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

HRID 19343Notes

Reaction equation

HRID 19343 reaction equation
Cl.[CH3:2][O:3][C:4](=[O:16])[CH:5]([NH2:15])[CH2:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].C(N(CC)C(C)C)(C)C.C1(C[C@H](N2[CH2:51][C:50]([O:52][C:53]3[C:58]([F:59])=[CH:57][CH:56]=[CH:55][C:54]=3[F:60])=[CH:49][C:48]2=[O:61])C(NC2C=CN(CC(O)(C)C)N=2)=O)CCCCC1>C(#N)C>[CH3:2][O:3][C:4](=[O:16])[CH:5]([N:15]1[CH2:51][C:50]([O:52][C:53]2[C:58]([F:59])=[CH:57][CH:56]=[CH:55][C:54]=2[F:60])=[CH:49][C:48]1=[O:61])[CH2:6][C:7]1[C:8]([Cl:14])=[CH:9][CH:10]=[CH:11][C:12]=1[Cl:13]

Participants

5

Reactant 3

HCID 81531Diisopropylethylamine2×HCID 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]-propionamideHCID 668949802-Amino-3-(2,6-dichloro-phenyl)-propionic acid methyl ester hydrochloride salt

Product 1

HCID 668937393-(2,6-Dichloro-phenyl)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl esterYield 13.1%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent2×

Conditions

Temperature
60 °C

Procedure

In a flask was placed 2-amino-3-(2,6-dichloro-phenyl)-propionic acid methyl ester hydrochloride salt (313 mg, 1.10 mmol), acetonitrile (5 mL) and N,N-diisopropylethylamine (200 μL, 1.23 mmol). This mixture was stirred at 60° C. for 1 h and then cooled to 25° C. The mixture was then treated with N,N-diisopropylethylamine (200 μL, 1.23 mmol) and heated at 80° C. and a solution of 4-bromo-3-(2,6-difluoro-phenoxy)-but-2-enoic acid ethyl ester (prepared as in Example 36, 321 mg, 1.00 mmol) in acetonitrile (1 mL) was added slowly. The mixture was heated at 100° C. for 16 h and then placed in a sealed microwave tube and heated at 140° C. for 1 h in the microwave. The mixture was then concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (40S column, 10% ethyl acetate/hexanes to 100% ethyl acetate) afforded 3-(2,6-dichloro-phenyl)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (58 mg, 12%) as a gold oil: HR-ES-MS m/z calculated for C20H15NO4Cl2F2 [M+H]+ 442.0419, observed 442.0420.

Workup

  1. customIn a flask was placed
  2. temperaturecooled to 25° C
  3. temperatureheated at 80° C.
  4. temperatureThe mixture was heated at 100° C. for 16 h
  5. customplaced in a sealed microwave tube
  6. temperatureheated at 140° C. for 1 h in the microwave
  7. concentrationThe mixture was then concentrated in vacuo with silica gel (2 g)
  8. customPurification by Biotage flash chromatography (40S column, 10% ethyl acetate/hexanes to 100% ethyl acetate)

Sources & evidence

ORD record
ord-f28c444f2451472ea95365698441e231
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Reaction notes

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