1. 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

2. 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 , 2013

3. 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

4. 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

5. 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   A2   

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

7. Design of a Convergent Route

8. Optimization and a 350-Gram Campaign

9. 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,

10. 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

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

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

13. 1,3-Dipolar Cycloadditions
Sales, Z. S.; Mani, N. S. Journal of Organic chemistry, 2009, 74,

14. 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,
Rosen, Mark D; et al Bioorganic & Medicinal Chemistry Letters (2009), 19,

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

16. 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,

17. 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

18. A Scalable Second Generation Route

19. A Scalable Second Generation Route

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

21. Plausible Mechanism
Deng, X.; Mani, N. S. J. Org. Chem. 2008, 73,

22. Concerted or Stepwise?

23. A Novel Route to Fused Triazoles

24. Dichlorovinyl ether formation

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

26. A Novel Route to Fused Triazoles

27. 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

28. Reaction Optimization

29. A Concise Route to Fused Triazoles

30. A One-Pot Synthesis