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Preparation method of phosphocholine alkyl ester

A technology of alkyl phosphate and choline, applied in the direction of phosphorus organic compounds, etc., can solve the problems of unstable intermediates, poor purity, difficult to purify, etc., and achieve the effects of simplified operation, improved purity and low price

Active Publication Date: 2012-06-13
NINGBO CHEMGOO PHAMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0017] The above method needs to prepare chlorinated cyclic phosphate ester formula (D-I), which has many unfavorable factors. First, this intermediate is unstable, poor in purity, and difficult to prepare
Secondly, the first step of the preparation of (D-I) needs to use highly toxic and dangerous phosphorus trichloride, which is not easy for industrial operation; the second step oxidation reaction is dangerous and the yield is low
In addition, we found that the purity of the intermediate (D-II) was poor; the intermediate (D-I) was not refined, and it was directly carried out in the next step of the reaction, resulting in poor quality of the final product and difficult to refine; the final product required a column Recrystallization after chromatography

Method used

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  • Preparation method of phosphocholine alkyl ester
  • Preparation method of phosphocholine alkyl ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Step 1: Preparation of Intermediate B Hexadecyl Cyclic Phosphate Compound

[0048] In a 500ml four-necked flask, put 27.9g (1.1eq) of phosphorus oxychloride and 100ml of dry tetrahydrofuran into a 500ml four-necked flask, stir, and cool the reaction in an ice-salt bath to below -5°C. Ethylamine 25g (1.5eq) - tetrahydrofuran 100ml solution, add dropwise for about 2 hours, then continue to keep warm at -5°C for 0.5h, filter, and wash the filter cake with 20ml tetrahydrofuran;

[0049] Transfer the filtrate and washing liquid back to the four-necked flask, stir, cool to about -5°C, start to drop a solution of 10.3g (1eq) of ethylene glycol and 40g (2.4eq) of triethylamine - 40ml of tetrahydrofuran for about 1h After the addition is complete, react overnight, and the reaction is basically complete, filter, wash the filter cake with 40ml of tetrahydrofuran, and evaporate the filtrate to dryness under reduced pressure;

[0050] Add 250ml of dichloromethane to the obtained re...

Embodiment 2

[0058] Step 1: Preparation of Intermediate B Hexadecyl Cyclic Phosphate Compound

[0059] In a 500L reaction kettle, put 11.5kg (1.5eq) of phosphorus oxychloride and 50L of dry dioxane, stir, and cool the reaction in an ice-salt bath to below -10°C. At the same time, add 12kg (1eq) of cetyl alcohol dropwise. - Potassium carbonate 15.2kg (2.2eq) - dioxane 100L solution, about 2h to complete the dropwise addition, then continue to keep warm at -10°C for 0.5h, filter, and wash the filter cake with 3L dioxane;

[0060] The filtrate and lotion were transferred back to the four-necked bottle, stirred, cooled to about -10°C, and began to dropwise add a solution of 4.66kg (1eq) of ethylene glycol and 15.2kg (2.2eq) of potassium carbonate dissolved in 100L of dioxane, The dropwise addition was completed in about 1 hour, and the reaction was completed for 12 hours. The reaction was basically complete, filtered, and the filter cake was washed with 3 L of dioxane, and the filtrate was eva...

Embodiment 3

[0072] Step 1: Preparation of Intermediate B Hexadecyl Cyclic Phosphate Compound

[0073] In a 20L reaction kettle, put 0.75kg (0.8eq) of phosphorus oxychloride and 2L of dry acetone, stir, cool the reaction in an ice-salt bath to below -8°C, and drop 1.5kg (1eq) of cetyl alcohol-pyridine 0.7kg (1.4eq) - acetone 6L solution, about 1h to complete the dropwise addition, then continue to keep warm at -8°C for 0.5h, filter, and wash the filter cake with 3L of acetone;

[0074] Transfer the filtrate and lotion back to the four-necked bottle, stir, cool to about -8°C, start to add dropwise the solution of 0.8kg (2eq) of ethylene glycol and 1kg (2eq) of pyridine dissolved in 2L of acetone, and the dropwise addition is completed in about 1 hour. After 12 hours of reaction, the reaction was basically complete, filtered, the filter cake was washed with 0.5L acetone, and the filtrate was evaporated to dryness under reduced pressure;

[0075] Add 1 L of cyclohexanone to the obtained resi...

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Abstract

The invention relates to a preparation method of phosphocholine alkyl ester. The method comprises the following steps of: a. carrying out an esterification reaction on cetyl alcohol and phosphorus oxychloride in an organic solvent under the action of an alkaline substance at (-20)-50 DEG C to obtain a substance A; b. carrying out a sufficient cyclization reaction on the substance A and ethylene glycol in an organic solvent under the action of an alkaline substance at (-20)-50 DEG C, carrying out solid-liquid separation on the obtained reaction liquid, concentrating the obtained liquid phase and dissolving in a solvent, washing with water and concentrating to obtain an intermediate B; and c. carrying out a sufficient ring-opening substitution reaction on the intermediate B obtained in the step b and trimethylamine in an organic solvent in a closed environment, carrying out solid-liquid separation on the obtained reaction liquid, and refining the obtained solid phase with a solvent to obtain a product. In the synthetic route adopted by the preparation method provided by the invention, no byproduct is generated in the final-step reaction, and the high-purity product can be obtained by a simple pulping and recrystallizing method after the reaction is finished; and the preparation method is suitable for industrial production.

Description

[0001] technical field [0002] The invention belongs to the technical field of organic chemistry, and relates to a method for preparing an oxyester of phosphorus, in particular to a method for preparing an alkyl choline phosphate. Background technique [0003] Miltefosine, namely Hexadecylphosphocholine, D-18506, is a choline phosphoryl alkyl ester, the Chinese name is miltefosine, mitefoxine or mitefoxine, and the chemical name is hexadecyl 2-(trimethyl Amino)ethyl phosphate, which has antineoplastic activity, is currently on the market for the treatment of a tropical infectious disease, leishmaniasis. Its anti-tumor activity was first studied by Dr. Eibl H of Max-Planck-Inst. In 1980, he published the synthesis of chromatographically pure Hexadecylphosphocholine to measure its isoelectric point properties. [0004] The preparation method of this phosphorylcholine alkyl ester (hereinafter referred to as mitfuroxine) can be represented by the following reaction formula: ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/09
Inventor 李昌龙楼科侠张少伟张达
Owner NINGBO CHEMGOO PHAMA TECH
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