Vanillic Acid → (4-Hydroxy-3-methoxyphenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4'-piperidine]-1'-yl)methanone

HRID 2204243Notes

Reaction equation

HRID 2204243 reaction equation
[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].S(Cl)(Cl)=O.[CH:17]1[N:25]2[C:20]([C:21]3([CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[O:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=32)=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl.CN(C=O)C.O1CCOCC1>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:32]2[CH2:31][CH2:30][C:21]3([O:22][C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[N:25]4[CH:17]=[CH:18][CH:19]=[C:20]34)[CH2:34][CH2:33]2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]

Participants

8

Reactant 4

HCID 8468Vanillic AcidHCID 8471TriethylamineHCID 24386Thionyl ChlorideHCID 58550727Spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4'-piperidine]

Product 1

HCID 58551823(4-Hydroxy-3-methoxyphenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4'-piperidine]-1'-yl)methanoneYield 56%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Procedure

4-Hydroxy-3-methoxy-benzoic acid (304 mg, 1.81 mmol) was stirred with thionyl chloride (645 mg, 395 μL, 5.42 mmol) in dichloromethane and 2 drops of DMF were added. After stirring for 2.5 h, the excess thionyl chloride and dichloromethane were removed in vacuo. The residue was added to a mixture of spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] (500 mg, 1.81 mmol), 1,4-dioxane (6.5 mL), and triethylamine (760 μL, 5.42 mmol). The mixture was stirred for 18 h at 90° C. before it was cooled to room temperature and was evaporated to dryness. The residue was dissolved in ethyl acetate, filtered and washed with 1N HCl (2×), a saturated sodium bicarbonate solution (2×), and brine. The organic layer was dried over sodium sulfate and was evaporated to dryness. The residue was purified by column chromatography (0-100% EtOAc/hexane) to give (4-hydroxy-3-methoxyphenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone (394 mg, 56%). ESI-MS m/z calc. 390.2, found 391.2 (M+1)+; Retention time: 2.56 minutes (4 min run).

Workup

  1. additionwere added
  2. customthe excess thionyl chloride and dichloromethane were removed in vacuo
  3. stirringThe mixture was stirred for 18 h at 90° C. before it
  4. customwas evaporated to dryness
  5. dissolutionThe residue was dissolved in ethyl acetate
  6. filtrationfiltered
  7. washwashed with 1N HCl (2×)
  8. dry with materialThe organic layer was dried over sodium sulfate
  9. customwas evaporated to dryness
  10. customThe residue was purified by column chromatography (0-100% EtOAc/hexane)

Sources & evidence

ORD record
ord-0db16dc8bd60497ab7ad990b34bed13a
Source dataset
uspto-grants-2016_06
Patent number
US09365588B2

Reaction notes

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