Acetic Acid → methyl ((3S,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-(methyl(oxetan-3-yl)amino)piperidin-4-yl)carbamate

HRID 921933Notes

Reaction equation

HRID 921933 reaction equation
[Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH3:17])[C:12]3=[N:18][CH:19]=[C:20]([C:21]#[N:22])[N:11]3[N:10]=2)=[CH:6][C:5]([C:23]#[N:24])=[CH:4][C:3]=1[N:25]1[CH2:30][CH2:29][C@@H:28]([NH:31][C:32](=[O:35])[O:33][CH3:34])[C:27](=O)[CH2:26]1.[O:37]1[CH2:40][CH:39]([NH2:41])[CH2:38]1.[CH:42](OC)(OC)OC.C(O)(=O)C.[C:53]([BH3-])#[N:54].[Na+].C=O>CN(C=O)C.CO>[Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH3:17])[C:12]3=[N:18][CH:19]=[C:20]([C:21]#[N:22])[N:11]3[N:10]=2)=[CH:6][C:5]([C:23]#[N:24])=[CH:4][C:3]=1[N:25]1[CH2:30][CH2:29][C@@H:28]([NH:31][C:32](=[O:35])[O:33][CH3:34])[C@H:27]([N:41]([CH3:42])[CH:39]2[CH2:40][O:37][CH2:38]2)[CH2:26]1.[Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH3:17])[C:12]3=[N:18][CH:19]=[C:20]([C:21]#[N:22])[N:11]3[N:10]=2)=[CH:6][C:5]([C:23]#[N:24])=[CH:4][C:3]=1[N:25]1[CH2:30][CH2:29][C@@H:28]([NH:31][C:32](=[O:35])[O:33][CH3:34])[C@@H:27]([N:54]([CH3:53])[CH:39]2[CH2:40][O:37][CH2:38]2)[CH2:26]1

Participants

10

Reactant 6

HCID 176Acetic Acid2×HCID 712FormaldehydeHCID 9005Trimethyl orthoformateHCID 5003444Sodium cyanoborohydride2×HCID 98339233-OxetanamineHCID 89934113(R)-methyl (1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-oxopiperidin-4-yl)carbamate

Product 2

HCID 118263115methyl ((3S,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-(methyl(oxetan-3-yl)amino)piperidin-4-yl)carbamateHCID 118263116methyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-(methyl(oxetan-3-yl)amino)piperidin-4-yl)carbamate

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6228DimethylformamideSolvent

Procedure

(R)-methyl (1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-oxopiperidin-4-yl)carbamate (44 mg, 0.039 mmol) was dissolved in DMF (2.5 ml) and methanol (1 ml). oxetan-3-amine (20 μl, 0.039 mmol) and trimethyl orthoformate (0.25 ml, 2.262 mmol) were added. Acetic acid (0.05 ml, 0.873 mmol) was added drop wise until pH ˜5. The reaction mixture was stirred at room temperature for 10 minutes. sodium cyanoborohydride (21 mg, 0.334 mmol) was added and stirring at room temperature continued for 1 hour. Formaldehyde (50 μl, 0.672 mmol) and additional sodium cyanoborohydride (21 mg, 0.334 mmol) and acetic acid (0.05 ml, 0.873 mmol) were added and the mixture stirred at room temperature for 3 hours, then evaporated in a nitrogen stream overnight. The crude mixture of the 2 diastereomeric products was dissolved in DMSO, filtered and purified by prep HPLC with the following conditions: Column: XBridge C18, 19×mm, 5-μm particles; Mobile Phase A: 5:95 methanol: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol: water with 10-mM ammonium acetate; Gradient: 50-90% B over 30 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give methyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-(methyl(oxetan-3-yl)amino)piperidin-4-yl)carbamate (1.7 mg) (Example 750) and methyl ((3S,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-(methyl(oxetan-3-yl)amino)piperidin-4-yl)carbamate (1.9 mg) (Example 751)

Workup

  1. stirringstirring at room temperature
  2. waitcontinued for 1 hour
  3. stirringthe mixture stirred at room temperature for 3 hours
  4. customevaporated in a nitrogen
  5. waitstream overnight
  6. additionThe crude mixture of the 2 diastereomeric products
  7. dissolutionwas dissolved in DMSO
  8. filtrationfiltered
  9. custompurified by prep HPLC with the following conditions
  10. waitGradient: 50-90% B over 30 minutes
  11. customa 5-minute hold
  12. additionFractions containing the desired product
  13. customdried via centrifugal evaporation

Sources & evidence

ORD record
ord-589b83a0d8744bf58c4d2f68a641e383
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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