Triethylamine → 4-[3-[4-[Bis(4-Fluorophenyl)hydroxymethyl]-1-piperidinyl]-propoxy]-alpha-hydroxy-3-methoxybenzeneacetic acid (phenylmethyl) ester

HRID 1460253Notes

Reaction equation

HRID 1460253 reaction equation
[C:1]1([CH2:7][O:8][C:9](=[O:25])[CH:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21]Cl)=[C:14]([O:23][CH3:24])[CH:13]=2)[OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[OH:35])=[CH:30][CH:29]=1.C(N(CC)CC)C.C(Cl)Cl.CO.[OH-].[NH4+]>C(O)C1C=CC=CC=1>[C:1]1([CH2:7][O:8][C:9](=[O:25])[CH:10]([OH:11])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:39]3[CH2:40][CH2:41][CH:36]([C:34]([C:42]4[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=4)([C:31]4[CH:30]=[CH:29][C:28]([F:27])=[CH:33][CH:32]=4)[OH:35])[CH2:37][CH2:38]3)=[C:14]([O:23][CH3:24])[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 13814470[alpha,alpha-Bis(4-fluorophenyl)]-4-piperidinemethanol hydrochlorideHCID 150203684-(3-Chloropropoxy)-3-methoxymandelic acid phenylmethyl esterHCID 21896990Dichloromethane methanol ammonium hydroxide

Product 1

HCID 150203694-[3-[4-[Bis(4-Fluorophenyl)hydroxymethyl]-1-piperidinyl]-propoxy]-alpha-hydroxy-3-methoxybenzeneacetic acid (phenylmethyl) esterYield 54.3%

Reagents, catalysts & solvents 1

HCID 244Benzyl AlcoholSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of 0.637 g (0.00175 mole) 4-(3-chloropropoxy)-3-methoxymandelic acid phenylmethyl ester, 0.545 g (0.00180 mole) of [α,α-bis(4-fluorophenyl)]-4-piperidinemethanol hydrochloride, and 0.3 ml (0.0025 mole) of triethylamine in 3 ml of benzyl alcohol was heated under nitrogen atmosphere at 110° C. for 7 hours while the reaction was monitored by TLC (silica gel, methylene chloride/methanol/ammonium hydroxide 90:10:1). The reaction mixture was concentrated in vacuo, ethyl ether (60 ml) and hexanes (40 ml) were added to the oily residue, and the solution was kept in the refrigerator for 2 hours. The solid that formed was filtered, washed with ether and dissolved in methylene chloride (40 ml). The methylene chloride solution was washed with water (3×10 ml) and dried (sodium sulfate), and the solvent was evaporated in vacuo to give 0.6 g of an oil. Final purification was done using 6 tapered silica gel plates 20×20 cm eluting with methylene chloride/methanol/ammonium hydroxide (90:5:0.5). The TLC sections containing the product were scraped off, and eluted with the above solvent system to give 0.4 g (34%) of the product as a light-amber oil. 1H NMR and mass spectral analysis support the structure assigned.

Workup

  1. concentrationThe reaction mixture was concentrated in vacuo, ethyl ether (60 ml) and hexanes (40 ml)
  2. additionwere added to the oily residue
  3. customThe solid that formed
  4. filtrationwas filtered
  5. washwashed with ether
  6. dissolutiondissolved in methylene chloride (40 ml)
  7. washThe methylene chloride solution was washed with water (3×10 ml)
  8. dry with materialdried (sodium sulfate)
  9. customthe solvent was evaporated in vacuo

Sources & evidence

ORD record
ord-82affff4e32b4fc3965913ab65a1dfb8
Source dataset
uspto-grants-1991_12
Patent number
US05070087

Reaction notes

Loading…