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Trihydrate 3-amino propyl amine ethyl phosphorothioic acid high purity stable crystal and preparation thereof

A technology of aminopropylamine ethylthiophosphoric acid and trihydrate, which is applied in the direction of chemical instruments and methods, drug combinations, compounds of Group 5/15 elements of the periodic table, etc., and can solve the problems of purity, crystallization properties and stability. It can clarify other problems, achieve the effect of improving stability and reducing side effects

Active Publication Date: 2009-04-22
MERRO PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The synthesized product was only qualitatively analyzed, but the purity, crystalline properties and stability were not clear

Method used

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  • Trihydrate 3-amino propyl amine ethyl phosphorothioic acid high purity stable crystal and preparation thereof
  • Trihydrate 3-amino propyl amine ethyl phosphorothioic acid high purity stable crystal and preparation thereof
  • Trihydrate 3-amino propyl amine ethyl phosphorothioic acid high purity stable crystal and preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1 Preparation of high-purity and stable 3-aminopropylamine ethyl phosphorothioate trihydrate

[0032] Step 1: Synthesis

[0033] Add 13.6kg of pure water and 19.2mol (7.6kg) of sodium thiophosphate dodecahydrate into a 50L stainless steel reactor, and add N-(2-bromoethyl)-1,3-propanediamine dihydrobromic acid under stirring. Salt 19.8mol (6.8kg, 3% excess), slowly add 11.0kg DMSO while maintaining the reaction temperature not exceeding 25°C. After dripping DMSO, monitor the reaction solution with silver nitrate solution until no black precipitate is precipitated. After the reaction is over, the reaction solution is cooled to 0° C., and stirred for 5 minutes every hour for 18 hours. After centrifugal filtration, 6.1 kg of crude 3-aminopropylamine ethyl phosphorothioate trihydrate was obtained.

[0034] Step 2: Purification by recrystallization for the first time

[0035] Add 22.0kg of pure water into a 50L stainless steel crystallization kettle, add 6.1kg of crude 3-...

Embodiment 2

[0040] Example 2 Preparation of high-purity and stable 3-aminopropylamine ethyl phosphorothioate trihydrate

[0041] Step 1: Synthesis

[0042] Add 13.6kg of pure water and 19.2mol (7.6kg) of sodium thiophosphate dodecahydrate into a 50L stainless steel reactor, and add N-(2-bromoethyl)-1,3-propanediamine dihydrobromic acid under stirring. Salt 19.5mol (6.7kg, 2% excess), stir to dissolve, slowly add 11.0kg DMSO while maintaining the reaction temperature not exceeding 25℃, monitor the reaction solution with silver nitrate solution, until no black precipitate precipitates, the reaction is over, the reaction solution is cooled down It was stirred at 0°C for 5 minutes per hour, maintained for 18 hours, and centrifuged to obtain 6.0 kg of 3-aminopropylamine ethyl phosphorothioate solid.

[0043] Step 2: Purification by recrystallization for the first time

[0044] Add 22.0kg of pure water to a 50L stainless steel crystallization kettle, add 6.0kg of synthetic crude 3-aminopropylamine ...

Embodiment 3

[0049] Example 3 Crystal purity of high-purity 3-aminopropylamine ethyl phosphorothioate trihydrate

[0050] Table 1 shows the comparison of the content of 3-aminopropylamine ethyl phosphorothioate trihydrate prepared by the method of the present invention and the content of amifostine on the market and the content of related substances:

[0051]

[0052] It can be seen from Table 1 that the content of amifostine trihydrate crystals prepared by the present invention is higher than that of amifostine trihydrate purchased on the market, and the related substances thiols, disulfide compounds and other related substances are much lower than the current ones. Products purchased on the market.

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Abstract

The invention relates to the field of chemosynthesis, a trihydrate 3-aminopropyl amine ethyl thiophosphoric acid(amifostine)stable crystal and a preparation method thereof. The method comprises the following steps: step one, according to the molar ratio of between 1.01 to 1.0 and 1.2 to 1.0, N-(2-bromethyl)-1,3-propane diamine bi-hydrobromide and sodium thiophosphate are dissolved in water, are added with a polar aprotic solvent as an accelerant and react at a temperature of between 10 and 40 DEG C; after reaction, the mixture is directly cooled to precipitate a coarse product of trihydrate amifostine; step two, the coarse product of the trihydrate amifostine obtained in the step one is subjected to primary recrystallization and purification, is dissolved in the water and is precipitated out through methanol to obtain anhydrous amifostine; and step three, the anhydrous amifostine obtained in the step two is subjected to secondary recrystallization and purification, is dissolved in the water and is decolored through active carbon; and the trihydrate amifostine crystal is precipitated out through ethanol. The purity of the crystal is more than or equal to 99.5 percent; the content of mercaptan is less than or equal to 0.1 percent; the content of other relevant substances is less than or equal to 0.1 percent; and a product is stable and is suitable for scale production.

Description

Technical field [0001] The present invention relates to the field of chemical synthesis, and more specifically, to a pan-cell protective agent trihydrate 3-aminopropylamine ethyl phosphorothioate (also known as amifostine) high-purity stable crystals and a preparation method thereof. Background technique [0002] 3-Aminopropylamine ethyl phosphorothioate, the trade name is Amifostine (Amifostine, also known as WR-2721, Ethyol), and its structural formula is: [0003] [0004] Amifostine was screened out of 4,400 compounds by American soldiers in the 1950s, code-named WR2721, used as a protective agent for nuclear radiation. Amifostine is activated by alkaline phosphatase (AKP) in the body and then dephosphorylates its phosphorylation group and becomes an active metabolite H containing free sulfhydryl groups. 2 N-(CH 2 ) 3 -NH-(CH 2 ) 2 -SH, it can selectively ingest normal tissue cells, scavenge oxygen free radicals, and repair damaged molecules. Amifostine is a broad-spectrum ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/165A61P35/00A61P39/06
Inventor 孟庆伟苗蔚荣宫斌廉明明张成海陈祥麟董述祥
Owner MERRO PHARMA
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