Preparation method of semaglutide and intermediate of semaglutide

A technology of samoglutide and intermediates, applied in the field of medicinal chemistry, can solve the problems of increasing the difficulty of coupling, affecting the purity of crude peptides, affecting the yield and the like

Inactive Publication Date: 2016-07-13
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, when using this method, on the one hand, the removal of the side chain is not easy to control, there is incomplete removal of the protecting group or the shedding of other protecting groups in the process, resulting in various by-products, which affect the purity of the crude peptide; on the other hand , the coupling of the side chain is equivalent to prolonging the coupling of the peptide sequence, increasing the difficulty of coupling, affecting the purity of the crude peptide, and thus affecting the final yield

Method used

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  • Preparation method of semaglutide and intermediate of semaglutide
  • Preparation method of semaglutide and intermediate of semaglutide

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[0091] The invention discloses a preparation method of samaglutide and an intermediate thereof. Those skilled in the art can refer to the content herein to obtain samaglutide. In particular, it should be noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The preparation method and application of the present invention have been described through preferred embodiments, and relevant personnel can obviously make changes or appropriate changes and combinations to the preparation method and application herein without departing from the content, spirit and scope of the present invention to realize and Apply the technology of the present invention.

[0092] All the reagents and raw materials used in the preparation method of samaglutide and its intermediate provided by the present invention can be purchased from the market.

[0093] See Table 1 for the Chinese-English com...

Embodiment 1 18

[0098] Embodiment 1 octadecanedioic acid monomethyl ester is synthesized

[0099] Weigh 87g (0.5mol) of octadecanedioic acid into a three-necked flask, add 500mL of DCM, stir to dissolve, add 16g (0.5mol) of methanol, dropwise add 0.05g of concentrated sulfuric acid, stir until reflux, and react for 4 hours. TLC monitors that the reaction is completed, the reaction solution is cooled, and 2% Na is added 2 CO 3 (Mass volume percentage) The aqueous solution was extracted twice with 100 mL, the aqueous layer was extracted twice with 100 mL DCM, the organic phases were combined, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to obtain 69.5 g of the product.

[0100] Adopt mass spectrometry and proton nuclear magnetic resonance spectrum to detect the resulting product, the mass spectrogram of gained is shown in figure 1 , as can be seen from the figure, MS, m / z329.19 (M+H) + ; Gained proton nuclear magnetic resonance spectrum data ...

Embodiment 2

[0101] Embodiment 2 degree of substitution is the synthesis of Fmoc-Lys(Alloc)-2CTC resin of 0.60mmol / g

[0102] Weigh 20 g of 2-CTC resin (purchased from Tianjin Nankai Synthetic Technology Co., Ltd.) with a degree of substitution of 1.0 mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, and swell the resin with DMF for 30 minutes, then take 9.05 gFmoc-Lys(Alloc)-OH was dissolved in DMF, activated by adding 6.65mL DIEA in an ice-water bath, and then added to the above-mentioned reaction column filled with resin. After 2 hours of reaction, 10mL of anhydrous methanol was added to block for 1 hour. Wash 3 times with DMF and 3 times with DCM, then block with anhydrous methanol for 30 minutes, shrink and dry with methanol to obtain Fmoc-Lys(Alloc)-2CTC resin, and the detected substitution degree is 0.605mmol / g.

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Abstract

The invention belongs to the technical field of pharmaceutical chemistry, and discloses a preparation method of semaglutide and an intermediate of semaglutide. The preparation method comprises: obtaining a compound having a structure represented as the formula I by taking a resin, activating the resin, and coupling L-glycine, L-arginine, L-glycine, L-arginine, L-valine, L- leucine, L-tryptophan, L-alanine, L-isoleucine, L-phenylalanine, and L-glutamic acid to the activated resin step by step so as to obtain a first peptide resin; taking the first peptide resin, and coupling amino acids or amino acid derivatives to the second peptide resin step by step; and taking the second peptide resin, and performing cracking and purifying to obtain semaglutide. According to the method, the compound having a structure represented as the formula I is taken as an intermediate and coupling of each amino acid or amino acid derivative step by step through solid-phase synthesis is carried out, thereby improving the yield of semaglutide. In the formula I, R1 is selected from Fmoc, Boc, and ivDde, and R2 is selected from tBu, Dmab, and Bzl.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of samaglutide and an intermediate thereof. Background technique [0002] Diabetes is a series of clinical syndromes caused by absolute or relative insufficiency of insulin in the body, which is closely related to genetics. The main clinical manifestations of diabetes are polydipsia, polyuria, polyphagia and weight loss, as well as high blood sugar and glucose in urine. There are four types of diabetes: type 1 diabetes, type 2 diabetes, other types of diabetes, and gestational diabetes. Any type of diabetes causes the beta cells in the pancreas to fail to produce enough insulin to lower blood sugar levels, resulting in hyperglycemia. According to the World Health Organization report in 2011, 346 million people worldwide suffer from diabetes. In 2004, an estimated 3.4 million people died from diseases caused by hyperglycemia. More tha...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605C07K1/06C07K1/04C07C271/22C07C237/22
CPCY02P20/55
Inventor 陈永汉刘建马亚平袁建成
Owner HYBIO PHARMA
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