Potassium Carbonate → (R)-3-[(R)-7-((E)-2-ethoxy-vinyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 519139Notes

Reaction equation

HRID 519139 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2Br)[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:37]([O:39]/[CH:40]=[CH:41]/B1OC(C)(C)C(C)(C)O1)[CH3:38]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2/[CH:38]=[CH:37]/[O:39][CH2:40][CH3:41])[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

7

Reactant 3

HCID 11430Potassium CarbonateHCID 219739081-Ethoxyethene-2-boronic acid pinacol esterHCID 86727530(R)-3-((R)-7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 86727529(R)-3-[(R)-7-((E)-2-ethoxy-vinyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl esterYield 75.2%

Reagents, catalysts & solvents 3

HCID 178418807HCID 178418807, compoundCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

To a mixture of (R)-3-((R)-7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.5 g, 0.625 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.05 g, 0.06 mmol) and K2CO3 (0.43 g, 1.87 mmol) in dioxane (24 mL) and water (4 mL) was added 2-((E)-2-ethoxy-vinyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.123 g, 0.62 mmol) and the reaction mixture was stirred at 100° C. for 3 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel (eluting with 50% EtOAc in petroleum ether) to give (R)-3-[(R)-7-((E)-2-ethoxy-vinyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.22 g, 74%) as a light yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.16 (s, 1H), 6.73 (s, 1H), 6.61 (d, J=12.4 Hz, 1H), 6.07 (s, 1H), 5.56 (d, J=12.4 Hz, 1H), 4.65 (m, 1H), 4.48 (m, 2H), 3.90 (m, 1H), 3.80 (m, 2H), 3.64 (m, 1H), 3.40 (m, 2H), 3.09-3.30 (m, 1H), 2.22 (m, 1H), 1.82 (m, 1H), 1.42 (m, 12H), 1.28 (t, J=7.2 Hz, 3H). LC/MS (Table 1, Method 2) Rt=1.100 min.; MS m/z: 472 [M+H]+. SFC (Table 1, Method 37) Rt=2.183 min.

Workup

  1. temperatureThe reaction mixture was cooled to ambient temperature
  2. concentrationconcentrated in vacuo
  3. customto give the crude product, which
  4. customwas purified by column chromatography on silica gel (eluting with 50% EtOAc in petroleum ether)

Sources & evidence

ORD record
ord-93b9e72e75d34f55a559689a3bebdb68
Source dataset
uspto-grants-2015_08
Patent number
US09115151B2

Reaction notes

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