Toluene → N-(2-(2-(2-(3-bromo-2,5-dioxo-pyrrol-1-yl)ethoxy)ethoxy)ethyl)-5-(2-oxo-1,3,3a,4,6,6a-hexahydrothieno(3,4-d)imidazol-6-yl)pentanamide

HRID 929383Notes

Reaction equation

HRID 929383 reaction equation
[Br:1][C:2]1[C:3]([O:5][C:6](=[O:8])[CH:7]=1)=O.FC(F)(F)C([O-])=O.[O:16]=[C:17]1[NH:21][CH:20]2[CH:22]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][NH3+:40])=[O:30])[S:23][CH2:24][CH:19]2[NH:18]1.C1(C)C=CC=CC=1.CO.C(Cl)Cl>CC(O)=O>[Br:1][C:2]1[C:3](=[O:5])[N:40]([CH2:39][CH2:38][O:37][CH2:36][CH2:35][O:34][CH2:33][CH2:32][NH:31][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH:22]2[CH:20]3[NH:21][C:17](=[O:16])[NH:18][CH:19]3[CH2:24][S:23]2)[C:6](=[O:8])[CH:7]=1

Participants

6

Reactant 4

HCID 1140TolueneHCID 800273-Bromo-2,5-furandioneHCID 21226129Dichloromethane methanolHCID 86668289HCID 86668289, compound

Product 1

HCID 86668288N-(2-(2-(2-(3-bromo-2,5-dioxo-pyrrol-1-yl)ethoxy)ethoxy)ethyl)-5-(2-oxo-1,3,3a,4,6,6a-hexahydrothieno(3,4-d)imidazol-6-yl)pentanamideYield 52%

Reagents, catalysts & solvents 1

HCID 176Acetic AcidSolvent

Conditions

Temperature
170 °C

Procedure

Monobromomaleic anhydride (45.0 mg, 0.25 mmol, 1 eq) was added in one portion to a solution of 2-(2-(2-(5-(2-oxo-1,3,3a,4,6,6a-hexahydrothieno(3,4-d)imidazol-6-yl)pentanoylamino)ethoxy)ethoxy)ethylammonium 2,2,2-trifluoroacetate (124 mg, 0.25 mmol, 1 eq) in AcOH (10 mL) and the reaction mixture heated to 170° C. for 3 h. Upon cooling to 21° C. toluene was added and the AcOH azeotropically removed in vacuo (×2) to give crude product. Column chromatography (gradient 2-10% MeOH/CH2Cl2) yielded the desired compound as a white solid (70.0 mg, 0.13 mmol, 52% yield). m.p. 95-98° C.; [α]D20.0+65.1 (c 0.15, MeOH); 1H NMR (600 MHz, CD3OD) δ 7.17 (s, 1H, CHCBr), 4.51 (dd, J=5.0, 8.0 Hz, 1H, NHC(O)NHCH), 4.33 (dd, J=5.0, 8.0 Hz, 1H, NHC(O)NHCH), 3.77 (t, J=5.5 Hz, 2H, OCH2), 3.68 (t, J=5.5 Hz, 2H, OCH2), 3.63 (m, 2H, OCH2), 3.58 (m, 2H, OCH2), 3.53 (t, J=5.5 Hz, 2H, NCH2), 3.37 (t, J=5.5 Hz, 2H, NCH2), 3.24 (td, J=5.0, 8.0 Hz, 1H, SCH), 2.95 (dd, J=5.0, 12.5 Hz, 1H, SCHH), 2.73 (d, J=12.5 Hz, 1H, SCHH), 2.26 (t, J=7.0 Hz, 2H, NHC(O)CH2CH2CH2), 1.69 (m, 4H, CH2CH2CH2), 1.47 (quintet, J=7.0 Hz, 2H, CH2CH2CH2); 13C NMR (150 MHz, CD3OD) δ 176.12 (s), 170.13 (s), 166.97 (s), 166.08 (s), 133.63 (s), 132.05 (d), 71.22 (t), 71.11 (t), 70.61 (t), 68.69 (t), 63.35 (d), 61.61 (d), 57.03 (d), 41.09 (t), 40.31 (t), 39.09 (t), 36.75 (t), 29.78 (t), 29.50 (t), 26.87 (t); IR (MeOH) 3355, 2970, 1737 cm−1; HRMS (ES) calcd for C20H29N4O6NaSBr [M+Na]+ 555.0889, observed 555.0905.

Workup

  1. additionwas added
  2. customthe AcOH azeotropically removed in vacuo (×2)
  3. customto give crude product

Sources & evidence

ORD record
ord-b522272060864791a5fad1ced96b1d1d
Source dataset
uspto-grants-2016_03
Patent number
US09295729B2

Reaction notes

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