Ammonium Chloride → 4-(1,4-Dioxaspiro[4,5]dec-8-yl)-1-(4-ethoxy-2,3-difluorophenyl)cyclohexanol

HRID 2039381Notes

Reaction equation

HRID 2039381 reaction equation
[CH2:1]([O:3][C:4]1[C:5]([F:11])=[C:6]([F:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2].C([Li])(CC)C.[O:17]1[C:21]2([CH2:26][CH2:25][CH:24]([CH:27]3[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]3)[CH2:23][CH2:22]2)[O:20][CH2:19][CH2:18]1.[Cl-].[NH4+]>C1COCC1>[O:17]1[C:21]2([CH2:22][CH2:23][CH:24]([CH:27]3[CH2:32][CH2:31][C:30]([C:7]4[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([F:11])[C:6]=4[F:10])([OH:33])[CH2:29][CH2:28]3)[CH2:25][CH2:26]2)[O:20][CH2:19][CH2:18]1

Participants

6

Reactant 4

HCID 25517Ammonium ChlorideHCID 8109134-(1,4-Dioxa-spiro(4.5)dec-8-yl)-cyclohexanoneHCID 27829281-Ethoxy-2,3-DifluorobenzeneHCID 178418400CID 53628100

Product 1

HCID 597736464-(1,4-Dioxaspiro[4,5]dec-8-yl)-1-(4-ethoxy-2,3-difluorophenyl)cyclohexanol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

3-Ethoxy-1,2-difluorobenzene (s65) (10.0 g) and THF (200 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to −74° C. sec-Butyllithium (1.00 M, in n-hexane-cyclohexane; 64.0 ml) was added dropwise in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. 4-(1,4-Dioxaspiro[4.5]decan-8-yl)-cyclohexanone (s66) (12.8 g) in THF (50 ml) solution was added dropwise in the temperature range of −75° C. to −70° C., and the stirring was continued for another 8 hours while the mixture was allowed to come to 25° C. The reaction mixture was treated with an aqueous solution of ammonium chloride (3%), and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. Distillation of the solvent under reduced pressure gave 4-(1,4-dioxaspiro[4.5]decan-8-yl)-1-(4-ethoxy-2,3-difluorophenyl)-cyclohexanol. The compound was mixed with p-toluenesulfonic acid (0.68 g) and toluene (200 ml), and the mixture was heated to reflux for 2 hours while distilled water was removed. After the reaction mixture had been cooled to 30° C., it was treated with water, and the aqueous layer was extracted with toluene. The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder. Pd/C (0.3 g) was added to the purified product and the mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed, and then solvent was distilled off. The residue was purified by recrystallization from a mixed solvent of THF and heptane (THF:heptane=1:9 by volume) to give 8-[4-(4-ethoxy-2,3-difluorophenyl)-cyclohexenyl]-1,4-dioxaspiro[4.5]decane (s67) (7.7 g). The yield based on the compound (s65) was 35.2%.

Workup

  1. additionwas added dropwise in the temperature range of −74° C. to −70° C.
  2. waitthe stirring was continued for another 8 hours while the mixture
  3. customto come to 25° C
  4. extractionthe aqueous layer was extracted with ethyl acetate
  5. washThe combined organic layers were washed with water
  6. dry with materiala saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate
  7. distillationDistillation of the solvent under reduced pressure

Sources & evidence

ORD record
ord-a5131130240f4364b956d0864b1adad6
Source dataset
uspto-grants-2013_11
Patent number
US08580146B2

Reaction notes

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