Lithium hydroxide, monohydrate → 2-[(Biphenyl-4-ylmethyl)-amino]-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone

HRID 1093770Notes

Reaction equation

HRID 1093770 reaction equation
Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Cl.[NH2:16][CH2:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[CH2:22][CH2:21]1)=[O:19].O[Li].O>CN(C=O)C>[C:6]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:8][C:3]([CH2:2][NH:16][CH2:17][C:18]([N:20]2[CH2:25][CH2:24][CH:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])[CH2:22][CH2:21]2)=[O:19])=[CH:4][CH:5]=1

Participants

5

Reactant 3

HCID 168937Lithium hydroxide, monohydrateHCID 2577161,1'-Biphenyl, 4-(bromomethyl)-HCID 665915282-Amino-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride

Product 1

HCID 578745102-[(Biphenyl-4-ylmethyl)-amino]-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanoneYield 11.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A mixture of biphenyl-4-yl-methanol (250 mg, 1.35 mmol) and aqueous HBr (48%) (3 mL) was stirred at 10° C. for 3 hrs. After completion of the reaction, the mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer collected was concentrated under reduced pressure to afford 330 mg (98.5% Yield) 4-bromomethyl-biphenyl. 4-Bromomethyl-biphenyl (120 mg, 0.485 mmol) was added to a stirred mixture of 2-amino-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (134 mg, 0.44 mmol) (prepared according to Step 1 and 5 of the General Scheme), LiOH.H2O (40 mg, 0.97 mmol) and 4 Å molecular sieves (350 mg) in DMF (4 mL) and stirring was continued overnight. The reaction mixture was filtered and filtrate was diluted with cold water, extracted with ethyl acetate and organic layer was dried over sodium sulfate. The organic layer was concentrated under reduced pressure. Purification by column chromatography (using neutral alumina and 5% MeOH in DCM as eluent) to afford 22 mg (11.4% Yield) of 2-[(biphenyl-4-ylmethyl)-amino]-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone. LC/MS [M+H]+: 435, 90.56%. 1H NMR (CDCl3): δ7.64-7.52 (m, 4H), 7.5-7.3 (m, 6H), 7.24-7.15 (dt, 1H), 7.0-6.86 (m, 2H), 4.6 (q, 1H), 4.0-3.8 (m, 3H), 3.7-3.6 (m, 3H), 3.5 (s, 2H), 3.4-3.3 (m, 1H), 2.0-1.8 (m, 4H).

Workup

  1. customprepared
  2. filtrationThe reaction mixture was filtered
  3. additionfiltrate was diluted with cold water
  4. extractionextracted with ethyl acetate and organic layer
  5. dry with materialwas dried over sodium sulfate
  6. concentrationThe organic layer was concentrated under reduced pressure
  7. customPurification by column chromatography (using neutral alumina and 5% MeOH in DCM as eluent)

Sources & evidence

ORD record
ord-2a76988e417a48f883e31944f8c40774
Source dataset
uspto-grants-2012_03
Patent number
US08129376B2

Reaction notes

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