Sodium Hydroxide → tert-Butyl 3-(2-methyl-4-((4-methylpiperazin-1-yl)methyl)phenoxy)azetidine-1-carboxylate

HRID 1035174Notes

Reaction equation

HRID 1035174 reaction equation
[H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:7]=[CH:6][C:5]=1[OH:18].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>[CH3:3][C:4]1[CH:9]=[C:8]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:7]=[CH:6][C:5]=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 580431092-Methyl-4-((4-methylpiperazin-1-yl)methyl)phenol

Product 1

HCID 58043145tert-Butyl 3-(2-methyl-4-((4-methylpiperazin-1-yl)methyl)phenoxy)azetidine-1-carboxylateYield 64%

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-water bath. A solution of 9A (2.0 g, 9.1 mmol) in DMF (15 mL) was added drop-wise over 15 minutes. The mixture was stirred for 15 minutes and then tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (3.0 g, 11.8 mmol) in DMF (15 mL) was added. The mixture was heated to 80° C. over night and then cooled to RT. Water and some aqueous NaOH were added and the mixture was extracted three times with DCM. 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 2.18 g (64%) of 9B as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 1.45 (s, 9H), 2.22 (s, 3H), 2.28 (s, 3H), 2.30-2.63 (bm, 8H), 3.40 (s, 2H), 3.96-4.04 (m, 2H), 4.24-4.34 (m, 2H), 4.79-4.89 (m, 1H), 6.37 (d, 1H), 7.03 (d, 1H), 7.11 (s, 1H).

Workup

  1. temperaturewas cooled by an ice-water bath
  2. temperaturecooled to RT
  3. extractionthe mixture was extracted three times with DCM
  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-3e7ef3a1c1f34714b78ca08f77183d3a
Source dataset
uspto-grants-2013_10
Patent number
US08546375B2

Reaction notes

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