Sodium hydride → 6-tert-Butyl 1-ethyl (E)-(S)-5-[(tert-butoxycarbonyl)amino]-2-(3-fluoropropyl)hex-2-enedioate

HRID 1473715Notes

Reaction equation

HRID 1473715 reaction equation
C(OP([CH:9]([CH2:15][CH2:16][CH2:17][F:18])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[C:21]([O:25][C:26]([NH:28][C@@H:29]([CH2:37][CH:38]=O)[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:27])([CH3:24])([CH3:23])[CH3:22]>C1COCC1>[C:21]([O:25][C:26]([NH:28][C@H:29]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH2:37]/[CH:38]=[C:9](\[CH2:15][CH2:16][CH2:17][F:18])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:27])([CH3:24])([CH3:22])[CH3:23].[C:21]([O:25][C:26]([NH:28][C@H:29]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH2:37]/[CH:38]=[C:9](/[CH2:15][CH2:16][CH2:17][F:18])\[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:27])([CH3:24])([CH3:22])[CH3:23]

Participants

6

Reactant 3

HCID 24758Sodium hydrideHCID 10901762tert-Butyl (S)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoateHCID 86678426Ethyl 2-(diethoxyphosphoryl)-5-fluoropentanoate

Product 2

HCID 866784276-tert-Butyl 1-ethyl (E)-(S)-5-[(tert-butoxycarbonyl)amino]-2-(3-fluoropropyl)hex-2-enedioateHCID 866784286-tert-Butyl 1-ethyl (Z)-(S)-5-[(tert-butoxycarbonyl)amino]-2-(3-fluoro-propyl)hex-2-enedioate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
0 °C

Procedure

A solution of ethyl 2-(diethoxyphosphoryl)-5-fluoropentanoate (1.30 g, 4.12 mmol) in dry THF (15 mL) was added dropwise at 0° C. to a solution of sodium hydride (0.20 g, 60% on mineral oil, 4.94 mmol) in dry THF (35 mL). After stirring for 15 min tert-Butyl (S)-2-[(tert-butoxycarbonyl)amino]-4-oxobutanoate (1.13 g, 4.12 mmol) was added as a solution in dry THF (15 mL) dropwise to the reaction mixture. After stirring for 90 min at 0° C. the reaction was quenched by addition of saturated sodium bicarbonate solution (50 mL). After phase separation the aqueous layer was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried over sodium sulphate, concentrated under reduced pressure and the residue was purified by column chromatography (silica, hexanes/ethyl acetate gradient) to give 6-tert-Butyl 1-ethyl (E)-(S)-5-[(tert-butoxycarbonyl)amino]-2-(3-fluoropropyl)hex-2-ene-dioate and 6-tert-Butyl 1-ethyl (Z)—(S)-5-[(tert-butoxycarbonyl)amino]-2-(3-fluoropropyl)hex-2-enedioate as a mixture of diastereomers which were separated by HPLC (Chiralpak IC 5 μm 250×30 mm, hexane/2-propanol 90:10, 50 mL/min) to give 6-tert-Butyl 1-ethyl (E)-(S)-5-[(tert-butoxycarbonyl)amino]-2-(3-fluoropropyl)hex-2-enedioate (1e) (0.75 g, 1.86 mmol, 45%) and 6-tert-Butyl 1-ethyl (Z)—(S)-5-[(tert-butoxycarbonyl)amino]-2-(3-fluoropropyl)hex-2-enedioate (1d) (0.23 g, 0.56 mmol, 14%).

Workup

  1. customwas quenched by addition of saturated sodium bicarbonate solution (50 mL)
  2. customAfter phase separation the aqueous layer
  3. extractionwas extracted with ethyl acetate (3×50 mL)
  4. dry with materialthe combined organic layers were dried over sodium sulphate
  5. concentrationconcentrated under reduced pressure
  6. customthe residue was purified by column chromatography (silica, hexanes/ethyl acetate gradient)

Sources & evidence

ORD record
ord-46d0f98f3b7d48c78d38db771cbb5e9e
Source dataset
uspto-grants-2015_04
Patent number
US09017645B2

Reaction notes

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