WO2010016005 Substituted 2-heterocyclyamino pyrazine compounds as CHK-1 inhibitors

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Scaffold: Amino pyrazine

Biological target:

Check point kinase: CHK-1

Activity:

Inhibitor

Steps Conditions Reactions
a  Diethyl carbonate / NaH / Dioxane Ester synthesis (Nucleophilic substitution)
b

 1. TFA

 2. CBz-Cl / DCM 

Boc Deprotection / CBz Protection
c

 HSCH2CH2SH / lnCl3

Ketone protection
d

 NaOH aq / MeOH

Carboxylic acid synthesis (Ester hydrolysis)
e

 DPPA / Et3N / t-BuOH

Carbamate synthesis (Curtius rearrangement)
f

 HF / pyridine / DCM

Fluorination
g  TFA / DCM Boc deprotection
Steps Conditions Reactions
a CBz-Cl / Et3N / DCM CBz protection
b MsCl / Et3N Mesyl synthesis
c Et3 Alkene synthesis
d m-CPBA / DCM Epoxide synthesis 
e Et3N.3HF Fluorination
f MsCl / Et3N / DCM Mesyl synthesis
g NaN3 / DMF Azido synthesis
h PPh3 / H2O / THF Primary amine synthesis (Staudinger reaction)
Steps Conditions Reactions
a DIAD / PPh3 / p-nitrobenzoic acid / THF Ester synthesis (Mitsunobu reaction)
b LiOH aq / THF Hydroxyl synthesis (Ester hydrolysis)
c MsCl / Et3N / DCM Mesyl synthesis
d NaN3 / DMF Azido synthesis
e PPh3 / H2O / THF Primary amine synthesis (Staudinger reaction)
Steps Conditions Reactions
a

1. ammonia / EtOH 

2. Boc2O / DCM

Epoxide opening / Boc protection 
b Separation Chiral separation
c MeI / NaH / THF Methoxy synthesis
d HCl / Dioxane Boc deprotection
Steps Conditions Reactions
a

MsCl / DCM

Mesyl synthesis                  
b Zn / NaI / DME Methoxy deprotection
c H2 / Pd-C / MeOH Cbz deprotection
Steps Conditions Reactions
a MsCl / Et3N / DCM Mesyl synthesis
b TBAF / THF Fluorination
c AcOH / THF / H2O THP deprotection
d MsCl / Et3N / DCM Mesyl synthesis
e NaN3 / DMF Azido synthesis
f PPh3 / H2O / THF Primary amine synthesis (Staudinger reaction)
Steps Conditions Reactions
a Et3N / NMP Secondary amine synthesis (Nucleophilic substitution)
b Cs2CO3 / DMF Tertiary amine synthesis (Nucleophilic substitution)
c HCl / Dioxane Boc deprotection
Steps Conditions Reactions
a (CH3)2CH-MgCl / nBu3SnCl / THF Tributyltin synthesis
b Pd(PPh3)4 / Xylene Stille coupling
Steps Conditions Reactions
a Pd(AcO)2 / PPh3 / K2CO3 / dioxane Heck reaction
b CsF / DMSO Secondary amine synthesis (nucleophilic substitution)
Steps Conditions Reactions
a Pd(PPh3)2Cl2 / CuI / DIEA / DMF Sonogashira reaction
b K2CO3 / MeOH  Trimethylsilyl deprotection
c DBU / ACN Cyclisation
d CsF / DMSO Secondary amine synthesis (Nucleophilic substitution)
Steps Conditions Reactions
a Pd(dba)3 / BINAP / Cs2CO3 / Toluene Buchwald-Hartwig amination
Steps Conditions Reactions
a Pd(dba)3 / BippyPhos / Cs2CO3 / MeOH Buchwald-Hartwig reaction
Steps Conditions Reactions
a ZnCN / S-Phos / Pd2(dba)3 / DMF / H2 Cyanide synthesis

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