Nitrogen → (S)-tert-butyl 2-(5-((4-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)phenyl)ethynyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

HRID 1919180Notes

Reaction equation

HRID 1919180 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2C=C[C:11]3[N:15]=[C:14]([C@@H:16]4[CH2:20][CH2:19][CH2:18][N:17]4[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[NH:13][C:12]=3[CH:28]=2)=[CH:4][CH:3]=1.[C:29]([C:31]1[NH:35][C:34]([C@@H:36]2[CH2:40][CH2:39][CH2:38][N:37]2[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[N:33][CH:32]=1)#[CH:30].[CH2:48](N(CC)CC)[CH3:49].N#N>CN(C=O)C.[Cu]I.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:44]([O:43][C:41]([N:37]1[CH2:38][CH2:39][CH2:40][C@H:36]1[C:34]1[NH:33][C:32]2[CH:48]=[C:49]([C:2]3[CH:3]=[CH:4][C:5]([C:8]#[C:28][C:12]4[NH:13][C:14]([C@@H:16]5[CH2:20][CH2:19][CH2:18][N:17]5[C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])=[N:15][CH:11]=4)=[CH:6][CH:7]=3)[CH:30]=[CH:29][C:31]=2[N:35]=1)=[O:42])([CH3:47])([CH3:46])[CH3:45]

Participants

8

Reactant 4

HCID 947NitrogenHCID 8471TriethylamineHCID 58384622(S)-tert-butyl 2-(6-(4-bromophenyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylateHCID 58498809(S)-tert-butyl 2-(5-ethynyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

Product 1

HCID 58384709(S)-tert-butyl 2-(5-((4-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)phenyl)ethynyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
50 °C

Procedure

A solution of (S)-tert-butyl 2-(6-(4-bromophenyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (674 mg, 1.53 mmol, for its preparation, see PCT Publication No. WO 2008/021927)), (S)-tert-butyl 2-(5-ethynyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (518 mg, 1.98 mmol), copper(I) iodide (29.0 mg, 0.152 mmol) and triethylamine (0.64 mL, 4.6 mmol) in DMF (15 mL) was degassed under vacuum for 10 min and backfilled with N2. Pd(Ph3P)4 (176 mg, 0.152 mmol) was then added and the reaction was sealed and heated at 50° C. for 16 h. The reaction mixture was concentrated to remove the volatiles and the residue was dissolved into a minimal amount of MeOH and then partitioned between EtOAc and water. The layers were separated and the organic layer was concentrated and purified on a BIOTAGE® (300 g silica gel, eluted with 20 to 100% EtOAc/DCM) to yield (S)-tert-butyl 2-(5-((4-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)phenyl)ethynyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (305 mg) and a mixture of this product with (2S,2′S)-tert-butyl 2,2′-(5,5′-(buta-1,3-diyne-1,4-diyl)bis(1H-imidazole-5,2-diyl))dipyrrolidine-1-carboxylate. The mixture was further purified by preparative HPLC (acetonitrile/water/0.1% TFA) to provide a TFA salt of (S)-tert-butyl 2-(5-((4-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)phenyl)ethynyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (100 mg) and a TFA salt of (2S,2′S)-tert-butyl 2,2′-(5,5′-(buta-1,3-diyne-1,4-diyl)bis(1H-imidazole-5,2-diyl))dipyrrolidine-1-carboxylate (128 mg) as white solid.

Workup

  1. customthe reaction was sealed
  2. concentrationThe reaction mixture was concentrated
  3. customto remove the volatiles
  4. dissolutionthe residue was dissolved into a minimal amount of MeOH
  5. custompartitioned between EtOAc and water
  6. customThe layers were separated
  7. concentrationthe organic layer was concentrated
  8. custompurified on a BIOTAGE® (300 g silica gel, eluted with 20 to 100% EtOAc/DCM)

Sources & evidence

ORD record
ord-db8db4347d4046589f1e1cb8a1757a6a
Source dataset
uspto-grants-2013_12
Patent number
US08618153B2

Reaction notes

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