Diisopropylethylamine → (2S)-tert-butyl 2-(4-(methoxy)-1-(4-bromophenyl)-1,4-dioxobutan-2-ylcarbamoyl)pyrrolidine-1-carboxylate

HRID 80393Notes

Reaction equation

HRID 80393 reaction equation
CN(C(ON1N=N[C:11]2[CH:12]=[CH:13][CH:14]=N[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH:26]([C:32]([C:34]1[CH:39]=[CH:38][C:37]([Br:40])=[CH:36][CH:35]=1)=[O:33])[CH2:27][C:28]([O:30][CH3:31])=[O:29].[C:41]([N:48]1[CH2:55][CH2:54][CH2:53][C@H:49]1[C:50]([OH:52])=[O:51])([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42].[CH3:56]CN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C.C(OCC)(=O)C.O>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][CH:26]([NH:25][C:50]([C@@H:49]1[CH2:53][CH2:54][CH2:55][N:48]1[C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])=[O:52])[C:32]([C:34]1[CH:35]=[CH:36][C:37]([Br:40])=[CH:38][CH:39]=1)=[O:33])[C:10]1[CH:56]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:31][O:30][C:28](=[O:29])[CH2:27][CH:26]([NH:25][C:50]([C@@H:49]1[CH2:53][CH2:54][CH2:55][N:48]1[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[O:51])[C:32]([C:34]1[CH:35]=[CH:36][C:37]([Br:40])=[CH:38][CH:39]=1)=[O:33]

Participants

10

Reactant 5

HCID 81531DiisopropylethylamineHCID 850831,2-Pyrrolidinedicarboxylic acid, 1-(1,1-dimethylethyl) ester, (2S)-HCID 516892Sodium BicarbonateHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 57610979HCID 57610979, compound

Product 2

HCID 57610926(2S)-tert-butyl 2-(4-(methoxy)-1-(4-bromophenyl)-1,4-dioxobutan-2-ylcarbamoyl)pyrrolidine-1-carboxylateYield 49%HCID 68625018(2S)-tert-butyl 2-(4-(benzyloxy)-1-(4-bromophenyl)-1,4-dioxobutan-2-ylcarbamoyl)pyrrolidine-1-carboxylateYield 8.7%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
24 °C

Procedure

HATU (10.5 g, 27.6 mmol) was added to a solution of Example J6, methyl 3-amino-4-(4-bromophenyl)-4-oxobutanoate (10 g, 27.6 mmol), (S)—N-Boc-proline (7.13 g, 33.1 mmol), and Hunig's Base (45 mL, 276 mmol) in DMF (150 mL) and stirred for 18 hours at 24° C. The reaction was diluted with ethyl acetate (2 vol) and H2O (¼ vol) and sat NaHCO3 (⅛ vol). Filter through diatomaceous earth (Celite®) to remove tin salts. Extract aqueous layer (2×) with ethyl acetate, and concentrate combined organic to remove solvents (high vacuum on rotory evaporator). The residue was subject to a short silica gel chromatography to remove by-products, and the resultant crude product was charged (CH2Cl2) a 65 (M) Biotage silica gel cartridge. Gradient elution 15-70% B over 2 L (A=Hexanes; B=ethyl acetate) gave a less polar band of (2S)-tert-butyl 2-(4-(benzyloxy)-1-(4-bromophenyl)-1,4-dioxobutan-2-ylcarbamoyl)pyrrolidine-1-carboxylate 1.35 g (8.7%) and more polar Example J7, (2S)-tert-butyl 2-(4-(methoxy)-1-(4-bromophenyl)-1,4-dioxobutan-2-ylcarbamoyl)pyrrolidine-1-carboxylate 7.6 g (49%). RT=2.0 minutes (condition 1); LCMS: Anal. C21H27BrN2O6 Calcd. 383; found: 383 (M-Boc).

Workup

  1. filtrationFilter through diatomaceous earth (Celite®)
  2. customto remove tin salts
  3. concentrationExtract aqueous layer (2×) with ethyl acetate, and concentrate
  4. customto remove
  5. customsolvents (high vacuum on rotory evaporator)
  6. customto remove by-products
  7. additionthe resultant crude product was charged (CH2Cl2) a 65 (M) Biotage silica gel cartridge
  8. washGradient elution 15-70% B over 2 L (A=Hexanes

Sources & evidence

ORD record
ord-fc9a8403acfb4ac0a5367ebe8966940b
Source dataset
uspto-grants-2014_09
Patent number
US08846023B2

Reaction notes

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