1,4-Dioxane → Benzyl [2-{[(4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}pyridin-3-yl)amino]carbonyl}-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)quinolin-3-yl]carbamate

HRID 924476Notes

Reaction equation

HRID 924476 reaction equation
Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:36][C:37](=[O:46])[O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:8]([C:12]([NH:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[N:21]3[CH2:26][C@H:25]([CH3:27])[CH2:24][C@H:23]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:22]3)=[O:13])=[N:9]2)=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1.[CH3:61][N:62]1[CH2:67][CH:66]=[C:65](B2OC(C)(C)C(C)(C)O2)[CH2:64][CH2:63]1>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl.O>[C:32]([O:31][C:29]([NH:28][C@H:23]1[CH2:24][C@@H:25]([CH3:27])[CH2:26][N:21]([C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[NH:14][C:12]([C:8]2[C:7]([NH:36][C:37](=[O:46])[O:38][CH2:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[CH:6][C:5]3[C:10](=[CH:11][C:2]([C:65]4[CH2:66][CH2:67][N:62]([CH3:61])[CH2:63][CH:64]=4)=[CH:3][CH:4]=3)[N:9]=2)=[O:13])[CH2:22]1)=[O:30])([CH3:35])([CH3:34])[CH3:33]

Participants

7

Reactant 4

HCID 312751,4-DioxaneHCID 62657Potassium Phosphate, TribasicHCID 207733711-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridineHCID 86726913Benzyl (7-bromo-2-{[(4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}pyridin-3-yl)amino]carbonyl}quinolin-3-yl)carbamate

Product 1

HCID 86726921Benzyl [2-{[(4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}pyridin-3-yl)amino]carbonyl}-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)quinolin-3-yl]carbamateYield 30%

Reagents, catalysts & solvents 2

HCID 178439015HCID 178439015, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
90 °C

Procedure

A pressure vial was charged with benzyl (7-bromo-2-{[(4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}pyridin-3-yl)amino]carbonyl}quinolin-3-yl)carbamate (0.029 g, 0.043 mmol), K3PO4 (0.0181 g, 0.0852 mmol), 1,4-dioxane (0.55 mL), water (0.092 mL) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (0.014 g, 0.063 mmol). The mixture was deoxygenated with nitrogen for 10 min. Dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.0022 g, 0.0028 mmol) was added. The mixture was sealed with screw cap, then heated at 90° C. for 1.5 h. The mixture was quenched with water and extracted with EtOAc. The combined organic extracts were dried and concentrated under reduced pressure. The residue was purified by flash chromatography on 20 g silica gel, eluting with 0-30% MeOH in EtOAc, to yield the sub-title compound (0.009 g, 30%). LCMS calc. for C40H48N7O5 [M+H]+: m/z=706.4. found: 706.5.

Workup

  1. customThe mixture was deoxygenated with nitrogen for 10 min
  2. customThe mixture was sealed with screw
  3. customcap
  4. customThe mixture was quenched with water
  5. extractionextracted with EtOAc
  6. customThe combined organic extracts were dried
  7. concentrationconcentrated under reduced pressure
  8. customThe residue was purified by flash chromatography on 20 g silica gel
  9. washeluting with 0-30% MeOH in EtOAc

Sources & evidence

ORD record
ord-b097d03149e44891aede42b122fdd7f5
Source dataset
uspto-grants-2016_03
Patent number
US09278950B2

Reaction notes

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