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Ammonium Chloride → 1-(2,3-Difluoro-4-(4-pentylcyclohexyl)phenyl)-4-(4-ethoxy-2,3-difluorophenyl)cyclohexanol

HRID 1943559
Notes
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Reaction equation

HRID 1943559 reaction equation
[CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C([Li])(CC)C.[CH2:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:39][CH2:38][C:37](=[O:40])[CH2:36][CH2:35]2)=[C:30]([F:41])[C:29]=1[F:42])[CH3:26].[Cl-].[NH4+]>C1COCC1.C1(C)C=CC=CC=1.C1CCCCC1.CCCCCC>[F:18][C:14]1[C:13]([F:19])=[C:12]([CH:9]2[CH2:10][CH2:11][CH:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]2)[CH:17]=[CH:16][C:15]=1[C:37]1([OH:40])[CH2:36][CH2:35][CH:34]([C:31]2[CH:32]=[CH:33][C:28]([O:27][CH2:25][CH3:26])=[C:29]([F:42])[C:30]=2[F:41])[CH2:39][CH2:38]1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

9

Reactant 4

HCID 25517Ammonium ChlorideHCID 111611214-(4-Ethoxy-2,3-difluorophenyl)cyclohexanoneHCID 199109694-Pentyl-(2,3-difluorophenyl)cyclohexaneHCID 178418400CID 53628100

Product 1

HCID 670824391-(2,3-Difluoro-4-(4-pentylcyclohexyl)phenyl)-4-(4-ethoxy-2,3-difluorophenyl)cyclohexanolYield 99.3%

Reagents, catalysts & solvents

4
HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent2×HCID 8058HexaneSolventHCID 8078CyclohexaneSolvent

Conditions

Temperature
0 °C

Procedure

4-Pentyl-(2,3-difluorophenyl)cyclohexane (10) (5.0 g) and THF (100 ml) were put in a reaction vessel under a nitrogen atmosphere, and cooled to −74° C. sec-Butyllithium (1.00 M, in a n-hexane and cyclohexane solution; 23.0 ml) was added dropwise thereto in the temperature range of −74° C. to −70° C., and the mixture was stirred for another 2 hours. 1-(4-Ethoxy-2,3-difluorophenyl)-cyclohexan-4-one (50) (4.8 g) dissolved in THF (150 ml) was slowly added dropwise thereto in the temperature range of −74° C. to −70° C., and the stirring was continued for another 8 hours while the mixture was allowed to return to 25° C. The reaction mixture obtained was poured into a vessel containing an aqueous solution of ammonium chloride (3%; 500 ml) and toluene (300 ml) which had been cooled to 0° C., and mixed. The mixture was then allowed to stand until it had separated into organic and aqueous phases, and extraction into an organic phase was carried out. The organic phase obtained was fractionated, washed sequentially with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, giving 9.7 g of 1-(2,3-difluoro-4-(4-pentylcyclohexyl)phenyl)-4-(4-ethoxy-2,3-difluorophenyl)cyclohexanol (51). The compound (51) obtained was a yellow solid.

Workup

  1. addition23.0 ml) was added dropwise
  2. additionwas slowly added dropwise
  3. waitin the temperature range of −74° C. to −70° C., and the stirring was continued for another 8 hours while the mixture
  4. customto return to 25° C
  5. customThe reaction mixture obtained
  6. additionwas poured into a vessel
  7. additionmixed
  8. customhad separated into organic and
  9. extractionaqueous phases, and extraction into an organic phase
  10. customThe organic phase obtained
  11. washwashed sequentially with water
  12. dry with materiala saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate
  13. distillationThen, the solvent was distilled off under reduced pressure

Sources & evidence

ORD record
ord-e3328f74e1f2473eb92ca05d62dd96fa
Source dataset
uspto-grants-2013_03
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08394294B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes