Trifluoroacetic acid → (4R)-4-(Benzyloxy)-1-{[(9H-fluoren-9-yl)methoxy]carbonyl}-L-proline

HRID 625880Notes

Reaction equation

HRID 625880 reaction equation
[CH2:1]([O:8][C@H:9]1[CH2:13][NH:12][C@H:11]([C:14]([OH:16])=[O:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+].[C:30](Cl)(=[O:46])[O:31][CH2:32][CH:33]1[C:45]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:39]2[C:34]1=[CH:35][CH:36]=[CH:37][CH:38]=2>O1CCOCC1.O>[CH:44]1[C:45]2[CH:33]([CH2:32][O:31][C:30]([N:12]3[CH2:13][C@H:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:10][C@H:11]3[C:14]([OH:16])=[O:15])=[O:46])[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:40]=2[CH:41]=[CH:42][CH:43]=1

Participants

7

Reactant 4

HCID 6422Trifluoroacetic acidHCID 11430Potassium CarbonateHCID 343679-Fluorenylmethyl chloroformateHCID 10563127(4R)-4-(Phenylmethoxy)-L-proline

Product 1

HCID 21063752(4R)-4-(Benzyloxy)-1-{[(9H-fluoren-9-yl)methoxy]carbonyl}-L-prolineYield 62.3%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 312751,4-DioxaneSolvent

Procedure

To a solution of (2S,4R)-4-(benzyloxy)pyrrolidine-2-carboxylic acid, TFA (522 mg, 1.557 mmol) in 1,4-dioxane (4 mL) and water (16 mL) was added potassium carbonate (861 mg, 6.23 mmol) followed by (9H-fluoren-9-yl)methyl carbonochloridate (403 mg, 1.557 mmol) at 0° C. The mixture was stirred at RT for 18 hrs and 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 0.1% TFA buffer) to afford the pure product (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(benzyloxy)pyrrolidine-2-carboxylic acid (430 mg, 62.3% yield) as a white solid. 1H NMR (500 MHz, methanol-d4) d 7.86-7.76 (m, 2H), 7.71-7.57 (m, 2H), 7.44-7.27 (m, 9H), 4.58-4.50 (m, 2H), 4.49-4.33 (m, 3H), 4.29-4.19 (m, 2H), 3.72-3.49 (m, 2H), 2.49 (br. s., 1H), 2.10 (ddd, J=13.4, 8.2, 4.8 Hz, 1H). ESI-MS (+) m/z=444 (M+H).

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 0.1% TFA buffer)

Sources & evidence

ORD record
ord-8721bca482484d5eab14207e8a91e2da
Source dataset
uspto-grants-2016_04
Patent number
US09308236B2

Reaction notes

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