Sulfoxonium, trimethyl-, iodide (1:1) → HCID 67113774, compound

HRID 1507680Notes

Reaction equation

HRID 1507680 reaction equation
[I-].C[S+](C)(C)=O.[CH3:7]C(C)([O-])C.[K+].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C@@:20]2([OH:44])[CH2:25][CH2:24][N:23]([C:26](=[O:41])[C@H:27]([NH:31][C:32]([CH:34]3[CH2:40][CH2:39][C:36]4([O:38][CH2:37]4)[CH2:35]3)=[O:33])[CH:28]([CH3:30])[CH3:29])[CH2:22][C:21]2([CH3:43])[CH3:42])=[CH:16][CH:15]=1>C(O)(C)(C)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C@@:20]2([OH:44])[CH2:25][CH2:24][N:23]([C:26](=[O:41])[C@H:27]([NH:31][C:32]([CH:34]3[CH2:40][CH2:39][C:36]4([O:38][CH2:7][CH2:37]4)[CH2:35]3)=[O:33])[CH:28]([CH3:30])[CH3:29])[CH2:22][C:21]2([CH3:42])[CH3:43])=[CH:16][CH:15]=1

Participants

5

Reactant 3

HCID 74498Sulfoxonium, trimethyl-, iodide (1:1)HCID 23665647Potassium tert-butoxideHCID 86668867HCID 86668867, compound

Product 1

HCID 67113774HCID 67113774, compound

Reagents, catalysts & solvents 1

HCID 6386tert-ButanolSolvent

Conditions

Temperature
50 °C

Procedure

A suspension of trimethylsulfoxonium iodide (67.8 mg, 0.308 mmol) in tert-butanol (2 mL) was treated with potassium tert-butoxide (34.6 mg, 0.308 mmol). The mixture was heated at 50° C. for 1 hour, then treated with N-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)-1-oxaspiro[2.4]heptane-5-carboxamide (46 mg, 0.099 mmol), and the reaction was stirred at 50° C. for 2 days. The reaction was quenched with saturated ammonium chloride (1 mL), and the mixture was poured into ethyl acetate (15 mL). The layers were separated, and the organic phase was washed 3× with water and once with brine, then dried over sodium sulfate and concentrated in vacuo. The crude material was purified via preparative LC/MS with the following conditions: Column. Waters SunFire C18, 19×150 mm, 5-μm particles; Guard Column. None; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the desired product as a diastereomeric mixture was 15.4 mg, and its purity was 96%. Two analytical LC/MS injections were used to determine the final purity. Injection 1 conditions: Column: Supelco Ascentis Express C18, 4.6×50 mm, 2.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 45° C.; Gradient: 0-100% B over 5.3 minutes, then a 1.7-minute hold at 100% B; Flow: 3 mL/min. Retention time=2.91. Injection 2 conditions: Column: Waters XBridge C18, 4.6×50 mm, 2.5-1 μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% ammonium hydroxide; Mobile Phase B: 95:5 acetonitrile:water with 0.1% ammonium hydroxide; Temperature: 45° C.; Gradient: 0-100% B over 7 minutes, then a 1-minute hold at 100% B; Flow: 3 mL/min. Retention time=3.79 minutes. Proton NMR was acquired in deuterated methanol. MS (ESI+)=476.9 (M+H)+. 1H NMR (400 MHz, CD3OD) (NMR shows several rotomers) δ ppm 7.53-7.42 (m, 2 H), 7.36-7.26 (m, 2 H), 4.83-4.76 (m, 1 H), 4.58-4.42 (m, 2 H), 4.13-3.98 (m, 1 H), 3.66-3.58 (bd, 1 H, J=13.3 Hz), 3.58-3.46 (m, 1 H), 3.22-3.06 (m, 1 H), 2.95-2.86 (m, 0.4H), 2.83-2.56 (m, 3.2 H), 2.38-1.69 (m, 7 H), 1.59 (d, 0.5 H, J=14.3 Hz), 1.51 (d, 0.5 H, J=14.6 Hz), 1.47-1.42 (m, 0.2 H), 1.04 (d, 1.5 H, J=6.5 Hz), 0.98 (t, 1.5 H, J=6.2 Hz), 0.92 (d, 3 H, J=5.3 Hz), 0.81 (d, 3 H, J=4.8 Hz), 0.75 (br. s, 3 H.).

Workup

  1. customThe reaction was quenched with saturated ammonium chloride (1 mL)
  2. additionthe mixture was poured into ethyl acetate (15 mL)
  3. customThe layers were separated
  4. washthe organic phase was washed 3× with water
  5. dry with materialonce with brine, then dried over sodium sulfate
  6. concentrationconcentrated in vacuo
  7. customThe crude material was purified via preparative LC/MS with the following conditions
  8. waitGradient: 15-100% B over 15 minutes
  9. customa 5-minute hold
  10. additionFractions containing the desired product
  11. customdried via centrifugal evaporation
  12. custom45° C.
  13. waitGradient: 0-100% B over 5.3 minutes
  14. customa 1.7-minute hold
  15. custom45° C.
  16. waitGradient: 0-100% B over 7 minutes
  17. customa 1-minute hold

Sources & evidence

ORD record
ord-6d5ec31ae8134407a4b0ef13f3cca8d7
Source dataset
uspto-grants-2015_12
Patent number
US09221819B2

Reaction notes

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