Lithium Hexamethyldisilazide → HCID 67437844, compound

HRID 335958Notes

Reaction equation

HRID 335958 reaction equation
Cl[C:2]1[N:7]=[CH:6][C:5]2[O:8][C:9]3[C:14]([C@@:15]4([CH2:19][S:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:16]4)[C:4]=2[CH:3]=1)=[CH:13][C:12]([C:28]1[C:29]([F:34])=[N:30][CH:31]=[CH:32][CH:33]=1)=[CH:11][CH:10]=3.Cl.[F:36][C:37]1([F:42])[CH2:41][CH2:40][NH:39][CH2:38]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O.CCOC(C)=O>[F:36][C:37]1([F:42])[CH2:41][CH2:40][N:39]([C:2]2[N:7]=[CH:6][C:5]3[O:8][C:9]4[C:14]([C@@:15]5([CH2:19][S:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[N:16]5)[C:4]=3[CH:3]=2)=[CH:13][C:12]([C:28]2[C:29]([F:34])=[N:30][CH:31]=[CH:32][CH:33]=2)=[CH:11][CH:10]=4)[CH2:38]1

Participants

6

Reactant 3

HCID 2733832Lithium Hexamethyldisilazide4×HCID 249034823,3-Difluoropyrrolidine hydrochloride4×HCID 86658498HCID 86658498, compound

Product 1

HCID 67437844HCID 67437844, compoundYield 23%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Procedure

A vial was charged with (S)-tert-butyl (3-chloro-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-thiazol]-2′-yl)carbamate (290 mg, 0.58 mmol), RuPhos-precatalyst (42.4 mg, 0.058 mmol) and 3,3-difluoropyrrolidine hydrochloride (167 mg, 1.16 mmol). The vial was sealed before evacuating and backfilling with nitrogen. The solids were suspended in 1,4-dioxane (2 mL) before adding lithium bis(trimethylsilyl)amide solution (1.0M in THF; 2.33 mL, 2.33 mmol) at ambient temperature. The reaction was stirred at ambient temperature for 20 h. Additional amounts of 3,3-difluoropyrolidine HCl (167 mg, 1.16 mmol), lithium bis(trimethylsilyl)amide solution (1.0M in THF; 1.16 mL, 1.162 mmol), and RuPhos-precatalyst (42.4 mg, 0.058 mmol) were added. After 23 h total reaction time, additional amounts of 3,3-difluoropyrrolidine hydrochloride (167 mg, 1.16 mmol), lithium bis(trimethylsilyl)amide solution (1.0M in THF; 1.16 mL, 1.16 mmol), and RuPhos-precatalyst (42.4 mg, 0.058 mmol) were added. After 29 h total reaction time, additional amounts of 3,3-difluoropyrrolidine hydrochloride (167 mg, 1.16 mmol), lithium bis(trimethylsilyl)amide solution (1.0M in THF; 1.16 mL, 1.16 mmol), and RuPhos-precatalyst (42.4 mg, 0.058 mmol) were added. After 45 h total reaction time, the reaction was diluted with water and EtOAc. The organic layer was separated, washed with brine, and dried over sodium sulfate. The solvent was removed under reduced pressure and the crude was purified by silica gel chromatography to afford (S)-tert-butyl (3-(3,3-difluoropyrolidin-1-yl)-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-thiazol]-2′-yl)carbamate (76.1 mg, 0.13 mmol, 23.0% yield).

Workup

  1. customThe vial was sealed
  2. custombefore evacuating
  3. waitAfter 45 h total reaction time
  4. customThe organic layer was separated
  5. washwashed with brine
  6. dry with materialdried over sodium sulfate
  7. customThe solvent was removed under reduced pressure
  8. customthe crude was purified by silica gel chromatography

Sources & evidence

ORD record
ord-d6bf603441bf47a0886af478df7bf0d8
Source dataset
uspto-grants-2014_11
Patent number
US08883782B2

Reaction notes

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