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Ammonium Chloride → 8-(4'-Ethoxy-2,2',3,3'-tetrafluoro-1,1'-biphenyl-4-yl)-1,4-dioxaspiro[4.5]decan-8-ol

HRID 2088248
Notes
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Reaction equation

HRID 2088248 reaction equation
[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])=[C:6]([F:18])[C:5]=1[F:19])[CH3:2].C([Li])(CC)C.[O:25]1[C:29]2([CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]2)[O:28][CH2:27][CH2:26]1.[Cl-].[NH4+]>CCCCCC.C1CCCCC1.C1COCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:32]3([OH:35])[CH2:33][CH2:34][C:29]4([O:28][CH2:27][CH2:26][O:25]4)[CH2:30][CH2:31]3)=[C:12]([F:16])[C:11]=2[F:17])=[C:6]([F:18])[C:5]=1[F:19])[CH3:2]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

9

Reactant 4

HCID 25517Ammonium ChlorideHCID 5674151,4-Dioxaspiro[4.5]decan-8-oneHCID 58453709HCID 58453709, compoundHCID 178418400CID 53628100

Product 1

HCID 674329368-(4'-Ethoxy-2,2',3,3'-tetrafluoro-1,1'-biphenyl-4-yl)-1,4-dioxaspiro[4.5]decan-8-ol

Reagents, catalysts & solvents 4

HCID 8028
Tetrahydrofuran
Solvent
2×
HCID 8058HexaneSolvent
HCID 8078CyclohexaneSolvent
HCID 8857Ethyl AcetateSolvent

Procedure

4′-Ethoxy-2,2′,3,3′-tetrafluoro-1,1′-biphenyl (s-25) (50 g) and THF (500 ml) were put in a reaction vessel under an atmosphere of nitrogen and cooled to −74° C. sec-Butyllithium (a 1.00 M solution in n-hexane and cyclohexane; 222 ml) was added dropwide thereto in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. Then, 1,4-dioxaspiro[4.5]decan-8-one (s-12) (28.8 g) dissolved in THF (200 ml) was added dropwise thereto 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 poured into a vessel containing an aqueous solution of ammonium chloride (3%; 500 ml) and ethyl acetate (500 ml), and mixed with them. The mixture was then allowed to stand until it had separated into organic and aqueous phases, and the extraction was carried out. The combined organic phase was washed successively with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off to give 8-(4′-ethoxy-2,2′,3,3′-tetrafluoro-1,1′-biphenyl-4-yl)-1,4-dioxaspiro[4.5]decan-8-ol. p-Toluenesulfonic acid (1.5 g) and toluene (300 ml) were added to the compound 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., water (300 ml) and toluene (300 ml) were added to the mixture, and mixed with it. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and the extraction was carried out. The combined organic phase was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. The resulting solution was purified by column chromatography using silica gel as a stationary phase powder and toluene as an eluent. The product was dissolved in a mixed solvent of toluene (100 ml) and Solmix A-11 100 ml), Pd/C (2.5 g) was added thereto, and the mixture was stirred at room temperature under an atmosphere of hydrogen until hydrogen absorption had ceased. After the completion of the reaction, Pd/C was removed and the solvent was distilled off. The resulting residue was purified by column chromatography using silica gel as a stationary phase powder and toluene as an eluent, and then by recrystallization from Solmix A-11 to give 8-(4′-ethoxy-2,2′,3,3′-tetrafluoro-1,1′-biphenyl-4-yl)-1,4-dioxaspiro[4.5]decane (s-26) (31.9 g). The yield based on the compound (s-25) was 42.0%.

Workup

  1. addition222 ml) was added dropwide
  2. additionwas added dropwise
  3. waitin the temperature range of −75° C. to −70° C., and the stirring was continued for another 8 hours while the mixture
  4. customto come to 25° C
  5. additionThe reaction mixture was poured into a vessel
  6. additionmixed with them
  7. customhad separated into organic and aqueous phases
  8. extractionthe extraction
  9. washThe combined organic phase was washed successively with water
  10. dry with materiala saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate
  11. distillationThen, the solvent was distilled off

Sources & evidence

ORD record
ord-b0faefac69704894807144f4b981a445
Source dataset
uspto-grants-2013_05
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08435422B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes