Method for preparing amifostine

A technology of amifostine and amino group is applied in the preparation field of adjuvant therapeutic agent amifostine, which can solve the problems of industrialized production obstacles, difficult long-distance transportation, feasibility limitation and the like, and achieves the effects of low price, safe use and simplified production process.

Active Publication Date: 2012-09-12
NANJING CHENGONG PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0019] The inventor team compared the above different synthesis methods. The first method is the synthesis method of amifostine, which is currently more commonly used. The raw materials used are cheap, the reaction conditions are mild, and it is suitable for industrial production; but ethylene oxide is a toxic carcinogen It is flammable and explosive, not easy to transport over long distances, and is controlled by the public security department, so it has strong regional characteristics
Method 2 has the fewest reaction steps and provides the most direct method to obtain N-(2-hydroxyethyl)-1,3-propanediamine, an important intermediate of amifostine. It avoids the use of ethylene oxide and is

Method used

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  • Method for preparing amifostine
  • Method for preparing amifostine
  • Method for preparing amifostine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] a) Add phthalimide (147g, 1.00 mol), N,N-dimethylformamide (DMF) 700mL, triethylamine ( 101g, 1.00 mol), after the addition, control the temperature of the reaction solution at 0°C to 5°C, start to slowly add 1,3-dibromopropane (202g, 1.00 mol), and control the temperature of the reaction solution at 10°C to Stir at 15°C for 3 hours. After the reaction was completed, concentrated under reduced pressure to recover N,N-dimethylformamide (DMF), added 500 mL of water to the concentrate, and solids were precipitated, filtered, and the filter cake was recrystallized once with 90% ethanol, dried in vacuo at 40°C to obtain N-( 3-Bromopropyl) phthalimide weighed 268g (1.00 mol), measured the melting point of 72°C to 75°C, and the yield was 100%.

[0062] b) In a reaction flask equipped with stirring and a thermometer, add N-(3-bromopropyl)phthalimide (268g, 1.00mol) and 600mL of acetonitrile prepared in the previous step to control the temperature of the reaction solution Slow...

Embodiment 2

[0069] a) Add phthalimide (147g, 1.00 mol), dimethyl sulfoxide 700mL, and sodium carbonate (53g, 0.5 mol) to the reaction flask equipped with stirring, thermometer and dropping device. , control the temperature of the reaction solution at 0° C. to 5° C., start to slowly add 1,3-dibromopropane (404 g, 2.00 mol) dropwise, and then control the temperature of the reaction solution at 1° C. to 5° C. and stir for 5 hours. After the reaction was completed, concentrated under reduced pressure to recover dimethyl sulfoxide, added 500 mL of water to the concentrate, and solids were precipitated, filtered, and the filter cake was recrystallized once with 90% ethanol, and dried under vacuum at 40°C to obtain N-(3-bromopropyl) o-phenyl Dicarboximide weighs 268g (1.00 mol), and its melting point is 72°C to 75°C. The yield is 100%.

[0070] b) In a reaction flask equipped with stirring and a thermometer, add N-(3-bromopropyl)phthalimide (268g, 1.00mol) prepared in the previous step reaction,...

Embodiment 3

[0077] a) Add phthalimide (147g, 1.00mol), dioxane 700mL, and sodium methoxide (1.5mol) into a reaction flask equipped with a stirring, thermometer, and dropping device. After the addition, control the reaction The liquid temperature was 0°C-5°C, and 1,3-dibromopropane (202 g, 1.00 mol) was slowly added dropwise. After the dropwise addition, the reaction liquid temperature was controlled at 5°C-10°C and stirred for 4 hours. After the reaction was completed, the dioxane was concentrated under reduced pressure to recover dioxane, the concentrate was added with 500 mL of water, and a solid precipitated out, filtered, and the filter cake was recrystallized once with 90% ethanol, and dried under vacuum at 40°C to obtain N-(3-bromopropyl)phthalic dioxane Formimide weighed 268g (1.00 mol), measured melting point 72°C-75°C, yield 100%.

[0078]b) In a reaction flask equipped with stirring and a thermometer, add N-(3-bromopropyl)phthalimide (268g, 1.00mol) prepared in the previous step...

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Abstract

The invention relates to a method for preparing amifostine, comprising the following steps: a) reacting phthalimide with 1,3-dibromopropane in dipolar aprotic solvents to genenrate N-(3-bromopropyl) phthalimide; and b)reacting N-(3-bromopropyl) phthalimide with 2-oxazolidinone in dipolar aprotic solvents to generate 2,2-[3-(2-carbonyl-3-oxazole)propyl]-1H-isoindole-1,3(2H)-diketone; and using the one-pot process to prepare the amifostine directly from the intermediate 2,2-[3-(2-carbonyl-3-oxazole)propyl]-1H-isoindole-1,3(2H)-diketone, thus the production process can be simplified, and the production cost can be saved. In addition, primary amine is obtained by hydrazinolysis, thus the reaction conditions are mild, the side effect is low, and the post-treatment is simple. The method has the characteristics of easy obtainment of raw materials, low price, safe and convenient usage, little pollution, easy transportation, and the like.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical engineering, and in particular relates to a preparation method of amifostine, an adjuvant therapeutic agent for tumor radiotherapy or cytotoxic chemotherapy. Background technique [0002] Amifostine is the first broad-spectrum normal cell protective agent recognized by international authorities, and is mainly used for adjuvant therapy of various cancers. Applying this product before chemotherapy for lung cancer, ovarian cancer, breast cancer, nasopharyngeal cancer, bone tumor, digestive tract tumor, blood system tumor and other cancer patients can significantly reduce the damage caused by chemotherapy drugs to the kidney, bone marrow, heart, Ear and nervous system toxicity without reducing the efficacy of chemotherapy drugs. Applying this product before radiotherapy can significantly reduce the occurrence of xerostomia and mucositis. Amifostine was first developed by the U.S. Army Researc...

Claims

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Application Information

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IPC IPC(8): C07F9/165
Inventor 郭昭
Owner NANJING CHENGONG PHARM CO LTD
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