Methanol → 2-[2-Fluoro-4-(4-methanesulfonyloxy-cyclohexyl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester

HRID 1027416Notes

Reaction equation

HRID 1027416 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:32][CH2:31][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]4)=[CH:19][C:18]=3[F:30])[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:40][S:41](Cl)(=[O:43])=[O:42].CO>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:28][CH2:27][CH:26]([O:29][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:25][CH2:24]4)=[CH:19][C:18]=3[F:30])[CH2:13][CH2:12]2)[CH2:31][CH2:32]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

6

Reactant 4

HCID 887MethanolHCID 8471TriethylamineHCID 31297Methanesulfonyl chlorideHCID 674790852-[2-Fluoro-4-(4-hydroxy-cyclohexyl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester

Product 1

HCID 866780962-[2-Fluoro-4-(4-methanesulfonyloxy-cyclohexyl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl esterYield 64.6%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Procedure

To a solution of 2-[2-fluoro-4-(4-hydroxy-cyclohexyl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (530 mg, 1.18 mmol) in DCM (8 mL) was added Et3N (179 mg, 0.3 mL, 1.77 mmol, 1.5 equiv.). The solution was cooled to an ice-water bath and then de-aerated by vacuum/nitrogen exchange. To this solution was transferred a solution of methanesulfonyl chloride (202 mg, 1.77 mmol, 1.5 equiv.) in DCM (2 mL). The clear solution was stirred with the ice-water bath on all the time for 1 h. TLC (5% MeOH in DCM indicated that the reaction was complete. The reaction was quenched by diluting with DCM (10 mL), followed by addition of NaHCO3 aq. (5 mL). The two layers were separated and the aqueous layer was extracted with DCM (2×5 mL). The combined extracts were washed with NaHCO3 aq. (5 mL), brine (5 mL) and dried (K2CO3). The solution was filtered through a silica gel pad, eluted with 5% MeOH in DCM. The filtrate was concentrated to dryness and purified again on a silica gel column, eluted with 5% MeOH in DCM to eliminate the minor component to afford 0.4 g (64% yield) of the title compound as an off-white wax-like solid material.

Workup

  1. temperatureThe solution was cooled to an ice-water bath
  2. customThe reaction was quenched
  3. additionby diluting with DCM (10 mL)
  4. additionfollowed by addition of NaHCO3 aq. (5 mL)
  5. customThe two layers were separated
  6. extractionthe aqueous layer was extracted with DCM (2×5 mL)
  7. washThe combined extracts were washed with NaHCO3 aq. (5 mL), brine (5 mL)
  8. dry with materialdried (K2CO3)
  9. filtrationThe solution was filtered through a silica gel pad
  10. washeluted with 5% MeOH in DCM
  11. concentrationThe filtrate was concentrated to dryness
  12. custompurified again on a silica gel column
  13. washeluted with 5% MeOH in DCM

Sources & evidence

ORD record
ord-9d27d08ab58e41c487b27a38b0812f81
Source dataset
uspto-grants-2014_05
Patent number
US08735385B2

Reaction notes

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