Diisopropylethylamine → (5R)-2,2-dimethyl-5-((1S)-3-methyl-1-{[4-(5-phenyl-1,2,4-oxadiazol-3-yl)-1-piperazinyl]carbonyl}butyl)-1,3-dioxolan-4-one

HRID 888235Notes

Reaction equation

HRID 888235 reaction equation
[CH3:1][C:2]1([CH3:16])[O:6][C@H:5]([C@H:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([OH:10])=O)[C:4](=[O:15])[O:3]1.C(O[CH:29]([CH3:31])[CH3:30])(=O)[C@@H](CC(OC(C)C)=O)O.CCN(C(C)C)C(C)C.[OH:41][N:42]1[C:46]2[N:47]=[CH:48][CH:49]=[CH:50][C:45]=2N=N1.F[P-](F)(F)(F)(F)F.FC(N(C)C)=[N+](C)C.ONC(=O)[C@@H](O)[C@@H](C([N:77]1[CH2:82][CH2:81][N:80](C2C=C(C)C=CN=2)[CH2:79][C@@H:78]1C)=O)CC(C)C>C(Cl)Cl>[CH3:16][C:2]1([CH3:1])[O:3][C:4](=[O:15])[C@@H:5]([C@@H:7]([C:8]([N:77]2[CH2:82][CH2:81][N:80]([C:46]3[N:47]=[C:48]([C:49]4[CH:50]=[CH:45][CH:30]=[CH:29][CH:31]=4)[O:41][N:42]=3)[CH2:79][CH2:78]2)=[O:10])[CH2:11][CH:12]([CH3:14])[CH3:13])[O:6]1

Participants

8

Reactant 6

HCID 81531Diisopropylethylamine2×HCID 181649HOAtHCID 2774761Tetramethylfluoroformamidinium hexafluorophosphateHCID 10921962Diisopropyl (R)-(+)-malateHCID 11625068HCID 11625068, compound2×HCID 22876674HCID 22876674, compound

Product 1

HCID 58487984(5R)-2,2-dimethyl-5-((1S)-3-methyl-1-{[4-(5-phenyl-1,2,4-oxadiazol-3-yl)-1-piperazinyl]carbonyl}butyl)-1,3-dioxolan-4-oneYield 42%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
-15 °C

Procedure

To a cold solution (−15° C.) of (2S)-2-[(4R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoic acid (150 mg, 0.65 mmol, prepared according to WO 94/02447 or similarly to Seebach et al., 1990, Org. Syntheses, Coll. Vol. III, p 153-159 but starting from diisopropyl (R)-(+)-malate) in anhydrous DCM (1.8 mL) were added DIEA (115 μL, 0.69 mmol), 1-hydroxy-7-azabenzotriazole (89 mg, 0.65 mmol, Fluka) and fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (206 mg, 0.78 mmol, Aldrich). The reaction mixture was stirred at −15° C. for 15 min and at RT for 1 h, then cooled at 0° C. A solution of 1-(5-phenyl-[1,2,4]oxadiazol-3-yl)piperazine (230 mg, 0.78 mmol, Intermediate 11 parent form) and DIEA (115 μL, 0.69 mmol) in anhydrous DCM (1 mL) was added. The reaction mixture was stirred for 5 hours at RT and then poured on a silica column (wet with c-Hex/EtOAc 4:1). Purification was performed with a gradient cHex/EtOAc 4:1 to c-Hex/EtOAc 3:1 to give 120 mg (42%) of the title compound as a white powder. HPLC, Rt: 4.5 min (purity: 100%). LC/MS, M+(ESI): 443.3.

Workup

  1. temperaturecooled at 0° C
  2. stirringThe reaction mixture was stirred for 5 hours at RT
  3. customPurification

Sources & evidence

ORD record
ord-e51d647cb72c42ff807064b14691e066
Source dataset
uspto-grants-2012_08
Patent number
US08247437B2

Reaction notes

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