A kind of preparation method of falmustine

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

Active Publication Date: 2016-04-27
SINOPHARM A THINK PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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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  • A kind of preparation method of falmustine
  • A kind of preparation method of falmustine
  • A kind of preparation method of falmustine

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

[0028] a) Aminolysis reaction of 1-aminoethyl diethyl phosphate and carmustine in the reaction medium to obtain the compound shown in formula (II); the reaction medium includes water;

[0029] b) Nitrosating the compound represented by formula (II) into formustine;

[0030]

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

[0032]

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

[0034]

[0035] The 1-aminoethyl phosphate diethyl ester 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 thereto. The molar ratio of the 1-aminoethyl diethyl phosphate to the ca...

Embodiment 1

[0045] (1) Put 5.10 g (0.0279 mol) of 1-aminoethyl phosphate diethyl ester in a 50 mL reaction flask, add 4.68 mL of purified water, then add 2.0 g (0.0093 mol) of carmustine at room temperature, and React for 2 hours, then cool to room temperature, wash with 10% dilute hydrochloric acid, extract with dichloromethane, dry, evaporate to dryness under reduced pressure, then wash with 20 mL of purified water, extract with dichloromethane (3×20 mL), combine the extracts, Dry over sodium sulfate, filter, and evaporate to dryness under reduced pressure to obtain the reaction product.

[0046](2) Add 8.0mL of formic acid to the reaction product obtained in the above steps, keep the reaction temperature at 0°C~5°C, add 1.4g (3mol) of sodium nitrite in batches, it takes 1.5h to complete the addition, and carry out nitrosation for 0.5h , then distill off formic acid under reduced pressure at less than 35°C, dissolve the residue in 20mL of dichloromethane, wash with purified water (20mL×...

Embodiment 2

[0049] (1) Put 3.98g (0.0186mol) of 1-aminoethyl diethylphosphate in a 50mL reaction flask, add 4.68mL of purified water, then add 2.0g (0.0093mol) of carmustine at room temperature, and React for 2 hours, then cool to room temperature, wash with 10% dilute hydrochloric acid, extract with dichloromethane, dry, evaporate to dryness under reduced pressure, then wash with 20 mL of purified water, extract with dichloromethane (3×20 mL), combine the extracts, Dry over sodium sulfate, filter, and evaporate to dryness under reduced pressure to obtain the reaction product.

[0050] (2) Add 8.0mL of formic acid to the reaction product obtained in the above steps, keep the reaction temperature at 0°C~5°C, add 1.4g (3mol) of sodium nitrite in batches, it takes 1.5h to complete the addition, and carry out nitrosation for 0.5h , then distill off formic acid under reduced pressure at less than 35°C, dissolve the residue in 20mL of dichloromethane, wash with purified water (20mL×3), dry over...

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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 invention relates to the technical field of medicinal chemistry, and more specifically relates to a preparation method of formustine. Background technique [0002] Fotemustine, the chemical name is (R,S)-diethyl {1-[3-(2-chloroethyl)-3-nitrosourea]ethyl} phosphate, the English name is Fotemustine, commercial The name "Wuhuolong", the molecular formula is C 9 h 19 ClN 3 o 5 P, has the structure of formula (I). [0003] [0004] Formustine is a nitrosourea antineoplastic drug developed by the French company Servier. It has alkylation, carbamylation and experimental broad-spectrum antitumor activity. Its molecular structure contains an alanine Ligands such as bioelectronics (amino-1-ethyl phosphate), so drug molecules can easily penetrate cells and pass through the blood-brain barrier for the treatment of primary malignant brain tumors and disseminated malignant melanoma (including brain sites) . After intravenous infusion of this product, t...

Claims

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Application Information

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Patent Type & Authority Patents(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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