4-Methylmorpholine → HCID 59053851, compound

HRID 1405416Notes

Reaction equation

HRID 1405416 reaction equation
Cl.Cl.[F:3][C:4]([F:20])([F:19])[C:5]1[N:9]2[CH2:10][CH2:11][NH:12][C:13]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:8]2=[CH:7][CH:6]=1.[CH:21]([O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][C:26]=1[O:34][CH3:35])([CH3:23])[CH3:22].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.CN1CCOCC1>C(Cl)Cl.O>[CH:21]([O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([N:16]2[CH2:15][CH2:14][C:13]3([NH:12][CH2:11][CH2:10][N:9]4[C:5]([C:4]([F:3])([F:19])[F:20])=[CH:6][CH:7]=[C:8]34)[CH2:18][CH2:17]2)=[O:30])=[CH:27][C:26]=1[O:34][CH3:35])([CH3:23])[CH3:22]

Participants

8

Reactant 5

HCID 79724-MethylmorpholineHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 20639154-Isopropoxy-3-methoxybenzoic acidHCID 68153240HCID 68153240, compound

Product 1

HCID 59053851HCID 59053851, compoundYield 96.5%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

To a stirred solution of 6-(trifluoromethyl)spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazine-1,4′-piperidine]dihydrochloride (475 mg, 1.43 mmol), 4-isopropoxy-3-methoxy-benzoic acid (361 mg, 1.72 mmol) and 1-hydroxybenzotriazole (232 mg, 1.72 mmol) in CH2Cl2 (5.5 mL) at ambient temperature was added 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine (266 mg, 1.72 mmol) followed by 4-methylmorpholine (786 μL, 7.15 mmol). The mixture was stirred for 16 h at room temperature. The mixture was poured into water and was extracted with EtOAc (3×). The organics were combined, washed with 0.1 N HCl, 1N NaOH, water, brine, dried (Na2SO4) and evaporated to dryness. The residue was purified by column chromatography (0-100% ethyl acetate/hexanes) to give (4-isopropoxy-3-methoxy-phenyl)-[6-(trifluoromethyl)spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone (623 mg, 96%). ESI-MS m/z calc. 451.2, found 452.3 (M+1)+; Retention time: 1.30 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.03 (d, J=1.9 Hz, 1H), 6.98 (dd, J=8.2, 1.9 Hz, 1H), 6.88 (d, J=8.3 Hz, 1H), 6.54 (d, J=3.7 Hz, 1H), 5.93 (d, J=3.8 Hz, 1H), 4.56 (dd, J=12.2, 6.1 Hz, 1H), 4.52 (s, 1H), 3.94 (s, 2H), 3.88 (s, 3H), 3.69 (s, 1H), 3.47 (s, 2H), 3.27 (s, 2H), 1.87 (s, 4H), 1.38 (d, J=6.1 Hz, 6H).

Workup

  1. extractionwas extracted with EtOAc (3×)
  2. washwashed with 0.1 N HCl, 1N NaOH, water, brine
  3. dry with materialdried (Na2SO4)
  4. customevaporated to dryness
  5. customThe residue was purified by column chromatography (0-100% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-f8265f83cd3245b081106d6dfac810b8
Source dataset
uspto-grants-2014_12
Patent number
US08916565B2

Reaction notes

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