Morpholine → HCID 178428079, compound

HRID 1399779Notes

Reaction equation

HRID 1399779 reaction equation
Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=3[CH3:22])[CH:9]=[N:10][C:5]2=[C:4]([O:23]C)[CH:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>O.Cl>[CH3:22][C:13]1[C:14]([C:18]([F:21])([F:19])[F:20])=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][N:8]1[C:6]2=[N:7][C:2]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:3][C:4]([OH:23])=[C:5]2[N:10]=[CH:9]1

Participants

5

Reactant 2

HCID 8083MorpholineHCID 896478905-Chloro-7-(methyloxy)-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-3H-imidazo[4,5-b]pyridine

Product 1

HCID 178428079HCID 178428079, compoundYield 17.77%

Reagents, catalysts & solvents 2

HCID 313Hydrochloric AcidSolventHCID 962WaterSolvent

Procedure

5-chloro-7-(methyloxy)-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-3H-imidazo[4,5-b]pyridine (45 mg, 0.126 mmol) was suspended in 1.5 mL of morpholine in a microwave vial and the mixture was irradiated in a microwave oven at 130° C. for 45 min, then for additional 3 h, another 3 h and then additional 12 h. Product is slowly forming (as observed by LC/MS) going through the formation of the 7-hydroxy derivative first. The mixture was then irradiated for 3 h at 200° C., to provide complete conversion to the desired product. An additional aliquot of 5-chloro-7-(methyloxy)-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-3H-imidazo[4,5-b]pyridine (60 mg, 0.169 mmol) was suspended in morpholine (1.5 mL) and irradiated in a microwave oven at 200° C. for 3 h. The reaction was not completed, so it was irradiated again in the microwave at 200° C. for 150 min. The two reaction mixtures were combined and diluted with water and 1 N HCl was added to pH 4-5. The precipitate formed was collected by filtration, washed with water and dried. The solid was dissolved in DMSO and purified by Reverse phase-HPLC (25 to 80% AcCN in water plus 0.1% TFA). Two peaks closely eluted on the HPLC and were isolated for the product. The slower retention time peak presented 2% impurity so it was kept separated. The collected fractions were neutralized by the addition of NaHCO3 sat sol and the solvent volume was reduced to ½-⅓ of the original. The precipitates were collected washed with water and dried in a vacuum oven at 45° C. for 5 h to give 3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-5-(4-morpholinyl)-3H-imidazo[4,5-b]pyridin-7-ol (21 mg, 0.052 mmol, 17.77% yield) which was submitted for testing, and the less pure sample of 3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-5-(4-morpholinyl)-3H-imidazo[4,5-b]pyridin-7-ol (18 mg, 0.046 mmol, 15.54% yield), which was stored as is. MS (ES+) m/e 393 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 10.85 (br. s., 1H), 7.99 (s, 1H), 7.62 (d, J=8.08 Hz, 1H), 7.34 (t, J=7.83 Hz, 1H), 7.26 (d, J=7.58 Hz, 1H), 6.07 (s, 1H), 5.41 (s, 2H), 3.57-3.76 (m, 4H), 3.24-3.40 (m, 4H), (CH3 peak under DMSO peak).

Workup

  1. customirradiated in a microwave oven at 200° C. for 3 h
  2. customwas irradiated again in the microwave at 200° C. for 150 min
  3. customThe two reaction mixtures
  4. additionwas added to pH 4-5
  5. customThe precipitate formed
  6. filtrationwas collected by filtration
  7. washwashed with water
  8. customdried
  9. dissolutionThe solid was dissolved in DMSO
  10. custompurified by Reverse phase-HPLC (25 to 80% AcCN in water plus 0.1% TFA)
  11. washTwo peaks closely eluted on the HPLC
  12. customwere isolated for the product
  13. customwas kept separated
  14. additionThe collected fractions were neutralized by the addition of NaHCO3
  15. customThe precipitates were collected
  16. washwashed with water
  17. customdried in a vacuum oven at 45° C. for 5 h

Sources & evidence

ORD record
ord-6cd548957e824d70b39f6abb9e6785c0
Source dataset
uspto-grants-2014_12
Patent number
US08906910B2

Reaction notes

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