Potassium Carbonate → (S)-1-(((9H-Fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid

HRID 625881Notes

Reaction equation

HRID 625881 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:23](Cl)(=[O:39])[O:24][CH2:25][CH:26]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2>O1CCOCC1.O>[CH:37]1[C:38]2[CH:26]([CH2:25][O:24][C:23]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C@H:10]3[C:14]([OH:16])=[O:15])=[O:39])[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]=2[CH:34]=[CH:35][CH:36]=1

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 343679-Fluorenylmethyl chloroformateHCID 1501850(S)-4-N-Boc-piperazine-2-carboxylic acid

Product 1

HCID 7128304(S)-1-(((9H-Fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acidYield 30%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 312751,4-DioxaneSolvent

Procedure

To a solution of (S)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (500 mg, 2.171 mmol) in 1,4-dioxane (5 mL) and water (20 mL) was added potassium carbonate (1200 mg, 8.69 mmol) followed by (9H-fluoren-9-yl)methyl carbonochloridate (562 mg, 2.171 mmol) at 0° C. The mixture was stirred at RT for 18 hrs and then treated with water (10 ml). The resulting mixture was extracted with diethyl ether (2×15 ml). The aqueous phase was acidified with aq. HCl (1M) to pH 2-3, and extracted with DCM (3×20 ml). The combined organic layers were dried over MgSO4 and concentrated to give the crude product. The crude product was purified via prep HPLC (10-100% CH3CN:Water with 0.1% TFA buffer) to afford the product (S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (294 mg, 30% yield) as a white solid. 1H NMR (500 MHz, methanol-d4) d 7.83 (t, J=6.6 Hz, 2H), 7.68-7.58 (m, 2H), 7.45-7.38 (m, 2H), 7.38-7.30 (m, 2H), 4.65 (br. s., 1H), 4.58 (d, J=13.7 Hz, 1H), 4.55-4.39 (m, 3H), 4.33-4.18 (m, 1H), 2.91-2.85 (m, 4H), 1.47 (s, 9H). ESI-MS(+) m/z=475 (M+Na).

Workup

  1. extractionThe resulting mixture was extracted with diethyl ether (2×15 ml)
  2. extractionextracted with DCM (3×20 ml)
  3. dry with materialThe combined organic layers were dried over MgSO4
  4. concentrationconcentrated
  5. customto give the crude product
  6. customThe crude product was purified via prep HPLC (10-100% CH3CN:Water with 0.1% TFA buffer)

Sources & evidence

ORD record
ord-5d52d27016044ec2805e286ccf8dbbae
Source dataset
uspto-grants-2016_04
Patent number
US09308236B2

Reaction notes

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