Dichloromethane → 6-(6-(2-Hydroxypropan-2-yl)pyridin-3-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

HRID 717178Notes

Reaction equation

HRID 717178 reaction equation
Br[C:2]1[N:3]=[C:4]2[N:11]([CH2:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:10][C:9](=[O:19])[NH:8][C:5]2=[N:6][CH:7]=1.C[Sn](C)(C)[C:22]1[CH:23]=[CH:24][C:25]([C:28]([OH:31])([CH3:30])[CH3:29])=[N:26][CH:27]=1.ClCCl>CN(C)C=O>[OH:31][C:28]([C:25]1[N:26]=[CH:27][C:22]([C:2]2[N:3]=[C:4]3[N:11]([CH2:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[CH2:10][C:9](=[O:19])[NH:8][C:5]3=[N:6][CH:7]=2)=[CH:23][CH:24]=1)([CH3:30])[CH3:29]

Participants

5

Reactant 3

HCID 6344DichloromethaneHCID 666077842-(5-(Trimethylstannyl)pyridin-2-yl)propan-2-olHCID 715670846-Bromo-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

Product 1

HCID 582983126-(6-(2-Hydroxypropan-2-yl)pyridin-3-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-oneYield 35.8%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
125 °C

Procedure

6-Bromo-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (35.98 g, 110 mmol), 2-(5-(trimethylstannyl)pyridin-2-yl)propan-2-ol (See Example 5.E) (33.0 g, 110 mmol) and [1,1′-bis(diphenyl-phosphino)ferrocene]dichloro-palladium(II) complex with dichloromethane (1:1) (8.05 g, 11.00 mmol) were combined in a sealed tube and suspended in N,N-dimethylformamide (288 mL). The reaction was then heated to 125° C. for 2 h. The reaction was cooled slightly and poured while still warm onto a silica gel column and purified using an Biotage SP1 (0-100% (5% methanol in ethyl acetate) in hexanes). The desired fractions were combined and organic volatiles removed under reduced pressure. The residue was triturated with 20% ethyl acetate in hexanes followed by several washes with denatured ethanol. The slightly yellow solid was dried under reduced pressure to afford the desired compound (15.08 g, 39.3 mmol, 35.8% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 11.32 (s, 1H), 9.07 (d, J=1.56 Hz, 1H), 8.29 (dd, J=8.59, 2.34 Hz, 1H), 8.05 (s, 1H), 7.72 (d, J=8.20 Hz, 1H), 5.26 (s, 1H), 4.21 (s, 2H), 3.83 (d, J=2.73 Hz, 2H), 3.51 (d, J=7.42 Hz, 2H), 3.27 (t, J=11.32 Hz, 2H), 2.09 (br. s., 1H), 1.61 (d, J=11.3 Hz, 2H), 1.46 (s, 6H), 1.24-1.38 (m, 2H); MS (ESI) m/z 384.2 [M+1]+; mp 268-269° C.

Workup

  1. temperatureThe reaction was cooled slightly
  2. additionpoured
  3. temperaturewhile still warm onto a silica gel column
  4. custompurified
  5. customorganic volatiles removed under reduced pressure
  6. customThe residue was triturated with 20% ethyl acetate in hexanes
  7. customThe slightly yellow solid was dried under reduced pressure

Sources & evidence

ORD record
ord-df8e32e1eab34620831d1cca5af852f8
Source dataset
uspto-grants-2015_11
Patent number
US09193692B2

Reaction notes

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