2-[4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-piperidine-1-sulfonyl]-3H-imidazole-4-carboxylic acid ethyl ester → 2,6-Di-tert-butyl-4-{1-[5-(1-hydroxy-1-methyl-ethyl)-1H-imidazole-2-sulfonyl]-piperidin-4-ylsulfanyl}-phenol

HRID 599481Notes

Reaction equation

HRID 599481 reaction equation
C(OC([C:6]1[NH:7][C:8]([S:11]([N:14]2[CH2:19][CH2:18][CH:17]([S:20][C:21]3[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([OH:31])=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:22]=3)[CH2:16][CH2:15]2)(=[O:13])=[O:12])=[N:9][CH:10]=1)=O)C.C[Mg]Cl>C1COCC1>[C:27]([C:25]1[CH:26]=[C:21]([S:20][CH:17]2[CH2:18][CH2:19][N:14]([S:11]([C:8]3[NH:7][C:6]([C:24]([OH:31])([CH3:25])[CH3:23])=[CH:10][N:9]=3)(=[O:12])=[O:13])[CH2:15][CH2:16]2)[CH:22]=[C:23]([C:32]([CH3:34])([CH3:33])[CH3:35])[C:24]=1[OH:31])([CH3:30])([CH3:29])[CH3:28]

Participants

4

Reactant 2

HCID 866354322-[4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-piperidine-1-sulfonyl]-3H-imidazole-4-carboxylic acid ethyl esterHCID 178418332HCID 178418332, compound

Product 1

HCID 579312122,6-Di-tert-butyl-4-{1-[5-(1-hydroxy-1-methyl-ethyl)-1H-imidazole-2-sulfonyl]-piperidin-4-ylsulfanyl}-phenolYield 180.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To 2-[4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-piperidine-1-sulfonyl]-3H-imidazole-4-carboxylic acid ethyl ester (Ex. 8b, 230 mg, 0.44 mmol) in 3 mL of THF was added dropwise a 3.0 M THF solution of MeMgCl (0.85 mL, 2.55 mmol) at 0° C. The reaction was allowed to warm to room temperature, stirred for 5 h, and then quenched with saturated NaH2PO4 (20 mL). The mixture was extracted with Ethyl acetate (40+20 mL) and the combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by chromatography (3-30% Ethyl acetate/hexanes) to afford the title compound as a clear gum (202 mg, 90%). 1H NMR (400 MHz, CDCl3): δ 10.76 (bs, 0.4H), 10.72 (bs, 0.6H), 7.23 (s, 2H), 7.02 (s, 0.6H), 6.97 (s, 0.4H), 5.30 (s, 1H), 3.77-3.74 (m, 2H), 2.97-2.82 (m 3H), 1.98-1.95 (m, 2H), 1.69-1.57 (m, 8H), 1.41 (s, 18H). 13C NMR (100 MHz): δ 154.5, 152.1, 141.2, 140.9, 136.9, 132.9, 132.0, 125.8, 122.1, 113.2, 69.5, 68.4, 46.0, 44.6, 34.5, 31.7, 31.5, 30.6, 30.4, 30.2. ESI/CI-MS m/z 510 ([M+H]+), 508 ([M−H]−). Three HPLC (reverse-phase, C18) methods were used to determine the purity of the title compound. Method 1: gradient elution, 40% to 85% solvent B (A=aqueous 0.1% H3PO4, B=MeCN) in 15 min. Purity (UV-VIS): 98.6% (238 nm); Method 2: gradient elution, 40% to 95% solvent B (A=10 mM NH4OAc, B=MeCN) in 6 min. Purity (UV-VIS λ): 99.2% (238 nm), 99.4% (254 nm); Method 3: gradient elution, 50% to 99% solvent B (A=aqueous 0.1% H3PO4, B=MeCN) in 15 min. Purity (UV-VIS): 98.4% (215 nm), 98.9% (254 nm), 98.7 (238 nm).

Workup

  1. customquenched with saturated NaH2PO4 (20 mL)
  2. extractionThe mixture was extracted with Ethyl acetate (40+20 mL)
  3. dry with materialthe combined organic phase was dried over Na2SO4
  4. concentrationconcentrated under reduced pressure
  5. customThe crude product was purified by chromatography (3-30% Ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-ccfd9b6ecb6b454db8c7d9a30454be70
Source dataset
uspto-grants-2011_03
Patent number
US07897776B2

Reaction notes

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