ChemicalBook CAS DataBase List Panobinostat

Panobinostat synthesis

6synthesis methods

Product Name:Panobinostat
CAS Number:404950-80-7
Molecular formula:C21H23N3O2
Molecular Weight:349.43

Panobinostat, also known as NVP LBH-589 or LBH-589, is a cinnamic hydroxamic acid analogue with potential antineoplastic activity. Panobinostat selectively inhibits histone deacetylase (HDAC), inducing hyperacetylation of core histone proteins, which may result in modulation of cell cycle protein expression, cell cycle arrest in the G2/M phase and apoptosis. In addition, this agent appears to modulate the expression of angiogenesis-related genes, such as hypoxia-inducible factor-1alpha (HIF-1a) and vascular endothelial growth factor (VEGF), thus impairing endothelial cell chemotaxis and invasion. On 2/23/2015, it received FDA accelerated approval for use in patients with multiple myeloma who had received at least 2 previous treatments, including bortezomib and an immunomodulatory agent. Synthetic Description Reference: Chen, Shanwen & Zhang, Peiming & Chen, Huali & Yu, Yu & Gan, Zongjie. (2018). An Improved and Efficient Synthesis of Panobinostat. Journal of Chemical Research. 42. 471-473. 10.3184/174751918X15357309308931. Synthetic Description Reference: Bair, Kenneth Walter; Green, Michael A.; Perez, Lawrence B.; Remiszewski, Stacy W.; Sambucetti, Lidia; Versace, Richard William; Sharma, Sushil Kumar. Preparation of hydroxamic acids as deacetylase inhibitors. WO 2002022577. (Assignee Novartis AG, Switz.; Novartis-Erfindungen Verwaltungsgesellschaft mbH; Novartis Pharma GmbH) Synthetic Description Reference: Chen, Ying-Nan Pan; Lassota, Peter; Wood, Alexander Wallace. Cyclooxygenase-2 inhibitor-histone deacetylase inhibitor combination for treatment of premalignant colon lesions, colon cancer, and other malignancies. WO 2003039599. (Assignee Novartis AG, Switz.; Novartis Pharma Gmbh) Synthetic Description Reference: Lassota, Piotr. Rapid method for screening compounds for in vivo activity. WO 2002055742. (Assignee Novartis Ag, Switz.; Novartis-Erfindungen Verwaltungsgesellschaft m.b.H.; Novartis Pharma Gmb) Synthetic Description Reference: Izumo, Seigo; Shetty, Suraj Shivappa. Preparation of cinnamic acid N-hydroxy amides as histone deacetylase inhibitors for the treatment of pathologic cardiac hypertrophy and heart failure. WO 2007021682. (Assignee Novartis A.-G., Switz.; Novartis Pharma G.m.b.H.) Synthetic Description Reference: Acemoglu, Murat; Bajwa, Joginder S.; Parker, David John; Slade, Joel. Process for preparation of (2E)-N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide. WO 2007146718. (Assignee Novartis A.-G., Switz.; Novartis Pharma G.m.b.H.) Synthetic Description Reference: Siripragada, Mahender Rao; Vohra, Irfan; Parikh, Chirag; Buddh, Mayur; Joshi, Akash; Thirunavakarasu, Ananda Babu; Parikh, Pinky. Preparation of novel salts and polymorphic forms of Panobinostat. WO 2017221163. (Assignee Alembic Pharmaceuticals Limited, India) Synthetic Description Reference: Xu, Yongxiang. Synthesis of Panobinostat and intermediates. CN 106674079. (Assignee Nanjing Cavendish Bio-Engineering Technology Co., Ltd., Peop. Rep. China) Synthetic Description Reference: Gan, Zongjie. Panobinostat intermediate, its synthesis and application. CN 108794375. (Assignee Chongqing University of Medical Sciences, Peop. Rep. China)

Synthetic Routes

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Reference: Chen, Shanwen & Zhang, Peiming & Chen, Huali & Yu, Yu & Gan, Zongjie. (2018). An Improved and Efficient Synthesis of Panobinostat. Journal of Chemical Research. 42. 471-473. 10.3184/174751918X15357309308931.

441741-66-8 Synthesis

Panobinostat Carboxylic Acid Methyl Ester Hydrochloride

441741-66-8
19 suppliers
$165.00/5mg

404950-80-7
242 suppliers
$28.00/1unit

Yield:404950-80-7 94.6%

Reaction Conditions:

Stage #1:(E)-3-[4-[[2-(2-methyl-1H-indol-3-yl)ethylamino]methyl]phenyl]acrylic acid methyl ester hydrochloride with sodium hydroxide in methanol at -15 - -10; for 0.166667 h;
Stage #2: with hydroxylamine hydrochloride in methanol at -15 - -10; for 3.66667 h;

Steps:

11 Embodiment 11(E)- N - hydroxy -3 - [4 - [[ [2 - (2 - methyl - 1H - indole -3 - yl) ethyl] amino] methyl] phenyl] acrylamide
To a 250 ml four-necked flask was added (E) -3- [4 - [[2- (2-methyl-1H-indol-3-yl)(15 g, 0.039 mol), methanol (75 ml), cooled at -10 ° C to 15 ° C with stirring, and rapidly precipitated with sodium hydroxide (4.68 g, 0.71 m 1 ) In methanol solution, drop the mixture, stir lOmin, dropping hydroxylamine solution (32. 52g 50% aqueous solution corresponding to hydroxylamine hydrochloride 16.268,0.234111001), dropping finished at -10 ° (: - 15 ° (temperature insulation Stir for 2 hours.The reaction mixture was warmed to 0 ° C, kept at 0-5 ° C for 30 min, then warmed to 20 ° C, kept at 20-25 ° C for 1 hour, drop in water 38 ml, stir l0 min, Filtered and rinsed with 38 ml of water. The resulting filtrate was adjusted to pH 10 with an aqueous solution of hydrochloric acid (about 18. 5 g of an aqueous solution of 2 mol / L) to 10. The crystals were stirred at 20-25 ° C and treated with hydrochloric acid (About 15.5 g of 2 mol / L of aqueous solution), continue to adjust the PH value of the solution to 8-9, stirring at 20-25 ° C for 1 hour, continue to adjust the pH of the solution to 3-4, stirring for 1 hour , The solid was filtered and the filter cake was rinsed with 50 ml of a methanolic water mixture (ν / ν = 1: 1) and dried to a constant weight in a 50 ° hot air oven to give a solid 12. 89 g, yield 94. 6% :

References:

Nanjing Kawendixu Biological Engineering Co., Ltd.;Xu Yongxiang CN106674079, 2017, A Location in patent:Paragraph 0089; 0090; 0091

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441741-65-7 Synthesis