Synthesis of Ledipasvir through a Late-Stage Cyclopropanation and Fluorination Process

Chennam Ramu; T. Kumaraguru; M. Sridhar Reddy; Haridas B. Rode; Subhash Ghosh; Ch. Raji Reddy; Gangarajula Sudhakar

doi:10.1055/s-0042-1751437

Synthesis, Inhaltsverzeichnis

Synthesis 2024; 56(04): 603-610
DOI: 10.1055/s-0042-1751437

special topic

Synthetic Development of Key Intermediates and Active Pharmaceutical Ingredients (APIs)

Synthesis of Ledipasvir through a Late-Stage Cyclopropanation and Fluorination Process

Chennam Ramu

^aOrganic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad-500007, Telangana, India

^bAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India

,

T. Kumaraguru

^aOrganic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad-500007, Telangana, India

^bAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India

,

M. Sridhar Reddy

^aOrganic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad-500007, Telangana, India

^bAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India

,

Haridas B. Rode

^aOrganic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad-500007, Telangana, India

^bAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India

,

Subhash Ghosh

^aOrganic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad-500007, Telangana, India

^bAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India

,

Ch. Raji Reddy

^aOrganic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad-500007, Telangana, India

^bAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India

,

Gangarajula Sudhakar ∗

^aOrganic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad-500007, Telangana, India

^bAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India

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Abstract

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Abstract

We have designed and developed an easily accessible advanced intermediate of ledipasvir that allowed late-stage cyclopropanation and difluorination, thereby providing a novel and more efficient process for the preparation of ledipasvir in the longest linear sequence of 8 steps with 20% overall yield.

Key words

ledipasvir - hepatitis C virus - late-stage fluorination - late-stage cyclopropanation - Boc-4-methylene-l-proline - harvoni - direct-acting antivirals

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Referenzen

References
1 Lavanchy D. Clin. Microbiol. Infect. 2011; 17: 107
2 https://www.who.int/en/news-room/fact sheets/detail/hepatitis-c (accessed Mar 23, 2023)

3a Gentile I, Buonomo AR, Borgia F, Castaldo G, Borgia G. Expert Opin. Invest. Drugs 2014; 23: 561
3b Smith MA, Chan J, Mohammad RA. Ann. Pharmacother. 2015; 49: 343
3c Link JO, Taylor JG, Xu L, Mitchell M, Guo H, Liu H, Kato D, Kirschberg T, Sun J, Squires N, Parrish J, Kellar T, Yang ZY, Yang C, Matles M, Wang Y, Wang K, Cheng G, Tian Y, Mogalian E, Mondou E, Cornpropst M, Perry J, Desai MC. J. Med. Chem. 2014; 57: 2033

4a Guo H, Kato D, Kirschberg TA, Liu H, Link JO, Mitchell ML, Parrish JP, Squires N, Sun J, Taylor J, Bacon EM, Canales E, Cho A, Cottell JJ, Desai MC, Halcomb RL, Krygowski ES, Lazerwith SE, Liu Q, Mackman R, Pyun HJ, Saugier JH, Trenkle JD, Tse WC, Vivian RW, Schroeder SD, Watkins WJ, Xu L, Yang ZY, Kellar T, Sheng X, Clarke MO. N. H, Chou CH, Graupe M, Jin H, McFadden R, Mish MR, Metobo SE, Phillips BW, Venkataramani C. WO 2010132601A1, 2010
4b Scott RW, Vitale JP, Matthews KS, Teresk MG, Formella A, Evans JW. US 20130324740A1, 2013

5a Stella L, Abraham H, Dupont JF, Tinant B, Declercq JP. Tetrahedron Lett. 1990; 31: 2603
5b Scott RW, Vitale JP, Matthews KS, Teresk MG, Formella A, Evans JW. (Gilead Sciences) WO 2013184702, 2013
5c Guo H, Kato D, Kirschberg TA, Liu H, Link JO, Mitchell ML, Parrish JP, Sun J, Taylor J, Bacon EM, Canales E, Cho A, Kim CU, Cottell JJ, Desai MC, Halcomb RL, Lazerwith SE, Mackman RL, Pyun H.-J, Saugier JH, Trenkle JD, Tse WC, Watkins WJ, Xu L. (Gilead Sciences) US 8088368B2, 2012
5d See Scheme 4B for a representative synthetic sequence.

6 Shen Z, Dornan PK, Khan HA, Woo TK, Dong VM. J. Am. Chem. Soc. 2009; 131: 1077
7 Flick AC, Ding HX, Leverett CA, Kyne RE. Jr, Liu KK.-C, Fink SJ, O’Donnell CJ. Bioorg. Med. Chem. 2016; 24: 1937
8 Du X, Zhu G, Chen C. CN 104211677A, 2014
9 A two-step synthetic sequence for fragment I from either direct fluorination on compound 6 or fluorination on compound 2 followed by Friedel–Crafts acylation would have shortened the route, but our efforts in this direction were not successful.

10a Littler BJ, Aizenberg M, Ambhaikar NB, Blythe TA, Curran TT, Dvornikovs V, Jung YC, Jurkauskas V, Lee EC, Looker AR, Luong H, Martinot TA, Miller DB, Neubert-Langille BJ, Otten PA, Rose PJ, Ruggiero PL. Org. Process Res. Dev. 2015; 19: 270
10b Qiu Y.-L, Peng X, Kim IJ, Cao H, Tang D, Or YS, Wang G, Xu G. WO 2012158861A2, 2012
10c Durand X, Hudhomme P, Khan JA, Young DW. J. Chem. Soc., Perkin Trans. 1 1996; 1131

11 Tymtsunik AV, Bilenko VA, Ivon YM, Grygorenko OO, Komarov IV. Tetrahedron Lett. 2012; 53: 3847
12 Gütz C, Bänziger M, Bucher C, Galvão TR, Waldvogel SR. Org. Process Res. Dev. 2015; 19: 1428

13a Ye S, Yu Z.-X. Org. Lett. 2010; 12: 804
13b Charette AB, Beauchemin A. Org. React. 2001; 58: 1
13c Denmark SE, Stiff CM. J. Org. Chem. 2000; 65: 5875
13d Renuad P, Fox MA. J. Org. Chem. 1988; 53: 3745
13e Furukawa J, Kawabata N, Nishimura J. Tetrahedron Lett. 1966; 7: 3353
13f Simmons HE, Smith RD. J. Am. Chem. Soc. 1958; 80: 5323

14 Kuwano R, Kameyama N, Ikeda R. J. Am. Chem. Soc. 2011; 133: 7312

15a Suzuki A. Proc. Jpn. Acad., Ser. B 2004; 80 (08) 359
15b Chemler SR, Trauner D, Danishefsky SJ. Angew. Chem. Int. Ed. 2001; 40: 4544
15c Meng D, Bertinato P, Balog A, Su D, Kamenecka T, Sorensen EJ, Danishefsky SJ. J. Am. Chem. Soc. 1997; 119: 10073
15d Miyaura N, Suzuki A. Chem. Rev. 1995; 95: 2457
15e Miyaura N, Yanagi T, Suzuki A. Synth. Commun. 1981; 11: 513

16a Ji M, Tian X, Zong X, Xu H, Li R, Zhang X. CN 105524049A, 2016
16b Zhang Y, Shen C, Chen S, Hu G, Wei Y, Yu L, Tao X. US 20170253614A1, 2017
16c Lavoie R, James CA, Ruediger EH. WO 2010138488, 2010

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