Tetrahydrofuran → Tert-butyl 4-{3-[(3R)-3-{[(1 S)-3-tert-butoxy-1-{5-[(4-hydroxyphenyl)ethynyl]pyridin-3-yl}-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate

HRID 526387Notes

Reaction equation

HRID 526387 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.C[Si]([C:47]#[C:48][C:49]1[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>COCCOC.C(N)CCC.O.[Cu](I)I.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>[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])([CH3:39])[CH3:40])=[O:36])[CH2:33][CH2:34]2)[CH2:21]1)=[O:19])[C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:47]#[C:48][C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=2)[CH:3]=1)([CH3:15])([CH3:14])[CH3:16]

Participants

10

Reactant 4

HCID 8028TetrahydrofuranHCID 2724141Tetrabutylammonium FluorideHCID 107502104-((Trimethylsilyl)ethynyl)phenolHCID 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-carboxylate

Product 1

HCID 117653683Tert-butyl 4-{3-[(3R)-3-{[(1 S)-3-tert-butoxy-1-{5-[(4-hydroxyphenyl)ethynyl]pyridin-3-yl}-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylateYield 39.9%

Reagents, catalysts & solvents 5

HCID 83717Copper iodideCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 8007ButylamineSolventHCID 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 (400 mg, 0.61 mol), copper iodide (14 mg, 70 μmol), tetrakis(triphenylphosphine)palladium(0) (71 mg, 60 μmol) and 4-[(trimethylsilyl)ethynyl]phenol (234 mg, 1.23 mmol) in 1,2-dimethoxyethan (3.5 mL) and n-butyl amine (0.91 mL) was added a 1 M tetra-n-butyl ammonium fluoride solution in THF (800 μL, 0.8 mmol) over 60 minutes at 80° C. After 10 additional minutes at 80° C. the mixture was diluted with water after cooling to room temperature 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 338 mg of tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-{5-[(4-hydroxyphenyl)ethynyl]pyridin-3-yl}-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate

Workup

  1. extractionextracted with ethyl acetate
  2. dry with materialThe organic phase was dried over sodium sulfate
  3. concentrationconcentrated in vacuum
  4. customThe residue was purified by preparative HPLC

Sources & evidence

ORD record
ord-18172c53d8f6466cabf9e0cd0a7ce64c
Source dataset
uspto-grants-2016_05
Patent number
US09345793B2

Reaction notes

Loading…