Preparation method for trihydrate 3-amino propyl aminoethyl thiophosphoric acid

A technology of aminopropylamine ethyl thiophosphoric acid and sodium thiophosphate, applied in chemical instruments and methods, compounds of Group 5/15 elements of the periodic table, organic chemistry, etc., can solve the cost-atom-economical solvent residue and residual solvent detection is inconvenient, the reaction effect is poor, the crude product purity is low, etc., to achieve the effect of improving atom economy, easy control, and high purity

Active Publication Date: 2014-12-24
CHINA NAT MEDICINES GUORUI PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The technical problem solved by the present invention is in order to overcome the irritating and toxic solvents such as DMF and DMSO that are difficult to remove in the existing amifostine preparation method, or the use of PEG such molecular weight is relatively large. , the atomic economy of the reaction and the detection of subsequent solvent residues and residual solvents have certain problems and inconvenience, or the defects of poor reaction effect and low purity of the crude product provide a trihydrate 3-aminopropylamine ethyl alcohol The preparation method of phosphorothioate

Method used

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  • Preparation method for trihydrate 3-amino propyl aminoethyl thiophosphoric acid
  • Preparation method for trihydrate 3-amino propyl aminoethyl thiophosphoric acid
  • Preparation method for trihydrate 3-amino propyl aminoethyl thiophosphoric acid

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Embodiment 1

[0030] N-(2-bromoethyl)-1,3-propanediamine dihydrobromide (9g), sodium thiophosphate dodecahydrate (10g) and water (20ml) were stirred and mixed, and ethanol (20ml) was added , reacted at 20°C for 5 hours, added ethanol (40ml), filtered, washed the filter cake with a small amount of ethanol to obtain crude amifostine (6.3g), dried in vacuum at <30°C, HPLC purity 98.1%, yield 94%. The residual ethanol is <1000ppm detected by gas phase. (The residue limit of ethanol in the Pharmacopoeia is 5000ppm)

[0031]

Embodiment 2

[0033] N-(2-bromoethyl)-1,3-propanediamine dihydrobromide (9g), sodium thiophosphate dodecahydrate (10g) and water (15ml) were stirred and mixed, and ethanol (5ml) was added , reacted at 25°C for 5 hours, added ethanol (55ml), filtered, washed the filter cake with a small amount of ethanol to obtain crude amifostine (6.0g), dried under vacuum at <30°C, HPLC purity 98.0%, yield 89.5%. The residual ethanol is <1000ppm detected by gas phase.

Embodiment 3

[0035] N-(2-bromoethyl)-1,3-propanediamine dihydrobromide (9g), sodium thiophosphate dodecahydrate (10g) and water (25ml) were stirred and mixed, and ethanol (60ml) was added , reacted at 10°C for 6 hours, added ethanol (10ml), filtered, washed the filter cake with a small amount of ethanol to obtain crude amifostine (5.9g), dried under vacuum at <30°C, HPLC purity 98.4%, yield 88%. The residual ethanol is <1500ppm detected by gas phase.

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Abstract

The invention discloses a preparation method for trihydrate 3-amino propyl aminoethyl thiophosphoric acid. The preparation comprises the following steps of reacting N-(2-bromoethyl)-1,3-propane diamine and sodium thiophosphate in water and an organic solvent. The organic solvent is one or more selected from ethanol, methanol, isopropanol, acetic acid, acetone, acetonitrile and tetrahydrofuran. The preparation method provided by the invention is mild in conditions, takes use of the most common organic solvent, is fast in reaction speed, is safe and reliable, and is convenient for operations and relatively low in cost. Besides, residual solvent can be removed and detected easily; the purity of the obtained crude product is relatively high (98%); and the preparation method is suitable for industrial production. A reaction equation is shown in the description.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of 3-aminopropylamine ethylthiophosphoric acid trihydrate. Background technique [0002] Amifostine (Amiforstine), the chemical name is 3-aminopropylamine ethyl phosphorothioate trihydrate, and its structural formula is shown in formula (I): [0003] [0004] Originally, amifostine was a nuclear radiation protection agent developed by the United States. The US FDA (Food and Drug Administration) approved it for marketing in 1996. It is clinically used as an adjuvant drug for radiotherapy and chemotherapy to protect normal human tissue cells from the damage of radiotherapy and chemotherapy. [0005] Amifostine is hydrolyzed by phosphatase in the human body, removes the phosphate group, and becomes an active metabolite containing a sulfhydryl group. This active metabolite can selectively enter the normal tissue cells of the human body to remove oxygen free...

Claims

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Application Information

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Patent Type & AuthorityApplications(China)
IPC IPC(8): C07F9/165
Inventor张福利裘鹏程潘林玉倪国伟陈学峰蒋敏王健
OwnerCHINA NAT MEDICINES GUORUI PHARMA