Cyclopropanecarbonyl chloride → HCID 53242133, compound

HRID 1019517Notes

Reaction equation

HRID 1019517 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH2:26][CH3:27])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:7]2.[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1>C1COCC1>[CH2:26]([O:25][C:20]1[CH:19]=[C:18]([C@H:12]([N:8]2[C:9](=[O:11])[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[NH:1][C:31]([CH:28]3[CH2:30][CH2:29]3)=[O:32])[CH2:7]2)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:23]=[CH:22][C:21]=1[OH:24])[CH3:27]

Participants

4

Reactant 2

HCID 77637Cyclopropanecarbonyl chlorideHCID 67253153HCID 67253153, compound

Product 1

HCID 53242133HCID 53242133, compoundYield 20%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

To a mixture of (S)-7-amino-2-(1-(3-ethoxy-4-hydroxyphenyl)-2-(methylsulfonyl)ethyl)isoindolin-1-one (5.86 g, 15.0 mol) in THF (60 mL) was added cyclopropanecarbonyl chloride (1.5 mL, 16.1 mmol). The mixture was heated to 60° C. for 1 hour then cooled to room temperature. The solvent was removed and the crude residue purified using column chromatography (MeOH/CH2Cl2; 0-5% over 60 minutes) to give 4.7 g of crude, 68% yield. Further purification was then carried out by prep-HPLC to give (S)—N-(2-(1-(3-ethoxy-4-hydroxyphenyl)-2-(methylsulfonyl)ethyl)-3-oxoisoindolin-4-yl)cyclopropanecarboxamide as a white solid (1.38 g, 20% yield). HPLC: HPLC: Hypersil DBS C8 column, 250×4.6 mm, 5 μm; 99/1 to 85/15 over 15 min Gradient CH3CN/10 mM aq. KH2PO4, 1.0 mL/min, 35° C., run time 20 minutes: tR 12.45 minutes. 1H-NMR (DMSO-d6): 10.51 (1H, s), 9.07 (1H, s), 8.22-8.25 (1H, d), 7.47-7.53 (1H, t), 7.18-7.20 (1H, d), 7.01 (1H, d), 6.78-6.86 (2H, m), 5.82-5.87 (1H, m), 4.61-4.67 (1H, d), 3.91-4.33 (5H, m), 3.02 (3H, s), 1.76-1.82 (1H, m), 1.31-1.36 (3H, t), 0.82-0.96 (4H, m); LC-MS ES+ (M+1) 459.

Workup

  1. temperaturethen cooled to room temperature
  2. customThe solvent was removed
  3. customthe crude residue purified
  4. customcolumn chromatography (MeOH/CH2Cl2; 0-5% over 60 minutes)
  5. customto give 4.7 g of crude, 68% yield
  6. customFurther purification

Sources & evidence

ORD record
ord-47be04e92bee4ff1a74d7c01bd6204a0
Source dataset
uspto-grants-2014_05
Patent number
US08716252B2

Reaction notes

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