Water → HCID 86689080, compound

HRID 1625928Notes

Reaction equation

HRID 1625928 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl.[NH:26]1[CH2:31][CH2:30][S:29](=[O:33])(=[O:32])[CH2:28][CH2:27]1.C(N(CC)CC)C.O>C1COCC1.CN(C1C=CN=CC=1)C>[OH2:10].[O:32]=[S:29]1(=[O:33])[CH2:30][CH2:31][N:26]([C:19]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH3:24])=[CH:23][CH:22]=2)=[O:21])[CH2:27][CH2:28]1

Participants

7

Reactant 4

HCID 962WaterHCID 8471TriethylamineHCID 12324096Thiomorpholine 1,1-dioxide hydrochlorideHCID 684418986-[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid

Product 1

HCID 86689080HCID 86689080, compound

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 8028TetrahydrofuranSolvent2×

Procedure

6-[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (23.0 g, 70.1 mmol) and 1,1-carbonyldiimidazole (15.3 g, 94.6 mol, 1.35 eq.) were dissolved in THF (120 mL) and the resulting solution was stirred for one hour at room temperature. This solution was then added to a suspension of thiomorpholine-1,1-dioxide HCl (16.9 g, 98.5 mmol), DMAP (400 mg, 3.27 mmol) and triethylamine (9.78 g, 96.7 mmol) in THF (120 mL). The resulting mixture was heated to reflux temperature and subsequently stirred at this temperature for 50 hours. The mixture was cooled to room temperature and then treated within one hour with water (300 mL). From the resulting suspension THF was distilled off under reduced pressure and with a jacket temperature of 60° C. and continuously replaced by ethanol (426 g) at constant volume. The suspension was cooled to room temperature and stirred for 2 hours. The crystals were filtered off, washed with a mixture of ethanol (100 mL) and water (100 mL) and subsequently dried at 55° C./<25 mbar until constant weight to afford 28.9 g (92%) of Form B as a colorless solid with purity of 99.7% (area) as measured by HPLC.

Workup

  1. temperatureThe resulting mixture was heated
  2. temperatureto reflux temperature
  3. stirringsubsequently stirred at this temperature for 50 hours
  4. temperatureThe mixture was cooled to room temperature
  5. distillationFrom the resulting suspension THF was distilled off under reduced pressure and with a jacket temperature of 60° C.
  6. temperatureThe suspension was cooled to room temperature
  7. stirringstirred for 2 hours
  8. filtrationThe crystals were filtered off
  9. washwashed with a mixture of ethanol (100 mL) and water (100 mL)
  10. customsubsequently dried at 55° C./<25 mbar until constant weight
  11. customto afford 28.9 g (92%) of Form B as a colorless solid with purity of 99.7% (area)

Sources & evidence

ORD record
ord-8f5e1c6a5a694065a30829ec42fe9d6e
Source dataset
uspto-grants-2014_07
Patent number
US08785435B2

Reaction notes

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