Method for synthesizing busulfan

A synthesis method and busulfan technology are applied in the preparation of sulfonates, organic chemistry, etc., and can solve the problems of difficulty in obtaining injection busulfan samples and difficult to remove.

Active Publication Date: 2012-04-11
暨明医药科技(苏州)有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Such by-products are carcinogenic and belong to the category of strict control in the raw material drug standards. The control standard is no more than 6 ppm. These by-products are insoluble in water and soluble in organic solvents, and are not easy to remove in post-processing. , so it is difficult to obtain samples of busulfan for injection that meet FDA standards

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  • Method for synthesizing busulfan
  • Method for synthesizing busulfan
  • Method for synthesizing busulfan

Examples

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Embodiment 1

[0017] Embodiment 1, a kind of synthetic method of busulfan, it uses 1,4-butanediol, methanesulfonic anhydride is main raw material, with triethylamine, pyridine, diethylisopropylamine or sodium bicarbonate At least one kind of base is used as a solvent with acetone, tetrahydrofuran, acetonitrile or ether, and the entire reaction process is carried out under nitrogen protection; the specific steps are: add methanesulfonic anhydride in the reaction vessel, add a solvent to dissolve, and wait until the methanesulfonic anhydride is completely dissolved Finally, cool the system down to -20°C, add 1,4-butanediol and alkali to the solvent to dissolve, mix well and add the mixture dropwise to the above system, and maintain the temperature in the system at -20°C during the dropwise addition. ℃; then stirred at room temperature, suction filtered, and the filter cake was washed with deionized water and solvent to obtain the crude product of white solid busulfan; wherein: the molar ratio ...

Embodiment 2

[0018] Embodiment 2, a kind of synthetic method of busulfan, it uses 1,4-butanediol, methanesulfonic anhydride is main raw material, with triethylamine, pyridine, diethylisopropylamine or sodium bicarbonate At least one kind of base is used as a solvent with acetone, tetrahydrofuran, acetonitrile or ether, and the entire reaction process is carried out under nitrogen protection; the specific steps are: add methanesulfonic anhydride in the reaction vessel, add a solvent to dissolve, and wait until the methanesulfonic anhydride is completely dissolved Finally, cool down the system to 5°C, add 1,4-butanediol and alkali into the solvent to dissolve, mix well and add the mixture dropwise to the above system, and maintain the temperature in the system at 35°C during the dropping process; Then stir at room temperature, filter with suction, and wash the filter cake with deionized water and solvent to obtain the crude product of white solid busulfan; wherein: the molar ratio of 1,4-buta...

Embodiment 3

[0020] Embodiment 3, a kind of synthetic method of busulfan, it uses 1,4-butanediol, methanesulfonic anhydride is main raw material, with triethylamine, pyridine, diethylisopropylamine or sodium bicarbonate At least one kind of base is used as a solvent with acetone, tetrahydrofuran, acetonitrile or ether, and the entire reaction process is carried out under nitrogen protection; the specific steps are: add methanesulfonic anhydride in the reaction vessel, add a solvent to dissolve, and wait until the methanesulfonic anhydride is completely dissolved Finally, cool down the system to 0°C, add 1,4-butanediol and alkali into the solvent to dissolve, mix well and add the mixture dropwise to the above system, and maintain the temperature in the system at -5°C during the dropping process Then stir at room temperature, filter with suction, and wash the filter cake with deionized water and solvent to obtain the crude product of white solid busulfan; wherein: the molar ratio of 1,4-butan...

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Abstract

The invention discloses a method for synthesizing busulfan, which is characterized in that: 1,4-butanediol and methanesulfonic anhydride is taken as main materials; at least one of triethylamine, pyridine, diethylisopropyl amine or sodium bicarbonate is taken as alkali; acetone, tetrahydrofuran, acetonitrile or diethyl ether is taken as solvent; and the whole reaction process is carried out underthe protection of nitrogen gas. The invention also further discloses a method for re-crystallizing busulfan. The methanesulfonic anhydride is used to replace methanesulfonyl chloride so that chlorine-containing product is avoided being produced in the synthesis technology; excessive methanesulfonic anhydride can be reacted with the alkali to form salt, and the salt can be ensured to be all removed after being repeatedly washed by large amounts of water, so that types and content of impurities in the busulfan can be effectively controlled. The method disclosed by the invention is simple, reasonable and easy to operate. The busulfan prepared by re-crystallization can be directly used for preparing injection.

Description

technical field [0001] The invention relates to a synthesis method of a drug raw material, in particular to a synthesis method of busulfan. Background technique [0002] Busulfan, also known as Baixue Fuen, Maryland. The chemical name is 1, 4-butanediol dimesylate, and the English name is: Busulfan. It is a sulfonic acid alkylating agent antitumor drug. The solid busulfan is a white crystalline powder, and its solubility in acetone at 25°C It is 2.4g / 100ml, the solubility in ethanol is 0.1g / 100ml, almost odorless, and the melting point is 114-118℃. Insoluble in water, but can be slowly dissolved, while hydrolysis occurs. Busulfan for injection is a colorless or almost colorless clear liquid. [0003] Busulfan is a bifunctional alkylating agent of bis-methylsulfonate, which is a non-specific drug for the cell cycle. When it enters the human body, the ring structure of the sulfonate group is opened, and it destroys the structure and function of DNA by alkylating with guan...

Claims

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Application Information

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IPC IPC(8): C07C309/66C07C303/28
Inventor 陈剑戈
Owner 暨明医药科技(苏州)有限公司
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