Download PDF
Synlett 2006(3): 0475-0477  
DOI: 10.1055/s-2006-926234
LETTER
© Georg Thieme Verlag Stuttgart · New York

Efficient Synthesis of Valsartan, a Nonpeptide Angiotensin II Receptor ­Antagonist

Chen Zhanga, Guojun Zhengb, Lijing Fanga, Yulin Li*a
a State Key Laboratory of Applied Organic Chemistry and Institute of Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
Fax: +86(931)8912283; e-Mail: liyl@lzu.edu.cn;
b Zhejiang Hisun Pharmaceutical Co., Ltd, 46 Waisha Road, Taizhou 318000, P. R. of China
Further Information

Publication History

Received 28 October 2005
Publication Date:
06 February 2006 (online)

    Permissions and Reprints All articles of this category

Abstract

A highly efficient and convergent approach to the synthesis of the angiotensin II receptor antagonist valsartan (1), one of the most important agents used in antihypertensive therapy today, is described. Directed ortho-metalation of 4-bromotoluene provides the key boronic acid intermediate 11 which was subjected to palladium-catalyzed Suzuki coupling. This method overcomes many of the drawbacks associated with the previously reported syntheses. The saponification of the methyl ester in valsartan was realized in a convenient and economical manner, which is more suitable for ­industrial production.

Key words

valsartan - antihypertensive therapy - directed ortho-metalation - palladium-catalyzed Suzuki coupling - methyl ester ­saponification

    References and Notes

  • 1 Duncia JV. Chiu AT. Carini DJ. Gregory GB. Johnson AL. Price WA. Wells GJ. Wong PC. Calabrese JC. Timmermans PBMWM. J. Med. Chem.  1990,  33:  1312 
    CrossrefGoogle Scholar
  • 2 Wyvratt MJ. Patchett AA. Med. Res. Rev.  1985,  5:  483 
    Google Scholar
  • 3a Bühlmayer P. Furet P. Criscione L. de Gasparo M. Whitebread S. Schmidlin T. Lattmann R. Wood J. Bioorg. Med. Chem. Lett.  1994,  4:  29 
    Google Scholar
  • 3b Criscione L. de Gasparo M. Bühlmayer P. Whitebread S. Ramjoué HR. Wood J. Br. J. Pharmacol.  1993,  110:  761 
    Google Scholar
  • 3c Sioufi A. Marfil F. Godbillon J. J. Liq. Chromatogr.  1994,  17:  2179 
    Google Scholar
  • 4 Naka T, Kato T, and Nishikawa K. inventors; U.S. Patent US  5196444. 
  • 5 Matsuoka RT, and Liu P. inventors; U.S. Patent US  6294675. 
  • 6 Carini DJ. Duncia JV. Aldrich PE. Chiu AT. Johnson AL. Pierce ME. Price WA. Santella JB. Wells GJ. Wexler RR. Wong PC. Yoo W.-E. Timmermans PBMWM. J. Med. Chem.  1991,  34:  2525 
    CrossrefGoogle Scholar
  • 7a Sharp MJ. Snieckus V. Tetrahedron Lett.  1985,  26:  5997 
    CrossrefGoogle Scholar
  • 7b Alo BI. Kandil A. Patil PA. Sharp MJ. Siddiqui MA. Snieckus V. J. Org. Chem.  1991,  56:  3763 
    CrossrefGoogle Scholar
  • 7c Unrau CM. Campbell MG. Snieckus V. Tetrahedron Lett.  1992,  33:  2773 
    CrossrefGoogle Scholar
  • 8a Negishi E. King AO. Okukado N. J. Org. Chem.  1977,  42:  1821 
    CrossrefGoogle Scholar
  • 8b Mantlo NB. Chakravarty PK. Ondeyka DL. Siegl PKS. Chang RS. Lotti VJ. Faust KA. Chen T.-B. Schorn TW. Sweet CS. Emmert SE. Patcheet AA. Greenlee WJ. J. Med. Chem.  1991,  34:  2922 
    CrossrefGoogle Scholar
  • 9 Wittenberger SJ. Donner BG. J. Org. Chem.  1993,  58:  4139 
    CrossrefGoogle Scholar
  • For previous syntheses, see:
  • 10a Bühlmayer P, Ostermayer F, and Schmidlln T. inventors; Eur. Pat. Appl. EP  443983. 
    CrossrefGoogle Scholar
  • 10b Bühlmayer P, Ostermayer F, and Schmidlln T. inventors; U.S. Patent US  5339578. 
    CrossrefGoogle Scholar
  • 10c Bühlmayer P. Furet P. Criscione L. de Gasparo M. Whitebread S. Schmidlin T. Lattmann R. Wood J. Bioorg. Med. Chem. Lett.  1994,  4:  29 
    CrossrefGoogle Scholar
  • 10d Cepanec I, Mladen L, Stefanija K, Anamarija B, Vinka D, and Anita S. inventors; PCT Int. Appl. WO  049586. 
    CrossrefGoogle Scholar
  • 11a Schuman RF, King AO, and Anderson RK. inventors; U.S. Patent US  5039814. 
    Crossref
  • 11b Russell RK. Murray WV. J. Org. Chem.  1993,  58:  5023 
    CrossrefGoogle Scholar
  • 12a Miyaura N. Ishiyama T. Saskai H. Ishikawa M. Satoh M. Suzuki A. J. Am. Chem. Soc.  1989,  111:  314 
    Google Scholar
  • 12b Suzuki A. Pure Appl. Chem.  1991,  63:  419 
    Google Scholar
  • 12c For a review of palladium-catalyzed carbon-carbon bond formation see: Kalinin VN. Synthesis  1992,  431 
    Google Scholar
13

Experimental Procedure and Spectroscopic Data of the Key Compounds: N -Pentanoyl- N -{[2′-(2 N -trityl-tetrazole-5-yl)(1,1′-biphenyl)-4-yl]methyl}-l- valine Methyl Ester ( 12). A mixture of toluene (4.5 mL) and H2O (2 mL) was degassed by vacuum/nitrogen purges (3×). N-pentanoyl-N-[4-(4′,4′,5′,5′-tetramethyl-1′,3′,2′-dioxaborolan-2′-yl)benzyl]-l-valine methyl ester (11) (1.03 g, 2.4 mmol), 5-(2′-bromophenyl)-2-trityl-2H-tetrazole (4, 934 mg, 2 mmol), Na2CO3 (424 mg, 4 mmol) and Pd(PPh3)4 (115 mg) were added. This mixture was degassed (3×) and the reaction mixture was heated at 80 °C under a nitrogen atmosphere for 10 h. Then the resulting mixture was extracted by EtOAc (3 × 50 mL), washed with H2O and brine, dried over anhyd Na2SO4 and filtered. Evaporation of the solvent followed by flash column chromatography on silica gel (hexane-Et2O, 2:1) to obtain the coupling product 12 as a colorless oil (1.32 g, 80%). [α]D 24 -35 (c 8, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.79-0.99 (m), 1.16-1.78 (m), 2.13-2.35 (m), 3.28 (s), 3.35 (s, 3H, OCH3), 4.00 (d, J = 11 Hz), 4.19 (d, J = 15 Hz), 4.52 (s, 2 H, CH2Ar), 4.81-4.90 (m), 6.97-7.52 (m), 7.81-7.87 (m). 13C NMR (75 MHz, CDCl3): δ = 13.87, 18.77, 19.98, 22.36, 27.49, 27.71, 33.33, 45.34, 48.44, 51.53, 61.90, 65.80, 82.85, 125.57, 126.29, 127.63, 128.22, 128.91, 129.42, 130.18, 130.44, 130.73, 135.70, 136.73, 140.08, 141.24, 141.53, 164.16, 170.28, 170.99, 174.47. MS (FAB): m/z calcd [M+]: 691; found: 714 [M + Na+]. IR (film): νmax = 3061, 2961, 2872, 2246, 1740, 1651, 1468, 1448, 1204, 1029, 1006, 910, 733, 701, 641 cm-1.
N -Pentanoyl- N -{[2′-(1 H -tetrazole-5-yl)(1,1′-biphenyl)-4-yl]methyl}-l -valine ( 1)
N-Pentanoyl-N-{[2′-(2N-trityl-tetrazole-5-yl)(1,1′-biphenyl)-4-yl]methyl}-l-valine methyl ester (12) (150 mg, 0.22 mmol) was added 1 N NaOH (1 mL) or p-TsOH (10 mg) in MeOH (3 mL) and refluxed for 1 h to remove the protecting trityl group, then 3 N NaOH (1 mL) was added to the reaction and the mixture continued to reflux for another 8 h. Subsequently, the MeOH was removed under reduced pressure and the residue was diluted with EtOAc (100 mL) and distilled H2O (20 mL). Concentrated HCl was added dropwise into the mixture until the pH reached to 3.0. Then the organic phase was separated and the aqueous phase was extracted by EtOAc (3 × 50 mL). The combined organic extracts were dried over anhyd Na2SO4 and filtered. Evaporation of the solvent gave the crude product (92 mg, 98%) and the anticipated product, valsartan (1) was recrystallized from EtOAc; mp 116-117 °C; [α]D 24 -63 (c 3, MeOH). 1H NMR (400 MHz, CD3OD): δ = 0.77-0.90 (m, CH3), 0.92-0.99 (m, CH3), 1.00-1.12 (m, CH3), 1.21-1.33 (m, CH2), 1.35-1.43 (m, CH2), 1.44-1.59 (m, CH2), 1.63-1.67 (m, CH2), 2.14-2.37 (m), 2.49-2.55 (m), 2.60-2.68 (m), 3.30-3.34 (m), 4.11-4.13 (m), 4.57-4.79 (m), 7.00-7.24 (m, 4 H, Ar), 7.50-7.62 (m, 2 H, Ar), 7.63-7.65 (m, 2 H, Ar). 13C NMR (100 MHz, CD3OD): δ = 14.17, 19.29, 19.43, 20.03, 20.59, 23.28, 23.35, 28.40, 28.51, 29.13, 34.35, 34.44, 47.35, 50.59, 64.95, 67.88, 124.09, 124.26, 127.75, 128.63, 128.81, 128.94, 129.77, 130.29, 131.58, 131.76, 132.45, 138.66, 138.85, 139.41, 139.61, 143.01, 143.14, 156.56, 156.68, 172.88, 173.51, 176.91, 177.12. MS (FAB): m/z calcd [M+]: 435; found: 436 [M + H+], 458 [M+ + Na]. IR (KBr): νmax = 3430, 3116, 2963, 2933, 2873, 2745, 2615, 1733, 1602, 1472, 1410, 1274, 1205, 1163, 1106, 1054, 998, 938, 853, 814, 759, 683, 623, 561,
519 cm-1.