Potassium Phosphate, Tribasic → (2-{4,4-Dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-4-{5-[(5-{[(3R,5S)-3,5-dimethylmorpholin-4-yl]carbonyl}pyridin-2-yl)amino]-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl}pyridin-3-yl)methyl Acetate

HRID 1022210Notes

Reaction equation

HRID 1022210 reaction equation
Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[C@@H:24]([CH3:25])[CH2:23][O:22][CH2:21][C@H:20]3[CH3:26])=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:27]([O:30][CH2:31][C:32]1[C:33]([N:47]2[CH2:58][CH2:57][N:56]3[C:49](=[CH:50][C:51]4[CH2:52][C:53]([CH3:60])([CH3:59])[CH2:54][C:55]=43)[C:48]2=[O:61])=[N:34][CH:35]=[CH:36][C:37]=1B1OC(C)(C)C(C)(C)O1)(=[O:29])[CH3:28].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:27]([O:30][CH2:31][C:32]1[C:33]([N:47]2[CH2:58][CH2:57][N:56]3[C:49](=[CH:50][C:51]4[CH2:52][C:53]([CH3:60])([CH3:59])[CH2:54][C:55]=43)[C:48]2=[O:61])=[N:34][CH:35]=[CH:36][C:37]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[C@@H:24]([CH3:25])[CH2:23][O:22][CH2:21][C@H:20]3[CH3:26])=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1)(=[O:29])[CH3:28]

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 517045Sodium AcetateHCID 86684419(2-(7,7-dimethyl-1-oxo-3,4,7,8-tetrahydro-1H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2(6H)-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methyl acetateHCID 866845736-Chloro-4-(5-((3R,5S)-3,5-dimethylmorpholine-4-carbonyl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one

Product 1

HCID 86684574(2-{4,4-Dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-4-{5-[(5-{[(3R,5S)-3,5-dimethylmorpholin-4-yl]carbonyl}pyridin-2-yl)amino]-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl}pyridin-3-yl)methyl Acetate

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
100 °C

Procedure

A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 321a (140 mg, 0.37 mmol), (2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methyl acetate 199e (355 mg, 0.74 mmol), K3PO4 (157 mg, 0.74 mmol), sodium acetate (61 mg, 0.74 mmol), 1,1′-bis(diphenylphosphino) ferrocenedichloropalladium(II) (36 mg, 0.040 mmol), acetonitrile (10 mL), and water (0.2 mL). The system was subjected to three cycles of vacuum/nitrogen flush and heated at 100° C. under N2 protection for 1.5 h. Analysis of reaction mixture by LCMS showed complete conversion to the desired product. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between dichloromethane (30 mL) and water (30 mL). The aqueous layer was separated and extracted with dichloromethane (3×20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified by gel-silica column chromatography eluting with 60:1 dichloromethane/methanol to afford 320b (105 mg, 41%) as a black solid. MS-ESI: [M+H]+ 695.3

Workup

  1. customA 50-mL round-bottomed flask equipped with a reflux condenser
  2. customflush
  3. customAnalysis of reaction mixture by LCMS

Sources & evidence

ORD record
ord-d8d5fc8bc4a84d67832323736a57dfb5
Source dataset
uspto-grants-2014_05
Patent number
US08716274B2

Reaction notes

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