1-Hydroxybenzotriazole → HCID 87317055, compound

HRID 448478Notes

Reaction equation

HRID 448478 reaction equation
Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[F:44][C:45]([F:61])([F:60])[C:46]1[CH:47]=[C:48]([CH2:56][C:57](O)=[O:58])[CH:49]=[C:50]([C:52]([F:55])([F:54])[F:53])[CH:51]=1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[F:44][C:45]([F:60])([F:61])[C:46]1[CH:47]=[C:48]([CH2:56][C:57]([NH:2][CH2:3][C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[C:6](=[O:22])[N:7]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:8]3=[O:13])=[O:58])[CH:49]=[C:50]([C:52]([F:53])([F:54])[F:55])[CH:51]=1

Participants

7

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 1235873,5-Bis(trifluoromethyl)phenylacetic acidHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 219885254-(aminomethyl)-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione hydrochloride

Product 1

HCID 87317055HCID 87317055, compoundYield 54%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 3,5-di-(trifluoromethyl)-phenylacetic acid (0.7 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The reaction mixture was stirred at room temperature overnight and was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (40 mL), 1NHCl (2×30 mL), water (40 mL), and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (eluent:EtOAc: CH2Cl2 3:7) to afford 2-(3,5-bis-trifluoromethyl-phenyl)-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-acetamide (0.6 g, 54%) as a white solid: mp 202-204° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=13.69 min. (97%); 1H NMR (DMSO-d6) δ 2.03-2.08 (m, 1H), 2.51-2.63 (m, 2H), 2.84-2.92 (m, 1H), 3.82 (s, 2H), 4.75 (d, J=5.8 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.7 Hz, 1H), 7.67-7.83 (m, 3H), 8.00 (s, 3H), 8.82 (t, J=5.8 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 21.93, 30.89, 37.91, 40.88, 48.83, 117.94, 120.21 (120.26, 120.31), 121.98, 117.94 (121.55, 125.17, 128.75), 127.19, 130.14, 129.28 (129.71, 130.57), 131.54, 133.27, 134.60, 138.86, 139.45, 166.87, 167.39, 169.43, 169.76, 172.71; Anal. Calcd. for C24H17N3O5F6: C, 53.24; H, 3.16; N, 7.76; F, 21.05. Found: C, 53.16; H, 2.99; N, 7.73; F, 21.14.

Workup

  1. stirringThe reaction mixture was stirred at room temperature overnight
  2. concentrationwas concentrated in vacuo
  3. dissolutionThe residue was dissolved in CH2Cl2 (80 mL)
  4. washwashed with water (40 mL), 1NHCl (2×30 mL), water (40 mL), and brine (40 mL)
  5. dry with materialdried over MgSO4
  6. customSolvent was removed in vacuo
  7. customthe residue was purified by ISCO silica gel flash chromatography (eluent:EtOAc: CH2Cl2 3:7)

Sources & evidence

ORD record
ord-1f2137e53a6548648809b0ad14446a47
Source dataset
uspto-grants-2013_07
Patent number
US08481568B2

Reaction notes

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