Acetic Acid → HCID 178491013, compound

HRID 511607Notes

Reaction equation

HRID 511607 reaction equation
[Cl:1][C:2]1[C:3]([C:50]([F:53])([F:52])[F:51])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH2:11][CH:12]3[CH2:15][CH:14]([NH:16][CH2:17][C@@H:18]4[C@H:22]5[O:23][C:24]([CH3:27])([CH3:26])[O:25][C@H:21]5[C@H:20]([N:28]5[C:32]6[N:33]=[CH:34][N:35]=[C:36]([NH:37][CH2:38][C:39]7[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:40]=7[O:47][CH3:48])[C:31]=6[CH:30]=[CH:29]5)[CH2:19]4)[CH2:13]3)[NH:7][C:6]=2[CH:49]=1.[C:54]([BH3-])#N.[Na+].C(O)(=O)C.C=O>CO>[Cl:1][C:2]1[C:3]([C:50]([F:51])([F:52])[F:53])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH2:11][CH:12]3[CH2:13][CH:14]([N:16]([CH2:17][C@@H:18]4[C@H:22]5[O:23][C:24]([CH3:26])([CH3:27])[O:25][C@H:21]5[C@H:20]([N:28]5[C:32]6[N:33]=[CH:34][N:35]=[C:36]([NH:37][CH2:38][C:39]7[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:40]=7[O:47][CH3:48])[C:31]=6[CH:30]=[CH:29]5)[CH2:19]4)[CH3:54])[CH2:15]3)[NH:7][C:6]=2[CH:49]=1

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 712FormaldehydeHCID 5003444Sodium cyanoborohydrideHCID 178491006HCID 178491006, compound

Product 1

HCID 178491013HCID 178491013, compoundYield 80.7%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent2×

Procedure

A solution of 7-((3aS,4R,6R,6aR)-6-(((3-(2-(6-chloro-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (76 mg, 0.10 mmol) in methanol (2.5 mL) was treated with sodium cyanoborohydride (84 mg, 1.3 mmol). The pH of the solution was adjusted to ˜6 by the dropwise addition of a 10% (v/v) solution of glacial acetic acid in methanol. The mixture was treated with 37% aqueous formaldehyde (0.12 mL, 1.7 mmol) dropwise and the mixture was stirred at room temperature till complete by LCMS. After 2 h, the reaction was complete and the reaction mixture was concentrated to remove the methanol. The aqueous solution that remained was diluted with 7 mL NaHCO3 and the aqueous phase was extracted with three 10 mL portions of CH2Cl2. The organic phase was dried over Na2SO4, filtered, and concentrated to yield a colorless stiff foam/glass. The crude material was purified by flash chromatography (20 g silica gel; 4% 7N NH3 in CH3OH/CH2Cl2) to yield the title compound (62 mg, 80%) as a colorless glass: MS (ESI+) for C39H45ClF3N7O4 m/z 768.0 (M+H)+; MS (ESI−) for C39H45ClF3N7O4 m/z 766.3 (M−H)−; HPLC purity 92.1% (ret. time, 3.29 min).

Workup

  1. concentrationthe reaction mixture was concentrated
  2. customto remove the methanol
  3. additionThe aqueous solution that remained was diluted with 7 mL NaHCO3
  4. extractionthe aqueous phase was extracted with three 10 mL portions of CH2Cl2
  5. dry with materialThe organic phase was dried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customto yield a colorless stiff foam/glass
  9. customThe crude material was purified by flash chromatography (20 g silica gel; 4% 7N NH3 in CH3OH/CH2Cl2)

Sources & evidence

ORD record
ord-c3eb48d438d94b2da20ccfdbc4bc77e8
Source dataset
uspto-grants-2015_08
Patent number
US09096634B2

Reaction notes

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