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

HRID 1751442Notes

Reaction equation

HRID 1751442 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23](Br)[CH:24]=3)[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[C:37]([N:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[C:44]1[NH:45][C:46]([C:49]2[CH:54]=[CH:53][C:52](B3OC(C)(C)C(C)(C)O3)=[CH:51][CH:50]=2)=[CH:47][N:48]=1)=[O:38])C1C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO[CH2:74][CH2:75][O:76][CH3:77]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:52]4[CH:51]=[CH:50][C:49]([C:46]5[NH:45][C:44]([CH:40]6[CH2:41][CH2:42][CH2:43][N:39]6[C:37](=[O:38])[CH:9]([NH:8][C:6]([O:5][CH3:1])=[O:7])[CH:10]6[CH2:74][CH2:75][O:76][CH2:77][CH2:11]6)=[N:48][CH:47]=5)=[CH:54][CH:53]=4)[CH:24]=3)[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

6

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 62657Potassium Phosphate, TribasicHCID 58185449tert-butyl (2S)-2-[5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylateHCID 696755202-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid benzyl ester

Product 1

HCID 696752322-(5-{6-[4-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl esterYield 84%

Reagents, catalysts & solvents 1

HCID 178418397HCID 178418397, compoundCatalyst

Conditions

Temperature
80 °C

Procedure

To a solution of 2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (2.26 g, 5.11 mmol) and 2-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid benzyl ester (3.00 g, 6.34 mmol) in DME (25 mL) was added Tetrakis(triphenylphosphine)Palladium (0.30 g, 0.26 mmol) and aqueous potassium phosphate (2M, 7.6 mL, 15.2 mmol). The solution was degassed with argon for 15 min and heated to 80° C. for 18 h with stirring. The solution was cooled, filtered and diluted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude oil was purified by column chromatography (SiO2, 30→100% EtOAc (10% MeOH) in Hexanes) to provide 2-(5-{6-[4-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (4.31 g, 84%). LCMS-ESI+: calc'd for C43H44N6O4: 708.34 (M+); Found: 709.58 (M+H+).

Workup

  1. customThe solution was degassed with argon for 15 min
  2. temperatureThe solution was cooled
  3. filtrationfiltered
  4. additiondiluted with EtOAc
  5. washThe organic layer was washed with brine
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated
  8. customThe crude oil was purified by column chromatography (SiO2, 30→100% EtOAc (10% MeOH) in Hexanes)

Sources & evidence

ORD record
ord-35b473f118e641fca1d05f846c0174e0
Source dataset
uspto-grants-2015_10
Patent number
US09156823B2

Reaction notes

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