Isobutyric Acid → HCID 73505389, compound

HRID 1508300Notes

Reaction equation

HRID 1508300 reaction equation
Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:11]2([C:28]([F:31])([F:30])[F:29])[CH2:15][C:14]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C:21]3([CH2:27][NH:26][CH2:25]3)[O:20][CH2:19]4)=[N:13][CH2:12]2)[CH:6]=[C:7]([Cl:10])[C:8]=1[F:9].CCN(C(C)C)C(C)C.[C:41](O)(=[O:45])[CH:42]([CH3:44])[CH3:43].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[Cl:10][C:7]1[CH:6]=[C:5]([C:11]2([C:28]([F:30])([F:29])[F:31])[CH2:15][C:14]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C:21]3([CH2:25][N:26]([C:41](=[O:45])[CH:42]([CH3:44])[CH3:43])[CH2:27]3)[O:20][CH2:19]4)=[N:13][CH2:12]2)[CH:4]=[C:3]([Cl:2])[C:8]=1[F:9]

Participants

6

Reactant 4

HCID 6590Isobutyric AcidHCID 81531DiisopropylethylamineHCID 111923Propylphosphonic anhydrideHCID 90000850HCID 90000850, compound

Product 1

HCID 73505389HCID 73505389, compoundYield 42.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a stirred solution of 5′-(3-(3,5-dichloro-4-fluorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]hydrochloride (Preparation 9, 1 g, 2.02mmol) in THF (20 mL) was added DIPEA (3.53 mL, 20.24 mmol), isobutyric acid (0.368 g, 4.05 mmol) and T3P (2.94 mL, 10.12 mmol, 5 eq) at room temperature. Resulting reaction mixture was stirred at room temperature for 16 hours. After complete conversion of starting material, reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3×30 mL). Combined organic layer was washed with sodium bicarbonate solution (35 mL), brine (35 mL), dried over sodium sulfate and concentrated to get brown semi solid (1.1 g, crude). Crude compound was purified by column chromatography using 100-200 mesh silica gel. Desired compound was eluted in 0.5% methanol in dichloromethane to get pale green solid (0.45 g). 1H NMR (400 MHz, DMSO-d6) δ: 1.01-1.05 (m, 6H), 2.54-2.57 (m, 1H), 3.74 (d, J=18.12 Hz, 1H), 3.86 (d, J=18.08 Hz, 1H), 4.12 (s, 2H), 4.41-4.45 (m, 3H), 4.81 (d, J=17.36 Hz, 1H), 5.12 (s, 2H), 7.66 (d, J=7.96 Hz, 1H), 7.76 (d, J=6.24 Hz, 2H), 7.85 (s, 1H), 7.93 (d, J=7.88 Hz, 1H), LC-MS (m/z): 529.1 (M+H),

Workup

  1. customResulting
  2. customreaction mixture
  3. customAfter complete conversion of starting material, reaction mixture
  4. customwas quenched with water (30 mL)
  5. extractionextracted with ethyl acetate (3×30 mL)
  6. washCombined organic layer was washed with sodium bicarbonate solution (35 mL), brine (35 mL)
  7. dry with materialdried over sodium sulfate
  8. concentrationconcentrated
  9. customto get brown semi solid (1.1 g, crude)
  10. customCrude compound was purified by column chromatography
  11. washDesired compound was eluted in 0.5% methanol in dichloromethane

Sources & evidence

ORD record
ord-9184fa9d42084f3eb65355b342a93854
Source dataset
uspto-grants-2015_12
Patent number
US09221835B2

Reaction notes

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