Potassium Carbonate → 4-Cyano-2-{5-[6-(4-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 2039219Notes

Reaction equation

HRID 2039219 reaction equation
[CH3:1][O:2][C:3](=[O:38])[NH:4][CH:5]([C:9]([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26](B4OC(C)(C)C(C)(C)O4)=[CH:25][CH:24]=3)=[CH:21][N:22]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:39]([O:43][C:44]([N:46]1[CH2:50][CH:49]([C:51]#[N:52])[CH2:48][CH:47]1[C:53]1[NH:54][C:55]([C:58]2[CH:67]=[CH:66][C:65]3[C:60](=[CH:61][CH:62]=[C:63](Br)[CH:64]=3)[CH:59]=2)=[CH:56][N:57]=1)=[O:45])([CH3:42])([CH3:41])[CH3:40].C([O-])([O-])=O.[K+].[K+]>COCCOC.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:39]([O:43][C:44]([N:46]1[CH2:50][CH:49]([C:51]#[N:52])[CH2:48][CH:47]1[C:53]1[NH:54][C:55]([C:58]2[CH:67]=[CH:66][C:65]3[C:60](=[CH:61][CH:62]=[C:63]([C:26]4[CH:25]=[CH:24][C:23]([C:20]5[NH:19][C:18]([CH:17]6[CH2:16][C:13]7([CH2:14][CH2:15]7)[CH2:12][N:11]6[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:38])[CH:6]([CH3:8])[CH3:7])=[N:22][CH:21]=5)=[CH:28][CH:27]=4)[CH:64]=3)[CH:59]=2)=[CH:56][N:57]=1)=[O:45])([CH3:42])([CH3:41])[CH3:40]

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 66620446[2-Methyl-1-(6-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-propyl]-carbamic acid methyl esterHCID 666210142-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 666211324-Cyano-2-{5-[6-(4-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl esterYield 51%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 80711,2-DimethoxyethaneSolvent

Procedure

[2-Methyl-1-(6-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-propyl]-carbamic acid methyl ester (997 mg, 1.91 mmol), 2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester, Pd(PPh3)4 (184 mg, 0.159 mmol), and K2CO3 (2 M in H2O, 1.9 mL, 3.8 mmol) were combined in 1,2-dimethoxyethane (16 mL) The reaction mixture was degassed with bubbling N2 for 10 minutes then heated to reflux for 3.5 h. After heating, the reaction mixture was cooled to RT, diluted with EtOAc and washed with H2O and brine. The organic phase was dried over MgSO4, then filtered and concentrated. The resulting residue was purified with silica column chromatography 0% to 100% (10% MeOH/DCM)/EtOAc to afford the title compound (641 mg, 51%).

Workup

  1. customwas degassed with bubbling N2 for 10 minutes
  2. temperaturethen heated
  3. temperatureto reflux for 3.5 h
  4. temperatureAfter heating
  5. additiondiluted with EtOAc
  6. washwashed with H2O and brine
  7. dry with materialThe organic phase was dried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe resulting residue was purified with silica column chromatography 0% to 100% (10% MeOH/DCM)/EtOAc

Sources & evidence

ORD record
ord-0091ffc755f44e01aea2c9848213a50d
Source dataset
uspto-grants-2013_11
Patent number
US08575118B2

Reaction notes

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