Hydrochloric Acid → 3-(4-hydroxy-1-oxo-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione

HRID 709538Notes

Reaction equation

HRID 709538 reaction equation
N[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].N([O-])=[O:21].[Na+].Cl.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>CC#N.O>[OH:21][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 5770ReserpineHCID 216326LenalidomideHCID 23668193Sodium Nitrite

Product 1

HCID 250155823-(4-hydroxy-1-oxo-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
2.5 °C

Procedure

A 250 mL-3N-RBF was charged with 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione and H2O (10 vol) and cooled to 0-5° C. NaNO2 (1.1 eq) and HCl (1.1 eq) were added, and the mixture was stirred for 30 minutes. The mixture was then heated to 75-80° C. for 2 hours. The mixture was cooled to room temperature, filtered and dried in vacuo (18 h, 35-40° C.). The crude product was purified by prep-HPLC (Conditions: C18 Symmetry Column, 90:10 H2O: MeCN isocratic, 60 mL/min flow rate, product retention time ˜30 min) to give an off-white solid (240 mg, 2.4%, 99.5 HPLC AP); mp 296.39° C.; HPLC: Hypersil DBS C8 5 m column, 250×4.6 mm, 35° C.; 99:1 to 85:15 Gradient CH3CN/10 mM aq. KH2PO4, 1.0 mL/min over 20 minutes; 7.60 min, 99.5% AP at 210/240 nm: 1H-NMR (DMSO-d6): 10.97 (1H, br s), 10.11 (1H, br s), 7.34 (1H, t), 7.17 (1H, d), 7.03 (1H, d), 5.09 (1H, dd), 4.25 (2H, dd), 2.97-2.85 (1H, m), 2.62-2.36 (2H, m), 2.03-1.96 (1H, m) ppm; 13C-NMR (DMSO-d6): 172.85, 171.04, 168.27, 152.55, 133.41, 129.44, 127.94, 117.97, 113.71, 51.59, 45.09, 31.22, 22.42 ppm; LC-MS ES+ (M+1) 261; CHN-Analysis, calcd for C13H12N2O4: C, 60.00%; H, 4.65%; N, 10.76%. Found: C, 59.54%; H, 4.88%; N, 10.48%.

Workup

  1. temperatureThe mixture was then heated to 75-80° C. for 2 hours
  2. temperatureThe mixture was cooled to room temperature
  3. filtrationfiltered
  4. customdried in vacuo (18 h, 35-40° C.)
  5. customThe crude product was purified by prep-HPLC (Conditions: C18 Symmetry Column, 90:10 H2O: MeCN isocratic, 60 mL/min flow rate, product retention time ˜30 min)
  6. customto give an off-white solid (240 mg, 2.4%, 99.5 HPLC AP)
  7. custom7.60 min, 99.5% AP

Sources & evidence

ORD record
ord-44872b712deb4fc7b0ea51e23c2be30d
Source dataset
uspto-grants-2015_11
Patent number
US09181216B2

Reaction notes

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