2-(5-(Trimethylstannyl)pyridin-2-yl)propan-2-ol → HCID 178496591, compound

HRID 1047247Notes

Reaction equation

HRID 1047247 reaction equation
C[Sn](C)(C)[C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:12])([CH3:11])[CH3:10])=[N:7][CH:8]=1.Br[C:16]1[N:21]=[C:20]2[N:22]([C@H:27]3[CH2:32][CH2:31][C@H:30]([O:33][CH3:34])[CH2:29][CH2:28]3)[C:23](=[O:26])[CH2:24][NH:25][C:19]2=[N:18][CH:17]=1>CN(C)C=O>[OH:12][C:9]([C:6]1[N:7]=[CH:8][C:3]([C:16]2[N:21]=[C:20]3[N:22]([C@H:27]4[CH2:32][CH2:31][C@H:30]([O:33][CH3:34])[CH2:29][CH2:28]4)[C:23](=[O:26])[CH2:24][NH:25][C:19]3=[N:18][CH:17]=2)=[CH:4][CH:5]=1)([CH3:11])[CH3:10]

Participants

4

Reactant 2

HCID 666077842-(5-(Trimethylstannyl)pyridin-2-yl)propan-2-olHCID 178496590HCID 178496590, compound

Product 1

HCID 178496591HCID 178496591, compoundYield 42%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
120 °C

Procedure

2-(5-(Trimethylstannyl)pyridin-2-yl)propan-2-ol (See Example 5.E) (9.43 g, 31.4 mmol), 7-bromo-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (10.02 g, 29.4 mmol), [1,1′-bis(diphenyl-phosphino)-ferrocene]dichloropalladium(II)dichloromethane adduct (2.398 g, 2.94 mmol) and N,N-dimethylformamide (25 mL) were combined in a round-bottom flask with a stirbar. The atmosphere in the vessel was removed under vacuum and replaced with nitrogen gas three times. The resulting mixture was stirred vigorously and heated at 120° C. under nitrogen for 35 min. The resulting mixture was purified using flash chromatography, split into 4 separate columns, (2-15% methanol in dichloromethane). Fractions containing the desired product were combined and most of the solvent removed under reduced pressure. The resulting mixture was purified using reverse-phase preparatory HPLC (20-40% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min), split into 6 runs. Fractions containing the desired product were combined and all of the acetonitrile and some of the water were removed under reduced pressure at 25° C. The remaining yellow solution was loaded onto 50 g of Strata X-C ion exchange resin from Phenomenex. The column was washed successively with water, acetonitrile, methanol and then 5% ammonium hydroxide in methanol. The product eluted with the 5% ammonium hydroxide in methanol wash and was concentrated under reduced pressure and dried under high vacuum to give the desired product (4.85 g, 12.20 mmol, 42% yield) as a pink foam-solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.03 (d, J=1.56 Hz, 1H), 8.28 (s, 1H), 8.24 (dd, J=2.34, 8.20 Hz, 1H), 7.74 (d, J=7.81 Hz, 1H), 7.61 (s, 1H), 5.26 (s, 1H), 4.90 (tt, J=3.71, 12.10 Hz, 1H), 4.13 (s, 2H), 3.28 (s, 3H), 3.20 (tt, J=4.00, 10.84 Hz, 1H), 2.58 (qd, J=2.93, 12.82 Hz, 2H), 2.14 (d, J=10.15 Hz, 2H), 1.68 (d, J=10.93 Hz, 2H), 1.47 (s, 6H), 1.17-1.35 (m, 2H); MS (ESI) m/z 398.3 [M+1]+; mp 196-198° C. (uncorrected).

Workup

  1. customThe atmosphere in the vessel was removed under vacuum
  2. customThe resulting mixture was purified
  3. customsplit into 4
  4. customseparate columns, (2-15% methanol in dichloromethane)
  5. additionFractions containing the desired product
  6. customremoved under reduced pressure
  7. customThe resulting mixture was purified
  8. customreverse-phase preparatory HPLC (20-40% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min)
  9. customsplit into 6 runs
  10. additionFractions containing the desired product
  11. customall of the acetonitrile and some of the water were removed under reduced pressure at 25° C
  12. washThe column was washed successively with water, acetonitrile, methanol
  13. washThe product eluted with the 5% ammonium hydroxide in methanol
  14. washwash
  15. concentrationwas concentrated under reduced pressure
  16. customdried under high vacuum

Sources & evidence

ORD record
ord-169fa8b707744d519e2c8ae5a43e19bf
Source dataset
uspto-grants-2013_10
Patent number
US08569494B2

Reaction notes

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