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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

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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 DMF residues to the skin, but , because DMSO itself also has certain toxicity, therefore, there may still be potential irritation to the human body in the finished amifostine prepared by this kind of solvent method

Method used

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

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Experimental program
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Effect test

Embodiment 1

[0040] Embodiment 1 Amifostine synthesis process of the present invention

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

[0042] b. After reacting for 24 hours, add 163ml of concentrated ammonia water-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 min, stand at 4°C for crystallization. ...

Embodiment 2

[0043] Embodiment 2 Amifostine synthesis process of the present invention

[0044] First synthesize according to the technique of embodiment 1 and obtain the amifostine crude product, then carry out the following operations to refine:

[0045] One-time refining: Take 1 g of the above crude product, add 10 ml of aqueous solution containing 5% ethanol to dissolve, add 0.02 g of activated carbon and 1.0 g of 201×7 type strongly acidic anion exchange resin, stir in an oil bath at 30°C for 10 min, filter under normal pressure, and add water The phase was kept and stirred in a 30°C oil bath, 4ml of 99.5% ethanol was added dropwise, and then the bath temperature was gradually decreased from 30°C to room temperature. At this time, a large amount of white solids had precipitated, and then stood at 4°C for 2h, filtered with suction, and vacuum-dried at 30°C to obtain 0.78g of a white primary refined product, with a yield of 78%, and a content of about 98% as determined by HPLC.

[0046...

Embodiment 3

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

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

[0049] Table 1

[0050]

[0051] As can be seen from Table 1, the consumption ratio of water and PEG plays an important role in the yield and purity of the reaction: when the weight ratio of sodium salt and bromine salt was at 1: 0.8-1.3, the weight ratio of water and PEG was at 4 :1~1:3, the yield of product is all above 54%, and the purity is higher than 73%; When the weight ratio of water and PEG is at 4:1~1.6:1, the yield of product is all above 83% , and the purity is higher than 87%, showing that this condition is better than the existing pure water reaction system (such as Li Jiaming,...

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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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