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

HRID 603493Notes

Reaction equation

HRID 603493 reaction equation
[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]3)[C:5]([Cl:28])=[CH:4][N:3]=1.[H-].[Na+].I[CH3:32]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:32])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]3)[C:5]([Cl:28])=[CH:4][N:3]=1

Participants

5

Reactant 3

HCID 6328Methyl iodideHCID 24758Sodium hydrideHCID 59300519ethyl ((1S)-5-{3-[(2,5-dichloro-4-pyrimidinyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate

Product 1

HCID 59300554ethyl ((1S)-5-{3-[(2,5-dichloro-4-pyrimidinyl)(methyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetateYield 82%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of Example 441 (520 mg, 1.23 mmol) in DMF (15 mL) at 0° C. was added portionwise NaH (95 mg, 2.45 mmol, 60% dispersion in mineral oil) [H2 evolution]. The heterogeneous mixture was stirred for 30 min, then iodomethane (0.31 mL, 4.90 mmol) was added. After 18 h of agitation at rt, the excess NaH was quenched by the slow addition of NH4Cl (10% solution in water) [H2 evolution]. The resulting mixture was concentrated under reduced pressure, brought to basic pH using a saturated solution of NaHCO3, and the product was extracted with EtOAc. The combined organic layers were washed with water and brine, after which they were dried (Na2SO4), filtered, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (4:1 hexanes/EtOAc) to yield the product (442 mg, 82%). 1H NMR (400 MHz, CDCl3): δ 1.30 (t, 3H), 1.75-1.82 (m, 1H), 2.12-2.20 (m, 2H), 2.30-2.45 (m, 2H), 2.70 (dd, 1H), 2.72-2.90 (m, 2H), 3.30 (s, 3H), 3.44-3.54 (m, 1H), 3.84 (t, 2H), 3.95 (t, 2H), 4.16 (q, 2H), 6.65 (d, 1H), 6.75 (s, 1H), 7.05 (d, 1H), 8.15 (s, 1H).

Workup

  1. waitAfter 18 h of agitation at rt
  2. customthe excess NaH was quenched by the slow addition of NH4Cl (10% solution in water) [H2 evolution]
  3. concentrationThe resulting mixture was concentrated under reduced pressure
  4. extractionthe product was extracted with EtOAc
  5. washThe combined organic layers were washed with water and brine
  6. dry with materialafter which they were dried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe residue was purified by silica gel chromatography (4:1 hexanes/EtOAc)

Sources & evidence

ORD record
ord-969f3766e87f445a97bab80938eea49b
Source dataset
uspto-grants-2011_03
Patent number
US07906653B2

Reaction notes

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