Hexamethyldisilazane → HCID 67188487, compound

HRID 546236Notes

Reaction equation

HRID 546236 reaction equation
C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[CH:15]1([S:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([N:28]([C@H:30]([CH3:39])[C@H:31]([OH:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH3:29])=[O:27])=[CH:21][CH:20]=2)[CH2:17][CH2:16]1.C(OC(=O)NC1C=CC=C(CN2C=CC(NC(=O)[C@@H](C3C=CC(S(C)(=O)=O)=C(Cl)C=3)[CH2:62][CH:63]3[CH2:67][CH2:66][CH2:65][CH2:64]3)=N2)C=1)(C)(C)C>O1CCCC1.C(OCC)(=O)C>[CH:63]1([CH2:62][C@H:25]([C:22]2[CH:21]=[CH:20][C:19]([S:18][CH:15]3[CH2:17][CH2:16]3)=[CH:24][CH:23]=2)[C:26]([N:28]([C@H:30]([CH3:39])[C@H:31]([OH:38])[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH3:29])=[O:27])[CH2:67][CH2:66][CH2:65][CH2:64]1

Participants

7

Reactant 4

HCID 13838HexamethyldisilazaneHCID 59347116HCID 59347116, compoundHCID 67190452HCID 67190452, compoundHCID 178418339Butyllithium

Product 1

HCID 67188487HCID 67188487, compoundYield 65%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-78 °C

Procedure

A round bottom flask with a stir bar and argon inlet was charged with tetrahydrofuran (10 mL) and cooled to −78° C. 1,1,1,3,3,3-hexamethyldisilazane (1.2 mL, 5.69 mmol) was then added followed by the dropwise addition of a solution of n-butyl lithium (2.5M solution in hexanes, 2.12 mL, 5.32 mmol) and it was stirred at −78° C. for 15 min. After this time, a solution of 2-(4-cyclopropylsulfanyl-phenyl)-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-acetamide (900 mg, 2.53 mmol) in tetrahydrofuran (6 mL) was added dropwise over 10 min keeping the reaction below −60° C. It was then stirred for 15 min, warmed to 0° C. and stirred for 20 min and then recooled to −78° C. It was then treated with a solution of iodomethylcyclopentane (prepared in PCT WO 2004/052869 A1 Example 1, 798 mg, 3.79 mmol) in 2,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (643 μL, 5.32 mmol) dropwise. The reaction was then stirred at −78° C. for 30 min and then warmed to 0° C. and stirred for 3 h. The reaction was then diluted with ethyl acetate (30 mL) and washed with a saturated aqueous ammonium chloride solution (3×10 mL). The aqueous layers were then combined and extracted with ethyl acetate (2×10 mL). The organics were then washed with a saturated aqueous brine solution (15 mL) and dried over sodium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (12 g column, 25% ethyl acetate/hexanes to 40% ethyl acetate/hexanes) afforded (R)-3-cyclopentyl-2-(4-cyclopropylsulfanyl-phenyl)-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-propionamide (719 mg, 65%) as a clear colorless oil: [α]25589=−52.6° (c=0.19, methanol); ES-HRMS m/e calcd for C27H35NO2S (M+H)+ 438.2462, observed 438.2461.

Workup

  1. customthe reaction below −60° C
  2. stirringIt was then stirred for 15 min
  3. temperaturewarmed to 0° C.
  4. stirringstirred for 20 min
  5. customrecooled to −78° C
  6. stirringThe reaction was then stirred at −78° C. for 30 min
  7. temperaturewarmed to 0° C.
  8. stirringstirred for 3 h
  9. washwashed with a saturated aqueous ammonium chloride solution (3×10 mL)
  10. extractionextracted with ethyl acetate (2×10 mL)
  11. washThe organics were then washed with a saturated aqueous brine solution (15 mL)
  12. dry with materialdried over sodium sulfate
  13. filtrationfiltered
  14. concentrationconcentrated in vacuo
  15. customPurification on an AnaLogix Intelliflash system (12 g column, 25% ethyl acetate/hexanes to 40% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-ac489a23281f4ecbab1af9df52384a8b
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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