Triphenylphosphine → benzyl-(R)-2-(2-(3-trifluoromethylphenyl)-4-((4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)propanate

HRID 68620Notes

Reaction equation

HRID 68620 reaction equation
[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:25]=[CH:26][C:27]=2[OH:28])[CH2:12][N:13]([CH3:24])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:6]=[CH:7][CH:8]=1.[CH2:31]([O:38][C:39](=[O:43])[C@@H:40](O)[CH3:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:31]([O:38][C:39](=[O:43])[C@H:40]([O:28][C:27]1[CH:26]=[CH:25][C:11]([CH2:12][N:13]([CH3:24])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:10][C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:29])[F:30])[CH:4]=1)[CH3:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1

Participants

6

Reactant 4

HCID 11776TriphenylphosphineHCID 220568ethyl N-ethoxycarbonyliminocarbamateHCID 11052238benzyl (2S)-2-hydroxypropanoateHCID 66868277N-(3-(3-trifluoromethylphenyl)-4-hydroxybenzyl)-4-fluoro-N-methylbenzenesulfonamide

Product 1

HCID 67528769benzyl-(R)-2-(2-(3-trifluoromethylphenyl)-4-((4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)propanateYield 17.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of N-(3-(3-trifluoromethylphenyl)-4-hydroxybenzyl)-4-fluoro-N-methylbenzenesulfonamide (36) (50.0 mg, 0.114 mmol, 1 eq) and (S)-benzyl-2-hydroxypropanoate (21 μL, 0.125 mmol, 1.1 eq, Aldrich, Milwaukee, Wis., USA) in THF (2 mL) at 0° C. was added diethyl azodicarboxylate (20 μL, 0.125 mmol, 1.1 eq) and triphenylphosphine (33 mg, 0.125 mmol, 1.1 eq). After stirring at 0° C. for 4 h, the mixture was extracted between saturated sodium bicarbonate and EtOAc, dried (Na2SO4), concentrated in vacuo, and purified on via silica gel chromatography (linear gradient of 5-10% EtOAc/hexane). The isolated material was further purified via reversed phase semi-preparative HPLC to give 12 mg of benzyl-(R)-2-(2-(3-trifluoromethylphenyl)-4-((4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)propanate. This intermediate was stirred in the presence of 10 mg of 10% Pd/C under a hydrogen atmosphere in EtOH. (5 mL) at room temperature for 16 h. The reaction mixture was then filtered through a celite pad and the filtrate was concentrated in vacuo. The crude residue was purified via reversed phase semi-preparative HPLC to give 7.8 mg of (R)-2-(2-(3-trifluoromethylphenyl)-4-((4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)propanoic acid (Example 35). 1HNMR (CDCl3, 400 MHz): δ 7.78 (m, 3H), 7.64(d, 1H), 7.48 (m, 2H), 7.25 (m, 3H), 7.17 (d, 1H), 6.73 (d, 1H), 4.87 (m, 1H), 4.04 (s, 2H), 2.53 (s, 3H), 1.32 (d, 3H). MS (ESI): MH+=512.1. HPLC (Method B) tR=3.48 min.

Workup

  1. extractionthe mixture was extracted between saturated sodium bicarbonate and EtOAc
  2. dry with materialdried (Na2SO4)
  3. concentrationconcentrated in vacuo
  4. custompurified on via silica gel chromatography (linear gradient of 5-10% EtOAc/hexane)
  5. customThe isolated material was further purified via reversed phase semi-preparative HPLC

Sources & evidence

ORD record
ord-73dfcbb07ac34b5097d56dd71b353d9e
Source dataset
uspto-grants-2014_09
Patent number
US08822467B2

Reaction notes

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