Sodium Carbonate → 7-(2,6-Dimethyl-pyridin-3-yl)-3-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-cinnoline

HRID 551573

Reaction equation

HRID 551573 reaction equation
Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([CH2:12][CH2:13]Cl)[N:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:16][C:17]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=[C:19]([CH3:32])[N:18]=1.C([O-])([O-])=O.[Na+].[Na+].C([C@@H]([C@H](C(O)=O)O)O)(O)=O.[CH3:49][C@@H:50]1[CH2:54][CH2:53][CH2:52][NH:51]1.[OH-].[Na+].[Cl-].[Na+].O>C(O)(C)C.C1(C)C=CC=CC=1.C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:32][C:19]1[C:20]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([CH2:12][CH2:13][N:51]4[CH2:52][CH2:53][CH2:54][C@H:50]4[CH3:49])[N:8]=[N:9]3)=[CH:4][CH:3]=2)=[CH:21][CH:22]=[C:17]([CH3:16])[N:18]=1

Participants

10

Reactant 5

HCID 10340Sodium CarbonateHCID 11858493(R)-2-methylpyrrolidine L-tartrateHCID 219800342,6-Dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineHCID 671047587-Bromo-4-chloro-3-(2-chloro-ethyl)-cinnolineHCID 131715167NaOH brine

Product 1

HCID 671042137-(2,6-Dimethyl-pyridin-3-yl)-3-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-cinnoline

Reagents, catalysts & solvents 4

HCID 178418476HCID 178418476, compoundCatalystHCID 1140TolueneSolvent2×HCID 6342AcetonitrileSolventHCID 21881414Toluene isopropyl alcoholSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of the product from Example 169C (0.100 g, 0.328 mmol), 2,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (0.077 g, 0.328 mmol), Pd(PPh3)2Cl2 (0.012 g, 0.017 mmol), and 1 M Na2CO3 (0.820 mL, 0.820 mmol) in de-gassed isopropanol/toluene (5 mL, 1:1) was heated to 90° C. under a dry nitrogen atmosphere for 24 hours. After cooling, the reaction mixture was filtered, diluted with 20 mL water, extracted twice with 25 mL dichloromethane, and concentrated under reduced pressure. Next, (2R)-2-methylpyrrolidine (L)-tartrate (0.100 g, 0.425 mmol) was partitioned between toluene (0.5 mL) and 5M NaOH/brine (1:1, 1 mL total). The toluene phase (0.5 mL) was subsequently added to a solution of the above crude material in acetonitrile (3 mL) and the resulting mixture was heated to 85° C. in a sealed tube for 48 hours. Upon cooling, the mixture was concentrated under reduced pressure and purified by column chromatography (100% dichloromethane to 95:5 dichloromethane/methanol) to provide the title compound. 1H NMR (CD3OD, 300 MHz) δ 8.38 (m, 1H), 8.19 (s, 1H), 8.06 (d, J=9 Hz, 1H), 7.84 (dd, J=3, 9 Hz, 1H), 7.76 (d, J=9 Hz, 1H), 7.27 (d, J=9 Hz, 1H), 3.52-3.28 (m, 4H), 2.78-2.62 (m, 2H), 2.59 (s, 3H), 2.52 (s, 3H), 2.46-2.39 (m, 1H), 2.08-1.98 (m, 1H), 1.86-1.78 (m, 2H), 1.56-1.42 (m, 1H), 1.18 (d, J=6 Hz, 3H). MS (ESI) [M+H]+ at 347.

Workup

  1. temperatureAfter cooling
  2. filtrationthe reaction mixture was filtered
  3. additiondiluted with 20 mL water
  4. extractionextracted twice with 25 mL dichloromethane
  5. concentrationconcentrated under reduced pressure
  6. temperaturethe resulting mixture was heated to 85° C. in a sealed tube for 48 hours
  7. temperatureUpon cooling
  8. concentrationthe mixture was concentrated under reduced pressure
  9. custompurified by column chromatography (100% dichloromethane to 95:5 dichloromethane/methanol)

Sources & evidence

ORD record
ord-552e1b56eea84068bdb2355a9395cf50
Source dataset
uspto-grants-2011_05
Patent number
US07947711B2

Linked notes

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