Nitrogen → HCID 86696343, compound

HRID 870647Notes

Reaction equation

HRID 870647 reaction equation
Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH:19]([CH3:21])[CH3:20])[C:16](=[O:18])[CH3:17])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:22]([C:25]1[S:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:24])[CH3:23].O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].ClCCl.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>[C:22]([C:25]1[S:29][C:28]([C:2]2[N:6]3[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH:19]([CH3:21])[CH3:20])[C:16](=[O:18])[CH3:17])[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)=[CH:27][CH:26]=1)(=[O:24])[CH3:23]

Participants

9

Reactant 5

HCID 947Nitrogen2×HCID 6344DichloromethaneHCID 4143377(5-Acetylthiophen-2-yl)boronic acidHCID 22031701Potassium phosphate, tribasic, monohydrateHCID 86696342HCID 86696342, compound

Product 1

HCID 86696343HCID 86696343, compound

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 N-(3-((3-bromoimidazo[1,2-b]pyridazin-6-yl)amino)propyl)-N-isopropylacetamide (219.2 mg, 0.6 mmol), (5-acetylthiophen-2-yl)boronic acid [206551-43-1] (128.4 mg, 0.8 mmol), potassium phosphate tribasic monohydrate [27176-10-9] (266.5 mg, 1.3 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II), complex with dichloromethane [95464-05-4] (53.6 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 and ethyl acetate. The phase separated extract was dried (MgSO4) and evaporated to yield a dark brown solid. Product was purified by preparative RP-HPLC. Purified chromatography fractions were combined and partitioned between aqueous saturated sodium bicarbonate and ethyl acetate. The organic extract dried (CaSO4) and evaporated to provide N-(3-((3-(5-acetylthiophen-2-yl)imidazo[1,2-b]pyridazin-6-yl)amino)propyl)-N-isopropylacetamide as 45.7 mg of yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05-1.20 (m, 4H) 1.24 (br. s., 1H) 1.86-2.03 (m, 4H) 2.49-2.56 (m, 6H) 3.24-3.48 (m, 5H) 6.76 (dd, J=9.73, 1.14 Hz, 1H) 7.33-7.43 (m, 1H) 7.79-7.84 (m, 1H) 7.97 (d, J=4.04 Hz, 1H) 8.14 (d, J=5.05 Hz, 1H). LRMS (ESI) m/z 400.2 [(M+H)]+, calc'd for C20H25N5O2S: 399.52.

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 yield a dark brown solid
  14. customProduct was purified by preparative RP-HPLC
  15. customPurified chromatography fractions
  16. custompartitioned between aqueous saturated sodium bicarbonate and ethyl acetate
  17. extractionThe organic extract
  18. dry with materialdried (CaSO4)
  19. customevaporated

Sources & evidence

ORD record
ord-ee8240fdcc6f4217ac41cf247f8c5a32
Source dataset
uspto-grants-2015_03
Patent number
US08969565B2

Reaction notes

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