Triethylamine → 1-{6-Benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-3,4-dihydro-1H-isoquinolin-2-yl}-2,2-dimethylpropan-1-one

HRID 397036

Reaction equation

HRID 397036 reaction equation
[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=1)[NH:14][CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:40][C:41]([CH3:46])([CH3:45])[C:42](Cl)=[O:43]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=1)[N:14]([C:42](=[O:43])[C:41]([CH3:46])([CH3:45])[CH3:40])[CH2:13][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 62493Pivaloyl chlorideHCID 181724176-Benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline

Product 1

HCID 120859491-{6-Benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-3,4-dihydro-1H-isoquinolin-2-yl}-2,2-dimethylpropan-1-oneYield 58.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of 6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline (0.015 g, 0.04 mmol) and Et3N (0.01 ml, 0.07 mmol) in anhydrous THF (0.35 ml) was added to a solution of trimethylacetyl chloride (0.04 mmol) in anhydrous THF (0.4 ml) at rt in a sealed reaction vessel. The resulting suspension was stirred at rt for 20 hr, then evaporated to dryness. The product was suspended in a mixture of H2O (0.4 ml) and saturated NaHCO3 solution (0.4 ml), then extracted with CH2Cl2 (3×0.75 ml). The combined extracts were evaporated to dryness to give the crude product. Purification by reverse-phase HPLC, eluting first with gradient. Purification by reverse-phase HPLC on a Primesphere (Phenomenex 2320 West 205th St. Torrance, Calif. 90501) C-18HC (50.0 mm×10.0 mm column with 5 m particle size) column, eluting with a linear gradient starting at time 0 min. of H2O:CH3CN:1% TFA/H2O (85:10:5), increasing to H2O:CH3CN:1% TFA/H2O (5:90:5) at 8 min., detected on a Micromass Platform 2 mass spectrometer (DAD 190-600 nM) gave material which, after evaporation to dryness, was purified by reverse-phase HPLC on a Primesphere C-18HC (3.0 mm×2.0 mm column with 5 m particle size) column, eluting with a linear gradient starting at time 0 min. of H2O:CH3CN:TFA (99.9:0:0.1), increasing to H2O:CH3CN:TFA (0:99.9:0.1) at 4 min., detected with a UV detector (300 nM +/−90 nM and 254 nM +/−25 nM), gave an eluent that was evaporated to dryness to give 0.012 g (56% yield) of the pure product. MS 513 m/e (M++1).

Workup

  1. customevaporated to dryness
  2. additionThe product was suspended in a mixture of H2O (0.4 ml) and saturated NaHCO3 solution (0.4 ml)
  3. extractionextracted with CH2Cl2 (3×0.75 ml)
  4. customThe combined extracts were evaporated to dryness
  5. customto give the crude product
  6. customPurification by reverse-phase HPLC
  7. washeluting first with gradient
  8. customPurification by reverse-phase HPLC on a Primesphere (Phenomenex 2320 West 205th St. Torrance, Calif. 90501) C-18HC (50.0 mm×10.0 mm column with 5 m particle size) column
  9. washeluting with a linear gradient
  10. customstarting at time 0 min. of H2O
  11. temperatureCH3CN:1% TFA/H2O (85:10:5), increasing to H2O
  12. waitCH3CN:1% TFA/H2O (5:90:5) at 8 min.
  13. customgave material which
  14. customafter evaporation to dryness
  15. customwas purified by reverse-phase HPLC on a Primesphere C-18HC (3.0 mm×2.0 mm column with 5 m particle size) column
  16. washeluting with a linear gradient
  17. customstarting at time 0 min. of H2O:CH3CN:TFA (99.9:0:0.1)
  18. temperatureincreasing to H2O:CH3CN:TFA (0:99.9:0.1) at 4 min.
  19. customgave an eluent
  20. customthat was evaporated to dryness

Sources & evidence

ORD record
ord-53166311344040c38aaf620899cd877b
Source dataset
uspto-grants-2003_08
Patent number
US06608203B2

Linked notes

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