1,2-Dichloroethane → (2R)-2-tert-Butoxycarbonylamino-3-[4-(2-indol-1-yl-acetylamino)-benzylsulfanyl]-propionic Acid

HRID 900365Notes

Reaction equation

HRID 900365 reaction equation
N1(CC(O)=O)C2C(=CC=CC=2)C=C1.COC(=O)[C@@H](NC(OC(C)(C)C)=O)CSCC1C=CC(N)=CC=1.C(Cl)CCl.C(N(CC)CC)C.C[O:49][C:50](=[O:82])[C@@H:51]([NH:74][C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[CH2:52][S:53][CH2:54][C:55]1[CH:60]=[CH:59][C:58]([NH:61][C:62](=[O:73])[CH2:63][N:64]2[C:72]3[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=3)[CH:66]=[CH:65]2)=[CH:57][CH:56]=1.[OH-].[Na+].Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.CO.C1COCC1>[C:78]([O:77][C:75]([NH:74][C@@H:51]([CH2:52][S:53][CH2:54][C:55]1[CH:60]=[CH:59][C:58]([NH:61][C:62](=[O:73])[CH2:63][N:64]2[C:72]3[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=3)[CH:66]=[CH:65]2)=[CH:57][CH:56]=1)[C:50]([OH:82])=[O:49])=[O:76])([CH3:81])([CH3:79])[CH3:80]

Participants

12

Reactant 7

HCID 111,2-DichloroethaneHCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 14798Sodium HydroxideHCID 904481H-Indole-1-acetic acidHCID 68818292HCID 68818292, compoundHCID 68819053(2R)-2-tert-butoxycarbonylamino-3-[4-(2-indol-1-yl-acetylamino)-benzylsulfanyl]-propionic acid methyl ester

Product 1

HCID 68819586(2R)-2-tert-Butoxycarbonylamino-3-[4-(2-indol-1-yl-acetylamino)-benzylsulfanyl]-propionic Acid

Reagents, catalysts & solvents 4

HCID 142844-(Dimethylamino)pyridineCatalystHCID 887MethanolSolvent2×HCID 6344DichloromethaneSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

A solution of indol-1-yl-acetic acid (1.25 g, 7.14 mmol), (2R)-3-(4-amino-benzylsulfanyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester (2.67 g, 7.85 mmol), EDC (1.71 g, 8.93 mmol), triethylamine (2.48 mL, 17.85 mmol) and DMAP (87 mg, 0.714 mmol) in DCM (50 mL) was stirred at ambient temperature. Upon completion (TLC: 2% methanol in dichloromethane), the reaction was quenched with water (75 mL) and extracted with ethyl acetate (3×50 mL). The combined extract was washed sequentially with water and brine, dried over anhydrous MgSO4, filtered, concentrated in vacuo and purified by flash chromatography (SiO2; 30-40% ethyl acetate/heptane as eluent). To a stirred solution of (2R)-2-tert-butoxycarbonylamino-3-[4-(2-indol-1-yl-acetylamino)-benzylsulfanyl]-propionic acid methyl ester (0.470 g, 0.945 mmol) in methanol (3 mL) and THF (12 mL) was added 2N NaOH solution (2.5 mL, 5.3 mmol). Upon completion (TLC 10% methanol in dichloromethane), the mixture was acidified to pH 2 with 2N HCl solution and extracted with ethyl acetate (3×20 mL). The combined extract was washed sequentially with water and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to yield the titled compound as a light yellow solid. Rf=0.40 (20% methanol in dichloromethane); 1H NMR (CDCl3, 300 MHz) δ 7.71 (1H, d, J=7 Hz, Ar—H), 7.37-7.20 (6H, m, Ar—H), 7.16 (1H, d, J=3 Hz, Ar—H), 7.00 (1H, m, Ar—H), 6.69 (1H, d, J=3 Hz, Ar—H), 4.95 (2H, s, NCH2CO), 4.38 (1H, m, CHN), 3.66 (2H, s, PhCH2S), 2.85 (2H, m, CH2CHN), 1.45 (9H, s, CMe3); ESI-LCMS e/z calculated for C25H29N3O5S 483.183, found 484 (M+H)+, 506 (M+Na)+.

Workup

  1. customUpon completion (TLC: 2% methanol in dichloromethane), the reaction was quenched with water (75 mL)
  2. extractionextracted with ethyl acetate (3×50 mL)
  3. extractionThe combined extract
  4. washwas washed sequentially with water and brine
  5. dry with materialdried over anhydrous MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. custompurified by flash chromatography (SiO2; 30-40% ethyl acetate/heptane as eluent)
  9. extractionextracted with ethyl acetate (3×20 mL)
  10. extractionThe combined extract
  11. washwas washed sequentially with water and brine
  12. dry with materialdried over anhydrous MgSO4
  13. filtrationfiltered
  14. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-e388346ccfa14a2d9c321638403e27ae
Source dataset
uspto-grants-2008_04
Patent number
US07358248B2

Reaction notes

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