4-Chloro-3-methylphenol → HCID 59443291, compound

HRID 588044Notes

Reaction equation

HRID 588044 reaction equation
Cl[C:2](OC1C=CC([N+]([O-])=O)=CC=1)=[O:3].[Cl:14][C:15]1[C:16]([CH3:22])=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1.CCN(C(C)C)C(C)C.CS(O)(=O)=O.[NH2:37][CH2:38][C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[C:44](=[O:48])[N:43]([CH:49]1[CH2:54][CH2:53][C:52](=[O:55])[NH:51][C:50]1=[O:56])[CH2:42]2>CC#N>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:2](=[O:3])[NH:37][CH2:38][C:39]2[CH:40]=[C:41]3[C:45](=[CH:46][CH:47]=2)[C:44](=[O:48])[N:43]([CH:49]2[CH2:54][CH2:53][C:52](=[O:55])[NH:51][C:50]2=[O:56])[CH2:42]3)=[CH:17][C:16]=1[CH3:22]

Participants

6

Reactant 4

HCID 17324-Chloro-3-methylphenolHCID 81531Diisopropylethylamine2×HCID 821294-Nitrophenyl chloroformateHCID 866307653-(5-(Aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione methanesulfonate

Product 1

HCID 59443291HCID 59443291, compoundYield 14%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent2×

Procedure

To the solution of para-nitro-phenyl chloroformate (1000 mg, 0.5 mmol) in CH3CN (5 mL), was added the CH3CN solution (5 mL) of 4-chloro-m-cresol (71.3 mg, 0.5 mmol) and DIPEA (0.24 mL, 1.5 mmol) dropwise at room temperature. The mixture was stirred at room temperature for min. 3-(5-Aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonic acid salt (0.37 g, 1 mmol) was added followed by additional DIPEA (0.24 mL, 1.5 mmol). The mixture was stirred overnight at ambient temperature. The mixture was then filtered. The resulted solid was purified on silica gel column eluted using methanol and methylene chloride to give [2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-carbamic acid 4-chloro-3-methyl-phenyl ester as a white solid (30 mg, 14% yield). HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 50/50, CH3CN/0.1% H3PO4: tR=3.0 min (97%); mp 225-227 0C; 1H NMR (DMSO-d6) δ 1.91-2.08 (m, 1H, CHH), 2.32 (s, 3H, CH3), 2.40 (dd, J=4.3, 12.8 Hz, 1H, CHH), 2.63 (br. s., 1H, CHH), 2.83-3.02 (m, 1H, CHH), 4.22-4.56 (m, 4H, CH2, CH2), 5.12 (dd, J=5.1, 13.2 Hz, 1H, NCH), 7.01 (dd, J=2.3, 8.7 Hz, 1H, Ar), 7.17 (d, J=2.3 Hz, 1H, Ar), 7.40 (d, J=8.7 Hz, 1H, Ar), 7.46 (d, J=7.4 Hz, 1H, Ar), 7.55 (s, 1H, Ar), 7.72 (d, J=7.9 Hz, 1H, Ar), 8.47 (t, J=6.0 Hz, 1H, NH), 10.99 (s, 1H, NH). 13C NMR (DMSO-d6) δ 19.52, 22.49, 31.20, 44.04, 47.15, 51.59, 121.03, 122.04, 123.04, 124.43, 127.01, 129.33, 130.58, 136.54, 142.45, 143.35, 145.35, 149.62, 154.43, 167.87, 170.99, 172.86: LC-MS: 442; Anal Calcd for C22H20ClN3O6C, 59.80; H, 4.56; N, 9.51. Found: C, 59.74; H, 4.45; N, 9.58.

Workup

  1. stirringThe mixture was stirred overnight at ambient temperature
  2. filtrationThe mixture was then filtered
  3. customThe resulted solid was purified on silica gel column
  4. washeluted

Sources & evidence

ORD record
ord-a061d2bd0ab64bf4b85367b0ba549191
Source dataset
uspto-grants-2016_01
Patent number
US09227954B2

Reaction notes

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