Morpholine → HCID 68981699, compound

HRID 2105305Notes

Reaction equation

HRID 2105305 reaction equation
[CH3:1][O:2][C:3]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>O=S(Cl)Cl.C1COCC1.Cl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:7]

Participants

7

Reactant 3

HCID 8083MorpholineHCID 757764-Nitro-o-anisic acidHCID 81531Diisopropylethylamine

Product 1

HCID 68981699HCID 68981699, compound

Reagents, catalysts & solvents 3

HCID 313Hydrochloric AcidSolventHCID 8028TetrahydrofuranSolventHCID 24386Thionyl ChlorideSolvent

Procedure

2-methoxy-4-nitro-benzoic acid Compound 127a (11.0 g, 55.8 mmol) was refluxed in SOCl2 (50 mL) for 1 hr, then cooled to ambient temperature and evaporated down. The oil was resuspended in DCM and evaporated down a second time. The residue was then taken up in THF (150 mL) and cooled to 0° C. A mixture of morpholine Compound 50b (4.85 mL, 55.8 mmol) and DIEA (29.2 mL, 167 mmol) in THF (50 mL) was added dropwise. The reaction was stirred for 2 hrs before diluting with 1N HCl and extracting with ethyl acetate. The combined organic layer was separated and dried (MgSO4), then filtered and concentrated to give (2-methoxy-4-nitro-phenyl)-morpholin-4-yl-methanone Compound 127b (13.1 g). MS 267 (MH+). Borane dimethylsulfide (9.3 mL, 97.7 mmol) was combined with Compound 127b (13 g, 48.9 mmol) in THF (260 mL) and refluxed for 2 hrs. The reaction was chilled in ice and MeOH (25 mL) was carefully added. The mixture was subsequently diluted with 1N HCl, then stirred for 1 hr before adjusting the pH to 10 with 1N NaOH and extracted with ethyl acetate. The organic extracts were dried over Na2SO4 and evaporated down to give 4-(2-methoxy-4-nitro-benzyl)-morpholine Compound 127c (10 g). MS 253 (MH+). Using the procedure of Example 80, Compound 127c was used in place of 5-(2-chloro-4-nitro-phenoxy)-2-methyl-pyridine Compound 80c to give 3-methoxy-4-morpholin-4-ylmethyl-phenylamine Compound 127d. 1H NMR (400 MHz, CDCl3) δ 6.83 (1H, J=8.3 Hz, d), 6.19 (1H, J=2.0 Hz, d), 6.10 (1H, J=8.3 Hz, 2.0 Hz, dd), 3.66 (3H, s), 3.53 (4H, m), 3.28 (2H, s), 2.30 (4H, m). MS 223 (MH+). Using the procedure of Example 1, Compound 168 was used in place of Compound 1 and Compound 127d was used in place of 4-piperidin-1-ylmethyl-phenylamine Compound 1k to give Compound 176 as a HCl salt. 1H NMR (400 MHz, CDCl3) δ 10.65 (1H, br s), 10.24 (1H, s), 8.69 (1H, s), 7.62-7.39 (8H, m), 7.22 (1H, t), 7.13 (4H, d), 4.25 (2H, br s), 3.99-3.72 (7H, m), 3.32-3.21 (2H, m), 3.16-3.00 (2H, m). MS 609 (MH+).

Workup

  1. customevaporated down
  2. customevaporated down a second time
  3. temperaturecooled to 0° C
  4. additionwas added dropwise
  5. extractionextracting with ethyl acetate
  6. customThe combined organic layer was separated
  7. dry with materialdried (MgSO4)
  8. filtrationfiltered
  9. concentrationconcentrated

Sources & evidence

ORD record
ord-5b91efba284743f5860f8a4540f60152
Source dataset
uspto-grants-2009_08
Patent number
US07579356B2

Reaction notes

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