Cesium carbonate → methyl (S)-1-((S)-2-(4-((2R,5R)-5-(4-chloro-3-nitrophenyl)-1-(3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl)pyrrolidin-2-yl)-2-nitrophenylcarbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

HRID 1429242Notes

Reaction equation

HRID 1429242 reaction equation
Cl[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][C@H:10]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=3)[N:9]2[C:23]2[CH:28]=[C:27]([F:29])[C:26]([N:30]3[CH2:35][CH2:34][CH:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:32][CH2:31]3)=[C:25]([F:42])[CH:24]=2)=[CH:4][C:3]=1[N+:43]([O-:45])=[O:44].[C:46]([C@@H:49]1[CH2:53][CH2:52][CH2:51][N:50]1[C:54](=[O:64])[C@@H:55]([NH:59][C:60](=[O:63])[O:61][CH3:62])[CH:56]([CH3:58])[CH3:57])(=[O:48])[NH2:47].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C@@H:10]2[N:9]([C:23]3[CH:24]=[C:25]([F:42])[C:26]([N:30]4[CH2:35][CH2:34][CH:33]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[CH2:32][CH2:31]4)=[C:27]([F:29])[CH:28]=3)[C@@H:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:47][C:46]([C@@H:49]4[CH2:53][CH2:52][CH2:51][N:50]4[C:54](=[O:64])[C@@H:55]([NH:59][C:60](=[O:63])[O:61][CH3:62])[CH:56]([CH3:58])[CH3:57])=[O:48])=[C:3]([N+:43]([O-:45])=[O:44])[CH:4]=3)[CH2:12][CH2:11]2)=[CH:14][C:15]=1[N+:20]([O-:22])=[O:21]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 582268331-(4-((2R,5R)-2,5-Bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-phenylpiperidineHCID 68574976methyl (S)-1-((S)-2-carbamoylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Product 1

HCID 86657192methyl (S)-1-((S)-2-(4-((2R,5R)-5-(4-chloro-3-nitrophenyl)-1-(3,5-difluoro-4-(4-phenylpiperidin-1-yl)phenyl)pyrrolidin-2-yl)-2-nitrophenylcarbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamateYield 43.4%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

1-(4-((2R,5R)-2,5-Bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-phenylpiperidine (0.745 g, 1.14 mmol) was dissolved in dioxane (12 mL) in a tube and treated with methyl(S)-1-((S)-2-carbamoylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (0.309 g, 1.14 mmol), cesium carbonate (0.409 g, 1.25 mmol), Xantphos (0.066 g, 0.11 mmol), and tris(dibenzylideneacetone)dipalladium(0) (0.052 g, 0.057 mmol). Nitrogen was bubbled through this mixture for 15 minutes, then the tube was sealed and heated at 100° C. for 2 hours. The mixture was diluted with water, extracted into dichloromethane, concentrated, and purified by chromatography, eluting with 0-5% methanol in dichloromethane to give 0.44 g (43%) of a dark yellow solid.

Workup

  1. customNitrogen was bubbled through this mixture for 15 minutes
  2. customthe tube was sealed
  3. additionThe mixture was diluted with water
  4. extractionextracted into dichloromethane
  5. concentrationconcentrated
  6. custompurified by chromatography
  7. washeluting with 0-5% methanol in dichloromethane

Sources & evidence

ORD record
ord-08aefa8fce9544188737b3826f9aefc0
Source dataset
uspto-grants-2015_01
Patent number
US08937150B2

Reaction notes

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