Method for synthesizing chlorambucil

A technology of chlorambucil and chlorambucil, applied in chemical instruments and methods, preparation of organic compounds, organic chemistry and other directions, can solve the problems of low product yield, complicated post-processing purification process, many synthesis steps and the like , to achieve the effect of simple reaction and post-processing purification process, high reaction region selectivity and yield, and high anti-tumor effect

Active Publication Date: 2021-07-16
NANJING TECH UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0002] Chlorambucil (CB-1348, leukeran) belongs to aromatic nitrogen mustard, it is white crystal, m.p.64~67℃, insoluble in water, soluble in ethanol and chloroform, etc. Chlorambucil was synthesized in the 1950s , the four-carbon lipid chain in the molecule improves the lipophilicity of the molecule, while the free carboxylic acid increases the hydrophilicity, and the partition coefficient in benzene / water is 0.67. The mechanism of action of chlorambucil is the same as that of other nitrogen mustard drugs, mainly causing The cross-linking of DNA chains affects the function of DNA. Drug resistance is mainly due to the increase in the activity of glutathione S-transferase. The anti-tumor effect of mustard is lower than that of chlorambucil, but the dechlorination ethyl effect is slow, so the action time is longer, and it is mainly used for chronic lymphocytic leukemia, ovarian cancer and low-grade non-Hodgkin's lymphoma
[0003] The existing synthetic method of chlorambucil generally has many synthetic steps, poor reaction regioselectivity, low product yield, mild reaction conditions, complex reaction and post-treatment purification process, etc.

Method used

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  • Method for synthesizing chlorambucil
  • Method for synthesizing chlorambucil
  • Method for synthesizing chlorambucil

Examples

Experimental program
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Effect test

Embodiment 1

[0029] (1) Under an inert atmosphere, 4-bromo-N,N-bis(2-chloroethyl)aniline, N-(quinoline-8- base) but-3-enamide, palladium chloride, tri-n-butylphosphine tetrafluoroborate, potassium carbonate, benzoic acid and dimethyl sulfoxide in a molar volume ratio of 0.1mmol: 2mL was added to Mix in the reaction vessel;

[0030] (2) Place the reaction vessel in an oil bath at 135°C and stir vigorously for 24 hours. The reaction product is washed with petroleum ether and ethyl acetate at a ratio of 1:5 to separate and purify the chromatographic silica gel column to obtain a compound with a leaving group. Detection determined that the compound was 4-(4-(bis(2-chloroethyl)amino)phenyl)-N-(quinolin-8-yl)butyramide;

[0031] (3) After adding the compound capable of leaving the group into an aqueous solution of sodium hydroxide and heating to reflux for 12 hours, acidify to obtain chlorambucil, and the yield of chlorambucil is 41%.

Embodiment 2

[0033] (1) Under an inert atmosphere, 4-bromo-N,N-bis(2-chloroethyl)aniline, N-(quinoline-8- base) but-3-enamide, palladium chloride, tri-n-butylphosphine tetrafluoroborate, potassium carbonate, benzoic acid and dimethyl sulfoxide in a molar volume ratio of 0.1mmol: 2mL was added to Mix in the reaction vessel;

[0034] (2) Place the reaction vessel in an oil bath at 135°C and stir vigorously for 24 hours. The reaction product is washed with petroleum ether and ethyl acetate at a ratio of 1:5 to separate and purify the chromatographic silica gel column to obtain a compound with a leaving group. Detection confirmed that the compound was 4-(4-(bis(2-chloroethyl)amino)phenyl)-N-(quinolin-8-yl)butyramide.

[0035] (3) After adding the compound capable of leaving the group into an aqueous solution of sodium hydroxide and heating to reflux for 12 hours, acidify to obtain chlorambucil, and the yield of chlorambucil is 6%.

Embodiment 3

[0037] (1) Under an inert atmosphere, 4-bromo-N,N-bis(2-chloroethyl)aniline, N-(quinoline-8- base) but-3-enamide, palladium chloride, tri-n-butylphosphine tetrafluoroborate, potassium carbonate, benzoic acid and dimethyl sulfoxide in a molar volume ratio of 0.1mmol: 2mL was added to Mix in the reaction vessel;

[0038](2) The reaction vessel was placed in an oil bath at 135°C and stirred vigorously for 24 hours, and the reaction product was washed with petroleum ether and ethyl acetate at a ratio of 1:5 to separate and purify the chromatographic silica gel column to obtain a compound with a leaving group. Detection confirmed that the compound was 4-(4-(bis(2-chloroethyl)amino)phenyl)-N-(quinolin-8-yl)butyramide.

[0039] (3) After adding the compound capable of leaving the group into an aqueous solution of sodium hydroxide and heating to reflux for 12 hours, acidify to obtain chlorambucil, and the yield of chlorambucil is 9%.

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Abstract

The invention discloses a method for synthesizing chlorambucil, which relates to the technical field of organic chemistry, and comprises the following steps: S1, adding a mixture of 4-bromo-N, N-bis (2-chloroethyl) aniline, N-(quinolin-8-yl) butyl 3-enamide, palladium chloride, tri-n-butylphosphine tetrafluoroborate, potassium carbonate and benzoic acid at ratio of 10.83%: 10.83%-32.50%: 0.22%-2.17%: 0.43%-2.17%: 10.83%-54.17%: 10.83%-54.17% and dimethyl sulfoxide at molar volume ratio of 0.1 mmol: 2 mL to a reaction vessel for uniform mixing; and S2, placing the reaction container in an oil bath at 135-145 DEG C, and violently stirring to react for 24 hours. According to the invention, through the coupling reaction, 8-aminoquinoline is designed as a compound of a leaving group to control regioselectivity and chemical selectivity in the reaction, so that the problem of excessive steps in the existing synthesis process of chlorambucil is effectively solved; the method has the characteristics of high reaction region selectivity and yield, mild reaction conditions and simple reaction and post-treatment purification processes.

Description

technical field [0001] The invention relates to the technical field of organic chemistry, in particular to a method for synthesizing chlorambucil. Background technique [0002] Chlorambucil (CB-1348, leukeran) belongs to aromatic nitrogen mustard, it is white crystal, m.p.64~67℃, insoluble in water, soluble in ethanol and chloroform, etc. Chlorambucil was synthesized in the 1950s , the four-carbon lipid chain in the molecule improves the lipophilicity of the molecule, while the free carboxylic acid increases the hydrophilicity, and the partition coefficient in benzene / water is 0.67. The mechanism of action of chlorambucil is the same as that of other nitrogen mustard drugs, mainly causing The cross-linking of DNA chains affects the function of DNA. Drug resistance is mainly due to the increase in the activity of glutathione S-transferase. The anti-tumor effect of mustard is lower than that of chlorambucil, but the dechlorination ethyl effect is slow, so the action time is l...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/02C07C229/42C07D215/40
CPCC07C227/02C07D215/40C07C229/42
Inventor 吴晓进邵慧慧
Owner NANJING TECH UNIV
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