Dichloromethane → ethyl ((1S)-5-{3-[[2,5-bis(4-methoxyphenyl)-4-pyrimidinyl](methy)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate

HRID 2235961Notes

Reaction equation

HRID 2235961 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[CH2:12]([O:14][C:15](=[O:40])[CH2:16][C@H:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][CH2:27][CH2:28][CH2:29][N:30]([C:32]3[C:37](Cl)=[CH:36][N:35]=[C:34](Cl)[N:33]=3)[CH3:31])=[CH:23][CH:24]=2)[CH2:19][CH2:18]1)[CH3:13].C(Cl)Cl.[C:44](=[O:47])([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:12]([O:14][C:15](=[O:40])[CH2:16][C@H:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][CH2:27][CH2:28][CH2:29][N:30]([C:32]3[C:37]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)=[CH:36][N:35]=[C:34]([C:3]4[CH:8]=[CH:7][C:6]([O:47][CH3:44])=[CH:5][CH:4]=4)[N:33]=3)[CH3:31])=[CH:23][CH:24]=2)[CH2:19][CH2:18]1)[CH3:13]

Participants

8

Reactant 4

HCID 6344DichloromethaneHCID 10340Sodium CarbonateHCID 201262(4-Methoxyphenyl)boronic acidHCID 59300554ethyl ((1S)-5-{3-[(2,5-dichloro-4-pyrimidinyl)(methyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate

Product 1

HCID 59300448ethyl ((1S)-5-{3-[[2,5-bis(4-methoxyphenyl)-4-pyrimidinyl](methy)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetateYield 64.8%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 1140TolueneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
75 °C

Procedure

To a mixture of 4-methoxyphenylboronic acid (142 mg, 0.913 mmol) and ethyl((1S)-5-{3-[(2,5-dichloro-4-pyrimidinyl)(methyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 442, 100 mg, 0.228 mmol ) in toluene (5 mL) and 1,4-dioxane (1.25 mL) was added PdCl2(dppf).CH2Cl2(19 mg, 0.023 mmol). The mixture was purged with argon for 15 min after which sodium carbonate (1.2 mL, 2.40 mmol, 2 M aqueous solution) was added. The mixture was stirred at 75° C. for 18 h, cooled to rt, and then washed with a saturated sodium bicarbonate solution. The organic layer was separated from the mixture and the aqueous phase extracted with EtOAc. The combined organic phases were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (1:4 EtOAc/Hexanes) to give (86 mg, 64%) of the desired product. 1H NMR (400 MHz, CDCl3): δ 1.30 (t, 3H), 1.70-1.80 (m, 1H), 2.15-2.20 (m, 2H), 2.28-2.45 (m, 2H), 2.70 (dd, 1H), 2.72-2.90 (m, 2H), 2.80 (s, 3H), 3.45-3.55 (m, 1H), 3.75 (t, 2H), 3.85 (s, 3H), 3.92 (s, 3H), 3.95 (t, 2H), 4.20 (q, 2H), 6.65 (d, 1H), 6.7 (s, 1H), 6.9 (d, 2H), 6.95 (d, 2H), 7.05 (s, 1H), 7.32 (d, 2H), 8.15 (s, 1H), 8.40 (d, 2H).

Workup

  1. additionwas added
  2. temperaturecooled to rt
  3. washwashed with a saturated sodium bicarbonate solution
  4. customThe organic layer was separated from the mixture
  5. extractionthe aqueous phase extracted with EtOAc
  6. dry with materialThe combined organic phases were dried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe residue was purified by flash column chromatography (1:4 EtOAc/Hexanes)

Sources & evidence

ORD record
ord-366bc65cea85438fa2bed5953d8d6753
Source dataset
uspto-grants-2010_05
Patent number
US07714004B2

Reaction notes

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