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

HRID 603494Notes

Reaction equation

HRID 603494 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[Cl:12][C:13]1[N:18]=[C:17]([N:19]([CH3:39])[CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[C@H:29]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:28][CH2:27]3)[C:16](Cl)=[CH:15][N:14]=1.C(Cl)Cl.C([O-])([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]>[Cl:12][C:13]1[N:18]=[C:17]([N:19]([CH3:39])[CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[C@H:29]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:28][CH2:27]3)[C:16]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:15][N:14]=1

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 59300424ethyl((1S)-5-{3-[[2-chloro-5-(4-methoxyphenyl)-4-pyrimidinyl](methyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetateYield 79.3%

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 mixture of 4-methoxyphenylboronic acid (28.5 mg, 0.183 mmol) and ethyl ((1S)-5-{3-[(2,5-dichloro-4-pyrimidinyl)(methyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 442, 80 mg, 0.183 mmol) in toluene (6.72 mL) and 1,4-dioxane (1.68 mL) was added PdCl2(dppf).CH2Cl2 (15 mg, 0.018 mmol). The mixture was purged with argon for 15 min after which a 2 M Na2CO3 aqueous solution (1.68 mL, 1.83 mmol) was added. The mixture was stirred and heated at 75° C. for 2 h, the reaction mixture was allowed cool to rt, and then washed with a saturated aqueous solution of NaHCO3. The organic layer was separated and the aqueous phase extracted with EtOAc (2×). The combined organic phases were dried, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (1:3 EtOAc/Hexanes) to give the product (74 mg, 79%). 1H NMR (400 MHz, CDCl3): δ 1.25 (t, 3H), 1.70-1.79 (m, 1H), 2.15-2.20 (m, 2H), 2.28-2.42 (m, 2H), 2.66 (dd, 1H), 2.72-2.90 (m, 2H), 3.31 (s, 3H), 3.44-3.54 (m, 1H), 3.82 (s, 3H), 3.84 (t, 2H), 3.95 (t, 2H), 4.16 (q, 2H), 6.65 (d, 1H), 6.72 (s, 1H), 6.91 (d, 2H), 7.05 (s, 1H), 8.15 (s, 1H), 8.25 (d, 2H); LC-MS: RT=3.51 min, (M+H)+ 510.5.

Workup

  1. additionwas added
  2. temperaturethe reaction mixture was allowed cool to rt
  3. washwashed with a saturated aqueous solution of NaHCO3
  4. customThe organic layer was separated
  5. extractionthe aqueous phase extracted with EtOAc (2×)
  6. customThe combined organic phases were dried
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe residue was purified by silica gel flash column chromatography (1:3 EtOAc/Hexanes)

Sources & evidence

ORD record
ord-29995d3ba6aa483baba7255681ee8e01
Source dataset
uspto-grants-2011_03
Patent number
US07906653B2

Reaction notes

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