Dimethyl Sulfoxide → 3-{4-[1-(4'-tert-Butyl-biphenyl-4-ylmethyl)-3-methyl-butyl]-benzoylamino}-propionic acid

HRID 251312Notes

Reaction equation

HRID 251312 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][CH:3]=1.P([CH2:19][CH2:20][CH2:21][CH3:22])(CCCC)CCCC.[H-].[Na+].CO[C:27](=[O:40])[C:28]1[CH:33]=[CH:32][C:31]([C:34](=O)[CH2:35][CH:36]([CH3:38])[CH3:37])=[CH:30][CH:29]=1.C(N([CH2:46][CH3:47])CC)C.Cl.C[O:50][C:51](=[O:55])[CH2:52][CH2:53][NH2:54].CCN=C=N[CH2:61][CH2:62][CH2:63]N(C)C.[CH3:67]S(C)=O>C(OCC)(=O)C.CN(C1C=CN=CC=1)C>[C:62]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:22]=[CH:21][C:20]([CH2:19][CH:34]([C:31]3[CH:30]=[CH:29][C:28]([C:27]([NH:54][CH2:53][CH2:52][C:51]([OH:50])=[O:55])=[O:40])=[CH:33][CH:32]=3)[CH2:35][CH:36]([CH3:37])[CH3:38])=[CH:47][CH:46]=2)=[CH:4][CH:3]=1)([CH3:63])([CH3:67])[CH3:61]

Participants

11

Reactant 8

HCID 679Dimethyl SulfoxideHCID 8471TriethylamineHCID 13831TributylphosphineHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 24758Sodium hydrideHCID 685274-Bromobenzyl bromideHCID 2734767Methyl 3-aminopropanoate hydrochlorideHCID 56593012Methyl 4-(3-methylbutanoyl)benzoate

Product 1

HCID 248589563-{4-[1-(4'-tert-Butyl-biphenyl-4-ylmethyl)-3-methyl-butyl]-benzoylamino}-propionic acid

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of 1-bromo-4-bromomethyl-benzene (1.80 g, 7.2 mmol) in DMSO (15 ml) is added PBu3 (2.18 g, 10.8 mmol). The resulting mixture is stirred at 60° C. for 23 h. The reaction solution is then cooled down to room temperature, and NaH (432 mg, 10.8 mmol) is added, followed by the addition of 4-(3-methyl-butyryl)-benzoic acid methyl ester (Preparation 2) (1.74 g, 7.92 mmol). The reaction mixture is stirred at room temperature for about 48 h, and then diluted with ethyl acetate. The organic portion is washed with 1N HCl, water, brine, dried over MgSO4, and concentrated. The resulting residue is hydrolyzed in THF using 5N NaOH. The reaction is neutralized with 5N HCl, extracted with diethyl ether. The organic phase is washed with water, dried, filter and concentrated. The resulting residue is taken into dichloromethane (150 ml). To the solution is added triethyl amine (6.41 ml, 46 mmol), followed by the addition of DMAP (5 mg), 3-amino-propionic acid methyl ester hydrochloride (3.21 g, 23 mmol) and EDCI (8.83 g, 46 mmol). The reaction mixture is stirred at room temperature for 2 days. The reaction mixture is loaded on a silica gel column and eluted with a gradient from 0-100% ethyl acetate in hexanes to afford 2.60 g of the titled compound.

Workup

  1. temperatureThe reaction solution is then cooled down to room temperature
  2. stirringThe reaction mixture is stirred at room temperature for about 48 h
  3. washThe organic portion is washed with 1N HCl, water, brine
  4. dry with materialdried over MgSO4
  5. concentrationconcentrated
  6. extractionextracted with diethyl ether
  7. washThe organic phase is washed with water
  8. customdried
  9. filtrationfilter
  10. concentrationconcentrated
  11. stirringThe reaction mixture is stirred at room temperature for 2 days
  12. washeluted with a gradient from 0-100% ethyl acetate in hexanes

Sources & evidence

ORD record
ord-e9b28b8bc0b046a7ac092cdd1be36b77
Source dataset
uspto-grants-2011_01
Patent number
US07863329B2

Reaction notes

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