Potassium Carbonate → 4,4-Difluoro-2-(5-{4-[6-(2-{1-[2-methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 1751457Notes

Reaction equation

HRID 1751457 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:36]5[NH:37][C:38]([CH:41]6[CH2:45][CH2:44][CH2:43][N:42]6C(OCC6C=CC=CC=6)=O)=[N:39][CH:40]=5)[CH:32]=4)[CH:27]=3)=[CH:22][CH:21]=2)=[CH:18][N:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:62][O:63][C:64]([NH:66][CH:67]([CH:71]1[CH2:76][CH2:75][O:74][CH2:73][CH2:72]1)[C:68](O)=[O:69])=[O:65].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCO.[Pd].C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:13])([F:14])[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:36]5[NH:37][C:38]([CH:41]6[CH2:45][CH2:44][CH2:43][N:42]6[C:68](=[O:69])[CH:67]([NH:66][C:64]([O:63][CH3:62])=[O:65])[CH:71]6[CH2:76][CH2:75][O:74][CH2:73][CH2:72]6)=[N:39][CH:40]=5)[CH:32]=4)[CH:27]=3)=[CH:24][CH:25]=2)=[CH:18][N:19]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]

Participants

9

Reactant 5

HCID 11430Potassium CarbonateHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 585162412-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acidHCID 69675276HCID 69675276, compound

Product 1

HCID 696718604,4-Difluoro-2-(5-{4-[6-(2-{1-[2-methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl esterYield 14.5%

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 702EthanolSolventHCID 6344DichloromethaneSolvent

Procedure

To a solution of 2-[5-(4-{6-[2-(1-Benzyloxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)-1H-imidazol-2-yl]-4,4-difluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (0.25 g, 0.34 mmol) in EtOH (3.5 mL) was added Palladium on carbon (10%, 0.18 g, 0.02 mmol) and Potassium Carbonate (0.14 g, 1.0 mmol). The slurry was stirred at room temperature under an atmosphere of H2 for 5 h. The slurry was filtered through celite and washed with EtOH. The filtrate was concentrated to an oil and diluted with CH2Cl2 (3 mL) and DMF (2 mL). Methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid (0.11 g, 0.50 mmol), HATU (0.15 g, 0.40 mmol), and DIPEA (0.3 mL, 1.7 mmol) were added. The resulting solution was stirred at room temperature for 5 h. The solution was diluted with CH2Cl2 and washed with saturated sodium bicarbonate. The organic layer was dried over Na2SO4 and concentrated. The crude oil was concentrated and purified by preparative HPLC (Gemini, 15→50% MeCN in H2O (0.1% TFA)) to provide to provide 4,4-Difluoro-2-(5-{4-[6-(2-{1-[2-methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.04 g, 14%). LCMS-ESI+: calc'd for C44H49F2N7O6: 809.37 (M+); Found: 810.79 (M+H+).

Workup

  1. filtrationThe slurry was filtered through celite
  2. washwashed with EtOH
  3. concentrationThe filtrate was concentrated to an oil
  4. additiondiluted with CH2Cl2 (3 mL) and DMF (2 mL)
  5. stirringThe resulting solution was stirred at room temperature for 5 h
  6. washwashed with saturated sodium bicarbonate
  7. dry with materialThe organic layer was dried over Na2SO4
  8. concentrationconcentrated
  9. concentrationThe crude oil was concentrated
  10. custompurified by preparative HPLC (Gemini, 15→50% MeCN in H2O (0.1% TFA))
  11. customto provide

Sources & evidence

ORD record
ord-62218c305dd541f98ad0efdc673a6996
Source dataset
uspto-grants-2015_10
Patent number
US09156823B2

Reaction notes

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