Chloroform → 1-[3-[5-[[1-(tert-Butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]phenyl]-3-phenyl-2(S)-propanol

HRID 2095345Notes

Reaction equation

HRID 2095345 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH2:8][C@@H:9]([OH:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[C:18]([O:22][C:23]([N:25]1[CH2:28][CH2:27][C@H:26]1[CH2:29][O:30][C:31]1[CH:32]=[N:33][CH:34]=[C:35]([Sn](C)(C)C)[CH:36]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(Cl)(Cl)Cl.[F-].[Cs+]>CN1CCCC1=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>[C:18]([O:22][C:23]([N:25]1[CH2:28][CH2:27][C@H:26]1[CH2:29][O:30][C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[C:4]([CH2:8][C@@H:9]([OH:17])[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[CH:6][CH:7]=2)[CH:34]=[N:33][CH:32]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]

Participants

8

Reactant 4

HCID 6212ChloroformHCID 25953Cesium fluorideHCID 105744715-Iodo-A-85380, 5-trimethylstannyl N-boc derivativeHCID 593712931-(3-bromophenyl)-3-phenyl-2(S)-propanol

Product 1

HCID 593715891-[3-[5-[[1-(tert-Butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]phenyl]-3-phenyl-2(S)-propanolYield 66.3%

Reagents, catalysts & solvents 3

HCID 83681Tris(1,1-dimethylethyl)phosphineCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
80 °C

Procedure

To a solution/suspension of 1-(3-bromophenyl)-3-phenyl-2(S)-propanol (260 mg, 0.89 mmol), 3-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5(trimethylstannyl)pyridine (417 mg, 0.98 mmol, 1.1 equiv.), Pd2dba3.CHCl3 (13.8 mg, 13.5 μmol, 15 mequiv.) and CsF (270 mg, 1.78 mmol, 2.0 equiv.) in N-methylpyrrolidone (1.0 mL) contained in a dried 100 mL round-bottom flask was added P(t-Bu)3 (10 wt % in hexane, 106 μL, 33 μmol) by syringe at room temperature under N2. The mixture was stirred for 3 h at 80° C., after which time TLC analysis indicated that the starting material had disappeared. After cooling, the reaction was quenched with saturated aqueous NH4Cl solution, and the mixture was extracted with EtOAc (3×50 mL). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was applied onto a silica gel column, which was eluted with CH2Cl2/MeOH 70:1 to give the product (280 mg, 66%) as a yellow oil. 1H NMR (CDCl3, 300 MHz) δ 8.48 (br s, 1H), 8.35 (br s, 1H), 7.52-7.41 (m, 3H), 7.39-7.25 (m, 7H), 4.58 (m, 1H), 4.43 (m, 1H), 4.23 (dd, 1H, J=9.9, 3.0 Hz), 4.15 (m, 1H), 3.94 (t, 2H, J=7.2 Hz), 3.12-2.78 (m, 4H), 2.43-2.27 (m, 2H), 1.58 (OH and water), 1.43 (s, 9H). LC-MS (ESI) m/z 475 (M+H+).

Workup

  1. temperatureAfter cooling
  2. customthe reaction was quenched with saturated aqueous NH4Cl solution
  3. extractionthe mixture was extracted with EtOAc (3×50 mL)
  4. dry with materialdried over anhydrous Na2SO4
  5. concentrationconcentrated under vacuum
  6. washwas eluted with CH2Cl2/MeOH 70:1

Sources & evidence

ORD record
ord-91636a810813494f9a41774265ca084c
Source dataset
uspto-grants-2013_05
Patent number
US08445684B2

Reaction notes

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