Diisopropylethylamine → 4-[[[[(RS)-1-[[4-(4-bromophenoxy)phenyl]methyl]-2-piperidinyl]methyl]methylamino]methyl]benzoic acid

HRID 1046334

Reaction equation

HRID 1046334 reaction equation
Cl.[CH3:2][N:3]([CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][NH:6]1.C(N(C(C)C)CC)(C)C.[Br:31][C:32]1[CH:46]=[CH:45][C:35]([O:36][C:37]2[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=2)=[CH:34][CH:33]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>ClC(Cl)C>[Br:31][C:32]1[CH:46]=[CH:45][C:35]([O:36][C:37]2[CH:44]=[CH:43][C:40]([CH2:41][N:6]3[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]3[CH2:4][N:3]([CH2:11][C:12]3[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=3)[CH3:2])=[CH:39][CH:38]=2)=[CH:34][CH:33]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2724942TriacetoxyborohydrideHCID 106362404-(4-Bromophenoxy)benzaldehydeHCID 68489203Methyl 4-((methyl(piperidin-2-ylmethyl)amino)methyl)benzoate hydrochloride salt

Product 1

HCID 684871564-[[[[(RS)-1-[[4-(4-bromophenoxy)phenyl]methyl]-2-piperidinyl]methyl]methylamino]methyl]benzoic acidYield 13.2%

Reagents, catalysts & solvents 1

HCID 63651,1-DichloroethaneSolvent

Procedure

A slurry of methyl 4-((methyl(piperidin-2-ylmethyl)amino)methyl)benzoate hydrochloride salt (200 mg, 0.58 mmol) in dichloroethane (6 mL) was stirred as diisopropylethylamine (225 mg, 1.74 mmol) was added. After 30 minutes, 4-(4-bromophenoxy)benzaldehyde (160 mg, 0.58 mmol) was added to the reaction mixture. After 20 minutes, solid triacetoxyborohydride (147 mg, 0.7 mmol) was added and the reaction was stirred for 17 hours. Solvent was removed under reduced pressure. The residue was dissolved in a mixture of THF and methanol and treated with lithium hydroxide to give a basic solution. The reaction was stirred for 17 hours, concentrated to dryness, and purified by reverse phase preparative HPLC using a gradient of acetonitrile in water containing 0.1% TFA. Relevant fractions were combined to give 40 mg of 4-[[[[(RS)-1-[[4-(4-bromophenoxy)phenyl]methyl]-2-piperidinyl]methyl]methylamino]methyl]benzoic acid; 1NMR (400 MHz, DMSO-d6) δ 7.93 (d, 2H), 7.57 (d, 2H), 7.52 (m, 4H), 7.06 (d, 2H), 6.96 (d, 2H), 4.61 (dbr, 2H), 4.18 (dbr, 2H), 3.24 (m, 1H), 2.34 (s, 3H), 2.00 (m, 1H), 1.63 (m, 5H) ppm.

Workup

  1. additionwas added
  2. waitAfter 20 minutes
  3. customSolvent was removed under reduced pressure
  4. dissolutionThe residue was dissolved in a mixture of THF and methanol
  5. additiontreated with lithium hydroxide
  6. customto give a basic solution
  7. stirringThe reaction was stirred for 17 hours
  8. concentrationconcentrated to dryness
  9. custompurified by reverse phase preparative HPLC

Sources & evidence

ORD record
ord-8f2901b2d323462b8ae4a2c960cd3036
Source dataset
uspto-grants-2013_10
Patent number
US08569303B2

Linked notes

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