Synthesis of Cinacalcet Hydrochloride: A Case Study on the Impact of Agitation Speed on the Reaction Kinetics of Schiff’s Base during Scale-up

Megafine Publication Number: MF/33/2017

Abstract

During the process development of Cinacalcet hydrochloride, a calcimimetic agent, we encountered an unexpected substantial increase in the content of impurities in the product while scaling up the process in the pilot plant. Detailed investigation led to the conclusion that the agitation speed of the reaction mass impacted the reaction kinetics of Schiff’s base, leading to the formation of the impurities and lowering the product yield to ca. 40%. The present work reports details of an investigation carried out to control the formation of impurities to achieve an efficient and one-pot process for Cinacalcet hydrochloride with an overall yield of ca. 70%.

Keywords

Cinacalcet - calcimimetic drug - agitation speed - reaction kinetics - Schiff’s base - tips speed - scale-up

• References

• 1a Zlokarnik M. In Dimensional Analysis and Scale-up in Chemical Engineering. Springer-Verlag; Berlin, Heidelberg: 1991: 5-22
• 1b Bisio A. Kabel RL. Scale-up of Chemical Processes: Conversion from Laboratory Scale Tests to Successful Commercial Size Design. 1st ed. Wiley; New York: 1985: 699
• 2 David S. D.; Don’t Get Mixed up by Scale-Up, in Chemical Processing; 2005, 81-100
• 3a Herbert SC. Annu. Rev. Med. 2006; 57: 349
• 3b Sorbera LA. Castaner RM. Bayes M. Drugs Future 2002; 27: 831
• 3c Franceschini N. Joy MS. Kshirsagar A. Expert Opin. Invest. Drugs 2003; 12: 1413
• 4a Nemeth EF. Van Wagenen BC. Balandrin MF. delMar EG. Moe ST. US Patent US 6011068, 2000 ; Chem. Abstr. 2001, 135, 352750.
• 4b Van Wagene BC. Balandrin MF. Delmar EG. Nemeth EF. US Patent US 6211244, 2001 ; Chem. Abstr. 2001, 134, 280612.
• 4c Wang X. Chen Y. Crockett R. Briones J. Yan T. Orihuela C. Zhi B. Tetrahedron Lett. 2004; 45: 8355
• 5a Padi PR. Akrundi SP. Suthrpu SK. Kolla NK. PCT Appl. WO 2008058235, 2008 ; Chem. Abstr. 2008, 148, 561587.
• 5b Oliver T. Charles B. Robert L. John MM. Tamim RM. PCT Appl. WO 2009002427, 2009 ; Chem. Abstr. 2008, 150, 98009.
• 5c Revital LL. Amihai E. Shlomit W. Sharon A. Yuriy R. Revital R. PCT Appl. WO 2006125026, 2006 ; Chem. Abstr. 2006, 146, 7705.
• 5d Gorakshanath BS. Navnath CN. Shrikant PD. Raghunath BT. Vijayavitthal TM. Org. Process Res. Dev. 2011; 15: 455
• 6 Marta BX. Rosana L. Carmen E. Santiago V. Synthesis 2016; 48: 783
• 7 Vijayavitthal TM. Gorakshanath BS. Sharad SI. Navnath CN. Panchangam R. Vankwala PJ. Synth. Commun. 2011; 41: 341
• 8 Raj K. Vijayavitthal TM. Bhaduri AP. Nat. Prod. Lett. 1995; 7: 51
• 9 Process for preparation of 3-[3-(trifluoromethyl)phenyl]propanal (3): To the stirred solution of 3-[3-(trifluoromethyl)phenyl]propan-1-ol (100 g, 0.49 mole) in MDC (3.8 L) was added pyridinium chlorochromate (Corey-Suggs reagent, 137.23 g, 0.64 mole). The resultant reaction mass was stirred, heated at reflux temperature and maintained at the same temperature. Upon completion of reaction (TLC), the reaction mass was filtered. The filtrate was diluted with purified water (1.0 L) and the layers were separated. The organic layer was washed with 10% sodium bicarbonate (1.0 L) solution followed by brine (1.0 L) and concentrated under reduced pressure to give an oil (83.0 g). The inorganic residue present in the oil was removed by suspending the oil in n-heptane, with stirring for 20–30 min, filtering the solution through a Hyflow bed and concentration of the mother liquor under reduced pressure provided pure oil of compound 3. Yield 79.0 g (79.78%); GC purity 97.5%; MS: m/z = 202.10 [M⁺]; ¹H NMR (DMSO-d₆): δ = 9.82 (s, 1 H), 7.47–7.39 (m, 4 H, Ar-H), 3.03–2.98 (t, 2 H), 2.84–2.79 (t, 2 H).
• 10 ICH (International Conference on Harmonization) guideline. http://www.ich.org/products/guidelines/quality/article/quality guidelines.html. Accessed on 18 Oct. 2016.