Preparation method by using amine and imine nitrogen methylation and application thereof

A technology of trimethylphenyl and p-methoxyphenyl, applied in the field of compound synthesis, can solve problems such as limited application, complicated separation and purification steps, etc., and achieve the effects of abundant sources, low cost, and high conversion number

Active Publication Date: 2017-06-27
湖北骐盛医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there are also shortcomings in the above methods, such as the use of uncommercialized catalysts, and the system is a homogeneous reaction, which leads to cumbersome operation and separation and purification steps, which greatly limits its application in actual production.

Method used

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  • Preparation method by using amine and imine nitrogen methylation and application thereof
  • Preparation method by using amine and imine nitrogen methylation and application thereof
  • Preparation method by using amine and imine nitrogen methylation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Preparation of Compound II-1

[0048]

[0049] A, add activated carbon supported platinum catalyst (Pt / C, 0.18mg platinum, 0.0009mmol, 0.3mol%) in 10mL Schlenk (Schlenk) tube, after vacuumizing and changing argon, add solvent (toluene) 1mL; The consumption of activated carbon-supported platinum catalyst is 0.3% of the amount of starting material I-1, and the ratio of the amount of starting material I-1 to the milliliter of solvent toluene is 0.3;

[0050] B. Under the protection of argon, add phenylsilane (157.8 mg, 1.5 mmol), I-1 (R 1 = p-chlorophenyl) (38.3mg, 0.3mmol) and formic acid (41.4mg, 0.9mmol); the ratio of the amount of substance of the phenylsilane to the starting material I-1 is 5.0; the formic acid to the starting material The ratio of the amount of I-1 substance is 3.0;

[0051] C, the whole reaction system is stirred and reacted at 80°C; the reaction time is 15 hours;

[0052] D, after the reaction is over, add ethyl acetate 3mL to the system for ...

Embodiment 2

[0056] Preparation of Compound II-2

[0057]

[0058] Add activated carbon-supported platinum catalyst (Pt / C, 0.18mg platinum, 0.0009mmol, 0.3mol%) into a 10mL Schlenk tube, and add 1mL of solvent (toluene) after vacuuming and exchanging argon. Under argon protection, phenylsilane (157.8mg, 1.5mmol), I-2(R 1 = p-methoxyphenyl) (36.9 mg, 0.3 mmol) and formic acid (41.4 mg, 0.9 mmol). The whole reaction system was stirred and reacted at 80° C., and the reaction time was 15 hours. After the reaction was over, 3 mL of ethyl acetate was added to the system for dilution, and the reaction was quenched with aqueous sodium hydroxide solution (3mol / L, 3 mL), extracted with ethyl acetate (3×10 mL), and after the organic phase was separated, it was washed with anhydrous Na 2 SO 4 Dry, filter and remove solvent by rotary evaporation. The residue was separated and purified by ethyl acetate / petroleum ether=1:100 mixed solvent column chromatography to obtain the target product II-243.1...

Embodiment 3

[0061] Preparation of Compound II-3

[0062]

[0063] Add activated carbon-supported platinum catalyst (Pt / C, 0.18mg platinum, 0.0009mmol, 0.3mol%) into a 10mL Schlenk tube, and add 1mL of solvent (toluene) after vacuuming and exchanging argon. Under argon protection, phenylsilane (157.8mg, 1.5mmol), I-3(R 1 =2,4,6-Trimethylphenyl) (40.6 mg, 0.3 mmol) and formic acid (41.4 mg, 0.9 mmol). The whole reaction system was stirred and reacted at 80° C., and the reaction time was 15 hours. After the reaction was over, 3 mL of ethyl acetate was added to the system for dilution, and the reaction was quenched with aqueous sodium hydroxide solution (3mol / L, 3 mL), extracted with ethyl acetate (3×10 mL), and after the organic phase was separated, it was washed with anhydrous Na 2 SO 4 Dry, filter and remove solvent by rotary evaporation. The residue was separated and purified by ethyl acetate / petroleum ether=1:50 mixed solvent column chromatography to obtain the target product II-3...

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Abstract

The invention discloses a preparation method by using amine and imine nitrogen methylation and application thereof. The preparation method comprises the following steps: A, adding an active carbon loaded platinum catalyst into a Schlenk tube, and after vacuumizing to replace argon, adding a solvent; B, under protection of argon, separately adding phenylsilane, an initial raw material and formic acid; C, stirring the whole reaction system at a certain temperature to react; and D, after reaction, adding ethyl acetate into the system to dilute, stopping the reaction by using a sodium hydroxide aqueous solution, performing extraction with ethyl acetate, separating out an organic phase, drying and filtering the organic phase, and performing rotatable evaporation to remove the solvent. Column chromatography is performed on residues by using ethyl acetate / petroleum ether mixed solvent to obtain a target product, wherein the ethyl acetate and petroleum ether are different in proportion. According to the application of the method in isotope labeled drug synthesis, the dosage of a catalyst is extremely low, the cost is quite low, and the method is suitable for large-scaled production, can be suitable for amine and imine with different substituents, and suitable for realizing methylation conveniently on nitrogen atoms in a natural product structure to prepare drug molecules.

Description

technical field [0001] The invention relates to the field of compound synthesis, more specifically to a method for preparing amine and imine nitrogen methylation, and also relates to the application of the method for preparing amine and imine nitrogen methylation in the synthesis of isotope-labeled drugs. Background technique [0002] In nature, proteins, nucleic acids, hormones, antibiotics and alkaloids all contain amino groups, which are derivatives of amine compounds. Therefore, amine compounds containing substituents, as important structural units, are widely used in the fields of organic synthesis, biological preparations, material science, pesticides and pharmaceuticals. For example, the antifungal drug Butenafine, the drug Cinacalcet for treating parathyroid disorders, and the dopaminergic agonist Piribedil are all substituted amine compounds. [0003] In the synthesis method of amine compounds containing substituents, the strategy of direct reaction of amine or imi...

Claims

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Application Information

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IPC IPC(8): C07C211/48C07C209/46C07C213/02C07C217/84C07C323/36C07D317/66C07C211/58C07C211/54C07C229/60C07C227/08C07C215/16C07C255/24C07C253/30C07C209/52C07C217/56C07D209/08A61K51/04
CPCA61K51/0406A61K51/0425A61K51/0446C07C209/46C07C209/52C07C213/02C07C227/08C07C253/30C07C323/36C07D209/08C07D317/66C07C211/48C07C217/84C07C211/58C07C211/54C07C229/60C07C215/16C07C255/24C07C217/56
Inventor 朱磊汪连生李博解李伟付伯桥
Owner 湖北骐盛医药科技有限公司
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