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DOI: 10.1055/s-2006-926234
Efficient Synthesis of Valsartan, a Nonpeptide Angiotensin II Receptor Antagonist
Publikationsverlauf
Publikationsdatum:
06. Februar 2006 (online)
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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
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References and Notes
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.