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Method of synthesizing ifosfamide

A technology of ifosfamide and its synthesis method, which is applied in the fields of chemical instruments and methods, compounds of Group 5/15 elements of the periodic table, organic chemistry, etc., and can solve problems such as complex post-processing, inconvenient industrial production, and long reaction time , to achieve the effect of easy industrial production, convenient source and simple operation

Inactive Publication Date: 2007-10-24
深圳万乐药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This route undergoes a four-step reaction. Similar to route 1, the reaction time of this route is long, the yield is about 20%, and the post-treatment is relatively complicated. At the same time, it is inconvenient for industrial production due to the need to use a large amount of ether and ethyleneimine.

Method used

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  • Method of synthesizing ifosfamide
  • Method of synthesizing ifosfamide
  • Method of synthesizing ifosfamide

Examples

Experimental program
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Effect test

Embodiment 1

[0033] 1. Preparation of intermediate 3-(2-chloroacetyl)-2-[(2-chloroethyl)amino]-tetrahydro-2H-1,3,2-oxaphosphorus-2-oxide:

[0034] Add a dichloromethane solution of 0.068mol / 30ml of phosphorus oxychloride to a 250ml four-necked flask, cool with ice water, and add dropwise a mixed solution of 0.066mol of aminopropanol, 0.134mol of triethylamine and 10ml of dichloromethane, and stir thoroughly , A large amount of white matter is generated. After the dropwise addition, the reaction was carried out at -5°C for 2 hours. Then 0.062 mol of chloroethylamine hydrochloride was added to the reaction solution, and then 0.124 mol of triethylamine was added dropwise to complete the reaction in about 3 hours. Cool in an external ice bath, slowly add dropwise a dichloromethane solution of 0.062mol / 60ml of chloroacetyl chloride, and control the internal temperature at -5°C, and continue the reaction for 5 hours after the dropwise addition is completed. The triethylamine hydrochloride was remove...

Embodiment 2

[0047] 1. Preparation of intermediate 3-(2-chloroacetyl)-2-[(2-chloroethyl)amino]-tetrahydro-2H-1,3,2-oxaphosphorus-2-oxide:

[0048] Add phosphorus oxychloride in methylene chloride solution 13.1mol / 6000ml into a 50L reactor, cool the ice-water mixture, and slowly add a mixed solution of 13.2mol aminopropanol, 26.7mol triethylamine and 2000ml methylene chloride, and stir thoroughly , A large amount of white matter is generated. After the addition is complete, react at room temperature 25°C for 8 hours. Then 13.0 mol of chloroethylamine hydrochloride was added to the reaction solution, and then 25.1 mol of triethylamine was slowly added to complete the reaction, and the reaction was completed in about 5 hours. Cool outside with ice water, slowly add 12.5mol / 12000ml of dichloromethane solution of chloroacetyl chloride and control the inner temperature at 20°C. After completion, the reaction was continued for 10 hours. The triethylamine hydrochloride was removed by filtration, and t...

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Abstract

The invention discloses a synthesizing method of ifosfamide, which comprises the following steps: adopting propanolamine as raw material to ring with phosphorus oxytrichloride to obtain phosphorus oxychloride; adding chlorethamin hydrochlorate to substitute to obtain phosphamide; adding chloracetyl chloride to substitute to obtain 3-(2-chloracetyl )-2-[(2-chloroethyl ) amino]-tetrahydrochysene -2H-1,3,2-phosphor-2-oxide as intermediate; reducing the intermediate and alkaline hydroxide to obtain the product.

Description

Technical field [0001] The invention relates to a method for synthesizing ifosfamide, in particular, to a synthesis reaction carried out with aminopropanol as a starting material. Background technique [0002] Ifosfamide is a phosphoramide derivative, it is suitable for the treatment of testicular cancer, ovarian cancer, breast cancer, sarcoma, malignant lymphoma and lung cancer. Its chemical name is N,3-bis(2-chloroethyl)tetrahydro-2H-1,3,2-oxazepine-2-amino-2-oxide. The existing synthetic route is as follows: [0003] [0004] Route 1 uses ethyleneimine as the starting material to obtain ifosfamide through a three-step reaction. This route has a long reaction time, relatively complicated product processing, and a yield of about 20%. At the same time, the reagent ethyleneimine is highly toxic and unsuitable. Industrial production. [0005] Route 2 uses the same intermediate 2-chloro-3-(2-chloroethyl)-tetrahydro-2H-1,3,2-oxaphosphorus-2-oxide as in Route 1, and is then combined...

Claims

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Application Information

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IPC IPC(8): C07F9/6584
Inventor 苏军李早龙苏云淡宝玉荣
Owner 深圳万乐药业有限公司
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