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Method for preparing thiotepa

A technology of thiotepa and organic solvents, which is applied in the field of preparation of ethyleneimine alkylating agents, can solve the problems of low yield, difficult to control the quality of intermediates, and large impurities, and achieve high yield, less three wastes, and simple operation Effect

Active Publication Date: 2018-09-04
HEILONGJIANG FUHE HUAXING PHARMA GROUP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The intermediate aziridine and lye prepared by this route are not separated, the quality of the intermediate is not easy to control, the substitution reaction is carried out in water, a large amount of impurities is produced, and the yield is extremely low, less than 10%.

Method used

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  • Method for preparing thiotepa
  • Method for preparing thiotepa
  • Method for preparing thiotepa

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] The preparation method of embodiment 1 thiotepa

[0032] Table 1. Preparation of required raw materials and organic solvent consumption of thiotepa

[0033]

[0034] S1: Add ethyleneimine and 870mL organic solvent into the low-temperature reaction kettle, turn on the refrigerant interlayer to cool down, and circulate the temperature. When the temperature in the reaction kettle drops to 16.5°C, turn on the stirring paddle;

[0035] S2: Dissolve thion trichloride in 1690mL organic solvent and add it dropwise to the reaction kettle. When the thion trichloride organic solvent is added dropwise to 828.1mL, the predetermined amount Y=0.49mol / When 1mol=49%, add the acid-binding agent dropwise, the dropping rate of the acid-binding agent is 3.06 times of the dropping rate of the phosphorus thionium chloride organic solvent, and keep the temperature at 16.5°C for 32 minutes;

[0036] S3: Filtrate, distill the filtrate to remove the organic solvent under reduced pressure to ...

Embodiment 2

[0037] The preparation method of embodiment 2 thiotepa

[0038] Table 2. Preparation of required raw materials and organic solvent consumption of thiotepa

[0039]

[0040] S1: Add ethyleneimine and 1119mL organic solvent into the low-temperature reaction kettle, turn on the refrigerant interlayer to cool down, and circulate the temperature. When the temperature in the reaction kettle drops to 17°C, turn on the stirring paddle;

[0041] S2: Dissolve thion trichloride in 1521mL of organic solvent and add it dropwise to the reaction kettle. When the organic solvent of thion trichloride is added dropwise to 745.29mL, the predetermined amount of thion trichloride added Y=0.49mol / When 1mol=49%, add the acid-binding agent dropwise, the dropping rate of the acid-binding agent is 3.05 times of the dropping rate of the phosphorous trichloride organic solvent, and keep the temperature at 17°C for 30 minutes;

[0042] S3: Filtrate, distill the filtrate to remove the organic solvent ...

Embodiment 3

[0043] The preparation method of embodiment 3 thiotepa

[0044] Table 3. Preparation of required raw materials and organic solvent consumption of thiotepa

[0045]

[0046] S1: Add ethyleneimine and 1198mL organic solvent into the low-temperature reaction kettle, turn on the refrigerant interlayer to allow cooling, and circulate the temperature to cool down. When the temperature in the reaction kettle drops to 15°C, turn on the stirring paddle;

[0047] S2: Dissolve thion tribromide in 1352mL organic solvent and add it dropwise to the reaction kettle. When the thion tribromide organic solvent is added dropwise to 662.48mL, the predetermined amount of thion trichloride added Y=0.49mol / When 1mol=49%, add the acid-binding agent dropwise, the dropping speed of the acid-binding agent is 3.07 times of the dropping speed of the tribromothion organic solvent, and keep the temperature at 15°C for 45 minutes;

[0048] S3: Filtrate, distill the filtrate to remove the organic solvent...

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Abstract

The invention provides a method for preparing thiotepa. The method comprises the following steps: cooling ethylenimine and an organic solvent to a temperature of 15-17 DEG C, dropping an organic solvent of trihalothiophosphorus, dropping an acid-binding agent when the trihalothiophosphorus is dropped to reach a scheduled quantity Y of 49%, maintaining the temperature of 15-17 DEG C, and reacting for 30-45 minutes; filtering, performing reduced pressure distillation on the filtrate to remove the organic solvent so as to obtain the residue, and purifying, so as to obtain the thiotepa. The raw materials and reagent used in the preparation method provided by the invention are cheap and readily available, the produced three wastes are less, and the method is simple in operation, high in yield and suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of preparation methods of ethyleneimine alkylating agents, and in particular relates to a preparation method of thiotepa. Background technique [0002] Thiotepa, whose chemical name is 1,1'1"-thiophosphinotriaziridine, is an alkylating agent developed by Cyanamid Company of the United States. It is used for ovarian cancer, breast cancer, bladder cancer and other diseases Treatment. The compound has undergone clinical research by Adienne SA, and in 2017, the US FDA approved the compound for combined use in myelosuppression. [0003] Thiotepa has the following structure: [0004] [0005] According to literature reports, the synthetic routes of thiotepa mainly contain the following types at present: [0006] US2670347 disclosed the preparation method of Thiotepa for the first time. In this method, ethyleneimine, triethylamine and anhydrous benzene are cooled to below 0°C, and the solution of phosphorus tr...

Claims

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Application Information

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IPC IPC(8): C07F9/564
CPCC07F9/564
Inventor 吴光彦
Owner HEILONGJIANG FUHE HUAXING PHARMA GROUP