2-(6-{5-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-pyridin-3-yl)-2-methyl-propionic acid methyl ester → 2-(6-{5-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-pyridin-3-yl)-2-methyl-propionic acid

HRID 2069723Notes

Reaction equation

HRID 2069723 reaction equation
C[O:2][C:3](=[O:46])[C:4]([C:7]1[CH:8]=[N:9][C:10]([NH:13][C:14]2[C:15](=[O:45])[N:16]([CH3:44])[CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N:26]4[N:35]=[CH:34][C:33]5[C:28](=[C:29]([F:40])[CH:30]=[C:31]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:32]=5)[C:27]4=[O:41])[C:21]=3[CH2:42][OH:43])[CH:19]=2)=[CH:11][CH:12]=1)([CH3:6])[CH3:5].[H-].[OH-].[Li+]>O1CCOCC1.O>[C:36]([C:31]1[CH:32]=[C:33]2[C:28](=[C:29]([F:40])[CH:30]=1)[C:27](=[O:41])[N:26]([C:22]1[C:21]([CH2:42][OH:43])=[C:20]([C:18]3[CH:19]=[C:14]([NH:13][C:10]4[N:9]=[CH:8][C:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:46])=[O:2])=[CH:12][CH:11]=4)[C:15](=[O:45])[N:16]([CH3:44])[CH:17]=3)[CH:25]=[CH:24][CH:23]=1)[N:35]=[CH:34]2)([CH3:39])([CH3:37])[CH3:38]

Participants

5

Reactant 2

HCID 594738262-(6-{5-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-pyridin-3-yl)-2-methyl-propionic acid methyl esterHCID 86597229HCID 86597229, compound

Product 1

HCID 469088042-(6-{5-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-pyridin-3-yl)-2-methyl-propionic acidYield 86%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Procedure

2-(6-{5-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-pyridin-3-yl)-2-methyl-propionic acid methyl ester (390 mg, 0.62 mmol) was dissolved in dioxane (5 ml). Lithium hydroxide monohydride (78 mg, 1.86 mmol) was dissolved in 5 ml of water and added dropwise. The reaction was heated at 50 degrees centigrade for three hours. The reaction mixture was concentrated, ethyl acetate was added and the layers were separated. The aqueous layer was acidified with 1 M HCL. Ethyl acetate was added and the layers were separated. The organic layer was dried and concentrated. Isopropyl acetate was added to the residue and the mixture was heated to form a solution which was cooled to room temperature and allowed to stand at room temperature for several hours. The amorphous solid was filtered and dried to give 325 mg (86%) of 2-(6-{5-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-pyridin-3-yl)-2-methyl-propionic acid. A portion of this material was recrystallized from acetonitrile to provide a crystalline solid. MS: (M+H)+=612; MP=218.0-220.0° C. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.38 (s, 9 H) 1.46 (s, 6 H) 3.17 (d, J=4.91 Hz, 1 H) 3.60 (s, 3 H) 4.27-4.42 (m, 2 H) 4.57-4.66 (m, 1 H) 7.26 (d, J=8.69 Hz, 1 H) 7.33-7.45 (m, 3 H) 7.54 (s, 2 H) 7.75 (d, J=13.22 Hz, 1 H) 7.87 (s, 1H) 8.18 (d, J=2.27 Hz, 1 H) 8.51 (d, J=2.64 Hz, 1 H) 8.60 (s, 1 H) 8.65 (d, J=1.89 Hz, 1H) 12.35 (br s, 1 H).

Workup

  1. additionadded dropwise
  2. temperatureThe reaction was heated at 50 degrees centigrade for three hours
  3. concentrationThe reaction mixture was concentrated
  4. additionethyl acetate was added
  5. customthe layers were separated
  6. additionEthyl acetate was added
  7. customthe layers were separated
  8. customThe organic layer was dried
  9. concentrationconcentrated
  10. additionIsopropyl acetate was added to the residue
  11. temperaturethe mixture was heated
  12. customto form a solution which
  13. waitto stand at room temperature for several hours
  14. filtrationThe amorphous solid was filtered
  15. customdried

Sources & evidence

ORD record
ord-7947dd6c3dec4605b5f7b95cbbc4fdbc
Source dataset
uspto-grants-2012_10
Patent number
US08299077B2

Reaction notes

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