Triethylamine → methyl 3-(4-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorobenzamido)propanoate

HRID 1627260Notes

Reaction equation

HRID 1627260 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([O:24][CH3:25])[CH:18]=3)[C:15]([S:26][CH2:27][C:28]3[C:36]([F:37])=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][C:29]=3[F:38])=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:40][O:41][C:42](=[O:46])[CH2:43][CH2:44][NH2:45].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([O:24][CH3:25])[CH:18]=3)[C:15]([S:26][CH2:27][C:28]3[C:36]([F:37])=[CH:35][C:31]([C:32]([NH:45][CH2:44][CH2:43][C:42]([O:41][CH3:40])=[O:46])=[O:33])=[CH:30][C:29]=3[F:38])=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8]

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 2734767Methyl 3-aminopropanoate hydrochlorideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 66739827HCID 66739827, compound

Product 1

HCID 66741184methyl 3-(4-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorobenzamido)propanoate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A mixture of 4-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorobenzoic acid (0.85 mmol from previous step) and β-alanine methyl ester hydrochloride (139 mg, 1.0 mmol) in DCM (10 mL) was treated with Et3N (0.36 mL, 2.6 mmol) and HATU (390 mg, 1.0 mmol) at ambient temperature. After stirring for 16 h at ambient temperature the reaction mixture was quenched by the addition of H2O, 1N HCl, and DCM. The aqueous layer was extracted with DCM. The combined extracts were washed with satd NaHCO3, dried over Na2SO4 and concentrated under reduced pressure to afford crude product. This material was purified by flash chromatography (silica gel, EtOAc/Hex, 0:100 to 100:0) to give methyl 3-(4-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorobenzamido)propanoate as a clear syrup, that was carried on to the next step directly. 1H NMR (400 MHz, CDCl3) δ 7.31-7.23 (m, 2H), 7.19 (s, 1H), 7.09 (d, J=2.2 Hz, 1H), 6.99 (t, J=5.5 Hz, 1H), 6.88 (ddd, J=10.7, 9.6, 5.4 Hz, 2H), 6.26 (ddd, J=8.5, 3.8, 2.5 Hz, 1H), 5.91 (dd, J=7.5, 2.4 Hz, 1H), 4.16-4.08 (m, 2H), 3.76-3.66 (m, 5H), 3.50 (s, 3H), 2.66 (t, J=5.9 Hz, 2H), 1.89 (s, 1H), 1.54 (s, 3H), 1.47 (s, 3H); MS (EI) m/z 666 (MH+).

Workup

  1. customwas quenched by the addition of H2O, 1N HCl, and DCM
  2. extractionThe aqueous layer was extracted with DCM
  3. washThe combined extracts were washed with satd NaHCO3
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated under reduced pressure
  6. customto afford crude product
  7. customThis material was purified by flash chromatography (silica gel, EtOAc/Hex, 0:100 to 100:0)

Sources & evidence

ORD record
ord-ed10baab6e874ffd9fef11eb2c66ae6d
Source dataset
uspto-grants-2014_07
Patent number
US08785488B2

Reaction notes

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