Syntheses of Cinacalcet: An Enantiopure Active Pharmaceutical Ingredient (API)

Abstract

Cinacalcet hydrochloride is the only approved drug acting as calcimimetic, a new class of compounds used in the therapy of secondary hyperparathyroidism and parathyroid carcinoma. Several generic drug manufacturers and research groups from academia have reported alternative approaches to this molecule, mainly from (R)-(+)-1-(1-naphthyl)ethylamine. There are mainly three strategies that have been used to couple this readily accessible enantiopure amine to the other part of the molecule: amide formation followed by reduction, reaction with an aldehyde and reduction of the resulting imine, and nucleophilic substitution with a suitable partner that carries a leaving group. More exotic approaches have also been disclosed. In the present review all of them are discussed.

1 Introduction

2 Synthetic Approaches Involving the Synthesis of an Amide Followed by Its Reduction

2.1 Approaches Involving Saturated Amide 2 from Acid 3

2.2 Approaches Involving Acrylamide 5

2.3 Alternatives Approaches Involving Amides

3 Synthetic Approaches Involving a Reductive Amination

3.1 Processes for the Synthesis of 3-(Trifluoromethyl)cinnamaldehyde (18) and 3-[3-(Trifluoromethyl)phenyl]propanal (20)

3.2 Processes Involving 18

3.3 Processes Involving 20

4 Synthetic Approaches Involving a Substitution Reaction

4.1 Substitutions Involving Alkyl Halides or Pseudohalides

4.2 Substitutions Involving Allyl Halides or Pseudohalides

4.3 Substitution Involving a Propynyl Mesylate

4.4 Direct Substitution without Activating the Hydroxyl Group

5 Miscellaneous Synthetic Approaches

6 Conclusions

Key words

amides - amines - drugs - Mannich bases - reduction

• References

• 1 These authors contributed equally to this work.
• 2 Nemeth EF, Van Wagenen BC, Balandrin MF. PCT Int. Appl. WO9304373, 1993 ; Chem. Abstr. 1993, 119, 63054.
• 3 Locatelli F, Pontoriero G, Limardo M, Tentori F. Expert Rev. Endocrinol. Metab. 2006; 1: 167
• 4a Palmer SC, Nistor I, Craig JC, Pellegrini F, Messa P, Tonelli M, Covic A, Strippoli GF. PLoS Med. 2013; 10: e1001436
• 4b Verheyen N, Pilz S, Eller K, Kienreich K, Fahrleitner-Pammer A, Pieske B, Ritz E, Tomaschitz A. Expert Opin. Pharmacother. 2013; 14: 793
• 5 Catalog suppliers like Aldrich and Acros sell small-scale quantities. Larger quantities are available from BASF, Chiron and Finorga.
• 6 Catalog suppliers like Aldrich and Acros sell small-scale quantities. Larger quantities are available, from Central Glass, Indofine and TCI.
• 7 Brown TH, Blakemore RC, Durant GJ, Emmett JC, Ganellin CR, Parsons ME, Rawlings DA, Walker TF. Eur. J. Med. Chem. 1988; 23: 53
• 8a Knoevenagel E. Chem. Ber. 1898; 31: 2585
• 8b Doebner O. Chem. Ber. 1900; 33: 2140
• 8c See also references 16a and 24.
• 9a Bumagin NA, More PG, Beletskaya IP. J. Organomet. Chem. 1989; 371: 397
• 9b Beller M, Kuehlein K. Synlett 1995; 441
• 10 Thiel OR, Bernard C, Tormos W, Brewin A, Hirotani S, Murakami K, Saito K, Larsen RD, Martinelli MJ, Reider PJ. Tetrahedron Lett. 2008; 49: 13
• 11a Padi PR, Akundi SP, Suthrapu SK, Kolla NK, Kotagiri VK, Neelam UK, Baddam SR, Manne N. PCT Int. Appl. WO2008058235, 2008 ; Chem. Abstr. 2008, 148, 561587.
• 11b Padi PR, Akundi SP, Suthrapu SK, Kolla NK, Kotagiri VK, Neelam UK, Baddam SR, Manne N, Devarakonda SN, Thaimattam R, Raghupati B, Vasamsetti SK. PCT Int. Appl. WO2008058236, 2008 ; Chem. Abstr. 2008, 148, 537933.
• 12 Geoghegan K, Kelleher S, Evans P. J. Org. Chem. 2011; 76: 2187
• 13a Wang X, Chen Y, Crockett R, Briones J, Yan T, Orihuela C, Zhi B, Ng J. Tetrahedron Lett. 2004; 45: 8355
• 13b For the synthesis of related impurities, see: Lei F, Qu B, Li X, Guo L, Guan M, Hai L, Jin H, Wu Y. Synth. Commun. 2014; 44: 2879
• 14 (Sandoz AG), EP 1990333, 2008 ; Chem. Abstr. 2008, 149, 533935.
• 15 Srinivasan CV, Johar PS, Wadhwa L. PCT Int. Appl. WO2008035381, 2008 ; Chem. Abstr. 2008, 148, 379220.
• 16a Agarwal RM, Bhirud S, Pillai CB, Maloyesh B. PCT Int. Appl. WO2008117299, 2008 ; Chem. Abstr. 2007, 148, 426540.
• 16b Bijukumar G, Maloyesh B, Bhaskar BS, Rajendra A. Synth. Commun. 2008; 38: 1512
• 17 Reeves JT, Tan Z, Marsini MA, Han ZS, Xu Y, Reeves DC, Lee H, Lu BZ, Senanayake CH. Adv. Synth. Catal. 2013; 355: 47
• 18 Thiel O, Bernard C, Larsen R, Martinelli MJ, Raza MT. PCT Int. Appl. WO2009002427, 2009 ; Chem. Abstr. 2008, 150, 98009.
• 19 Reddy SR. D, Velivela SR, Rane DR, Punna S, Naini V. Indian Pat. Appl. IN 2013CH02896, 2013 ; Chem. Abstr. 2015, 163, 412018.
• 20 Sorribes I, Junge K, Beller M. J. Am. Chem. Soc. 2014; 136: 14314
• 21 Fu M.-C, Cheng W.-M, Fu Y. Angew. Chem. Int. Ed. 2015; 54: 9042
• 22a Divvela VN. S. R, Guntupally S, Deekonda S, Racha L, Ray UK, Islam A, Meenakshisunderam S. PCT Int. Appl. WO2010128388, 2010 ; Chem. Abstr. 2013, 159, 608398.
• 22b Rao DV. N. S, Lenin R, Satheesh D, Ray UK, Sivakumaran M. Indian Pat. Appl. IN 2009CH01069, 2009 ; Chem. Abstr. 2013, 161, 389729.
• 22c Rao DV. N. S, Lenin R, Satheesh D, Ray UK, Sivakumaran M. Indian Pat. Appl. IN 2009CH01070, 2009 ; Chem. Abstr. 2013, 161, 404480.
• 22d Rao DV. N. S, Lenin R, Satheesh D, Ray UK, Sivakumaran M. Indian Pat. Appl. IN 2009CH01071, 2009 ; Chem. Abstr. 2013, 161, 375752.
• 23 Shimpi N, Bijukumar GP, Nadkami SS. Indian Pat. Appl. IN 2009MU00189, 2009 ; Chem. Abstr. 2010, 154, 87954.
• 24 Shimpi N, Bijukumar GP, Prabhavat MD, Nadkami SS. Indian Pat. Appl. IN 2009MU01367, 2009 ; Chem. Abstr. 2010, 154, 409666.
• 25 Parthasaradhi Reddy B, Rathnakar Reddy K, Muralidhara Reddy D, Raji Reddy R, Mukunda Reddy J, Vamsi Krishna B. PCT Int. Appl. WO2012007954, 2012 ; Chem. Abstr. 2012, 156, 175011.
• 26 Aissaoui H, Boss C, Gude M, Koberstein R, Sifferlen T. PCT Int. Appl. WO2007122591, 2007 ; Chem. Abstr. 2007, 147, 502350.
• 27 Bhobe AM, Lamture JB, Nair DS, Kulkarni SR.. Indian Pat. Appl. IN 2011MU00087, 2011 ; Chem. Abstr. 2012, 158, 11310.
• 28 Allegrini P, Attolino E, Rossi D. EP2327684, 2011 ; Chem. Abstr. 2011, 154, 614838.
• 29 Szekeres T, Répási J, Szabó A, Mangion B. PCT Int. Appl. WO2008035212, 2008 ; Chem. Abstr. 2008, 148, 402864.
• 30a Chavakula R, Mutyala NR, Chennupati SR. J. Indian Chem. Soc. 2013; 90: 1259
• 30b Narayana RM, Ramadas C, Srinivasa RC, Sandeep G. PCT Int. Appl. WO2014016847, 2014 ; Chem. Abstr. 2014, 160, 264927.
• 31 Gupta N, Khairnar PK. K, Lunagariya J, Kumar P, Dubey SK. Indian Pat. Appl. IN 2008DE02268, 2008 ; Chem. Abstr. 2010, 153, 286719.
• 32 Lednicer D, Emmery DE. J. Med. Chem. 1968; 11: 1258
• 33 Ferrari M, Ghezzi M, Bonaldi M. PCT Int. Appl. WO2009153814, 2009 ; Chem. Abstr. 2009, 152, 74740.
• 34 Sebastian S, Peri SR. S, Ramamurthy K, Pradhan NS. PCT Int. Appl. WO2010067204, 2010 ; Chem. Abstr. 2010, 153, 97594.
• 35 Veerappan V, Sankareswaran S, Viswanathan SK. R, Sakthivelmurugan S. PCT Int. Appl. WO2014020574, 2014 ; Chem. Abstr. 2014, 160, 278695.
• 36a Nemeth EF, Van Wagenen BC, Balandrin MF, Delmar EG, Moe ST. PCT Int. Appl. WO9511221, 1995 ; Chem. Abstr. 1996, 125, 142305.
• 36b Van Wagenen BC, Moe ST, Balandrin MF, Delmar EG, Nemeth EF. PCT Int. Appl. WO9612697, 1996 ; Chem. Abstr. 1996, 125, 142305.
• 37 Sinore S, Shah C, Jagtap A, Roy M, Hariharan S. Indian Pat. Appl. IN 2012MU03068, 2012 ; Chem. Abstr. 2014, 162, 287140.
• 38 Kumar NU, Reddy BS, Reddy VP, Bandichhor R. Tetrahedron Lett. 2012; 52: 4354
• 39 Rai VC, Naithani PK, Merwade AY, Deo K. Indian Pat. Appl. IN 2012MU03420, 2012 ; Chem. Abstr. 2014, 162, 326943.
• 40 Wang G, Chen C, Du T, Zhong W. Adv. Synth. Catal. 2014; 356: 1747
• 41 Szekeres T, Répási J, Szabó A, Benito M, Mangion B. PCT Int. Appl. WO2008068625, 2008 ; Chem. Abstr. 2008, 149, 38959.
• 42 Mangion B. PCT Int. Appl. WO2009039241, 2009 ; Chem. Abstr. 2009, 150, 359931.
• 43 Chavakula R, Mutyala NR, Chennupati SR. J. Indian Chem. Soc. 2013; 90: 2291
• 44 Dwivedi SP. D, Prasad A, Desai JA, Naik AV. PCT Int. Appl. WO2014178068, 2014 ; Chem. Abstr. 2014, 161, 698287.
• 45 Barniol-Xicota M, Turcu AL, Codony S, Escolano C, Vázquez S. Tetrahedron Lett. 2014; 55: 2548
• 46a Guérin C, Bellosta V, Guillamot G, Cossy J. Eur. J. Org. Chem. 2012; 2990
• 46b Lifshitz-Liron R, Raizi Y, Ramaty R. PCT Int. Appl. WO2006127932, 2006 ; Chem. Abstr. 2006, 146, 27637.
• 47 Gome B, Levenfeld L. PCT Int. Appl. WO2008063645, 2008 ; Chem. Abstr. 2008, 148, 568869.
• 48a Kankan RN, Rao DR, Birari DR. PCT Int. Appl. WO2010100429, 2010 ; Chem. Abstr. 2010, 153, 382679.
• 48b Another of Cipla’s patents discloses similar procedures but using racemic intermediates: Rao DR, Kankan RN, Birari DR. PCT Int. Appl. WO2010010359, 2010 ; Chem. Abstr. 2010, 152, 191790.
• 49 Xu M, Yue H, Min Z. US Pat. Appl. Publ. US20150080608, 2015 ; Chem. Abstr. 2015, 162, 437916.
• 50 O’Hagan and co-workers have used this approach for the synthesis of two fluorinated analogues of cinacalcet, see: Chia PW, Brennan SC, Slawin AM. Z, Riccardi D, O’Hagan D. Org. Biomol. Chem. 2012; 10: 7922; see section 5 for details
• 51 Chidambaram VS, Johar PS, Prajapaty R, Sharma E, Wadhwa L. PCT Int. Appl. WO2010004588, 2010 ; Chem. Abstr. 2010, 152, 144330.
• 52 Arava VR, Gorentla L, Dubey PK. Beilstein J. Org. Chem. 2012; 8: 1366
• 53 Jiang X, Chu L, Qing F.-L. J. Org. Chem. 2012; 77: 1251
• 54 Mukhtar S, Nair DS, Medhane RR, Maheshwari N, Tewari N, Prasad M. PCT Int. Appl. WO2011033473, 2011 ; Chem. Abstr. 2011, 154, 360701.
• 55 Tewari N, Maheshwari N, Medhane R, Nizar H, Prasad M. Org. Process Res. Dev. 2012; 16: 1566
• 56 Allegrini P, Attolino E, Rossi D. EP2022777, 2009 ; Chem. Abstr. 2008, 150, 77352.
• 57a Vlasakova R, Hajicek J. PCT Int. Appl. WO2013075679, 2013 ; Chem. Abstr. 2013, 159, 42445.
• 57b For a possible mechanism for this reaction, see: Fujita K, Enoki Y, Yamaguchi R. Tetrahedron 2008; 64: 1943
• 58 Prediger P, da Silva AR, Correia CR. D. Tetrahedron 2014; 70: 3333
• 59 Lifshitz-Liron R. PCT Int. Appl. WO2007127449, 2007 ; Chem. Abstr. 2007, 147, 502111.
• 60 Goodman CA, Janci EM, Onwodi O, Simpson CC, Hamaker CG, Hitchcock SR. Tetrahedron Lett. 2015; 56: 4468
• 61a Catozzi N, Foletto J, Forcato M, Giovanetti R, Soriato G, Verzini M. PCT Int. Appl. WO2010049293, 2010 ; Chem. Abstr. 2010, 152, 525525.
• 61b Catozzi N, Cotarca L, Foletto J, Forcato M, Giovanetti R, Soriato G. PCT Int. Appl. WO2010094674, 2010 ; Chem. Abstr. 2010, 153, 358731.
• 61c Catozzi N, Cotarca L, Foletto J, Forcato M, Giovanetti R, Soriato G, Verzini M. PCT Int. Appl. WO2011029833, 2011 ; Chem. Abstr. 2011, 154, 360700.
• 62a Mathad VT, Niphade NC, Shinde GB, Ippar SS, Deshmukh SP, Panchangam RK. PCT Int. Appl. WO2010103531, 2010 ; Chem. Abstr. 2010, 153, 431072.
• 62b Shinde GB, Niphade NC, Deshmukh SP, Toche RB, Mathad VT. Org. Process Res. Dev. 2011; 15: 455
• 63 Schneider J.-M, Madec J, Kreimerman S, Guillamot G. PCT Int. Appl. WO2014037563, 2014 ; Chem. Abstr. 2014, 160, 427611.
• 64 For a very recent review on the preparation and utility of the pentafluorosylfanyl group in organic compounds, see: Savoie PR, Welch JT. Chem. Rev. 2015; 115: 1130