Chloride → HCID 68953351, compound

HRID 1960034Notes

Reaction equation

HRID 1960034 reaction equation
[Cl-:1].[CH2:2]([O:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH:14]([C@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22]2[C:31]([CH2:32]O)=[CH:30][C:29]3[C:24](=[CH:25][C:26]([F:35])=[C:27]([F:34])[CH:28]=3)[N:23]=2)[CH2:13][CH2:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:2]([O:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH:14]([C@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22]2[C:31]([CH2:32][Cl:1])=[CH:30][C:29]3[C:24](=[CH:25][C:26]([F:35])=[C:27]([F:34])[CH:28]=3)[N:23]=2)[CH2:13][CH2:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1

Participants

7

Reactant 4

HCID 312ChlorideHCID 962WaterHCID 81531DiisopropylethylamineHCID 57861233HCID 57861233, compound

Product 1

HCID 68953351HCID 68953351, compound

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Procedure

Methaneslufonyl chloride (1.52 mL, 20 mmol) is added dropwise to a mixture of (2-{(R)-2-[4-(benzyloxymethyl)cyclohexyl]pyrrolidin-1-yl}-6,7-difluoroquinolin-3-yl)methanol (7.03 g, 15 mmol) and N,N-diisopropylethylamine (DIPEA, 3.41 mL, 15 mmol) in toluene (75 mL) at 0° C. The reaction mixture is stirred at ambient temperature for 1 hour. To the mixture, water and ethyl acetate are added, and the organic layer is washed with sat. NaHCO3 aq, brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is dissolved with toluene and concentrated in vacuo to give crude 2-{(R)-2-[4-(benzyloxymethyl)cyclohexyl]pyrrolidin-1-yl}-3-(chloromethyl)-6,7-difluoroquinoline. To a mixture of N-[3,5-bis(trifluoromethyl)benzyl]-N-(2-methyl-2H-tetrazol-5-yl)amine (5.88 g, 18 mmol) in DMF (60 mL) is added potassium tert-butoxide (2.03 g, 18 mmol) at 0° C., and the resulting mixture is stirred for 30 min at the same temperature. A crude 2-{(R)-2-[4-(benzyloxymethyl)cyclohexyl]pyrrolidin-1-yl}-3-(chloromethyl)-6,7-difluoroquinoline dissolved in DMF (30 mL) is added dropwise to the mixture at 0° C., and the resulting mixture is stirred for 1 hour at the same temperature. Potassium tert-butoxide (1.70 g, 14 mmol) is added to the reaction mixture, and the mixture is stirred another 1 hour at room temperature. After adding water, the mixture is extracted with ethyl acetate. The combined organic layer is washed with brine, dried over magnesium sulfate, filtrated, and concentrated. The resulting mixture is purified by silica gel column chromatography to give trans-N-(2-{(R)-2-[4-(2-benzyloxymethyl)cyclohexyl]pyrrolidin-1-yl}-6,7-difluoroquinolin-3-ylmethyl)-N-[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amine as a yellow amorphous solid.

Workup

  1. washthe organic layer is washed with sat. NaHCO3 aq, brine
  2. dry with materialdried over magnesium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated in vacuo
  5. dissolutionThe residue is dissolved with toluene
  6. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-9fb55c3b44f84d1d81447573a2a0c26a
Source dataset
uspto-grants-2013_04
Patent number
US08410275B2

Reaction notes

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