Acetic Acid → 3-[(2-Benzyloxy-ethyl)-(2-chloro-5-methoxy-phenyl)-amino]-2-hydroxy-cyclohex-1-ene carboxylic acid ethyl ester

HRID 1753917Notes

Reaction equation

HRID 1753917 reaction equation
[CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[Cl:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:31]([O:33][C:34]([C:36]1[CH2:41][CH2:40][CH2:39][CH:38](Br)[C:37]=1[OH:43])=[O:35])[CH3:32].C(O)(=O)C>C1COCC1.C1(C)C=CC=CC=1>[CH2:31]([O:33][C:34]([C:36]1[CH2:41][CH2:40][CH2:39][CH:38]([N:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[Cl:20])[C:37]=1[OH:43])=[O:35])[CH3:32]

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 3251421Potassium bis(trimethylsilyl)amideHCID 590519613-Bromo-2-hydroxy-cyclohex-1-enecarboxylic acid ethyl esterHCID 66679111(2-Benzyloxy-ethyl)-(2-chloro-5-methoxyphenyl)amine

Product 1

HCID 666798493-[(2-Benzyloxy-ethyl)-(2-chloro-5-methoxy-phenyl)-amino]-2-hydroxy-cyclohex-1-ene carboxylic acid ethyl esterYield 104.9%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

(2-Benzyloxy-ethyl)-(2-chloro-5-methoxyphenyl)amine (3) (10.0 g, 34.2 mmol) was stirred in dry THF (100 mL) at −40° C. under nitrogen and potassium bis(trimethylsilyl)amide (143.0 mL of a 0.5 M solution in toluene, 72.0 mmol) was added over 30 min. 3-bromo-2-hydroxycyclohex-1-enecarboxylic acid ethyl ester (4) (8.5 g, 34.2 mmol) in dry THF (10 mL) was then added and allowed to warm to RT over a period of 1.5 h. Acetic acid (10.0 g, 166 mmol, 10.0 mL) was added and concentrated in vacuo to remove the THF. Ethyl acetate (200 mL) and 10% aqueous potassium carbonate (100 mL) was added and the mixture vigorously shaken. The ethyl acetate solution was separated, dried over magnesium sulfate and concentrated in vacuo to afford 16.5 g (quantitative) of 3[(2-Benzyloxy-ethyl)-(2-chloro-5-methoxy-phenyl)-amino]-2-hydroxy-cyclohex-1-ene carboxylic acid ethyl ester (5) as a gum which was used crude in the next step. HPLC (Gemini 150×4.6 mm, 50-95% methanol/water over 20 min) of crude reaction mixture, 18.9 min (38%), 19.2 min (25%), 23.1 min (28%).

Workup

  1. concentrationconcentrated in vacuo
  2. customto remove the THF
  3. additionEthyl acetate (200 mL) and 10% aqueous potassium carbonate (100 mL) was added
  4. customThe ethyl acetate solution was separated
  5. dry with materialdried over magnesium sulfate
  6. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-cf94c899b08e492189b4ad4922ff06ae
Source dataset
uspto-grants-2015_10
Patent number
US09168317B2

Reaction notes

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