Pyridine → N-[4-(4-chlorophenyl)-1-oxophthalazin-2(1H)-yl]-2-[(1S,2S,5R)-3,3-difluoro-6,6-dimethylbicyclo[3.1.1]hept-2-yl]acetamide

HRID 469589Notes

Reaction equation

HRID 469589 reaction equation
[F:1][C:2]1([F:15])[CH2:7][C@H:6]2[CH2:8][C@H:4]([C:5]2([CH3:10])[CH3:9])[C@@H:3]1[CH2:11][C:12](Cl)=[O:13].[NH2:16][N:17]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:34].N1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:34])[N:17]([NH:16][C:12](=[O:13])[CH2:11][C@@H:3]3[C:2]([F:15])([F:1])[CH2:7][C@H:6]4[CH2:8][C@@H:4]3[C:5]4([CH3:10])[CH3:9])[N:26]=2)=[CH:28][CH:29]=1

Participants

5

Reactant 3

HCID 1049PyridineHCID 671613672-amino-4-(4-chlorophenyl)phthalazin-1(2H)-oneHCID 866537462-((1S,2S,5R)-3,3-difluoro-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)acetyl chloride

Product 1

HCID 53239544N-[4-(4-chlorophenyl)-1-oxophthalazin-2(1H)-yl]-2-[(1S,2S,5R)-3,3-difluoro-6,6-dimethylbicyclo[3.1.1]hept-2-yl]acetamide

Reagents, catalysts & solvents 1

HCID 6212ChloroformSolvent

Procedure

To a mixture of the above crude 2-((1S,2S,5R)-3,3-difluoro-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)acetyl chloride (50 mg, 0.211 mmol) and the product from Example 86A (57.4 mg, 0.211 mmol) in 10 mL of CHCl3 was added pyridine (0.051 mL, 0.634 mmol). The reaction is stirred at rt for 12 hours and then reluxed for 16 hours, and quenched with 1M NaHCO3 (10 mL). The aq layer was extracted with EtOAc (2×20 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-40% of EtOAc in hexanes). 1H NMR (300 MHz, DMSO-d6) δ ppm 11.51 (s, 1H), 8.39-8.43 (m, 1H), 7.94-8.00 (m, 2H), 7.70-7.76 (m, 1H), 7.58-7.70 (m, 4H), 2.92-3.09 (m, 1H), 2.81 (dd, J=15.3, 6.4 Hz, 1H), 2.36-2.45 (m, 3H), 2.11-2.16 (m, 1H), 1.93-2.04 (m, 1H), 1.27 (s, 3H), 1.08-1.20 (m, 2H), 1.01 (s, 3H); MS (ESI+) M/Z 472 (M+H)+.

Workup

  1. waitreluxed for 16 hours
  2. customquenched with 1M NaHCO3 (10 mL)
  3. extractionThe aq layer was extracted with EtOAc (2×20 mL)
  4. dry with materialthe combined organic layers were dried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was purified by column chromatography

Sources & evidence

ORD record
ord-25057e2013a04c2ab6544895d81e37db
Source dataset
uspto-grants-2014_01
Patent number
US08629143B2

Reaction notes

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