Water → HCID 46199031, compound

HRID 588040Notes

Reaction equation

HRID 588040 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](N1C=CN=C1)(N1C=CN=C1)=[O:27].[NH2:38][C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][CH:48]=1)[CH2:45][N:44]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:43][CH2:42]2.O>CN(C=O)C>[C:52]([O:51][C:49]([N:44]1[CH2:43][CH2:42][C:41]2[C:46](=[CH:47][CH:48]=[C:39]([NH:38][C:26]([NH:6][CH2:7][C:8]3[CH:9]=[C:10]4[C:14](=[CH:15][CH:16]=3)[C:13](=[O:17])[N:12]([CH:18]3[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]3=[O:25])[CH2:11]4)=[O:27])[CH:40]=2)[CH2:45]1)=[O:50])([CH3:55])([CH3:54])[CH3:53]

Participants

6

Reactant 4

HCID 962WaterHCID 682631,1'-CarbonyldiimidazoleHCID 27563716-Amino-2-N-Boc-1,2,3,4-tetrahydro-isoquinoline2×HCID 866307653-(5-(Aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione methanesulfonate

Product 1

HCID 46199031HCID 46199031, compoundYield 53%

Reagents, catalysts & solvents 1

HCID 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 tert-butyl 6-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (273 mg, 1.1 mmol). The resulting mixture was stirred at rt overnight and the reaction progress was monitored by LCMS. After 48 h, additional tert-butyl 6-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (50 mg, 0.2 mmol) was transferred to the reaction mixture and stirring continued for another 24 h. The reaction mixture was acidified with acidic acid and water. The volatiles were removed in vacuo and the residue was dissolved in DMF and purified using C-18 preparatory HPLC to give 6-{3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-ureido}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester as a white solid (290 mg, 53% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min. 240 nm, 40/60 CH3CN/0.1% H3PO4, 5.02 min (96.5%); mp: 230-232 0C; 1H NMR (DMSO-d6) δ 1.42 (s, 9H, (CH3)3), 1.90-2.11 (m, 1H, CHH), 2.23-2.47 (m, 1H, CHH), 2.60 (d, J=17.9 Hz, 1H, CHH), 2.70 (t, J=5.6 Hz, 2H, CH2), 2.81-3.06 (m, 1H, CHH), 3.51 (t, J=5.7 Hz, 2H, CH2), 4.18-4.58 (m, 6H, CH2, CH2, CH2), 5.11 (dd, J=4.9, 13.2 Hz, 1H, CH), 6.72 (t, J=5.9 Hz, 1H, NH), 7.00 (d, J=8.3 Hz, 1H, Ar), 7.17 (d, J=8.1 Hz, 1H, Ar), 7.27 (br. s., 1H, Ar), 7.44 (d, J=7.9 Hz, 1H, Ar), 7.51 (s, 1H, Ar), 7.69 (d, J=7.9 Hz, 1H, Ar), 8.56 (s, 1H, NH), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.46, 28.07, 28.44, 31.16, 41.51, 42.75, 45.04, 47.08, 51.55, 78.81, 116.01, 117.49, 121.87, 122.90, 126.20, 126.36, 126.88, 130.25, 134.70, 138.56, 142.35, 144.86, 153.97, 155.21, 167.93, 170.96, 172.83; LCMS: MH=548: Anal Calcd for C29H33N5O6+1.1H2O: C, 61.39: H, 6.25; N, 12.34.

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. customThe volatiles were removed in vacuo
  7. dissolutionthe residue was dissolved in DMF
  8. custompurified

Sources & evidence

ORD record
ord-baa99fc041194d039c02d35b90691708
Source dataset
uspto-grants-2016_01
Patent number
US09227954B2

Reaction notes

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