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A kind of preparation method of miltefosine

A technology of miltefosine and cetyl alcohol, which is applied in the field of preparation of miltefosine, can solve the problems of large amount of dimethyl sulfate, difficulty in purification, limited application, etc., and achieves cheap and easy raw materials Obtaining and benefiting the effect of industrial scale-up

Active Publication Date: 2021-11-30
CHENGDU BAISHIXING SCI & TECH IND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in the actual reaction, it is found that the amount of dimethyl sulfate is relatively large, and the reaction is relatively complicated, which brings great difficulties to the purification and purification, and also limits its application in production scale-up

Method used

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  • A kind of preparation method of miltefosine
  • A kind of preparation method of miltefosine

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] S1: Stir and dissolve 24.2g of n-hexadecanol (0.1mol) in 100mL of tetrahydrofuran, then add 11.2g of triethylamine (0.11mol), continue to stir well, and dissolve 18.4g of phosphorus oxychloride (0.12mol) Add it to 10mL of tetrahydrofuran, then lower the temperature to below 15°C, and slowly add it dropwise to the reaction system, controlling the temperature not to exceed 20°C. After the drop is complete, stir and react at 20°C for 2 hours, and the raw materials basically disappear under TLC monitoring. Then 10.68g of dimethylethanolamine (0.12mol) and 12.2g of triethylamine (0.12mol) were dissolved in 150mL of tetrahydrofuran, and the temperature was controlled below 40°C and added dropwise to the reaction system, and reacted at room temperature for 2 hours. The temperature was raised to 40° C. and stirring was continued for 15 minutes, and the starting material basically disappeared as monitored by TLC.

[0028] S2: Cool the system to 5°C overnight, then filter, add 50...

Embodiment 2

[0031] S1: Stir and dissolve 36.3g of n-hexadecanol (0.15mol) in 150mL of tetrahydrofuran, then add 16.8g of triethylamine (0.165mol), continue to stir well, and dissolve 27.6g of phosphorus oxychloride (0.18mol) Into 15mL of tetrahydrofuran, then lower the temperature to below 15°C, and slowly add it dropwise to the reaction system, controlling the temperature not to exceed 20°C. After the drop is complete, stir and react at 20°C for 2 hours, and the raw materials basically disappear under TLC monitoring. Then 16g of dimethylethanolamine (0.18mol) and 18.3g of triethylamine (0.18mol) were dissolved in 225mL of tetrahydrofuran, and the temperature was controlled below 40°C and added dropwise to the reaction system, and reacted at room temperature for 2 hours. The temperature was raised to 40° C. and stirring was continued for 15 minutes, and the starting material basically disappeared as monitored by TLC.

[0032] S2: Cool the system to 5°C overnight, then filter, add 75mL of ...

Embodiment 3

[0035] S1: Stir and dissolve 242g of n-hexadecanol (1mol) in 1000mL of tetrahydrofuran, then add 112g of triethylamine (1.1mol), continue to stir well, and dissolve 184g of phosphorus oxychloride (1.2mol) into 100mL of tetrahydrofuran Then lower the temperature to below 15°C, slowly add dropwise to the reaction system, control the temperature not to exceed 20°C, stir and react at 20°C for 2 hours after dropping, TLC monitors that the raw materials basically disappear. Then 107g of dimethylethanolamine (1.2mol) and 122g of triethylamine (1.2mol) were dissolved in 1500mL of tetrahydrofuran, and the temperature was controlled below 40°C and added dropwise to the reaction system, and reacted at room temperature for 2 hours. The temperature was raised to 40° C. and stirring was continued for 15 minutes, and the starting material basically disappeared as monitored by TLC.

[0036] S2: Cool the system to 5°C overnight, then filter, add 500mL of 2mol / L hydrochloric acid (1mol) dropwis...

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Abstract

The invention belongs to the technical field of organic chemistry, and discloses a preparation method of miltefosine, which is characterized in that it comprises the following steps: S1: reacting cetyl alcohol, phosphine oxychloride and dimethylethanolamine to generate cetyl Alkyl amine phosphate solution; S2: the ammonium cetyl phosphate solution obtained in the S1 step is made into the hydrochloride of ammonium cetyl phosphate; S3: the ammonium cetyl phosphate solution obtained in step S2 is obtained Then react with dimethyl sulfate to generate miltefosine, and obtain pure miltefosine after refining and purification. The raw materials of the method are cheap and easy to obtain, the reaction is simple, the operation is simple and convenient, and it is beneficial to industrial scale-up.

Description

technical field [0001] The invention belongs to the technical field of organic chemistry, and in particular relates to a preparation method of miltefosine. Background technique [0002] Miltefosine (miltefosine), chemical name hexadecylphosphocholine (HePC), is a zwitterionic compound. It is an alkylphosphocholine drug originally developed as an antitumor drug, which has cell membrane targeting, and has shown significant selective antitumor and antiprotozoal activities in animal experiments and clinical applications. As an antineoplastic drug, miltefosine is mainly used for the local treatment of epidermal metastasis of breast cancer, and for the treatment of skin and visceral leishmaniasis in antiprotozoal infection. In the treatment of visceral leishmaniasis, oral miltefosine has better curative effect, lower toxicity, and can be administered orally compared with commonly used sodium stibogluconate, pentamidine, and amphotericin B liposome injections. Drug, patient toler...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/09
CPCC07F9/091
Inventor 石常青
Owner CHENGDU BAISHIXING SCI & TECH IND
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