Ammonium Chloride → (3-Carbamoyl-5-chloro-indol-1-yl)-acetic acid tert-butyl ester

HRID 1527212Notes

Reaction equation

HRID 1527212 reaction equation
[C:1]([O:5][C:6]([CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:11]([C:19]([OH:21])=O)=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].C[N:25](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:11]([C:19](=[O:21])[NH2:25])=[CH:10]1)([CH3:4])([CH3:3])[CH3:2]

Participants

6

Reactant 4

HCID 25517Ammonium Chloride2×HCID 81531Diisopropylethylamine2×HCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 682837821-tert-Butoxycarbonylmethyl-5-chloro-1H-indole-3-carboxylic acid

Product 1

HCID 68283031(3-Carbamoyl-5-chloro-indol-1-yl)-acetic acid tert-butyl ester

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a mixture of 1-tert-butoxycarbonylmethyl-5-chloro-1H-indole-3-carboxylic acid (400 mg, 1.29 mmol) in CH2Cl2 (6 mL) were added successively NH4Cl (138 mg, 2.58 mmol), HBTU (1.22 g, 3.23 mmol) and DIPEA (0.902 mL, 5.17 mmol). Stirring was continued at RT for 16 h. Additional aliquots of NH4Cl (2 equiv) and DIPEA (4 equiv) were added to the reaction mixture. After stirring for 4 h, the reaction mixture was diluted with CH2Cl2 and the solution was washed with water (2×), 0.1N aqueous HCl (2×), saturated aqueous NaHCO3 (2×) and brine, dried (Phase separator) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc/c-hexane gradient 2:1 to 1:0) to give the title compound as a white solid. TLC Rf (EtOAc/c-hexane 2:1)=0.20; MS (LC/MS): 309 [M+H]+, 617 [2M+H]+; tR (HPLC conditions b): 4.75 min.

Workup

  1. stirringAfter stirring for 4 h
  2. washthe solution was washed with water (2×), 0.1N aqueous HCl (2×), saturated aqueous NaHCO3 (2×) and brine
  3. customdried (Phase separator)
  4. concentrationconcentrated in vacuo
  5. customThe residue was purified by flash column chromatography on silica gel (EtOAc/c-hexane gradient 2:1 to 1:0)

Sources & evidence

ORD record
ord-763d57ed96a64c9fb2b6da2f0dd59682
Source dataset
uspto-grants-2015_07
Patent number
US09085555B2

Reaction notes

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