Methanol → N-Cyclopropyl-4-methyl-3-[1-oxo-7-(piperidin-4-yloxy)isoquinolin-2(1H)-yl]benzamide

HRID 506979Notes

Reaction equation

HRID 506979 reaction equation
[CH:1]1([NH:4][C:5](=[O:25])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([OH:23])=[CH:18][CH:19]=4)[C:14]3=[O:24])[CH:7]=2)[CH2:3][CH2:2]1.[F-].[Cs+].C(OC([N:35]1[CH2:40][CH2:39][CH:38](OS(C)(=O)=O)[CH2:37][CH2:36]1)=O)(C)(C)C.CO>CC(N(C)C)=O.C(OCC)(=O)C.Cl.O1CCOCC1>[CH:1]1([NH:4][C:5](=[O:25])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:23][CH:38]5[CH2:39][CH2:40][NH:35][CH2:36][CH2:37]5)=[CH:18][CH:19]=4)[C:14]3=[O:24])[CH:7]=2)[CH2:3][CH2:2]1

Participants

9

Reactant 4

HCID 887MethanolHCID 25953Cesium fluorideHCID 41848691-(tert-Butoxycarbonyl)-4-(methanesulfonyloxy)piperidine2×HCID 11515516N-Cyclopropyl-3-(7-hydroxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzamide

Product 1

HCID 67018601N-Cyclopropyl-4-methyl-3-[1-oxo-7-(piperidin-4-yloxy)isoquinolin-2(1H)-yl]benzamide

Reagents, catalysts & solvents 4

HCID 313Hydrochloric AcidSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolventHCID 31374DimethylacetamideSolvent

Procedure

N-Cyclopropyl-3-(7-hydroxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzamide (200 mg) was stirred with cesium fluoride (364 mg) and 4-methanesulfonyloxypiperidine-1-carboxylic acid tert-butyl ester (251 mg) in DMA (1.5 ml) at 85° C. for 24 hours (during this time further additions (4×125 mg) of 4-methanesulfonyloxypiperidine-1-carboxylic acid tert-butyl ester took place). The reaction mixture was diluted with ethyl acetate and washed with 1N NaOH (2×), water (3×), brine, dried (magnesium sulfate) and concentrated to a brown oil. Purification by column chromatography with a gradient of 50% ethyl acetate/iso-hexane to 100% ethyl acetate gave a cream coloured solid. The solid was dissolved in 4M HCl in dioxane solution (1 ml) and methanol (0.5 ml) and stirred for 16 hours at room temperature. The reaction mixture was concentrated and the residue was purified 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 N-cyclopropyl-4-methyl-3-[1-oxo-7-(piperidin-4-yloxy)isoquinolin-2(1H)-yl]benzamide as a cream coloured foam solid (146 mg); NMR Spectrum: (DMSOd6) 0.55 (m, 2H), 0.69 (m, 2H), 1.50 (m, 2H), 1.95 (m, 2H), 2.10 (s, 3H), 2.60 (m, 2H), 2.84 (m, 1H), 2.96 (m, 2H), 4.54 (m, 1H), 6.71 (d, 1H), 7.20 (d, 1H), 7.41 (d, 1H), 7.49 (d, 1H), 7.67 (s, 1H), 7.80 (d, 1H), 7.83 (s, 1H), 7.87 (d, 1H), 8.42 (d, 1H); Mass Spectrum: M+H+ 418.

Workup

  1. washwashed with 1N NaOH (2×), water (3×), brine
  2. dry with materialdried (magnesium sulfate)
  3. concentrationconcentrated to a brown oil
  4. customPurification by column chromatography with a gradient of 50% ethyl acetate/iso-hexane to 100% ethyl acetate
  5. customgave a cream
  6. concentrationThe reaction mixture was concentrated
  7. customthe residue was purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK)
  8. additiona 99:1 mixture of methanol and aqueous ammonia solution

Sources & evidence

ORD record
ord-2970d222f0aa46cfa4c22a2d6d8ec963
Source dataset
uspto-grants-2010_08
Patent number
US07786115B2

Reaction notes

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