Sodium Bicarbonate → 4-[4-(4'-{2-[(2S,4S)-4-Methoxy-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-piperazin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester

HRID 1500534Notes

Reaction equation

HRID 1500534 reaction equation
[CH3:1][O:2][C:3](=[O:38])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][C@@H:14]([O:16][CH3:17])[CH2:13][C@H:12]1[C:18]1[NH:19][CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][CH:24]=2)[N:22]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][CH:49]([N:52]2[CH2:57][CH2:56][N:55]([C:58](=[O:72])[NH:59][C:60]3[CH:65]=[CH:64][C:63](Br)=[C:62]([O:67][C:68]([F:71])([F:70])[F:69])[CH:61]=3)[CH2:54][CH2:53]2)[CH2:48][CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40].C(=O)(O)[O-].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>O1CCOCC1.O.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].C(#N)C>[C:39]([O:43][C:44]([N:46]1[CH2:47][CH2:48][CH:49]([N:52]2[CH2:57][CH2:56][N:55]([C:58](=[O:72])[NH:59][C:60]3[CH:65]=[CH:64][C:63]([C:26]4[CH:25]=[CH:24][C:23]([C:21]5[N:22]=[C:18]([C@@H:12]6[CH2:13][C@H:14]([O:16][CH3:17])[CH2:15][N:11]6[C:9](=[O:10])[C@@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:38])[CH:6]([CH3:7])[CH3:8])[NH:19][CH:20]=5)=[CH:28][CH:27]=4)=[C:62]([O:67][C:68]([F:70])([F:71])[F:69])[CH:61]=3)[CH2:54][CH2:53]2)[CH2:50][CH2:51]1)=[O:45])([CH3:42])([CH3:40])[CH3:41]

Participants

9

Reactant 4

HCID 516892Sodium BicarbonateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 867005114-[4-(4-Bromo-3-trifluoromethoxy-phenylcarbamoyl)-piperazin-1-yl]-piperidine-1-carboxylic acid tert-butyl esterHCID 178502456HCID 178502456, compound

Product 1

HCID 1785024624-[4-(4'-{2-[(2S,4S)-4-Methoxy-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-piperazin-1-yl]-piperidine-1-carboxylic acid tert-butyl esterYield 68.5%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 6342AcetonitrileSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

A solution of [(S)-1-((2S,4S)-4-methoxy-2-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (35.5 mg, 0.067 mmol; Preparation 26), 4-[4-(4-bromo-3-trifluoromethoxy-phenylcarbamoyl)-piperazin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (37.1 mg, 0.067 mmol) and sodium bicarbonate (29.4 mg, 0.35 mmol) in 1,4-dioxane (2.8 mL) and water (129 μL) was degassed with nitrogen for 20 min. Pd2(dba)3 (12.33 mg, 0.013 mmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos) (32.09 mg, 0.067 mmol) were added and the reaction was degassed with nitrogen for 15 min. The resulting solution was heated at 90° C. for 60 h, concentrated, diluted with methanol, filtered through a pad of Celite®, concentrated under vacuum, and purified by reverse phase HPLC. Fractions containing product were combined and lyophilised overnight to afford a white powder. Impure fractions were combined and concentrated under vacuum, dissolved in 1:1 acetic acid:ACN solution to provide the di-TFA salt of the title compound (40 mg, 54% yield) (m/z): [M+H]+ calcd for C43H57F3N8O8 871.43 found 871.8.

Workup

  1. customthe reaction was degassed with nitrogen for 15 min
  2. concentrationconcentrated
  3. additiondiluted with methanol
  4. filtrationfiltered through a pad of Celite®
  5. concentrationconcentrated under vacuum
  6. custompurified by reverse phase HPLC
  7. additionFractions containing product
  8. customto afford a white powder
  9. concentrationconcentrated under vacuum
  10. dissolutiondissolved in 1:1 acetic acid

Sources & evidence

ORD record
ord-88fbab837832473c9bece6cb891976d3
Source dataset
uspto-grants-2015_12
Patent number
US09206159B2

Reaction notes

Loading…