Acetic Acid → (+/-)-2-((3-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-(oxetan-3-ylamino)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino) imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

HRID 921673Notes

Reaction equation

HRID 921673 reaction equation
[NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([Cl:32])=[C:10]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH:24]4[CH2:26][CH2:25]4)[C:20]4=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:19]4[N:18]=3)[CH:11]=[C:12]([C:14]#[N:15])[CH:13]=2)[CH2:4][C@H:3]1[O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].C(OC)(OC)OC.CC(O)=O.[O:52]1[CH2:55][C:54](=O)[CH2:53]1.[BH3-]C#N.[Na+]>CO.CCOC(C)=O.C1COCC1>[Si:34]([O:33][C@H:3]1[C@H:2]([NH:1][CH:54]2[CH2:55][O:52][CH2:53]2)[CH2:7][CH2:6][N:5]([C:8]2[C:9]([Cl:32])=[C:10]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH:24]4[CH2:25][CH2:26]4)[C:20]4=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:19]4[N:18]=3)[CH:11]=[C:12]([C:14]#[N:15])[CH:13]=2)[CH2:4]1)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36]

Participants

9

Reactant 5

HCID 176Acetic AcidHCID 9005Trimethyl orthoformateHCID 5003444Sodium cyanoborohydrideHCID 150242543-OxetanoneHCID 86708502(+/-) 2-((3-((3R,4R)-4-amino-3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

Product 1

HCID 86708540(+/-)-2-((3-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-(oxetan-3-ylamino)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino) imidazo[2,1-f][1,2,4]triazine-7-carbonitrileYield 45.4%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

(+/−)2-((3-((3R,4R)-4-amino-3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 171C)(60 mg, 0.104 mmol) was taken up in MeOH (1 mL) and THF (1 mL) and trimethyl orthoformate (0.859 mL, 7.77 mmol), AcOH (0.024 mL, 0.414 mmol), and oxetan-3-one (0.066 mL, 1.036 mmol) were added. The reaction was stirred at room temperature for 2 h, then NaCNBH3 (65.1 mg, 1.036 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with sat'd NaHCO3, then brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography, eluting with 0-3% MeOH/DCM. (+/−)-2-((3-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-(oxetan-3-ylamino)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino) imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (30 mg) was obtained as a white foam.

Workup

  1. stirringthe reaction was stirred at room temperature overnight
  2. washwashed with sat'd NaHCO3
  3. dry with materialThe organic layer was dried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe material was purified by flash column chromatography
  7. washeluting with 0-3% MeOH/DCM

Sources & evidence

ORD record
ord-a97b04eb2de047cf8a12042047eafffa
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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