4-Methylmorpholine → N-(2-methoxyethyl)-N-methyl-4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]benzamide

HRID 1675091Notes

Reaction equation

HRID 1675091 reaction equation
[CH3:1][N:2]1C[CH2:6][O:5][CH2:4][CH2:3]1.[F:8][C:9]([F:35])([F:34])[C:10]1[N:14]2[N:15]=[C:16]([N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1.ClC1N=C(OC)N=C(OC)N=1.COCCNC>CN(C=O)C>[CH3:6][O:5][CH2:4][CH2:3][N:2]([CH3:1])[C:29](=[O:30])[C:28]1[CH:32]=[CH:33][C:25]([CH:22]2[CH2:21][CH2:20][N:19]([C:16]3[CH:17]=[CH:18][C:13]4[N:14]([C:10]([C:9]([F:34])([F:8])[F:35])=[N:11][N:12]=4)[N:15]=3)[CH2:24][CH2:23]2)=[CH:26][CH:27]=1

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 184502-Chloro-4,6-dimethoxy-1,3,5-triazineHCID 300977(2-Methoxyethyl)(methyl)amineHCID 673391044-[1-[3-(Trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]benzoic acid

Product 1

HCID 44125833N-(2-methoxyethyl)-N-methyl-4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]benzamideYield 79.4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

4-Methylmorpholine (17.56 mL, 159.70 mmol) was added dropwise to 4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]benzoic acid (25 g, 63.88 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (13.46 g, 76.66 mmol) suspended in DMF (250 mL) at 0° C. The resulting suspension was stirred for 10 minutes, then 2-methoxy-N-methylethanamine (5.69 g, 63.88 mmol) was added and the mixture warmed to ambient temperature and stirred for 16 hours. The reaction mixture was concentrated and diluted with DCM (1000 mL) and washed with water (500 mL). The aqueous phase was re-extracted with DCM (500 mL), then the combined organics were washed with saturated NaHCO3 (500 mL) and saturated brine (250 mL), and dried over MgSO4, filtered and evaporated to afford crude product. The crude product was triturated with ether, and the resulting solid was collected by filtration and dried under vacuum, then purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford N-(2-methoxyethyl)-N-methyl-4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]benzamide (23.45 g, 79%) as a solid.

Workup

  1. stirringstirred for 16 hours
  2. concentrationThe reaction mixture was concentrated
  3. additiondiluted with DCM (1000 mL)
  4. washwashed with water (500 mL)
  5. extractionThe aqueous phase was re-extracted with DCM (500 mL)
  6. washthe combined organics were washed with saturated NaHCO3 (500 mL) and saturated brine (250 mL)
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. customevaporated
  10. customto afford crude product
  11. customThe crude product was triturated with ether
  12. filtrationthe resulting solid was collected by filtration
  13. customdried under vacuum
  14. custompurified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM
  15. customPure fractions were evaporated to dryness

Sources & evidence

ORD record
ord-50025e99aa124325a352813318bd3ecc
Source dataset
uspto-grants-2011_08
Patent number
US08003649B2

Reaction notes

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