Acetic Anhydride → 1-(3-(1-(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)-1-hydroxyprop-2-yn-1-yl)azetidin-1-yl)ethanone

HRID 526857Notes

Reaction equation

HRID 526857 reaction equation
[NH:1]1[CH2:4][CH:3]([C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([O:19][CH3:20])[C:13]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[C:12]3[Cl:32])([OH:8])[C:6]#[CH:7])[CH2:2]1.CCN(CC)CC.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C(Cl)Cl>[Cl:32][C:12]1[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([C:5]([CH:3]3[CH2:4][N:1]([C:40](=[O:42])[CH3:41])[CH2:2]3)([OH:8])[C:6]#[CH:7])[CH:10]=2)[N:15]=[C:14]([O:19][CH3:20])[C:13]=1[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=1

Participants

5

Reactant 3

HCID 7918Acetic AnhydrideHCID 8471TriethylamineHCID 1180062791-(Azetidin-3-yl)-1-(4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)prop-2-yn-1-ol

Product 1

HCID 1180062291-(3-(1-(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)-1-hydroxyprop-2-yn-1-yl)azetidin-1-yl)ethanone

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
40 °C

Procedure

To a flask containing crude 1-(azetidin-3-yl)-1-(4-chloro-2-methoxy-3-(4-(trifluoromethyl)-benzyl)quinolin-6-yl)prop-2-yn-1-ol (130 mg, 0.28 mmol, Example 16) was added DCM (10 mL) followed by Et3N (0.2 mL, 1.44 mmol) and acetic anhydride (0.1 mL, 1.06 mmol) at room temperature. The mixture was heated to 40° C. for 2 hours and then quenched with a solution of saturated aqueous NaHCO3. The aqueous portion was extracted with DCM (3×35 mL) and the combined organics were dried over MgSO4, filtered and concentrated to dryness. Chromatography on silica gel using (5% MeOH-DCM) provided the title compound as an off white amorphous solid. 1H NMR (500 MHz, CD3OD) δ 8.44 (d, J=1.9 Hz, 1H), 7.94 (d, J=8.7 Hz, 1H), 7.91-7.82 (m, 1H), 7.55 (d, J=8.2 Hz, 2H), 7.42 (d, J=8.1 Hz, 2H), 4.40 (s, 2H), 4.36-4.18 (m, 1H), 4.16-4.01 (m, 4H containing a singlet at 4.07), 4.05-3.98 (m, 1H), 3.93-3.80 (m, 1H), 3.28 (s, 1H), 3.24-3.09 (m, 1H), 1.85 (d, J=3.3 Hz, 3H); MS (ESI): mass calcd. for C26H22ClF3N2O3, 502.1, m/z found 503.2 [M+H]+. 1-(3-(1-(4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)-1-hydroxyprop-2-yn-1-yl)azetidin-1-yl)ethanone was purified by chiral SFC: (Stationary phase: CHIRALPAK AD-H, 5 μm, 250×20 mm), Mobile phase: 70% CO2, 30% MeOH), to give 2 enantiomers. The first eluting enantiomer was Example 7b and the second eluting enantiomer was Example 7c.

Workup

  1. customquenched with a solution of saturated aqueous NaHCO3
  2. extractionThe aqueous portion was extracted with DCM (3×35 mL)
  3. dry with materialthe combined organics were dried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated to dryness

Sources & evidence

ORD record
ord-d2127649c04846e58bf0ac370175a664
Source dataset
uspto-grants-2016_05
Patent number
US09346782B2

Reaction notes

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