A kind of preparation method of 2-(tert-butylamino) carbonyl pyridine compound

A technology of tert-butylamino and carbonylpyridine, which is applied in the field of preparation of 2-(tert-butylamino)carbonylpyridine compounds, can solve the problems of complicated operation, reduced yield, long reaction time and the like

Active Publication Date: 2016-05-25
SHANGHAI INST OF PHARMA IND CO LTD +1
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Problems solved by technology

This reaction also uses tert-butyl acetate, the operation is more complicated and the reaction time is longer
[0007] When 2-(tert-butylamino)carbonylpyridine is synthesized by the method reported by DorisP.Schumache et al., in addition to generating 3-methyl-2-(tert-butylamino)carbonylpyridine, 3-methyl-2-pyridinecarboxylic acid will also be generated, Therefore the yield decreases

Method used

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  • A kind of preparation method of 2-(tert-butylamino) carbonyl pyridine compound
  • A kind of preparation method of 2-(tert-butylamino) carbonyl pyridine compound
  • A kind of preparation method of 2-(tert-butylamino) carbonyl pyridine compound

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[0022] Specifically, the preparation method of the 2-(tert-butylamino)carbonylpyridine compound with the structure shown in the formula II provided by the present invention comprises steps:

[0023] In the first step, a 2-cyanopyridine compound having a structure as shown in formula I, tert-butanol and a solvent are mixed to obtain a reaction solution 1;

[0024] In the second step, concentrated sulfuric acid is added dropwise to the reaction solution 1, and then the temperature is raised to 60°C-the reflux temperature of the solvent for reaction to obtain the reaction solution 2;

[0025] In the third step, the reaction solution 2 and water were mixed, and then the aqueous phase was adjusted to pH=9-10 with concentrated ammonia water to obtain 2-(tert-butylamino)carbonylpyridine compounds with the structure shown in formula II.

[0026] In the above first step, the solvent is selected from formic acid, acetic acid or a mixture thereof.

[0027] In the above first step, the m...

Embodiment 1

[0045] Preparation of 3-methyl-2-(tert-butylamino)carbonylpyridine

[0046]Add 2-cyano-3-picoline (5.00g, 42.3mmol), tert-butanol (13.0ml, 138mmol), formic acid (19.9ml, 517mmol), glacial acetic acid (7.5ml, 130mmol) into the dry reactor , stirred at room temperature for 5 minutes. Then, concentrated sulfuric acid (2.0ml, 39.6mmol) was slowly added dropwise to the reaction solution, and the reaction was completed within 30 minutes, and then the temperature was gradually raised to 60°C. After the reaction, the reaction solution was cooled to room temperature, the solvent was evaporated under reduced pressure, 20.0ml of water was added to the residue to dissolve, and then the aqueous phase was adjusted to pH=9-10 with 15.0ml of concentrated ammonia water. Extracted with toluene, and evaporated the solvent under reduced pressure to obtain 8.37 g of crystals, with a yield of 98.64% and a GC purity of 95.90%. Recrystallized from petroleum ether to obtain 6.47g of white crystals, ...

Embodiment 2

[0048] Preparation of 3-methyl-2-(tert-butylamino)carbonylpyridine

[0049] Add 2-cyano-3-picoline (5.00g, 42.3mmol), tert-butanol (17.5ml, 186mmol), formic acid (15.0ml, 390mmol), glacial acetic acid (7.5ml, 130mmol) into the dry reactor , stirred at room temperature for 5 minutes. Then, concentrated sulfuric acid (2.0ml, 39.6mmol) was slowly added dropwise to the reaction solution, and the reaction was completed within 30 minutes, and then the temperature was gradually raised to 60°C. After the reaction, the reaction solution was cooled to room temperature, the solvent was evaporated under reduced pressure, 20.0ml of water was added to the residue to dissolve, and then the aqueous phase was adjusted to pH=9-10 with 15.0ml of concentrated ammonia water. Extracted with toluene, and evaporated the solvent under reduced pressure to obtain 8.12 g of crystals, yield 95.80%, GC purity 96.00% [GC normalization method: chromatographic column (5%) phenyl-(95%) methylpolysiloxane Alk...

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Abstract

The invention discloses a preparation method of a 2-(tert-butylamino)carbonylpyridine compound. A structure of the 2-(tert-butylamino)carbonylpyridine compound is represented as formula II. The preparation method includes a step of carrying out a reaction between a 2-cyanopyridine compound and tert-butyl alcohol to obtain the compound represented as formula II, wherein the structure of the 2-cyanopyridine compound is represented as formula I, a catalyst in the reaction is concentrated sulfuric acid and a solvent of the reaction is selected from formic acid, acetic acid or a mixture of the formic acid and the acetic acid.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of 2-(tert-butylamino)carbonylpyridine compounds. Background technique [0002] 2-(tert-butylamino)carbonylpyridines are the main intermediates for the synthesis of tricyclic ketones (compounds of the following formula III), and tricyclic ketones are the main intermediates for the synthesis of loratadine (IV), desloratadine (V), An important intermediate of second-generation antihistamines such as patadine (VI). In addition, 2-(tert-butylamino)carbonylpyridine can also be used as a synthetic precursor of 4-phosphatase inhibitor (compound of formula VII), a potential candidate drug for the treatment of chronic respiratory diseases (such as impotence pulmonary disease and asthma, etc.). [0003] [0004] DorisP.Schumacher (J.Org.Chem.1989,54(9),2242-2244) et al. reported the synthesis of 2-(tert-butylamino)carbonylpyridine, using concentrated sulfuric acid as ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/81
CPCC07D213/81
Inventor 张广周后元庄守群王国平袁博王宏博
Owner SHANGHAI INST OF PHARMA IND CO LTD
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