Efficient Synthesis of Valsartan, a Nonpeptide Angiotensin II Receptor ­Antagonist

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.

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

References and Notes

<A NAME="RW07405ST-1">1</A> 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 

<A NAME="RW07405ST-2">2</A> Wyvratt MJ. Patchett AA. Med. Res. Rev.  1985,  5:  483 

<A NAME="RW07405ST-3A">3a</A> Bühlmayer P. Furet P. Criscione L. de Gasparo M. Whitebread S. Schmidlin T. Lattmann R. Wood J. Bioorg. Med. Chem. Lett.  1994,  4:  29 

<A NAME="RW07405ST-3B">3b</A> Criscione L. de Gasparo M. Bühlmayer P. Whitebread S. Ramjoué HR. Wood J. Br. J. Pharmacol.  1993,  110:  761 

<A NAME="RW07405ST-3C">3c</A> Sioufi A. Marfil F. Godbillon J. J. Liq. Chromatogr.  1994,  17:  2179 

<A NAME="RW07405ST-4">4</A> Naka T, Kato T, and Nishikawa K. inventors; U.S. Patent US  5196444. 

<A NAME="RW07405ST-5">5</A> Matsuoka RT, and Liu P. inventors; U.S. Patent US  6294675. 

<A NAME="RW07405ST-6">6</A> 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 

<A NAME="RW07405ST-7A">7a</A> Sharp MJ. Snieckus V. Tetrahedron Lett.  1985,  26:  5997 

<A NAME="RW07405ST-7B">7b</A> Alo BI. Kandil A. Patil PA. Sharp MJ. Siddiqui MA. Snieckus V. J. Org. Chem.  1991,  56:  3763 

<A NAME="RW07405ST-7C">7c</A> Unrau CM. Campbell MG. Snieckus V. Tetrahedron Lett.  1992,  33:  2773 

<A NAME="RW07405ST-8A">8a</A> Negishi E. King AO. Okukado N. J. Org. Chem.  1977,  42:  1821 

<A NAME="RW07405ST-8B">8b</A> 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 

<A NAME="RW07405ST-9">9</A> Wittenberger SJ. Donner BG. J. Org. Chem.  1993,  58:  4139 

For previous syntheses, see:

<A NAME="RW07405ST-10A">10a</A> Bühlmayer P, Ostermayer F, and Schmidlln T. inventors; Eur. Pat. Appl. EP  443983. 

<A NAME="RW07405ST-10B">10b</A> Bühlmayer P, Ostermayer F, and Schmidlln T. inventors; U.S. Patent US  5339578. 

<A NAME="RW07405ST-10C">10c</A> Bühlmayer P. Furet P. Criscione L. de Gasparo M. Whitebread S. Schmidlin T. Lattmann R. Wood J. Bioorg. Med. Chem. Lett.  1994,  4:  29 

<A NAME="RW07405ST-10D">10d</A> Cepanec I, Mladen L, Stefanija K, Anamarija B, Vinka D, and Anita S. inventors; PCT Int. Appl. WO  049586. 

<A NAME="RW07405ST-11A">11a</A> Schuman RF, King AO, and Anderson RK. inventors; U.S. Patent US  5039814. 

<A NAME="RW07405ST-11B">11b</A> Russell RK. Murray WV. J. Org. Chem.  1993,  58:  5023 

<A NAME="RW07405ST-12A">12a</A> Miyaura N. Ishiyama T. Saskai H. Ishikawa M. Satoh M. Suzuki A. J. Am. Chem. Soc.  1989,  111:  314 

<A NAME="RW07405ST-12B">12b</A> Suzuki A. Pure Appl. Chem.  1991,  63:  419 

<A NAME="RW07405ST-12C">12c</A> For a review of palladium-catalyzed carbon-carbon bond formation see: Kalinin VN. Synthesis  1992,  431 

<A NAME="RW07405ST-13">13</A>

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): ν_max = 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): ν_max = 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.