Diethyl Ether → (3R,5S)-3-{Cyclopropyl-[4-(3-methoxy-propyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo-[1,4]oxazin-6-yl]-carbamoyl}-5-phenylacetylamino-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester

HRID 1698338Notes

Reaction equation

HRID 1698338 reaction equation
[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][C@@H:22]([NH:24][C:25](OC(C)(C)C)=[O:26])[CH2:21][C@@H:20]([C:32]([OH:34])=O)[CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.ClC(O[CH2:39][CH:40]([CH3:42])[CH3:41])=O.CCN([CH2:48][CH3:49])CC.[CH:50]1([NH:53][C:54]2[CH:55]=[CH:56][C:57]3[O:62][C:61]([CH3:64])([CH3:63])[C:60](=[O:65])[N:59]([CH2:66][CH2:67][CH2:68][O:69][CH3:70])[C:58]=3[CH:71]=2)[CH2:52][CH2:51]1.[Mg+2].[Br-].[Br-].O(CC)[CH2:76]C>C1COCC1>[CH:6]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][C@@H:22]([NH:24][C:25](=[O:26])[CH2:42][C:40]4[CH:39]=[CH:49][CH:48]=[CH:76][CH:41]=4)[CH2:21][C@@H:20]([C:32](=[O:34])[N:53]([CH:50]4[CH2:51][CH2:52]4)[C:54]4[CH:55]=[CH:56][C:57]5[O:62][C:61]([CH3:64])([CH3:63])[C:60](=[O:65])[N:59]([CH2:66][CH2:67][CH2:68][O:69][CH3:70])[C:58]=5[CH:71]=4)[CH2:19]3)=[O:17])[C:13]3[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1

Participants

8

Reactant 6

HCID 3283Diethyl EtherHCID 8471TriethylamineHCID 62365Isobutyl chloroformateHCID 82241Magnesium BromideHCID 577903556-Cyclopropylamino-4-(3-methoxy-propyl)-2,2-dimethyl-4H-benzo[1,4]oxazin-3-oneHCID 57870328rel-(3R,5S)-1-(((9H-Fluoren-9-yl)methoxy)carbonyl)-5-((tert-butoxycarbonyl)amino)piperidine-3-carboxylic acid

Product 1

HCID 67272727(3R,5S)-3-{Cyclopropyl-[4-(3-methoxy-propyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo-[1,4]oxazin-6-yl]-carbamoyl}-5-phenylacetylamino-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (3R,5S)-5-tert-Butoxycarbonylamino-piperidine-1,3-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester (338 mg, 0.73 mmol) in THF (5.0 mL), isobutyl chloroformate (0.1 mL, 0.79 mmol) and Et3N (0.1 mL, 0.79 mmol) are added at 0° C. After stirring for 1 h at the same temperature, the resulting precipitate is filtered off and the filtrate is concentrated. The evaporated residue is dissolved in THF (5 ml), 6-Cyclopropylamino-4-(3-methoxy-propyl)-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one (200 mg, 0.66 mmol) and MgBr2.OEt2 (189 mg, 0.73 mmol) are added at room temperature. After stirring for 2 h, the reaction is quenched with H2O and resulting mixture is extracted with AcOEt, washed with 1N HCl solution, sat. NaHCO3aq and brine. The organic layer is dried (MgSO4), concentrated and purified by silica gel column chromatography to afford the title compound as a white amorphous solid. MS: 753 [M+H]+; tR (HPLC, CombiScreen ODS-AM 50×4.6 mm; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 2 min, flow 2.0 ml/min): 4.77 min.

Workup

  1. filtrationthe resulting precipitate is filtered off
  2. concentrationthe filtrate is concentrated
  3. dissolutionThe evaporated residue is dissolved in THF (5 ml)
  4. stirringAfter stirring for 2 h
  5. customthe reaction is quenched with H2O
  6. customresulting mixture
  7. extractionis extracted with AcOEt
  8. washwashed with 1N HCl solution, sat. NaHCO3aq and brine
  9. dry with materialThe organic layer is dried (MgSO4)
  10. concentrationconcentrated
  11. custompurified by silica gel column chromatography

Sources & evidence

ORD record
ord-5c45f68e47ce420d8cc193c63fa760b2
Source dataset
uspto-grants-2012_04
Patent number
US08163773B2

Reaction notes

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