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Preparation method of loxenatide and analogue thereof

A technology of analogs and peptide resins, which is applied in the field of large-scale industrial preparation of loxenatide, can solve the problems of not being suitable for industrial production, and achieve the effects of stable quality, simple process operation and high purity

Pending Publication Date: 2018-05-25
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This method is not suitable for industrial production

Method used

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  • Preparation method of loxenatide and analogue thereof
  • Preparation method of loxenatide and analogue thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Embodiment 1: the synthesis of loxenatide resin peptide

[0052] Weigh 120g Rink Amide-AM Resin (loading capacity: 0.5mmol / g, 60mmol) into the reactor, add 1.2L 20% piperidine / DMF mixed solution, react by bubbling nitrogen for 5-6 minutes, and drain. Add 1.2 L of 20% piperidine / DMF mixed solution, react by bubbling nitrogen gas for 20-25 minutes, and drain. The resin was washed 4 times with 1.2L DMF.

[0053] Weigh 32.4g HOBt (240mmol), 140.6g Fmoc-Cys(Trt)-OH (240mmol), 30.3g DIC (240mmol) dissolved in 0.6L DMF and 0.6L DCM, stir well, add the above solution into the reactor middle. Control the reaction temperature at 20-25°C, and react for about 4 hours. The end point shall be based on the negative result of the ninhydrin test. Add 1.2L of 20% piperidine / DMF mixed solution into the reactor for 5-6 minutes by bubbling nitrogen gas, and then drain it. . Add 1.2 L of 20% piperidine / DMF mixed solution, react by bubbling nitrogen gas for 20-25 minutes, and drain. The ...

Embodiment 2

[0057] Embodiment 2: the synthesis of loxenatide crude product

[0058] Prepare 1 L of lysate, including 900 ml of trifluoroacetic acid, 50 ml of 1,2-ethanedithiol, 25 ml of triisopropylsilane, and 25 ml of water. Cool down to 10-20°C.

[0059] Get the obtained loxenatide resin peptide 100g in embodiment 1, join in the 2L reaction bottle. The prepared lysate was added, and the reaction was stirred at room temperature for 3 hours. After filtration, the filtrate was added to 10L ether. After standing, it was filtered, and the filter cake was washed with ether. Vacuum drying gave 45 g of crude loxenatide. Gained sample carries out HPLC detection, D-His 1 - The impurity of loxenatide is 0.79%. Spectrum such as figure 1 shown.

Embodiment 3

[0060] Embodiment 3: the synthesis of loxenatide crude product

[0061] Prepare 1 L of lysate, including 900 ml of trifluoroacetic acid, 50 g of dithiothreitol, 25 ml of triisopropylsilane, and 25 ml of water. Cool down to 5-10°C.

[0062] Get the obtained loxenatide resin peptide 100g in embodiment 1, join in the 2L reaction bottle. The prepared lysate was added, and the reaction was stirred at room temperature for 3 hours. After filtration, the filtrate was added to 10L ether. After standing, it was filtered, and the filter cake was washed with ether. Vacuum drying to obtain loxenatide crude product 46.8g, D-His 1 - The impurity of loxenatide is 0.71%, and the spectrum is as follows figure 1 shown.

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Abstract

The invention relates to a preparation method of loxenatide and an analogue thereof. The method comprises the following steps: performing deprotection on amine resin serving as a raw material; sequentially connecting amino acids carrying protecting groups in a one-by-one condensation manner till synthesis of resin peptide is finished; cracking and purifying to obtain the loxenatide and the analogue thereof. The preparation method disclosed by the invention has the advantages of stable process, reliable quality and suitability for large-scale production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a method for industrialized large-scale preparation of loxenatide. Background technique [0002] Diabetes is a metabolic disorder caused by a variety of etiologies. According to the statistics of the International Diabetes Federation (IDF), there were more than 371 million diabetic patients worldwide in 2012, and the death toll was as high as 4.8 million. It is estimated that there will be nearly 552 million patients worldwide by 2030. Among them, patients with type Ⅱ diabetes accounted for more than 90%. [0003] Polyethylene glycol loxenatide is a long-acting hypoglycemic drug for the treatment of type 2 diabetes, developed by Jiangsu Hansoh Pharmaceutical Company. The existing results show that it can be administered once a week, reduces the frequency of administration, and improves the patient's compliance. It is a new type of long-acting hypoglycemic agent. ...

Claims

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Application Information

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IPC IPC(8): C07K14/575C07K1/06C07K1/04
CPCC07K14/575Y02P20/55
Inventor 周明朱后田袁恒立王生斌张丰盈
Owner JIANGSU HANSOH PHARMA CO LTD
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