Diethyl Ether → tert-butyl [4-(2-{(1S,2R)-2-[1-(5-ethoxypyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2,6-difluorophenyl]acetate

HRID 1474731Notes

Reaction equation

HRID 1474731 reaction equation
[Cl-].[C:2]([O:6][C:7](=[O:10])[CH2:8][Zn+])([CH3:5])([CH3:4])[CH3:3].CCOCC.Br[C:17]1[C:43]([F:44])=[CH:42][C:20]([O:21][CH2:22][CH2:23][C@@H:24]2[CH2:26][C@@H:25]2[CH:27]2[CH2:32][CH2:31][N:30]([C:33]3[N:38]=[CH:37][C:36]([O:39][CH2:40][CH3:41])=[CH:35][N:34]=3)[CH2:29][CH2:28]2)=[CH:19][C:18]=1[F:45].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1COCC1.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]>[CH2:40]([O:39][C:36]1[CH:35]=[N:34][C:33]([N:30]2[CH2:29][CH2:28][CH:27]([C@H:25]3[CH2:26][C@H:24]3[CH2:23][CH2:22][O:21][C:20]3[CH:42]=[C:43]([F:44])[C:17]([CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:10])=[C:18]([F:45])[CH:19]=3)[CH2:32][CH2:31]2)=[N:38][CH:37]=1)[CH3:41]

Participants

7

Reactant 4

HCID 3283Diethyl EtherHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 1176783442-(4-((1R,2S)-2-(2-(4-bromo-3,5-difluorophenoxy)ethyl)cyclopropyl)piperidin-1-yl)-5-ethoxypyrimidineHCID 178451183HCID 178451183, compound

Product 1

HCID 89583942tert-butyl [4-(2-{(1S,2R)-2-[1-(5-ethoxypyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2,6-difluorophenyl]acetate

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
65 °C

Procedure

A 0.5 M solution of 2-(tert-butyloxy)-2-oxoethylzinc chloride in Et2O (43 mL, 21.2 mmol) was added to a mixture of 2-(4-((1R,2S)-2-(2-(4-bromo-3,5-difluorophenoxy)ethyl)cyclopropyl)piperidin-1-yl)-5-ethoxypyrimidine (3.4 g, 7.05 mmol), Pd2(dba)3 (0.484 g, 0.529 mmol), and X-PHOS (504 mg, 1.06 mmol) in anhydrous THF (10 mL). The mixture was stirred and heated at 65° C. overnight. The mixture was cooled to rt and filtered through celite, washing the filtercake with excess EtOAc. The volatiles were removed and the residue was purified by column chromatography on silica gel (KP-Sil 100 g SNAP column, Biotage system) eluting with 5-40% EtOAc:hexanes over 12 CV to afford the title compound. LC/MS (m/z): 518 (M+H)+.

Workup

  1. temperatureThe mixture was cooled to rt
  2. filtrationfiltered through celite
  3. washwashing the filtercake with excess EtOAc
  4. customThe volatiles were removed
  5. customthe residue was purified by column chromatography on silica gel (KP-Sil 100 g SNAP column, Biotage system)
  6. washeluting with 5-40% EtOAc

Sources & evidence

ORD record
ord-8decba6702354ccc9c34a1992e099e89
Source dataset
uspto-grants-2015_04
Patent number
US09018224B2

Reaction notes

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