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Novel synthesis method of 2-methyl-1-substituted phenyl-2-propylamine compounds

A compound, a new synthesis technology, applied in the preparation of organic compounds, chemical instruments and methods, preparation of functional groups substituted with amino groups, etc., can solve problems such as unusable, and achieve the effect of simple operation, simplified reaction route, and easy-to-obtain raw materials

Inactive Publication Date: 2019-04-26
CHANGZHOU UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, since this method uses catalytic hydrogenation (Pd / C as a catalyst) in the last step, reactions such as dehalogenation will occur, so this method cannot be used for the synthesis of 2-methyl-1-bromophenyl-2-propylamine, etc. Similar derivatives containing bromine atoms, iodine atoms, etc.

Method used

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  • Novel synthesis method of 2-methyl-1-substituted phenyl-2-propylamine compounds
  • Novel synthesis method of 2-methyl-1-substituted phenyl-2-propylamine compounds
  • Novel synthesis method of 2-methyl-1-substituted phenyl-2-propylamine compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment A

[0022] Preparation of 2-methyl-1-(2-methylphenyl)-2-propanamine (4a; R=2-Me)

[0023] Step 1: Preparation of 2-methyl-1-(2-methylphenyl)-2-butyronitrile (2a; R=2-Me)

Embodiment 1

[0024] Example 1: Dissolve diisopropylamine (1.88mL, 13.4mmol, 1.1eq) in 10mL of tetrahydrofuran, ice-bath to -78°C, and 2 Under protection, n-butyllithium (2.8mL, 7.0mmol, 1.1eq) was added dropwise, and after stirring for 30min, light yellow LDA was prepared. Isobutyronitrile (2.39mL, 26.6mmol, 1.1eq) was added dropwise to the reaction, stirred for 1 hour, then 2-methylbenzyl chloride (1.5g, 10.6mmol) was added, and the reaction was stopped after stirring for 25min. Add 10mL of 10% hydrochloric acid and 30ml of water to the mixture to quench the reaction, extract 3 times with 20mL of ethyl acetate, wash 3 times with 15mL of water and 3 times with 15mL of saturated brine, pour the organic phase Put it into a clean Erlenmeyer flask, add an appropriate amount of anhydrous sodium sulfate to dry for half an hour. After purification by column chromatography, a pale yellow liquid was obtained with a yield of 98%. 1 H NMR (300MHz, CDCl 3 ): δ7.30-7.16 (m, 4H), 2.88 (s, 2H), 2.38 (...

Embodiment 2

[0026] Example 2: Take 2-methyl-1-(2-methylphenyl)-2-butyronitrile 2a (1.4g, 8.1mmol) and add it to a 50mL single-necked flask, then add KOH (1.13g, 20.2mmol, 2.5eq) and ethylene glycol (15mL), heated to reflux at 175°C for 6 hours and stopped the reaction, then added a 10% hydrochloric acid solution to the reaction solution to adjust the pH=1; first extracted 3 times with 20mL of ethyl acetate ; then extracted 3 times with 15mL of water, washed three times with 15mL of saturated brine; the organic phase was poured into a clean Erlenmeyer flask, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain a brown liquid with a yield of 89% . 1 H NMR (300MHz, CDCl 3 ): δ7.17-7.12(m, 4H), 2.97(s, 2H), 2.33(s, 3H), 1.24(d, J=9.6Hz, 6H).

[0027] Step 3: 2-Methyl-1-(2-methylphenyl)-2-propanamine (4a; R=2-Me)

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Abstract

The invention discloses a novel synthesis method of 2-methyl-1-substituted phenyl-2-propylamine compounds, and belongs to the field of material synthesis. The method comprises steps as follows: substituted benzyl halide is taken as a raw material and subjected to a reaction with isobutyronitrile under the action of alkali, obtained 2-methyl-1-substituted phenyl-2-butyronitrile is hydrolyzed and subjected to reactions of Curtius rearrangement and the like, and 2-methyl-1-substituted phenyl-2-propylamine is produced. On the basis of an original method, reaction steps are shortened, the total yield is obviously increased, and meanwhile, the novel method is provided for synthesis of substituted phenyl-2-propylamine derivatives containing bromine atoms and iodine atoms.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a new synthesis method of 2-methyl 1-substituted phenyl-2-propanamine compounds. Background technique [0002] Asthma is a common non-communicable chronic disease that affects the health of about 330 million people worldwide, and its morbidity and mortality are increasing every year. The pathogenesis of asthma is affected by its own genetics and the external environment , the research on asthma has become a hot field in the medical field. BI167107 is a long-acting beta 2 Receptor agonists have a good effect on bronchial asthma and chronic obstructive pulmonary disease. The structures of BI167107 and other similar compounds contain a 2-methyl-1-(2-methylphenyl)-2- The side chain of propylamine is one of the key points in the synthesis of this type of compound. [0003] [0004] In 2015, Chen Xin et al. (CN 105085278 A) used 2-methylbenzyl chloride as the starting material, and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C209/22C07C211/27C07C211/29
CPCC07C51/08C07C209/22C07C253/30C07C211/27C07C211/29C07C57/30C07C57/58C07C255/35C07C255/33
Inventor 陈新朱兰平高铭梅赵帅
Owner CHANGZHOU UNIV
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