Dicyclohexylcarbodiimide → rac (3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl 2-(phosphonooxy)propanoate

HRID 1430887Notes

Reaction equation

HRID 1430887 reaction equation
[Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([N:15]([CH2:25][CH3:26])CC3C=CC(OC)=CC=3)[C:12]3=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:11]3[N:10]=2)=[CH:6][C:5]([C:32]#[N:33])=[CH:4][C:3]=1[N:34]1[CH2:39][CH2:38][C@@H:37]([NH:40][C:41](=[O:44])[O:42][CH3:43])[C@H:36]([OH:45])[CH2:35]1.C([O:53][P:54]([O:64][CH:65]([CH3:69])[C:66](O)=[O:67])([O:56]CC1C=CC=CC=1)=[O:55])C1C=CC=CC=1.C1CCC(N=C=NC2CCCCC2)CC1.ClC1C(NC2N=C(N(CC)CC3C=CC(OC)=CC=3)C3=NC=C(C#N)N3N=2)=CC(C#N)=CC=1N1CC[C@@H](NC(OC)=O)[C@H](C(OP(OCC2C=CC=CC=2)(OCC2C=CC=CC=2)=O)(C)C([O-])=O)C1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[P:54]([O:64][CH:65]([CH3:69])[C:66]([O:45][CH:36]1[CH:37]([NH:40][C:41]([O:42][CH3:43])=[O:44])[CH2:38][CH2:39][N:34]([C:3]2[CH:4]=[C:5]([C:32]#[N:33])[CH:6]=[C:7]([NH:8][C:9]3[N:14]=[C:13]([NH:15][CH2:25][CH3:26])[C:12]4=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:11]4[N:10]=3)[C:2]=2[Cl:1])[CH2:35]1)=[O:67])([OH:56])([OH:55])=[O:53]

Participants

7

Reactant 4

HCID 10868DicyclohexylcarbodiimideHCID 899186732-((Bis(benzyloxy)phosphoryl)oxy)propanoic acidHCID 131732393methyl((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamateHCID 131732397(3R,4R) 1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4((methoxycarbonyl)amino)piperidin-3-yl-2-((bis(benzyloxy)phosphoryl)oxy)propanoate

Product 1

HCID 89919020rac (3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl 2-(phosphonooxy)propanoate

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent2×

Procedure

To a solution of methyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate (0.040 g, 0.063 mmol), 2-((bis(benzyloxy)phosphoryl)oxy)propanoic acid (0.067 g, 0.19 mmol) in DCM (2 mL) was added DCC (0.039 g, 0.190 mmol) followed DMAP (0.77 mg, 0.006 mmol) and stirred at room temperature for 30 min. After completion of starting material (by LC-MS), reaction mixture was diluted with DCM (50 mL), filtered through celite and filtrate was washed with water and brine solution (5 mL). Combined organic extracts were dried over anhydrous Na2SO4, concentrated and purified by flash chromatography on silica gel using an ISCO system (eluted with 1:1 Hexanes and EtOAc) to give diastereomeric mixture of (3R,4R) 1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4 ((methoxycarbonyl)amino)piperidin-3-yl-2-((bis(benzyloxy)phosphoryl)oxy)propanoate (0.060 g,) as gummy liquid.

Workup

  1. customAfter completion of starting material (by LC-MS), reaction mixture
  2. filtrationfiltered through celite and filtrate
  3. washwas washed with water and brine solution (5 mL)
  4. dry with materialCombined organic extracts were dried over anhydrous Na2SO4
  5. concentrationconcentrated
  6. custompurified by flash chromatography on silica gel using
  7. washan ISCO system (eluted with 1:1 Hexanes and EtOAc)
  8. customto give diastereomeric

Sources & evidence

ORD record
ord-d30735fcf0a64fcb94943778cb34ae9f
Source dataset
uspto-grants-2015_01
Patent number
US08940736B2

Reaction notes

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