Nitrogen → 1-(4-(3-(3-Methoxypyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)-3,3-dimethylbutan-1-one di-hydrochloride salt

HRID 870738Notes

Reaction equation

HRID 870738 reaction equation
Br[C:2]1[N:6]2[N:7]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17](=[O:23])[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:13][CH2:12]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.O.[CH3:25][O:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1B(O)O.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[Cl:45]CCl.N#N>COCCOC.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].O>[ClH:45].[ClH:45].[CH3:25][O:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1[C:2]1[N:6]2[N:7]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17](=[O:23])[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:13][CH2:12]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1

Participants

9

Reactant 5

HCID 947Nitrogen2×HCID 6344DichloromethaneHCID 22031701Potassium phosphate, tribasic, monohydrateHCID 467390183-Methoxypyridine-4-boronic acid hydrateHCID 866964461-(4-(3-Bromoimidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)-3,3-dimethylbutan-1-one

Product 1

HCID 898026331-(4-(3-(3-Methoxypyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)-3,3-dimethylbutan-1-one di-hydrochloride saltYield 248%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
85 °C

Procedure

To a mixture of 1-(4-(3-bromoimidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)-3,3-dimethylbutan-1-one (168.9 mg, 0.4 mmol), 3-methoxypyridine-4-boronic acid hydrate [1072952-50-1] (82.3 mg, 0.5 mmol), potassium phosphate tribasic monohydrate [27176-10-9] (210.4 mg, 0.9 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane [95464-05-4] (33.8 mg, 0.1 mmol) contained in a 25 mL round bottomed flask was added a solution of 30% (v/v) water in 1,2-dimethoxyethane (13 mL) 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 85° C. for 17 h then cooled and partitioned between brine (pH adjusted to 10 with 3N aqueous sodium hydroxide) 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 59.7 mg of 1-(4-(3-(3-methoxypyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)-3,3-dimethylbutan-1-one di-hydrochloride salt as a light yellow powder, mp. 211-212° C. (dec). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00-1.04 (m, 9H) 2.26-2.35 (m, 2H) 3.57-3.66 (m, 4H) 3.70 (br. s., 4H) 4.14-4.21 (m, 3H) 7.68 (d, J=9.85 Hz, 1H) 8.20 (dd, J=10.10, 2.02 Hz, 1H) 8.65 (d, J=2.53 Hz, 2H) 8.75-8.80 (m, 1H) 9.04-9.10 (m, 1H). 13C NMR (100 MHz, DMSO-d6) δ ppm 29.70, 30.94, 43.69, 45.00, 45.43, 45.70, 57.70, 115.22, 119.35, 121.79, 124.70, 126.64, 130.45, 134.42, 135.21, 136.68, 152.58, 155.32, 169.63. LRMS (ESI) m/z 409.2 [(M+H)]+, calc'd for C22H28N6O2: 408.50.

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 (
  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-7109439ca2e541229263748f82e399eb
Source dataset
uspto-grants-2015_03
Patent number
US08969565B2

Reaction notes

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