Thioanisole → methyl (4S)-2-{5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazole-4-carboxylate

HRID 2239051Notes

Reaction equation

HRID 2239051 reaction equation
C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:36][O:37][C:38](=[O:89])[C@@H:39]([CH2:68][S:69]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[NH:40][C:41]([C:43]1[NH:44][C:45]2[C:50]([CH:51]=1)=[CH:49][C:48]([O:52][CH2:53][CH2:54][O:55][CH3:56])=[CH:47][C:46]=2[N:57]([CH3:67])[S:58]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][N:62]=1)(=[O:60])=[O:59])=O.C1(SC)C=CC=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:56][O:55][CH2:54][CH2:53][O:52][C:48]1[CH:49]=[C:50]2[C:45](=[C:46]([N:57]([CH3:67])[S:58]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][N:62]=3)(=[O:60])=[O:59])[CH:47]=1)[NH:44][C:43]([C:41]1[S:69][CH2:68][C@H:39]([C:38]([O:37][CH3:36])=[O:89])[N:40]=1)=[CH:51]2

Participants

7

Reactant 5

HCID 7520ThioanisoleHCID 13097Triphenylphosphine OxideHCID 67749Trifluoromethanesulfonic anhydrideHCID 516892Sodium BicarbonateHCID 59135628N-({5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}carbonyl)-S-trityl-D-cysteine methyl ester

Product 1

HCID 57476261methyl (4S)-2-{5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazole-4-carboxylateYield 98.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Conditions

Temperature
0 °C

Procedure

To a solution of triphenylphosphine oxide (1.3 g) in dichloromethane (3 mL) was added dropwise trifluoromethanesulfonic anhydride (0.59 mL) at 0° C., and the mixture was stirred at 0° C. for 15 min. The obtained suspension was diluted with dichloromethane (5 mL), and a solution of N-({5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}carbonyl)-S-trityl-D-cysteine methyl ester (0.60 g) and thioanisole (0.74 mL) in dichloromethane (8 mL) was added. The reaction mixture was stirred at 0° C. for 2 hr, and saturated aqueous sodium hydrogencarbonate solution was added. The mixture was concentrated, and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-1:1, volume ratio) to give a mixture (0.39 g) of methyl (4S)-2-{5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazole-4-carboxylate and triphenylphosphine oxide. The obtained mixture of the ester and triphenylphosphine oxide was dissolved in tetrahydrofuran (3 mL), sodium borohydride (0.010 mg) was added at 0° C., and methanol (1.5 mL) was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 30 min, and then at room temperature for 2 hr. Water was added, the mixture was concentrated, and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to basic silica gel column chromatography, and eluted with hexane-ethyl acetate-methanol (4:1:0-0:10:1, volume ratio) to give the title compound (0.076 g, yield 20%) as colorless crystals. melting point 146.6-146.7° C.

Workup

  1. stirringThe reaction mixture was stirred at 0° C. for 2 hr
  2. concentrationThe mixture was concentrated
  3. extractionthe residue was extracted with ethyl acetate
  4. washThe ethyl acetate layer was washed with water and saturated brine
  5. dry with materialdried (MgSO4)
  6. concentrationconcentrated
  7. washeluted with hexane-ethyl acetate (4:1-1:1, volume ratio)

Sources & evidence

ORD record
ord-99651663e9c04267b9bba7f1ee0870ec
Source dataset
uspto-grants-2010_05
Patent number
US07718798B2

Reaction notes

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