Water → tert-Butyl methyl {(3R,4S,5S)-1-[3-({[3-{[(benzyloxy)carbonyl]amino}-7-(3,6-dihydro-2H-pyran-4-yl)quinolin-2-yl]carbonyl}amino)pyridin-4-yl]-5-methylpiperidine-3, 4-diyl}biscarbamate

HRID 924529Notes

Reaction equation

HRID 924529 reaction equation
CC1(C)C(C)(C)OB([C:9]2[CH2:10][CH2:11][O:12][CH2:13][CH:14]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:24]([O:31][C:32]([NH:34][C:35]1[C:36]([C:46]([NH:48][C:49]2[CH:50]=[N:51][CH:52]=[CH:53][C:54]=2[N:55]2[CH2:60][C@H:59]([CH3:61])[C@H:58]([NH:62][C:63](=[O:66])[O:64][CH3:65])[C@H:57]([NH:67][C:68](=[O:74])[O:69][C:70]([CH3:73])([CH3:72])[CH3:71])[CH2:56]2)=[O:47])=[N:37][C:38]2[C:43]([CH:44]=1)=[CH:42][CH:41]=[C:40](Br)[CH:39]=2)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>O1CCOCC1.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>[CH2:24]([O:31][C:32]([NH:34][C:35]1[C:36]([C:46]([NH:48][C:49]2[CH:50]=[N:51][CH:52]=[CH:53][C:54]=2[N:55]2[CH2:60][C@H:59]([CH3:61])[C@H:58]([NH:62][C:63](=[O:66])[O:64][CH3:65])[C@H:57]([NH:67][C:68](=[O:74])[O:69][C:70]([CH3:73])([CH3:72])[CH3:71])[CH2:56]2)=[O:47])=[N:37][C:38]2[C:43]([CH:44]=1)=[CH:42][CH:41]=[C:40]([C:9]1[CH2:10][CH2:11][O:12][CH2:13][CH:14]=1)[CH:39]=2)=[O:33])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1

Participants

7

Reactant 4

HCID 962WaterHCID 62657Potassium Phosphate, TribasicHCID 112180533,6-Dihydro-2H-pyran-4-boronic acid pinacol esterHCID 86726961tert-Butyl methyl [(3R,4S,5S)-1-(3-{[(3-{[(benzyloxy)carbonyl]amino}-7-bromoquinolin-2-yl)carbonyl]amino}pyridin-4-yl)-5-methylpiperidine-3, 4-diyl]biscarbamate

Product 1

HCID 86726968tert-Butyl methyl {(3R,4S,5S)-1-[3-({[3-{[(benzyloxy)carbonyl]amino}-7-(3,6-dihydro-2H-pyran-4-yl)quinolin-2-yl]carbonyl}amino)pyridin-4-yl]-5-methylpiperidine-3, 4-diyl}biscarbamateYield 31.4%

Reagents, catalysts & solvents 2

HCID 178439015HCID 178439015, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
60 °C

Procedure

A vial was charged with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (104 mg, 0.493 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (35 mg, 0.045 mmol), and K3PO4 (180 mg, 0.849 mmol). The vial was sealed with a septum and purged with nitrogen three times). A solution of tert-butyl methyl [(3R,4S,5S)-1-(3-{[(3-{[(benzyloxy)carbonyl]amino}-7-bromoquinolin-2-yl)carbonyl]amino}pyridin-4-yl)-5-methylpiperidine-3,4-diyl]biscarbamate (200 mg, 0.262 mmol) in 1,4-dioxane (2.0 mL) was added, followed by deoxygenated water (0.50 mL, 28 mmol). The reaction was heated at 60° C. for 2 h. The mixture was purified by preparative LCMS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a yellow solid (63.0 mg, 31%). LCMS calc. for C41H48N7O8 (M+H)+: m/z=766.4. Found: 766.4.

Workup

  1. customThe vial was sealed with a septum
  2. custompurged with nitrogen three times)
  3. customThe mixture was purified by preparative LCMS (pH=10 method
  4. washXBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH)

Sources & evidence

ORD record
ord-9b2a144aac164eb9a4bdbd64e70a407e
Source dataset
uspto-grants-2016_03
Patent number
US09278950B2

Reaction notes

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