Acetic Acid → HCID 86708667, compound

HRID 921777Notes

Reaction equation

HRID 921777 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:5]([C:15]#[N:16])=[CH:4][C:3]=1[NH:17][C:18]1[N:23]=[C:22]([NH:24][CH:25]2[CH2:27][CH2:26]2)[C:21]2=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:20]2[N:19]=1.[O:33]1[CH2:36][C:35](=O)[CH2:34]1.COC(OC)OC.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH:35]3[CH2:36][O:33][CH2:34]3)[CH2:11][CH2:10]2)[C:5]([C:15]#[N:16])=[CH:4][C:3]=1[NH:17][C:18]1[N:23]=[C:22]([NH:24][CH:25]2[CH2:26][CH2:27]2)[C:21]2=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:20]2[N:19]=1

Participants

8

Reactant 5

HCID 176Acetic AcidHCID 9005Trimethyl orthoformateHCID 5003444Sodium cyanoborohydrideHCID 150242543-OxetanoneHCID 86708668HCID 86708668, compound

Product 1

HCID 86708667HCID 86708667, compoundYield 32.2%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Procedure

A suspension of 2-((2-chloro-5-cyano-4-(piperidin-4-ylamino)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 410) (36 mg, 0.080 mmol), oxetan-3-one (116 mg, 1.604 mmol), trimethylorthoformate (0.443 mL, 4.01 mmol), and acetic acid (0.046 mL, 0.802 mmol) in a mixture of MeOH (0.5 mL) and DCM (0.5 mL) was stirred at room temperature for 15 min. Sodium cyanoborohydride (1M in THF, 0.802 mL, 0.802 mmol) was added and the reaction was left stirring for 9 hrs. It was partitioned between EtOAc and sat. aq. NaHCO3 solution. After stirring for 15 min, the aqueous phase was separated and washed with EtOAc (3×) and then a mixture of 10% MeOH in DCM (4×). The combined organic phases were dried with sodium sulfate and the solvent removed. Preparative HPLC (Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 20-mM ammonium acetate; Gradient: 10-100% B over 30 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min) afforded the title compound (13 mg).

Workup

  1. waitthe reaction was left
  2. stirringstirring for 9 hrs
  3. customIt was partitioned between EtOAc and sat. aq. NaHCO3 solution
  4. stirringAfter stirring for 15 min
  5. customthe aqueous phase was separated
  6. washwashed with EtOAc (3×)
  7. additiona mixture of 10% MeOH in DCM (4×)
  8. dry with materialThe combined organic phases were dried with sodium sulfate
  9. customthe solvent removed
  10. waitGradient: 10-100% B over 30 minutes
  11. customa 5-minute hold

Sources & evidence

ORD record
ord-0ede49404e724c41aa9b85b341639ef2
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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