1,2-Dimethoxyethane → HCID 89980000, compound

HRID 926303Notes

Reaction equation

HRID 926303 reaction equation
Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][N:14]=[C:13]([N:18]3[CH:22]=[N:21][C:20]([CH:23]4[CH2:25][CH2:24]4)=[N:19]3)[CH:12]=[C:7]12.[F:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:23]1([C:20]2[N:21]=[CH:22][N:18]([C:13]3[CH:12]=[C:7]4[C:8]5[C:3]([CH2:4][CH2:5][N:6]4[C:16](=[O:17])[CH2:15][N:14]=3)=[C:2]([C:30]3[CH:31]=[N:32][C:27]([F:26])=[CH:28][CH:29]=3)[CH:11]=[CH:10][CH:9]=5)[N:19]=2)[CH2:24][CH2:25]1

Participants

7

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 10340Sodium CarbonateHCID 2783397(6-Fluoropyridin-3-yl)boronic acidHCID 89979954HCID 89979954, compound

Product 1

HCID 89980000HCID 89980000, compoundYield 99.7%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
85 °C

Procedure

Example 95-2. 9-bromo-2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (5.7 g, 14.31 mmol), (6-fluoropyridin-3-yl)boronic acid (4.03 g, 28.6 mmol) and a solution of Na2CO3 (7.58 g, 71.6 mmol) in water (28 mL) was treated with DME (114 mL). The suspension was degassed, Pd(PPh3)4 (2.48 g, 2.15 mmol) was added and the mixture was heated at 85° C. for 2 h. The mixture was allowed to warm to RT and the solvent was removed under reduced pressure. The residue was dissolved in DCM and extracted with water, saturated aqueous NaHCO3 solution and brine. The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash-column chromatography over silicagel (Biotage Isolera Four, eluent: 70% AcOEt in heptane for 3 min, then from 70% AcOEt in heptane to 100% AcOEt in heptane in 50 min, 100% AcOEt in heptane for 10 min) to yield a beige foam (5.91 g). The residue was dissolved in DCM (100 mL) and MP-TMT resin (4.0 g, 0.71 mmol/g) was added and the mixture was stirred for 2.5 h. The resin was filtered off and the solvent was removed under reduced pressure to yield a yellow foam. The foam was crystallized from hot n-butanol (50 mL) to afford the title compound as white crystals (4.8 g). UPLC-MS: MS 415.4 (M+H+); UPLC rt 1.02 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.79-0.87 (m, 2 H), 0.89-0.99 (m, 2 H), 1.98-2.07 (m, 1 H), 2.87 (t, J=6.11 Hz, 2 H), 3.72 (t, J=6.11 Hz, 2 H), 4.30 (s, 2 H), 7.05 (s, 1 H), 7.31 (dd, J=8.44, 2.57 Hz, 1 H), 7.47-7.56 (m, 2 H), 7.89-7.97 (m, 1 H), 8.07 (td, J=8.13, 2.57 Hz, 1 H), 8.30 (d, J=2.45 Hz, 1 H), 9.00 (s, 1 H).

Workup

  1. customThe suspension was degassed
  2. temperatureto warm to RT
  3. customthe solvent was removed under reduced pressure
  4. dissolutionThe residue was dissolved in DCM
  5. extractionextracted with water, saturated aqueous NaHCO3 solution and brine
  6. dry with materialThe combined organic layers were dried with sodium sulfate
  7. filtrationfiltered
  8. customthe solvent was removed under reduced pressure
  9. customThe crude product was purified by flash-column chromatography over silicagel (Biotage Isolera Four, eluent
  10. waitfrom 70% AcOEt in heptane to 100% AcOEt in heptane in 50 min

Sources & evidence

ORD record
ord-432bfb382a9144b09d79c9d19cad7507
Source dataset
uspto-grants-2016_03
Patent number
US09284331B2

Reaction notes

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