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N-(2)-L-alanyl-L-glutamine compound prepared by adopting particle crystal form optimization technique and preparation thereof

A glutamine and compound technology, applied in the field of N--L-alanyl-L-glutamine compounds and their preparations, can solve the problems of lack of crystal morphology optimization process, many steps, and low overall yield

Active Publication Date: 2015-11-25
HAINAN LINGKANG PHARMA CO LTD +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are many steps in this line and the synthesis is cumbersome, so the total yield is very low
[0008] The conventional preparation methods of the above three kinds of alanylglutamine, in addition to the above-mentioned defects, lack the optimization process of the crystal form in the preparation process, so there are unilateral limitations in the performance of the compounds

Method used

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  • N-(2)-L-alanyl-L-glutamine compound prepared by adopting particle crystal form optimization technique and preparation thereof
  • N-(2)-L-alanyl-L-glutamine compound prepared by adopting particle crystal form optimization technique and preparation thereof
  • N-(2)-L-alanyl-L-glutamine compound prepared by adopting particle crystal form optimization technique and preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Example 1 Preparation of N-(2)-L-alanyl-L-glutamine compound

[0041] 1. Synthesis of Boc-L-Alanine

[0042] Add 500.15g of water, 50.03g of 2-methyltetrahydrofuran, 5.01g of L-alanine to the reactor, add 1.21g of sodium hydroxide and 6.03g of di-tert-butyl dicarbonate at 0°C, and react at 18°C ​​for 10 hours. Adjust the pH to 2.1 with dilute hydrochloric acid, extract 3 times with ethyl acetate, wash 3 times with saturated brine, add anhydrous Na to the organic phase 2 SO 4 Drying for 5 hours, filtering, and rotary evaporation at a temperature of 30° C. and a pressure of -0.5 MPa to obtain 4.75 g of Boc-L-alanine with a yield of 94.81%.

[0043] 2. Synthesis of N-carboxyl anhydride

[0044] Mix 4.50g of Boc-L-alanine, 18.02g of bis(trichloromethyl)carbonate, and 36.53g of 2-methyltetrahydrofuran, react at 0°C for 2 hours, and spin down at a temperature of 30°C and a pressure of -0.5MPa. Evaporate and concentrate to about 30ml, add 80ml of n-hexane, let stand for 20min, filter...

Embodiment 2

[0048] Example 2 Preparation of N-(2)-L-alanyl-L-glutamine compound

[0049] 1. Synthesis of Boc-L-Alanine

[0050] Add 500.05g of water, 50.12g of 2-methyltetrahydrofuran, 5.00g of L-alanine to the reactor, add 1.50g of sodium hydroxide and 6.13g of di-tert-butyl dicarbonate at 0℃, and react at 17℃ for 10 hours , Adjust the pH to 1.8 with dilute hydrochloric acid, extract 3 times with ethyl acetate, wash 3 times with saturated brine, add anhydrous Na to the organic phase 2 SO 4 After drying for 5 hours, filtering, and rotary evaporation at a temperature of 30° C. and a pressure of -0.5 MPa to obtain 4.83 g of Boc-L-alanine with a yield of 96.60%.

[0051] 2. Synthesis of N-carboxyl anhydride

[0052] Mix Boc-L-alanine 4.50g, bis(trichloromethyl)carbonate 18.13g, 2-methyltetrahydrofuran 35.08g, and react at 0°C for 1.5 hours. At a temperature of 30°C and a pressure of -0.5MPa, Concentrate by rotary evaporation to about 30ml, add 80ml of n-hexane, let stand for 20min, filter with suc...

Embodiment 3

[0056] Example 3: Preparation of N-(2)-L-alanyl-L-glutamine compound

[0057] 1. Synthesis of Boc-L-Alanine

[0058] Add 500.51g of water, 50.35g of 2-methyltetrahydrofuran, 5.00g of L-alanine to the reactor, add 2.03g of sodium hydroxide and 6.02g of di-tert-butyl dicarbonate at 2°C, and react at 16°C for 12 hours , Adjust the pH to 2.5 with dilute hydrochloric acid, extract 3 times with ethyl acetate, wash 3 times with saturated brine, add anhydrous Na to the organic phase 2 SO 4 After drying for 5 hours, filtering, and rotary evaporation at a temperature of 30° C. and a pressure of -0.5 MPa to obtain 4.77 g of Boc-L-alanine with a yield of 95.40%.

[0059] 2. Synthesis of N-carboxyl anhydride

[0060] Mix 4.53g of Boc-L-alanine, 18.04g of bis(trichloromethyl)carbonate, and 36.15g of 2-methyltetrahydrofuran, and react at 1°C for 2 hours. At a temperature of 30°C and a pressure of -0.5MPa, Concentrate by rotary evaporation to about 30ml, add 80ml of n-hexane, let stand for 20min, f...

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Abstract

The invention discloses a method for preparing an N-(2)-L-alanyl-L-glutamine compound. The N-(2)-L-alanyl-L-glutamine compound is prepared by adopting a particle process crystal product molecule assembly and form optimization technique. The compound has the characteristics of high purity, high yield, low hygroscopicity and good stability. Meanwhile, the invention also discloses a pharmaceutical composition prepared from the alanyl glutamine prepared by the method. The pharmaceutical composition is prepared through the steps of preparing the alanyl glutamine into a 10-30% aqueous solution, adsorbing the aqueous solution with medicinal activated charcoal according to the ratio (w / v) of 0.1-0.5%, then, carrying out big-dish freeze-drying, and carrying out aseptic packaging. The whole preparation process is simple in operation and does not need any excipient, and the product has better stability compared with the products in the past.

Description

Technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to an N-(2)-L-alanyl-L-glutamine compound prepared by adopting a particle process crystal product molecular assembly and morphology optimization technology and a preparation thereof. Background technique [0002] Glutamine is one of the most abundant amino acids in the human body. As an essential amino acid in the body, it has important and unique metabolic functions for various organs and tissue cells. However, due to its instability to acid, alkali and high temperature, its clinical application Restricted. Alanylglutamine, a dipeptide product formed by the condensation of glutamine and alanine, has good water solubility and can withstand high temperature disinfection. It remains stable after two years at room temperature and can be quickly decomposed in the human body. It becomes L-glutamine and L-alanine to make up for the deficiency of L-glutamine, so it is widely used a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/062C07K1/18A61K38/05A61P3/02
Inventor 陶灵刚郝红勋王静康
Owner HAINAN LINGKANG PHARMA CO LTD
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