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Preparation method of Apremilast

A technology of apremilast and preparation steps, which is applied in the field of preparation of apremilast, can solve the problems of harsh reaction conditions, long reaction steps, unfavorable industrialization, etc., and achieve the effects of easy availability of raw materials, promotion of development, and simple process

Active Publication Date: 2014-06-18
徐州鑫辉生物能源科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Compared with the resolution, the above-mentioned chiral synthesis method has the characteristics of novel reaction design, cost reduction, economical and environmental protection, etc., but the above-mentioned method needs to use some uncommon chiral catalysts, the reaction conditions are relatively harsh, and the reaction steps are long, so it is not suitable conducive to industrialization

Method used

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  • Preparation method of Apremilast
  • Preparation method of Apremilast
  • Preparation method of Apremilast

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Add (R)-1-(α-aminobenzyl)-2-naphthol (II) (2.5g, 10mm01), triethylamine (1.2g, 12mm01) and methanol 50mL in a three-neck reaction flask, stir 3-Ethoxy-4-methoxybenzaldehyde (III) (1.8 g, 10 mmOl) was added, and after 24 hours of reaction at room temperature, a solid was formed, and the reaction was completed by TLC detection. Filtered, the filter cake was washed with cold methanol, and dried in vacuo to obtain a white solid (1R,3S)-1-phenyl-3-(3-ethoxy-4-methoxyphenyl)-2,3-dihydro- 3.7 g of 1H-naphtho[1,2-e][1,3]oxazine (IV), yield 90.0%.

Embodiment 2

[0032] Add (1R,3S)-1-phenyl-3-(3-ethoxy-4-methoxyphenyl)-2,3-dihydro-1H-naphthalene to a nitrogen atmosphere and a dry three-neck reaction flask [1,2-e][1,3]oxazine (IV) (2.1g, 5mm01) and 25mL of anhydrous-treated fresh tetrahydrofuran, add dimethyl sulfone monolithium dropwise under stirring at 0-5°C Salt (0.64g, 6.25mm01) in tetrahydrofuran solution, after dropping, raised to room temperature, stirred and reacted for 1 hour, and detected the reaction by TLC. The reaction was quenched with saturated ammonium chloride. Extracted 3 times with ethyl acetate, combined the organic phases and dried over anhydrous magnesium sulfate. Concentrated under reduced pressure, the residue was recrystallized with ethanol and water (1:1) to obtain off-white solid N-[(2S)-(1-(3-ethoxy-4-methoxyphenyl)-2- Methylsulfonylethyl)]-(1R)-(α-aminobenzyl)-2-naphthol (V) 2.2g, yield 87.1%.

Embodiment 3

[0034] Add N-[(2S)-(1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl)]-(1R)-(α- Aminobenzyl)-2-naphthol (V) (1.3g, 2.5mm01), 10% palladium carbon (65mg, 5% w / w) and methanol 50mL, according to the hydrogenation reduction operating procedure, the hydrogen pressure is controlled to be 2KG, and the temperature It is 30-40°C and reacts until no hydrogen is absorbed. Filter and recover the catalyst. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from methanol to obtain (S)-2-[1-(3-ethoxy-4-methoxyphenyl)]-1-methanesulfonyl-2-ethylamine ( Intermediate B) 0.6g, yield 87.9%.

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Abstract

The invention discloses a preparation method of Apremilast (I). The preparation method comprises the following steps: carrying out condensation on (R)-1-(Alpha-amino-benzyl)-2-isonaphthol (II) and 3-ethyoxyl-4-methoxybenaldehyde (III) to generate (1R, 3S)-1-phenyl-3-(3-ethyoxyl-4-methoxyphenyl)-2,3-dihydro-1H-naphthyl[1, 2-e][1, 3] oxazine (IV), carrying out cycloaddition reaction on the intermediate (IV) and a dimethyl sulfone organolithium salt to generate N-[(2S)-(1-(3-ethyoxyl-4-methoxyphenyl)-2-methylsulfonyl ethyl)]-(1R)-(Alpha-amino-benzyl)-2-isonaphthol (V), carrying out a hydrogenation reduction reaction on the intermediate (V) to prepare (S)-2-[1-(3- ethyoxyl-4-methoxyphenyl)]-1-methylsulfonyl-2-ethylamine (intermediate B), and carrying out condensation on the intermediate B and 3-acetamido phthalic anhydride (intermediate A) to prepare the Apremilast (I). The preparation method disclosed by the invention uses easily available raw materials and concise process, is economical, environment-friendly and suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and in particular relates to a preparation method of apremilast. Background technique [0002] Apremilast is a new type of small molecule oral drug of phosphodiesterase (PDE-4) inhibitors developed by Celgene Corporation. Because the compound does not have a standard Chinese translation, the applicant transliterates it here For "Apremilast". Clinical trials have shown that the compound plays a role by regulating the network of intracellular pro-inflammatory and anti-inflammatory factors, and has obvious therapeutic effects on psoriatic arthritis, and is expected to become an effective and safe drug for the treatment of moderate to severe plaque psoriasis. options, and also provide additional options for the long-term management of psoriatic arthritis. [0003] The chemical name of Apremilast is: (S)-2-[1-(3-ethoxy-4-metho...

Claims

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Application Information

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IPC IPC(8): C07D209/48
CPCC07D209/48
Inventor 许学农
Owner 徐州鑫辉生物能源科技有限公司
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