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A kind of synthetic method of almotriptan

A synthetic method, the technology of almotriptan, applied in the field of almotriptan synthesis, achieves the effects of high purity, wide industrial application, and short synthetic route

Inactive Publication Date: 2017-10-31
CHINA AGRI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the research on the nickel-catalyzed arylation reaction of methylsulfonamide is still blank, so the research on the arylation of sulfonamide and bromobenzene is more innovative and has application value, so as to generate almotriptan in one step, which is of great importance. significance

Method used

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  • A kind of synthetic method of almotriptan
  • A kind of synthetic method of almotriptan
  • A kind of synthetic method of almotriptan

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preparation example Construction

[0028] The synthetic method of almotriptan of the present invention comprises the steps:

[0029] Under the protection of argon, vacuum-dry the nickel salt, add an anhydrous organic solvent and a phosphine ligand, and stir at room temperature for 1 hour. The molar equivalent ratio of the phosphine ligand to the nickel salt is 1:1 to 2:1;

[0030] Then add alkaline substances to the above mixed solution, stir at room temperature for 1h and lower the reaction temperature to 0°C, add 1-methylsulfonylpyrrolidine and 3,5-disubstituted indole derivatives, phosphine ligand and 1-methyl The ratio of sulfonylpyrrolidine is 1:5 to 1:10, the molar equivalent ratio of 1-methylsulfonylpyrrolidine to alkaline substance is 1:1 to 1:4, and the ratio of 1-methylsulfonylpyrrolidine to alkaline substance is 1:1 to 1:4. The molar equivalent ratio of 3,5-disubstituted indole derivatives is 1:1 to 1:3;

[0031] Raise the temperature to 80° C. and stir for 12-24 h to continue the reaction. After qu...

Embodiment 1

[0042] The synthetic method of the almotriptan of embodiment 1, comprises the steps:

[0043] Under argon protection, add NiCl in a dry Schlenk bottle (Schlenk bottle) 2 (25.9mg, 0.2mmol), after vacuum drying for 2h, add anhydrous tetrahydrofuran (5mL) and phosphine ligand (132.4mg, 0.24mmol), stir at room temperature for 1h, phosphine ligand and NiCl 2 The molar equivalent ratio is 6:5. The chemical formula of the phosphine ligand is as follows:

[0044]

[0045] Then lithium tert-butoxide (320.0mg, 4.0mmol) was added to the above mixture, stirred at room temperature and the reaction temperature was lowered to 0°C, and 1-methylsulfonylpyrrolidine (298.4mg, 2.0mmol) was added dropwise with commercially available 3,5-disubstituted indole bromide (641.3mg, 2.4mmol), the ratio of phosphine ligand to 1-methylsulfonylpyrrolidine is 3:25, 1-methylsulfonylpyrrolidine to tert-butanol The molar equivalent ratio of lithium is 1:2, and the molar equivalent ratio of 1-methylsulfonyl...

Embodiment 2

[0050] The synthetic method of the almotriptan of embodiment 2, comprises the steps:

[0051] Under the protection of argon, add NiBr in a dry Schlenk bottle 2 (43.7mg, 0.2mmol), after vacuum drying for 2h, add anhydrous tetrahydrofuran (5mL) and phosphine ligand (132.4mg, 0.24mmol), stir at room temperature for 1h, phosphine ligand and NiBr 2 The molar equivalent ratio is 6:5. The chemical formula of the phosphine ligand is as follows:

[0052]

[0053] Then lithium tert-butoxide (320.0mg, 4.0mmol) was added to the above mixture, stirred at room temperature and the reaction temperature was lowered to 0°C, and 1-methylsulfonylpyrrolidine (298.4mg, 2.0mmol) was added dropwise with commercially available 3,5-disubstituted indole bromide (641.3mg, 2.4mmol), the ratio of phosphine ligand to 1-methylsulfonylpyrrolidine is 3:25, 1-methylsulfonylpyrrolidine to tert-butanol The molar equivalent ratio of lithium is 1:2, and the molar equivalent ratio of 1-methylsulfonylpyrrolidin...

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Abstract

The invention relates to the technical field of medicines, and particularly relates to a method for synthesizing almotriptan. The method comprises the following steps: drying nickel salt in vacuum under protection of argon, adding an anhydrous organic solvent and phosphine ligand, and stirring at room temperature; then, adding an alkaline substance in the mixed solution, stirring at room temperature, adding tetrahydropyrrole methyl sulfonamide and 3,5-disubstituted indole derivative; and keeping on reaction, extracting and drying after the reaction is quenched, and concentrating at reduced pressure, and purifying to obtain almotriptan. The reaction general formula is shown in the specification. The method is simple and short in synthesis route, only needs one-step reaction. The almotriptan has the characteristics of high yield, high purity and the like, has a yield of 80-92 percent and purity of 90-95 percent, and has wide industrial application.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a method for synthesizing almotriptan. Background technique [0002] Migraine, as a chronic neurovascular disease, presents a trend of frequent occurrence in the Chinese population. And almotriptan and its derivatives as a class of 5-HT 1B / 1D Receptor agonist drugs, due to their good therapeutic effect and few side effects, are widely used in clinical treatment, with annual sales reaching hundreds of millions of dollars, and have a very broad market prospect. From the analysis of the structure of almotriptan, it is mainly divided into sulfonamide group and substituted indole group. Therefore, the transition metal catalyzed method can be used to obtain almotriptan in one step. [0003] [0004] In 2008, Zhou et al. reported a palladium-catalyzed Negishi cross-coupling reaction of methanesulfonamide and halogenated arenes, in the Pd(OAc) 2 Under the catalysis of Xphos, exce...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/14
CPCC07D209/14
Inventor 郑冰高贵陈相助张媛媛侯士聪王敏
Owner CHINA AGRI UNIV