4-(2,6-Diamino-pyrimidin-4-yloxy)-benzoic acid hydrazide → 6-{4-[5-(4-chloro-3-trifluoromethyl-phenylamino)-4H-[1,2,4]triazol-3-yl]phenoxy}-pyrimidine-2,4-diamine

HRID 387439Notes

Reaction equation

HRID 387439 reaction equation
[NH2:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([NH:15][NH2:16])=O)=[CH:11][CH:10]=2)[CH:5]=[C:4]([NH2:19])[N:3]=1.I.CS[C:23](=[NH:36])[NH:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=1>N1C=CC=CC=1>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:23]2[NH:36][C:13]([C:12]3[CH:17]=[CH:18][C:9]([O:8][C:6]4[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH2:19])[CH:5]=4)=[CH:10][CH:11]=3)=[N:15][N:16]=2)=[CH:26][C:27]=1[C:32]([F:33])([F:34])[F:35]

Participants

4

Reactant 2

HCID 591353394-(2,6-Diamino-pyrimidin-4-yloxy)-benzoic acid hydrazideHCID 1785040011-[4-chloro-3-(trifluoromethyl)phenyl]-S-methylisothiourea hydroiodide

Product 1

HCID 1785079266-{4-[5-(4-chloro-3-trifluoromethyl-phenylamino)-4H-[1,2,4]triazol-3-yl]phenoxy}-pyrimidine-2,4-diamineYield 50.6%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Procedure

4-[(2,6-diaminopyrimidin-4-yl)oxy]benzohydrazide (1.48 g, 5.68 mmol) and S-methyl N-[4-chloro-3-(trifluoromethyl)phenyl]isothiourea hydroiodide (2.33 g, 5.89 mmol) were suspended in 30 mL of anhydrous pyridine. The reaction mixture was refluxed for 18 hours under Ar atmosphere. The formed yellow solution was cooled down to ambient temperature and pyridine was removed in vacuo. The resulting yellow foamy solid was re-dissolved in 50 mL of 5:1 EtOAc/MeOH; ca. 15 g of silica gel was added and solvent was removed in vacuo. The impregnated silica gel was packed into ISCO column and the product was purified using ISCO system (80 g pre-packed column, 50 min run, 0% to 10% gradient of solvent B in solvent A [Solvent A—4 mL of MeOH, 4 ml, of Et3N in 4 L of CH2Cl2; Solvent B—4 mL of Et3N in 4 L of MeOH]). Solvent was removed in vacuo to give the title product as a white solid (1.33 g). Yield 50.5%.

Workup

  1. temperatureThe reaction mixture was refluxed for 18 hours under Ar atmosphere
  2. custompyridine was removed in vacuo
  3. dissolutionThe resulting yellow foamy solid was re-dissolved in 50 mL of 5:1 EtOAc/MeOH
  4. additionca. 15 g of silica gel was added
  5. customsolvent was removed in vacuo
  6. customthe product was purified
  7. customISCO system (80 g pre-packed column, 50 min run, 0% to 10% gradient of solvent B in solvent A [Solvent A—4 mL of MeOH, 4 ml, of Et3N in 4 L of CH2Cl2; Solvent B—4 mL of Et3N in 4 L of MeOH])
  8. customSolvent was removed in vacuo

Sources & evidence

ORD record
ord-72f8e43f01ca4a7888db5ee90438059b
Source dataset
uspto-grants-2013_02
Patent number
US08372971B2

Reaction notes

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