Sodium Carbonate → 6-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-4'-fluorobiphenyl-3-carbonitrile

HRID 923252Notes

Reaction equation

HRID 923252 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]1[N:14]2[CH:15]=[N:16][CH:17]=[C:13]2[CH2:12][CH2:11]1)[C:5]#[N:6].[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+].[OH-].[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>[CH:17]1[N:16]=[CH:15][N:14]2[CH:10]([C:9]3[C:2]([C:22]4[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=4)=[CH:3][C:4]([C:5]#[N:6])=[CH:7][CH:8]=3)[CH2:11][CH2:12][C:13]=12

Participants

7

Reactant 4

HCID 10340Sodium CarbonateHCID 14797Potassium HydroxideHCID 2856454-Fluorophenylboronic acidHCID 588270573-bromo-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile

Product 1

HCID 588271906-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-4'-fluorobiphenyl-3-carbonitrile

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
130 °C

Procedure

To a solution of 3-bromo-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile (0.100 g, 0.347 mmol) and 4-fluorophenylboronic acid (0.158 g, 1.04 mmol) in DME (2 mL), aqueous solutions of Na2CO3 (0.69 mL, 2 M) and KOH (0.17 mL, 2 M) are added. After degassing with nitrogen, Pd(PPh3)4 (0.040 g, 0.035 mmol) is added. Mixture is heated in a microwave reactor at 130° C., for 20 minutes. LCMS showed consumption of starting material. The solution is then diluted with ethyl acetate and saturated aqueous sodium bicarbonate. The resulting aqueous layer is extracted further with ethyl acetate (3×). The combined organic layers are washed with brine and dried over anhydrous sodium sulfate. After concentration, crude product is purified by flash chromatography (Hexane/EtOAc, and then 10% MeOH/DCM) followed by preparative HPLC (0-50% acetonitrile with 0.1% TEA in 21 minutes). After concentration and free basing, 6-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-4′-fluorobiphenyl-3-carbonitrile is obtained as a white powder. MS (ESI) m/z 304.0 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 2.38-2.54 (m, 1H), 2.76-3.03 (m, 3H), 5.33 (app t, J=6.7 Hz, 1H), 6.79 (s, 1H), 7.01 (d, J=8.1 Hz, 1H), 7.15-7.24 (m, 3H), 7.29 (dd, J=13.4, 5.1 Hz, 2H), 7.54-7.65 (m, 2H).

Workup

  1. additionis added
  2. customconsumption of starting material
  3. additionThe solution is then diluted with ethyl acetate and saturated aqueous sodium bicarbonate
  4. extractionThe resulting aqueous layer is extracted further with ethyl acetate (3×)
  5. washThe combined organic layers are washed with brine
  6. dry with materialdried over anhydrous sodium sulfate
  7. concentrationAfter concentration, crude product
  8. customis purified by flash chromatography (Hexane/EtOAc
  9. customfollowed by preparative HPLC (0-50% acetonitrile with 0.1% TEA in 21 minutes)
  10. concentrationAfter concentration and free basing

Sources & evidence

ORD record
ord-6c6208d1cf794eaea28dba199ceb9deb
Source dataset
uspto-grants-2016_03
Patent number
US09278969B2

Reaction notes

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