Acetic Acid → 3-cyano-4-hydroxy-7-(3-morpholin-4-ylpropoxy)-5-(tetrahydro-2H-pyran-4-yloxy)quinoline

HRID 347443Notes

Reaction equation

HRID 347443 reaction equation
[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[OH:13])=[C:10]([O:14][CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[CH:9]=[C:8](F)[CH:7]=2)#[N:2].[N:22]1([CH2:28][CH2:29][CH2:30][OH:31])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.CC(C)([O-])C.[K+].C(O)(=O)C>CS(C)=O.O>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[OH:13])=[C:10]([O:14][CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[CH:9]=[C:8]([O:31][CH2:30][CH2:29][CH2:28][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH:7]=2)#[N:2]

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 1995763-Morpholino-1-propanolHCID 23665647Potassium tert-butoxideHCID 178510317HCID 178510317, compound

Product 1

HCID 1785103203-cyano-4-hydroxy-7-(3-morpholin-4-ylpropoxy)-5-(tetrahydro-2H-pyran-4-yloxy)quinolineYield 44%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolvent

Conditions

Temperature
60 °C

Procedure

A mixture of 3-cyano-7-fluoro-4-hydroxy-5-(tetrahydro-2H-pyran-4-yloxy)quinoline (864 mg), 3-morpholin-4-ylpropan-1-ol (876 mg) and potassium tert-butoxide (1.0M solution in tetrahydrofuran; 9.0 ml) in anhydrous dimethyl sulphoxide (30 ml) was heated at 60° C. for 8 hours. The solution was cooled and then diluted with water (120 ml). Acetic acid was added until pH5 was reached. The solution was pumped onto a cation exchange cartridge (Waters Oasis MCX 6.0 g) and washed on with water. The column was flushed successively with water (200 ml), methanol/water (1:1; 200 ml) and methanol (200 ml). The product was eluted off the column with methanol containing triethylamine (1%). The fractions containing the product were combined and evaporated. The residue was further purified by chromatography on a Redisep silica cartridge (40 g) eluting with a gradient of methanol in dichloromethane (5–20%). This gave the title compound as an white solid (540 mg, 44%); NMR spectrum: (DMSOd6; 373° K) 1.73 (m, 2H), 1.91 (m, 4H), 2.39 (m, 4H), 2.45 (t, 2H), 3.49 (m, 2H), 3.58 (m, 4H), 3.95 (m, 2H), 4.10 (t, 2H), 4.64 (m, 1H), 6.46 (d, 1H), 6.60 (d, 1H), 8.24 (s, 1H); Mass spectrum: M+H+ 414.

Workup

  1. temperatureThe solution was cooled
  2. washwashed on with water
  3. customThe column was flushed successively with water (200 ml), methanol/water (1:1; 200 ml) and methanol (200 ml)
  4. washThe product was eluted off the column with methanol
  5. additioncontaining triethylamine (1%)
  6. additionThe fractions containing the product
  7. customevaporated
  8. customThe residue was further purified by chromatography on a Redisep silica cartridge (40 g)
  9. washeluting with a gradient of methanol in dichloromethane (5–20%)

Sources & evidence

ORD record
ord-cb595adce3014ef98ebdd70ad2f7280e
Source dataset
uspto-grants-2007_02
Patent number
US07173135B2

Reaction notes

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