Industrial method for preparing apremilast and intermediate thereof

Abstract

The invention discloses an industrial method for preparing high-purity apremilast (described in formula I) and an intermediate thereof. With 3-nitrophthalic acid (compound II) adopted as the starting raw material, and organic acid or acid anhydride adopted as the solvent, the method comprises the following steps: preparing high-purity 3-acetamido phthalic anhydride (compound IV) through different intermediates; directly enabling the obtained undried product to react with (S)-1-(3-oxethyl-4-methoxy phenyl)-2-mesyl) ethylamine (compound V) or the salt during reflux in glacial acetic acid, so as to obtain the apremilast. The preparation method is easy to operate, low in energy consumption, high in yield, and applicable to industrial production.

Description

technical field

[0001] The invention relates to an industrialization method for preparing apremilast and an intermediate thereof, in particular to an industrialization method for a small molecule inhibitor of phosphodiesterase 4 (PDE4) apremilast and an intermediate thereof. The invention belongs to the field of medicinal chemistry. Background technique

[0002] Apremilast (Compound I, chemical name: (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetyl Aminoisoindoline-1,3-dione) is a small molecule inhibitor of phosphodiesterase 4 (PDE4) that specifically acts on cyclic adenosine monophosphate (cAMP), and PDE4 inhibition leads to intracellular Elevated levels of cAMP reduce joint swelling and improve the physiology of the joint area. The structural formula is as follows:

[0003]

[0004] The drug was approved for marketing in the United States in March 2014 for the treatment of psoriatic arthritis. Currently, there are mainly CN1652772A, CN102702070, ...

Examples

Embodiment 1

[0026] Embodiment 1: Preparation of 3-aminophthalic acid

[0027] 2-Nitrophthalic acid (1.0kg), glacial acetic acid (8.5L), and 10% Pd / C (30g) were added to the autoclave in turn, replaced with nitrogen twice, and hydrogen was introduced to 1MPa, and the pressure was maintained at room temperature. React under pressure until no more hydrogen is absorbed, vent, blow with nitrogen, cool, and filter to obtain 920 g of a product containing palladium on carbon, with a solvent content of about 15%.

Embodiment 2

[0028] Embodiment 2: Preparation of 3-acetamidophthalic anhydride

[0029] Transfer the undried product obtained in Example 1 into a 5L three-necked flask, add acetic anhydride (4.5L), heat to reflux for 1-2 hours, filter while hot, wash with glacial acetic acid, and then cool the filtrate to 0-5°C. Stir until the product is fully separated, filter, and wash with glacial acetic acid to obtain 827 g of yellow needle-like crystals, containing about 12% solvent, 728 g after drying, 75% yield in two steps, and 99.8% by HPLC.

Embodiment 3

[0030] Embodiment 3: the preparation of Apremilast

[0031] The above undried product (728g after drying), glacial acetic acid (4.2L), (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonyl)ethyl Amine N-acetyl-L-leucine salt (1570g, ee99.3%) was added to the reaction flask in turn, and heated to reflux for 1 hour. After TLC detected that the raw materials disappeared, the reaction was terminated, glacial acetic acid was recovered under reduced pressure, and dichloromethane was added. Dissolve in 10L, successively wash with 5L of water, 5L of saturated aqueous sodium bicarbonate solution, 5L of saturated sodium chloride, dry over anhydrous magnesium sulfate, concentrate to dryness under reduced pressure, add 10L of absolute ethanol, reflux for 30 minutes, filter, wash with ethanol, After drying at 60°C, 1584 g of the product was obtained, with a yield of 97%, an HPLC above 99.8%, and an ee of 99.2%.

technical field

[0001] The invention relates to an industrialization method for preparing apremilast and an intermediate thereof, in particular to an industrialization method for a small molecule inhibitor of phosphodiesterase 4 (PDE4) apremilast and an intermediate thereof. The invention belongs to the field of medicinal chemistry. Background technique

[0002] Apremilast (Compound I, chemical name: (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetyl Aminoisoindoline-1,3-dione) is a small molecule inhibitor of phosphodiesterase 4 (PDE4) that specifically acts on cyclic adenosine monophosphate (cAMP), and PDE4 inhibition leads to intracellular Elevated levels of cAMP reduce joint swelling and improve the physiology of the joint area. The structural formula is as follows:

[0003]

[0004] The drug was approved for marketing in the United States in March 2014 for the treatment of psoriatic arthritis. Currently, there are mainly CN1652772A, CN102702070, ...

Examples

Embodiment 1

[0026] Embodiment 1: Preparation of 3-aminophthalic acid

[0027] 2-Nitrophthalic acid (1.0kg), glacial acetic acid (8.5L), and 10% Pd / C (30g) were added to the autoclave in turn, replaced with nitrogen twice, and hydrogen was introduced to 1MPa, and the pressure was maintained at room temperature. React under pressure until no more hydrogen is absorbed, vent, blow with nitrogen, cool, and filter to obtain 920 g of a product containing palladium on carbon, with a solvent content of about 15%.

Embodiment 2

[0028] Embodiment 2: Preparation of 3-acetamidophthalic anhydride

[0029] Transfer the undried product obtained in Example 1 into a 5L three-necked flask, add acetic anhydride (4.5L), heat to reflux for 1-2 hours, filter while hot, wash with glacial acetic acid, and then cool the filtrate to 0-5°C. Stir until the product is fully separated, filter, and wash with glacial acetic acid to obtain 827 g of yellow needle-like crystals, containing about 12% solvent, 728 g after drying, 75% yield in two steps, and 99.8% by HPLC.

Embodiment 3

[0030] Embodiment 3: the preparation of Apremilast

[0031] The above undried product (728g after drying), glacial acetic acid (4.2L), (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonyl)ethyl Amine N-acetyl-L-leucine salt (1570g, ee99.3%) was added to the reaction flask in turn, and heated to reflux for 1 hour. After TLC detected that the raw materials disappeared, the reaction was terminated, glacial acetic acid was recovered under reduced pressure, and dichloromethane was added. Dissolve in 10L, successively wash with 5L of water, 5L of saturated aqueous sodium bicarbonate solution, 5L of saturated sodium chloride, dry over anhydrous magnesium sulfate, concentrate to dryness under reduced pressure, add 10L of absolute ethanol, reflux for 30 minutes, filter, wash with ethanol, After drying at 60°C, 1584 g of the product was obtained, with a yield of 97%, an HPLC above 99.8%, and an ee of 99.2%.

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