Hydrochloric Acid → HCID 178483063, compound

HRID 1984898Notes

Reaction equation

HRID 1984898 reaction equation
Br[C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][CH2:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][NH:16][C:17]3[N:26]=[C:25]([N:27]([CH3:29])[CH3:28])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)[CH2:11][CH2:10]2)=[C:4]([O:32][C:33]([F:36])([F:35])[F:34])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:43]1(B(O)O)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.[ClH:52]>C1(C)C=CC=CC=1.CCOC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.CO>[ClH:52].[ClH:52].[CH3:28][N:27]([CH3:29])[C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([NH:16][CH2:15][C@H:12]2[CH2:13][CH2:14][C@H:9]([CH2:8][NH:7][CH2:6][C:5]3[CH:30]=[CH:31][C:2]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[CH:3][C:4]=3[O:32][C:33]([F:36])([F:35])[F:34])[CH2:10][CH2:11]2)[N:26]=1

Participants

10

Reactant 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 66827Phenylboronic AcidHCID 178483062HCID 178483062, compound

Product 1

HCID 178483063HCID 178483063, compoundYield 21%

Reagents, catalysts & solvents 5

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 887MethanolSolventHCID 962WaterSolventHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent2×

Conditions

Temperature
130 °C

Procedure

To a solution of trans-N2-{4-[(4-bromo-2-trifluoromethoxy-benzylamino)-methyl]-cyclohexylmethyl}-N4,N4-dimethyl-quinazoline-2,4-diamine obtained in step B of example 15 (300 mg, 0.529 mol) in toluene (6.6 mL) were added MeOH (2.2 mL), 2 M aqueous K2CO3 (2.2 mL), phenylboronic acid (77 mg, 0.635 mmol), and tetrakis (triphenylphosphine) palladium (61 mg, 0.053 mmol). The reaction mixture was stirred at 130° C. for 12 hr. The mixture was poured into water, and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated and, purified by flash chromatography (NH-silica gel, 33% CHCl3 in hexane and silica gel, 9% MeOH in CHCl3) to give pale yellow oil. To a solution of above oil in EtOAc (2 mL) was added 4 M hydrogen chloride in EtOAc (0.1 mL). The mixture was stirred at ambient temperature for 20 min and concentrated. A solution of the residue in Et2O (2 mL) was stirred at ambient temperature for 30 min. The precipitate was collected by filtration, washed with Et2O, and dried under reduced pressure to give trans-N4,N4-dimethyl-N2-(4-{[(3-trifluoromethoxy-biphenyl-4-ylmethyl)-amino]-methyl}-cyclohexylmethyl)-quinazoline-2,4-diamine dihydrochloride (70 mg, 21%) as a white solid.

Workup

  1. extractionthe aqueous layer was extracted with CHCl3 (three times)
  2. dry with materialThe combined organic layer was dried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. custompurified by flash chromatography (NH-silica gel, 33% CHCl3 in hexane and silica gel, 9% MeOH in CHCl3)
  6. customto give pale yellow oil
  7. stirringThe mixture was stirred at ambient temperature for 20 min
  8. concentrationconcentrated
  9. stirringA solution of the residue in Et2O (2 mL) was stirred at ambient temperature for 30 min
  10. filtrationThe precipitate was collected by filtration
  11. washwashed with Et2O
  12. customdried under reduced pressure

Sources & evidence

ORD record
ord-b1793724f28f419fabebf4ca9f4a815d
Source dataset
uspto-grants-2009_06
Patent number
US07544690B2

Reaction notes

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