Sodium Hydroxide → tert-Butyl 3-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenoxy)azetidine-1-carboxylate

HRID 1035195Notes

Reaction equation

HRID 1035195 reaction equation
[H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([OH:18])[CH:7]=[CH:8][C:9]=1[CH2:10][N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.CS(O[CH:24]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]1)(=O)=O.[OH-].[Na+]>CN(C=O)C.O>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[CH2:10][N:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]1)[O:18][CH:24]1[CH2:25][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27]1

Participants

7

Reactant 4

HCID 14798Sodium HydroxideHCID 24758Sodium hydrideHCID 10753243Tert-butyl 3-(methanesulfonyloxy)azetidine-1-carboxylateHCID 580431263-Fluoro-4-((4-methylpiperazin-1-yl)methyl)phenol

Product 1

HCID 58043154tert-Butyl 3-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenoxy)azetidine-1-carboxylateYield 45%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent3×

Conditions

Temperature
80 °C

Procedure

A mixture of NaH (55-65% disp. in oil, 0.50 g, 11.5 mmol) in dry DMF (10 mL) under nitrogen was cooled by an ice-bath. A solution of 29B (1.3 g, 5.8 mmol) in DMF (25 mL) was added drop-wise over 10 minutes. The mixture was stirred for 20 minutes and then tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (1.7 g, 6.9 mmol) in DMF (15 mL) was added. The mixture was heated to 80° C. for six days and then cooled to RT. Water and some aqueous NaOH was added and the mixture was extracted three times with EtOAc. The combined organic solutions were dried (MgSO4) and evaporated. The residue was purified by column chromatography on SiO2 using 5% triethylamine in EtOAc as eluent. There was obtained 0.98 g (45%) of 29C as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 1.45 (s, 9H), 2.28 (s, 3H), 2.28-2.72 (bm, 8H), 3.52 (s, 2H), 3.91-4.03 (m, 2H), 4.22-4.33 (m, 2H), 4.76-4.89 (m, 1H), 6.39-6.52 (m, 2H), 7.19-7.28 (m, 1H).

Workup

  1. temperaturewas cooled by an ice-bath
  2. temperaturecooled to RT
  3. extractionthe mixture was extracted three times with EtOAc
  4. dry with materialThe combined organic solutions were dried (MgSO4)
  5. customevaporated
  6. customThe residue was purified by column chromatography on SiO2 using 5% triethylamine in EtOAc as eluent

Sources & evidence

ORD record
ord-91703a78c315464fb867fc9ca5c2e816
Source dataset
uspto-grants-2013_10
Patent number
US08546375B2

Reaction notes

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