by using a simple, convenient and practical air oxidation method to obtain pramlintide acetate, wherein a crude product is only needed to be purified once by using a reversed-phase high-performance liquid chromatography and refined once to obtain a refined liquid, the purity of a refined product is larger than 99%, the total purification yield is up to 51.2%, the production efficiency of the product is effectively increased, and the quality of the product is effectively improved. The preparation method is simple in preparation process and convenient to operate.

Description

technical field [0001] The invention relates to a preparation method of a medicine, in particular to a preparation method of a hypoglycemic polypeptide medicine pramlintide acetate. Background technique [0002] Pramlintide Acetate (Cas No: 196078-30-5) is a human amylin analogue developed by Amylin Corporation of the United States. It is mainly used for the treatment of type Ⅰ and Ⅱ diabetes mellitus that cannot achieve the ideal blood sugar control effect even with insulin , where amylin refers to a hormone produced by pancreatic β cells that assists the body in regulating blood sugar. The molecular formula of pramlintide is C 171 h 267 N 51 o 53 S 2 , the corresponding molecular weight is 3949.4, and the amino acid sequence is: Lys-Cys-Asn-Thr-Ala-Thr-Cys-Ala-Thr-Gln-Arg-Leu-Ala-Asn-Phe-Leu-Val-His-Ser- Ser-Asn-Asn-phe-Gly-Pro-Ile-Leu-Pro-Pro-Thr-Asn-Val-Gly-Ser-Asn-Thr-Tyr-NH 2 . U.S. Patent No. 5,424,394 discloses the synthesis of pramlintide acetate by sequenti...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/575C07K1/20C07K1/16C07K1/10C07K1/04
CPCY02P20/55
Inventor 谢义鹏李元波曹康平王强伍普华袁森林王颖
Owner YANGTZE RIVER PHARM GRP SICHUAN HAIRONG PHARM CO LTD
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