Phosgene → 3-(4-{[(3,5-Dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-3-hydroxymethyl-benzyl)-1-ethyl-1-phenyl-urea

HRID 251081Notes

Reaction equation

HRID 251081 reaction equation
[CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].CCN(C(C)C)C(C)C.[C:19](Cl)(Cl)=[O:20].[NH2:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:33][N:34]([CH2:45][C:46]2[C:51]([CH3:52])=[CH:50][C:49]([CH3:53])=[CH:48][N:47]=2)[CH:35]2[C:44]3[N:43]=[CH:42][CH:41]=[CH:40][C:39]=3[CH2:38][CH2:37][CH2:36]2)=[C:29]([CH2:31][OH:32])[CH:30]=1>C1(C)C=CC=CC=1.CN(C=O)C>[CH3:52][C:51]1[C:46]([CH2:45][N:34]([CH2:33][C:28]2[CH:27]=[CH:26][C:25]([CH2:24][NH:23][C:19](=[O:20])[N:3]([CH2:1][CH3:2])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:30][C:29]=2[CH2:31][OH:32])[CH:35]2[C:44]3[N:43]=[CH:42][CH:41]=[CH:40][C:39]=3[CH2:38][CH2:37][CH2:36]2)=[N:47][CH:48]=[C:49]([CH3:53])[CH:50]=1

Participants

7

Reactant 4

HCID 6371PhosgeneHCID 7670N-EthylanilineHCID 81531Diisopropylethylamine2×HCID 67271935(5-Aminomethyl-2-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-phenyl)-methanol

Product 1

HCID 672721823-(4-{[(3,5-Dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-3-hydroxymethyl-benzyl)-1-ethyl-1-phenyl-ureaYield 78.8%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 6228DimethylformamideSolvent

Procedure

To a solution of N-ethylaniline (23 μL, 0.18 mmol) in toluene (3 mL) was added DIPEA (63 μL, 0.36 mmol) and phosgene (99 μL, 2.2M in toluene, 0.22 mmol). The mixture was stirred for 2 hours at room temperature under N2 and then the solvent was removed under reduced pressure to give a white solid. A solution of (5-aminomethyl-2-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-phenyl)-methanol (0.075 g, 0.18 mmol) and DIPEA (63 μL, 0.36 mmol) in DMF (4 mL) was added to the white residue and the resulting mixture was stirred for 16 hours. The solvent was removed under reduced pressure and the resulting residue was suspended in CH2Cl2 (30 mL) and quenched with saturated aqueous NaHCO3 (30 mL). The mixture was extracted with CH2Cl2 (3×30 mL) and the combined organic extracts were washed with brine (3×20 mL) and then dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 93:5:2, v/v/v) afforded 3-(4-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-3-hydroxymethyl-benzyl)-1-ethyl-1-phenyl-urea as a white foamy solid (0.080 g, 78%). 1H NMR (CDCl3) δ 1.10 (t, 3H, J=9.0 Hz), 1.60 (m, 1H), 1.99 (m, 1H), 2.19 (m, 2H), 2.20 (s 3H), 2.24 (s, 3H), 2.64 (m, 1H), 2.78 (m, 1H), 3.63 (d, 2H, J=12.0 Hz), 3.70-3.79 (m, 3H), 3.86 (t, 1H, J=7.5 Hz), 4.11 (m, 2H), 4.31 (d+m, 2H), 4.42 (m, 1H), 7.05 (m, 2H), 7.14-7.38 (m, 9H), 8.15 (s, 1H), 8.37 (d, 1H, J=3.0 Hz). HPLC: 99%.

Workup

  1. customthe solvent was removed under reduced pressure
  2. customto give a white solid
  3. stirringthe resulting mixture was stirred for 16 hours
  4. customThe solvent was removed under reduced pressure
  5. customquenched with saturated aqueous NaHCO3 (30 mL)
  6. extractionThe mixture was extracted with CH2Cl2 (3×30 mL)
  7. washthe combined organic extracts were washed with brine (3×20 mL)
  8. dry with materialdried (Na2SO4)
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. customPurification by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 93:5:2, v/v/v)

Sources & evidence

ORD record
ord-d0f4b5cd828c4a42a7d5ffe8aa3a3968
Source dataset
uspto-grants-2011_01
Patent number
US07863293B2

Reaction notes

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