Morpholine → HCID 66600187, compound

HRID 1621475Notes

Reaction equation

HRID 1621475 reaction equation
Br[C:2]1[CH:3]=[C:4]([C:17]2[N:25]=[C:24]([CH3:26])[N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.CC(C)([O-])C.[Na+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:16][O:15][C:12]1[N:11]=[CH:10][C:9]([NH:8][C:5]2[C:4]([C:17]3[N:25]=[C:24]([CH3:26])[N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)=[CH:3][C:2]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:7][N:6]=2)=[CH:14][CH:13]=1

Participants

7

Reactant 5

HCID 8083MorpholineHCID 312751,4-DioxaneHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 23676156Sodium t-butoxideHCID 66600480HCID 66600480, compound

Product 1

HCID 66600187HCID 66600187, compoundYield 33.4%

Reagents, catalysts & solvents 1

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Conditions

Temperature
97.5 °C

Procedure

A mixture of 5-bromo-N-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-amine (0.310 g, 0.625 mmol) (Example 64 intermediate), morpholine (0.054 g, 0.625 mmol) (Aldrich, St. Louis, Mo.), sodium tert-butoxide (0.090 g, 0.937 mmol) (Aldrich, St. Louis, Mo.), tris(dibenzylideneacetone)dipalladium (0) (0.011 g, 0.012 mmol) (Aldrich, St. Louis, Mo.) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.022 g, 0.037 mmol) (Strem Chemicals, Inc., Newburyport, Mass.) in dioxane (100 mL, 941 mmol) was deoxygenated and stirred at 95-100° C. under N2 for three hours. The reaction mixture was diluted with ethyl acetate and washed with water (3×). The organic layer was concentrated, adsorbed onto a plug of silica gel and chromatographed through a RediSep®, Teledyne ISCO, Lincoln, Nebr., pre-packed silica gel column (120 g), eluting with a gradient of 10% to 50% ethyl acetate in hexane to give N-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)-5-morpholinopyridin-2amine (0.105 g, 33% yield). The residue was treated with trifluoroacetic acid (Aldrich, St. Louis, Mo.) and dichloromethane to give N-(3-(2-methyl-9H-purin-6-yl)-5-morpholinopyridin-2-yl)-1H-indazol-4-amine. MS (ESI pos. ion) m/z 419 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.46 ((br. s., 1H); 9.56 ((br. s., 1H); 8.56 (d, J=0.39 Hz, 1H); 8.51-8.53 (m, 1H); 8.12 (d, J=1.37 Hz, 2H); 6.82 (d, J=9.00 Hz, 1H); 3.78-3.86 (m, 7H); 3.11 (br. s., 2H); 3.12 (t, J=4.89 Hz, 2H); 2.84 (s, 3H).

Workup

  1. customwas deoxygenated
  2. additionThe reaction mixture was diluted with ethyl acetate
  3. washwashed with water (3×)
  4. concentrationThe organic layer was concentrated
  5. customchromatographed through a RediSep®, Teledyne ISCO, Lincoln, Nebr
  6. wash, pre-packed silica gel column (120 g), eluting with a gradient of 10% to 50% ethyl acetate in hexane

Sources & evidence

ORD record
ord-7b9ae78a13b64347abde91dc7bd7c8e7
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

Loading…