Pyridine → N-isoxazol-3-yl-4-methyl-3-[1-oxo-7-(2-piperidin-1-ylethoxy)isoquinolin-2(1H)-yl]benzamide

HRID 506987Notes

Reaction equation

HRID 506987 reaction equation
[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:16][CH:17]=2)[C:12]1=[O:30].C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[NH2:43][C:44]1[CH:48]=[CH:47][O:46][N:45]=1>C(Cl)Cl.CN(C=O)C.C(OCC)(=O)C>[O:46]1[CH:47]=[CH:48][C:44]([NH:43][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][C:15]([O:21][CH2:22][CH2:23][N:24]5[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]5)=[CH:16][CH:17]=4)[C:12]3=[O:30])[CH:4]=2)=[N:45]1

Participants

8

Reactant 4

HCID 1049PyridineHCID 65578Oxalyl chlorideHCID 18102163-IsoxazolamineHCID 670185784-Methyl-3-[1-oxo-7-(2-piperidin-1-ylethoxy)isoquinolin-2(1H)-yl]benzoic acid

Product 1

HCID 67018575N-isoxazol-3-yl-4-methyl-3-[1-oxo-7-(2-piperidin-1-ylethoxy)isoquinolin-2(1H)-yl]benzamide

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

4-Methyl-3-[1-oxo-7-(2-piperidin-1-ylethoxy)isoquinolin-2(1H)-yl]benzoic acid (439 mg) was dissolved in methylene chloride (5 ml) and DMF (3 drops) and cooled to 0° C. under an argon atmosphere. Oxalyl chloride (0.19 ml) was added and the reaction mixture stirred at room temperature for 2 hours. Pyridine (0.90 ml) and 3-aminoisoxazole (0.40 ml) were added and the reaction mixture stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with 1N NaOH, dried (magnesium sulfate) and concentrated. Purification by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to give a solid. The solid was triturated with ethyl acetate to give N-isoxazol-3-yl-4-methyl-3-[1-oxo-7-(2-piperidin-1-ylethoxy)isoquinolin-2(1H)-yl]benzamide as a solid (95 mg); NMR Spectrum: (DMSOd6) 1.40 (m, 2H), 1.45 (m, 4H), 2.15 (s, 3H), 2.49 (m, 4H), 2.70 (m, 2H), 4.15 (m, 2H), 6.75 (d, 1H), 7.05 (d, 1H), 7.25 (d, 1H), 7.43 (d, 1H), 7.60 (d, 1H), 7.68 (d, 1H), 7.73 (d, 1H), 8.00 (s, 1H), 8.05 (d, 1H), 8.85 (s, 1H), 11.50 (s, 1H); Mass Spectrum: M+H+ 473.

Workup

  1. stirringthe reaction mixture stirred at room temperature for 2 hours
  2. washwashed with 1N NaOH
  3. dry with materialdried (magnesium sulfate)
  4. concentrationconcentrated
  5. customPurification by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK)
  6. additiona 99:1 mixture of methanol and aqueous ammonia solution
  7. customto give a solid
  8. customThe solid was triturated with ethyl acetate

Sources & evidence

ORD record
ord-529599ea4c77418790db86d53f8e32f3
Source dataset
uspto-grants-2010_08
Patent number
US07786115B2

Reaction notes

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