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Preparation method of Sotorasib intermediate

An intermediate and reaction time technology, applied in the direction of organic chemistry, can solve the problems of expensive palladium catalysts and organozinc reagents, high requirements for anaerobic conditions, and high costs, and achieve the effect of improving molecular utilization and reaction efficiency

Inactive Publication Date: 2021-11-05
CHEMFUTURE PHARMATECH JIANGSU
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

First of all, the raw materials are not easy to obtain, usually through nitration reaction, and the reaction product contains unavoidable positional isomers, which need to be purified by rectification, the operation is complicated, and the conversion rate is low
Secondly, palladium catalysts and organozinc reagents are expensive, the cost is high, and the reaction requires high anaerobic conditions

Method used

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  • Preparation method of Sotorasib intermediate
  • Preparation method of Sotorasib intermediate
  • Preparation method of Sotorasib intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0029] A preparation method of Sotorasib intermediate 2-isopropyl-3-amino-4-picoline, comprising the steps of:

[0030] Step 1: Add 3-cyano-4-methyl-2-pyridone (135g, 1mol) and toluene (500mL) into the reaction flask, add phosphorus oxychloride (230g, 1.5mol) under stirring, and react after adding The solution was heated to 100°C, stirred and reacted for 8 hours, the reaction solution was cooled down, then slowly poured into ice water (2000mL), stirred for 2 hours, a solid was produced, filtered, and dried to obtain 2-chloro-3-cyano-4- Picoline (130 g, yield: 85%).

[0031] Step 2: Add 2-chloro-3-cyano-4-methylpyridine (30g, 0.2mol), 1,2-bisdiphenylphosphinoethane nickel chloride (10.6g, 0.02mol) and THF (300mL), lower the temperature to -5°C, add isopropyl magnesium chloride (200mL, 0.4mol, 2M) dropwise, after the dropwise addition, keep warm at 0°C for 2 hours; add 10% dilute hydrochloric acid to the reaction solution to quench reaction, adjusted to pH=5, extracted with et...

Embodiment 2

[0035] A preparation method of Sotorasib intermediate 2-isopropyl-3-amino-4-picoline, comprising the steps of:

[0036] Step 1: Add 3-cyano-4-methyl-2-pyridone (13.5g, 0.1mol) and toluene (50mL) into the reaction flask, add phosphorus oxybromide (43g, 0.15mol) under stirring, and complete the addition Afterwards, the reaction solution was heated to 100°C, stirred and reacted for 8 hours, the reaction solution was cooled down, then slowly poured into ice water (200mL), stirred for 2 hours, a solid was produced, filtered, and dried to obtain 2-bromo-3-cyano- 4-Methylpyridine (16.3 g, yield: 83%).

[0037] Step 2: Add 2-bromo-3-cyano-4-methylpyridine (3.9g, 0.02mol) and 1,2-bisdiphenylphosphineethane nickel chloride (1.06g, 0.002mol) into the reaction flask and THF (30mL), lower the temperature to -5°C, add isopropylmagnesium chloride (20mL, 0.04mol, 2M) dropwise, after the addition, keep warm at 0°C for 2 hours; add 10% dilute hydrochloric acid to the reaction solution to quenc...

Embodiment 3

[0041] A preparation method of Sotorasib intermediate 2-isopropyl-3-amino-4-picoline, comprising the steps of:

[0042] Step 1: Add 3-cyano-4-methyl-2-pyridone (13.5g, 0.1mol) and dimethylformamide (50mL) into the reaction flask, and add phosphorus oxychloride (30g, 0.2mol ), after the addition, the reaction solution was heated to 100°C, stirred and reacted for 8 hours, the reaction solution was cooled, then slowly poured into ice water (200mL), stirred for 2 hours, solids were produced, filtered, and dried to obtain 2-chloro-3 -Cyano-4-picoline (11.5 g, yield: 75%).

[0043] Step 2: Add 2-chloro-3-cyano-4-methylpyridine (3g, 0.02mol), iron acetylacetonate (0.70g, 0.002mol) and THF (30mL) into the reaction flask, cool down to -5°C, Add isopropylmagnesium chloride (20mL, 0.4mol, 2M) dropwise. After the dropwise addition, keep warm at 0°C for 2 hours; Ester extraction (15mL*2), combined organic phases, washed the organic phase with saturated brine (10mL) once, dried the organi...

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Abstract

The invention discloses a preparation method of a Sotorasib intermediate 2-isopropyl-3-amino-4-methylpyridine. The preparation method comprises the following specific steps of: (1) carrying out a reaction on 3-cyano-4-methyl-2-pyridone and a halogenating reagent to obtain 2-halogenated-3-cyano-4-methylpyridine; (2) making the 2-halogenated-3-cyano-4-methylpyridine with an isopropyl Grignard reagent under the action of a catalyst, so as to obtain 2-isopropyl-3-cyano-4-methylpyridine; (3) carrying out hydrolysis on the 2-isopropyl-3-cyano-4-methylpyridine, so as to obtain 2-isopropyl-4-methyl nicotinamide; and (4) carrying out Hofmann rearrangement on the 2-isopropyl-4-methyl nicotinamide, sodium hydroxide and a sodium hypochlorite solution, so as to obtain the 2-isopropyl-3-amino-4-methylpyridine. The preparation 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 preparation method of a Sotorasib intermediate. Background technique [0002] Sotorasib (AMG510) is a "first-in-class" KRAS G12C mutant inhibitor developed by Amgen, and 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] 2-isopropyl-amino-4-picoline is the key intermediate for the synthesis of Sotorasib. The method disclosed in the current patent uses 2-bromo-3-amino-4-picoline as a raw material, under the action of a palladium catalyst, Obtained by Negishi coupling reaction with isopropylzinc bromide. This method has several disadvantages. First of all, the raw materials are not easy to obtain, usually need to go through nitration reaction, and the ...

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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