Sodium cyanoborohydride → HCID 66611333, compound

HRID 1621912Notes

Reaction equation

HRID 1621912 reaction equation
[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.[CH3:8][O:9][C:10]1[CH:51]=[CH:50][C:13]([CH2:14][N:15]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([C:23]3[C:24]([NH:31][C:32]4[CH:33]=[N:34][C:35]([O:39][CH3:40])=[C:36]([F:38])[CH:37]=4)=[N:25][CH:26]=[C:27]([CH:30]=3)[CH:28]=O)[N:17]=2)=[CH:12][CH:11]=1.C([BH3-])#N.[Na+]>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[F:38][C:36]1[CH:37]=[C:32]([NH:31][C:24]2[C:23]([C:18]3[N:19]=[C:20]([CH3:22])[N:21]=[C:16]([N:15]([CH2:41][C:42]4[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=4)[CH2:14][C:13]4[CH:12]=[CH:11][C:10]([O:9][CH3:8])=[CH:51][CH:50]=4)[N:17]=3)=[CH:30][C:27]([CH2:28][N:3]3[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]3[CH3:1])=[CH:26][N:25]=2)[CH:33]=[N:34][C:35]=1[O:39][CH3:40]

Participants

6

Reactant 3

HCID 5003444Sodium cyanoborohydrideHCID 12012220(3S)-3-methylmorpholineHCID 715003625-(4-(Bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinaldehyde

Product 1

HCID 66611333HCID 66611333, compoundYield 105.9%

Reagents, catalysts & solvents 2

HCID 76524Titanium tetraethoxideCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
70 °C

Procedure

(S)-3-Methylmorpholine (Aldrich, 0.105 g, 1.041 mmol) and 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinaldehyde (Example 143, Step 2; 0.310 g, 0.520 mmol) were suspended in THF (3 mL) and titanium (IV) ethoxide (0.60 mL, 2.90 mmol) was added. The mixture was sealed and heated at 70° C. overnight. The light brown solution was cooled to 0° C. and excess sodium cyanoborohydride (0.327 g, 5.20 mmol) was added, and the mixture was stirred at 0° C. for 2 h. The resulting solution was quenched with a couple drop of MeOH followed by water. DCM was added to the entire mass and vigorously stirred for 10 min. The mixture was filtered and passed through a short path of Celite® (diatomaceous earth). The filter cake was washed with DCM (3×10 mL). The combined organic phases were concentrated to give a crude residue. Flash column chromatographic purification (short column, SiO2, 100% DCM to 5% MeOH in DCM) provided (S)-4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-((3-methylmorpholino)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (375 mg) as a yellow solid, which was deprotected under similar conditions according to the procedure reported previously (Example 178, Step 4) to afford the title compound (199 mg, 82%) as a yellow solid. m/z (ESI, +ve ion) 441 (M+H)+. 1H NMR (400 MHz, CDCl3) δ (rotatomer mixtures) 12.09 (br. s., 1H) 9.01 (br. s., 1H) 8.15-8.56 (m, 2H) 8.05 (br. s., 1H) 7.26 (br. s., 1H) 4.88-6.53 (m, 1H) 4.32 (br. s., 1H) 4.03 (br. s., 3H) 3.84 (br. s., 4H) 3.57 (br. s., 2H) 2.91 (br. s., 2H) 2.55 (br. s., 3H) 1.21 (d, J=5.28 Hz, 3H).

Workup

  1. customThe mixture was sealed
  2. temperatureThe light brown solution was cooled to 0° C.
  3. customThe resulting solution was quenched with a couple drop of MeOH
  4. additionDCM was added to the entire mass
  5. stirringvigorously stirred for 10 min
  6. filtrationThe mixture was filtered
  7. washThe filter cake was washed with DCM (3×10 mL)
  8. concentrationThe combined organic phases were concentrated
  9. customto give a crude residue
  10. customFlash column chromatographic purification (short column, SiO2, 100% DCM to 5% MeOH in DCM)

Sources & evidence

ORD record
ord-ff2213a1f70246a0a6b89740923fa1e3
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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