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18162-48-6872-50-4Methylene ChloridenaphthaleneTHFTitanium Dioxide
ChemicalBook CAS DataBase List Apremilast

Apremilast synthesis

3synthesis methods
Apremilast, also known as CC-10004, is a thalidomide analog and is an orally available small molecule inhibitor of phosphodiesterase 4 (PDE4). Apremilast specifically inhibits PDE4 and inhibits spontaneous production of TNF-alpha from human rheumatoid synovial cells. It has anti-inflammatory activity. Apremilast was approved by the USFDA in March 2014 for treatment of adults with active psoriatic arthritis. It is also being tested for its efficacy in treating other chronic inflammatory diseases such as ankylosing spondylitis, Behcet's disease, and rheumatoid arthritis.
Synthetic Routes
  • ROUTE 1

    • 202112073970164251.jpg

    Syu, Jin-Fong; Gopula, Balraj; Jian, Jia-Hong; Li, Wei-Sian; Kuo, Ting-Shen; Wu, Ping-Yu; Henschke, Julian P.; Hsieh, Meng-Chi; Tsai, Ming-Kang; Wu, Hsyueh-Liang. Asymmetric Synthesis of β-Aryl β-Imido Sulfones Using Rhodium Catalysts with Chiral Diene Ligands: Synthesis of Apremilast. Organic Letters. Volume 21. Issue 12. Pages 4614-4618. Journal; Online Computer File. (2019).

  • ROUTE 2

    • 202112072468447652.jpg

    Man, Hon-Wah; Schafer, Peter; Wong, Lu Min; Patterson, Rebecca T.; Corral, Laura G.; Raymon, Heather; Blease, Kate; Leisten, Jim; Shirley, Michael A.; Tang, Yang; Babusis, Darius M.; Chen, Roger; Stirling, Dave; Muller, George W. Discovery of (S)-N-{2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide (Apremilast), a Potent and Orally Active Phosphodiesterase 4 and Tumor Necrosis Factor-α Inhibitor. Journal of Medicinal Chemistry. Volume 52. Issue 6. Pages 1522-1524. Journal. (2009).

  • ROUTE 3

    • 202112075597630207.jpg

    Ruchelman, Alexander L.; Connolly, Terrence J. Enantioselective synthesis of the apremilast aminosulfone using catalytic asymmetric hydrogenation. Tetrahedron: Asymmetry. Volume 26. Issue 10-11. Pages 553-559. Journal; Online Computer File. (2015).

  • ROUTE 4

    • 202112074537106069.jpg

    Stavber, Gaj. A novel synthetic pathway towards apremilast. Assignee Lek Pharmaceuticals d.d., Slovenia. WO 2016202806. (2016).

  • ROUTE 5

    • 202112078177823093.jpg

    Dandala, Ramesh; Jayachandra, Sureshbabu; Kaushik, Vipin Kumar; Achanta, Nageshwara Rao; Dorasala, Sivaprasad. Process for the enantiomeric resolution of apremilast intermediates. Assignee Mylan Laboratories Limited, India. WO 2016174685. (2016).

  • ROUTE 6

    • 202112076575027949.jpg

    Siripragada, Mahender Rao; Panchasara, Dinesh; Patel, Ilesh; Prajapati, Bhavesh; Shah, Ankit. An improved process for the preparation of apremilast and its polymorphic forms. Assignee Alembic Pharmaceuticals Limited, India. IN 2015MU04347. (2017).

202112073970164251.jpg

Syu, Jin-Fong; Gopula, Balraj; Jian, Jia-Hong; Li, Wei-Sian; Kuo, Ting-Shen; Wu, Ping-Yu; Henschke, Julian P.; Hsieh, Meng-Chi; Tsai, Ming-Kang; Wu, Hsyueh-Liang. Asymmetric Synthesis of β-Aryl β-Imido Sulfones Using Rhodium Catalysts with Chiral Diene Ligands: Synthesis of Apremilast. Organic Letters. Volume 21. Issue 12. Pages 4614-4618. Journal; Online Computer File. (2019).

6296-53-3 Synthesis
1,3-Dioxo-2-isoindolineaceticacid

6296-53-3
300 suppliers
$6.00/250mg

608141-42-0 Synthesis
(S)-1-(3-Ethoxy-4-Methoxyphenyl)-2-(Methylsulfonyl)ethanaMine

608141-42-0
221 suppliers
$10.00/250mg

Apremilast

608141-41-9
491 suppliers
$50.00/1g

-

Yield:608141-41-9 97%

Reaction Conditions:

with acetic acid for 1 h;Reflux;Large scale;

Steps:

3 Preparation of apremilast

The unbaked product (728 g after drying), glacial acetic acid (4. 2 L), (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethanamine(1570 g, 99.3%) Followed by adding the reaction flask, heating to reflux reaction for 1 hour, After the TLC was detected, the reaction was stopped and the reaction was terminated. The reaction was terminated under reduced pressure, and 10L of methylene chloride was dissolved. After washing with 5 L of water, 5 L of water saturated with aqueous sodium bicarbonate, 5 L of saturated sodium chloride, dried over anhydrous magnesium sulfate, Concentrated to dry, add anhydrous ethanol 10L, reflux 30 minutes, filtration, ethanol washing, 60 ° C drying to obtain product 1584g, the yield of 97%, HPLC 99. 8% or more, 99.2%.

References:

CN105294534,2016,A Location in patent:Paragraph 0030; 0031

6296-53-3 Synthesis
1,3-Dioxo-2-isoindolineaceticacid

6296-53-3
300 suppliers
$6.00/250mg

608141-43-1 Synthesis
(S)-1-(3-Ethoxy-4-Methoxyphenyl)-2-(Methylsulfonyl)ethylaMine N-acetyl-L-leucine salt

608141-43-1
183 suppliers
$18.00/1g

Apremilast

608141-41-9
491 suppliers
$50.00/1g

References
608141-42-0 Synthesis
(S)-1-(3-Ethoxy-4-Methoxyphenyl)-2-(Methylsulfonyl)ethanaMine

608141-42-0
221 suppliers
$10.00/250mg

Benzoyl chloride, 4-[(2-chloroethyl)sulfonyl]-

7185-00-4
0 suppliers
inquiry

Apremilast

608141-41-9
491 suppliers
$50.00/1g

References

Apremilast Related Search:

Nintedanib Avanafil Apremilast 3-Ethoxy-4-methoxybenzaldehyde oxime Apremilast Apremilast 3-Ethoxy-4-Methoxy-alpha-[(Methylsulfonyl)Methyl]-benzeneMethanaMine (S)-1-(3-Ethoxy-4-Methoxyphenyl)-2-(Methylsulfonyl)ethylaMine N-acetyl-L-leucine salt 1,3-Dioxo-2-isoindolineaceticacid