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Preparation method of fotemustine

A formustine and reaction medium technology, applied in the field of medicinal chemistry, can solve the problems of low product purity and low yield, and achieve the effects of high purity, high yield and suitability for industrial production

Active Publication Date: 2014-10-29
SINOPHARM A THINK PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But the productive rate of this preparation method is low, and the resulting product purity is low

Method used

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  • Preparation method of fotemustine

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[0027] The present invention provides a preparation method of formustine, which comprises the following steps:

[0028] a) 1-aminoethyl diethyl phosphate and carmustine undergo amination reaction in the reaction medium to obtain the compound represented by formula (II); the reaction medium includes water;

[0029] b) The compound represented by formula (II) is subjected to nitrosation and converted into formustine;

[0030]

[0031] The present invention uses 1-aminoethyl diethyl phosphate and carmustine as raw materials, wherein the structural formula of 1-aminoethyl diethyl phosphate is:

[0032]

[0033] The chemical name of carmustine is: 1,3-bis(2-chloroethyl)-1-urea nitrite, and the structural formula is:

[0034]

[0035] The diethyl 1-aminoethyl phosphate and carmustine described in the present invention are raw materials well known to those skilled in the art, and the present invention has no particular limitation on this. The molar ratio of the diethyl 1-aminoethyl phosphate ...

Embodiment 1

[0045] (1) Put 5.10g (0.0279mol) of diethyl 1-aminoethyl phosphate in a 50mL reaction flask, add 4.68mL of purified water, and then add 2.0g (0.0093mol) of carmustine at room temperature. Reacted for 2h, then cooled to room temperature, washed with 10% dilute hydrochloric acid, extracted with dichloromethane, dried, evaporated to dryness under reduced pressure, washed with 20mL purified water, extracted with dichloromethane (3×20mL), and combined the extracts. The reaction product is obtained by drying with sodium sulfate, filtering, and evaporating to dryness under reduced pressure.

[0046] (2) Add 8.0 mL of formic acid to the reaction product obtained in the above steps, maintain the reaction temperature at 0℃~5℃, add 1.4g (3mol) of sodium nitrite in batches, need 1.5h to complete, and carry out nitrosation for 0.5h , Then evaporate the formic acid under reduced pressure at less than 35°C. The residue was dissolved in 20 mL of dichloromethane, washed with purified water (20 mL...

Embodiment 2

[0049] (1) Put 3.98g (0.0186mol) of diethyl 1-aminoethyl phosphate in a 50mL reaction flask, add 4.68mL of purified water, and then add 2.0g (0.0093mol) of carmustine at room temperature. Reacted for 2h, then cooled to room temperature, washed with 10% dilute hydrochloric acid, extracted with dichloromethane, dried, evaporated to dryness under reduced pressure, washed with 20mL purified water, extracted with dichloromethane (3×20mL), and combined the extracts. The reaction product is obtained by drying with sodium sulfate, filtering, and evaporating to dryness under reduced pressure.

[0050] (2) Add 8.0 mL of formic acid to the reaction product obtained in the above steps, maintain the reaction temperature at 0℃~5℃, add 1.4g (3mol) of sodium nitrite in batches, need 1.5h to complete, and carry out nitrosation for 0.5h , Then evaporate the formic acid under reduced pressure at less than 35°C. The residue was dissolved in 20 mL of dichloromethane, washed with purified water (20 mL...

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Abstract

The invention provides a preparation method of fotemustine. The preparation method comprises the following steps: carrying out an aminolysis reaction between 1-amino ethyl diethyl phosphate and carmustine in a reaction medium to obtain a compound shown in a formula (II), wherein the reaction medium comprises water; and carrying out nitrosation on the compound shown in the formula (II) to obtain fotemustine. The method provided by the invention can prepare fotemustine with the yield being greater than 25% and the purity being higher than 99.73%. In addition, by using carmustine as a raw material to replace a highly toxic liquid reagent 2-chlorethyl isocyanate, environment-friendly synthesis of fotemustine is realized; therefore, the preparation method is more suitable for industrial production.

Description

Technical field [0001] The present invention relates to the technical field of medicinal chemistry, and more specifically, to a preparation method of formustine. Background technique [0002] Formustine, chemical name is (R,S)-diethyl{1-[3-(2-chloroethyl)-3-nitrosourea]ethyl} phosphate, English name is Fotemustine, product Name "Wuhuolong", molecular formula is C 9 H 19 ClN 3 O 5 P has the structure of formula (I). [0003] [0004] Formustine is a nitrosourea anti-tumor drug developed by the French company Servier. It has alkylation, carbamylation and experimental broad-spectrum anti-tumor activities. Its molecular structure contains an alanine Bioelectronics and other ligands (amino-1-ethyl phosphate), so drug molecules easily penetrate cells and pass through the blood-brain barrier, and are used to treat primary malignant brain tumors and disseminated malignant melanomas (including intracerebral sites) . After intravenous infusion of this product in human body, the plasma eli...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/40
Inventor 王淑娟贾志丹张华徐昊柳大勇
Owner SINOPHARM A THINK PHARMA
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