Tris(1,1-dimethylethyl)phosphine → N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluoro-3-hydroxyphenyl)-5-fluoropicolinamide

HRID 2192672Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 2192672
Br[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[C@@H:17]2[CH2:22][C@H:21]([CH3:23])[CH2:20][C@H:19]([NH:24]C(=O)OC(C)(C)C)[CH2:18]2)=[O:9])[CH:5]=[CH:4][C:3]=1[F:32].[F:33][C:34]1[C:39]([OH:40])=[CH:38][CH:37]=[C:36]([F:41])[C:35]=1B(O)O.[F-].[K+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1COCC1>[NH2:24][C@H:19]1[CH2:20][C@@H:21]([CH3:23])[CH2:22][C@@H:17]([C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[NH:10][C:8](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([F:32])=[C:2]([C:35]3[C:36]([F:41])=[CH:37][CH:38]=[C:39]([OH:40])[C:34]=3[F:33])[N:7]=2)[CH2:18]1

Komponenten

8

Edukt 4

HCID 83681Tris(1,1-dimethylethyl)phosphineHCID 522689Potassium FluorideHCID 445581212,6-Difluoro-3-hydroxybenzeneboronic acidHCID 86639735tert-butyl ((1S,3R,5S)-3-(3-(6-bromo-5-fluoropicolinamido)pyridin-4-yl)-5-methylcyclohexyl)carbamate

Produkt 1

HCID 46179015N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluoro-3-hydroxyphenyl)-5-fluoropicolinamide

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 9811564Bis(dibenzylideneacetone)palladiumKatalysatorHCID 962WaterLösungsmittelHCID 8028TetrahydrofuranLösungsmittel

Reaktionsbedingungen

Temperatur
100 °C

Versuchsvorschrift

To a solution of tert-butyl (1S,3R,5S)-3-(3-(6-bromo-5-fluoropicolinamido)pyridin-4-yl)-5-methylcyclohexylcarbamate (1.0 equiv.) in a microwave vial was added 2,6-difluoro-3-hydroxyphenylboronic acid (5.0 equiv.), KF (5.5 equiv.) and Pd2(dba)3 (0.2 equiv.) followed by THF and water (10:1, 0.03 M). To this mixture was added P(t-Bu)3 (0.4 equiv.) and the reaction was heated in the microwave at 100° C. for 30 min. The organic phase was then separated, the aqueous layer was washed with ethyl acetate, and the organics were combined and concentrated in vacuo. The crude mixture was purified via prep-HPLC, the product fractions were lyophilized and the resulting BOC group was deprotected as described in Method 9 yielding, after RP HPLC purification and lyophilization, N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluoro-3-hydroxyphenyl)-5-fluoropicolinamide as the TFA salt. LCMS (m/z): 457.2 (MH+); LC Rt=2.17 min.

Aufarbeitung

  1. customThe organic phase was then separated
  2. washthe aqueous layer was washed with ethyl acetate
  3. concentrationconcentrated in vacuo
  4. customThe crude mixture was purified via prep-HPLC, the product fractions
  5. customafter RP HPLC purification and lyophilization, N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluoro-3-hydroxyphenyl)-5-fluoropicolinamide as the TFA salt

Quellen und Nachweise

ORD-Eintrag
ord-b3a5d355b4e74a7698583cd5cd748866
Quelldatensatz
uspto-grants-2012_12
Patentnummer
US08329732B2

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