Tetrabutylammonium Fluoride → tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-({[4-(2-fluoroethoxy)phenyl]ethynyl}pyridin-3-yl)-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate

HRID 526356Notes

Reaction equation

HRID 526356 reaction equation
Br[C:2]1[CH:3]=[C:4]([C@@H:8]([NH:17][C:18]([C@@H:20]2[CH2:25][CH2:24][CH2:23][N:22]([C:26](=[O:42])[CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)[CH2:21]2)=[O:19])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:5]=[N:6][CH:7]=1.[F:43][CH2:44][CH2:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]#[C:54][Si](C)(C)C)=[CH:49][CH:48]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>COCCOC.C(N)CCC.C1COCC1.O.[Cu](I)I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:13]([O:12][C:10](=[O:11])[CH2:9][C@H:8]([NH:17][C:18]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26](=[O:42])[CH2:27][CH2:28][CH:29]2[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:34]2)[CH2:21]1)=[O:19])[C:4]1[C:5]([C:54]#[C:53][C:50]2[CH:51]=[CH:52][C:47]([O:46][CH2:45][CH2:44][F:43])=[CH:48][CH:49]=2)=[N:6][CH:7]=[CH:2][CH:3]=1)([CH3:14])([CH3:16])[CH3:15]

Participants

10

Reactant 3

HCID 2724141Tetrabutylammonium FluorideHCID 71259834tert-butyl 4-[3-((3R)-3-{[(1S)-1-(5-bromopyridin-3-yl)-3-tert-butoxy-3-oxopropyl]carbamoyl}piperidin-1-yl)-3-oxopropyl]piperidine-1-carboxylateHCID 89407531{[4-(2-Fluoroethoxy)phenyl]ethynyl}(trimethyl)silane

Product 1

HCID 89407747tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-({[4-(2-fluoroethoxy)phenyl]ethynyl}pyridin-3-yl)-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylateYield 39%

Reagents, catalysts & solvents 6

HCID 83717Copper iodideCatalystHCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 962WaterSolventHCID 8007ButylamineSolventHCID 8028TetrahydrofuranSolventHCID 80711,2-DimethoxyethaneSolvent

Procedure

To a degassed solution of tert-butyl 4-[3-((3R)-3-{[(1S)-1-(5-bromopyridin-3-yl)-3-tert-butoxy-3-oxopropyl]carbamoyl}piperidin-1-yl)-3-oxopropyl]piperidine-1-carboxylate (example 27c, 100 mg, 150 μmol), copper iodide (3.5 mg, 20 μmol), tetrakis(triphenylphosphine) palladium(0) (17.7 mg, 20 μmol) and {[4-(2-fluoroethoxy)phenyl]ethynyl}(trimethyl)silane (73 mg, 310 μmol) in 1,2-dimethoxyethan (0.9 mL) and n-butyl amine (0.23 mL) was added a 1 M tetra-n-butyl ammonium fluoride solution in THF (200 μL) over 15 minutes at 80° C. After 20 additional minutes at 80° C. (36 mg, mmol) was added, the mixture was diluted with water after 20 minutes and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuum. The residue was purified by preparative HPLC to yield 43 mg of tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-({[4-(2-fluoroethoxy)phenyl]ethynyl}pyridin-3-yl)-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.

Workup

  1. additionAfter 20 additional minutes at 80° C. (36 mg, mmol) was added
  2. extractionextracted with ethyl acetate
  3. dry with materialThe organic phase was dried over sodium sulfate
  4. concentrationconcentrated in vacuum
  5. customThe residue was purified by preparative HPLC

Sources & evidence

ORD record
ord-341c219956f24170a357cea0c9e4a69f
Source dataset
uspto-grants-2016_05
Patent number
US09345793B2

Reaction notes

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