Potassium Phosphate, Tribasic → 2-{5'-[5-((2S,5R)-2,5-Dimethyl-4-oxetan-3-yl-piperazin-1-yl)-pyridin-2-ylamino]-4-hydroxymethyl-1'-methyl-6'-oxo-1',6'-dihydro-[3,3']bipyridinyl-5-yl}-3,4,6,7,8,9-hexahydro-2H-pyrazino[1,2-a]indol-1-one

HRID 1021769Notes

Reaction equation

HRID 1021769 reaction equation
Br[C:2]1[CH:9]=[N:8][CH:7]=[C:6]([N:10]2[CH2:22][CH2:21][N:13]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=4[CH:20]=[C:12]3[C:11]2=[O:23])[C:3]=1[CH:4]=[O:5].[CH3:24][C@H:25]1[CH2:30][N:29]([CH:31]2[CH2:34][O:33][CH2:32]2)[C@H:28]([CH3:35])[CH2:27][N:26]1[C:36]1[CH:37]=[CH:38][C:39]([NH:42][C:43]2[C:44](=[O:59])[N:45]([CH3:58])[CH:46]=[C:47](B3OC(C)(C)C(C)(C)O3)[CH:48]=2)=[N:40][CH:41]=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].C(#N)C.O>[CH3:24][C@H:25]1[CH2:30][N:29]([CH:31]2[CH2:34][O:33][CH2:32]2)[C@H:28]([CH3:35])[CH2:27][N:26]1[C:36]1[CH:37]=[CH:38][C:39]([NH:42][C:43]2[C:44](=[O:59])[N:45]([CH3:58])[CH:46]=[C:47]([C:2]3[CH:9]=[N:8][CH:7]=[C:6]([N:10]4[CH2:22][CH2:21][N:13]5[C:14]6[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=6[CH:20]=[C:12]5[C:11]4=[O:23])[C:3]=3[CH2:4][OH:5])[CH:48]=2)=[N:40][CH:41]=1

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 517045Sodium AcetateHCID 866837683-(5-((2S,5R)-2,5-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-oneHCID 866841693-Bromo-5-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)isonicotinaldehyde

Product 1

HCID 866842802-{5'-[5-((2S,5R)-2,5-Dimethyl-4-oxetan-3-yl-piperazin-1-yl)-pyridin-2-ylamino]-4-hydroxymethyl-1'-methyl-6'-oxo-1',6'-dihydro-[3,3']bipyridinyl-5-yl}-3,4,6,7,8,9-hexahydro-2H-pyrazino[1,2-a]indol-1-oneYield 11%

Reagents, catalysts & solvents 3

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

Procedure

A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 3-bromo-5-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2a]indol-2(1H)-yl)isonicotinaldehyde 101f (200 mg, 0.54 mmol), 3-(5-((2S,5R)-2,5-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 155a (267 mg, 0.54 mmol), Pd(dppf)Cl2 (44 mg, 0.054 mmol), K3PO4 (229 mg, 1.08 mmol), sodium acetate (89 mg, 1.08 mmol), water (0.2 mL) and acetonitrile (10 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 157 (35.5 mg, 11%) as a yellow solid. MS-ESI: [M+H]+ 665.4. 1H NMR (500 MHz, CDCl3) δ 8.65-8.63 (m, 2H), 8.50 (s, 1H), 7.80 (s, 1H), 7.87 (s, 1H), 7.48-7.47 (m, 1H), 7.36 (d, J=7.5 Hz, 1H), 6.88 (s, 1H), 6.81 (d, J=9.0 Hz, 1H), 4.75-4.54 (m, overlap, 6H), 4.37-4.13 (m, overlap, 4H), 4.00-3.95 (m, 1H), 3.74-3.73 (m, 1H), 3.72 (s, 3H), 3.19-3.15 (m, 1H), 2.91-2.90 (m, 1H), 2.74-2.44 (m, overlap, 7H), 1.92-1.88 (m, 2H), 1.81-1.79 (m, 2H), 0.90-0.89 (m, 6H).

Workup

  1. customA 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser
  2. customAfter three cycles of vacuum/argon flush
  3. temperaturethe mixture was heated
  4. temperatureat reflux for 2 h
  5. filtrationfiltered
  6. concentrationThe filtrate was concentrated under reduced pressure
  7. customthe residue was purified by reverse-phase prep-HPLC

Sources & evidence

ORD record
ord-4e09470c99ea49eabd09fef5d624711f
Source dataset
uspto-grants-2014_05
Patent number
US08716274B2

Reaction notes

Loading…