Water → 4-(difluoromethoxy)-6'-(3-fluoropropoxy)-5''-methyl-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazole]-4''(3''H)-thione

HRID 1467928Notes

Reaction equation

HRID 1467928 reaction equation
[F:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:26]=[C:25]2[C:9]([CH2:10][C:11]3([C:18]42[NH:22][C:21](=[S:23])[C:20]([CH3:24])=[N:19]4)[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]3)=[CH:8][CH:7]=1.FS([C:31]([F:36])([F:35])C(O)=O)(=O)=O.O.CCOC(C)=O>C(#N)C>[F:35][CH:31]([F:36])[O:17][CH:14]1[CH2:15][CH2:16][C:11]2([C:18]3([NH:22][C:21](=[S:23])[C:20]([CH3:24])=[N:19]3)[C:25]3[C:9](=[CH:8][CH:7]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][F:1])[CH:26]=3)[CH2:10]2)[CH2:12][CH2:13]1

Participants

6

Reactant 4

HCID 962WaterHCID 8857Ethyl AcetateHCID 27375162,2-Difluoro-2-(fluorosulfonyl)acetic acid2×HCID 867066866'-(3-Fluoropropoxy)-4-hydroxy-5''-methyl-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazole]-4''(3''H)-thione2×

Product 1

HCID 867066854-(difluoromethoxy)-6'-(3-fluoropropoxy)-5''-methyl-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazole]-4''(3''H)-thioneYield 103.5%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
60 °C

Procedure

6′-(3-Fluoropropoxy)-4-hydroxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione (Intermediate 33, 290 mg, 0.77 mmol) was suspended in dry acetonitrile (10 mL). Cuprous iodide (14.67 mg, 0.08 mmol) was added and the resulting mixture was heated at 60° C. for 5 min under an atmosphere of argon. 2-(Fluorosulphonyl)difluoroacetic acid (0.127 mL, 1.16 mmol) was added in a stream and the reaction mixture was heated for 20 min. Additional 2-(Fluorosulphonyl)difluoroacetic acid (0.042 mL, 0.39 mmol) was added, and the mixture was heated for an additional 45 min. The mixture was cooled to r.t. Water and EtOAc were added, and the phases were separated and the aqueous phase was re-extracted with EtOAc twice. The combined organic phases were dried using a phase separator and concentrated to give 340 mg of 4-(difluoromethoxy)-6′-(3-fluoropropoxy)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione, which was suspended in ammonia (7 M in methanol, 4 mL, 28 mmol), and heated in the MW at 100° C. for 60 min. The mixture was concentrated, re-dissolved in ammonia (7 M in methanol, 4 mL, 28 mmol) and heated at 100° C. for 60 min. This procedure was repeated eight times in total. The mixture was cooled to r.t., concentrated, and purified by flash column chromatography using a gradient of 0-50% EtOAc in heptane, followed by 0-20% MeOH (containing 1% NH3) in EtOAc, to give 82 mg (25% yield) of the title compound. MS (MM-ES+APCI)+m/z 410.2 [M+H]+.

Workup

  1. temperaturethe reaction mixture was heated for 20 min
  2. temperaturethe mixture was heated for an additional 45 min
  3. temperatureThe mixture was cooled to r.t
  4. customthe phases were separated
  5. extractionthe aqueous phase was re-extracted with EtOAc twice
  6. customThe combined organic phases were dried
  7. concentrationconcentrated

Sources & evidence

ORD record
ord-aaab3860be8d439ea2201dc1765f510a
Source dataset
uspto-grants-2015_04
Patent number
US09000182B2

Reaction notes

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