Thyrotropin-releasing hormone and preparation method of pharmaceutically usable salt thereof

A thyrotropin and hormone-releasing technology, which is applied in the preparation methods of peptides, chemical instruments and methods, organic chemistry, etc., can solve problems such as inconvenience of thyrotropin-releasing hormone, and achieve improved yield, high product purity, and high yield. high effect

Inactive Publication Date: 2012-04-18
张伟
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] This shows that the above-mentioned existing preparation method of thyrotropin-releasing hormone still has inconvenience and defect, and urgently needs to be further improved

Method used

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Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0061] Preparation of TRH pharmaceutically acceptable salts

[0062] The TRH free base is then reacted with an acid to obtain a pharmaceutically acceptable salt. Described acid is tartaric acid, fumaric acid, maleic acid, acetic acid, oxalic acid, lactic acid, citric acid, malic acid, benzoic acid, methanesulfonic acid, sorbic acid, glutamic acid, aspartic acid, hydrochloric acid, sulfuric acid, Phosphoric acid, nitric acid, hydrobromic acid or hydroiodic acid. For example, reaction with L-tartaric acid in ethanol solution gives crystalline TRH tartrate.

example 1

[0063] Example 1 Z-L-pGlu-L-His-L-Pro-NH 2 preparation of

[0064] Z-L-pGlu-L-His was dried at 60°C and 0.1mmHg vacuum for 24 hours to obtain anhydrous Z-L-pGlu-L-His. Anhydrous Z-L-pGlu-L-His (11g, 27.47mmol) was dissolved in 60mL of anhydrous DMF, cooled to -20°C, solid CDI (4.5g, 27.47mmol) was added, kept at -15°C and stirred for 45 minutes . Then, add L-Pro-NH 2 (3.1 g, 27.47 mmol), stirred at -15°C for 1 hour, then naturally warmed to room temperature, and stirred for 3 hours. Pour the reaction solution into 1.5L ether with stirring, let it stand for 24 hours, pour off the supernatant, then add 2L THF and heat slightly to 60°C to dissolve the residue on the bottle wall, and then stir the The solution was poured into 1.5L of anhydrous diethyl ether to produce a large amount of white powdery solid, which was continuously stirred at room temperature for 15 minutes, suction filtered, and the white powder was washed with anhydrous diethyl ether (200 mL each time, 3 times)...

example 2

[0066] Example 2 Z-L-pGlu-L-His-L-Pro-NH 2 preparation of

[0067] Z-L-pGlu-L-His (11 g, 25.74 mmol) was dissolved in 55 mL of anhydrous DMF, cooled to -15 °C, solid CDI (10.4 g, 64.34 mmol) was added, kept at -10 °C and stirred for 30 minutes. Then add L-Pro-NH 2 (2.9g, 25.74mmol), stirred at -10°C for 1 hour, then naturally warmed to room temperature, and stirred for 5 hours. Pour the reaction solution into 2L of ether with stirring, let it stand for 48 hours, pour off the supernatant, then add 1.2L of absolute ethanol and heat slightly to 75°C to dissolve the residue on the bottle wall, and then fully stir Slowly pour 2L of isopropyl ether into the ethanol solution to produce a large amount of white powdery solid, continue to stir at room temperature for 2 hours, filter with suction, wash the white powder with anhydrous ether (200mL each time, 3 times), and obtain 12.6g ( Yield 97%) Z-L-pGlu-L-His-L-Pro-NH 2 , HPLC detection purity 98.5%.

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Abstract

The invention relates to thyrotropin-releasing hormone (TRH) and a preparation method of a pharmaceutically usable salt thereof. The method comprises: reacting Z-L-pGlu-L-His with carbonyldiimidazole (CDI); adding L-Pro-NH2 to perform a reaction; mixing the reaction product with a poor solvent, standing solution and removing supernate to obtain a residue; adding a solvent into the residue to formsolution of the residue; and mixing the solution of the residue with the poor solvent, filtering the solution and processing a filter cake to obtain Z-L-pGlu-L-His-L-Pro-NH2, performing the catalytichydrogenation of the Z-L-pGlu-L-His-L-Pro-NH2 to obtain the TRH and salinizing the Z-L-pGlu-L-His-L-Pro-NH2 optionally. The method of the advantages that: CDI is used as a condensing agent; the reaction speed is high; the excess charging of the reaction raw material is avoided; the post processing of the product does not require a recrystallization step; the Z-L-pGlu-L-His-L-Pro-NH2 can be obtained by simply adding an insoluble solvent into a reaction mixture; and the yield is improved greatly.

Description

technical field [0001] The invention relates to a preparation method of polypeptide medicine in the field of pharmacy, in particular to a large-scale preparation method of thyrotropin-releasing hormone and a pharmaceutically acceptable salt thereof. Background technique [0002] Thyroid-stimulating hormone-releasing hormone, also known as thyroid-stimulating hormone-releasing factor, is abbreviated as TRH or TRF in English. The chemical structure of TRH is L-pyroglutamyl-L-histidyl-L-proline Amide (L-pGlu-L-His-L-Pro-NH 2 ). TRH is a hormone secreted by the hypothalamus, which exists in humans and various animals. In addition to stimulating the synthesis and secretion of thyroid-stimulating hormone (TSH), it can also cause the release of prolactin. In addition, TRH also has a good promoting effect on the central nervous system, such as promoting the recovery of spinal cord injury, accelerating the recovery of cranial nerve injury caused by local ischemia and hypoxia, impro...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/097C07K1/06C07K1/02
CPCY02P20/55
Inventor 辛军韩震张伟
Owner 张伟
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