A New Route to Roflumilast via Copper-Catalyzed Hydroxylation

Feng Ni; Jianqi Li

doi:10.1055/s-0032-1317527

Synthesis, Table of Contents

Synthesis 2012; 44(23): 3598-3602
DOI: 10.1055/s-0032-1317527

paper

A New Route to Roflumilast via Copper-Catalyzed Hydroxylation

Feng Ni

^aNovel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, 1320 West Beijing Road, Shanghai 200040, P. R. of China

^bShanghai Engineering Research Center of Pharmaceutical Process, 1320 West Beijing Road, Shanghai 200040, P. R. of China Fax: +86(21)65312830 Email: li.jianqi@sipi.com.cn

,

Jianqi Li*

^aNovel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, 1320 West Beijing Road, Shanghai 200040, P. R. of China

^bShanghai Engineering Research Center of Pharmaceutical Process, 1320 West Beijing Road, Shanghai 200040, P. R. of China Fax: +86(21)65312830 Email: li.jianqi@sipi.com.cn

› Author Affiliations

Abstract

All articles of this category

Abstract

A new route to Roflumilast, a selective phosphodiesterase type 4 (PDE 4) inhibitor, is described. The synthetic procedure starts from 4-hydroxy-3-iodobenzoic acid to access the key intermediate 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid via copper-catalyzed hydroxylation and utilizes amide coupling to accomplish the synthesis of Roflumilast in 80% overall yield.

Key words

Roflumiast - PDE4 inhibitor - preparation - hydroxylation - copper catalyzed

Full Text

References

References

1a Lahu G, Nassr N, Hunnemeyer A. Expert Opin. Drug Metab. Toxicol. 2011; 7: 1577
1b Cazzola M, Picciolo S, Matera MG. Expert Opin. Pharmacother. 2010; 11: 441
1c Field SK. Expert Opin. Invest. Drugs 2008; 17: 811

2a Marin L, Colombo P, Bebawy M, Young PM, Traini D. Expert Opin. Drug Delivery 2011; 8: 1205
2b Gross NJ. J. Chronic Obstruct. Pulm. Dis. 2011; 8: 244

3a Williams EL, Wu T.-C. WO 2004033430 2004 ; Chem. Abstr. 2004, 140, 33920.
3b Kohl B, Mueller B, Palosch W. WO 2004080967 2004 ; Chem. Abstr. 2004, 141, 277503.
3c Cook DC, Jones HR, Kabir H, Lythgoe DJ, McFarlane IM, Pemberton C, Thatcher AA, Thompson DM, Walton JB. Org. Process Res. Dev. 1998; 2: 157

4a Amari G, Armani E, Ghidini E. WO 2008006509 2008 ; Chem. Abstr. 2008, 148, 168589.
4b Bose P, Sachdeva YP, Bathore RS, Kumar Y. WO 2005026095 2005 ; Chem. Abstr. 2005, 142, 336129.
4c Liao MY, Li R, Yang SN, Zhang LD, Ding L. CN 102093194 2010 ; Chem. Abstr. 2010, 155, 67699.

5a Kormos CM, Leadbeater NE. Tetrahedron 2006; 62: 4728
5b Zhao DB, Wu NJ, Zhang S, Xi PH, Su XY, Lan JB, You JS. Angew. Chem. Int. Ed. 2009; 48: 8729
5c Tlili A, Xia N, Monnier F, Taillefer M. Angew. Chem. Int. Ed. 2009; 48: 8725
5d Paul R, Ali MA, Punniyamurthy T. Synthesis 2010; 4268
5e Maurer S, Liu W, Zhang XJ, Jiang YW, Ma DW. Synlett 2010; 976
5f Yang D, Fu H. Chem.–Eur. J. 2010; 16: 2366
5g Jing L, Wei J, Zhou L, Huang Z, Li Z, Zhou X. Chem. Commun. 2010; 46: 4767
5h Balkrishna SJ, Kumar S. Synthesis 2012; 44: 1417
5i Xu RS, Yue L, Pan YJ. Tetrahedron 2012; 68: 5046
5j Yang K, Jiang S, Yao Z, Wang ZY, Li Z. Org. Lett. 2011; 13: 4340
5k Zhang H, Ma DW, Cao WG. Synlett 2007; 2: 243

6a Wang Y, Huang TN. Tetrahedron Lett. 1998; 39: 9605
6b Akhlaghinia B, Rahmani M. J. Braz. Chem. Soc. 2010; 21: 3

7 Sperry JB, Sutherland K. Org. Process Res. Dev. 2011; 15: 721

8a Cockerill GS, Levett PC, Whiting DA. J. Chem. Soc., Perkin Trans. 1 1995; 1103
8b Speicher A, Backes T, Hesidens K, Kolz J. Beilstein J. Org. Chem. 2009; 5: 71

9 The standard sample was purchased from Sigma-Aldrich. ¹H NMR (400 MHz, DMSO-d ₆): δ = 13.04 (br, 1 H), 10.80 (s, 1 H), 7.80 (d, J = 8.0 Hz, 1 H), 7.43 (s, 1 H), 7.13 (d, J = 8.0 Hz, 1 H).
10 The byproducts were isolated by column chromatography (hexane–EtOAc, 10:1) and confirmed by ¹H NMR. Dimer byproducts: ¹H NMR (400 MHz, CDCl₃): δ = 7.65 (d, J = 8.0 Hz, 2 H), 7.61 (s, 2 H), 7.34 (d, J = 8.0 Hz, 2 H), 6.97 (d, J = 76.0 Hz, 1 H), 3.92 (s, 6 H), 3.90 (d, J = 6.4 Hz, 4 H), 1.16–1.36 (m, 2 H), 0.55–0.68 (m, 4 H), 0.28–0.37 (m, 4 H). Trimer byproducts: ¹H NMR (400 MHz, CDCl₃): δ = 7.63 (d, J = 8.0 Hz, 3 H), 7.56 (s, 3 H), 7.52 (d, J = 8.0 Hz, 3 H), 7.06 (s, 1 H), 3.91 (s, 9 H), 3.78 (d, J = 6.4 Hz, 6 H), 1.10–1.26 (m, 3 H), 0.53–0.65 (m, 6 H), 0.27–0.36 (m, 6 H).
11 Amschler H, Flockerzi D, Gutterer B, Hatzelmann A, Schudt C, Beume R, Kilian U, Wolf HP. O. WO 9501338 1995 ; Chem. Abstr. 1995, 122, 239550.

Supplementary Material

Supporting Information