Hydrochloric Acid → 4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-hydroxy-cyclohexanecarboxylic acid ethyl ester

HRID 849318Notes

Reaction equation

HRID 849318 reaction equation
Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:17][CH3:18])=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.O1CCCC1.C([Li])CCC.[CH2:29]([O:31][C:32]([CH:34]1[CH2:39][CH2:38][C:37](=[O:40])[CH2:36][CH2:35]1)=[O:33])[CH3:30].Cl>C1(C)C=CC=CC=1>[CH2:29]([O:31][C:32]([CH:34]1[CH2:39][CH2:38][C:37]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([CH2:17][CH3:18])=[N:7][N:8]3[CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:4][CH:3]=2)([OH:40])[CH2:36][CH2:35]1)=[O:33])[CH3:30]

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 8028TetrahydrofuranHCID 317638Ethyl 4-oxocyclohexanecarboxylateHCID 118089646-Bromo-1-cyclohexyl-3-ethyl-1H-indazoleHCID 178418339Butyllithium

Product 1

HCID 110257404-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-hydroxy-cyclohexanecarboxylic acid ethyl esterYield 82%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a solution of 6bromo-1-cyclohexyl-3-ethyl-1H-indazole (12.7 g, 41.3 mmol) in toluene (64 mL) was added tetrahydrofuran (6.70 mL, 82.6 mmol). The solution was cooled to -78° C. and n-butyllithium (17.3 mL of a 2.5M solution in hexanes, 43.4 mmol) was added dropwise. The solution was stirred 10 minutes and added to a solution of 4-oxo-cyclohexanecarboxylic acid ethyl ester (8.80 g, 51.7 mmol) in toluene (127 mL) at -78° C. The reaction mixture was stirred for 15 minutes and poured into 1N aqueous hydrochloric acid (200 mL). The layers were separated and the aqueous layer was reextracted with toluene (60 mL). The organic extracts were combined and dried over magnesium sulfate, filtered, and concentrated to an oil which was purified by filtration through a pad of silica gel eluting with 4:1 hexanes/ethyl acetate. The product-rich fractions were concentrated to yield 4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-hydroxy-cyclohexanecarboxylic acid ethyl ester (13.5 g, 82%) as a mixture of diastereoisomers. Upon standing, one of the diastereoisomers crystallized and was isolated by trituration with hexanes. 1H NMR (400 MHz, CDCl3) δ 1.25-1.40 (m, 4), 1.27 (t, 3, J=7.1), 1.35 (t, 3, J=7.7), 1.65-2.07 (m, 15), 2.37-2.44 (m, 1), 2.96 (q, 2, J=7.7), 4.15 (q, 2, J=7.1), 4.30-4.38 (m, 1), 7.13 (d, 1, J=8.5), 7.58 (s, 1), 7.63 (d, 1, J=8.5). 13C NMR (100 MHz, CDCl3) δ 14.16, 14.26, 20.69, 24.60, 25.39, 25.91, 32.54, 38.22, 42.57, 57.59, 60.34, 72.80, 104.49, 116.80, 120.28, 121.26, 139.84, 146.09, 146.93, 175.63. Analysis calculated for C24H34N2O3 : C, 72.33; H, 8.60; N, 7.03. Found: C, 72.11; H, 8.55; N, 6.92.

Workup

  1. stirringThe reaction mixture was stirred for 15 minutes
  2. customThe layers were separated
  3. dry with materialdried over magnesium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated to an oil which
  6. filtrationwas purified by filtration through a pad of silica gel eluting with 4:1 hexanes/ethyl acetate
  7. concentrationThe product-rich fractions were concentrated

Sources & evidence

ORD record
ord-9cce8728564c42cdaf5dc3c2067c41b5
Source dataset
uspto-grants-2000_01
Patent number
US06011159

Reaction notes

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