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Process for the preparation of (omega-aminoalkylamino)alkyl halides and conversion to amifostine

A technology of aminoalkylamino and alkyl halide dihydrohalides, which is applied in the field of preparation of alkyl halides, and can solve the problems of not reaching the ideal output and long time

Inactive Publication Date: 2008-12-10
ALBEMARLE CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The problem with using the above methods to produce (ω-aminoalkylamino)alkyl halides on a commercial scale is that these methods all take a considerable amount of time and often do not achieve the desired yields

Method used

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  • Process for the preparation of (omega-aminoalkylamino)alkyl halides and conversion to amifostine
  • Process for the preparation of (omega-aminoalkylamino)alkyl halides and conversion to amifostine
  • Process for the preparation of (omega-aminoalkylamino)alkyl halides and conversion to amifostine

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preparation example Construction

[0047] B. Preparation and purification of amifostine monohydrate and amifostine trihydrate

[0048] In another aspect of the present invention, (ω-aminoalkylamino)alkyl halide dihydrohalides of formula (III) can be used to prepare different synthetic products. For example, compounds of formula (III) can be used in the manufacture of useful medical compounds such as amifostine (Ethyol ) including a large number of cell protection / radiation protection agents. These compounds are generally called "S-ω-(ω-aminoalkylamino)alkyl dihydrogenphosphorylsulfonyl" (formula IV), and can be synthesized according to the method in scheme II:

[0049]

[0050] Scheme II

[0051] According to this process, a compound of general formula (III), such as 2-(3-aminopropylamino)ethylbromodihydrobromide, can be contacted with sodium thiophosphate sufficient to form a compound of formula (IV) and a hydrate thereof. a period of time.

[0052] Crude phosphorothioate compounds of formula (IV) su...

example 1

[0058] Example 1: Laboratory preparation of 2-(3-aminopropylamino)ethyl bromide dihydrobromide

[0059] In a nitrogen-purged glove box, a 3-liter four-neck round bottom flask equipped with mechanical stirring, thermocouple, nitrogen inlet connector, and septum was charged with 2-(3-aminopropylamino)ethanol ( 144 g; 1.22 mol) and sulfolane (1.00 L; 10.5 mol). Move this to a fume hood where the nitrogen line is connected, replaced by bulkheads to support 1 / 8 inch diameter Teflon Connectors for tubing (to connect with HBr fine compressed gas cylinders). While stirring, hydrogen bromide (HBr) gas was introduced below the liquid surface at a rate that allowed the temperature to rise to about 130°C. After the exotherm had ceased and HBr had ceased to be taken up, the addition was stopped; two equivalents had reacted, yielding the dihydrobromide salt of the starting alcohol. Replace the connector on the reaction flask with an isobaric dropping funnel containing phosphorus tribrom...

example 2

[0061] Example 2: Synthesis of sodium thiophosphate

[0062] Prepare sodium thiophosphate and its hydrate according to the method described in the literature [Inorganic Synthesis, 5:102 (1957); ibid.17:193 (1997)]. reaction. The only difference is that phosphorus trichloride sulfur is slowly added to the caustic solution at reflux in order to control the exothermic reaction.

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Abstract

The present invention relates to processes for the preparation of (Omega-aminoalkylainino)alkyl halides, their conversion to S-Omega-(Omega-aminoalkylamino)alkyl phosphothioates, and purification of the crystalline products of the reaction. The preparation process for the (Omega-aminoalkylamino)alkyl halides comprises contacting an appropriate alcohol with a brominating agent in the presence of a sulfone solvent under temperature and pressure conditions suitable to effect salt formation without subsequent premature precipitation. The process is especially useful for converting (Omega-aminoalkylamino) ethyl alcohol to amifostine.

Description

technical field [0001] The present invention provides for the preparation of (ω-aminoalkylamino)alkyl halides, especially 2-(3-aminopropylamino)ethyl bromide dihydrobromide and its subsequent conversion to and purification of S-ω-(ω -Aminoalkylamino)alkyl dihydrogen phosphorothioate (S-ω-(ω-aminoalkylamino)alkyl dihydrogen phosphorothioate) such as amifostine monohydrate and amifostine trihydrate. Background of the invention [0002] With the increasing incidence of cancer and related diseases requiring chemotherapy and / or radiation therapy, there is increased interest in radioprotective drugs that reduce the biological effects of ionizing radiation, including lethality, mutagenicity, and carcinogenicity. Amino alcohols, one of the most intensively studied groups of radioprotective drugs, have been used clinically to minimize damage to normal physiological tissues during chemotherapy. One of the most widely studied of these compounds, WR-2721 (S-2-(3-aminopropylamino) ethyl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C209/74C07C213/08C07F9/165
CPCC07C209/74C07C213/08C07F9/1651C07C211/15C07C215/14
Inventor 爱德华·G.·萨姆塞尔
Owner ALBEMARLE CORP
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