Diisopropylethylamine → 1-(3-(4-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydrofuran-3-yl)phenyl)-3-fluoroazetidin-1-yl)-2-(methylsulfonyl)ethanone

HRID 2277736Notes

Reaction equation

HRID 2277736 reaction equation
Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2([C:26]([F:29])([F:28])[F:27])[O:14][CH:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4([F:25])[CH2:24][NH:23][CH2:22]4)=[CH:17][CH:16]=3)[CH2:11]2)[CH:6]=[C:7]([Cl:9])[CH:8]=1.CCN(C(C)C)C(C)C.[CH3:39][S:40]([CH2:43][C:44](O)=[O:45])(=[O:42])=[O:41].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2([C:26]([F:27])([F:29])[F:28])[O:14][CH:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4([F:25])[CH2:22][N:23]([C:44](=[O:45])[CH2:43][S:40]([CH3:39])(=[O:42])=[O:41])[CH2:24]4)=[CH:17][CH:16]=3)[CH2:11]2)[CH:6]=[C:7]([Cl:9])[CH:8]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 111923Propylphosphonic anhydrideHCID 37328412-Methanesulfonylacetic acidHCID 897253993-(4-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydrofuran-3-yl)phenyl)-3-fluoroazetidine hydrochloride2×

Product 1

HCID 716578281-(3-(4-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydrofuran-3-yl)phenyl)-3-fluoroazetidin-1-yl)-2-(methylsulfonyl)ethanoneYield 54.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a stirred solution of 3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydrofuran-3-yl)phenyl)-3-fluoroazetidine hydrochloride (Example 1, Intermediate 3) (0.25 g, 0.535 mmol) in THF (5 mL) was added DIPEA (0.933 mL, 5.35 mmol) at room temperature and stirred for 10 minutes at room temperature. Methane sulfonyl acetic acid (0.147 g, 1.07 mmol), T3P (50% solution in ethyl acetate, 1.6 mL, 2.675 mmol) were added at room temperature. Resulting reaction mixture was stirred for 16 hours at room temperature under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (5×25 mL). Combined organic layer was washed with saturated solution of NaHCO3 (2×100 mL), dried over sodium sulphate and concentrated in vacuo to get pale yellow oil (0.32 g, crude). Crude was purified by column chromatography using 100-200 mesh silica gel. Desired product gets eluted in 0.6% MeOH in DCM to afford white semisolid (0.160 g), which was triturated with DCM: n-pentane (1:10; 2×5 mL) to afford product as off white solid. Yield: 0.145 g (49.15%). 1H NMR (400 MHz, DMSO-d6) δ: 3.11 (s, 3H), 3.20 (d, J=17.16 Hz, 1H), 3.65 (d, J=17.12 Hz, 1H), 4.24 (s, 2H), 4.34 (d, J=21.6 Hz, 2H), 4.70 (d, J=21.52 Hz, 2H), 7.27 (d, J=7.96 Hz, 2H), 7.47 (d, J=9.36 Hz, 2H), 7.73 (d, J=3.92 Hz, 3H). LC-MS (m/z): =550.1 (M−H). HPLC purity: 98.75%.

Workup

  1. customResulting
  2. customreaction mixture
  3. stirringwas stirred for 16 hours at room temperature under nitrogen atmosphere
  4. customAfter complete consumption of starting material, reaction mixture
  5. customwas quenched with water (20 mL)
  6. extractionextracted with ethyl acetate (5×25 mL)
  7. washCombined organic layer was washed with saturated solution of NaHCO3 (2×100 mL)
  8. dry with materialdried over sodium sulphate
  9. concentrationconcentrated in vacuo
  10. customto get pale yellow oil (0.32 g, crude)
  11. customCrude was purified by column chromatography
  12. washDesired product gets eluted in 0.6% MeOH in DCM

Sources & evidence

ORD record
ord-36578e422aed44e39b5e371a6bbbf59d
Source dataset
uspto-grants-2015_09
Patent number
US09133172B2

Reaction notes

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