p-Toluenesulfonic acid → HCID 46841133, compound

HRID 1846317Notes

Reaction equation

HRID 1846317 reaction equation
[NH2:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[O:5].[Si]([O:30][CH2:31][CH2:32][O:33][C:34]1[C:41]([CH3:42])=[CH:40][C:37]([CH:38]=O)=[CH:36][C:35]=1[CH3:43])(C(C)(C)C)(C)C.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O.[Cl-].[Li+]>[OH:30][CH2:31][CH2:32][O:33][C:34]1[C:41]([CH3:42])=[CH:40][C:37]([C:38]2[N:6]([C:7]3[CH:8]=[CH:9][C:10]([N:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)=[CH:11][CH:12]=3)[C:4](=[O:5])[C:3]3[C:2](=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:1]=2)=[CH:36][C:35]=1[CH3:43]

Participants

7

Reactant 4

HCID 6101p-Toluenesulfonic acidHCID 16769039HCID 16769039, compoundHCID 23665763Sodium Bisulfite2×HCID 866219154-(2-(Tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylbenzaldehyde

Product 1

HCID 46841133HCID 46841133, compoundYield 8.2%

Reagents, catalysts & solvents 2

HCID 31374DimethylacetamideSolventHCID 433294Lithium ChlorideSolvent

Conditions

Temperature
120 °C

Procedure

To a stirred solution of 2-amino-N-(4-morpholinophenyl)benzamide (1.71 g, 5.75 mmol) in DMA (20 mL) was added 4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylbenzaldehyde (1.77 g, 5.75 mmol), NaHSO3 (0.66 g, 6.33 mmol), and p-TsOH (0.22 g, 1.15 mmol). The reaction mixture was heated at 120° C. overnight, then heated to 140° C., and additional sodium bisulfite (2.60 g, 25 mmol) was added. After an additional 17 hours, the reaction mixture was cooled and diluted with 5% lithium chloride solution (120 mL), extracted with ethyl acetate (200 mL), and then washed with water (2×100 mL) and then brine (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was triturated with 1:1 hexanes/methylene chloride. Purification by flash chromatography on silica gel, eluting with 30% ethyl acetate/hexanes to 70% ethyl acetate/hexanes, afforded the title compound as a white solid (0.223 g, 8%). 1H-NMR (500 MHz, DMSO-d6) δ 8.16 (dd, J=7.98, 1.3 Hz, 1H), 7.87 (td, J=8.4, 1.5 Hz, 1H), 7.72 (d, J=7.9 Hz, 1H), 7.57 (td, J=8.1, 1.1 Hz, 1H), 7.11 (d, J=8.9 Hz, 2H), 7.03 (s, 2H), 6.86 (d, J=9.0 Hz, 2H), 4.82 (br s, 1H), 3.68-3.72 (m, 6H), 3.63-3.67 (m, 2H), 3.08-3.09 (m, 4H), 2.10 (s, 6H).

Workup

  1. temperatureheated to 140° C.
  2. temperaturethe reaction mixture was cooled
  3. extractionextracted with ethyl acetate (200 mL)
  4. washwashed with water (2×100 mL)
  5. dry with materialThe organic layer was dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue was triturated with 1:1 hexanes/methylene chloride
  9. customPurification by flash chromatography on silica gel
  10. washeluting with 30% ethyl acetate/hexanes to 70% ethyl acetate/hexanes

Sources & evidence

ORD record
ord-d7fc248b4d9d4ff6b69446bf2b8f8cc1
Source dataset
uspto-grants-2015_02
Patent number
US08952021B2

Reaction notes

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