1,4-Dioxane → benzyl [2-[({4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}amino)carbonyl]-7-(3,6-dihydro-2H-pyran-4-yl)quinolin-3-yl]carbamate

HRID 924467Notes

Reaction equation

HRID 924467 reaction equation
Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:39][C:40](=[O:49])[O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=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]([C:27]([F:30])([F:29])[F:28])[CH2:24][C@H:23]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:22]3)=[O:13])=[N:9]2)=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1.CC1(C)C(C)(C)OB([C:72]2[CH2:73][CH2:74][O:75][CH2:76][CH:77]=2)O1>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:35]([O:34][C:32]([NH:31][C@H:23]1[CH2:24][C@@H:25]([C:27]([F:30])([F:29])[F:28])[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:39][C:40](=[O:49])[O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:6][C:5]3[C:10](=[CH:11][C:2]([C:72]4[CH2:77][CH2:76][O:75][CH2:74][CH:73]=4)=[CH:3][CH:4]=3)[N:9]=2)=[O:13])[CH2:22]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]

Participants

7

Reactant 4

HCID 312751,4-DioxaneHCID 62657Potassium Phosphate, TribasicHCID 112180533,6-Dihydro-2H-pyran-4-boronic acid pinacol esterHCID 86726911Benzyl {7-bromo-2-[({4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}amino)carbonyl]quinolin-3-yl}carbamate

Product 1

HCID 86726912benzyl [2-[({4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}amino)carbonyl]-7-(3,6-dihydro-2H-pyran-4-yl)quinolin-3-yl]carbamateYield 498.3%

Reagents, catalysts & solvents 2

HCID 178439015HCID 178439015, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
80 °C

Procedure

A pressure vial was charged with benzyl {7-bromo-2-[({4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}amino)carbonyl]quinolin-3-yl}carbamate (0.032 g, 0.043 mmol), K3PO4 (0.0181 g, 0.0852 mmol), 1,4-dioxane (0.55 mL), water (0.092 mL) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (0.013 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 reaction mixture was sealed with a screw cap and heated at 80° C. for 1 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 a 20 g silica gel column, eluting with 0-100% EtOAc in hexanes, to give benzyl [2-[({4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}amino)carbonyl]-7-(3,6-dihydro-2H-pyran-4-yl)quinolin-3-yl]carbamate (0.16 g, 50%, LCMS calc. for C39H42F3N6O6[M+H]+: m/z=747.3. found: 747.4) and the corresponding benzyl carbamate deprotected product, tert-butyl [(3S,5R)-1-[3-({[3-amino-7-(3,6-dihydro-2H-pyran-4-yl)quinolin-2-yl]carbonyl}amino)pyridin-4-yl]-5-(trifluoromethyl)piperidin-3-yl]carbamate (0.13 g, 50%, LCMS calc. for C31H36F3N6O4 [M+H]+: m/z=613.3. found: 613.4).

Workup

  1. customThe mixture was deoxygenated with nitrogen for 10 min
  2. customThe reaction mixture was sealed with a 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 a 20 g silica gel column
  9. washeluting with 0-100% EtOAc in hexanes

Sources & evidence

ORD record
ord-bf3068235ea64653808e028747d1a6e7
Source dataset
uspto-grants-2016_03
Patent number
US09278950B2

Reaction notes

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