Nitrogen → HCID 89802612, compound

HRID 870771Notes

Reaction equation

HRID 870771 reaction equation
BrC1C=NN2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[O:18])[CH2:13][CH2:12]3)=NC=12.CC1(C)C(C)(C)OB([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:45]CCl.[N:48]#[N:49]>[Cu](Cl)Cl.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].CN(C=O)C>[ClH:45].[ClH:45].[N:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:9]1[N:48]2[N:49]=[C:8]([N:11]3[CH2:12][CH2:13][N:14]([C:17]([N:19]4[CH2:20][CH2:21][CH2:22][CH2:23]4)=[O:18])[CH2:15][CH2:16]3)[CH:9]=[CH:10][C:12]2=[N:11][CH:8]=1

Participants

9

Reactant 5

HCID 947Nitrogen2×HCID 6344DichloromethaneHCID 10796Cesium carbonateHCID 11241171Pyridine-2-boronic acid, pinacol esterHCID 89802303HCID 89802303, compound

Product 1

HCID 89802612HCID 89802612, compound

Reagents, catalysts & solvents 3

HCID 24014Cupric ChlorideCatalystHCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

To a mixture of [4-(3-bromo-pyrazolo[1,5-a]pyrimidin-5-yl)-piperazin-1-yl]-pyrrolidin-1-yl-methanone (381.0 mg, 01.0 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine [874186-98-8] (512.7 mg, 2.5 mmol), copper chloride [7758-89-6] (99.4 mg, 1.0 mmol), cesium carbonate [534-17-8] (651.8 mg, 2.0 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane [95464-05-4] (82.1 mg, 0.1 mmol) contained in a 25 mL round bottomed flask was added anhydrous DMF and a magnetic stir bar. The reaction pot was fitted to a reflux condenser, lowered into an ambient temperature oil bath, and the system taken through 10 evacuation/N2 blanket cycles while being rapidly stirred. The rapidly stirred, N2 blanketed, reaction was heated to an oil bath temperature of 100° C. for 17 h then cooled and partitioned between brine and ethyl acetate. The phase separated extract was dried (MgSO4) and evaporated to afford a brown oil which was purified by preparative RP-HPLC. Isolated product was dissolved in methanol, diluted with concentrated hydrochloric acid, evaporated to dryness, redissolved in methanol and precipitated by the addition of diethyl ether. Filtration of the precipitate yielded 83.2 mg of [4-(3-pyridin-2-yl-imidazo[1,2-b]pyridazin-6-yl)-piperazin-1-yl]-pyrrolidin-1-yl-methanone dihydrochloride salt as a light yellow powder, mp. 202-203° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.73-1.84 (m, 4H) 3.33 (t, J=6.44 Hz, 4H) 3.36-3.43 (m, 4H) 3.62-3.72 (m, 4H) 7.45-7.52 (m, 1H) 7.66 (d, J=10.11 Hz, 1H) 8.08 (td, J=7.83, 1.77 Hz, 1H) 8.18 (d, J=10.10 Hz, 1H) 8.54 (s, 1H) 8.60 (d, J=8.08 Hz, 1H) 8.72 (d, J=4.55 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ ppm 25.04, 45.05, 45.27, 47.84, 114.83, 121.12, 123.43, 123.55, 126.59, 127.01, 134.87, 138.20, 145.21, 149.07, 155.74, 161.49. LRMS (ESI) m/z 378.2 [(M+H)]+, calc'd for C20H23N7O: 377.45.

Workup

  1. customcontained in a 25 mL round bottomed flask
  2. customThe reaction
  3. custompot was fitted to a reflux condenser
  4. customlowered into an ambient temperature
  5. stirringThe rapidly stirred
  6. customreaction
  7. temperaturethen cooled
  8. custompartitioned between brine and ethyl acetate
  9. customThe phase separated
  10. extractionextract
  11. dry with materialwas dried (MgSO4)
  12. customevaporated
  13. customto afford a brown oil which
  14. customwas purified by preparative RP-HPLC
  15. dissolutionIsolated product was dissolved in methanol
  16. additiondiluted with concentrated hydrochloric acid
  17. customevaporated to dryness
  18. dissolutionredissolved in methanol
  19. customprecipitated by the addition of diethyl ether
  20. filtrationFiltration of the precipitate

Sources & evidence

ORD record
ord-1e584eebbd334fc9b1804493ad499fe1
Source dataset
uspto-grants-2015_03
Patent number
US08969565B2

Reaction notes

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