Synthesis method of pomalidomide intermediate

Abstract

The invention relates to a synthesis method of a pomalidomide intermediate, and especially relates to a synthesis method of a pomalidomide key intermediate 3-aminopiperidine-2, 6-dione hydrochloride.The method comprises the following steps: reacting a raw material L-glutamic acid with ammonia water to generate diammonium salt of L-glutamic acid, removing monomolecular ammonia gas from the diammonium salt of L-glutamic acid to cyclize to generate 3-aminopiperidine-2, 6-dione, dissolving the 3-aminopiperidine-2, 6-dione in ethanol, introducing hydrochloric acid gas into the system, filtering, and drying to obtain 3-aminopiperidine-2, 6-dione hydrochloride. Toxic and harmful substances are not used in the reaction, and the single-step reaction is simple and easy to carry out.

Description

technical field

[0001] The invention belongs to the technical field of chemical drug synthesis, and relates to a synthesis method of a pomalidomide intermediate, in particular to a synthesis of a key intermediate of pomalidomide, 3-aminopiperidine-2,6-dione hydrochloride method. Background technique

[0002] Pomalidomide, the chemical name is 3-amino-N-(2,6-dioxo-3-piperidinyl)phthalimide. On January 8, 2013, the US FDA approved it to treat patients with multiple myeloma.

[0003] Originating in plasma cells in the bone marrow, multiple myeloma is a malignant blood disease with a high mortality rate. The main clinical manifestations are anemia, bone pain, kidney damage, hypercalcemia, etc. The incidence rate is one in 100,000, and it mostly occurs in the elderly over 50 years old.

[0004] The structure of pomalidomide is similar to that of thalidomide, and the structural formula of pomalidomide is as follows:

[0005]

[0006] Pomalidomide has anti-tumor activity and...

Examples

preparation example Construction

[0043] Solution preparation

[0044] Blank solution: take diluting solvent, that is.

Embodiment 1

[0048] (1) Stir and disperse 29.4g of L-glutamic acid in 294g of water, slowly add 8.75g of ammonia water dropwise, keep the temperature below 15°C, and continue to heat and stir for 0.5h after dissolving to form the diammonium salt of L-glutamic acid.

[0049] (2) Heating to 60°C for 2 hours, the diammonium salt of L-glutamic acid removes a molecule of ammonia and cyclizes to form 3-aminopiperidine-2,6-dione, which is precipitated in water.

[0050] (3) Filter and dry at 105°C for 3 hours to obtain 21.4g of 3-aminopiperidine-2,6-dione. Dissolve 21g of 3-aminopiperidine-2,6-dione in 210g of ethanol and pour into the system Introduce hydrochloric acid gas, control the temperature to less than 15°C, until there is no more solid precipitation.

[0051] (4) Filter and dry at 70°C for 3 hours to obtain 27.0 g of the product 3-aminopiperidine-2,6-dione hydrochloride, with a total yield of 82.1% and a purity of 99.76%. (the product obtained in this embodiment uses the high-performan...

Embodiment 2

[0053] (1) Stir and disperse 29.4g of L-glutamic acid in 294g of water, slowly add 7g of ammonia water dropwise, keep the temperature below 15°C, and continue to heat and stir for 0.5h after dissolving to form the diammonium salt of L-glutamic acid.

[0054] (2) Heating to 60°C for 2 hours, the diammonium salt of L-glutamic acid removes a molecule of ammonia and cyclizes to form 3-aminopiperidine-2,6-dione, which is precipitated in water.

[0055] (3) Filter, dry at 105°C for 3 hours to obtain 18g of 3-aminopiperidine-2,6-dione, dissolve 18g of 3-aminopiperidine-2,6-dione in 180g of ethanol, and pass through the system Add hydrochloric acid gas and control the temperature to less than 15°C until no solid is precipitated.

[0056] (4) Filter and dry at 70°C for 3 hours to obtain 27.1 g of the product 3-aminopiperidine-2,6-dione hydrochloride, with a total yield of 82.3% and a purity of 99.35%.

technical field

[0001] The invention belongs to the technical field of chemical drug synthesis, and relates to a synthesis method of a pomalidomide intermediate, in particular to a synthesis of a key intermediate of pomalidomide, 3-aminopiperidine-2,6-dione hydrochloride method. Background technique

[0002] Pomalidomide, the chemical name is 3-amino-N-(2,6-dioxo-3-piperidinyl)phthalimide. On January 8, 2013, the US FDA approved it to treat patients with multiple myeloma.

[0003] Originating in plasma cells in the bone marrow, multiple myeloma is a malignant blood disease with a high mortality rate. The main clinical manifestations are anemia, bone pain, kidney damage, hypercalcemia, etc. The incidence rate is one in 100,000, and it mostly occurs in the elderly over 50 years old.

[0004] The structure of pomalidomide is similar to that of thalidomide, and the structural formula of pomalidomide is as follows:

[0005]

[0006] Pomalidomide has anti-tumor activity and...

Examples

preparation example Construction

[0043] Solution preparation

[0044] Blank solution: take diluting solvent, that is.

Embodiment 1

[0048] (1) Stir and disperse 29.4g of L-glutamic acid in 294g of water, slowly add 8.75g of ammonia water dropwise, keep the temperature below 15°C, and continue to heat and stir for 0.5h after dissolving to form the diammonium salt of L-glutamic acid.

[0049] (2) Heating to 60°C for 2 hours, the diammonium salt of L-glutamic acid removes a molecule of ammonia and cyclizes to form 3-aminopiperidine-2,6-dione, which is precipitated in water.

[0050] (3) Filter and dry at 105°C for 3 hours to obtain 21.4g of 3-aminopiperidine-2,6-dione. Dissolve 21g of 3-aminopiperidine-2,6-dione in 210g of ethanol and pour into the system Introduce hydrochloric acid gas, control the temperature to less than 15°C, until there is no more solid precipitation.

[0051] (4) Filter and dry at 70°C for 3 hours to obtain 27.0 g of the product 3-aminopiperidine-2,6-dione hydrochloride, with a total yield of 82.1% and a purity of 99.76%. (the product obtained in this embodiment uses the high-performan...

Embodiment 2

[0053] (1) Stir and disperse 29.4g of L-glutamic acid in 294g of water, slowly add 7g of ammonia water dropwise, keep the temperature below 15°C, and continue to heat and stir for 0.5h after dissolving to form the diammonium salt of L-glutamic acid.

[0054] (2) Heating to 60°C for 2 hours, the diammonium salt of L-glutamic acid removes a molecule of ammonia and cyclizes to form 3-aminopiperidine-2,6-dione, which is precipitated in water.

[0055] (3) Filter, dry at 105°C for 3 hours to obtain 18g of 3-aminopiperidine-2,6-dione, dissolve 18g of 3-aminopiperidine-2,6-dione in 180g of ethanol, and pass through the system Add hydrochloric acid gas and control the temperature to less than 15°C until no solid is precipitated.

[0056] (4) Filter and dry at 70°C for 3 hours to obtain 27.1 g of the product 3-aminopiperidine-2,6-dione hydrochloride, with a total yield of 82.3% and a purity of 99.35%.

Images