Method for synthesizing Palbociclib

Abstract

The invention belongs to the field of drug synthesis and relates to a method for synthesizing an antitumor drug, i.e., Palbociclib. The novel method for synthesizing the Palbociclib, provided by the invention, comprises the steps of subjecting a compound 4, which serves as a starting raw material, and a compound 5 to a cyclization reaction in an organic solvent, so as to prepare a compound 3, andthen, subjecting the compound 3, a compound 2 and cyclopentylamine to a one-pot process reaction, thereby preparing a compound 1. According to the method, the starting raw material is readily available, the reaction conditions are mild, the process route is simple and controllable, the yield of byproducts is low, and the total yield of the product is increased, so that the method is applicable toindustrial large-scale production.

Description

technical field

[0001] The invention belongs to the field of drug synthesis, and in particular relates to a synthesis method of an antineoplastic drug palbociclib. Background technique

[0002] Palbociclib (Palbociclib) is a cell cycle-dependent kinase (CDK4 / 6) inhibitor developed by Pfizer, which was granted the "Breakthrough Therapy" qualification by the US FDA in April 2013. Due to its good clinical performance in Phase III, Pfizer submitted a marketing application to the US FDA in August 2014 and obtained priority review qualifications for estrogen receptor positive (ER+) and human epidermal growth factor receptor 2 negative ( First-line treatment of HER2-) advanced breast cancer. The successful research of this drug will provide another important new option for patients with metastatic breast cancer.

[0003] The chemical name of palbociclib (Palbociclib, I) is: 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(1-piperazinyl)-2-pyridyl] Amino]pyrido[2,3-d]pyrimidin-7(8H)-one, i...

Examples

Embodiment 1

[0040] (1) Preparation of Compound 3

[0041] Add 18.62g of compound 4, 22.03g of compound 5, and 13.33g of aluminum trichloride into a three-neck flask, add 250ml of ethanol, stir at room temperature for 4h, add 4.00g of sodium hydroxide, stir at room temperature for 3h, adjust the pH to 5 with 2M dilute hydrochloric acid , stirred for 30 minutes and then raised to 60°C, cooled to room temperature after the solid was completely dissolved, filtered under reduced pressure, and dried to obtain 29.02g of compound 3 with a yield of 84.69% and a purity of 99.92%.

[0042] (2) Preparation of compound 1

[0043] Mix 17.12g of compound 3 with 200ml of isopropanol, add 4.26g of cyclopentylamine, control the temperature at 20-60°C, heat to reflux for 4h, add 2.70g of sodium methoxide, stir for 30min, add 6.46g of compound 2 for reflux reaction for 3h, drop to normal temperature, filtered, washed with deionized water, and dried in vacuum to obtain 20.15 g of compound 1 with a yield of 8...

Embodiment 2

[0045] (1) Preparation of Compound 3

[0046] Add 20.18g of compound 4, 22.03g of compound 5, and 24.33g of ferric chloride into the three-neck flask, add 250ml of dichloromethane, stir at room temperature for 4h, add 11.22g of potassium hydroxide, stir at room temperature for 3h, adjust the pH with 2M dilute hydrochloric acid to 5, stirred for 30 minutes and then raised to 60°C, cooled to room temperature after the solid was completely dissolved, filtered under reduced pressure, and dried to obtain 28.91g of compound 3 with a yield of 84.33% and a purity of 99.87%.

[0047] (2) Preparation of compound 1

[0048] Mix 17.12g of compound 3 with 200ml of dichloromethane, add 3.83g of cyclopentylamine, control the temperature at 20-60°C, heat to reflux for 4h, add 6.81g of sodium ethylate, stir for 30min, add 6.46g of compound 2 for reflux reaction for 3h, drop to normal temperature, filtered, washed with deionized water, and dried in vacuum to obtain 18.23 g of compound 1 with a...

Embodiment 3

[0050] (1) Preparation of Compound 3

[0051] Add 19.55g of compound 4, 22.03g of compound 5, 16.36g of zinc dichloride into the three-neck flask, add 250ml of methanol, stir at room temperature for 4h, 13.8g of potassium carbonate, stir at room temperature for 3h, adjust the pH to 5 with 2M dilute hydrochloric acid, and stir After 30 minutes, it was raised to 60°C, cooled to room temperature after the solid was completely dissolved, filtered under reduced pressure, and dried to obtain 28.98 g of compound 3 with a yield of 84.56% and a purity of 99.90%.

[0052] (2) Preparation of compound 1

[0053] Mix 17.12g of compound 3 with 200ml of ethanol, add 4.26g of cyclopentylamine, control the temperature at 20-60°C, heat and reflux for 4h, add 5.40g of sodium methoxide, stir for 30min, add 6.46g of compound 2 for reflux reaction for 3h, and lower to room temperature , filtered, washed with deionized water, and dried in vacuum to obtain 20.10 g of compound 1 with a yield of 89.65...

technical field

[0001] The invention belongs to the field of drug synthesis, and in particular relates to a synthesis method of an antineoplastic drug palbociclib. Background technique

[0002] Palbociclib (Palbociclib) is a cell cycle-dependent kinase (CDK4 / 6) inhibitor developed by Pfizer, which was granted the "Breakthrough Therapy" qualification by the US FDA in April 2013. Due to its good clinical performance in Phase III, Pfizer submitted a marketing application to the US FDA in August 2014 and obtained priority review qualifications for estrogen receptor positive (ER+) and human epidermal growth factor receptor 2 negative ( First-line treatment of HER2-) advanced breast cancer. The successful research of this drug will provide another important new option for patients with metastatic breast cancer.

[0003] The chemical name of palbociclib (Palbociclib, I) is: 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(1-piperazinyl)-2-pyridyl] Amino]pyrido[2,3-d]pyrimidin-7(8H)-one, i...

Examples

Embodiment 1

[0040] (1) Preparation of Compound 3

[0041] Add 18.62g of compound 4, 22.03g of compound 5, and 13.33g of aluminum trichloride into a three-neck flask, add 250ml of ethanol, stir at room temperature for 4h, add 4.00g of sodium hydroxide, stir at room temperature for 3h, adjust the pH to 5 with 2M dilute hydrochloric acid , stirred for 30 minutes and then raised to 60°C, cooled to room temperature after the solid was completely dissolved, filtered under reduced pressure, and dried to obtain 29.02g of compound 3 with a yield of 84.69% and a purity of 99.92%.

[0042] (2) Preparation of compound 1

[0043] Mix 17.12g of compound 3 with 200ml of isopropanol, add 4.26g of cyclopentylamine, control the temperature at 20-60°C, heat to reflux for 4h, add 2.70g of sodium methoxide, stir for 30min, add 6.46g of compound 2 for reflux reaction for 3h, drop to normal temperature, filtered, washed with deionized water, and dried in vacuum to obtain 20.15 g of compound 1 with a yield of 8...

Embodiment 2

[0045] (1) Preparation of Compound 3

[0046] Add 20.18g of compound 4, 22.03g of compound 5, and 24.33g of ferric chloride into the three-neck flask, add 250ml of dichloromethane, stir at room temperature for 4h, add 11.22g of potassium hydroxide, stir at room temperature for 3h, adjust the pH with 2M dilute hydrochloric acid to 5, stirred for 30 minutes and then raised to 60°C, cooled to room temperature after the solid was completely dissolved, filtered under reduced pressure, and dried to obtain 28.91g of compound 3 with a yield of 84.33% and a purity of 99.87%.

[0047] (2) Preparation of compound 1

[0048] Mix 17.12g of compound 3 with 200ml of dichloromethane, add 3.83g of cyclopentylamine, control the temperature at 20-60°C, heat to reflux for 4h, add 6.81g of sodium ethylate, stir for 30min, add 6.46g of compound 2 for reflux reaction for 3h, drop to normal temperature, filtered, washed with deionized water, and dried in vacuum to obtain 18.23 g of compound 1 with a...

Embodiment 3

[0050] (1) Preparation of Compound 3

[0051] Add 19.55g of compound 4, 22.03g of compound 5, 16.36g of zinc dichloride into the three-neck flask, add 250ml of methanol, stir at room temperature for 4h, 13.8g of potassium carbonate, stir at room temperature for 3h, adjust the pH to 5 with 2M dilute hydrochloric acid, and stir After 30 minutes, it was raised to 60°C, cooled to room temperature after the solid was completely dissolved, filtered under reduced pressure, and dried to obtain 28.98 g of compound 3 with a yield of 84.56% and a purity of 99.90%.

[0052] (2) Preparation of compound 1

[0053] Mix 17.12g of compound 3 with 200ml of ethanol, add 4.26g of cyclopentylamine, control the temperature at 20-60°C, heat and reflux for 4h, add 5.40g of sodium methoxide, stir for 30min, add 6.46g of compound 2 for reflux reaction for 3h, and lower to room temperature , filtered, washed with deionized water, and dried in vacuum to obtain 20.10 g of compound 1 with a yield of 89.65...

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