1,2-Dichloroethane → N-({3-[(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(methoxyimino) pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methyl)-3-(1-piperidinyl)propanamide

HRID 1242595Notes

Reaction equation

HRID 1242595 reaction equation
C([O:5][C:6]([NH:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([C@@H:15]2[CH2:19][C:18](=[N:20][O:21][CH3:22])[CH2:17][N:16]2[C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:27][CH:26]=2)=[O:24])[N:11]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+].[N:53]1([CH2:59][CH2:60]C(O)=O)[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1.C(Cl)CCl>CN(C1C=CN=CC=1)C>[C:28]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:27]=[CH:26][C:25]([C:23]([N:16]2[CH2:17][C:18](=[N:20][O:21][CH3:22])[CH2:19][C@H:15]2[C:12]2[N:11]=[C:10]([CH2:9][NH:8][C:6](=[O:5])[CH2:60][CH2:59][N:53]3[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]3)[O:14][N:13]=2)=[O:24])=[CH:30][CH:29]=1

Participants

7

Reactant 5

HCID 111,2-DichloroethaneHCID 10340Sodium CarbonateHCID 1177821-Piperidinepropanoic acidHCID 21863450Trifluoroacetic acid methylene chlorideHCID 587145494-{[(2S,4EZ)-2-(5-{[(tert-butoxycarbonyl)amino]methyl}-1,2,4-oxadiazol-3-yl)-4-(methoxyimino)pyrrolidinyl]carbonyl}-1,1'-biphenyl

Product 1

HCID 58714573N-({3-[(2S,4EZ)-1-([1,1'-biphenyl]-4-ylcarbonyl)-4-(methoxyimino) pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methyl)-3-(1-piperidinyl)propanamideYield 50%

Reagents, catalysts & solvents 1

HCID 142844-(Dimethylamino)pyridineCatalyst

Conditions

Temperature
0 °C

Procedure

4-{[(2S,4EZ)-2-(5-{[(tert-butoxycarbonyl)amino]methyl}-1,2,4-oxadiazol-3-yl)-4-(methoxyimino)pyrrolidinyl]carbonyl}-1,1′-biphenyl (Example 50) was treated with a 25% TFA/DCM solution at 0° C. The reaction was monitored by LC/MS and stopped after completion. The reaction was then made basic with sodium carbonate solution (10%) and extracted with DCM. The combined organic phases were dried over magnesium sulfate. Solvent removal afforded a crude product, which was used without purification in the next step. The residue was dissolved in DCM at room temperature, DMAP (1.1 equivalent) and 3-(1-piperidinyl)propanoic acid (1 equivalent) were added. The reaction mixture was then cooled down to 0° C. and EDC (1.1 equivalent) was added portion-wise. After stirring for 1 hour at 0° C., the reaction mixture was allowed to warm to room temperature. The reaction was monitored by TLC and LC/MS. Usually after 12 hours stirring at RT, the reaction mixture was hydrolyzed, washed with sodium carbonate solution (10%), dried over MgSO4, and evaporated in vacuo to give a crude product. Flash chromatography on silica gel, eluting with 60% EtOAc in hexane, gave the title compound as a mixture of E- and Z-isomers in 50% yield (87.4% purity by HPLC).

Workup

  1. extractionextracted with DCM
  2. dry with materialThe combined organic phases were dried over magnesium sulfate
  3. customSolvent removal
  4. customafforded a crude product, which
  5. customwas used without purification in the next step
  6. dissolutionThe residue was dissolved in DCM at room temperature
  7. temperatureto warm to room temperature
  8. stirringUsually after 12 hours stirring at RT
  9. washwashed with sodium carbonate solution (10%)
  10. dry with materialdried over MgSO4
  11. customevaporated in vacuo
  12. customto give a crude product
  13. washFlash chromatography on silica gel, eluting with 60% EtOAc in hexane

Sources & evidence

ORD record
ord-46cec265eae24c3a96647cf8a3f2abf8
Source dataset
uspto-grants-2006_10
Patent number
US07115639B2

Reaction notes

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