Acetic Acid → HCID 58529402, compound

HRID 1972968Notes

Reaction equation

HRID 1972968 reaction equation
[NH2:1][C:2]1[N:3]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][C:7]([C:11]1[CH:12]=[C:13]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:14]3[C:19]=1[C:18]([NH2:20])=[N:17][CH:16]=[N:15]3)=[CH:6]2.[C:34](O)(=O)[CH3:35].[C:38]([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CO>[NH2:1][C:2]1[N:3]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][C:7]([C:11]1[CH:12]=[C:13]([CH:21]3[CH2:26][CH2:25][N:24]([CH:35]4[CH2:34][CH2:38]4)[CH2:23][CH2:22]3)[N:14]3[C:19]=1[C:18]([NH2:20])=[N:17][CH:16]=[N:15]3)=[CH:6]2

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 516892Sodium BicarbonateHCID 5003444Sodium cyanoborohydrideHCID 58529681HCID 58529681, compound

Product 1

HCID 58529402HCID 58529402, compoundYield 32.5%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of 5-(3-amino-2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.228 mmol) in MeOH (2.3 mL) was added acetic acid (0.13 mL, 2.28 mmol, 10.0 eq), 3 Å molecular sieves (50 mg), [1-(ethoxycyclopropyl)-oxy]timethylsilane (0.28 mL, 1.37 mmol, 6.0 eq), and sodium cyanoborohydride (64.5 mg, 1.03 mmol, 4.5 eq). The reaction mixture was stirred at 60° C. under N2 for 18 h. The mixture was cooled to rt and aqueous, saturated NaHCO3 solution (1.0 mL) was added to quench the reaction. The mixture was partitioned between EtOAc and water. The organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified via preparative HPLC. The product containing fractions were collected, and the TFA from the eluent was removed via filtration through an acidic resin followed by washing with acetonitrile. The product was then eluted with 2M NH3 in MeOH. The MeOH was removed and the residue was crystallized from DCM-ether-hexane to provide the title compound (35.5 mg, 32.5%) as pink solid. 1H NMR (300 MHz, DMSO-d5) δ 7.87 (s, 1H), 7.70 (d, 1H), 7.34 to 7.29 (m, 2H), 7.27 to 7.21 (m, 3H), 7.15 (s, 1H), 6.73 (dd, 1H), 6.52 (s, 1H), 6.37 (s, 2H), 5.38 (s, 2H), 3.12 to 3.00 (m, 3H), 2.28 (t, 2H), 1.96 (d, 2H), 1.67 to 1.56 (m, 3H), 0.43 to 0.39 (m, 2H), 0.31 to 0.27 (m, 21-1); ES-MS m/z 479.2 [M+H]+, RT (min) 1.80.

Workup

  1. temperatureThe mixture was cooled to rt
  2. customto quench
  3. customthe reaction
  4. customThe mixture was partitioned between EtOAc and water
  5. washThe organic phase was washed with water and brine
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe crude was purified via preparative HPLC
  10. additionThe product containing fractions
  11. customwere collected
  12. customthe TFA from the eluent was removed via filtration through an acidic resin
  13. washby washing with acetonitrile
  14. washThe product was then eluted with 2M NH3 in MeOH
  15. customThe MeOH was removed
  16. customthe residue was crystallized from DCM-ether-hexane

Sources & evidence

ORD record
ord-4bad4179e6a2441bb2a2531274da1449
Source dataset
uspto-grants-2013_04
Patent number
US08431695B2

Reaction notes

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