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-[1-methyl-5-({5-[(2R)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]pyridine-3-carbaldehyde

HRID 1021761Notes

Reaction equation

HRID 1021761 reaction equation
Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:19][CH2:18][N:17]3[C:10](=[CH:11][C:12]4[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]=43)[C:9]2=[O:22])[C:3]=1[CH:23]=[O:24].[CH3:25][N:26]1[C:31](=[O:32])[C:30]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][N:43]([CH:46]4[CH2:49][O:48][CH2:47]4)[CH2:42][C@H:41]3[CH3:50])=[CH:36][N:35]=2)=[CH:29][C:28](C2C(C=O)=C(N3C=CN4C5CCCCC=5C=C4C3=O)N=CC=2)=[CH:27]1.[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>[CH3:20][C:14]1([CH3:21])[CH2:13][C:12]2[CH:11]=[C:10]3[N:17]([CH2:18][CH2:19][N:8]([C:4]4[C:3]([CH:23]=[O:24])=[C:2]([C:28]5[CH:29]=[C:30]([NH:33][C:34]6[CH:39]=[CH:38][C:37]([N:40]7[CH2:45][CH2:44][N:43]([CH:46]8[CH2:47][O:48][CH2:49]8)[CH2:42][C@H:41]7[CH3:50])=[CH:36][N:35]=6)[C:31](=[O:32])[N:26]([CH3:25])[CH:27]=5)[CH:7]=[CH:6][N:5]=4)[C:9]3=[O:22])[C:16]=2[CH2:15]1

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 517045Sodium AcetateHCID 768540784-chloro-2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta(4,5)pyrrolo(1,2-a)pyrazin-2-yl)nicotinaldehydeHCID 86684266(R)-4-(1-Methyl-5-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-2-(1-oxo-6,7,8,9-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)nicotinaldehyde

Product 1

HCID 866842732-{4,4-Dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-4-[1-methyl-5-({5-[(2R)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]pyridine-3-carbaldehydeYield 41.2%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
80 °C

Procedure

A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 4-chloro-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyri-dine-3-carbaldehyde 108a (105 mg, 0.30 mmol), 1-methyl-3-({5-[(2R)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-5-(tetra-methyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one 151g (216 mg, 0.45 mmol), PdCl2(dppf) (25 mg, 0.030 mmol), K3PO4 (126 mg, 0.60 mmol), sodium acetate (49 mg, 0.60 mmol), acetonitrile (15 mL), and water (1.5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 80° C. for 2 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 1:20 methanol/dichloromethane to afford 153a as a red solid (82 mg, 41%). MS-ESI: [M+H]+ 663

Workup

  1. customA 50-mL round-bottomed flask equipped with a reflux condenser
  2. customAfter three cycles of vacuum/argon flush
  3. filtrationIt was then filtered
  4. customthe filtrate was evaporated under reduced pressure
  5. customThe residue was purified by silica-gel column chromatography
  6. washeluting with 1:20 methanol/dichloromethane

Sources & evidence

ORD record
ord-5be6d7facd8644d1b419fa207c489d2d
Source dataset
uspto-grants-2014_05
Patent number
US08716274B2

Reaction notes

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