2-(6-bromo-1H-benzimidazol-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester → 2-[6-(5-{4-[2-(1-Formyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl}-thiophen-2-yl)-1H-benzoimidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 71733Notes

Reaction equation

HRID 71733 reaction equation
C([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:23]=[CH:22][C:21]([C:24]3[S:25][C:26](B4OC(C)(C)C(C)(C)O4)=[CH:27][CH:28]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.[C:38]([O:42][C:43]([N:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[C:50]1[NH:54][C:53]2[CH:55]=[C:56](Br)[CH:57]=[CH:58][C:52]=2[N:51]=1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>C(=O)([O-])[O-].[K+].[K+].C(COC)OC.C(OCC)(=O)C.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:38]([O:42][C:43]([N:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[C:50]1[NH:54][C:53]2[CH:55]=[C:56]([C:26]3[S:25][C:24]([C:21]4[CH:22]=[CH:23][C:18]([C:15]5[NH:14][C:13]([CH:9]6[CH2:10][CH2:11][CH2:12][N:8]6[CH:6]=[O:5])=[N:17][CH:16]=5)=[CH:19][CH:20]=4)=[CH:28][CH:27]=3)[CH:57]=[CH:58][C:52]=2[N:51]=1)=[O:44])([CH3:41])([CH3:40])[CH3:39]

Participants

7

Reactant 2

HCID 581852752-(6-bromo-1H-benzimidazol-2-yl)pyrrolidine-1-carboxylic acid tert-butyl esterHCID 666209802-(5-{4-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiophen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 866488742-[6-(5-{4-[2-(1-Formyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl}-thiophen-2-yl)-1H-benzoimidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl esterYield 66.2%

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 80711,2-DimethoxyethaneSolventHCID 8857Ethyl AcetateSolventHCID 11430Potassium CarbonateSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of 2-(5-{4-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiophen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.110 g), 2-(6-Bromo-1H-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.115 g) and Pd(PPh3)4 (0.012 g) in 2.0M potassium carbonate solution (0.32 mL) and dimethoxyethane (0.64 mL) was heated in microwave at 110° C. for 30 minutes. Reaction mixture was cooled, diluted with ethyl acetate, washed with brine, dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 50 to 100% ethyl acetate/hexanes) and preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA) to give 2-[6-(5-{4-[2-(1-Formyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl}-thiophen-2-yl)-1H-benzoimidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.085 g) as a bis-TFA salt: LCMS-ESI+: calc'd for C38H45N6O4S: 681.86 (M+H+). Found: 681.0 (M+H+).

Workup

  1. customReaction mixture
  2. temperaturewas cooled
  3. washwashed with brine
  4. dry with materialdried (MgSO4)
  5. concentrationconcentrated
  6. custompurified by flash column chromatography (silica gel, 50 to 100% ethyl acetate/hexanes) and preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA)

Sources & evidence

ORD record
ord-9725bed0fd41465b8c186e1b1e96ed9c
Source dataset
uspto-grants-2014_09
Patent number
US08822430B2

Reaction notes

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