Preparation method of lorlatinib intermediate compound

Abstract

The invention relates to a preparation method of a lorlatinib intermediate compound. 4-fluoroacetanilide is taken as a raw material and carry out visible light Fries rearrangement in the presence of avisible light catalyst and visible light to obtain an intermediate product (2-amino-5-fluoroacetophenone); and the intermediate product can directly carry out diazotization-iodination reactions without purification to obtain the lorlatinib intermediate compound (3-fluoro-6-iodoacetophenone). The raw materials are cheap and easily available. The post treatment has simple steps. The using amounts of chemical reagents in rearrangement reactions are only catalytic amounts. The energy source of the reactions is the visible light. The preparation method is green and environmentally friendly. A continuous flowing type photocatalytic reaction system is formed. The purification method and post treatment are simple and convenient. No extra production cost or environmental protection cost is generated. The novel preparation method of 3-fluoro-6-iodoacetophenone can be applied to the industry and generates economical benefits.

Description

technical field

[0001] The invention relates to the technical field of organic synthesis of intermediates, and relates to a preparation method of a lorlatinib intermediate compound, in particular to 3-fluoro-6-iodoacetophenone. Background technique

[0002] Lorlatinib is a new anti-cancer drug approved by the US FDA in 2018. This new small molecule drug is a new anti-drug resistance new ALK inhibitor developed by Pfizer. It is useful for the treatment of ALK positive Metastatic non-small cell lung cancer (NSCLC) has a good effect, especially can be effectively used in the investigational treatment of anaplastic lymphoma kinase positive (ALK+) metastatic (advanced) non-small cell lung cancer (NSCLC). Therefore, the demand for lorlatinib will increase in the future.

[0003] The main synthetic routes of lorlatinib currently reported all need to be prepared with 3-fluoro-6-iodo-acetophenone (hereinafter referred to as compound 1) as a reaction intermediate, and the structural ...

Examples

Embodiment 1

[0034] A preparation method of lorlatinib intermediate compound, comprising the steps of:

[0035] (1) Preparation of 2-amino-5-fluoroacetophenone:

[0036]Under the protection of argon atmosphere, add 15.3g (100mmol) 4-fluoroacetanilide (compound 4) and 200mL dioxane solvent in a 500mL single-necked bottle with a magnetic stirrer, and then add 306mg visible light catalyst to nitride Carbon (g-C 3 N 4 ) (w / w=2.35%), the temperature was raised to 40°C under stirring, and at the same time, a LED lamp with a power of 36 watts was used to illuminate the reaction system for photocatalytic Fries rearrangement reaction, and the reaction system was kept under light for 44 hours. After tracking the complete reaction of the raw materials, cool down to room temperature, filter the reaction solution with diatomaceous earth to remove the visible light catalyst and filter it with suction, wash the filter residue with 50mL of dioxane, collect the filtrate, and concentrate the filtrate unde...

Embodiment 2

[0044] (1) Preparation of 2-amino-5-fluoroacetophenone:

[0045] Under the protection of argon atmosphere, 23.0g (150mmol) of 4-fluoroacetanilide (compound 4) and 150mL of methyl tert-butyl ether solvent were added to a 500mL single-necked bottle with a magnetic stirrer, and then 338mg of visible light catalyst nitrogen carbon dioxide (g-C 3 N 4 ) (w / w=1.47%), heated up to 35°C under stirring, and at the same time, a LED lamp with a power of 72 watts was used to illuminate the reaction system for photocatalytic Fries rearrangement reaction, and the reaction system was kept under light for 48 hours. After tracking the reaction of the raw materials, it was lowered to room temperature, and the reaction solution was filtered with diatomaceous earth to remove the visible light catalyst and suction filtered, and the filter residue was washed with 50 mL of dioxane, and the filtrate was collected, and the filtrate was concentrated under reduced pressure to remove the solvent dioxane ...

technical field

[0001] The invention relates to the technical field of organic synthesis of intermediates, and relates to a preparation method of a lorlatinib intermediate compound, in particular to 3-fluoro-6-iodoacetophenone. Background technique

[0002] Lorlatinib is a new anti-cancer drug approved by the US FDA in 2018. This new small molecule drug is a new anti-drug resistance new ALK inhibitor developed by Pfizer. It is useful for the treatment of ALK positive Metastatic non-small cell lung cancer (NSCLC) has a good effect, especially can be effectively used in the investigational treatment of anaplastic lymphoma kinase positive (ALK+) metastatic (advanced) non-small cell lung cancer (NSCLC). Therefore, the demand for lorlatinib will increase in the future.

[0003] The main synthetic routes of lorlatinib currently reported all need to be prepared with 3-fluoro-6-iodo-acetophenone (hereinafter referred to as compound 1) as a reaction intermediate, and the structural ...

Examples

Embodiment 1

[0034] A preparation method of lorlatinib intermediate compound, comprising the steps of:

[0035] (1) Preparation of 2-amino-5-fluoroacetophenone:

[0036]Under the protection of argon atmosphere, add 15.3g (100mmol) 4-fluoroacetanilide (compound 4) and 200mL dioxane solvent in a 500mL single-necked bottle with a magnetic stirrer, and then add 306mg visible light catalyst to nitride Carbon (g-C 3 N 4 ) (w / w=2.35%), the temperature was raised to 40°C under stirring, and at the same time, a LED lamp with a power of 36 watts was used to illuminate the reaction system for photocatalytic Fries rearrangement reaction, and the reaction system was kept under light for 44 hours. After tracking the complete reaction of the raw materials, cool down to room temperature, filter the reaction solution with diatomaceous earth to remove the visible light catalyst and filter it with suction, wash the filter residue with 50mL of dioxane, collect the filtrate, and concentrate the filtrate unde...

Embodiment 2

[0044] (1) Preparation of 2-amino-5-fluoroacetophenone:

[0045] Under the protection of argon atmosphere, 23.0g (150mmol) of 4-fluoroacetanilide (compound 4) and 150mL of methyl tert-butyl ether solvent were added to a 500mL single-necked bottle with a magnetic stirrer, and then 338mg of visible light catalyst nitrogen carbon dioxide (g-C 3 N 4 ) (w / w=1.47%), heated up to 35°C under stirring, and at the same time, a LED lamp with a power of 72 watts was used to illuminate the reaction system for photocatalytic Fries rearrangement reaction, and the reaction system was kept under light for 48 hours. After tracking the reaction of the raw materials, it was lowered to room temperature, and the reaction solution was filtered with diatomaceous earth to remove the visible light catalyst and suction filtered, and the filter residue was washed with 50 mL of dioxane, and the filtrate was collected, and the filtrate was concentrated under reduced pressure to remove the solvent dioxane ...

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