A kind of synthetic method of trihydrate 3-aminopropylamine ethylthiophosphoric acid

A technology of aminopropylamine ethylthiophosphoric acid and its synthesis method, which is applied in the field of synthesis of trihydrate 3-aminopropylamineethylthiophosphoric acid to achieve good biocompatibility, high purity and high purity of the crude product Effect

Inactive Publication Date: 2011-11-30
成都大有得药业有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The preparation method using water-DMSO as a solvent has a greater improvement in the reaction effect than the method using pure water or water-DMF, and it also has a certain effect on reducing the irritation of D

Method used

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  • A kind of synthetic method of trihydrate 3-aminopropylamine ethylthiophosphoric acid
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  • A kind of synthetic method of trihydrate 3-aminopropylamine ethylthiophosphoric acid

Examples

Experimental program
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Effect test

Example Embodiment

[0040] Example 1 Synthesis process of amifostine of the present invention

[0041] a. Add sodium thiophosphate dodecahydrate (10.0 g, 25.2 mmol) and 25 ml of distilled water to a flask equipped with an internal temperature thermometer, stir and suspend, and use an ice water bath outside. First add N-(2-bromoethyl)-1,3-propanediamine dihydrobromide (9.5g, 27.7mmol) to obtain a light brown suspension system, and then add polyethylene glycol 400 that is PEG400 ( 10g), after stirring evenly, remove the ice-water bath and keep stirring at 5-10°C for reaction. During the reaction, the reaction system first turned into a light brown clear solution, and then turned into an off-white turbid system again.

[0042] b. After 24 hours of reaction, add 163ml of concentrated ammonia-methanol mixture (volume ratio 1 / 29) to the stirred reaction material at room temperature, and a white solid can be seen in the bottle. After stirring for about 10 minutes, stand still at 4°C for crystallization. F...

Example Embodiment

[0043] Example 2 Synthesis process of amifostine of the present invention

[0044] First, the crude amifostine was synthesized according to the process of Example 1, and then refined by the following operations:

[0045] One-time refining: Take 1g of the above crude product, add 10ml of 5% volume ethanol solution to dissolve, add 0.02g activated carbon and 1.0g 201×7 type strong acid anion exchange resin, stir in 30℃ oil bath for 10min, filter under normal pressure, and water The phase was kept in a 30°C oil bath with stirring and 4ml of 99.5% ethanol was added dropwise, and then the bath temperature was gradually reduced from 30°C to room temperature. At this time, a large amount of white solid has been precipitated, and then left standing at 4°C for 2h, suction filtration, and vacuum drying at 30°C to obtain 0.78g of a white primary refined product with a yield of 78% and a content determined by HPLC of about 98%.

[0046] Secondary refining: take 1g of the above-mentioned primary...

Example Embodiment

[0047] Example 3 Screening test of different conditions for the synthesis process of amifostine of the present invention

[0048] The following table is the experimental results obtained when preparing crude amifostine with different ingredient ratios and reaction temperatures according to the operation process of step a in Example 1 (the method of step b is the same)

[0049] Table 1

[0050]

[0051] It can be seen from Table 1 that the dosage ratio of water and PEG has an important influence on the yield and purity of the reaction: when the weight ratio of sodium salt to bromide salt is 1:0.8-1.3, the weight ratio of water to PEG is 4 :1~1:3, the product yield is above 54%, and the purity is higher than 73%; when the weight ratio of water to PEG is 4:1~1.6:1, the product yield is above 83% , And the purity is higher than 87%, indicating that the conditions are better than the existing pure water reaction system (such as Li Jiaming, etc., Anhui Chemical Industry, 2000, 2:17-18); w...

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Abstract

The invention relates to a synthesis method of 3-amino-propyl aminoethyl thiophosphate (amifostine) trihydrate. In the synthesis method, polyethylene glycol (PEG) is used as a reaction solvent, and has good biocompatibility and far lower irritation to a human body in comparison with dimethyl formamide (DMF) and dimethyl sulfoxide (DMSO); the amifostine obtained by the reaction has high purity; especially when PEG400 is used as the reaction solvent, the prepared amifostine trihydrate product has higher yield and crude product purity; and in the post-treatment method, concentrated ammonia water/methanol are used to replace pure methanol, so that the product yield is significantly improved, especially the crude product purity can be up to 95% or above, and high-purity amifostine can be more easily obtained through secondary refining.

Description

technical field [0001] The invention relates to a method for synthesizing trihydrated 3-aminopropylamine ethylthiophosphoric acid. Background technique [0002] Amifostine, whose chemical name is 3-aminopropylamine ethylthiophosphoric acid, also known as Amifostine, is the world's first broad-spectrum selective cytoprotective agent, which was first used to protect Nuclear radiation drug, but later found that it can be hydrolyzed by alkaline phosphatase bound to the cell membrane in tissues to produce an active metabolite WR-1065 (H 2 N-(CH 2 ) 3 -NH-(CH 2 ) 2 -SH), because thiol has the effect of scavenging free radicals in tissues, it can reduce the toxicity of cisplatin, cyclophosphamide and mitomycin. In 1995, the FDA officially approved Amifostine to be listed in the United States for ovarian cancer cisplatin chemotherapy nephrotoxicity protection, in 1996 FDA approved cisplatin chemotherapy nephrotoxicity protection for non-small cell lung cancer, and in 1999 FDA a...

Claims

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Application Information

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IPC IPC(8): C07F9/165
Inventor 黄文才张丹程度张春红陈文芝雷华
Owner 成都大有得药业有限公司
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