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Cesium fluoride → 2-hydroxy-N,N-dimethyl-2-{5-[3-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-pyridin-3-yl}-acetamide

HRID 886637
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Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 886637
[OH:1][CH:2]([C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:15]=[C:16]3[C:22](I)=[CH:21][N:20](COCC[Si](C)(C)C)[C:17]3=[N:18][CH:19]=2)[CH:13]=1)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4].[CH3:32][N:33]1[C:37]([Sn](CCCC)(CCCC)CCCC)=[CH:36][C:35]([C:51]([F:54])([F:53])[F:52])=[N:34]1.[F-].[Cs+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[Cu]I.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].CN(C=O)C>[OH:1][CH:2]([C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:15]=[C:16]3[C:22]([C:37]4[N:33]([CH3:32])[N:34]=[C:35]([C:51]([F:54])([F:53])[F:52])[CH:36]=4)=[CH:21][NH:20][C:17]3=[N:18][CH:19]=2)[CH:13]=1)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4]
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Komponenten

8

Edukt 4

HCID 25953Cesium fluorideHCID 83681Tris(1,1-dimethylethyl)phosphineHCID 120567101-Methyl-5-(tributylstannyl)-3-(trifluoromethyl)-1H-pyrazoleHCID 598248902-hydroxy-2-{5-[3-iodo-1(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-3-yl}-N,N-dimethyl-acetamide

Produkt 1

HCID 136014290
2-hydroxy-N,N-dimethyl-2-{5-[3-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-pyridin-3-yl}-acetamide
Ausbeute 8 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)KatalysatorHCID 44119782Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)KatalysatorHCID 6228DimethylformamideLösungsmittel

Versuchsvorschrift

A mixture of 2-hydroxy-2-{5-[3-iodo-1(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-3-yl}-N,N-dimethyl-acetamide (194 mg, 0.4 mmol), 1-methyl-5(tributylstannyl)3-(trifluoromethyl)-1H-pyrazole (186 mg, 0.4 mmol), CuI (7 mg, 0.04 mmol), CsF (107 mg, 0.7 mmol), dichlorobis(benzonitrile)palladium (II) (7 mg, 0.02 mmol), tri-t-butylphosphine 10% w/v in hexanes (10 μl, 0.04 mmol) and DMF were stirred at 100° C. under nitrogen overnight. The mixture was allowed to cool to room temperature and then extracted with ethyl acetate (2X). The combined organic layers were extracted with brine, dried with Na2SO4, decanted, and concentrated to dryness. The material was purified using silica gel chromatography and a gradient of ethyl acetate and hexane. The purified product was treated with dichloromethane/trifluoroacetate acid (1 ml/1 ml) at room temperature for 2 hours. The solvents were removed under vacuum and the crude was stirred in dichloromethane/ethylenediamine (1 ml/1 ml) for 2 hours at room temperature. Again the solvents was removed under vacuum and the crude was dissolved in DMSO, filtered and purified by reverse phase HPLC, lyophilized afforded 2-hydroxy-N,N-dimethyl-2-{5-[3-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-pyridin-3-yl}-acetamide (13.2 mg, 8% yield). 1H NMR (500 MHz, DMSO-d6) δ 2.80 (s, 3H), 2.94 (s, 3H), 5.56 (s, 1H), 5.80 (s, 1H), 7.08 (s, 1H), 7.98 (s, 1H), 8.04 (t, 1H), 8.26 (d, 1H), 8.50 (d, 1H), 8.58 (d, 1H), 8.88 (d, 1H), 12.40 (s, 1H). MS: m/z 445.0 (M+H+).

Aufarbeitung

  1. extractionextracted with ethyl acetate (2X)
  2. extractionThe combined organic layers were extracted with brine
  3. dry with materialdried with Na2SO4
  4. customdecanted
  5. concentrationconcentrated to dryness
  6. customThe material was purified
  7. additionThe purified product was treated with dichloromethane/trifluoroacetate acid (1 ml/1 ml) at room temperature for 2 hours
  8. customThe solvents were removed under vacuum
  9. customAgain the solvents was removed under vacuum
  10. dissolutionthe crude was dissolved in DMSO
  11. filtrationfiltered
  12. custompurified by reverse phase HPLC

Quellen und Nachweise

ORD-Eintrag
ord-5acc9d2791434031811e1820c80bed4d
Quelldatensatz
uspto-grants-2012_08
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US08242280B2

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