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 1523537Notes

Reaction equation

HRID 1523537 reaction equation
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

Participants

8

Reactant 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

Product 1

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

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
100 °C

Procedure

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.

Workup

  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

Sources & evidence

ORD record
ord-966d6b2a12e44844a27245efb5543502
Source dataset
uspto-grants-2015_07
Patent number
US09079889B2

Reaction notes

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