Methyl iodide → HCID 58169916, compound

HRID 384029Notes

Reaction equation

HRID 384029 reaction equation
[F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:47])[C:16]([N:18]2[CH2:38][CH2:37][C@:21]3([N:25](C(OC(C)(C)C)=O)[C@H:24]([C:33]([O:35][CH3:36])=[O:34])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=2[CH3:46])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Li+].[CH3:51][Si]([N-][Si](C)(C)C)(C)C.IC.C(O)(C(F)(F)F)=O>O1CCCC1>[F:10][C:9]([F:11])([F:12])[C:7]1[CH:6]=[C:5]([C@H:13]([N:15]([CH3:47])[C:16]([N:18]2[CH2:38][CH2:37][C@:21]3([NH:25][C@:24]([CH3:51])([C:33]([O:35][CH3:36])=[O:34])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=2[CH3:46])=[O:17])[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:49])[F:48])[CH:8]=1

Participants

6

Reactant 4

HCID 6328Methyl iodideHCID 6422Trifluoroacetic acidHCID 2733832Lithium HexamethyldisilazideHCID 58169901HCID 58169901, compound2×

Product 1

HCID 58169916HCID 58169916, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 1-(1,1-dimethylethyl) 2-methyl(2S,5S,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-1,8-diazaspiro[4.5]decane-1,2-dicarboxylate (Intermediate 43, 1 g, 1.421 mmol) in dry Tetrahydrofuran (THF) (16 ml) at −78° C. LiHMDS 1M in THF (2.132 ml, 2.132 mmol) was added and the reaction mixture was stirred for 10 mins at r.t. iodomethane (0.355 ml, 5.68 mmol) was then added and the reaction mixture was stirred for 30 mins at r.t. The reaction was quenched with brine (1 ml), diluted with water (10 ml) and extracted with ethyl acetate (3×30 ml). Combined organic layers were dried (Na2SO4), filtered and evaporated in vacuo. The residue was dissolved in Dichloromethane (15 ml) and the stirring solution was cooled at 0° C. TFA (5 ml, 64.9 mmol) was added and the reaction mixture was stirred at 0° C. for 1.30 h. The solvent and the excess of TFA were evaporated in vacuo. The residue was dissolved in 20 ml of ethyl acetate and washed with NaHCO3 sat. sol. (5 ml). The organic layer was dried, filtered and evaporated and the residue was purified by flash chromatography on silica gel using a Biotage SNAP 50 g as column and Cyclohexane to Cyclohexane/Ethyl acetate 1:1 as eluent affording the title compounds:

Workup

  1. customat −78° C
  2. additionwas then added
  3. customThe reaction was quenched with brine (1 ml)
  4. additiondiluted with water (10 ml)
  5. extractionextracted with ethyl acetate (3×30 ml)
  6. dry with materialCombined organic layers were dried (Na2SO4)
  7. filtrationfiltered
  8. customevaporated in vacuo
  9. dissolutionThe residue was dissolved in Dichloromethane (15 ml)
  10. temperaturethe stirring solution was cooled at 0° C
  11. stirringthe reaction mixture was stirred at 0° C. for 1.30 h
  12. customThe solvent and the excess of TFA were evaporated in vacuo
  13. dissolutionThe residue was dissolved in 20 ml of ethyl acetate
  14. washwashed with NaHCO3 sat. sol. (5 ml)
  15. customThe organic layer was dried
  16. filtrationfiltered
  17. customevaporated
  18. customthe residue was purified by flash chromatography on silica gel using a Biotage SNAP 50 g as column and Cyclohexane to Cyclohexane/Ethyl acetate 1:1 as eluent

Sources & evidence

ORD record
ord-436e78ccd6a04d49ac3a48b1b57e817c
Source dataset
uspto-grants-2013_02
Patent number
US08367692B2

Reaction notes

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