4-(tert-Butoxycarbonylaminomethyl)phenylboronic acid → Tert-butyl((4'-((1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-hydroxypropyl)-[1,1'-biphenyl]-4-yl)methyl)carbamate

HRID 2283168Notes

Reaction equation

HRID 2283168 reaction equation
[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][CH:20]([Cl:36])[C:21]([NH:23][C@H:24]([CH2:34][F:35])[C@H:25]([OH:33])[C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1)=[O:22]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:19][CH:20]([Cl:36])[C:21]([NH:23][C@H:24]([CH2:34][F:35])[C@@H:25]([C:26]1[CH:27]=[CH:28][C:29]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:11][CH:12]=2)=[CH:30][CH:31]=1)[OH:33])=[O:22]

Participants

6

Reactant 2

HCID 38631634-(tert-Butoxycarbonylaminomethyl)phenylboronic acidHCID 683504732,2-dichloro-N-[(1S,2R)-1-(fluoromethyl)-2-hydroxy-2-(4-iodophenyl)ethyl]acetamide

Product 1

HCID 117635614Tert-butyl((4'-((1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-hydroxypropyl)-[1,1'-biphenyl]-4-yl)methyl)carbamateYield 53.8%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

To solution of commercially available (4-(((tert-butoxycarbonyl)-amino)methyl)-phenyl)boronic acid (1.01 gm, 4.02 mmol) in 1,4-dioxane:water (12.3:3.8 mL) is added 2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-iodophenyl)propan-2-yl)acetamide (1.04 g, 2.56 mmol) and CS2CO3 (1.85 g, 5.67 mmol) and the resulting solution bubbled with nitrogen gas for 30 min. To this reaction mixture is added Pd(PPh3)4 (0.332 g, 0.29 mmol) and the resulting reaction mixture heated to 110° C. for 2 hours. The resulting reaction mixture is cooled, diluted with water and extracted with ethyl acetate. The organic layer dried over sodium sulfate and concentrated to give a crude residue, which is purified using column chromatography on silica gel eluting with 30% Ethyl acetate/hexane to give the title compound (668 mg). 1H NMR (400 MHz, CDCl3) δ: 1.46 (s, 8H), 4.30-4.32 (m, 1H), 4.34-4.35 (m, 2H), 4.44-4.47 (m, 0.5H), 4.55-4.59 (m, 1H), 4.68-4.69 (m, 0.5H), 4.85 (m, 1H), 5.15 (t, 1H, J=7.04 Hz), 5.87 (s, 1H), 7.04 (d, 1H, J=8.6 Hz), 7.34 (d, 2H, J=7.92 Hz), 7.44 (d, 2H, J=8.2 Hz), 7.53 (d, 2H, J=8.08 Hz), 7.57 (d, 2H, J=8.08 Hz). m/z (Cl) M−H 483

Workup

  1. customthe resulting solution bubbled with nitrogen gas for 30 min
  2. customthe resulting reaction mixture
  3. customThe resulting reaction mixture
  4. temperatureis cooled
  5. extractionextracted with ethyl acetate
  6. dry with materialThe organic layer dried over sodium sulfate
  7. concentrationconcentrated
  8. customto give a crude residue, which
  9. customis purified

Sources & evidence

ORD record
ord-80b65c7da747429ba9fc6a22eeb69be0
Source dataset
uspto-grants-2015_09
Patent number
US09145355B2

Reaction notes

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