Hydrochloric Acid → 4-[4-[5-(2,6-Difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]hexahydropyridazine

HRID 75173Notes

Reaction equation

HRID 75173 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[C:16]([CH:19]3[CH2:24][CH2:23][N:22](C(OCC)=O)[N:21](C(OCC)=O)[CH2:20]3)[S:17][CH:18]=2)[CH2:10]1.[OH-].[K+].Cl.C(=O)(O)[O-].[Na+]>C(O)C.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[CH:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[C:16]([CH:19]3[CH2:24][CH2:23][NH:22][NH:21][CH2:20]3)[S:17][CH:18]=2)[CH2:10]1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 14797Potassium HydroxideHCID 516892Sodium BicarbonateHCID 866744651,2-Diethyl 4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]tetrahydro-1,2-pyridazinedicarboxylate2×

Product 1

HCID 673224374-[4-[5-(2,6-Difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]hexahydropyridazine

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 962WaterSolvent

Conditions

Temperature
70 °C

Procedure

A mixture of 1,2-diethyl 4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]tetrahydro-1,2-pyridazinedicarboxylate (i.e. the product of Step G) (4.09 g, 0.0083 mol) and potassium hydroxide (2.32 g, 0.0414 mol) in ethanol (50 mL) and water (5 mL) was heated at reflux for 20 h. The reaction mixture was cooled, acidified by the addition of concentrated hydrochloric acid, and then warmed to about 70° C. for 10 minutes. The reaction mixture was cooled, neutralised by the addition of sodium bicarbonate. The reaction mixture was concentrated under reduced pressure and the resulting matterial was extracted with diethyl ether (3×), dried over magnesium sulfate, filtered and concentrated under reduced pressure to a tan oil (2.99 g). The oil was adsorbed onto Celite® (diatomaceous filter aid), and then by purified by silica gel column chromatography (5% to 100% gradient of methanol in chloroform as eluant) to provide the title compound (1.275 g).

Workup

  1. temperaturewas heated
  2. temperatureat reflux for 20 h
  3. temperatureThe reaction mixture was cooled
  4. temperatureThe reaction mixture was cooled
  5. concentrationThe reaction mixture was concentrated under reduced pressure
  6. extractionthe resulting matterial was extracted with diethyl ether (3×)
  7. dry with materialdried over magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure to a tan oil (2.99 g)
  10. customby purified by silica gel column chromatography (5% to 100% gradient of methanol in chloroform as eluant)

Sources & evidence

ORD record
ord-dd94339dac984d52b15bbb10543adaaf
Source dataset
uspto-grants-2014_09
Patent number
US08835427B2

Reaction notes

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