Trichloroacetic anhydride → 2-N-(2-methoxyethyl)-6-[5-(3-phenoxyazetidin-1-yl)-1,2,4-oxadiazol-3-yl]-2-N-phenyl-1,3,5-triazine-2,4-diamine

HRID 341455

Reaction equation

HRID 341455 reaction equation
Cl[C:2](Cl)(Cl)C(OC(=O)C(Cl)(Cl)Cl)=O.[NH2:14][C:15]1[N:20]=[C:19]([N:21]([CH2:28][CH2:29][O:30][CH3:31])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:18]=[C:17]([C:32](=[N:34][OH:35])[NH2:33])[N:16]=1.Cl.[O:37]([CH:44]1[CH2:47][NH:46][CH2:45]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH3:31][O:30][CH2:29][CH2:28][N:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:19]1[N:20]=[C:15]([NH2:14])[N:16]=[C:17]([C:32]2[N:33]=[C:2]([N:46]3[CH2:47][CH:44]([O:37][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH2:45]3)[O:35][N:34]=2)[N:18]=1

Participants

7

Reactant 4

HCID 20079Trichloroacetic anhydrideHCID 81531DiisopropylethylamineHCID 185264463-Phenoxyazetidine hydrochlorideHCID 1363771394-amino-N'-hydroxy-6-[(2 methoxyethyl)(phenyl)amino]-1,3,5-triazine-2-carboximidamide2×

Product 1

HCID 668028322-N-(2-methoxyethyl)-6-[5-(3-phenoxyazetidin-1-yl)-1,2,4-oxadiazol-3-yl]-2-N-phenyl-1,3,5-triazine-2,4-diamineYield 29%

Reagents, catalysts & solvents 2

HCID 1049PyridineSolventHCID 1140TolueneSolvent

Procedure

Trichloroacetic anhydride (0.181 mL, 0.989 mmol) was added to 4-amino-N′-hydroxy-6-[(2 methoxyethyl)(phenyl)amino]-1,3,5-triazine-2-carboximidamide (Intermediate 160, 0.250 g, 0.824 mmol) in toluene (10 mL) and stirred at room temperature for 5 min. Pyridine (3 mL) was added and the mixture was heated to 85 C for 1 h. The mixture was concentrated under vacuum and the residue dissolved in EtOAc. This was washed with water, saturated aq. sodium bicarbonate and then brine. The organic layer was dried over sodium sulfate and concentrated. The residue was dissolved in DMF (2 mL) and 3-phenoxyazetidine hydrochloride (0.13 g, 0.685 mmol) and DIPEA (0.499 mL, 1.370 mmol) were added. The mixture was stirred at room temperature for 13 h and was then concentrated under vacuum. The mixture was extracted with EtOAc (30 mL), washed with water, saturated aq. sodium bicarbonate and then brine. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by FCC, eluting with 0-2% MeOH in DCM. The crude material was further purified by FCC, eluting with 50% EtOAc in heptane then 0-2% MeOH in DCM to afford the title compound (0.091 g, 29%).

Workup

  1. temperaturethe mixture was heated to 85 C for 1 h
  2. concentrationThe mixture was concentrated under vacuum
  3. dissolutionthe residue dissolved in EtOAc
  4. washThis was washed with water, saturated aq. sodium bicarbonate
  5. dry with materialThe organic layer was dried over sodium sulfate
  6. concentrationconcentrated
  7. dissolutionThe residue was dissolved in DMF (2 mL)
  8. stirringThe mixture was stirred at room temperature for 13 h
  9. concentrationwas then concentrated under vacuum
  10. extractionThe mixture was extracted with EtOAc (30 mL)
  11. washwashed with water, saturated aq. sodium bicarbonate
  12. dry with materialThe organic layer was dried over sodium sulfate
  13. concentrationconcentrated under vacuum
  14. customThe residue was purified by FCC
  15. washeluting with 0-2% MeOH in DCM
  16. customThe crude material was further purified by FCC
  17. washeluting with 50% EtOAc in heptane

Sources & evidence

ORD record
ord-36f7457cdbbc457487b170de6428c06a
Source dataset
uspto-grants-2014_11
Patent number
US08895733B2

Linked notes

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