Morpholine → 1-(5-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-7-(4-morpholinyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]-thiazine 4,4-dioxide

HRID 1618677Notes

Reaction equation

HRID 1618677 reaction equation
Cl[C:2]1[CH:31]=[N:30][C:5]2[S:6](=[O:29])(=[O:28])[CH2:7][CH2:8][N:9]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]=4[F:20])[N:13]=[C:12]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[C:11]=3[CH3:27])[C:4]=2[CH:3]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[NH:66]1[CH2:71][CH2:70][O:69][CH2:68][CH2:67]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:20][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[C:10]([N:9]1[CH2:8][CH2:7][S:6](=[O:29])(=[O:28])[C:5]3[N:30]=[CH:31][C:2]([N:66]4[CH2:71][CH2:70][O:69][CH2:68][CH2:67]4)=[CH:3][C:4]1=3)=[C:11]([CH3:27])[C:12]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[N:13]2

Participants

7

Reactant 4

HCID 8083MorpholineHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23676156Sodium t-butoxideHCID 672857777-chloro-1-(5-fluoro-3-methyl-2-pyridin-2-ylquinolin-4-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine 4,4-dioxide

Product 1

HCID 509393421-(5-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-7-(4-morpholinyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]-thiazine 4,4-dioxide

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Procedure

Prepared according to procedure N by heating a solution of 7-chloro-1-(5-fluoro-3-methyl-2-pyridin-2-ylquinolin-4-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine 4,4-dioxide (34 mg, 0.075 mmol), Pd2dba3 (6.8 mg, 7.5 μmol), XPhos (7.13 mg, 0.015 mmol), morpholine (6.51 μL, 0.075 mmol) and sodium tert-butoxide (14.4 mg, 0.149 mmol) in toluene (2.0 mL) in the microwave for 2 h at 110° C. After this time the reaction was cooled to rt and partitioned between EtOAc (60 mL) and NaHCO3 (20 mL, saturated aqueous solution). The separated organic layer was dried over MgSO4, filtered and evaporated in vacuo. Purification by reverse phase HPLC (10 to 60% acetonitrile in water) gave 1-(5-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-7-(4-morpholinyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]-thiazine 4,4-dioxide. 1H NMR (400 MHz, chloroform-d) δ ppm 8.75 (1H, dt, J=4.8, 1.5 Hz), 8.05-8.12 (1H, m), 7.94 (2H, dt, J=4.6, 0.9 Hz), 7.87 (1H, d, J=2.3 Hz), 7.70 (1H, td, J=8.2, 5.4 Hz), 7.44 (1H, q, J=4.8 Hz), 7.23-7.30 (1H, m), 5.62 (1H, d, J=2.3 Hz), 4.17-4.32 (2H, m), 3.64-3.76 (5H, m), 3.49-3.60 (1H, m), 2.87-3.04 (4H, m), 2.46 (3H, s). Mass Spectrum (ESI) m/e=506.0 (M+1).

Workup

  1. customPrepared
  2. custompartitioned between EtOAc (60 mL) and NaHCO3 (20 mL, saturated aqueous solution)
  3. dry with materialThe separated organic layer was dried over MgSO4
  4. filtrationfiltered
  5. customevaporated in vacuo
  6. customPurification by reverse phase HPLC (10 to 60% acetonitrile in water)

Sources & evidence

ORD record
ord-2cf46056a32049f0b93988914bf8addc
Source dataset
uspto-grants-2014_07
Patent number
US08765940B2

Reaction notes

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