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

HRID 526389Notes

Reaction equation

HRID 526389 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:43]([C:45]1[CH:46]=[C:47]([OH:51])[CH:48]=[CH:49][CH:50]=1)#[CH:44]>CN(C=O)C.C(N)CCC.CS(C)=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[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36])[CH2:31][CH2:30]2)[CH2:21]1)=[O:19])[C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:44]#[C:43][C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([OH:51])[CH:46]=2)[CH:3]=1)([CH3:16])([CH3:14])[CH3:15]

Participants

8

Reactant 2

HCID 139144m-EthynylphenolHCID 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 71609226tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-{5-[(3-hydroxyphenyl)ethynyl]pyridin-3-yl}-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylateYield 91.2%

Reagents, catalysts & solvents 5

HCID 83717Copper iodideCatalystHCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 679Dimethyl SulfoxideSolventHCID 6228DimethylformamideSolvent2×HCID 8007ButylamineSolvent

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, 300 mg, 0.46 mmol), copper iodide (13 mg, 70 μmol) and tetrakis(triphenylphosphine) palladium(0) (53 mg, 50 μmol) in DMF (1.5 mL) and n-butyl amine (0.68 mL) was added a solution of 3-ethynylphenol (103 mg, 0.88 mmol) in DMF (1.0 mL) over 35 minutes at 100° C. After 5 additional minutes at 100° C. the mixture was diluted with DMSO and purified by preparative HPLC to yield 289 mg of tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-{5-[(3-hydroxyphenyl)ethynyl]pyridin-3-yl}-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.

Workup

  1. custompurified by preparative HPLC

Sources & evidence

ORD record
ord-7d41beb1a8664f7dad100088c3e0a815
Source dataset
uspto-grants-2016_05
Patent number
US09345793B2

Reaction notes

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