Triethylamine → (S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester

HRID 2365733Notes

Reaction equation

HRID 2365733 reaction equation
Cl.[CH3:2][O:3][C:4](=[O:14])[C@@H:5]([NH2:13])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C[O:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[CH2:25]Br.C(N(CC)CC)C>C(#N)C.O>[CH3:2][O:3][C:4](=[O:14])[C@@H:5]([N:13]1[CH2:25][C:19]2[C:18](=[CH:23][CH:22]=[CH:21][C:20]=2[F:24])[C:17]1=[O:16])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 19788116Methyl 2-(bromomethyl)-3-fluorobenzoateHCID 22861687methyl (2S)-2-amino-3-cyclohexylpropanoate hydrochloride

Product 1

HCID 70945620(S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl esterYield 57.2%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
82 °C

Procedure

A solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester hydrochloride (Novabiochem, 500 mg, 2.25 mmol) in acetonitrile (20 mL) was placed in a flask and treated with 2-bromomethyl-3-fluoro-benzoic acid methyl ester (557 mg, 2.25 mmol) and triethylamine (660 μL, 4.74 mmol). The reaction mixture was then heated at reflux (82° C.) overnight for 16 h. After this time, the reaction mixture was diluted with water (5 mL) and concentrated in vacuo to remove the acetonitrile. The remaining material was then diluted with another portion of water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were then dried over magnesium sulfate, filtered to remove the drying agent and the filtrate concentrated in vacuo. The crude material was purified using an Analogix Intelliflash 280 chromatography system (RS-40 silica gel column, 10-25% ethyl acetate/hexanes) to afford (S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester (411 mg, 57%) as a clear colorless oil: [α]30D=−17.3° (c=0.30, methylene chloride); HR-ES(+) m/e calcd for C18H22NO3F [M+H]+ 320.1657, observed 320.1656; 1H NMR (300 MHz, DMSO-d6) δ 7.54-7.63 (m, 2H), 7.42-7.54 (m, 1H), 4.96 (dd, J=4.53, 11.47 Hz, 1H), 4.49-4.65 (m, 2H), 3.63 (s, 3H), 1.48-1.99 (m, 7H), 0.74-1.23 (m, 6H).

Workup

  1. temperatureThe reaction mixture was then heated
  2. concentrationconcentrated in vacuo
  3. customto remove the acetonitrile
  4. additionThe remaining material was then diluted with another portion of water (10 mL)
  5. extractionextracted with ethyl acetate (3×20 mL)
  6. dry with materialThe combined organic layers were then dried over magnesium sulfate
  7. filtrationfiltered
  8. customto remove the drying agent
  9. concentrationthe filtrate concentrated in vacuo
  10. customThe crude material was purified

Sources & evidence

ORD record
ord-978942e4038e40c2b86e4b0cdb2b7d16
Source dataset
uspto-grants-2014_04
Patent number
US08697705B2

Reaction notes

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