4-(1-Piperidylmethyl)phenylboronic Acid → 5-(2-Methoxyethoxy)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile

HRID 1505976Notes

Reaction equation

HRID 1505976 reaction equation
Br[C:2]1[CH:21]=[N:20][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[C:9]([O:15][CH2:16][CH2:17][O:18][CH3:19])[C:8]=3[C:4]=2[CH:3]=1.[N:22]1([CH2:28][C:29]2[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(=O)([O-])[O-].[Na+].[Na+].C(#N)C.O.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]>[CH3:19][O:18][CH2:17][CH2:16][O:15][C:9]1[C:8]2[C:4]3[CH:3]=[C:2]([C:32]4[CH:31]=[CH:30][C:29]([CH2:28][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[CH:34][CH:33]=4)[CH:21]=[N:20][C:5]=3[NH:6][C:7]=2[CH:12]=[N:11][C:10]=1[C:13]#[N:14]

Participants

7

Reactant 2

HCID 230053434-(1-Piperidylmethyl)phenylboronic AcidHCID 670276773-bromo-5-(2-methoxy-ethoxy)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrile

Product 1

HCID 582665065-(2-Methoxyethoxy)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole-6-carbonitrileYield 32%

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 6342AcetonitrileSolventHCID 10340Sodium CarbonateSolvent

Conditions

Temperature
140 °C

Procedure

A degassed mixture of 3-bromo-5-(2-methoxy-ethoxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (50 mg, 0.10 mmol), 4-piperidin-1-ylmethylphenyl boronic acid (31 mg, 0.14 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9 mg, 0.012 mmol) in 2N aqueous sodium carbonate solution (0.42 mL) and acetonitrile (0.53 mL) were heated under microwave irradiation at 140° C. for 30 minutes. The reaction mixture was diluted with water (2 mL) and extracted with 10% MeOH in DCM. The combined organic phase was concentrated in vacuo and the resultant residue was purified by flash chromatography (silica, 500 mg column, Si-SPE, 0-20% methanol in DCM). The resultant residue was dissolved in a solution of 0.15M potassium hydroxide in methanol (7 mL) and stirred for 45 minutes. 1N Potassium dihydrogen phosphate (1 mL) was added then the mixture concentrated in vacuo. The resultant residue was diluted with water and the pH adjusted to 7 by the addition of 1N potassium dihydrogen phosphate. The aqueous phase was extracted with DCM (3×10 mL) and 20% ethanol in DCM (10 mL), the combined organic phase was dried over magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography (silica, 500 mg column, Si-SPE, 2-4% methanol in DCM) and trituration with acetonitrile to afford the title compound as a brown solid (14 mg, 32%). 1H NMR (CDCl3, 300 MHz): 9.91 (s, 1H), 9.09 (d, J=2.2 Hz, 1H), 8.93 (d, J=2.2 Hz, 1H), 8.80 (s, 1H), 7.67 (d, J=8.1 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 4.75-4.69 (m, 2H), 3.95-3.89 (m, 2H), 3.58 (s, 2H), 3.47 (s, 3H), 2.51-2.37 (m, 4H), 1.68-1.54 (m, 4H), 1.52-1.41 (m, 2H). LCMS (Method A): RT=6.27 min, M+H+=442.

Workup

  1. extractionextracted with 10% MeOH in DCM
  2. concentrationThe combined organic phase was concentrated in vacuo
  3. customthe resultant residue was purified by flash chromatography (silica, 500 mg column, Si-SPE, 0-20% methanol in DCM)
  4. dissolutionThe resultant residue was dissolved in a solution of 0.15M potassium hydroxide in methanol (7 mL)
  5. addition1N Potassium dihydrogen phosphate (1 mL) was added
  6. concentrationthe mixture concentrated in vacuo
  7. additionThe resultant residue was diluted with water
  8. additionthe pH adjusted to 7 by the addition of 1N potassium dihydrogen phosphate
  9. extractionThe aqueous phase was extracted with DCM (3×10 mL) and 20% ethanol in DCM (10 mL)
  10. dry with materialthe combined organic phase was dried over magnesium sulfate
  11. concentrationconcentrated in vacuo
  12. customThe resultant residue was purified by flash chromatography (silica, 500 mg column, Si-SPE, 2-4% methanol in DCM) and trituration with acetonitrile

Sources & evidence

ORD record
ord-8a2493cbe9d54898a46f1eda255dd0fe
Source dataset
uspto-grants-2015_12
Patent number
US09216980B2

Reaction notes

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