Lithium hydroxide, monohydrate → HCID 46908610, compound

HRID 2069719Notes

Reaction equation

HRID 2069719 reaction equation
C(OC([N:8]([C:44]1[CH:49]=[CH:48][C:47]([CH2:50][N:51]2[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]2)=[CH:46][N:45]=1)[C:9]1[C:14](=[O:15])[N:13]([CH3:16])[CH:12]=[C:11]([C:17]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[N:37]=[CH:36][C:35]4[C:30](=[C:31]([F:42])[CH:32]=[C:33]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:34]=4)[C:29]3=[O:43])[C:18]=2[CH2:19][O:20]C(=O)C)[CH:10]=1)=O)(C)(C)C.O.[OH-].[Li+]>O1CCOCC1.O.C(OCC)(=O)C>[C:38]([C:33]1[CH:34]=[C:35]2[C:30](=[C:31]([F:42])[CH:32]=1)[C:29](=[O:43])[N:28]([C:24]1[CH:25]=[CH:26][CH:27]=[C:17]([C:11]3[CH:10]=[C:9]([NH:8][C:44]4[CH:49]=[CH:48][C:47]([CH2:50][N:51]5[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]5)=[CH:46][N:45]=4)[C:14](=[O:15])[N:13]([CH3:16])[CH:12]=3)[C:18]=1[CH2:19][OH:20])[N:37]=[CH:36]2)([CH3:41])([CH3:39])[CH3:40]

Participants

6

Reactant 2

HCID 168937Lithium hydroxide, monohydrateHCID 59473775HCID 59473775, compound

Product 1

HCID 46908610HCID 46908610, compoundYield 15.1%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

Acetic acid 2-(5-{tert-butoxycarbonyl-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amino}-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-benzyl ester (1.5 g, 1.92 mmol) was dissolved in 19 ml of dioxane. Lithium hydroxide monohydrate (404 mg, 9.62 mmol) was dissolved in 19 ml of water and added dropwise. The reaction was heated at 50 degrees centigrade for 2 hrs. The reaction was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, dried and concentrated. The residue was dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol (20 ml) and heated in a microwave reactor at 140 degrees for 30 min. The reaction was concentrated and the residue was purified by flash chromatography using a gradient of 0% to 15% methanol in DCM. The residue was diluted with DCM and concentrated again. Isopropyl acetate was added and the mixture was heated in a water bath to form a solution. The solution was cooled to room temperature and allowed to stand at room temperature overnight. The solid that formed was filtered and dried to give 185 mg of 6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-phthalazin-1-one. A second crop of crystals yielded 88 mg of product for a combined yield of 273 mg (22.3%). MS: (M+H)+=638; MP=235.0-238.0° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39 (s, 9 H) 2.12 (s, 3 H) 2.19-2.41 (m, 8 H) 3.60 (s, 3 H) 4.32-4.40 (m, 2 H) 4.58-4.63 (m, 1 H) 4.60-4.61 (m, 1 H) 7.25 (d, J=8.59 Hz, 1 H) 7.34-7.44 (m, 3 H) 7.52 (s, 2 H) 7.52-7.54 (m, 1 H) 7.74 (dd, J=13.14, 1.52 Hz, 1 H) 7.87 (d, J=1.52 Hz, 1 H) 8.04 (d, J=2.02 Hz, 1 H).

Workup

  1. additionadded dropwise
  2. temperatureThe reaction was heated at 50 degrees centigrade for 2 hrs
  3. washwashed with saturated aqueous sodium bicarbonate
  4. customdried
  5. concentrationconcentrated
  6. dissolutionThe residue was dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol (20 ml)
  7. temperatureheated in a microwave reactor at 140 degrees for 30 min
  8. concentrationThe reaction was concentrated
  9. customthe residue was purified by flash chromatography
  10. additionThe residue was diluted with DCM
  11. concentrationconcentrated again
  12. additionIsopropyl acetate was added
  13. temperaturethe mixture was heated in a water bath
  14. customto form a solution
  15. customThe solid that formed
  16. filtrationwas filtered
  17. customdried

Sources & evidence

ORD record
ord-6555c44cfa65483eadc6f597a7818313
Source dataset
uspto-grants-2012_10
Patent number
US08299077B2

Reaction notes

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