Citric Acid → 6-{2-[2-(4-Chloro-phenyl)-2,4,5,6-tetrahydro-cyclopentapyrazol-3-yl]-2-cyclohexyl-ethoxy}-nicotinic acid methyl ester

HRID 889381Notes

Reaction equation

HRID 889381 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:14](NC3CCCCC3)=[O:15])=[C:11]3[CH2:29][CH2:30][CH2:31][C:10]3=[N:9]2)=[CH:4][CH:3]=1.[C:32]([O-])([O-])=[O:33].[K+].[K+].ClC1C=CC([N:45]2[C:49]([CH:50]([CH:57]3[CH2:62][CH2:61]CCC3)[CH2:51][O:52]S(C)(=O)=O)=C3CCCC3=N2)=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.CCOC(C)=O>[CH3:32][O:33][C:51](=[O:52])[C:50]1[CH:57]=[CH:62][C:61]([O:15][CH2:14][CH:13]([C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]3[CH2:31][CH2:30][CH2:29][C:11]=23)[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[N:45][CH:49]=1

Participants

7

Reactant 4

HCID 311Citric AcidHCID 11430Potassium CarbonateHCID 533902542-[2-(4-Chloro-phenyl)-2,4,5,6-tetrahydro-cyclopentapyrazol-3-yl]-2,N-dicyclohexyl-acetamideHCID 86657984Methanesulfonic acid 2-[2-(4-chloro-phenyl)-2,4,5,6-tetrahydro-cyclopentapyrazol-3-yl]-2-cyclohexyl-ethyl ester

Product 1

HCID 673871806-{2-[2-(4-Chloro-phenyl)-2,4,5,6-tetrahydro-cyclopentapyrazol-3-yl]-2-cyclohexyl-ethoxy}-nicotinic acid methyl esterYield 67%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of methyl 6-hydroxynicotinate 4 (80 mg, 0.19 mmol; CAS Reg. No. 10128-91-3) in dry DMF (3 ml) was added dry K2CO3 (29 mg, 0.226 mmol) at 0° C. The reaction mixture was stirred for 15 minutes at 0° C. Methanesulfonic acid 2-[2-(4-chloro-phenyl)-2,4,5,6-tetrahydro-cyclopentapyrazol-3-yl]-2-cyclohexyl-ethyl ester (35 mg, 0.227 mmol) dissolved in dry DMF (1 ml) was added at 0° C. The reaction mixture was heated to 100° C. in a sealed tube for 12 h. 10% Aqueous citric acid solution (10 ml) and EtOAc (5 ml) were added to the reaction mixture. The layers were separated and the aqueous layer was extracted one more time with EtOAc (5 ml). The combined organic layers were washed with brine (5 ml) and dried over Na2SO4. The solvent was removed under reduced pressure to give a residue which was purified by column chromatography over silica gel (20% EtOAc/hexane) to give the title compound (60.2 mg, 0.12 mmol; 67%) as off-white solid.

Workup

  1. additionwas added at 0° C
  2. temperatureThe reaction mixture was heated to 100° C. in a sealed tube for 12 h
  3. customThe layers were separated
  4. extractionthe aqueous layer was extracted one more time with EtOAc (5 ml)
  5. washThe combined organic layers were washed with brine (5 ml)
  6. dry with materialdried over Na2SO4
  7. customThe solvent was removed under reduced pressure
  8. customto give a residue which
  9. customwas purified by column chromatography over silica gel (20% EtOAc/hexane)

Sources & evidence

ORD record
ord-c16aff626632482693e797bb76495245
Source dataset
uspto-grants-2012_08
Patent number
US08252826B2

Reaction notes

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