Tetrahydrofuran → Di-tert-butyl (1S,2S,5R,6S)-2-[(tert-butoxycarbonyl)amino]bicyclo[3.1.0]hex-3-ene-2,6-dicarboxylate

HRID 2173006Notes

Reaction equation

HRID 2173006 reaction equation
C(N(CC)CC)C.[C:8]([O:12][C:13]([NH:15][C@@:16]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:21][C@H:20](O)[CH:19]2[CH:17]1[CH:18]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:14])([CH3:11])([CH3:10])[CH3:9].O1CCCC1.CC(C)([O-])C.[K+]>CC(C)=O.O>[C:8]([O:12][C:13]([NH:15][C@@:16]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:21]=[CH:20][C@@H:19]2[C@H:17]1[C@H:18]2[C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])=[O:14])([CH3:11])([CH3:9])[CH3:10]

Participants

7

Reactant 4

HCID 8028Tetrahydrofuran2×HCID 8471TriethylamineHCID 23665647Potassium tert-butoxideHCID 69676200HCID 69676200, compound

Product 1

HCID 71681345Di-tert-butyl (1S,2S,5R,6S)-2-[(tert-butoxycarbonyl)amino]bicyclo[3.1.0]hex-3-ene-2,6-dicarboxylateYield 95%

Reagents, catalysts & solvents 2

HCID 180AcetoneSolventHCID 962WaterSolvent

Conditions

Temperature
23 °C

Procedure

Triethylamine (735 mL, 5.30 mol) is added dropwise at 0° C. under N2 over 40 minutes to a solution of di-tert-butyl(2S,4S)-2-[(tert-butoxycarbonyl)amino]-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylate (995.4 g, 2.41 mol) in dry tetrahydrofuran (8.4 L) Methanesulfonyl chloride (373 mL, 4.82 mol) is added at 0° C. over 50 minutes. The reaction is warmed to 23° C. After 3 hours, the reaction if filtered to remove triethylamine hydrochloride salt. Wash the filter cake with dry tetrahydrofuran (2×2 L). The filtrate (13 L) is split into two equal parts. To one half of filtrate, add 1M potassium tert-butoxide in tetrahydrofuran (3.6 L, 3.6 mol) dropwise to the solution obtained in previous step (Crude V=6.5 L, 1.2 mol) at 15° C. over 2 hours 15 minutes then allow to warm to 23° C. After 2 hours 30 minutes the reaction is quenched by pouring into 10% aqueous acetic acid (950 mL). Separate the layers and extract the aqueous layer with ethyl acetate (1.7 L). The organic layers are combined and concentrated in vacuo to obtain a solid which is dissolved in acetone (1.45 L) and added to water (7.3 L). Stir the resulting suspension overnight at 23° C. Filter off the precipitate, wash with water (2×1 L), and dry in the vacuum oven at 40° C. to obtain the title compound (450.67 g, yield 95%). MS (m/z): 418 (M+23).

Workup

  1. additionis added at 0° C. over 50 minutes
  2. customthe reaction
  3. filtrationif filtered
  4. customto remove triethylamine hydrochloride salt
  5. washWash the filter cake with dry tetrahydrofuran (2×2 L)
  6. customThe filtrate (13 L) is split into two equal parts
  7. customobtained in previous step (Crude V=6.5 L, 1.2 mol) at 15° C. over 2 hours 15 minutes
  8. temperatureto warm to 23° C
  9. customAfter 2 hours 30 minutes the reaction is quenched
  10. additionby pouring into 10% aqueous acetic acid (950 mL)
  11. customSeparate the layers
  12. extractionextract the aqueous layer with ethyl acetate (1.7 L)
  13. concentrationconcentrated in vacuo
  14. customto obtain a solid which
  15. filtrationFilter off the precipitate
  16. washwash with water (2×1 L)
  17. customdry in the vacuum oven at 40° C.

Sources & evidence

ORD record
ord-02e0bdb7a66a45f9bab36e742d2b2e9b
Source dataset
uspto-grants-2015_06
Patent number
US09056844B2

Reaction notes

Loading…