WO2010055006 Naphthylic acids used as CRTH2 antagonists or partial agonists

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Scaffold: naphthalene

Biological target:

Prostaglandin D2 receptors: CRTH2

Activity:

Antagonist

Steps Conditions Reactions
a Dimethyl succinate, tBuOK, tBuOH reflux, 3h Stobbe condensation
b

Ac2O, NaOAc, reflux, 6h

Naphthalene formation
c NaOMe, MeOH, 1h Hydrolysis
d Benzyl bromide, K2CO3, acetone, reflux, 4h OBn formation (OH protection)
e LiAlH4, THF, 60oC, 1h Ester reduction (OH formation)
f PPh3, CCl4, THF reflux, 2h Chlorination
g Pd(PPh3)2Cl2, K2CO3, CO gaz, MeOH/THF 1/2 Carbonylation
h H2, Pd/C, MeOH Hydrogenolysis (OH deprotection)
Steps Conditions Reactions
a PPh3, DEAD, THF, 4h   Mitsunobu reaction 
b

5N LiOH, THF overnight

  Saponification (COOH formation)
c 5N HCl in MeOH, MeOH   Boc deprotection (Secondary amine formation)
d

1. Methanesulfonyl chloride, Et3N, THF overnight

2. 5N LiOH, THF overnight

N-sulfonylation

Saponification (COOH formation)
e Acetyl chloride, DMAP, THF overnight   N-acylation
f 5N LiOH, THF overnight   Saponification (COOH formation)
g Isocyanato-ethane, CH2Cl2, 4h   Urea formation
Steps Conditions Reactions
a (COCl)2, Methyl tert-butyl ether , DMF   Acid chloride formation
b

DIEA, Methyl tert-butyl ether

Wittig-type reaction
c KOtBu, N,N-Dimethyl acetamide


d 1M LiOH, EtOH, overnight then reflux 3h Saponification (COOH formation)then decarboxylation
e Ac2O, KOAc, 85oC, 10h Cyclization (Naphthalene formation)
f MeONa, MeOH, 20 min Hydrolysis
g (CF3SO2)O, Pyridine, CH2Cl2, 0oC Triflate formation (OH activation)
h Pd(OAc)2, dppf, CO, Et3N, DMF, 60oC, 4h Carbonylation
Steps Conditions Reactions
a

1. (CF3SO2)O, DIEA, CH3CN, -10oC

2. 1-phenyl-ethylamine, DIEA, 70oC, 2h

3. HCl 4N MeOH

   
b

10% Pd/C, HCOONH4, MeOH 65oC

Hydrogenolysis (Secondary amine formation)
c Boc2O, NaHCO3, dioxane overnight

Boc-formation (Amine protection)

Steps Conditions Reactions
a

(COCl)2, THF, DMF, 60oC, 2h

Acid chloride formation
b

  Et3N, CH2Cl2

N-acylation 
c   TFA, CH2Cl2, 4h

  Boc-deprotection (Secondary amine formation)

d Et3N, CH2Cl2 N-Sulfonylation
e NaOH, THF Hydrolysis

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