Cesium carbonate → 5-(4-(4-((3aR,6aR)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)phenyl)piperazin-1-yl)picolinonitrile

HRID 12973

Reaction equation

HRID 12973 reaction equation
[CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)=[CH:12][CH:11]=3)[CH2:6][CH2:7]2)[CH2:3]1.Br[C:23]1[CH:24]=[CH:25][C:26]([C:29]#[N:30])=[N:27][CH:28]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCCC1>[CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[CH:11]=[CH:12][C:13]([N:16]4[CH2:17][CH2:18][N:19]([C:23]5[CH:24]=[CH:25][C:26]([C:29]#[N:30])=[N:27][CH:28]=5)[CH2:20][CH2:21]4)=[CH:14][CH:15]=3)[CH2:6][CH2:7]2)[CH2:3]1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 8171545-Bromopyridine-2-carbonitrileHCID 68497954(3aR,6aR)-5-Methyl-1-(4-piperazin-1-yl-phenyl)-octahydro-pyrrolo[3,4-b]pyrrole

Product 1

HCID 247438155-(4-(4-((3aR,6aR)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)phenyl)piperazin-1-yl)picolinonitrile

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
120 °C

Procedure

The product of Example 75A (78.0 mg, 0.27 mmole), 5-bromo-2-cyanopyridine (74.8 mg, 0.41 mmole), palladium acetate (2.5 mg, 0.011 mmole), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (19.0 mg, 0.037 mmole), cesium carbonate (142.1 mg, 0.44 mmole) and 3 ml of tetrahydrofuran were mixed under N2 in a Emrys process vial. The vial was sealed and heated in the microwave for 2 hours at 120° C. using the Emrys Creator. The mixture was diluted with water and extracted with dichloromethane (4×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product which was purified by column chromatography (10% methanol and 1% ammonium hydroxide in dichloromethane) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 8.36 (d, J=2.71 Hz, 1H) 7.53 (d, J=8.82 Hz, 1H) 7.13 (dd, J=8.82, 3.05 Hz, 1H) 6.86-6.98 (m, 2H) 6.50-6.65 (m, 2H) 4.06 (t, J=8.65 Hz, 1H) 3.44-3.59 (m, 5H) 3.11-3.24 (m, 5H) 2.88-3.02 (m, 1H) 2.56-2.72 (m, 4H) 2.33 (s, 3H) 2.06-2.24 (m, 1H) 1.83-2.01 (m, 1H). MS: (M+H)+=389.

Workup

  1. customThe vial was sealed
  2. extractionextracted with dichloromethane (4×)
  3. washThe combined organic layers were washed with brine
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customto give the crude product which
  8. customwas purified by column chromatography (10% methanol and 1% ammonium hydroxide in dichloromethane)

Sources & evidence

ORD record
ord-ef22869ba1bd44429619dade03e21b59
Source dataset
uspto-grants-2010_06
Patent number
US07728031B2

Linked notes

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