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

HRID 273252

반응식

HRID 273252 반응식
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

참가 물질

10

반응물 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

생성물 1

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

시약·촉매·용매 4

HCID 178418476HCID 178418476, 화합물촉매HCID 1140Toluene용매2회HCID 6342Acetonitrile용매HCID 21881414Toluene isopropyl alcohol용매

반응 조건

온도
90 °C

실험 절차

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.

후처리

  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)

출처 및 근거

ORD 기록
ord-94e09fa8e95f43cab698680267c2fd5a
출처 데이터셋
uspto-grants-2008_11
특허 번호
US07456196B2

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