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 2046897ノート

反応式

HRID 2046897 の反応式
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

参加物

8

反応物 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

生成物 1

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

試薬・触媒・溶媒 3

HCID 9811564Bis(dibenzylideneacetone)palladium触媒HCID 962Water溶媒HCID 8028Tetrahydrofuran溶媒

反応条件

温度
100 °C

実験手順

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.

後処理

  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

出典と根拠

ORDレコード
ord-bf943d8b54d043c5acba2ef56c0f7a3a
出典データセット
uspto-grants-2013_11
特許番号
US08592455B2

反応ノート

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