1,2-Dichloroethane → [(R)-1-(3'-Chloro-biphenyl-4-ylmethyl)-3-methanesulfonylamino-3-oxo-propyl]-carbamic acid tert-butyl ester

HRID 1945095Notes

Reaction equation

HRID 1945095 reaction equation
C([O:3][C:4](=O)[CH2:5][C@H:6]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)=[CH:10][CH:9]=1)C.[OH-].[Na+].Cl.[CH3:33][S:34]([NH2:37])(=[O:36])=[O:35].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CCN(CC)CC>C1COCC1.CCO.CN(C=O)C.CCOC(C)=O>[C:25]([O:24][C:22](=[O:23])[NH:21][C@H:6]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)=[CH:10][CH:9]=1)[CH2:5][C:4]([NH:37][S:34]([CH3:33])(=[O:36])=[O:35])=[O:3])([CH3:28])([CH3:27])[CH3:26]

Participants

12

Reactant 7

HCID 111,2-DichloroethaneHCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 14798Sodium HydroxideHCID 72879MethanesulfonamideHCID 181649HOAtHCID 59607603(R)-ethyl 3-(tert-butoxycarbonylamino)-4-(3'-chlorobiphenyl-4-yl)butanoate

Product 1

HCID 59607782[(R)-1-(3'-Chloro-biphenyl-4-ylmethyl)-3-methanesulfonylamino-3-oxo-propyl]-carbamic acid tert-butyl esterYield 87.4%

Reagents, catalysts & solvents 4

HCID 702EthanolSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

(R)-3-tert-butoxycarbonylamino-4-(3′-chloro-biphenyl-4-yl)-butyric acid ethyl ester (250 mg, 0.598 mmol) is treated with 2M NaOH aqueous solution (1 mL) in THF (1 mL) and EtOH (2 mL). After being stirred for 1 h, the reaction mixture is acidified with 1M HCl and extracted with EtOAc. The organic layer is washed with brine, dried over Na2SO4 and concentrated in vacuo. To a solution of this residue in DMF (2 mL) are added methylsulfonamide (85 mg, 0.897 mmol), EDC (172 mg, 0.897 mmol), HOAt (98 mg, 0.718 mmol), and Et3N (0.125 mL, 0.897 mmol). After being stirred at room temperature overnight, the reaction mixture is diluted with EtOAc, washed with 1M HCl and brine. The organic layer is dried over Na2SO4 and concentrated. The residue is purified by flash column chromatograpy (silica gel, eluent: DCM/10% MeOH in DCM=100:0 to 0:100) to give [(R)-1-(3′-chloro-biphenyl-4-ylmethyl)-3-methanesulfonylamino-3-oxo-propyl]-carbamic acid tert-butyl ester (244 mg). HPLC retentions time=1.30 minutes (condition B); MS (m+1)=467; 1H NMR (400 Mz, DMSO-d6) δ ppm 1.30 (s, 9H), 2.41-2.48 (m, 2H), 2.70-2.78 (m, 2H), 3.18 (s, 3H), 3.99-4.11 (m, 1H), 7.28 (d, 2H, J=8.34 Hz), 7.38-7.44 (m, 1H), 7.48 (t, 1H, J=7.83 Hz), 7.59-7.66 (m, 3H), 7.69 (s, 1H).

Workup

  1. extractionextracted with EtOAc
  2. washThe organic layer is washed with brine
  3. dry with materialdried over Na2SO4
  4. concentrationconcentrated in vacuo
  5. stirringAfter being stirred at room temperature overnight
  6. washwashed with 1M HCl and brine
  7. dry with materialThe organic layer is dried over Na2SO4
  8. concentrationconcentrated
  9. customThe residue is purified by flash column chromatograpy (silica gel, eluent: DCM/10% MeOH in DCM=100:0 to 0:100)

Sources & evidence

ORD record
ord-50cb10d58ee740d096c10e6e1d43247b
Source dataset
uspto-grants-2013_03
Patent number
US08394853B2

Reaction notes

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