Dichloromethane → tert-Butyl 4-(5-(8-morpholino-2-((quinolin-2-ylsulfonyl)methyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazine-1-carboxylate

HRID 718602Notes

Reaction equation

HRID 718602 reaction equation
O[CH2:2][C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[N:22][CH:23]=1.C(Cl)Cl.S(Cl)(Cl)=O.[N:44]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46][C:45]=1[S:54]([O-:56])=[O:55].[Li+]>O.CCOC(C)=O.CC(C)=O>[O:14]1[CH2:13][CH2:12][N:11]([C:10]2[C:5]3[N:6]([C:17]([C:18]4[CH:19]=[CH:20][C:21]([N:24]5[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:26][CH2:25]5)=[N:22][CH:23]=4)=[C:3]([CH2:2][S:54]([C:45]4[CH:46]=[CH:47][C:48]5[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=5)[N:44]=4)(=[O:55])=[O:56])[N:4]=3)[N:7]=[CH:8][CH:9]=2)[CH2:16][CH2:15]1

Participants

8

Reactant 4

HCID 6344DichloromethaneHCID 24386Thionyl ChlorideHCID 117728756HCID 117728756, compoundHCID 117732471tert-Butyl 4-(5-(2-(hydroxymethyl)-8-morpholinoimidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazine-1-carboxylate

Product 1

HCID 117732477tert-Butyl 4-(5-(8-morpholino-2-((quinolin-2-ylsulfonyl)methyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazine-1-carboxylate

Reagents, catalysts & solvents 3

HCID 180AcetoneSolventHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Procedure

Compound 21a (152 mg, 0.307 mmol) was placed in an 8 mL vial equipped with a stir bar and then DCM (4 mL) was added and the solid dissolved. Thionyl chloride (54.7 μL, 0.750 mmol) was added dropwise via microsyringe and then the reaction was stirred at rt for 5 min. The solvent was removed under reduced pressure. The residue was placed in a 40 mL vial equipped with a stir bar and then acetone was added. Compound 24a (199 mg, 1.00 mmol) was dissolved in water (5 mL) and added to the stirred acetone solution. The reaction turned yellow immediately. The reaction was stirred at rt for 18 h and then diluted with EtOAc (30 mL). The organic layer was separated and then the aqueous layer was extracted with EtOAc (3×20 mL). The aqueous layer was then extracted with DCM (3×30 mL). The organic extracts were combined, dried over MgSO4, and filtered. The solvent was removed under reduced pressure. The crude residue was chromatographed on a 12 g SiO2 pre-packed column eluting with 0-80% ACN/DCM to afford compound 24b. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.47 (d, J=2.2 Hz, 1H), 8.33 (d, J=8.6 Hz, 1H), 8.29 (d, J=8.6 Hz, 1H), 7.93-7.98 (m, 2H), 7.92 (d, J=5.6 Hz, 1H), 7.85-7.90 (m, 1H), 7.83 (dd, J=8.8, 2.4 Hz, 1H), 7.72-7.78 (m, 1H), 6.68 (d, J=8.8 Hz, 1H), 5.93 (d, J=5.6 Hz, 1H), 5.07 (s, 2H), 3.59-3.64 (m, 4H), 3.55-3.59 (m, 4H), 3.36-3.41 (m, 4H), 3.29-3.36 (m, 4H), 1.51 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C34H38N8O5S: 671.3 (M+H). Found: 671.3.

Workup

  1. customvial equipped with a stir bar
  2. dissolutionthe solid dissolved
  3. customThe solvent was removed under reduced pressure
  4. customvial equipped with a stir bar
  5. additionacetone was added
  6. stirringThe reaction was stirred at rt for 18 h
  7. customThe organic layer was separated
  8. extractionthe aqueous layer was extracted with EtOAc (3×20 mL)
  9. extractionThe aqueous layer was then extracted with DCM (3×30 mL)
  10. dry with materialdried over MgSO4
  11. filtrationfiltered
  12. customThe solvent was removed under reduced pressure
  13. customThe crude residue was chromatographed on a 12 g SiO2 pre-packed column
  14. washeluting with 0-80% ACN/DCM

Sources & evidence

ORD record
ord-f5e57a49a52d4b5c91f0fa2fa7de71eb
Source dataset
uspto-grants-2015_11
Patent number
US09193736B2

Reaction notes

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