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

HRID 628699
Notes
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Reaction equation

HRID 628699 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]
ParticipantsProcedureWorkupSources & evidenceReaction notes

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 ester
Yield 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%). One component of the reaction was isolated 13C NMR (75 MHz, CDCl3) δC 14.3, 20.6, 21.8, 26.4, 38.6, 43.0, 55.8, 60.5, 68.7, 73.3, 93.4, 106.3, 108.2, 119.3, 121.5, 127.5, 127.6, 128.3, 135.7, 137.0, 137.9, 155.7, and 175.0.

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-27b3d2212b004187b405d0cbe8d0b60e
Source dataset
uspto-grants-2016_04
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09314541B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes