Hydrochloric Acid → HCID 59443301, compound

HRID 1091347Notes

Reaction equation

HRID 1091347 reaction equation
CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[C:26]([N:33]1[CH:37]=[CH:36]N=C1)(N1C=CN=C1)=[O:27].Cl.[Cl:39][C:40]1[CH:41]=C(C=[CH:45][C:46]=1[O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH3:54])N.Cl>CN(C=O)C.O>[Cl:39][C:40]1[CH:41]=[C:37]([NH:33][C:26]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[O:27])[CH:36]=[CH:45][C:46]=1[O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH3:54]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 46735571Benzenamine, 3-chloro-4-[2-(2-methoxyethoxy)ethoxy]-, hydrochloride (1:1)2×HCID 866307653-(5-(Aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione methanesulfonate

Product 1

HCID 59443301HCID 59443301, compoundYield 72%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (1.11 g, 3.0 mmol) and 1,1′-Carbonyldiimidazole (535 mg, 3.3 mmol) were suspended in dry DMF (20 mL) and the mixture was stirred at rt for 24 h. While stirring, a portion of the reaction mixture (6.7 mL, ˜1 mmol) was transferred to a vial containing 3-chloro-4-(2-(2-methoxyethoxy)ethoxy)aniline hydrochloride (310 mg, 1.1 mmol). The resulting mixture was stirred at rt overnight and the reaction progress was monitored by LCMS. After 48 h, additional 3-chloro-4-(2-(2-methoxyethoxy)ethoxy)aniline hydrochloride (56 mg, 0.2 mmol) was transferred to the reaction mixture and stirring continued for another 24 h. The reaction mixture was acidified with 1N HCl and water was added with stirring until a precipitate formed. The solid was collected by filtration, suction dried, then dissolved in DMF and purified using C-18 preparatory HPLC to give 1-(3-chloro-4-(2-(2-methoxyethoxy)ethoxy)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea as a white solid (390 mg, 72% yield): HPLC: Waters Symmetry C18, 5 wn, 3.9×150 mm, 1 ml/min, 240 nm. 30/70 CH3CN/0.1% H3PO4, 5.40 min (99.8%); mp: 188-190° C.; 1H NMR (DMSO-d6) δ 1.92-2.10 (m, 1H, CHH), 2.29-2.47 (m, 1H, CHH), 2.60 (dd, J=2.2, 15.4 Hz, 1H, CHH), 2.82-3.01 (m, 1H, CHH), 3.25 (s, 311, CH3), 3.46 (dd, J=3.7, 5.6 Hz, 2H, CH2), 3.61 (dd. J-3.8, 5.7 Hz, 2H, CH2), 3.73 (d, J=4.7 Hz, 2H, CH2), 4.09 (t, J=4.9 Hz, 2H, CH2), 4.24-4.55 (m, 4H, CH2, CH2), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CH), 6.77 (t, J=5.9 Hz, 1H, NH), 7.04 (d, J=9.1 Hz, 1H, Ar), 7.19 (dd, J=2.5, 9.0 Hz, 1H, Ar), 7.38-7.49 (m, 1H, Ar), 7.51 (s, 1H, Ar), 7.64 (d, J=2.6 Hz, 1H, Ar), 7.69 (d, J=7.7 Hz, 1H, Ar), 8.65 (s, 1H, NH), 10.98 (s, 1H, NH); 11C NMR (DMSO-d6) δ 22.51, 31.20, 42.80, 47.12, 51.56, 58.05, 68.80, 68.85, 69.84, 71.29, 114.66, 117.58, 119.49, 121.24, 121.88, 122.91, 126.89, 130.29, 134.53, 142.38, 144.84, 148.40, 155.25, 167.95, 171.01, 172.86; LCMS: MH=545, 547; Anal Calcd for C26H29ClN4O7+0.4H2O: C, 56.55; H, 5.44; N, 10.15. Found: C, 56.64; H, 5.34; N, 10.15.

Workup

  1. stirringWhile stirring
  2. stirringThe resulting mixture was stirred at rt overnight
  3. waitAfter 48 h
  4. stirringstirring
  5. waitcontinued for another 24 h
  6. additionwas added
  7. stirringwith stirring until a precipitate
  8. customformed
  9. filtrationThe solid was collected by filtration, suction
  10. customdried
  11. dissolutiondissolved in DMF
  12. custompurified

Sources & evidence

ORD record
ord-b3d88225b46b44f09a8ab53457bf27fe
Source dataset
uspto-grants-2012_03
Patent number
US08129375B2

Reaction notes

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