Hydrochloric Acid → HCID 59443301, compound

HRID 1880642Notes

Reaction equation

HRID 1880642 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 1 N 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 μm, 3.9×150 mm, 1 ml/min, 240 nm, 30/70 CH1CN/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, 3H, 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); 13C 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+0.4 H2O: 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-15bc4a94fe754eb888373b43c5073c4d
Source dataset
uspto-grants-2012_11
Patent number
US08318773B2

Reaction notes

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