Epichlorohydrin → HCID 89923334, compound

HRID 921937Notes

Reaction equation

HRID 921937 reaction equation
[NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([Cl:40])=[C:10]([NH:16][C:17]3[N:22]=[C:21]([N:23]([CH2:33][CH3:34])[CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[C:20]4=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:19]4[N:18]=3)[CH:11]=[C:12]([C:14]#[N:15])[CH:13]=2)[CH2:4][C@H:3]1[OH:41].CCN(C(C)C)C(C)C.Cl[CH2:52][CH:53]1[CH2:55][O:54]1>CN(C=O)C>[Cl:40][C:9]1[C:8]([N:5]2[CH2:6][CH2:7][C@@H:2]([N:1]3[CH2:55][CH:53]([OH:54])[CH2:52]3)[C@H:3]([OH:41])[CH2:4]2)=[CH:13][C:12]([C:14]#[N:15])=[CH:11][C:10]=1[NH:16][C:17]1[N:22]=[C:21]([N:23]([CH2:33][CH3:34])[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[C:20]2=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:19]2[N:18]=1

Participants

5

Reactant 3

HCID 7835EpichlorohydrinHCID 81531DiisopropylethylamineHCID 131734956HCID 131734956, compound

Product 1

HCID 89923334HCID 89923334, compoundYield 103.7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
70 °C

Procedure

(+/−)-2-((3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (29 mg, 0.046 mmol) was dissolved in DMF (1 ml) in a 4 ml vial. DIPEA (0.25 ml, 1.431 mmol) was added and the mixture warmed to 70° C. A solution of 2-(chloromethyl)oxirane (100 μl, 1.279 mmol) in DMF (1 ml) was added slowly. The reaction mixture was kept at 70° C. for 30 minutes. The crude reaction mixture was filtered through a MCX cartridge (Waters, 5 g adsorbent). The cartridge was washed with MeOH and the product eluted with a 1:1 mixture of (CH3CN+2 molar solution of NH3 in MeOH). Evaporation to dryness gave 30 mg of (+/−)-2-((2-chloro-5-cyano-3-((3R,4R)-3-hydroxy-4-(3-hydroxyazetidin-1-yl)piperidin-1-yl)phenyl)amino)-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile. The crude was used “as is” in the following deprotection

Workup

  1. customThe crude reaction mixture
  2. filtrationwas filtered through a MCX cartridge (Waters, 5 g adsorbent)
  3. washThe cartridge was washed with MeOH
  4. washthe product eluted with a 1:1 mixture of (CH3CN+2 molar solution of NH3 in MeOH)
  5. customEvaporation to dryness

Sources & evidence

ORD record
ord-357a865ce717490395624fff23fec28a
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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