Diisopropylethylamine → tert-butyl ((2S,3R)-1-((2S,4R)-4-hydroxy-2-(((1R,2S)-1-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidin-1-yl)-3,5-dimethyl-1-oxonon-8-en-2-yl)carbamate

HRID 523171Notes

Reaction equation

HRID 523171 reaction equation
FC(F)(F)C(O)=O.[NH2:8][C@:9]1([C:14]([NH:16][S:17]([C:20]2([CH3:23])[CH2:22][CH2:21]2)(=[O:19])=[O:18])=[O:15])[CH2:11][C@H:10]1[CH:12]=[CH2:13].[C:24]([O:28][C:29]([NH:31][C@@H:32]([C@H:44]([CH3:52])[CH2:45][C@H:46]([CH3:51])[CH2:47][CH2:48][CH:49]=[CH2:50])[C:33]([N:35]1[CH2:39][C@H:38]([OH:40])[CH2:37][C@H:36]1[C:41](O)=[O:42])=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[OH:40][C@H:38]1[CH2:39][N:35]([C:33](=[O:34])[C@@H:32]([NH:31][C:29](=[O:30])[O:28][C:24]([CH3:26])([CH3:25])[CH3:27])[C@H:44]([CH3:52])[CH2:45][CH:46]([CH3:51])[CH2:47][CH2:48][CH:49]=[CH2:50])[C@H:36]([C:41](=[O:42])[NH:8][C@:9]2([C:14](=[O:15])[NH:16][S:17]([C:20]3([CH3:23])[CH2:22][CH2:21]3)(=[O:19])=[O:18])[CH2:11][C@H:10]2[CH:12]=[CH2:13])[CH2:37]1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 90117938(2S,4R)-1-((2S,3R,5R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acidHCID 118415166(1R,2S)-1-amino-N-((1-methylcyclopropyl)sulfonyl)-2-vinylcyclopropanecarboxamide trifluoroacetic acid salt

Product 1

HCID 86683198tert-butyl ((2S,3R)-1-((2S,4R)-4-hydroxy-2-(((1R,2S)-1-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidin-1-yl)-3,5-dimethyl-1-oxonon-8-en-2-yl)carbamateYield 41.4%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

To a 500 mL round-bottom flask charged with (1R,2S)-1-amino-N-((1-methylcyclopropyl)sulfonyl)-2-vinylcyclopropanecarboxamide trifluoroacetic acid salt (7.53 g, 21.0 mmol) was added a solution of (2S,4R)-1-((2S,3R,5R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (8.82 g, 21.38 mmol) in CH2Cl2 (100 mL). To the solution was added N,N-diisopropylethylamine (15 mL, 86 mmol) and DMF (15 mL) to afford a homogeneous orange solution. The flask was placed in a room temperature water bath. To the stirred solution was added HATU (9.59 g, 25.2 mmol). The solution was stirred at room temperature for 20 h. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in EtOAc (300 mL) and transfered to a 1 L separatory funnel. The solution was washed with aq. 1M HCl (4×225 mL). The combined aqueous phases were extracted with EtOAc (150 mL). The combined organics were dried over MgSO4; filtered, then concentrated in vacuo. The resulting residue was dissolved in MeOH and concentrated onto Celite in vacuo; the resulting powder was subjected to silica gel chromatography (hexanes:acetone, 90:10 to 60:40) to afford tert-butyl ((2S,3R)-1-((2S,4R)-4-hydroxy-2-(((1R,2S)-1-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidin-1-yl)-3,5-dimethyl-1-oxonon-8-en-2-yl)carbamate as a colorless solid (5.56 g, 41%). MS: MS m/z 639.5 (M++1).

Workup

  1. customto afford a homogeneous orange solution
  2. customwas placed in a room temperature
  3. concentrationThe reaction mixture was concentrated in vacuo
  4. dissolutionthe resulting residue was dissolved in EtOAc (300 mL)
  5. customtransfered to a 1 L separatory funnel
  6. washThe solution was washed with aq. 1M HCl (4×225 mL)
  7. extractionThe combined aqueous phases were extracted with EtOAc (150 mL)
  8. dry with materialThe combined organics were dried over MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. dissolutionThe resulting residue was dissolved in MeOH
  12. concentrationconcentrated onto Celite in vacuo

Sources & evidence

ORD record
ord-eaa29d160a43427ca5fb56f22cc6d28a
Source dataset
uspto-grants-2016_05
Patent number
US09334279B2

Reaction notes

Loading…