Methyl iodide → (3-Methoxy-4-(2-methoxypropan-2-yl)phenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4'-piperidine]-1'-yl)methanone

HRID 1908152Notes

Reaction equation

HRID 1908152 reaction equation
[OH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:13]2[CH2:18][CH2:17][C:16]3([O:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[N:20]4[CH:28]=[CH:29][CH:30]=[C:19]34)[CH2:15][CH2:14]2)=[O:12])=[CH:7][C:6]=1[O:31][CH3:32])([CH3:4])[CH3:3].[H-].[Na+].[CH3:35]I>C1COCC1.CN(C=O)C>[CH3:32][O:31][C:6]1[CH:7]=[C:8]([C:11]([N:13]2[CH2:14][CH2:15][C:16]3([O:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[N:20]4[CH:28]=[CH:29][CH:30]=[C:19]34)[CH2:17][CH2:18]2)=[O:12])[CH:9]=[CH:10][C:5]=1[C:2]([O:1][CH3:35])([CH3:3])[CH3:4]

Participants

6

Reactant 3

HCID 6328Methyl iodideHCID 24758Sodium hydrideHCID 58551616HCID 58551616, compound2×

Product 1

HCID 54670839(3-Methoxy-4-(2-methoxypropan-2-yl)phenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4'-piperidine]-1'-yl)methanoneYield 35%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

(4-(2-Hydroxypropan-2-yl)-3-methoxyphenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone (crude material from step 1) was dissolved in a mixture of THF (3 mL) and DMF (3 mL). NaH (28 mg, 0.69 mmol) was added and the reaction mixture was allowed to stir for 2 minutes. MeI (54 μL, 0.86 mmol) was then added and the reaction mixture was allowed to stir for 1 h. The reaction mixture was evaporated to dryness and the residue was suspended in 25 mL of dichloromethane. The suspension was washed two times with a 1M solution of hydrochloric acid, followed by two washes with a saturated aqueous solution of sodium bicarbonate, followed by two washes of a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to yield the crude product. The crude material was purified by column chromatography utilizing a gradient of 0-35% ethyl acetate in hexanes give (3-methoxy-4-(2-methoxypropan-2-yl)phenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone (94 mg, 35% over 2 steps). ESI-MS m/z calc. 446.2. found 447.5 (M+1)+; Retention time: 7.60 minutes (15 min run). 1H NMR (400 MHz, DMSO) δ 7.68-7.65 (m, 1H), 7.50-7.49 (m, 1H), 7.40 (d, J=7.9 Hz, 1H), 7.17-6.98 (m, 5H), 6.29-6.28 (m, 1H), 6.18-6.17 (m, 1H), 4.49-4.34 (m, 1H), 3.83 (s, 3H), 3.80-3.41 (m, 3H), 3.13 (s, 3H), 2.11-1.81 (m, 4H) and 1.50 (s, 6H).

Workup

  1. stirringto stir for 1 h
  2. customThe reaction mixture was evaporated to dryness
  3. washThe suspension was washed two times with a 1M solution of hydrochloric acid
  4. dry with materialThe organic layer was dried over sodium sulfate
  5. filtrationfiltered
  6. customevaporated to dryness
  7. customto yield the crude product
  8. customThe crude material was purified by column chromatography

Sources & evidence

ORD record
ord-3549604229f64412a350b0de37f06fc6
Source dataset
uspto-grants-2013_12
Patent number
US08598164B2

Reaction notes

Loading…