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A kind of preparation method of Apremilast and its intermediate

A technology of intermediates and steps, which is applied in the field of preparation of Apremilast and its intermediates, can solve problems such as difficult operation, long reaction process, and reduced molecular utilization

Active Publication Date: 2016-07-27
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] Chinese patent document CN103864670A discloses a preparation method of Apremilast (Apremilast, I), using 4-methoxy-3-ethoxybenzaldehyde and (R)-α-1-phenyl-1-amino Acetalization of methyl-β-naphthol, ring-opening of dimethyl sulfone carbanion, hydrogen deprotection to obtain (S)-1-(4-methoxy-3-ethoxy)phenyl-2-(methylsulfonyl Acyl) ethylamine (II), the key intermediate II is aminated with 3-acetamidophthalic anhydride to prepare Apremilast; the method prepares the key intermediate II with a long reaction process, and uses butyllithium, which is not easy operation; at the same time, macromolecular chiral amines are also used, which reduces the utilization rate of molecules and has no industrial value

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  • A kind of preparation method of Apremilast and its intermediate
  • A kind of preparation method of Apremilast and its intermediate

Examples

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Effect test

Embodiment 1

[0049] Example 1: Preparation of (S)-1-(4-methoxy-3-ethoxy)phenyl-2-(methylsulfonyl)ethylamine (II)

[0050] Add 4.5 grams of L-proline, 1.5 grams of D-tartaric acid, and 140 grams of 5% ammonia-tetrahydrofuran solution to a 500-ml flask in turn, stir and dissolve, cool, and add 18.0 grams dropwise to keep the inner temperature between 20-25°C A mixed solution of (0.1 mole) 4-methoxy-3-ethoxybenzaldehyde, 23.5 grams (0.25 moles) dimethyl sulfone and 40 grams of tetrahydrofuran, dripped in about 1 hour, and then reacted at 20-25 ° C for 6 hours . Recover the solvent and ammonia under reduced pressure below 40°C, add 100 grams of water and 200 grams of 1,2-dichloroethane to the residue, stir for 30 minutes, separate the layers, and wash the separated water layer with 1,2-dichloroethane Ethyl chloride was extracted 3 times, 50 grams each time, and the separated aqueous layer could further reclaim L-proline, and the combined organic phase was dried with 20 grams of anhydrous sodi...

Embodiment 2

[0054] Example 2: Preparation of (S)-1-(4-methoxy-3-ethoxy)phenyl-2-(methylsulfonyl)ethylamine (II)

[0055] Add 4.5 grams of L-proline, 1.5 grams of D-tartaric acid, and 140 grams of 5% ammonia-cyclopentyl methyl ether solution to a 500-ml flask in turn, stir and dissolve, cool, and keep the inner temperature between 20-25°C A mixed solution of 18.0 grams (0.1 moles) of 4-methoxyl-3-ethoxybenzaldehyde, 23.5 grams (0.25 moles) of dimethyl sulfone and 40 grams of cyclopentyl methyl ether was added dropwise, and the dripping was completed in about 1 hour. Thereafter, the reaction was incubated at 20-25° C. for 6 hours. Recover the solvent and ammonia under reduced pressure below 40°C, add 100 grams of water and 200 grams of 1,2-dichloroethane to the residue, stir for 30 minutes, separate the layers, and wash the separated water layer with 1,2-dichloroethane Ethyl chloride was extracted 3 times, 50 grams each time, the separated aqueous layer was further reclaimed L-proline, the...

Embodiment 3

[0056] Embodiment 3: the preparation of Apremilast (Ⅰ)

[0057] Add 28.3 grams (0.1 mol, 98.8ee%) (S)-1-(4-methoxyl-3-ethoxyl)phenyl-2-(methylsulfonyl)ethane successively in a dry 250 ml glass flask Amine (II), 22.5 grams of 3-acetamidophthalic anhydride, 120 grams of acetic acid, after stirring for 30 minutes, add 2 grams of perchloric acid, react at 75-80°C for 30 minutes, then raise the temperature and reflux for 2 hours, Evaporate under reduced pressure to recover glacial acetic acid, lower the temperature to 20°C, add 200 grams of saturated saline and 150 grams of ethyl acetate, stir for 30 minutes, separate layers, extract the aqueous layer twice with ethyl acetate, 30 grams each time, combine the organic phase, 10 grams of anhydrous sodium sulfate were dried for 4 hours, filtered, the filtrate was concentrated under reduced pressure, and the residue was recrystallized with 100 grams of isopropanol to obtain 37.5 grams of white solid, apremilast (Ⅰ), yield 79.5%, optical...

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Abstract

The invention relates to a preparation method for apremilast and an intermediate of the apremilast. The preparation method comprises the following steps: enabling 4-methoxy-3-ethoxybenzaldehyde to have Mannich reaction with methylsulfonylmethane and ammonia under the action of L-proline and a promoter to obtain an intermediate, (S)-1-(4-methoxy-3-ethyoxyl)phenyl-2-(methylsulfonyl)ethylamine (II), and then amidating the intermediate (II) and 3-acetamido-phthalic anhydride to prepare the apremilast (I). According to the preparation method for the apremilast and the intermediate of the apremilast, the raw materials are easily available, the flow path is short, the process is simple and convenient, the product has high optical purity, and the industrial production is safe and environmentally friendly.

Description

technical field [0001] The invention relates to a preparation method of apremilast and its intermediate, belonging to the field of pharmaceutical biochemical industry. Background technique [0002] Apremilast, an oral drug developed by Celgene for the treatment of active psoriatic arthritis, is the first and only FDA-approved oral, option-based treatment for plaque psoriasis A phosphodiesterase 4 (PDE4) inhibitor was approved and launched by the FDA under the trade name Otezla (apremilast) in March 2014. Since its launch, it has become the first-choice oral drug for the treatment of psoriatic arthritis. [0003] The CAS number of Apremilast (Ⅰ) is 608141-41-9, and the chemical name is (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonyl Ethyl]-4-acetylaminoisoindoline-1,3-dione, the structural formula is as follows: [0004] [0005] The preparation method of Apremilast focuses on the use of (S)-1-(4-methoxy-3-ethoxy)phenyl-2-(methylsulfonyl)ethylamine (II) and 3-acetam...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C315/04C07C317/28C07D209/48
Inventor 戚聿新周立山陈军宋春鹏鞠立柱李新发
Owner XINFA PHARMA
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