Synthetic method of pyrrol-indole compound as drug intermediate

Abstract

The invention relates to a synthetic method of a pyrrol-indole compound shown in the formula (IV) (in the description). The method comprises the following steps: in a room-temperature and nitrogen environment, sequentially adding a compound shown in the formula (I) (in the description), a compound shown in the formula (II) (in the description), a compound shown in the formula (III) (in the description), a composite catalyst, gallium trichloride and organic alkali into an organic solvent, then, heating to 70-85 DEG C, performing full stirring reaction for 4-6 hours at the temperature of 70-85 DEG C, and performing postprocessing, so as to obtain the compound shown in the formula (IV), wherein in the formulas, R1 is selected from H or C1-C6 alkyl groups; R2 is selected from H, C1-C6 alkyl groups, C1-C6 alkoxy groups or halogen; A is substituted and unsubstituted C5-C8 naphthenic bases, or substituted and unsubstituted phenyl groups. According to the method, the appropriate reaction substrates, the catalyst, the organic alkali and the organic solvent are comprehensively selected and coordinated, and the gallium trichloride is used, so that the target product can be obtained with high yield, and the method has good application prospect and high market popularization value in the field of synthesis of medical intermediates.

Description

technical field

[0001] The invention relates to a method for synthesizing condensed ring compounds, more specifically to a method for synthesizing pyrroloindole compounds, and belongs to the field of synthesizing pharmaceutical intermediates. Background technique

[0002] In the fields of medicine, medical treatment, organic synthesis, etc., natural products containing indole structures occupy a very important position, because the structures containing indole often show good biological activities. Among the indole compounds, the pyrroloindole compounds are more important, which exist in a large number of alkaloids as the parent skeleton.

[0003] It is precisely because of the important role of pyrroloindole compounds that the development of new synthetic techniques for pyrroloindole compounds will facilitate the synthesis of drugs and their intermediates.

[0004] In recent years, a variety of synthetic methods for indole skeleton structures have been developed in the pri...

Examples

Embodiment 1

[0039]

[0040]At room temperature and under a nitrogen atmosphere, add 100 mmol of the above formula (I) compound, 140 mmol of the above formula (II) compound, 200mmol upper formula (III) compound, 15mmol composite catalyst (for 5mmolPd 2 (dba) 3 Mixture with 10mmol trimethylphosphine (copper hexafluoroacetylacetonate), 5mmol gallium trichloride and 200mmol organic base 2,4-lutidine, then heat up to 70°C and insulate and fully stir for 6 hours;

[0041] After the reaction is finished, filter the reaction system, cool the filtrate to room temperature, adjust the pH value to neutral, add deionized water to fully shake and wash, then extract 2-3 times with chloroform, combine the organic phases, and dry over anhydrous magnesium sulfate. After distillation under reduced pressure, the obtained residue was separated by silica gel column chromatography, and acetone and ethyl acetate in equal volume ratio were used as washing liquids to obtain the compound of the above formula (I...

Embodiment 2

[0044]

[0045] At room temperature and under a nitrogen atmosphere, add 100 mmol of the above formula (I) compound, 200 mmol of the above formula (II) compound, 250mmol formula (III) compound, 24mmol composite catalyst (for 6mmolPd 2 (dba) 3 Mixture with 18mmol trimethylphosphine (copper hexafluoroacetylacetonate), 8mmol gallium trichloride and 250mmol organic base 2,4-lutidine, then heat up to 80°C and insulate and fully stir for 5 hours;

[0046] After the reaction is finished, filter the reaction system, cool the filtrate to room temperature, adjust the pH value to neutral, add deionized water to fully shake and wash, then extract 2-3 times with chloroform, combine the organic phases, and dry over anhydrous magnesium sulfate. After distillation under reduced pressure, the obtained residue was separated by silica gel column chromatography, and acetone and ethyl acetate in equal volume ratio were used as washing liquids to obtain the compound of the above formula (IV) wi...

Embodiment 3

[0049]

[0050] At room temperature and under a nitrogen atmosphere, add 100 mmol of the above formula (I) compound, 170 mmol of the above formula (II) compound, 300mmol formula (III) compound, 20mmol composite catalyst (for 6mmolPd 2 (dba) 3 Mixture with 14mmol trimethylphosphine (copper hexafluoroacetylacetonate), 10mmol gallium trichloride and 300mmol organic base 2,4-lutidine, then heat up to 85°C and insulate and fully stir for 4 hours;

[0051] After the reaction is finished, filter the reaction system, cool the filtrate to room temperature, adjust the pH value to neutral, add deionized water to fully shake and wash, then extract 2-3 times with chloroform, combine the organic phases, and dry over anhydrous magnesium sulfate. After distillation under reduced pressure, the obtained residue was separated by silica gel column chromatography, and acetone and ethyl acetate in equal volume ratio were used as washing liquids to obtain the compound of the above formula (IV) w...

technical field

[0001] The invention relates to a method for synthesizing condensed ring compounds, more specifically to a method for synthesizing pyrroloindole compounds, and belongs to the field of synthesizing pharmaceutical intermediates. Background technique

[0002] In the fields of medicine, medical treatment, organic synthesis, etc., natural products containing indole structures occupy a very important position, because the structures containing indole often show good biological activities. Among the indole compounds, the pyrroloindole compounds are more important, which exist in a large number of alkaloids as the parent skeleton.

[0003] It is precisely because of the important role of pyrroloindole compounds that the development of new synthetic techniques for pyrroloindole compounds will facilitate the synthesis of drugs and their intermediates.

[0004] In recent years, a variety of synthetic methods for indole skeleton structures have been developed in the pri...

Examples

Embodiment 1

[0039]

[0040]At room temperature and under a nitrogen atmosphere, add 100 mmol of the above formula (I) compound, 140 mmol of the above formula (II) compound, 200mmol upper formula (III) compound, 15mmol composite catalyst (for 5mmolPd 2 (dba) 3 Mixture with 10mmol trimethylphosphine (copper hexafluoroacetylacetonate), 5mmol gallium trichloride and 200mmol organic base 2,4-lutidine, then heat up to 70°C and insulate and fully stir for 6 hours;

[0041] After the reaction is finished, filter the reaction system, cool the filtrate to room temperature, adjust the pH value to neutral, add deionized water to fully shake and wash, then extract 2-3 times with chloroform, combine the organic phases, and dry over anhydrous magnesium sulfate. After distillation under reduced pressure, the obtained residue was separated by silica gel column chromatography, and acetone and ethyl acetate in equal volume ratio were used as washing liquids to obtain the compound of the above formula (I...

Embodiment 2

[0044]

[0045] At room temperature and under a nitrogen atmosphere, add 100 mmol of the above formula (I) compound, 200 mmol of the above formula (II) compound, 250mmol formula (III) compound, 24mmol composite catalyst (for 6mmolPd 2 (dba) 3 Mixture with 18mmol trimethylphosphine (copper hexafluoroacetylacetonate), 8mmol gallium trichloride and 250mmol organic base 2,4-lutidine, then heat up to 80°C and insulate and fully stir for 5 hours;

[0046] After the reaction is finished, filter the reaction system, cool the filtrate to room temperature, adjust the pH value to neutral, add deionized water to fully shake and wash, then extract 2-3 times with chloroform, combine the organic phases, and dry over anhydrous magnesium sulfate. After distillation under reduced pressure, the obtained residue was separated by silica gel column chromatography, and acetone and ethyl acetate in equal volume ratio were used as washing liquids to obtain the compound of the above formula (IV) wi...

Embodiment 3

[0049]

[0050] At room temperature and under a nitrogen atmosphere, add 100 mmol of the above formula (I) compound, 170 mmol of the above formula (II) compound, 300mmol formula (III) compound, 20mmol composite catalyst (for 6mmolPd 2 (dba) 3 Mixture with 14mmol trimethylphosphine (copper hexafluoroacetylacetonate), 10mmol gallium trichloride and 300mmol organic base 2,4-lutidine, then heat up to 85°C and insulate and fully stir for 4 hours;

[0051] After the reaction is finished, filter the reaction system, cool the filtrate to room temperature, adjust the pH value to neutral, add deionized water to fully shake and wash, then extract 2-3 times with chloroform, combine the organic phases, and dry over anhydrous magnesium sulfate. After distillation under reduced pressure, the obtained residue was separated by silica gel column chromatography, and acetone and ethyl acetate in equal volume ratio were used as washing liquids to obtain the compound of the above formula (IV) w...

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