Neelakandha Mani New Chemical Technologies, Discovery Sciences

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Presentation transcript:

Neelakandha Mani New Chemical Technologies, Discovery Sciences Concise Routes to Fused Azole Heterocycles and Their Application in the Synthesis of Potential Drug Candidates. Neelakandha Mani New Chemical Technologies, Discovery Sciences

Priorities in Methods Development “The 21st century definition of the goals of synthesis should be based, as we have emphasized for some time, on safety, step and time economy, and environmental considerations”. Paul A. Wender Tetrahedron 7529-7550, 2013

Fused Pyrazoles: Synthesis of a 5HT7/5HT2A Dual Antagonist Serotonin Receptors: Successful Drug Targets 5-HT transporter (Prozac®, Celexa®) 5HT7/5HT2 Dual antagonist Ion channel 5-HT3 (Zofran®, Kytril®) Serotonin GPCR 5-HT1 (1A, 1B, 1D, 1E, 1F) (Imitrex®….) 5-HT2 (2A, 2B, 2C) (Risperdal®, Clozaril®… ) 5-HT4 (Propulsid®) 5-HT5 (5A,5B) 5-HT6 5-HT7 Serotonin receptors have proven to be highly relevant physiological drug targets

Why a Combination 5‑HT7 / 5‑HT2A Antagonist? Clinical Indications Schizophrenia Psychosis, bipolar disorders ADD, Substance Abuse Obsessive compulsive disorder Post-traumatic stress Depression, Anxiety Sleep disorders Risperidone r5-HT7 Ki = 29 nM h5-HT2A Ki = 0.8 nM

Discovery Synthesis Issues: Linear synthesis diazo compound - potential safety hazard cross-coupling at the last step - metal residue Carruthers, Nicholas I.; Chai, Wenying; Deng, Xiaohu; Dvorak, Curt A.; Kwok, Annette K.; Liang, Jimmy T.; Mani, Neelakandha; Rudolph, Dale A.; Wong, Victoria D. PCT Int. Appl. (2005), WO 2005040169 A2 20050506. 

One-pot, Three-component Pyrazole Synthesis Deng, X.; Mani, N. S. Org. Lett. 2006, 8, 3505.

Design of a Convergent Route

Optimization and a 350-Gram Campaign

The Last Step Discovery route: 5 linear steps Scale-up route: 3 linear steps, no column chromatography minimal metal residue Liang, J. T.; Deng, X.; Mani, N. S. Organic Process Research and Development 2011, 15, 876-882

Fused Pyrazoles: Synthesis of an HRI Kinase Inhibitor eIF2aP  translation,  apoptosis eIF2a  translation,  survival Protein synthesis a, b globin chains + Hb Hemoglobin synthetic pathway Heme-regulated eukaryotic initiating factor 2a (HRI) Kinase Regulates production of a and b globin Inhibitors of HRI kinase promote increased production of globins and and thus Increased hemoglobin levels—Potential treatment for anemia

Discovery Synthesis R1, R2 as defined in Rosen, M. D. et al Bioorganic & Medicinal Chemistry Letters (2009), 19, 6548-6551.

A New Route to Benzofuropyrazoles? Intramolecular 1,3-dipolar cycloaddition

1,3-Dipolar Cycloadditions Sales, Z. S.; Mani, N. S. Journal of Organic chemistry, 2009, 74, 891-894

A Concise Route Discovery route: 7 steps, multiple chromatographic purifications Scale-up route: 2 steps, one chromatographic purification Sales, Z. S.; Mani, N. S. Journal of Organic chemistry, 2009, 74, 891-894 Rosen, Mark D; et al Bioorganic & Medicinal Chemistry Letters (2009), 19, 6548-6551.

Fused Triazoles: Synthesis of a P2X7 Modulator Possible synthesis of tetrahydrotriazolopyridines

CuAAC Approach to 1,4,5-Trisubstituted-1,2,3-Triazoles Deng, X.; Liang, J. T.; Allison, B. B.; Dvorak, C.; McAllister, H.; Savall, B. M. and Mani, N. S. JOC, 2015, 11003-11012

A One-pot Regioselective Copper(I)-Catalyzed [3+2]-Azide-Alkyne Cycloaddition/Allylation Strategy Wu, Y-M.; Deng, J.; Li, Y.; Chen, Q-Y. Synthesis 2005, 1314; De Koning, C. B.; van Otterlo, W. A. L.; Michael, J. P. Tetrahedron 2003, 59, 8337

A Scalable Second Generation Route

A Scalable Second Generation Route

Acknowledgments Xiaohu Deng Jimmy Liang Zachary Sales Dan Pippel Jing Liu Anne Fitzgerald Brett Allison Christi Morrill Todd Jones

Plausible Mechanism Deng, X.; Mani, N. S. J. Org. Chem. 2008, 73, 2412-2415.

Concerted or Stepwise?

A Novel Route to Fused Triazoles

Dichlorovinyl ether formation

Intramolecular 1,3-dipolar Cycloaddition approach to Fused Pyrazoles Padwa, A.; Ku, H. J. Org. Chem, 1980, 45, 3756-3766 Chandrasekhar, S; Rajaiah, G; Srihari, P. Tetrahedron Letters, 2001, 42, 6599-6601

A Novel Route to Fused Triazoles

Synthesis of 1,4,5-Trisubstituted-1,2,3-Triazoles Regioselectivity Steven M. Weinreb etal. JOC, 2006, 8680 Floris P.J.T. Rutjes etal. Synlett, 2005, 3059

Reaction Optimization

A Concise Route to Fused Triazoles

A One-Pot Synthesis