Diisopropylethylamine → HCID 178426528, compound

HRID 588031Notes

Reaction equation

HRID 588031 reaction equation
I.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11](=[NH:14])SC)[CH:6]=[CH:7][C:8]=1[CH3:9].CS(O)(=O)=O.[NH2:20][CH2:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[C:27](=[O:31])[N:26]([CH:32]1[CH2:37][CH2:36][C:35](=[O:38])[NH:34][C:33]1=[O:39])[CH2:25]2.CCN(C(C)C)C(C)C>CN(C=O)C>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([NH:20][CH2:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[C:27](=[O:31])[N:26]([CH:32]2[CH2:37][CH2:36][C:35](=[O:38])[NH:34][C:33]2=[O:39])[CH2:25]3)=[NH:14])[CH:6]=[CH:7][C:8]=1[CH3:9]

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 866307653-(5-(Aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione methanesulfonate2×HCID 178503990HCID 178503990, compound

Product 1

HCID 178426528HCID 178426528, compoundYield 43.4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

In a microwave vial fitted with a stir bar, 1-(3-chloro-4-methyl-phenyl)-2-methyl-isothiourea hydroiodide (597 mg, 1.74 mmol), 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (560 mg, 1.52 mmol), and DIEA (1.1 mL, 6.06 mmol) were combined in anhydrous DMF (5 mL). The vial was sealed and irradiated in a microwave for 30 min at 120° C. To the reaction mixture was added an additional 100 mg of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate and the reaction was irradiated for 30 min at 120° C. This process was repeated twice more to consume all of the 1-(3-chloro-4-methyl-phenyl)-2-methyl-isothiourea hydroiodide starting material as it was found co-elute with the desired product on LCMS. The reaction mixture was acidified with acetic acid and the volatiles were evaporated in vacuo. The residue was dissolved in minimal DMF, filtered, and purified using C-18 preparatory HPLC. To the combined fractions containing the desired product, 1 N HCl was added and the solvents removed in vacuo. The obtained white solid was dissolved in minimal water and lyophilized to give 180 mg (27% yield) of N-(3-chloro-4-methyl-phenyl)-N′-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-guanidine hydrochloride: HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 20/80 CH3CN/0.1% H3PO4, 3.73 min (97.4%); mp: >400 0C; 1H NMR (DMSO-d6) δ 1.91-2.09 (m, 1H, CHH), 2.33 (s, 3H, CH3), 2.41 (dd, J=4.3, 13.2 Hz, 1H, CHH), 2.54-2.68 (m, 1H, CHH), 2.80-3.05 (m, 1H, CHH), 4.21-4.56 (m, 2H, CH2), 4.66 (d, J=5.7 Hz, 2H, CH2), 5.13 (dd, J=4.9, 13.2 Hz, 1H, CH), 7.14 (dd, J=1.9, 8.1 Hz, 1H, Ar), 7.34 (d, J=1.9 Hz, 1H, Ar), 7.42 (d, J=8.1 Hz, 1H, Ar), 7.51 (d, J=7.9 Hz, 1H, Ar), 7.61 (s, 1H, Ar), 7.76 (d, J=7.7 Hz, 1H, Ar), 7.98 (br. s., 1H, NH), 8.62 (br. s., 1H, NH), 10.16 (s, 1H, NH), 11.00 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.04, 24.19, 32.95, 46.33, 49.85, 54.03, 124.13, 125.48, 125.79, 127.28, 129.17, 132.57, 134.20, 135.82, 135.95, 136.64, 143.17, 144.68, 156.84, 170.94, 173.00, 175.82; LCMS: MH=440, 442; Anal Calcd for C22H23Cl2N5O3+2.3H2O+1.9HCl+0.2HCOOH: C, 44.72; H, 5.05; N, 11.74; Cl, 23.19. Found: C, 44.55; H, 4.71; N, 11.48; Cl, 22.92.

Workup

  1. customIn a microwave vial fitted with a stir bar
  2. customThe vial was sealed
  3. customirradiated in a microwave for 30 min at 120° C
  4. customthe reaction was irradiated for 30 min at 120° C
  5. customto consume all of the 1-(3-chloro-4-methyl-phenyl)-2-methyl-isothiourea hydroiodide starting material as it
  6. customthe volatiles were evaporated in vacuo
  7. dissolutionThe residue was dissolved in minimal DMF
  8. filtrationfiltered
  9. custompurified
  10. additionTo the combined fractions containing the desired product, 1 N HCl
  11. additionwas added
  12. customthe solvents removed in vacuo
  13. dissolutionThe obtained white solid was dissolved in minimal water

Sources & evidence

ORD record
ord-f72f8cd89f044e30a73f270e70a0a823
Source dataset
uspto-grants-2016_01
Patent number
US09227954B2

Reaction notes

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