Isobutyl chloroformate → tert-butyl (2S,4S)-2-[(5-bromo-2-carbamoylthiophen-3-yl)carbamoyl]-4-methylpyrrolidine-1-carboxylate

HRID 1052182Notes

Reaction equation

HRID 1052182 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:15][C@@H:14]([CH3:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)OCC(C)C.[NH2:25][C:26]1[CH:30]=[C:29]([Br:31])[S:28][C:27]=1[C:32]([NH2:34])=[O:33].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[Br:31][C:29]1[S:28][C:27]([C:32](=[O:33])[NH2:34])=[C:26]([NH:25][C:10]([C@@H:9]2[CH2:13][C@H:14]([CH3:16])[CH2:15][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:12])[CH:30]=1

Participants

8

Reactant 4

HCID 62365Isobutyl chloroformateHCID 516892Sodium BicarbonateHCID 219758623-Amino-5-bromothiophene-2-carboxamideHCID 26596883(4S)-1-(tert-Butoxycarbonyl)-4-methyl-L-proline

Product 1

HCID 86676210tert-butyl (2S,4S)-2-[(5-bromo-2-carbamoylthiophen-3-yl)carbamoyl]-4-methylpyrrolidine-1-carboxylateYield 68.6%

Reagents, catalysts & solvents 3

HCID 8028TetrahydrofuranSolventHCID 8471TriethylamineSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of (4S)-1-(tert-butoxycarbonyl)-4-methyl-L-proline (491 mg) and triethylamine (0.353 mL) in tetrahydrofuran (5 mL) was added 2-methylpropyl chlorocarbonate (0.292 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. Thereafter, to the reaction system was added 3-amino-5-bromothiophene-2-carboxamide (225 mg) produced in Example 1, step D, and the mixture was stirred at 60° C. for 24 hr. Ethyl acetate (20 mL) and aqueous sodium hydrogen carbonate (10 mL) were added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate (5 mL). The combined organic layers were washed with brine (5 mL) and dried over anhydrous sodium sulfate. Insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was crystallized from ethanol (5 mL). The obtained colorless solid was fractionated by high performance liquid chromatography (column: CHIRALPAK AD (50 mm i.d.×500 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (850/150), flow rate: 80 mL/min, column temperature: 30° C.) to give the title compound (302 mg) as a colorless solid.

Workup

  1. stirringthe mixture was stirred at 60° C. for 24 hr
  2. extractionthe separated aqueous layer was extracted with ethyl acetate (5 mL)
  3. washThe combined organic layers were washed with brine (5 mL)
  4. dry with materialdried over anhydrous sodium sulfate
  5. filtrationInsoluble material was filtered off
  6. concentrationthe filtrate was concentrated under reduced pressure
  7. customthe residue was crystallized from ethanol (5 mL)
  8. customwas fractionated by high performance liquid chromatography (column: CHIRALPAK AD (50 mm i.d.×500 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (850/150), flow rate: 80 mL/min, column temperature: 30° C.)

Sources & evidence

ORD record
ord-7efb3e89b40a414f9f590f0bd5e8d5e2
Source dataset
uspto-grants-2016_07
Patent number
US09388195B2

Reaction notes

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