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

HRID 924509Notes

Reaction equation

HRID 924509 reaction equation
Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:41][C:42](=[O:51])[O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=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])[C@H:24]([N:28]4[CH:32]=[CH:31][N:30]=[N:29]4)[C@H:23]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[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:74]2[CH2:75][CH2:76][O:77][CH2:78][CH:79]=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:37]([O:36][C:34]([NH:33][C@H:23]1[C@@H:24]([N:28]2[CH:32]=[CH:31][N:30]=[N:29]2)[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:41][C:42](=[O:51])[O:43][CH2:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)=[CH:6][C:5]3[C:10](=[CH:11][C:2]([C:74]4[CH2:79][CH2:78][O:77][CH2:76][CH:75]=4)=[CH:3][CH:4]=3)[N:9]=2)=[O:13])[CH2:22]1)=[O:35])([CH3:39])([CH3:38])[CH3:40]

Participants

7

Reactant 4

HCID 312751,4-DioxaneHCID 62657Potassium Phosphate, TribasicHCID 112180533,6-Dihydro-2H-pyran-4-boronic acid pinacol esterHCID 86726948Benzyl {7-bromo-2-[({4-[(3R,4S,5S)-3-[(tert-butoxycarbonyl)amino]-5-methyl-4-(1H-1,2,3-triazol-1-yl)piperidin-1-yl]pyridin-3-yl}amino)carbonyl]quinolin-3-yl}carbamate

Product 1

HCID 86726949Benzyl [2-[({4-[(3R,4S,5S)-3-[(tert-butoxycarbonyl)amino]-5-methyl-4-(1H-1,2,3-triazol-1-yl)piperidin-1-yl]pyridin-3-yl}amino)carbonyl]-7-(3,6-dihydro-2H-pyran-4-yl)quinolin-3-yl]carbamateYield 27%

Reagents, catalysts & solvents 2

HCID 178439015HCID 178439015, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
90 °C

Procedure

A pressure tube was charged with benzyl {7-bromo-2-[({4-[(3R,4S,5S)-3-[(tert-butoxycarbonyl)amino]-5-methyl-4-(1H-1,2,3-triazol-1-yl)piperidin-1-yl]pyridin-3-yl}amino)carbonyl]quinolin-3-yl}carbamate (15 mg, 0.020 mmol), K3PO4 (8.4 mg, 0.04 mmol), 1,4-dioxane (0.3 mL), water (0.04 mL) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (6.3 mg, 0.03 mmol). The reaction mixture was purged with nitrogen for 10 min., then dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (1.6 mg, 0.002 mmol) was added. The pressure tube was sealed and the reaction mixture was heated at 90° C. for 30 min then allowed to cool. The mixture was then filtered and 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 light yellow powder (4 mg, 27%). LCMS calc. for C41H46N9O6 (M+H)+: m/z=760.4. Found: 760.5.

Workup

  1. customThe reaction mixture was purged with nitrogen for 10 min.
  2. customThe pressure tube was sealed
  3. temperatureto cool
  4. filtrationThe mixture was then filtered
  5. custompurified by preparative LCMS (pH=10 method
  6. 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-029045f92b3e41dc85d1f8fd39e54f68
Source dataset
uspto-grants-2016_03
Patent number
US09278950B2

Reaction notes

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