1,2-Dimethoxyethane → (S)-benzyl 2-(5-(7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)dibenzo[b,d]thiophen-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

HRID 1751378Notes

Reaction equation

HRID 1751378 reaction equation
CC1(C)C(C)(C)OB([C:9]2[CH:42]=[CH:41][C:12]3[C:13]4[CH:19]=[CH:18][C:17]([C:20]5[CH:21]=[CH:22][C:23]6[N:27]=[C:26]([C@@H:28]7[CH2:32][CH2:31][CH2:30][N:29]7[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[NH:25][C:24]=6[CH:40]=5)=[CH:16][C:14]=4[S:15][C:11]=3[CH:10]=2)O1.Br[C:45]1[NH:49][C:48]([C@@H:50]2[CH2:54][CH2:53][CH2:52][N:51]2[C:55]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[O:56])=[N:47][CH:46]=1.C(=O)([O-])[O-].[K+].[K+].C(COC)OC>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.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C)C=O>[C:36]([O:35][C:33]([N:29]1[CH2:30][CH2:31][CH2:32][C@H:28]1[C:26]1[NH:25][C:24]2[CH:40]=[C:20]([C:17]3[CH:18]=[CH:19][C:13]4[C:12]5[CH:41]=[CH:42][C:9]([C:45]6[NH:49][C:48]([C@@H:50]7[CH2:54][CH2:53][CH2:52][N:51]7[C:55]([O:57][CH2:58][C:59]7[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=7)=[O:56])=[N:47][CH:46]=6)=[CH:10][C:11]=5[S:15][C:14]=4[CH:16]=3)[CH:21]=[CH:22][C:23]=2[N:27]=1)=[O:34])([CH3:39])([CH3:37])[CH3:38]

Participants

8

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 11430Potassium CarbonateHCID 56605305(S)-benzyl 2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylateHCID 67681976(S)-tert-butyl 2-(6-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)dibenzo[b,d]thiophen-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate

Product 1

HCID 67681931(S)-benzyl 2-(5-(7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)dibenzo[b,d]thiophen-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylateYield 70%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
85 °C

Procedure

A mixture of (S)-tert-butyl 2-(6-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)dibenzo[b,d]thiophen-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (870 mg, 1.5 mmol), (S)-benzyl 2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (620 mg, 1.8 mmol), tetrakis(triphenylphosphine)palladium(0) (170 mg, 0.15 mmol), PdCl2(dppf) (110 mg, 0.15 mmol), 2M aqueous potassium carbonate (2.2 mL, 4.4 mmol), dimethoxyethane (12.2 mL) and dimethylformamide (2.4 mL) was degassed with argon for 15 minutes. The reaction was then heated to 85° C. for 2 hours. Upon completion, the reaction was cooled to room temperature, diluted with ethyl acetate and filtered through Celite. The filtrate was washed with water and brine, dried (MgSO4) and concentrated. The resulting crude material was purified by flash column chromatography to yield (S)-benzyl 2-(5-(7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)dibenzo[b,d]thiophen-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (750 mg, 70%). LCMS-ESI+: calculated for C43H42N6O4S: 738.30; observed [M+1]+: 739.19.

Workup

  1. customwas degassed with argon for 15 minutes
  2. temperatureUpon completion, the reaction was cooled to room temperature
  3. additiondiluted with ethyl acetate
  4. filtrationfiltered through Celite
  5. washThe filtrate was washed with water and brine
  6. dry with materialdried (MgSO4)
  7. concentrationconcentrated
  8. customThe resulting crude material was purified by flash column chromatography

Sources & evidence

ORD record
ord-d96fb8289eb6450bbd1a0acb5bf8fe49
Source dataset
uspto-grants-2015_10
Patent number
US09156823B2

Reaction notes

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