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Preparation method of Otezla with high chiral purity

A high-purity, expert technology, applied in the field of Apremilast with high chiral purity, can solve the problems of long reaction time and lower chiral purity of Apremilast, and achieve the effect of shortening the reaction time

Inactive Publication Date: 2016-01-06
南京美嘉宁逸医药研究开发有限公司
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Problems solved by technology

[0005] But the existing (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1, 3-Diketone is composed of 3-acetamidophthalic anhydride and (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-ethane-2- Under the condition of acetic acid as the solvent, the base amine is refluxed and reacted overnight, the reaction time is long, and the chiral purity of apremilast is reduced

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  • Preparation method of Otezla with high chiral purity

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Embodiment 1

[0018] A preparation method of apremilast with high chiral purity, the compound 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-ethan-2-ylamine and the compound N-acetyl-L-leucine salt formation reaction to obtain compound (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-eth-2-yl Amine-N-acetyl-L-leucine salt, purified compound (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-ethyl- 2-ylamine-N-acetyl-L-leucine salt reacts with compound 3-acetamidophthalic anhydride in the presence of toluene and acetic acid to obtain compound (S)-2-[1-( 3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, recrystallized from a mixture of acetone and ethanol Apremilast with relatively pure stereoisomer was obtained.

[0019] Compound (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-eth-2-ylamine-N-acetyl-L-leucine salt The specific preparation method is: under the condition that the reaction temperature is 65-70°C and 280ml of methanol is selected a...

Embodiment 2

[0025] A preparation method of apremilast with high chiral purity, the compound 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-ethan-2-ylamine and the compound N-acetyl-L-leucine salt formation reaction to obtain compound (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-eth-2-yl Amine-N-acetyl-L-leucine salt, purified compound (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-ethyl- 2-ylamine-N-acetyl-L-leucine salt reacts with compound 3-acetamidophthalic anhydride in the presence of toluene and acetic acid to obtain compound (S)-2-[1-( 3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, recrystallized from a mixture of acetone and ethanol Apremilast with relatively pure stereoisomer was obtained.

[0026] Compound (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-eth-2-ylamine-N-acetyl-L-leucine salt The specific preparation method is: under the condition that the reaction temperature is 65-70°C and 420ml of methanol is selected a...

Embodiment 3

[0032] A preparation method of apremilast with high chiral purity, the compound 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-ethan-2-ylamine and the compound N-acetyl-L-leucine salt formation reaction to obtain compound (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-eth-2-yl Amine-N-acetyl-L-leucine salt, purified compound (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-ethyl- 2-ylamine-N-acetyl-L-leucine salt reacts with compound 3-acetamidophthalic anhydride in the presence of toluene and acetic acid to obtain compound (S)-2-[1-( 3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, recrystallized from a mixture of acetone and ethanol Apremilast with relatively pure stereoisomer was obtained.

[0033] Compound (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-eth-2-ylamine-N-acetyl-L-leucine salt The specific preparation method is as follows: 50g of compound 2-(3-ethoxy-4-methoxyphenyl)-1-(methanesulfonyl Acyl)-Eth-2-ylamine ...

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Abstract

The invention discloses a preparation method of Otezla with high chiral purity. 2-(3-ethoxy-4-methoxy phenyl)-1-(mesyl)-ethoxy-2-amino and N-acetyl-L-leucine have a salt-forming reaction to form (S)-2-(3-ethoxy-4-methoxy phenyl)-1-(mesyl)-ethoxy-2-amino-N-acetyl-L-leucine salt, the purified (S)-2-(3-ethoxy-4-methoxy phenyl)-1-(mesyl)-ethoxy-2-amino-N-acetyl-L-leucine salt reacts with 3-acetylamino phthalic anhydride to produce (S)-2-[1-(3-ethoxy-4-methoxy phenyl)-2-mesyl ethyl]-4-acetyl amino isoindoline-1,3-diketone in the presence of methylbenzene and acetic acid, and the Otezla with purifier stereoisomer is obtained through recrystallization with an acetone and ethanol mixed solvent. The method has the advantages as follows: through replacement of the solvent and addition of a catalyst, the reaction time is greatly shortened, and besides, the Otezla with the chiral purity up to 99.8% is prepared.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, in particular to a premilast with high chiral purity [0002] method of preparation. Background technique [0003] The chemical name of Apremilast is (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-4-acetylaminoisoindoline -1,3-diketone, its chemical structure is: [0004] Apremilast was approved by the US FDA on March 25, 2014, with a trade name of Otezla for the treatment of psoriatic arthritis. Apremilast is the first new type of phosphodiesterase (PDE4) inhibitor-type oral drug approved for marketing, manufactured by Celgene in Summit, New Jersey. It has good efficacy and high safety, and has changed the global psoriasis Current status of the treatment of arthritis. [0005] But the existing (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1, 3-Diketone is composed of 3-acetamidophthalic anhydride and (S)-2-(3-ethoxy-4-methoxyph...

Claims

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Application Information

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IPC IPC(8): C07D209/48
CPCC07D209/48C07B2200/07
Inventor 黄乐群胡丰锦
Owner 南京美嘉宁逸医药研究开发有限公司
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