Potassium Carbonate → {2-Methyl-1-[2-(5-(5-[4-(2-{1-[2-(methylperoxymethyl-amino)-2-phenyl-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-3a,6a-dihydro-thieno[3,2-b]thiophen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamic acid methyl ester

HRID 79942Notes

Reaction equation

HRID 79942 reaction equation
CO[C:3](=[O:39])[NH:4][CH:5](C1C=CC=CC=1)[C:6](=[O:32])[N:7]1[CH2:11][CH2:10][CH2:9][CH:8]1[C:12]1[NH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20](B3OC(C)(C)C(C)(C)O3)=[CH:19][CH:18]=2)=[CH:15][N:16]=1.[CH3:40][O:41][C:42](=[O:69])[NH:43][CH:44]([C:48]([N:50]1[CH2:54][CH2:53][CH2:52][CH:51]1[C:55]1[NH:56][C:57]([C:60]2[S:64][CH:63]3[CH:65]=[C:66](Br)[S:67][CH:62]3[CH:61]=2)=[CH:58][N:59]=1)=[O:49])[CH:45]([CH3:47])[CH3:46].[C:70]([O-:73])([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>[CH3:40][O:41][C:42](=[O:69])[NH:43][CH:44]([C:48]([N:50]1[CH2:54][CH2:53][CH2:52][CH:51]1[C:55]1[NH:56][C:57]([C:60]2[S:64][CH:63]3[CH:65]=[C:66]([C:20]4[CH:21]=[CH:22][C:17]([C:14]5[NH:13][C:12]([CH:8]6[CH2:9][CH2:10][CH2:11][N:7]6[C:6](=[O:32])[CH:5]([NH:4][CH2:3][O:39][O:73][CH3:70])[C:17]6[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=6)=[N:16][CH:15]=5)=[CH:18][CH:19]=4)[S:67][CH:62]3[CH:61]=2)=[CH:58][N:59]=1)=[O:49])[CH:45]([CH3:47])[CH3:46]

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 66620267HCID 66620267, compoundHCID 66621112(1-{2-[5-(5-Bromo-3a,6a-dihydro-thieno[3,2-b]thiophen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

Product 1

HCID 86648891{2-Methyl-1-[2-(5-(5-[4-(2-{1-[2-(methylperoxymethyl-amino)-2-phenyl-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-3a,6a-dihydro-thieno[3,2-b]thiophen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamic acid methyl esterYield 63.8%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
85 °C

Procedure

[2-Oxo-1-phenyl-2-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-ethyl]-carbamic acid methyl ester (204 mg, 0.385 mmol), (1-{2-[5-(5-Bromo-3a,6a-dihydro-thieno[3,2-b]thiophen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (137 mg, 0.268 mmol), Pd(PPh3)4 (31 mg, 0.0268 mmol) and K2CO3 (2M in H2O, 0.4 mL, 0.8 mmol) were combined in 1,2-dimethoxyethane (2.7 mL). After 10 min of degassing with bubbling N2, the reaction mixture was heated to 85° C. for 19 h. After this period, it was cooled and diluted MeOH. The suspension was filtered over a thiol SPE cartridge to remove the palladium, then concentrated. The crude residue was purified by HPLC to afford the title compound (103 mg, 46%). MS (ESI) m/z 835 [M+H]+.

Workup

  1. customAfter 10 min of degassing with bubbling N2
  2. waitAfter this period
  3. temperatureit was cooled
  4. filtrationThe suspension was filtered over a thiol SPE cartridge
  5. customto remove the palladium
  6. concentrationconcentrated
  7. customThe crude residue was purified by HPLC

Sources & evidence

ORD record
ord-2e14d64d10444b3ca306abad4891ea0c
Source dataset
uspto-grants-2014_09
Patent number
US08841278B2

Reaction notes

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