Pyrimidine derivative with ALK inhibitory activity, synthesis method and applications thereof

Abstract

The invention discloses a pyrimidine derivative with ALK inhibitory activity, a synthesis method and applications thereof. The method comprises the following steps: reacting a 4-aminopiperidine compound with halogenated aromatic hydrocarbon to obtain a secondary amine product, obtaining a BOC-removed piperidine compound under the action of trifluoroacetic acid, and reacting the BOC-removed piperidine compound with 2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidine-4-amine. The preparation method has the advantages that the preparation process is simple and easy to operate. The prepared product has ALK inhibitory activity and can be used for preparing an ALK inhibitor.

Description

technical field

[0001] The invention belongs to the field of medicinal chemistry, and more specifically relates to a structure of a pyrimidine derivative with ALK inhibitory activity and a preparation method thereof. Background technique

[0002] Lung cancer is one of the most common malignant tumors in the world, and its mortality rate ranks first among all malignant tumors. Lung cancer can be divided into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), of which 85% belong to non-small cell lung cancer. Most non-small cell lung cancer patients are already in the middle and advanced stages when they are diagnosed, and the 5-year survival rate is very low. With the deepening of scientific research, scientists have discovered that the anaplastic lymphoma kinase (ALK) fusion gene is one of the key genes driving non-small cell lung cancer.

[0003] At present, molecular targeted therapy is the most effective and most widely used treatment method among man...

Examples

Embodiment 1

[0037] Example 1: 5-chloro-2-(4-(5-isopropoxy-4-((5-isopropylpyrazin-2-yl)amino)-2-methylphenyl)piperidine- 1-yl)-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine

[0038]

[0039] Step 1: tert-butyl 4-(5-isopropoxy-4-((5-isopropylpyrazin-2-yl)amine)-2-methylphenyl)piperidine-1-carboxylate preparation of

[0040]Add tert-butyl 4-(4-amino-5-isopropoxy-2-methylphenyl)piperidine-1-carboxylate (220mg, 0.60mmol), 2-chloro- 5-isopropylpyrazine (110μL, 0.60mmol), 10mL of dioxane, add 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (34.7mg, 0.06mmol), acetic acid Palladium (6.8mg, 0.03mmol), sodium tert-butoxide (172.8mg, 1.80mmol), stirred, filled with argon and evacuated, heated to 120°C in an oil bath. React for 10 h, wash with water, extract three times with ethyl acetate, combine the organic phases, dry over anhydrous magnesium sulfate, filter and concentrate in vacuo. The crude material was purified by silica gel chromatography (petroleum ether: ethyl acetate = 20:1, 8:1) t...

Embodiment 2

[0048] Example 2: 5-chloro-2-(4-((5-isopropylpyrazin-2-yl)amino)piperidin-1-yl)-N-(2-(isopropylsulfonyl)benzene base) pyrimidin-4-amine

[0049]

[0050] Step 1: Preparation of tert-butyl 4-((5-isopropylpyrazin-2-yl)amino)piperidine-1-carboxylate

[0051] Add tert-butyl 4-aminopiperidine-1-carboxylate (150mg, 0.75mmol), 2-chloro-5-isopropylpyrazine (150μL, 0.75mmol) and 10mL toluene successively in a 50mL reaction flask, and add 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (43.5mg, 0.075mmol), palladium acetate (10mg, 0.045mmol), sodium tert-butoxide (216mg, 2.25mmol), stirring, Fill with argon to evacuate, and heat the oil bath to 120°C. Reacted for 4.5 hours, washed with water, extracted three times with ethyl acetate, combined organic phases, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (petroleum ether:ethyl acetate=50:1, 20:1, 8:1, 4:1) to obtain a light yellow solid with a ...

technical field

[0001] The invention belongs to the field of medicinal chemistry, and more specifically relates to a structure of a pyrimidine derivative with ALK inhibitory activity and a preparation method thereof. Background technique

[0002] Lung cancer is one of the most common malignant tumors in the world, and its mortality rate ranks first among all malignant tumors. Lung cancer can be divided into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), of which 85% belong to non-small cell lung cancer. Most non-small cell lung cancer patients are already in the middle and advanced stages when they are diagnosed, and the 5-year survival rate is very low. With the deepening of scientific research, scientists have discovered that the anaplastic lymphoma kinase (ALK) fusion gene is one of the key genes driving non-small cell lung cancer.

[0003] At present, molecular targeted therapy is the most effective and most widely used treatment method among man...

Examples

Embodiment 1

[0037] Example 1: 5-chloro-2-(4-(5-isopropoxy-4-((5-isopropylpyrazin-2-yl)amino)-2-methylphenyl)piperidine- 1-yl)-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine

[0038]

[0039] Step 1: tert-butyl 4-(5-isopropoxy-4-((5-isopropylpyrazin-2-yl)amine)-2-methylphenyl)piperidine-1-carboxylate preparation of

[0040]Add tert-butyl 4-(4-amino-5-isopropoxy-2-methylphenyl)piperidine-1-carboxylate (220mg, 0.60mmol), 2-chloro- 5-isopropylpyrazine (110μL, 0.60mmol), 10mL of dioxane, add 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (34.7mg, 0.06mmol), acetic acid Palladium (6.8mg, 0.03mmol), sodium tert-butoxide (172.8mg, 1.80mmol), stirred, filled with argon and evacuated, heated to 120°C in an oil bath. React for 10 h, wash with water, extract three times with ethyl acetate, combine the organic phases, dry over anhydrous magnesium sulfate, filter and concentrate in vacuo. The crude material was purified by silica gel chromatography (petroleum ether: ethyl acetate = 20:1, 8:1) t...

Embodiment 2

[0048] Example 2: 5-chloro-2-(4-((5-isopropylpyrazin-2-yl)amino)piperidin-1-yl)-N-(2-(isopropylsulfonyl)benzene base) pyrimidin-4-amine

[0049]

[0050] Step 1: Preparation of tert-butyl 4-((5-isopropylpyrazin-2-yl)amino)piperidine-1-carboxylate

[0051] Add tert-butyl 4-aminopiperidine-1-carboxylate (150mg, 0.75mmol), 2-chloro-5-isopropylpyrazine (150μL, 0.75mmol) and 10mL toluene successively in a 50mL reaction flask, and add 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (43.5mg, 0.075mmol), palladium acetate (10mg, 0.045mmol), sodium tert-butoxide (216mg, 2.25mmol), stirring, Fill with argon to evacuate, and heat the oil bath to 120°C. Reacted for 4.5 hours, washed with water, extracted three times with ethyl acetate, combined organic phases, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (petroleum ether:ethyl acetate=50:1, 20:1, 8:1, 4:1) to obtain a light yellow solid with a ...

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