Triethylamine → tert-butyl (3S)-3-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate

HRID 1426445Notes

Reaction equation

HRID 1426445 reaction equation
[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](O)=O)[CH:12]2[CH2:17][CH2:18][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH2:34][C:35]1[CH:39]=[C:38]([Br:40])[S:37][C:36]=1[C:41]([NH2:43])=[O:42]>O1CCCC1.O>[Br:40][C:38]1[S:37][C:36]2[C:41](=[O:42])[NH:43][C:14]([C@@H:13]3[CH:12]4[CH2:17][CH2:18][CH:9]([CH2:10][CH2:11]4)[N:8]3[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:34][C:35]=2[CH:39]=1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 62365Isobutyl chloroformateHCID 13712633(S)-2-(tert-Butoxycarbonyl)-2-azabicyclo[2.2.2]octane-3-carboxylic acidHCID 219758623-Amino-5-bromothiophene-2-carboxamide

Product 1

HCID 136333933tert-butyl (3S)-3-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-azabicyclo[2.2.2]octane-2-carboxylateYield 43.8%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
60 °C

Procedure

To a solution of (3S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.2]octane-3-carboxylic acid (0.511 g) and triethylamine (0.348 mL) in tetrahydrofuran (5 mL) was added isobutyl chloroformate (0.26 mL) while stirring under ice-cooling. After stirring at room temperature for 30 min, a solution of 3-amino-5-bromothiophene-2-carboxamide (0.221 g) produced in Example 1, step D, in tetrahydrofuran (1 mL) was added. The reaction system was stirred with heating at 60° C. for 4 days. Water was poured into the reaction system, and the mixture was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. 2M Aqueous sodium hydroxide solution (3.0 mL) and 1,2-dimethoxyethane (6.0 mL) were added to the residue, and the mixture was stirred with heating in a microwave reactor at 150° C. for 1 hr. Insoluble material was removed by filtration, and the mixture was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane) to give the title compound (193 mg) as a colorless solid. The optical purity was 70% ee. The analysis was performed by high performance liquid chromatography (column: CHIRALPAK AD-H (4.6 mm i.d.×250 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (800/200), flow rate: 1.0 mL/min, column temperature: 30° C., detection 220 nm).

Workup

  1. temperaturecooling
  2. stirringAfter stirring at room temperature for 30 min
  3. stirringThe reaction system was stirred
  4. extractionthe mixture was extracted with ethyl acetate
  5. dry with materialdried over anhydrous sodium sulfate
  6. customInsoluble material was removed by filtration
  7. concentrationthe filtrate was concentrated under reduced pressure
  8. addition2M Aqueous sodium hydroxide solution (3.0 mL) and 1,2-dimethoxyethane (6.0 mL) were added to the residue
  9. stirringthe mixture was stirred
  10. temperaturewith heating in a microwave reactor at 150° C. for 1 hr
  11. customInsoluble material was removed by filtration
  12. extractionthe mixture was extracted with ethyl acetate
  13. dry with materialdried over anhydrous sodium sulfate
  14. customInsoluble material was removed by filtration
  15. concentrationthe filtrate was concentrated under reduced pressure
  16. customThe residue was purified by basic silica gel column chromatography (ethyl acetate/hexane)

Sources & evidence

ORD record
ord-91130af1ec2b4587a440a92475818c87
Source dataset
uspto-grants-2015_01
Patent number
US08933069B2

Reaction notes

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