Sodium hydride → HCID 118184965, compound

HRID 2178988Notes

Reaction equation

HRID 2178988 reaction equation
[N:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:28]=1[C:27]1[CH2:26][CH2:25][CH2:24][C:23]=1[S:22]2>CN(C)C=O>[C:28]12[C:21](=[CH:20][CH:19]=[CH:18][C:17]=1[O:13][CH:10]1[CH2:9][CH2:8][CH:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[CH2:12][CH2:11]1)[S:22][C:23]1[CH2:24][CH2:25][CH2:26][C:27]2=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 118184966HCID 118184966, compoundHCID 178521573HCID 178521573, compound

Product 1

HCID 118184965HCID 118184965, compoundYield 30.8%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
80 °C

Procedure

To a solution of trans-4-(morpholin-4-yl)cyclohexan-1-ol (213 mg, 1.15 mmol, 2.00 equiv) in distilled N,N-dimethylformamide (10 mL) was added sodium hydride (69 mg, 2.88 mmol, 3.00 equiv, 60% dispersion in mineral oil) at room temperature and the resulting solution was stirred for 0.5 h at 80° C. in an oil bath under nitrogen. Then a solution of 12-chloro-7-thiatricyclo[6.4.0.0^[2,6]]dodeca-1(12),2(6),8,10-tetraene (120 mg, 0.57 mmol, 1.00 equiv) in 3 mL of DMF was added via syringe and the resulting mixture was stirred at 80° C. for 3 hours. After cooling, the reaction was quenched with water and extracted with 5×50 mL of dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The crude product (100 mg) was purified by preparative HPLC under the following conditions (Waters): Column: Xbridge Prep C18, 5 μm, 19*50 m; water (with 0.05% NH4HCO3) and CH3CN (10% CH3CN up to 40% CH3CN in 10 min); flow rate: 20 mL/min; UV detection at 254 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired 4-(4-[7-thiatricyclo[6.4.0.0^[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yloxy]cyclohexyl)morpholine (62.7 mg) as a white solid. MS (ES): m/z 359 (M+H)+. 1H NMR (300 MHz, CDCl3): δ 1.51-1.72 (4H, m), 1.82-2.06 (2H, m), 2.22-2.30 (3H, m), 2.42-2.50 (2H, m), 2.68 (4H, m), 2.78-3.06 (4H, m), 3.51-3.96 (4H, m), 4.30-4.48 (1H, m), 6.63 (1H, d, J=5.4 Hz), 8.25 (1H, d, J=5.4 Hz).

Workup

  1. stirringthe resulting mixture was stirred at 80° C. for 3 hours
  2. temperatureAfter cooling
  3. customthe reaction was quenched with water
  4. extractionextracted with 5×50 mL of dichloromethane
  5. dry with materialThe combined organic layers were dried over sodium sulfate
  6. concentrationconcentrated under vacuum
  7. customThe crude product (100 mg) was purified by preparative HPLC under the following conditions (Waters)
  8. waitwater (with 0.05% NH4HCO3) and CH3CN (10% CH3CN up to 40% CH3CN in 10 min)
  9. customThe product-containing fractions were collected
  10. custompartially evaporated
  11. customto remove water and CH3CN under reduced pressure
  12. waitThe residue was lyophilized overnight

Sources & evidence

ORD record
ord-d64bf0c398fe4e528164b01e3b0e7b4d
Source dataset
uspto-grants-2015_06
Patent number
US09067948B2

Reaction notes

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