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Synthesis method of 2-isopropyl-3-amino-4-methylpyridine

A technology of picoline and isopropyl, applied in the field of synthesis of 2-isopropyl-3-amino-4-picoline, can solve the problem of expensive palladium catalyst and organozinc reagent, high cost and anaerobic conditions Higher requirements and other issues, to achieve the effect of improving molecular utilization and reaction efficiency

Inactive Publication Date: 2021-09-07
CHEMFUTURE PHARMATECH JIANGSU
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In this method, palladium catalyst and organozinc reagent are expensive, the cost is higher, and the reaction requires higher anaerobic conditions

Method used

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  • Synthesis method of 2-isopropyl-3-amino-4-methylpyridine
  • Synthesis method of 2-isopropyl-3-amino-4-methylpyridine
  • Synthesis method of 2-isopropyl-3-amino-4-methylpyridine

Examples

Experimental program
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Effect test

Embodiment 1

[0028] A preparation method of 2-isopropyl-3-amino-4-picoline, comprising the steps of:

[0029] Step 1: Add 3-cyano-4-methyl-2-pyridone (13.5g, 0.1mol) and toluene (50mL) into the reaction flask, and add phosphorus oxybromide (43g, 0.15mol) under stirring; Afterwards, the reaction solution was heated to 100°C, stirred and reacted for 8 hours, the temperature of the reaction solution was lowered, and then slowly poured into ice water (200 mL), stirred for 2 hours, a solid was produced, filtered, and dried to obtain 2-bromo-3-cyano - 4-Methylpyridine (16.3 g, yield: 83%).

[0030] Step 2: Add 2-bromo-3-cyano-4-methylpyridine (350g, 1.8mol), ethanol (600mL), water (1.8L) and concentrated sulfuric acid (540g, 5.4mol) in the reaction flask, and heat to Stir at 90°C for 12 hours. After the reaction is complete, cool down to room temperature, distill ethanol off under reduced pressure, add sodium hydroxide solution to adjust the pH to 10, cool down to 5°C, stir for 2 hours, solids ...

Embodiment 2

[0034] A preparation method of 2-isopropyl-3-amino-4-picoline, comprising the steps of:

[0035] Step 1: Add 3-cyano-4-methyl-2-pyridone (135g, 1mol) and toluene (500mL) to the reaction flask, and add phosphorus oxybromide (573g, 2mol) under stirring; after the addition, the reaction solution Heat to 100°C, stir and react for 8 hours, then cool down the reaction solution, then slowly pour it into ice water (2L), stir for 2 hours, a solid is produced, filter, and dry to obtain 2-bromo-3-cyano-4- Picoline (160 g, yield: 81%).

[0036] Step 2: Add 2-bromo-3-cyano-4-methylpyridine (7g, 36mmol), ethanol (12mL), water (36mL) and concentrated sulfuric acid (10.5g, 108mmol) into the reaction flask, and heat to 80°C , stirred and reacted for 10 hours, after the reaction was completed, cooled to room temperature, distilled ethanol off under reduced pressure, added sodium hydroxide solution to adjust pH=10, cooled to 5°C, stirred for 2 hours, solids were produced, filtered, and dried to...

Embodiment 3

[0040] A preparation method of 2-isopropyl-3-amino-4-picoline, comprising the steps of:

[0041] Step 1: Add 3-cyano-4-methyl-2-pyridone (2.7g, 0.02mol) and toluene (10mL) into the reaction flask, and add phosphorus oxybromide (6.9g, 0.024mol) under stirring; After completion, the reaction solution was heated to 100°C, stirred and reacted for 8 hours, the temperature of the reaction solution was lowered, then slowly poured into ice water (40mL), stirred for 2 hours, a solid was produced, filtered, and dried to obtain 2-bromo-3-cyanide yl-4-methylpyridine (2.9 g, yield: 74%).

[0042] Step 2: Add 2-bromo-3-cyano-4-methylpyridine (7g, 36mmol), ethanol (12mL), water (36mL) and concentrated sulfuric acid (10.5g, 108mmol) into the reaction flask, and heat to 100°C , stirred and reacted for 14 hours. After the reaction was completed, the temperature was lowered to room temperature, the ethanol was evaporated under reduced pressure, the pH was adjusted to 10 by adding sodium hydroxide...

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Abstract

The invention discloses a preparation method of 2-isopropyl-3-amino-4-methylpyridine, and the preparation method comprises the following specific steps: (1) carrying out a reaction on 3-cyano-4-methyl-2-pyridone and phosphorus oxybromide to obtain 2-bromo-3-cyano-4-methylpyridine, (2) hydrolyzing the 2-bromo-3-cyano-4-methylpyridine by using concentrated sulfuric acid, so as to obtain 2-bromo-4-methyl nicotinamide; (3) reacting the 2-bromine-4-methyl nicotinamide with a sodium hypochlorite solution under the condition of sodium hydroxide, and carrying out Hofmann rearrangement to obtain 2-bromine-3-amino-4-methylpyridine; and (4) enabling the 2-bromo-3-amino-4-methylpyridine to react with an isopropyl Grignard reagent under the action of a catalyst containing iron or nickel, so as to obtain the 2-isopropyl-3-amino-4-methylpyridine. The method disclosed by the invention is low in cost and simple to operate, and is a novel method for synthesizing the 2-isopropyl-3-amino-4-methylpyridine.

Description

technical field [0001] The invention relates to the technical field of synthesis of pharmaceutical intermediates, in particular to a synthesis method of 2-isopropyl-3-amino-4-picoline. Background technique [0002] 2-Isopropyl-amino-4-picoline is a key intermediate in the synthesis of Sotorasib (AMG510), a "first-in-class" KRAS G12C mutant inhibitor developed by Amgen, which is The first KRAS G12C inhibitor to enter the clinic. In May 2021, Sotorasib was approved by the FDA for the treatment of patients with locally advanced or metastatic non-small cell lung cancer carrying a KRAS G12C mutation. [0003] [0004] The synthetic method of 2-isopropyl-amino-4-picoline disclosed in the current patent is to use 2-bromo-3-amino-4-picoline as raw material, under the action of palladium catalyst, bromide with isopropyl Zinc is obtained by Negishi coupling reaction. In this method, the palladium catalyst and the organozinc reagent are expensive, and the cost is relatively high,...

Claims

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Application Information

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IPC IPC(8): C07D213/73
CPCC07D213/73
Inventor 张浩波浦坤峰宋雪剑
Owner CHEMFUTURE PHARMATECH JIANGSU
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