Diisopropylethylamine → 3-Bicyclo[2.2.1]hept-2-yl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester

HRID 19355Notes

Reaction equation

HRID 19355 reaction equation
[CH3:1][O:2][C:3](=[O:14])[CH:4]([NH2:13])[CH2:5][CH:6]1[CH2:11][CH:10]2[CH2:12][CH:7]1[CH2:8][CH2:9]2.C(N(CC)C(C)C)(C)C.C1(C[C@H](N2[CH2:49][C:48]([O:50][C:51]3[C:56]([F:57])=[CH:55][CH:54]=[CH:53][C:52]=3[F:58])=[CH:47][C:46]2=[O:59])C(NC2C=CN(CC(O)(C)C)N=2)=O)CCCCC1>C(#N)C>[CH3:1][O:2][C:3](=[O:14])[CH:4]([N:13]1[CH2:49][C:48]([O:50][C:51]2[C:56]([F:57])=[CH:55][CH:54]=[CH:53][C:52]=2[F:58])=[CH:47][C:46]1=[O:59])[CH2:5][CH:6]1[CH2:11][CH:10]2[CH2:12][CH:7]1[CH2:8][CH2:9]2

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 142814412-Amino-3-bicyclo[2.2.1]hept-2-yl-propionic acid methyl esterHCID 44253752(S)-3-cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide

Product 1

HCID 668947413-Bicyclo[2.2.1]hept-2-yl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl esterYield 21.4%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
140 °C

Procedure

In a round bottom flask was placed 2-amino-3-bicyclo[2.2.1]hept-2-yl-propionic acid methyl ester (206 mg, 1.04 mmol), N,N-diisopropylethylamine (390 μL, 2.24 mmol) and 4-bromo-3-(2,6-difluoro-phenoxy)-but-2-enoic acid ethyl ester (prepared as in Example 36, 390 mg, 2.24 mmol) in acetonitrile (10 mL). This mixture was then split into two 5 mL portions and placed in two sealed microwave reaction tubes and heated in a microwave reactor at 140° C. for 1 h. The contents of the two reaction tubes were combined, concentrated in vacuo and diluted with dichloromethane (20 mL) and washed with a 1N aqueous hydrochloric acid solution (10 mL), a saturated sodium bicarbonate solution (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by AnaLogix IntelliFlash flash chromatography (12 g column, 15% ethyl acetate/hexanes to 30% ethyl acetate/hexanes) afforded 3-bicyclo[2.2.1]hept-2-yl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (87 mg, 15%) as a yellow oil.

Workup

  1. customIn a round bottom flask was placed
  2. customThis mixture was then split into two 5 mL portions
  3. customplaced in two sealed microwave reaction tubes
  4. customThe contents of the two reaction tubes
  5. concentrationconcentrated in vacuo
  6. additiondiluted with dichloromethane (20 mL)
  7. washwashed with a 1N aqueous hydrochloric acid solution (10 mL)
  8. dry with materiala saturated sodium bicarbonate solution (10 mL), dried over magnesium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customPurification by AnaLogix IntelliFlash flash chromatography (12 g column, 15% ethyl acetate/hexanes to 30% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-f4ff490e70f646ee8381e3bcaebe325b
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Reaction notes

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