WO2010020810 2-(Imidazolylamino)-pyridine derivatives and their use as JAK kinase inhibitors

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Biological target:

Janus kinase: JAK 

Activity:

Inhibitor

Steps Conditions Reactions
a

1. MeMgBr / THF

2. HCl 1M

Ketone synthesis
b NH2-OH / Et3N / EtOH Oxime synthesis
c

Ammonium hydroxide / ammonium acetate / Zinc / H2

Primary amine synthesis
d

1. HCl 4N / dioxane

2. (R)-mandelic acid / AcOEt

Primary amine chiral separation
Steps Conditions Reactions
a

1. LDA / TMS-Cl / THF

2. Methyl 2-methoxyacetate / THF

Nuclephilic substitution
b

NH2-OH / Et3N / EtOH

Oxime synthesis
c H2 / Pd-C / EtOAc / (R)-Mandelic acid   Primary amine chiral synthesis and separation
Steps Conditions Reactions
a Zn / ZnCN / dppf / Pd2dba3 / DMA Cyanide synthesis
b

1.MeMgBr / THF

2.anhydride acetic  / DCM


c

H2 / (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene (cyclooctadiene)rhodium(I)trifluoromethanesulfonate / MeOH

Amide chiral synthesis
d Boc2O / DMAP / THF  Boc protection
e HCl / dioxane / DCM N-Boc deprotection 
Steps Conditions Reactions
a racemic t-butyl sulfinamide / CuSO4 / DCM Imine synthesis 
b

MeMgBr / DCM

Nucleophilic substitution
c HCl / dioxane / MeOH                                  Primary amine synthesis
Steps Conditions Reactions
a Pd(PPh3)2Cl2 / CuI / tributyl(1-ethoxyvinyl)stannane / ACN Stille reaction
b

NaBH4 / MeOH

Hydroxyl synthesis (ketone reduction)
c

1.MsCl / Et3N / DCM

2.NaN3 / DMF                                

Azido synthesis
d H2 / Pd-C / MeOH Primary amine synthesis  
Steps Conditions Reactions
a

1. H2 / Pd-C / EtOH

2. Et3N / EtOH

Primary amine synthesis (nitro reduction) / Secondary amine synthesis (aromatic substitution)
Steps Conditions Reactions
a DIEA / Butanol   Secondary amine synthesis (aromatic substitution)
Steps Conditions Reactions
a Morpholine / EtOH Tertiary amine synthesis (aromatic substitution)

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