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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AI-Extracted 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...
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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.

Application Domain

Organic chemistry

Technology Topic

SulfoneEthylamines +5

Image

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

Examples

  • Experimental program(4)

Example Embodiment

[0029] Example 1:
[0030] Add (R)-1-(α-aminobenzyl)-2-naphthol (II) (2.5g, 10mm01), triethylamine (1.2g, 12mm01) and 50 mL of methanol to a three-necked reaction flask, stir under stirring 3-Ethoxy-4-methoxybenzaldehyde (III) (1.8 g, 10 mm01) was added, and after 24 hours of reaction at room temperature, a solid was formed, and TLC detected that the reaction was completed. Filtered, the filter cake was washed with cold methanol, and dried in vacuo to give a white solid (1R,3S)-1-phenyl-3-(3-ethoxy-4-methoxyphenyl)-2,3-dihydro- 1H-naphthalene[1,2-e][1,3]oxazine (IV) 3.7 g, yield 90.0%.

Example Embodiment

[0031] Embodiment 2:
[0032] Add (1R,3S)-1-phenyl-3-(3-ethoxy-4-methoxyphenyl)-2,3-dihydro-1H-naphthalene into a nitrogen atmosphere and a dry three-necked reaction flask [1,2-e][1,3]oxazine (IV) (2.1g, 5mm01) and 25mL of fresh tetrahydrofuran treated with anhydrous, dimethylsulfone monolithium was added dropwise at 0-5°C with stirring The tetrahydrofuran solution of salt (0.64g, 6.25mm01) was added dropwise, and the solution was warmed to room temperature, and the reaction was stirred for 1 hour, and the reaction was detected by TLC. The reaction was quenched with saturated ammonium chloride. It was extracted three times with ethyl acetate, and the organic phases were combined and dried over anhydrous magnesium sulfate. Concentrated under reduced pressure, the residue was recrystallized from ethanol and water (1:1) to give N-[(2S)-(1-(3-ethoxy-4-methoxyphenyl)-2- as an off-white solid Methanesulfonylethyl)]-(1R)-(α-aminobenzyl)-2-naphthol (V) 2.2 g, yield 87.1%.

Example Embodiment

[0033] Embodiment three:
[0034] N-[(2S)-(1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl)]-(1R)-(α- Aminobenzyl)-2-naphthol (V) (1.3g, 2.5mmOl), 10% palladium on carbon (65mg, 5%w/w) and methanol 50mL, according to the hydrogenation reduction operation procedure, control the hydrogen pressure to 2KG, the temperature It is 30-40 ℃, and the reaction is carried out until no more hydrogen is absorbed. Filter to recover the catalyst. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from methanol to give (S)-2-[1-(3-ethoxy-4-methoxyphenyl)]-1-methanesulfonyl-2-ethylamine ( Intermediate B) 0.6 g, yield 87.9%.
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