4-Methylmorpholine → (4-Hydroxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone

HRID 1405420Notes

Reaction equation

HRID 1405420 reaction equation
CN1CCOCC1.Cl.Cl.[CH3:10][N:11]1[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:15]2=[CH:16][CH:17]=[C:18]([C:19]([F:22])([F:21])[F:20])[N:14]2[CH2:13][CH2:12]1.[OH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][C:31]=1[O:39][CH3:40].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[OH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([N:26]2[CH2:27][CH2:28][C:23]3([N:11]([CH3:10])[CH2:12][CH2:13][N:14]4[C:18]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:16]=[C:15]34)[CH2:24][CH2:25]2)=[O:35])=[CH:32][C:31]=1[O:39][CH3:40]

Participants

7

Reactant 5

HCID 79724-MethylmorpholineHCID 8468Vanillic AcidHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 68153356HCID 68153356, compound

Product 1

HCID 68153242(4-Hydroxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanoneYield 58%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
60 °C

Procedure

4-Methyl morpholine (1.59 mL, 14.4 mmol) was added to a mixture of 2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]dihydrochloride (1.00 g, 2.89 mmol), 4-hydroxy-3-methoxy-benzoic acid (486 mg, 2.89 mmol), EDCI (831 mg, 4.33 mmol), HOBt (585 mg, 4.33 mmol) and DMF (10 mL) at room temperature. The mixture was heated at 60° C. overnight before it was cooled to room temperature and partitioned between ethyl acetate and 1N HCl. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was subjected to column chromatography (0-100% ethyl acetate/hexanes) to give (4-hydroxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone (690 mg, 58%). ESI-MS m/z calc. 423.2, found 424.1 (M+1)+; Retention time: 1.16 minutes (3 min run). 1H NMR (400 MHz, CD3CN) δ 7.04 (d, J=1.8 Hz, 1H), 6.94 (dd, J=8.1, 1.9 Hz, 1H), 6.87 (d, J=8.1 Hz, 1H), 6.82 (s, 1H), 6.62-6.56 (m, 1H), 6.05 (d, J =3.9 Hz, 1H), 4.35 (s, 1H), 4.00 (t, J=6.0 Hz, 2H), 3.89 (s, 3H), 3.64 (s, 2H), 3.36 (t, J=6.0 Hz, 2H), 3.29 (s, 1H), 2.36 (s, 3H), 2.16-2.04 (m, 2H), 1.81 (dd, J=17.1, 7.3 Hz, 2H).26-7.21 (m, 2H), 7.14 (t, J=8.1 Hz, 1H), 2.78 (d, J=1.4 Hz, 2H), 1.24 (d, J=0.8 Hz, 6H).

Workup

  1. temperaturewas cooled to room temperature
  2. custompartitioned between ethyl acetate and 1N HCl
  3. customThe layers were separated
  4. extractionthe aqueous layer was extracted with ethyl acetate (3×)
  5. washThe combined organics were washed with brine
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated

Sources & evidence

ORD record
ord-a9b2569db1334e1b91cb90da561fb8ae
Source dataset
uspto-grants-2014_12
Patent number
US08916565B2

Reaction notes

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